ABSTRACT
Synthetic methodology utilizing two aryne intermediates (i.e., a formal benzdiyne) enables the rapid generation of structurally complex molecules with diverse functionality. This report describes the sequential generation of two ortho-benzyne intermediates for the synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates have proven useful in medicinal chemistry and materials science, and the reported methodology provides a two-step route to functionally dense variants by way of 3-phosphonyl benzyne intermediates. The process begins with regioselective trapping of a 3-trifloxybenzyne intermediate by an O-silyl phosphite in an Abramov-like reaction to bond the strained Csp carbons with phosphorus and silicon. Standard aryne-generating conditions follow to convert the resulting 2-silylphenyl triflate into a 3-phosphonyl benzyne, which readily reacts with numerous aryne trapping reactants to form a variety of 2,3-difunctionalized aryl phosphonate products. DFT computational studies shed light on important mechanistic details and revealed that 3-phosphonyl benzynes are highly polarizable. Specifically, the distortion in the internal bond angles at each of the Csp atoms was strongly influenced by both the electronegativity of the phosphonate ester groups as well as the dielectric of the computational solvation model. These effects were verified experimentally as the regioselectivity of benzyl azide trapping increased with more electronegative esters and/or increasingly polar solvents. Conversely, replacing the conventional solvent, acetonitrile, with nonpolar alternatives provided attenuated or even inverted selectivities. Overall, these studies showcase new reactivity of benzyne intermediates and extend the aryne relay methodology to include organophosphonates. Furthermore, this work demonstrates that the regioselectivity of aryne trapping reactions could be tuned by simply changing the solvent.
Subject(s)
Benzene Derivatives , Molecular Structure , SolventsABSTRACT
Transmyocardial laser revascularization is an established therapy for refractory coronary artery disease. However, utilization of the technology is not as widespread as expected. This is despite the fact that the efficacy of the technology has been established in multiple prospective randomized trials. Furthermore, only about 5% of transmyocardial laser revascularization cases annually are performed in a minimally invasive fashion. We report a case of a female patient treated in a minimally invasive thoracoscopic fashion.
Subject(s)
Laser Therapy/methods , Myocardial Ischemia/surgery , Thoracic Surgery, Video-Assisted/methods , Transmyocardial Laser Revascularization/methods , Female , Humans , Middle Aged , Myocardial Ischemia/diagnosisABSTRACT
BACKGROUND: The Ponseti method has been shown to be the most effective treatment for congenital clubfoot. The current challenge is to establish sustainable national clubfoot treatment programs that utilize the Ponseti method and integrate it within a nation's governmental health system. The Brazilian Ponseti Program (Programa Ponseti Brasil) has increased awareness of the utility of the Ponseti method and has trained >500 Brazilian orthopaedic surgeons in it. METHODS: A group of 18 of those surgeons had been able to reproduce the Ponseti clubfoot treatment, and compiled their initial results through structured spreadsheet. RESULTS: The study compiled 1040 patients for a total of 1621 feet. The average follow-up time was 2.3 years with an average correction time of approximately 3 months. Patients required an average of 6.40 casts to achieve correction. CONCLUSIONS: This study demonstrates that good initial correction rates are reproducible after training; from 1040 patients only 1.4% required a posteromedial release. LEVEL OF EVIDENCE: Level IV.
Subject(s)
Casts, Surgical , Clubfoot/therapy , Manipulation, Orthopedic/methods , Tenotomy , Achilles Tendon/surgery , Child, Preschool , Developing Countries , Female , Health Services Accessibility/standards , Humans , Infant , Male , Program Evaluation , Tenotomy/methods , Treatment OutcomeABSTRACT
Fish oil (FO) is a potent anti-inflammatory and lipid-lowering agent. Because inflammation can modulate lipid metabolism and vice versa, we hypothesized that combining FO with cyclooxygenase inhibitors (COXIBs), well-known anti-inflammatory drugs, can enhance the anti-inflammatory and lipid-lowering effect of FO. LDLR(-/-) mice were fed a high-fat diet supplemented with 6% olive oil or FO for 12 wk in the presence or absence of indomethacin (Indo, 6 mg/l drinking water). FO reduced plasma total cholesterol by 30% but, in combination with Indo, exerted a greater decrease (44%). The reduction of liver cholesterol ester (CE) and triglycerides (TG) by FO (63% and 41%, respectively) was enhanced by Indo (80% in CE and 64% in TG). FO + Indo greatly increased the expression of genes modulating lipid metabolism and reduced the expression of inflammatory genes compared with control. The mRNA and/or protein expression of pregnane X receptor (PXR) and cytochrome P450 isoforms that alter inflammation and/or lipid metabolism are increased to a greater extent in mice that received FO + Indo. Moroever, the nuclear level of PXR is significantly increased in FO + Indo group. Combining FO with COXIBs may exert their beneficial effects on inflammation and lipid metabolism via PXR and cytochrome P450.
