Association of COMT Val158Met Polymorphism with Psychopathological Symptoms in Patients with Eating Disorders.

BACKGROUND: Dopamine physiological functions make dopaminergic genes suitable candidates for association studies in eating disorders (ED). A Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene, which is involved in dopamine degradation, has been studied in relation to ED. OBJECTIVE: We aimed to analyze the association between this polymorphism and general psychopathological symptoms that are often coupled to these disorders. METHOD: A total of 303 ED patients, diagnosed according to DSM-5 criteria, completed the SCL-90R questionnaire and were genotyped for the Val158Met polymorphism. RESULTS: There were significant differences in the global indices of the SCL-90R inventory between the three ED groups (Anorexia Nervosa (AN), Bulimia Nervosa (BN) and binge-eating disorder; ANOVA-p < 0.05). Females with BN showed the highest scores (worse symptomatology) of all participants. In this group, a gene-dose effect was observed on the psychometric evaluation of the patients, as Val/Val carriers displayed the highest scores for all the SCL-90R scales, followed by Val/Met and then Met/Met carriers. Significant differences between genotypes were observed in the Obsessive- Compulsive (p = 0.018), Paranoid Ideation (p = 0.0005) and Psychoticism (p = 0.039) scales, as well as in the PSDI (p = 0.014) general index. CONCLUSION: The results taken together suggest that COMT genetic variability may contribute to general psychopathological symptoms in patients with BN.

Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders.

Genetics variants in the NEGR1 gene, strongly expressed in the brain, have been reported to affect the neuronal control of food intake therefore inducing obesity. With the same rationale, we hypothesized that this genetic variability may be associated with psychological traits commonly displayed by eating disorder (ED) patients and/or with the risk for the disorder. We analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent regions of the NEGR1 gene. A total of 169 ED patients (106 with anorexia nervosa (AN) and 63 with bulimia nervosa (BN)) and 312 healthy subjects were genotyped. Personality traits and general psychopathological symptoms were assessed by the Eating Disorders Inventory Test-2 (EDI-2) and Symptom Checklist 90 Revised inventories. None of the SNPs or haplotypes analyzed were associated with a greater risk of ED or correlated with anthropometric parameters. However, in patients with BN, four SNPs (rs12740031, rs10789322, rs6659202 and rs591540) correlated with the scores in Drive for Thinness (DT), Ineffectiveness (I) and Interoceptive Awareness (IA) (Bonferroni-P<0.05 in all instances). The first two SNPs along with rs954299 and rs2422021 formed a haplotype block, which showed a consistent association with the EDI-2 score in BN patients (Bonferroni-P=0.01). A subsequent three-SNP sliding-window approach identified a central area, encompassing both the haplotype block and the individually relevant SNPs that strongly correlated with the scores of BN patients in DT, I, IA and Bulimia. No associations were identified in the AN group. These preliminary results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients.

A neutron diagnostic for high current deuterium beams.

A neutron diagnostic for high current deuterium beams is proposed for installation on the spectral shear interferometry for direct electric field reconstruction (SPIDER, Source for Production of Ion of Deuterium Extracted from RF plasma) test beam facility. The proposed detection system is called Close-contact Neutron Emission Surface Mapping (CNESM). The diagnostic aims at providing the map of the neutron emission on the beam dump surface by placing a detector in close contact, right behind the dump. CNESM uses gas electron multiplier detectors equipped with a cathode that also serves as neutron-proton converter foil. The cathode is made of a thin polythene film and an aluminium film; it is designed for detection of neutrons of energy >2.2 MeV with an incidence angle < 45°. CNESM was designed on the basis of simulations of the different steps from the deuteron beam interaction with the beam dump to the neutron detection in the nGEM. Neutron scattering was simulated with the MCNPX code. CNESM on SPIDER is a first step towards the application of this diagnostic technique to the MITICA beam test facility, where it will be used to resolve the horizontal profile of the beam intensity.

Variability of the L-Histidine decarboxylase gene in allergic rhinitis.

BACKGROUND: Nonsynonymous polymorphisms in genes coding for histamine-metabolizing enzymes, diamine oxidase and histamine N-methyltransferase are related to the risk of developing allergic diseases. The role of polymorphisms in the histidine decarboxylase gene remains unexplored. The objective of this study is to identify novel polymorphisms in the human histidine decarboxylase gene and to analyse the clinical association of nonsynonymous polymorphisms with rhinitis. METHODS: We performed a single-strand conformational polymorphism analysis of the histidine decarboxylase gene sequence. The presence of two nonsynonymous polymorphisms Thr31Met (rs17740607) and Glu644Asp (rs2073440) was analysed in 442 unrelated patients with allergic rhinitis, 233 of whom also had asthma, and in 486 healthy subjects. RESULTS: We observed three novel polymorphisms designated as ss50402829, ss50402830 and ss50402831-(rs17740607) with allele frequencies = 0.005, 0.208 and 0.073, respectively. Statistically significant differences were observed for the histidine decarboxylase Glu644Asp (rs2073440) polymorphism, with OR (95% CI) values for homozygous carriers of the Glu644 allele equal to 3.12 (1.75-5.56, P < 0.00005) for all patients, 3.38 (1.54-7.44, P = 0.002) for patients with rhinitis alone, and 2.92 (1.43-5.95), P = 0.003 for patients with rhinitis + asthma, when compared with healthy controls. A significant Glu644 gene-dose effect was observed for overall patients (P = 0.0001), for patients with rhinitis alone (P = 0.005) and for patients with rhinitis + asthma (P = 0.010). CONCLUSIONS: The HDC allele Glu644 in homozygosity increases the risk of developing rhinitis in the studied population. This adds to increasing evidence supporting a prominent role of genetic variations related to histamine homeostasis in the risk to develop allergic diseases.

Observation of the effects of dust particles on plasma fluctuation spectra.

Charged dust particles are theoretically expected to modify the amplitude and spectrum of plasma fluctuations, and this can eventually provide novel diagnostic tools. Direct experimental evidence of the effects of dust particles on the fluctuations of a low collisionality plasma is reported, in agreement with the expectations of kinetic theory.

Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam.

We investigated the role of NAT2 on clonazepam acetylation, using transiently expressed human NAT2 alleles. The NAT25*B and the NAT2*6A variant alleles cause a 20 and 22-fold reduction in the Vmax, respectively. We conclude that NAT2 is responsible for 7-aminoclonazepam acetylation and that NAT2 gene polymorphisms impair such metabolic pathway.

Inhibition of cytochrome P450 2C9 activity in vitro by 5-hydroxytryptamine and adrenaline.

In the present study, the occurrence of a modulatory effect of 14 neurotransmitters, precursors and metabolites on the cytochrome P450 2C9 (CYP2C9) enzyme activity, as determined by diclofenac 4-hydroxylation, was studied in human liver microsomes. Two indoleamines, 5-hydroxytryptamine (5-HT) and adrenaline, showed a non-competitive-type inhibitory effect of approximately 90% of the diclofenac 4-hydroxylase activity, with Ki values of 63.5 (0.7 and 156 (89.3 microM, respectively. The rest of substances analysed were weak inhibitors or had no inhibitory effect. CYP2C subfamily is present in human brain, although CYP2C9 isozyme has not yet been identified in this tissue, and CYP2C9 is involved in the metabolism of psychoactive drugs. Therefore, the fact that endogenous compounds could modulate the CYP2C9 activity, suggests that an hypothetical local activity of brain CYP2C9 might be susceptible to regulatory mechanisms. The possible clinical implications of this modulation are discussed.

Modulation of midazolam 1-hydroxylation activity in vitro by neurotransmitters and precursors.

OBJECTIVE: The aim of this study was to find whether endogenous substances could modulate CYP3A activity. There is evidence that CYP3A, a major phase-I xenobiotic metabolizing enzyme, is present in human brain but, at the present time, endogenous substrates for such an enzyme remain to be identified. A possible linkage between the CYP2D6 enzyme and serotonergic transmission has been recently reported by our group. In the same manner, structurally related enzymes such as CYP3A could also be related to endogenous compounds. METHODS: CYP3A activity was measured using the enzyme-specific substrate midazolam in human liver microsomes. Several neurotransmitters, precursors, and their metabolites, corresponding to three different metabolic routes, were assayed as putative modulators of CYP3A enzyme activity. These comprised serotonergic, catecolaminergic, and GABAergic transmitters and precursors. The inhibitory capacity of ketoconazole, a competitive inhibitor of CYP3A, was also analyzed for comparison. RESULTS: The kinetic analysis of the midazolam 1-hydroxylase activity measured in microsomes from five human liver samples indicated Km values (mean +/- SD) of 5.8 +/- 4.9 microM, and Vmax values of 1.7 +/- 1.4 nmol min(-1) per mg microsomal protein in all the samples used in the study. Of the 14 substances analyzed, adrenaline, serotonin, and 5-hydroxytriptofol were full inhibitors of CYP3A enzyme activity (Ki values of 42.3, 26.4, and 43 microM, respectively). The remaining substances were weak inhibitors or had no inhibitory effect. CONCLUSION: Brain CYP3A activity could be modulated by some neurotransmitters and precursors.

Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine.

Recent evidence supports a role for the CYP2D6 enzyme in the metabolism of tryptamine. Because of the partial overlapping between substrate and inhibitor specificities that characterize some cytochrome P450 enzymes, these finding raise the possibility that other cytochrome P450 enzymes may be modulated by endogenous compounds. In the present study, the occurrence of modulatory effect of 17 neurotransmitters, precursors and metabolites on the cytochrome P450 1A2 (CYP1A2) enzyme activity was studied in human liver microsomes. Two indoleamines, serotonin and tryptamine, showed a competitive inhibitory effect on the high-affinity component of the phenacetin O-de-ethylase activity. Both substances induced an inhibition of 100% of the activity, with Ki values of 35 and 45 microns for serotonin and tryptamine, respectively. The inhibitors did not affect the microsomal NADPH-reductase activity. Other substances, which were either poor or partial inhibitors, were dopamine, L-tyrosine, tryptophol, 5-hydroxytryptophol, adrenaline, indole-3-acetaldehyde, 5-hydroxytryptophan, noradrenaline, vanillylmandelic acid, indole-3-acetic acid, dihydroxyphenylacetic acid, and homovanillic acid. L-tryptophan, dihydroxyphenylalanine and 5-hyroxyindole acetic acid induced very low or no inhibitory effect. Tryptamine and serotonin metabolism in human liver microsomes was studied after inhibition of monoamine oxidase activity with the unspecific MAO inhibitor pargyline. Both serotonin and tryptamine were metabolized in human liver microsomes. However, the metabolism of both indoleamines was not significantly inhibited with the CYP1A2-specific inhibitor furafylline, thus indicating that the inhibition of CYP1A2 was not related to metabolic activity of the CYP1A2 enzyme on serotonin or tryptamine. The CYP1A2 enzyme is expressed in brain and is involved in the metabolism of psychoactive drugs. Therefore, the fact that endogenous compounds could modulate the CYP1A2 activity suggests that local activity of brain CYP1A2 might be susceptible to local regulatory mechanisms. This may have important clinical implications, one of them being that CYP1A2 activity in brain tissue might correlate poorly with that of liver, as observed in vivo. In addition, the influence of indoleamines on CYP1A2 activity might be partly responsible for a number of associations of CYP1A2 activity with nutritional and environmental factors.

Tryptamine: a possible endogenous substrate for CYP2D6.

The fact that CYP2D6 is not only expressed in liver but also in brain and the clinical association of this cytochrome with Parkinson's disease suggests the possibility of existence of some endogenous substrate, and among these perhaps one or more neurotransmitters could be metabolized by CYP2D6. In this study we explored such a possibility by studying the modulation of CYP2D6 activity by several neurotransmitters. Our findings confirm the occurrence of a competitive inhibition of dextromethorphan O-demethylation in the presence of tryptamine, with a Ki value of 44.6 microM. Tryptamine was metabolized in human liver microsomes by an enzyme activity with a K(m) of 3.6 +/- 0.9 microM. Such activity is NADPH dependent and is inhibited by quinidine and CYP2D6-specific substrates. The product of the reaction is tryptophol. These results suggest that tryptamine may be an endogenous substrate of CYP2D6.