eNOS G894T polymorphism as a mild predisposing factor for abdominal aortic aneurysm

ObjectiveAbdominal aortic aneurysm (AAA) represents a chronic degenerative condition associated with atherosclerosis. Actually, data from experimental and clinical studies suggest that nitric oxide (NO) is a modulator in maintaining endothelial function and antithrombotic intravascular environment. Reduced vascular NO generation in subjects carrying the rare variants of the eNOS gene might predispose to AAA. No information is available about the influence of the eNOS gene T-786C, G894T, and 4a/4b polymorphisms in the susceptibility to the disease.MethodsIn this study, we evaluated the role of these polymorphisms in the predisposition to AAA and their influence in hypertensive and normotensive patients. We studied 250 consecutive patients with AAA referred to the Unit of Vascular Surgery of the University of Florence compared with 250 truly healthy subjects with a negative history of vascular diseases. All subjects, patients, and controls, underwent duplex scanning examination, and to assess the presence of other atherosclerotic localizations, all patients underwent clinical and instrumental examinations.ResultsA significant difference in genotype distribution and allele frequency was observed for eNOS G894T but not for T-786C and 4a/4b polymorphisms. At the multivariate analysis after adjustment for traditional vascular risk factors and other atherosclerotic localizations, the eNOS 894T variant was significantly associated with AAA, according to dominant and recessive models (dominant model odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.21-3.93, P = .007; recessive model OR: 2.7, 95% CI: 1.42-5.20, P = .002). When patients with other atherosclerotic localizations were excluded from the analysis, the 894T variant still remained associated with the predisposition to AAA, according to the models considered (dominant model OR: 2.1, 95%CI: 1.23-3.92, P = .007; recessive model OR: 2.8, 95%CI: 1.45-5.24, P = .002).ConclusionsThe present study showed that the eNOS G894T polymorphism is a mild modulator of the predisposition to AAA apart from traditional risk factors, suggesting a genetic influence on the molecular mechanisms responsible for this complex disease

Recruitment maneuver in prevention of hypoxia during percutaneous dilational tracheostomy: Randomized trial

BACKGROUND: Percutaneous dilational tracheostomy (PDT) can potentially lead to hypoxia and alveolar derecruitment. The aim of this prospective study was to evaluate the efficacy of performing a recruitment maneuver (RM) before tracheostomy, in order to improve oxygenation. METHODS: We enrolled 29 eligible trauma patients with acute lung injury criteria requiring tracheostomy in a university ICU. Subjects were ventilated on volume controlled mechanical ventilation (tidal volume of 6 mL/kg) and FIO2set at 1.0. Subjects were randomized into 2 groups: RM group (subjects who underwent RM 10 min before PDT, 15 subjects) and no-RM group (subjects without application of RM before PDT, 14 subjects). RM was performed by imposition of continuous positive airway pressure of 40 cm H2O for 40 seconds. We collected gas exchange, respiratory, and hemodynamic data 5 times: 1 hour before RM, 5 min after RM, 5 min after PDT, 30 min after PDT, and 6 hours after PDT. RESULTS: Subjects who underwent RM had a significant increase in PaO2; 5 min after the maneuver, PaO2increased from 222.6 \uc2\ub1 33.4 mm Hg to 341.3 \uc2\ub1 33.1 mm Hg (P <.01) and was always significantly maintained throughout the following times of the study, compared to the no-RM group: in the RM and no-RM groups, respectively, 260.7 \uc2\ub1 35.4 mm Hg vs 108.5 \uc2\ub1 36.9 mm Hg 5 min after PDT; 285.6 \uc2\ub1 29.1 mm Hg vs 188.4 \uc2\ub1 21.4 mm Hg 30 min after PDT; and 226.3 \uc2\ub1 24.8 mm Hg vs 147.6 \uc2\ub1 42.8 mm Hg 6 h after PDT (P <.01). CONCLUSIONS: Our study suggests that application of RM before PDT could be useful to avoid hypoxemia following such procedure, by reducing fall in PaO2and preventing the decrease in oxygenation values below baseline at 6 hours. \uc2\ua9 2012 Daedalus Enterprises

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

The present paper describes the application of modern combinatorial and microwave assisted techniques for the lead discovery and optimization of novel non-nucleoside HIV-1-RT inhibitors. Starting from the parallel solid phase synthesis of highly substituted pyrimidinone derivatives, compound 12c was identified as interesting lead compound for further structure optimizations. The generation and screening of a small virtual combinatorial library led to the optimization of the lead structure 12c to give highly active derivatives (against HIV1-RT wild-type and mutant strains) in the nanomolar range. Moreover, a straightforward three-step parallel solution phase approach was developed for the generation of a small library of novel 4-dialkylamino-2-methylsulfonyl-6- vinylpyrimidines which were obtained in high yield after a simple ethyl acetate extraction with no need of further purification. Surprisingly, some of these derivatives showed a new competitive inhibition of HIV1-RT never reported in the literature for this class of compounds. Molecular modeling calculations were also performed to investigate the binding mode of all synthesized compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

The present paper describes the application of modern combinatorial and microwave assisted techniques for the lead discovery and optimization of novel non-nucleoside HIV-1-RT inhibitors. Starting from the parallel solid phase synthesis of highly substituted pyrimidinone derivatives, compound 12c was identified as interesting lead compound for further structure optimizations. The generation and screening of a small virtual combinatorial library led to the optimization of the lead structure 12c to give highly active derivatives (against HIV1-RT wild-type and mutant strains) in the nanomolar range. Moreover, a straightforward three-step parallel solution phase approach was developed for the generation of a small library of novel 4-dialkylamino-2-methylsulfonyl-6- vinylpyrimidines which were obtained in high yield after a simple ethyl acetate extraction with no need of further purification. Surprisingly, some of these derivatives showed a new competitive inhibition of HIV1-RT never reported in the literature for this class of compounds. Molecular modeling calculations were also performed to investigate the binding mode of all synthesized compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity

A Multidisciplinary Approach for the Identification ofNovel HIV-1 Non-Nucleoside Reverse TranscriptaseInhibitors: S-DABOCs and DAVPs

Among the FDA approved drugs for the treatment of AIDS, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first-line anti-HIV-1 therapy because of the less-severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti-HIV-1 agents. In this contest, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV-1 wild type and especially drug-resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S-DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S-DABO analogues: S-DABO cytosine analogues (S-DABOCs) and 4-dimethyamino-6-vinylpyrimidines (DAVPs)

Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via tachykinin synthesis induction

1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the β-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT – PCR), prior to and 30 – 40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, β-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production