Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ß=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (ß=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.

[Treatment of hyperthyroidism caused by Graves' disease or toxic multinodular goitre by radioiodine: over 80% cure retrospectively after one calculated dose]. / Behandeling van hyperthyreoïdie door de ziekte van Graves of toxisch multinodulair struma met jodium-131: retrospectief ruim 80% genezing na één berekende dosis.

OBJECTIVE: Assessment of the results of radioiodine therapy for hyperthyroidism one year after treatment. DESIGN: Retrospective study of patient reports and a literature search. METHOD: Data were collected from 159 patients with Graves' disease or toxic multinodular goitre who had been treated with a calculated dose of radioiodine (131I) during a four-year period (1994-1998) at the Bronovo Hospital, The Hague, the Netherlands. Percentages of hypothyroidism, euthyroidism and hyperthyroidism one year after the treatment were compared with results from the literature. RESULTS: Of the patients treated for Graves' disease 42% were hypothyroid, 38% were euthyroid and 20% were hyperthyroid one year after radioiodine therapy. For patients with toxic multinodular goitre the figures were 10%, 78% and 12% respectively. These results were comparable with those found in the literature. Two factors influenced the outcome of therapy in patients with Graves' disease: patients with persistent hyperthyroidism were on average younger and low thyroid weight increased the chance of hypothyroidism. Whether the hyperthyroidism was permanent or transient could only be established in less than half of all patients with hormone substitution after treatment, as the substitution had already been started in the first six months. CONCLUSION: One calculated dose of radioiodine can effectively cure hyperthyroidism in over 80% of the patients. It is recommended that an effort is made to discontinue radioiodine treatment after one year so as to exclude transient hypothyroidism and unjustified hormone substitution.

Efficient tumor eradication by adoptively transferred cytotoxic T-cell clones in allogeneic hosts.

Tumor-specific cytotoxic T cells (CTLs) can play an important role against cancer as illustrated by the observation that adoptive transfer of tumor-specific CTLs can mediate potent anti-tumor effects. Although such CTLs can be detected at the tumor site, relatively little is known about the mechanisms by which they enter the tumor. In this study, the role of major histocompatibility complex (MHC) class 1 molecules on vascular endothelium in the tumor in entry of, and tumor eradication by, tumor-specific CTL was investigated. Two H-2Db-restricted CTL clones recognizing peptide VNIRNCCYI on human adenovirus type 5 early region 1-(Ad5E1)-induced tumors were used to test whether CTLs were able to cross the vascular endothelium lacking the restricting MHC molecule. One CTL clone recognizes peptide VNIRNCCYI in the context of both H-2Db and H-2Dbm14 molecules. The other CTL clone recognizes this peptide only in the context of H-2Db. Adoptive transfer of these CTLs leads to eradication of Ad5E 1-induced, H-2Db-expressing tumors in B6(H-2Db+) and Bm14(H-2Db-) nude mice. Our data show that presentation of tumor-derived peptides by MHC molecules on endothelial cells of blood vessels in a tumor do not play a major role in eradication of tumors by adoptively transferred CTL in combination with interleukin-2. Moreover, our data show that successful adoptive CTL immunotherapy is possible across allogeneic barriers, without inducing severe side effects, provided the tumor expresses the MHC class 1-peptide complex recognized by the CTLs.