ABSTRACT
Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could hypothesize that genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (P = 0.001) and control smokers (P = 0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (P = 0.022) and African-American (P = 0.006) nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies.
Subject(s)
Nerve Tissue Proteins/genetics , Receptors, Nicotinic/genetics , Schizophrenia/genetics , Tobacco Use Disorder/genetics , Adult , Alleles , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Polymorphism, Single Nucleotide , Smoking/genetics , Tobacco Use Disorder/bloodABSTRACT
Voriconazole (UK-109,496) is a new triazole with in vitro activity against a wide spectrum of fungi including yeasts intrinsically resistant to fluconazole such as Candida krusei. In this study the efficacy of voriconazole was compared to amphotericin B and fluconazole in a neutropenic guinea pig model of hematogenously disseminated C. krusei infection. In guinea pigs, neutropenia was established by using cyclophosphamide (intraperitoneally, i.p., 100 mg/kg on day 1 and 4), and dexamethasone (orally, 2 mg/kg/day, for 8 days). Neutropenic guinea pigs were infected with 0.5 ml of yeast cell suspension (1 x 10(8) CFU) intravenously. Challenged animals were treated with antifungals starting 1 h postinfection for 7 days. The animals were divided into five groups: untreated control, amphotericin B (1 mg/kg i.p. on alternate days), fluconazole (20 mg/kg orally twice daily), and voriconazole (two groups: 5 and 10 mg/kg orally twice daily) groups. Guinea pigs were sacrificed 1 day after the last treatment. Brain, liver, and kidneys were removed and weighed, tissues were homogenized and fungal burden determined by serial quantitative counts. Voriconazole at dosages of 5 or 10 mg/kg b.i.d. was shown to be significantly more efficacious than either amphotericin B or fluconazole in eradicating C. krusei from brain, liver and kidney tissue. These data indicate that voriconazole could be efficacious for the treatment of infections caused by fluconazole-resistant Candida, such as C. krusei.