Search

Abstract: This paper presents a phytolith analysis of selected native plants and modern surface soils from southeastern Uruguay. A modern phytolith reference collection was established based on 60 Poaceae species, 22 non-Poaceae monocotyledonous species, 17 species of herbaceous dicotyledons, 9 woody dicotyledonous species, and 2 species of fern. Nine modern surface soil samples were analyzed from the most representative vegetation units of the region, including wetlands, wet prairies, upland prairies, riparian forest, and palm forest. Of the 50 non-Poaceae plant species analyzed, 25 contribute diagnostic phytoliths at different taxonomic levels corresponding to all the major ecological zones of southeastern Uruguay. Patterns of phytolith production and morphology were concordant with those observed in related taxa studied from other regions of the world. The modern soil analysis revealed significant patterns that differentiate a number of specific habitats, showing that distinct vegetational units may be discriminated by the phytolith signatures they produce. These results reinforce the utility of using phytoliths as significant indicators for vegetation units dominated both by monocotyledonous and dicotyledonous plant species, and demonstrate the potential of phytolith analysis for paleoecological and archeological reconstruction in this region. [Copyright &y& Elsevier]

Abstract: Objectives: The use of new antipsychotic drugs is associated with an increased risk of diabetes and metabolic syndrome, and the routine monitoring of blood lipids during treatment has been recommended. Recently, a new formula for the estimation of low-density lipoprotein (LDL) cholesterol from total cholesterol and triglycerides has been proposed by Anandaraja et al. (Int J Cardiol 2005; 102: 117), and the aim of our study was its evaluation in schizophrenic patients treated with antipsychotic drugs. Materials and methods: In 487 serum samples from schizophrenic patients treated with clozapine in polytherapy, the concentrations of LDL cholesterol were determined by agar gel electrophoresis and the formula of Friedewald et al. (Clin Chem 1972; 18: 499), and compared with the results of the Anandaraja''s formula. Results: A higher correlation and lower error of the estimate of the electrophoresis results was found with those of Friedewald (r =0.940, ma68=0.17 mmol/L) than those of Anandaraja (r =0.811, ma68=0.31 mmol/L). Similar results were obtained on making a dichotomy of the patients with and without metabolic syndrome lipid profile. A highly significant correlation was found between the high-density lipoprotein (HDL) cholesterol levels and the Anandaraja/Electrophoresis (r =0.817, p <0.001) and Anandaraja/Friedewald (r =0.977, p <0.001) ratios. Conclusions: According to our data, Anandaraja''s formula tends towards an overestimation or underestimation of LDL cholesterol levels, depending on whether the HDL cholesterol levels are high or low, which may be clinically significant. These results do not support the proposed better accuracy of the Anandaraja''s than the Friedewald''s formula. [Copyright &y& Elsevier]

Abstract: Objective : Therapeutic drug monitoring of clozapine may be useful for the clinical management of schizophrenic patients treated with this atypical antipsychotic drug. The aim of our study was the evaluation of three models for the prediction of steady-state trough clozapine concentration. Patients and methods : The trough serum concentrations of clozapine and norclozapine were determined by high-performance liquid chromatography in 296 samples from a group of 21 schizophrenic patients selected for their good therapeutic compliance. Also, the predicted clozapine concentrations were estimated by applying the models of Oyewumi et al. (Ther Drug Monit 1995; 17: 137), Perry et al. (Biol Psychiatry 1998; 44: 733) and Rostami-Hodjegan et al. (J Clin Psychopharmacol 2004; 24: 70). Results : The efficiency for the accurate estimation of clozapine concentrations as subtherapeutic (<240 ng/mL), therapeutic (240–750 ng/mL) or supratherapeutic (>750 ng/mL), using the models of Oyewumi et al., Perry et al., and Rostami-Hodjegan et al., was 82%, 71% and 77% respectively. Conclusions : The predictive model of Oyewumi et al., which shows an easy calculation way and the greater diagnostic efficiency, may be of clinical value for the prediction of clozapine concentration or the dose required to achieve a specified concentration. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance (DAOA and PPP1R1B) or protection against pathogens (APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model. [ABSTRACT FROM AUTHOR]

Genetic risk for schizophrenia is due to the joint effect of multiple genes acting mainly at two different processes, prenatal/perinatal neurodevelopment and adolescence/early adulthood synapse maturation. Identification of important genes at the second process is of relevance for early intervention. The aim of this work was to identify gene co-expression modules with altered expression in schizophrenia during adolescence/early adulthood. To this goal, we predicted frontal cortex gene expression in one discovery sample, the largest GWAS of schizophrenia from the Psychiatric Genomics Consortium, using S-prediXcan, and in one target sample, consisting of 625 schizophrenic patients and 819 controls from Spain, using prediXcan. Prediction models were trained on GTEx frontal cortex expression dataset. In parallel, we identified brain co-expression modules from BrainSpan using WGCNA. Then, we estimated polygenic risk scores based on predicted expression (PE-PRS) for each co-expression module in the target sample, based on PE-PRS model from the discovery sample. This analysis led to the identification of a module with mainly adolescence/adulthood expression whose PE-PRS was significantly associated with schizophrenia. The module was significantly enriched in synaptic processes. Several hub genes at this module are drugabble, according to the drug-gene interaction database, and/or involved in synaptic transmission, such as the voltage-gated ion channels SCN2B and KCNAB2 , the calcium calmodulin kinases CAMK2A and CAMK1G , or genes involved in synaptic vesicle cycle, such as DNM1 , or SYNGR1. Therefore, identification of this module may be the first step in patient stratification based on biology, as well as in drug design and drug repurposing efforts. • Genetically- regulated gene expression was predicted in schizophrenia/control samples. • Polygenic scores based on this prediction were estimated for gene co-expression modules. • The module with adolescence/adulthood expression with more variance explained was identified. • The module is enrich in genes involved in synaptic process. • Several hubs for this module, such as CAMK2A, CAMK1G, SCN2B, or KCNAB2, are drugabble. [ABSTRACT FROM AUTHOR]

A fraction of genetic risk to develop schizophrenia may be due to low-frequency variants. This multistep study attempted tofind low-frequency variants of high effect at coding regions of eleven schizophrenia susceptibility genes supported by genome-wide association studies (GWAS) and nine genes for the DISC1 interactome, a susceptibility gene-set. During the discovery step, a total of 125 kb per sample were resequenced in 153 schizophrenia patients and 153 controls from Galicia (NW Spain), and the cumulative role of low-frequency variants at a gene or at the DISC1 gene-set were analyzed by burden and variance-based tests. Relevant results were meta-analyzed when appropriate data were available. In addition, case-only putative damaging variants were genotyped in a further 419 cases and 398 controls. The discovery step revealed a protective effect of rare missense variants at NRXN1, a result supported by meta-analysis (OR = 0.67, 95% CI: 0.47-0.94, P = 0.021, based on 3848 patients and 3896 controls from six studies). The follow-up step based on case-only putative damaging variants revealed a promising risk variant at AKAP9. This variant, K873R, reached nominal significance after inclusion of 240 additional Spanish controls from databases. The variant, located in an ADCY2 binding region, is absent from large public databases. Interestingly, GWAS revealed an association between common ADCY2 variants and bipolar disorder, a disorder with considerable genetic overlap with schizophrenia. These data suggest a role of rare missense variants at NRXN1 and AKAP9 in schizophrenia susceptibility, probably related to alteration of the excitatory/inhibitory synaptic balance, deserving further investigation. [ABSTRACT FROM AUTHOR]

Several recurrent copy number variants (CNVs) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labor intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensitivity and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). Methods: We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. Results: The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10−6, allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. Conclusions: Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis. [Copyright &y& Elsevier]

Abstract: Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P =0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P =0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background [ABSTRACT FROM AUTHOR]

Abstract: A bioassay-guided fractionation of leaf extracts from Clytostoma callistegioides (Cham.) Bureau ex Griseb. (Bignoniaceae) led to isolation of a natural mixture of four fatty acids with anti-insect activity against aphids. The compounds were identified by GC–MS as palmitic, stearic, linoleic and linolenic acids and quantified as their methyl esters. The anti-aphid activity of the natural mixture was traced to linolenic and linoleic acids, as shown by the settling inhibition activity of synthetic samples. Interestingly, the saturated acids (palmitic and stearic) tested alone stimulated settling on one of the tested aphids (Myzus persicae), but not on the other tested species (Rhopalosiphum padi). Although ubiquitous, none of these free acids have been previously reported in this Bignoniaceae species. The leaf surface chemistry, which is likely involved in modulating aphid settling behavior, was further investigated for the occurrence of lipophilic substances by histochemical staining. Short, stalked glandular trichomes, previously undescribed for this species, stained with osmium tetroxide and Sudan III, suggesting that the secretion of the defensive acids is related to these surface trichomes. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the anti-insectan activity of extracts from different vegetative parts of ten plant species native to Uruguay. The selected plants belong to five families: Bignoniaceae: Clytostoma callistegioides, Dolichandra cynanchoides, Macfadyena unguis-cati; Sapindaceae: Dodonaea viscosa, Allophylus edulis, Serjania meridionalis; Lamiaceae: Salvia procurrens, Salvia guaranitica; Solanaceae: Lycium cestroides; and Phytolaccaceae: Phytolacca dioica. The extracts were evaluated in independent bioassays against four insect pests and one beneficial insect. Aphid settling inhibition was evaluated with a grass specialist, Rhopalosiphum padi, and a feeding generalist, Myzus persicae (both Hemiptera: Aphididae). Antifeedant activity was tested with adults of the specialist Epilachna paenulata (Coleoptera: Coccinellidae) and larvae of the generalist Spodoptera littoralis (Lepidoptera: Noctuidae). Finally, contact toxicity was assessed with honey bees, Apis mellifera (Hymenoptera: Apidae). Strong settling inhibition (SI) activity (expressed as %SI, where 100% means complete inhibition by the extract) was found only for the twig extracts of A. edulis (Sapindaceae) against M. persicae (%SI=77±4). Antifeedant activity (expressed as % of feeding reduction (FR), where 100% means no consumption on extract-treated diet) against E. paenulata was significant for the leaf extracts of L. cestroides (Solanaceae) (%FR=100±0) as well as of all Bignoniaceae and Sapindaceae species. No extracts were active against S. littoralis larvae, and most of them were innocuous to honey bees, with the exception of L. cestroides and S. meridionalis leaf extracts. [Copyright &y& Elsevier]