Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats

Background: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer. Methods: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent

Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study

Uremia-associated anorexia may be related to altered levels of long chain n-6 and n-3 polyunsaturated fatty acid (PUFA) derived circulating endocannabinoids (EC) and EC-like compounds that are known to mediate appetite. Our study's hypothesis was that such molecules are associated with appetite in patients with end-stage renal disease. A cross-sectional observational study was performed in 20 chronic hemodialysis patients (9 females, 11 males) and 10 healthy female controls in whom appetite was assessed using the Simplified Nutritional Appetite Questionnaire (SNAQ) and blood drawn in the fasting (and when applicable) pre-dialysis state. Blood levels of PUFA and EC were also measured. Higher blood levels of the long chain n-6 fatty acid 20:4n6 (arachidonic acid) and lower levels of the long chain n-3 fatty acid 20:5n3 (eicosapentaenoic acid) were observed in female hemodialysis patients compared to controls. No differences were observed between male and female patients. In female study participants strong correlations between specific EC-like compounds and total SNAQ scores were noted, including with the n-6 PUFA derived linoleoyl ethanolamide (L-EA; ρ=-0.60, P<.01) and the n-3 PUFA derived docosahexaenoyl ethanolamide (DH-EA; ρ=0.63, P<.01). The L-EA:DH-EA ratio was most strongly associated with the SNAQ score (ρ=-0.74, P≤.001), and its questions associated with appetite (ρ=-0.69, P≤.01) and satiety (ρ=-0.81, P≤.001). These findings support a link between circulating EC and appetite in hemodialysis patients

Infância, exclusão social e educação como utopia realizável

A infância, como construção social, tem sofrido, no decurso da 2ª modernidade, processos de reinstitucionalização que, em larga medida, põem em causa as representações e imagens das crianças, dominantes nos últimos 200 anos. A análise da (re)construção das identidades sociais e das subjectividades infantis constitui, desse modo, uma tarefa teórica da mais exigente actualidade. O que, entretanto, aqui se assinala é que este processo de reinstitucionalização da infância, apesar da construção de consensos globais sobre os direitos das crianças, tem vindo a aumentar os factores e as condições de exclusão das gerações mais jovens face aos direitos sociais e da cidadania. Neste artigo inventariam-se alguns dos principais indicadores de exclusão, considerando diversos espaços estruturais, e assinalam-se alguns dos pontos de ruptura por onde pode passar a construção de uma educação escolar centrada na afirmação activa dos direitos das crianças.Along the second modernity, childhood, as a social construction, has undergone reinstatement processes that question the representations and images of children that have prevailed over last two hundred years. An analysis of the (re) construction of the social identities and childhood subjectivity thus constitute a theoretical task of the most contemporary exigence. Nevertheless, even though a global consensus about children’s rights has been constructed, the increase of factors and conditions that exclude the youngest generations from social rights and citizenship, induced by this reinstatement process of childhood, is here emphasized. This paper lists some of the main indicators of exclusion, considering different structural spaces, and pinpoints some turning points through which the construction of a school education centered on the active affirmation of the children’s rights could be attained.CIFPEC/CIEC - Centro de Investigação em Estudos da Criança, UM (UI 644 e 317 da FCT

The coexistence of peace and conflict in South America: toward a new conceptualization of types of peace

South America's predominant democratic regimes and its increasing interdependence on regional trade have not precluded the emergence of militarized crises between Colombia and Venezuela or the revival of boundary claims between Chile and Peru. This way, how can we characterize a zone that, in spite of its flourishing democracy and dense economic ties, remain involved in territorial disputes for whose resolution the use of force has not yet been discarded? This article contends that existing classifications of zones of peace are not adequate to explain this unusual coexistence. Thus, its main purpose is to develop a new analytical category of regional peace for assessing this phenomenon: the hybrid peace. It aims to research the evolution of security systems in South America during the previous century and build a new, threefold classification of peace zones: negative peace zones, hybrid peace zones, and positive peace zones

The challenges of genome-wide interaction studies: Lessons to learn from the analysis of HDL blood levels

Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP6SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value, 1 · 1028 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30, 011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP6SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin