Dopaminergic brain systems have been documented to have a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The catechol-O-methyltransferase (COMT) is involved in the degradation of catecholamines and a functional polymorphism (Val158Met) has been suggested to influence enzyme activity. In this study we hypothesize that genetic variation in the COMT gene contributes to increased risk for cocaine dependence. Cocaine-dependent individuals (n ¼ 330) and screened unaffected normal controls (n ¼ 255) were genotyped for three SNPs in the COMT gene (rs737865, rs4680 (Val158Met), rs165599). All cases and controls were of African descent. Genotype and allele frequencies differed significantly for the Val158Met polymorphism between cases (f(Met) ¼ 35%) and controls (f(Met) ¼ 27%) (p ¼ 0.004; corrected p ¼ 0.014; OR 1.44; 95% CI 1.12-1.86). Haplotype analysis showed a significant association for a two-marker haplotype rs737865-Val158Met (p ¼ 0.005). Results suggest that variation in COMT increases risk for cocaine dependence. The low enzyme activity 158Met allele or haplotypes containing this variant might have functional effects on dopamine-derived reward processes and cortical functions resulting in increased susceptibility for cocaine dependence. Additional studies are required to elucidate the role of COMT in the pathophysiology of substance use disorders.

The endogenous opioid system has been shown to have a role in the biological processes involved in addiction to numerous drugs of abuse including cocaine. It has recently been reported that the variable nucleotide tandem repeat (VNTR) polymorphism in the 5' promoter region of the prodynorphin gene, which encodes the precursor for three endogenous opioid peptides, is associated with the cocaine dependent phenotype. In order to confirm this finding, we genotyped the prodynorphin promoter polymorphism in cocaine dependent (n = 167) and control (n = 88) individuals of African descent. The results from this experiment indicate a statistically significant (chi2 = 5.64, OR = 1.59, P = 0.018) association between the prodynorphin promoter VNTR polymorphism and the cocaine dependent phenotype. In contrast to previous work showing increased risk conferred by one or two copies of the prodynorphin VNTR, the genotyping results from this study indicate that persons with three or four copies of this polymorphism are more likely to become cocaine dependent. This disparity suggests that the prodynorphin promoter VNTR may not be the functional polymorphism associating with the cocaine dependent phenotype. It is possible that different alleles of the prodynorphin promoter VNTR in the independent populations used for this and the previous study may be in linkage disequilibrium with a yet to be identified functional polymorphism in this gene.

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12–17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50–800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817.

Richard et al kidney disease following definitive treatment should be considered for a referral to a nephrologist (or their general practitioner), especially if associated with proteinuria (Adopted from CUA guideline for followup of patients after treatment of non-metastatic RCC; conditional recommendation, low certainty in evidence of effects).

Linkage studies have suggested a susceptibility locus for schizophrenia (SZ) exists on chromosome 8p21–22. The vesicular monoamine transporter 1 gene (VMAT1), also known as SLC18A1, maps to this SZ susceptibility locus. Vesicular monoamine transporters are involved in the presynaptic vesicular packaging of monoamine neurotransmitters, which have been postulated to play a role in the etiology of SZ. Variations in the VMAT1 gene might affect transporter function and/or expression, and might be involved in the etiology of SZ. Genotypes of 62 patients with SZ and 188 control subjects were obtained for 4 missense single nucleotide polymorphisms (Thr4Pro, Thr98Ser, Thr136Ile, Val392Leu) and 2 noncoding single nucleotide polymorphisms (rs988713, rs2279709). All cases and controls were of European descent. The frequency of the minor allele of the Thr4Pro polymorphism was significantly increased in SZ patients when compared to controls (p = 0.0140; d.f. = 1; OR = 1.69; 95% CI = 1.11–2.57). Assuming a recessive mode of inheritance, the frequency of homozygote 4Pro carriers was significantly increased in the SZ patients when compared to controls (24 vs. 8%, respectively; p = 0.0006; d.f. = 1; OR = 3.74; 95% CI = 1.703–8.21). Haplotype analysis showed nominal significance for an individual risk haplotype (p = 0.013); however, after permutation correction, the global p value did not attain a statistically significant level (p = 0.07). Results suggest that variations in the VMAT1 gene may confer susceptibility to SZ in patients of European descent. Further studies are necessary to confirm this effect, and to elucidate the role of VMAT1 in central nervous system physiology and possible involvement in the genetic origins of SZ.