Heterocyclic amine-DNA adducts analyzed by 32P-postlabeling method

DNA adducts formed by 12 heterocyclic amines were analyzed by 32P-postlabeling method. Several DNA adducts were detected in rat liver by administration of each heterocyclic amine. Total adduct levels ranged from 0.5 for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to more than 250 for 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) per 10(7) nucleotides 24 hr after intragastric administration of these compounds. The N-hydroxy derivative of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was reactive toward DNA in vitro to form adducts. Addition of acetic anhydride to N-OH-MeIQx greatly enhanced its reactivity to DNA. 32P-Postlabeling analysis revealed that the MeIQx-DNA adducts formed in vivo and in vitro were identical. Thus, MeIQx would be metabolized in vivo to N-hydroxy form and further esterified to produce more reactive species, such as N-acetoxy form, which modify DNA to form adducts.     

Non-enzymatic glutathione conjugation of 2-nitroso-6-methyldipyrido [1,2-a: 3',2'-d] imidazole (NO-Glu-P-1) in vitro: N-hydroxy-sulfonamide, a new binding form of arylnitroso compounds and thiols

In order to study the possible detoxification mechanisms of the carcinogenic arylamine, 2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (Glu-P-1), the in vitro non-enzymatic reaction of 2-nitroso-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (NO-Glu-P-1) with reduced glutathione (GSH) was examined at pH 7.4 under both aerobic and anaerobic conditions. Two GSH-arylamine adducts were isolated and found to contain the Glu-P-1 and GSH moieties in a 1:1 molar ratio via an N-S linkage. Their structures were assigned as sulfinamide (-NH-SO-) and N-hydroxy-sulfonamide (-N(OH)-SO2-) by their behaviour under acidic and basic conditions and by UV-VIS, 1H-NMR, infrared and mass spectrometries. Also, a N-hydroxy-sulfonamide adduct was produced when NO-Glu-P-1 and cysteine were reacted at pH 7.4. The N-hydroxy-sulfonamide structure is a new binding form between arylnitroso compounds and thiols. The formation of these adducts may also take place in vivo as a detoxification of toxic arylamines since GSH is abundant in organs such as liver or kidney.     

An overview of malaria transmission from the perspective of Amazon Anopheles vectors

In the Americas, areas with a high risk of malaria transmission are mainly located in the Amazon Forest, which extends across nine countries. One keystone step to understanding the Plasmodium life cycle in Anopheles species from the Amazon Region is to obtain experimentally infected mosquito vectors. Several attempts to colonise Ano- pheles species have been conducted, but with only short-lived success or no success at all. In this review, we review the literature on malaria transmission from the perspective of its Amazon vectors. Currently, it is possible to develop experimental Plasmodium vivax infection of the colonised and field-captured vectors in laboratories located close to Amazonian endemic areas. We are also reviewing studies related to the immune response to P. vivax infection of Anopheles aquasalis, a coastal mosquito species. Finally, we discuss the importance of the modulation of Plasmodium infection by the vector microbiota and also consider the anopheline genomes. The establishment of experimental mosquito infections with Plasmodium falciparum, Plasmodium yoelii and Plasmodium berghei parasites that could provide interesting models for studying malaria in the Amazonian scenario is important. Understanding the molecular mechanisms involved in the development of the parasites in New World vectors is crucial in order to better determine the interaction process and vectorial competence.     

Exercise as a model to study redox homeostasis in blood: the effect of protocol and sampling point

Twenty males ran either on a level treadmill (nonmuscle-damaging condition) or on a downhill treadmill (muscle-damaging condition). Blood and urine samples were collected before and after exercise (immediately after, 1h, 4h, 24h, 48h, and 96h). The following assays were performed: F(2)-isoprostanes in urine, protein carbonyls in plasma, glutathione, superoxide dismutase, glutathione peroxidase, and catalase in erythrocytes. The main finding was that monophasic redox responses were detected after nonmuscle-damaging exercise compared to the biphasic responses detected after muscle-damaging exercise. Based on these findings, muscle-damaging exercise may be a more appropriate experimental model to induce physiological oxidative stress.     

Methodology of evaluation of morphology of the spine and the trunk in idiopathic scoliosis and other spinal deformities - 6th SOSORT consensus paper

Background

Comprehensive evaluation of the morphology of the spine and of the whole body is essential in order to correctly manage patients suffering from progressive idiopathic scoliosis. Although methodology of clinical and radiological examination is well described in manuals of orthopaedics, there is deficit of data which clinical and radiological parameters are considered in everyday practise. Recently, an increasing tendency to extend scoliosis examination beyond the measure of the Cobb angle can be observed, reflecting a more patient-oriented approach. Such evaluation often involves surface parameters, aesthetics, function and quality of life.

Aim of the study

To investigate current recommendations of experts on methodology of evaluation of the patient with spinal deformity, essentially idiopathic scoliosis.

Methods

Structured Delphi procedure for collecting and processing knowledge from a group of experts with a series of questionnaires and controlled opinion feedback was performed. Experience and opinions of the professionals - physicians and physiotherapists managing scoliosis patients - were studied. According to Delphi method a Meeting Questionnaire (MQ) has been developed, resulting from a preliminary Pre-Meeting Questionnaire (PMQ) which had been previously discussed and approved on line. The MQ was circulated among the SOSORT experts during Consensus Session on "Measurements" which took place at the Annual Meeting of the Society, totally 23 panellists being engaged. Clinical, radiological and surface topography parameters were checked for agreement.

Results

90% agreement or more was reached in 35 items and superior than 75% agreement was reached in further 25 items. An evaluation form was proposed to be used by clinicians and researchers.

Conclusion

The consensus was reached on evaluation of the morphology of the patient with idiopathic scoliosis, comprising clinical, radiological and, to less extend, surface topography assessment. Considering the variety of parameters indicated by the panellists, the Cobb angle, yet the gold standard, can be seen neither as the unique nor the only decisive parameter in the management of patients with idiopathic scoliosis.     

Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist

Montelukast and Zafirlukast are known leukotriene receptor antagonists prescribed in asthma treatment. However, these fall short as mono therapy and are frequently used in combination with inhaled glucocorticosteroids with or without long acting beta 2 agonists. Therefore, it is of interest to apply ligand and structure based virtual screening strategies to identify compounds akin to lead compounds Montelukast and Zafirlukast. Hence, compounds with structures having 95% similarity to these compounds were retrieved from NCBI׳s PubChem database. Compounds similar to lead were grouped and docked at the antagonist binding site of cysteinyl leukotriene receptor 1. This exercise identified compounds UNII 70RV86E50Q (Pub Cid 71587778) and Sure CN 9587085 (Pub Cid 19793614) with higher predicted binding compared to Montelukast and Zafirlukast. It is shown that the compound Sure CN 9587085 showed appreciable ligand receptor interaction compared to UNII 70RV86E50Q. Thus, the compound Sure CN 9587085 is selected as a potent antagonist to cysteinyl leukotriene receptor 1 for further consideration in vitro and in vivo validation.     

Mutagenicity of some synthetic quinolines and quinoxalines related to IQ, MeIQ or MeIQx in Ames test

3-Methyl- and 3,4-dimethyl-3H-imidazo[4,5-f]quinoline, 3,8-dimethyl-3H-imidazo[4,5-f]quinoxaline, N6-methyl- and N6,7-dimethylquinoline-5,6-diamine, as well as N6,3-dimethylquinoxaline-5,6-diamine, have been synthesized. Only the first-mentioned compound was active in Ames test; the response was equal for Salmonella typhimurium TA98 and TA100, regardless of enzymatic activation (S9). However, its mutagenicity to TA98 + S9 was 300-1300 times smaller than the values reported for the related compounds, 3-methyl- and 3,4-dimethyl-3H-imidazo[4,5-f]quinolin-2-amine ('IQ' and 'MeIQ'), and for 3,8-dimethyl-3H-imidazo[4,5-f]quinoxalin-2-amine ('MeIQx'). Hence, the presence of the imidazole ring and the 2-amino group in the molecule seems to be important for the high mutagenicity of the latter compounds.