Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

A practical solution to the formation of mixtures of E/Z and open/cyclic isomers in the reaction of (2R,4S)-4-hydroxy-2-methylpentanal (as its hemiacetal, a lactol) with conjugated phosphoranes (stabilised Wittig reagents) and Horner-Wadsworth-Emmons reagents is disclosed. The HWE reaction has a strong bias to give oxolanes. On the other hand, stabilised Wittig reagents give unsaturated carboxyl derivatives of configuration E (major) and oxolanes (minor); the latter can be avoided by addition of CF3CH2OH or using morpholine amide phosphorane.

Nonsurgical treatment of cyclic esotropia.

Cyclic esotropia is characterized by a 24-hour period of straight eye position followed by 24 hours of large-angle esotropia. Possible mechanisms include notably progressive loss of compensation of a latent strabismus. The classic treatment is surgical correction of the angle measured on the days with manifest deviation. We report the first case of cyclic esotropia successfully treated by prismatic correction of the latent strabismus present on "straight" days.

Complications of guided surgery and immediate loading in oral implantology: a report of 12 cases

Objectives: The growing interest in minimally invasive surgery, together with the possibility of fitting prostheses with immediate function, have led to the development of software capable of planning and manufacturing a surgical guide and prosthesis that can be placed upon conclusion of the implant surgery step. The present study evaluates the surgical and prosthetic complications of implant treatment with the guided surgery technique, together with patient comfort during and after treatment. Patients and methods: A retrospective observational study was made of 19 patients with partially or totally edentulous upper and/or lower maxillae, involving the placement of a total of 122 implants. All cases were planned and operated upon with the guided surgery technique. Results: A total of 122 implants were placed in 14 males and 5 females. The intraoperative surgical complications comprised a lack of primary stability, while the postoperative complications consisted of infections and a lack of implant osteointegration. Ten implants failed. The prosthetic complications in turn comprised loosening of the provisional prosthesis screws, prosthesis tooth fracture, and a lack of passive fit of the immediate prosthesis. The degree of patient satisfaction was evaluated using a verbal scale. Conclusions: Implant restoration with the guided surgery technique and immediate functional loading is a predictable procedure, provided patient selection and the surgical technique are adequate, affording lesser postoperative morbidity and increased patient satisfaction thanks to the immediate restoration of esthetics and function

β-Adrenergic modulation of skeletal muscle contraction: key role of excitation-contraction coupling.

Our aim is to describe the acute effects of catecholamines/β-adrenergic agonists on contraction of non-fatigued skeletal muscle in animals and humans, and explain the mechanisms involved. Adrenaline/β-agonists (0.1-30 μm) generally augment peak force across animal species (positive inotropic effect) and abbreviate relaxation of slow-twitch muscles (positive lusitropic effect). A peak force reduction also occurs in slow-twitch muscles in some conditions. β2 -Adrenoceptor stimulation activates distinct cyclic AMP-dependent protein kinases to phosphorylate multiple target proteins. β-Agonists modulate sarcolemmal processes (increased resting membrane potential and action potential amplitude) via enhanced Na(+) -K(+) pump and Na(+) -K(+) -2Cl(-) cotransporter function, but this does not increase force. Myofibrillar Ca(2+) sensitivity and maximum Ca(2+) -activated force are unchanged. All force potentiation involves amplified myoplasmic Ca(2+) transients consequent to increased Ca(2+) release from sarcoplasmic reticulum (SR). This unequivocally requires phosphorylation of SR Ca(2+) release channels/ryanodine receptors (RyR1) which sensitize the Ca(2+) -induced Ca(2+) release mechanism. Enhanced trans-sarcolemmal Ca(2+) influx through phosphorylated voltage-activated Ca(2+) channels contributes to force potentiation in diaphragm and amphibian muscle, but not mammalian limb muscle. Phosphorylation of phospholamban increases SR Ca(2+) pump activity in slow-twitch fibres but does not augment force; this process accelerates relaxation and may depress force. Greater Ca(2+) loading of SR may assist force potentiation in fast-twitch muscle. Some human studies show no significant force potentiation which appears to be related to the β-agonist concentration used. Indeed high-dose β-agonists (∼0.1 μm) enhance SR Ca(2+) -release rates, maximum voluntary contraction strength and peak Wingate power in trained humans. The combined findings can explain how adrenaline/β-agonists influence muscle performance during exercise/stress in humans.

Effect of partial-thickness tear on loading capacities of the supraspinatus tendon: a finite element analysis.

Partial-thickness tears of the supraspinatus tendon frequently occur at its insertion on the greater tubercule of the humerus, causing pain and reduced strength and range of motion. The goal of this work was to quantify the loss of loading capacity due to tendon tears at the insertion area. A finite element model of the supraspinatus tendon was developed using in vivo magnetic resonance images data. The tendon was represented by an anisotropic hyperelastic constitutive law identified with experimental measurements. A failure criterion was proposed and calibrated with experimental data. A partial-thickness tear was gradually increased, starting from the deep articular-sided fibres. For different values of tendon tear thickness, the tendon was mechanically loaded up to failure. The numerical model predicted a loss in loading capacity of the tendon as the tear thickness progressed. Tendon failure was more likely when the tendon tear exceeded 20%. The predictions of the model were consistent with experimental studies. Partial-thickness tears below 40% tear are sufficiently stable to persist physiotherapeutic exercises. Above 60% tear surgery should be considered to restore shoulder strength.

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

OBJECTIVES: The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND: Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. METHODS: Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. RESULTS: Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). CONCLUSIONS: This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).

Straightforward synthesis of cyclic and bicyclic peptides

Cyclic peptide architectures can be easily synthesized from cysteine-containing peptides with appending maleimides, free or protected, through an intramolecular Michael-type reaction. After peptide assembly, the peptide can cyclize either during the trifluoroacetic acid treatment, if the maleimide is not protected, or upon deprotection of the maleimide. The combination of free and protected maleimide moieties and two orthogonally protected cysteines gives access to structurally different bicyclic peptides with isolated or fused cycles.

Variable-stiffness composite panels: Defect tolerance under in-plane tensile loading

Automated Fiber Placement is being extensively used in the production of major composite components for the aircraft industry. This technology enables the production of tow-steered panels, which have been proven to greatly improve the structural efficiency of composites by means of in-plane stiffness variation and load redistribution. However, traditional straight-fiber architectures are still preferred. One of the reasons behind this is related to the uncertainties, as a result of process-induced defects, in the mechanical performance of the laminates. This experimental work investigates the effect of the fiber angle discontinuities between different tow courses in a ply on the un-notched and open-hole tensile strength of the laminate. The influence of several manufacturing parameters are studied in detail. The results reveal that 'ply staggering' and '0% gap coverage' is an effective combination in reducing the influence of defects in these laminates

Drug loading of mesoporous silicon particles

Porous silicon (PSi) is a promising material to be utilized in drug delivery formulations. The release rate of the drug compound can be controlled by changing the pore properties and surface chemistry of PSi. The loading of a poorly soluble drug into mesoporous silicon particles enhances its dissolution in the body. The drug loading is based on adsorption. The attainable maximum loaded amount depends on the properties of the drug compound and the PSi material, and on the process conditions. The loading solvent also essentially affects the adsorption process. The loading of indomethacin into PSi particles with varying surface modification was studied. Solvent mixtures were applied in the loading, and the loaded samples were analyzed with thermal analysis methods. The best degree of loading was obtained using a mixture of dichloromethane and methanol. The drug loads varied from 7.7 w-% to 26.8 w-%. A disturbing factor in the loading experiments was the tendency of indomethacin to form solvates with the solvents applied. In addition, the physical form and stability of indomethacin loaded in PSi and silica particles were studied using Raman spectroscopy. In the case of silica, the presence of crystalline drug as well as the polymorph form can be detected, but the method proved to be not applicable for PSi particles.

Tautomerism and Fragmentation of Biologically Active Hetero Atom (O, N)-Containing Acyclic and Cyclic Compounds Under Electron Ionization

In this thesis a total of 86 compounds containing the hetero atoms oxygen and nitrogen were studied under electron ionization mass spectrometry (EIMS). These compounds are biologically active and were synthesized by various research groups. The main attention of this study was paid on the fragmentations related to different tautomeric forms of 2- phenacylpyridines, 2-phenacylquinolines, 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo- [2,1-c][1,2,4]triazines and aryl- and benzyl-substituted 2,3-dihydroimidazo[1,2-a]pyrimidine-5,7-(1H,6H)-diones. Also regio/stereospecific effects on fragmentations of pyrrolo- and isoindoloquinazolinones and naphthoxazine, naphthpyrrolo-oxazinone and naphthoxazino-benzoxazine derivatives were screened. Results were compared with NMR data, when available. The first part of thesis consists of theory and literature review of different types of tautomerism and fragmentation mechanisms in EIMS. The effects of tautomerism in biological systems are also briefly reviewed. In the second part of the thesis the own results of the author, based on six publications,are discussed. For 2-phenacylpyridines and 2-phenacylquinolines the correlation of different Hammett substituent constants to the relative abundances (RA) or total ion currents (% TIC) of selected ions were investigated. Although it was not possible to assign most of the ions formed unambiguously to the different tautomers, the linear fits of their RAs and % TICs can be related to changing contributions of different tautomeric forms. For dioxoimidazotriazines and imidazopyrimidinediones the effects of substituents were rather weak. The fragmentations were also found useful for obtaining structural information. Some stereoisomeric pairs of pyrrolo- and isoindoloquinazolines and regiomeric pairs of naphtoxazine derivatives showed clear differences in thir mass spectra. Some mechanisms are suggested for their fragmentations.

Taajuusmuttajan vanheneminen syklisissä käytöissä

Tässä työssä tarkastellaan taajuusmuuttajan vanhenemista syklisissä käytöissä puolijohdetehokomponenttien osalta. Laitteiden vikaantumisprosessien analysoimiseksi työssä suunnitellaan syklinen kestotestausjärjestelmä, joka mahdollistaa useamman taajuusmuuttajan yhtäaikaisen vanhentamisen. Jaksottaisesti toistuvat kuormitussyklit rasittavat termomekaanisesti taajuusmuuttajan tehomoduulin sisäisiä rakenteita suurten lämpötilavaihtelujen johdosta. Teoriaosuuden pääpaino kohdistuu puolijohdetehokomponenttien rakenteeseen, vikaantumisprosesseihin ja eliniän kartoittamiseen. Työssä käydään läpi yleisimpien pienijännitteisten moottorinohjausinverttereiden tehomoduulien mekaaniset rakenteet, tyypillisemmät syklisestä kuormituksesta johtuvat vikaantumisprosessit sekä puolijohdetehokomponenttivalmistajien käyttämät syklisen eliniän testausmenetelmät. Loppuosassa työtä suunnitellaan taajuusmuuttajan syklinen kestotestausjärjestelmä laitteiden keinotekoista vanhentamista varten. Testausjärjestelmällä voidaan kuormittaa useampaa taajuusmuuttajaa vuorottain mielivaltaisella kuormitusvirtaprofiililla. Laitteita vanhennettiin kaksi testierää kuormittamalla niitä jaksottaisesti hissikäytön tyypillisellä kuormitusprofiililla. Puolijohdetehokomponentin vanhenemisen edistystä seurattiin termisen impedanssiketjun mittausmenetelmällä, joka perustuu IGBT:n kollektoriemitterijännitteen lämpötilariippuvuuteen. Testilaitteiden puolijohdetehokomponentit hajosivat syklisen eliniän päättymiseen teoriassa esitettyjen vikaantumisprosessien seurauksesta. Tehomoduulien vika-analyysi osoittaa syklisen kestotestausjärjestelmän soveltuvaksi menetelmäksi tutkia erilaisten kuormitusprofiilien vaikutusta taajuusmuuttajan vanhenemiseen.

Stereoselective syntheses of (+)- isoretronecanol and (+)-5-epi-tashiromine via addition of chiral titanium (iv) enolates to cyclic n-acyliminium ions

The stereoselective addition of the titanium (IV) enolates derived from (S)-4-isopropyl-N-4-chlorobutyryl-1,3-thiazolidine-2-thione (8) and from (S)-4-isopropyl-N-4-chloropentanoyl-1,3-thiazolidine-2-thione (9) to N-Boc-2-methoxypyrrolidine (5b) afforded the addition products (+)-10 and (+)-11 in 84% yield in both cases, as 8.6:1 and 10:1 diastereoisomeric mixtures, respectively. A three-step sequence allowed to convert these adducts to (+)-isoretronecanol (1) and (+)-5-epi-tashiromine (2) in 43% and 49% overall yield, respectively.