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Purine nucleotides and their analogs increase insulin secretion through activation of pancreatic β-cell P2Y receptors. The present study aimed at determining the role of glucose metabolism in the response to P2Y agonists and whether ATP-activated [K.sup.+] channels ([K.sub.ATP] channels) are involved in this response. The experiments were performed in the rat isolated pancreas, perfused with a Krebs-bicarbonate buffer supplemented with 2 g/l bovine serum albumin under dynamic glucose conditions from 5 mmol/l baseline to 11 mmol/l. ADPβS (0.5 µmol/l) was selected as a stable and selective P2Y agonist. This compound, ineffective on the 5 mmol/l glucose background, induced a significant threefold increase in insulin release triggered by the glucose challenge. The effect of ADPβS was markedly reduced (P < 0.001) in the presence of an inhibitor of glucose metabolism. In addition to glucose, the ADP analog also amplified the β-cell insulin response to 15 mmol/l methyl pyruvate (P < 0.05), but it was ineffective on the insulin response to 2.5 mmol/l methyl succinate. A nonmetabolic stimulus was applied using tolbutamide (185 µmol/l). Insulin secretion induced by the [K.sub.ATP] channel blocker was strongly reinforced by ADPβS (P < 0.001), which prompted us to check a possible interplay of [K.sub.ATP] channels in the effect of ADPβS. In the presence of diazoxide 250 µmol/l and 21 mmol/l KCl, ADPβS still amplified the second phase of glucose-induced insulin secretion (P < 0.001). We conclude that P2Y receptor activation is able to promote insulin secretion through a mechanism, involving β-cell metabolism and a rise in intracellular calcium; this effect does not result from a direct inhibitory effect on [K.sub.ATP] channels., Purine nucleotides (ATP and ADP) and their analogs have been shown to increase glucose-induced insulin secretion through activation of P2 receptors present on pancreatic β-cells (1). These receptors were characterized [...]

Background: Stereotactic laser amygdalohippocampotomy (SLAH) has recently been shown to be comparable to traditional temporal lobectomy procedures. The ideal extent and volume of laser ablations remains an area of investigation Methods: 65 patients treated with SLAH for MTS were considered in this retrospective study. Manual segmentations of ablations were created using post-procedure T1-MRI scans. Ablations were assessed in relation to whether they crossed the coronal plane of the superior lateral mesencephalic sulcus (LMS), the extent to which ablation crossed this landmark, and extent of ablation of the uncus. Analysis of was done with binary categorization of 12-month Engel classification score. Results: Distance of ablation posterior to the coronal plane of the LMS was not associated with better surgical outcome (Engel class 1: 6.32 ± 4.16 mm; Engel class 2-4: 7.93 ± 3.75mm; (p = 0.099)). Ratio of ablations extending posterior to the LMS was 0.82 (SD = .39) in Engel 1 patients, and 0.90 (SD = 0.3) in Engel 2-4 patients; (p = 0.370). Volume of ablation showed little correlation with outcome (Engel class 1: 6064 ± 2128 mm3; Engel class 2-4: 5828 ± 3031 mm3; (p=0.239)). Ablation of the uncus showed a strong association with better surgical outcome (Engel class 1: 0.71(SD = 0.31); Engel 2-4: 0.37 (SD = 0.36); p <0.001). Conclusions: Contrary to current practice, extension of ablation posterior to the LMS did not demonstrate improved outcome.

Spinal cord injury (SCI) is a complex disease that affects not only sensory and motor pathways below the neurological level of injury (NLI) but also all the organs and systems situated below this NLI. This multisystem impairment implies comprehensive management in dedicated SCI specialized centers, by interdisciplinary and multidisciplinary teams, able to treat not only the neurological impairment, but also all the systems and organs affected. After a brief history of the Spinal Cord Medicine, the author describes how to determine the level and severity of a SCI based on the International Standards for Neurological Classification of Spinal Cord Injury and the prognosis factors of recovery. This article provides also a review of the numerous SCI-related impairments (except for urinary, sexual problems and pain treated separately in this issue), their principles of management and related complications.

Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography ‘connectome blueprint’ to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

The observation of the spin Hall effect triggered intense research on pure spin current transport. With the spin Hall effect, the spin Seebeck effect and the spin Peltier effect already observed, our picture of pure spin current transport is almost complete. The only missing piece is the spin Nernst (–Ettingshausen) effect, which so far has been discussed only on theoretical grounds. Here, we report the observation of the spin Nernst effect. By applying a longitudinal temperature gradient, we generate a pure transverse spin current in a Pt thin film. For readout, we exploit the magnetization-orientation-dependent spin transfer to an adjacent yttrium iron garnet layer, converting the spin Nernst current in Pt into a controlled change of the longitudinal and transverse thermopower voltage. Our experiments show that the spin Nernst and the spin Hall effect in Pt are of comparable magnitude, but differ in sign, as corroborated by first-principles calculations.

Les rééducateurs manquent de preuves concernant leurs interventions auprès des enfants paralysés cérébraux (PC), notamment sur l’utilisation du plan incliné pour améliorer la marche en situation écologique. Nous nous proposons d’évaluer l’intérêt de la pente en rééducation sur la cinématique du genou et le renforcement musculaire de l’enfant diplégique ayant une marche de type « crouch gait ».

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985–2004 and followed up to the end of 2004–2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40–49 years vs 20–29 years, RR=1.15 (95% confidence interval (CI): 1.06–1.24), P-value<0.001; fathers⩾50 years vs 20–29 years, RR=1.66 (95% CI: 1.49–1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20–29 years, RR=1.18 (95% CI: 1.08–1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

Propagating quantum microwaves have been proposed and successfully implemented to generate entanglement, thereby establishing a promising platform for the realisation of a quantum communication channel. However, the implementation of quantum teleportation with photons in the microwave regime is still absent. At the same time, recent developments in the field show that this key protocol could be feasible with current technology, which would pave the way to boost the field of microwave quantum communication. Here, we discuss the feasibility of a possible implementation of microwave quantum teleportation in a realistic scenario with losses. Furthermore, we propose how to implement quantum repeaters in the microwave regime without using photodetection, a key prerequisite to achieve long distance entanglement distribution.

The period and quality factor Qof the Chandler wobble are functions of the internal structure and dissipation processes of the Earth. Better estimates of the period and Qof the Chandler wobble can therefore be used to better understand these properties of the Earth. Here the period and Qof the Chandler wobble are estimated by finding those values that minimize the power in the Chandler frequency band of the difference between observed and modeled polar motion excitation functions. The observations of the polar motion excitation functions that we used are derived from both space‐geodetic polar motion observations and from satellite laser ranging (SLR) and Gravity Recovery and Climate Experiment (GRACE) observations of the degree‐2 coefficients of the Earth's time‐varying gravitational field. The models of the polar motion excitation functions that we used are derived from general circulation models of the atmosphere and oceans and from hydrologic models. Our preferred values for the period and Qof the Chandler wobble that we estimated using this approach are 430.9 ± 0.7 solar days and 127 (56, 255), respectively. The period and Q of the Chandler wobble are estimated from SLR and GRACE dataAtmosphere, ocean, and hydrology models were also usedPreferred values are the period = 430.9 ± 0.7 days and Q = 127 (56, 255)

The laser parameters of flashlamp pumped Cr(2%),Er:YAG with Erbium concentrations of 30% and 50% were investigated and compared with unsensitized crystals. With short pulse durations (tp< 500 µs) Chromium improves the lasing performance. Thresholds as low as 8J have been achieved.

•he earliest account of open reduction and internal stabilization of rib fractures comes from Dr. Charles Locke Scudder in 1900 when he published, The Treatment of Fractures•Surgical stabilization of rib fractures (SSRF) has evolved over 120 years with numerous advancements and lessons learned along the way•Materials have evolved from sutures to wires to external and internal plates•Rib fixation methods have evolved from open suture and wire cerclage to minimally invasive video assisted thoracoscopic surgery internal plating

There are concerns that generic and brand antiepileptic drugs (AEDs) may not be therapeutically equivalent. This study investigated how generic AED substitution may have negative consequences.

In this article, the possible mechanisms resulting in strong ferromagnetic coupling in transition metal(TM)-doped ZnO and other diluted magnetic semiconductors (DMS) are reviewed and the prerequisites for the observation of room temperature ferromagnetism in TM-doped ZnO are defined. In order to study the ferromagnetic behavior we have grown epitaxial Zn0.95Co0.05O films simultaneously on (0001) ZnO and Al2O3 substrates by laser molecular beam epitaxy at different deposition temperatures. A systematic study of the structural and magnetic properties has been performed to reveal their interdependence. Room temperature ferromagnetism has been found in Zn0.95Co0.05O films grown on ZnO, whereas for films deposited on sapphire only weak ferromagnetic signals have been detected which could not unambiguously be separated from those of the substrate. The different behavior is explained by different structural properties and defect densities in both films. Our experimental findings are in good agreement with a spin split impurity band model, where strong ferromagnetic exchange in ZnO:Co2+ is obtained by a strong hybridization between the magnetic Co2+ ion states and the donor states due to a large density of native defects. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Abstract: One of the important predictions of the early phenomenological theories of superconductivity such as the London and Ginzburg–Landau (GL) theory is the quantization of magnetic flux in multiply connected superconductors, which is one of the first demonstrations of a quantum effect on a macroscopic scale. In this paper, which is devoted to Vitalij Lazarevich Ginzburg on the occasion of his 90th birthday, we analyze a superconducting cylinder acting as a flux box as well as a superconducting disk acting as a Cooper pair box in the framework of GL theory. We extend this analysis to leaky flux and Cooper pair boxes which are obtained by introducing weak links allowing for the entry and exit of flux quanta and Cooper pairs from the respective boxes at finite rates. Flux and Cooper pair slippage processes by coherent quantum tunneling result in effective two-level quantum systems forming the basis for flux and charge quantum bits presently considered for the solid-state implementation of quantum information processing. We show that the corresponding Hamiltonians describing the leaky flux and Cooper pair box can be transformed into each other by a canonical transformation.

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF1 antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF1 binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pKi value of 8.5. Compound 12a proved to be a functional CRF1 antagonist with pIC50 values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.

Immobilized lipase B from Candida antarctica (Novozyme 435) catalyzed the regioselective formation of ester bonds between organosilicon carboxylic diacids and a C1−O-alkylated sugar under mild reaction conditions (i.e., low temperature, neutral pH, solventless). Specifically, the acid-functionalized organosilicones reacted with the primary hydroxyl group at the C6 position of α,β-ethyl glucoside during the regioselective esterification. The pure organosilicon−sugar conjugates were prepared in a one-step reaction without protection−deprotection steps and without activation of the acid groups with the integrity of the siloxane bonds.

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.

A fast combinatorial approach to access information about the immobilization behavior and kinetics of enzymes on a variation of surfaces is presented. As a test system, Candida Antarctica Lipase B was immobilized on a self-assembled monolayer bearing a gradient of surface energy. The respective immobilization behavior was monitored by Fourier transform infrared microspectroscopy. In addition, the activity of the immobilized enzyme was monitored over the entire film in real time with a specially developed fluorescence activity assay embedded into a siloxane gel. It was found that the highest amount of active protein was immobilized on the hydrophilic end of the gradient surface. This effect is associated with a higher surface roughness of this area resulting in hydrophobic microenviroments in which the enzyme gets immobilized.

Two new classes of tricyclic-based corticotropin-releasing factor (CRF1) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF1 receptor (Ki = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC50 = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t1/2 = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (VD = 38, 44 L kg^-1) and rapid clearances (CL = 70, 43 mL min^-1 kg^-1). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84−86% were observed for 30 mg kg^-1 doses.

Abstract. Uncertainties in polar motion and length-of-day measurements are evaluated empirically using several data series from the space-geodetic techniques of the global positioning system (GPS), satellite laser ranging (SLR), and very long baseline interferometry (VLBI) during 1997–2002. In the evaluation procedure employed here, known as the three-corner hat (TCH) technique, the signal common to each series is eliminated by forming pair-wise differences between the series, thus requiring no assumed values for the “truth” signal. From the variances of the differenced series, the uncertainty of each series can be recovered when reasonable assumptions are made about the correlations between the series. In order to form the pair-wise differences, the series data must be given at the same epoch. All measurement data sets studied here were sampled at noon (UTC); except for the VLBI series, whose data are interpolated to noon and whose UT1 values are also numerically differentiated to obtain LOD. The numerical error introduced to the VLBI values by the interpolation and differentiation is shown to be comparable in magnitude to the values determined by the TCH method for the uncertainties of the VLBI series. The TCH estimates for the VLBI series are corrupted by such numerical errors mostly as a result of the relatively large data intervals. Of the remaining data sets studied here, it is found that the IGS Final combined series has the smallest polar motion and length-of-day uncertainties.

Immobilized Lipase B from Candida antartica (CAL-B, Novozyme 435) catalyzed terpolymerizations of bis(hydroxymethyl)butyric acid, BHB (AB2) and 1,8-octanediol (B2) with adipic acid (A2). The copolymerizations of these AB2, B2, and A2 monomers were conducted in bulk, at 80 °C, without activation of the acid groups. Carbon (¹³C) NMR studies using a series of model BHB derivatives showed that CAL-B was strictly selective for esterification of BHB hydroxyl groups while leaving the carboxylic acid unchanged. Thus, all polymerizations were conducted as if BHB were a B2 monomer and then formulating a 1 to 1 ratio of carboxylic acid to hydroxyl groups in the monomer feed. By varying the monomer feed ratio, copolyesters with 9−45 mol % BHB−adipate units were formed with Mw values between 21 900 and 2300 g/mol. By this direct polymerization without protection−deprotection chemistry, a series of linear aliphatic copolyesters with controlled quantities of pendant free acid groups was prepared. Thermal and crystalline properties of the copolyesters were studied by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and wide-angle X-ray scattering (WAXS). Increasing the BHB content in the copolyesters resulted in melting temperature depressions that were well described by Baur's equation for random copolymers where BHB−adipate units are excluded from the crystal phase of the crystallizable 1,8-octanediol−adipate units.

Immobilized Lipase B from Candida antartica (Novozyme 435) catalyzed bulk polycondensations at 70 °C for 42 h that resulted in hyperbranched polyesters with octanediol-adipate and glycerol-adipate repeat units. Instead of using organic solvents, the monomers adipic acid (A2), 1,8-octanediol (B2), and glycerol (B‘B2) were combined to form monophasic ternary mixtures. During the first 18 h of a copolymerization with monomer feed ratio (A2 to B2 to B‘B2) 1.0:0.8:0.2 mol/mol, the regioselectivity of Novozyme 435 resulted in linear copolyesters. Extending the reaction to 42 h gave hyperbranched copolymers with dendritic glycerol units. The % regioselectivity for esterifications at the primary glycerol positions ranged from 77 to 82% and was independent of glycerol content in the monomer feed. Variation of glycerol in the monomer feed gave copolymers with degree of branching (DB) from 9 to 58%. In one example, a hyperbranched copolyester with 18 mol % glycerol−adipate units was formed in 90% yield, with Mw 75 600 (by SEC-MALLS), Mw/Mn 3.1, and DB 19%. Generalized structures were created to depict that for hyperbranched glycerol copolyesters and the progression of products formed at reaction times from 5 min to 42 h.

Random copolymers were prepared by Candida antarctica lipase B (Novozyme-435) catalyzed copolymerization of ω-pentadecalactone (PDL) with ε-caprolactone (CL). Over the whole composition range PDL−CL copolymers are highly crystalline (melting enthalpy by differential scanning calorimetry, above 100 J/g; crystallinity degree by wide-angle X-ray scattering, WAXS, 60−70%). The copolymers melt at temperatures that linearly decrease with composition from that of poly(ω-pentadecalactone) (PPDL; 97°C) to that of poly(ε-caprolactone) (PCL; 59 °C). The WAXS profiles of PCL and PPDL homopolymers are very similar, except for the presence in PPDL of the (001) reflection at 2θ = 4.58° that corresponds to a 19.3 Å periodicity in the chain direction. In PDL−CL copolymers the intensity of this reflection decreases with increasing content of CL units and vanishes at 50 mol % CL, as a result of randomization of the ester group alignment and loss of chain periodicity. PDL−CL copolymers crystallize in a lattice that gradually changes from that of one homopolymer to that of the other, owing to comonomer isomorphous substitution. Cocrystallization of comonomer units is also shown by a random PDL−CL copolymer obtained in a polymerization/transesterification reaction catalyzed by C. antarctica lipase B (Novozyme-435) starting from preformed PCL and PDL monomer.

(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.

The selective esterification of starch nanoparticles was performed using as catalyst Candida antartica Lipase B (CAL-B) in its immobilized (Novozym 435) and free (SP-525) forms. The starch nanoparticles were made accessible for acylation reactions by formation of Aerosol-OT (AOT, bis(2-ethylhexyl)sodium sulfosuccinate) stabilized microemulsions. Starch nanoparticles in microemulsions were reacted with vinyl stearate, ε-caprolactone, and maleic anhydride at 40 °C for 48 h to give starch esters with degrees of substitution (DS) of 0.8, 0.6, and 0.4, respectively. Substitution occurred regioselectively at the C-6 position of the glucose repeat units. Infrared microspectroscopy (IRMS) revealed that AOT-coated starch nanoparticles diffuse into the outer 50 μm shell of catalyst beads. Thus, even though CAL-B is immobilized within a macroporous resin, CAL-B is sufficiently accessible to the starch nanoparticles. When free CAL-B was incorporated along with starch within AOT-coated reversed micelles, CAL-B was also active and catalyzed the acylation with vinyl stearate (24 h, 40 °C) to give DS = 0.5. After removal of surfactant from the modified starch nanoparticles, they were dispersed in DMSO or water and were shown to retain their nanodimensions.

A novel concept for the metal-free synthesis of block copolymers combining enzymatic ring-opening polymerization and nitroxide-mediated living free-radical polymerization from a bifunctional initiator is presented. Block copolymers comprising a poly(styrene) and poly(caprolactone) block were obtained in two consecutive polymerization steps (macroinitiation) and in a one-pot cascade approach without intermediate transformation or work up step. By optimization of the reaction conditions a high selectivity of both transformations could be realized in the cascade polymerization, resulting in high block copolymer yields. The same concept was successfully applied to enzymatic resolution polymerization of racemic 4-methyl-ε-caprolactone combined with the living free-radical polymerization of styrene yielding block copolymers with high enantiomeric excess in the 4-methyl-ε-caprolactone block.

We report the ring-opening polymerization reaction of ε-caprolactone in supercritical carbon dioxide (scCO2) using an enzyme catalyst, Lipase B from Candida antarctica supported on macroporous beads (Novozym-435). Ring-opening polymerization of lactones is more commonly performed in organic solvents or in bulk using a Lewis acid catalyst. Recently there has been much interest in the replacement of such catalysts by enzymes. We demonstrate that the enzymatic route is viable in scCO2, yielding poly(ε-caprolactone) (Mn = 12 000−37 000 g mol^-1) with molecular weights very similar to those obtained from the same enzyme catalysts in organic solvents, but with lower polydispersities (typical PDI = 1.4−1.6) and higher yields of polymer product (typically 95−98%). In the same process the unique “gaslike” mass transfer properties of scCO2 can also be exploited to remove quantitatively any unconverted monomer and low molecular weight oligomers by scCO2 extraction. It is also shown that the enzyme catalyst can be cleaned and recycled using scCO2, while still producing high molecular weight polymer (Mn = 35 000−37 000 g mol^-1). Thus, a combination of enzyme catalyst and scCO2 can be used repeatedly to prepare biodegradable poly(ε-caprolactone) (PCL) in the complete absence of potentially toxic organic solvents or metal catalysts.

The purpose of this study was to determine if a specially designed suction device, tunneled through a vent hole in the coracoid process to a position deep in the glenoid vault, would eliminate radiolucent lines around the keel of a glenoid component on immediate postoperative radiographs. Literature reviews and cadaver studies were used to develop a predictable anatomic relationship between the medullary canal of the coracoid process and the glenoid vault. Details of these studies were applied to develop an effective surgical procedure. Thirty consecutive total shoulder arthroplasties were preformed, using the keeled appliance from the Zimmer, Bigliani-FlatowTM, or the Tonier, AequalisTM, system. The suction device was advanced through a vent in the coracoid process decompressing the glenoid vault. This approach was relatively simple, adding only an average of 6 minutes to the operation, and resulted in no significant complications. In this series only 2 radiolucent lines were noted on the immediate post operative X-rays. One line in zone 2 (the tip of the keel) was less than 1 mm thick, and a second in zone 3 (the inferior limb of the keel) was greater than 2 mm. This surgical technique eliminates most postoperative lucent lines by facilitating the penetration of the cement into the glenoid vault.

Lipases from different sources were screened to determine their relative performance to catalyze ω-pentadecalactone (PDL) ring-opening polymerization from the hydroxyl group of 2-hydroxyethyl methacrylate (2-HEMA) and ω-hydroxyl-ω‘-methacrylate−poly(ethylene glycol) [PEGMA (Mn 360)]. Novozym 435 was found to be the most active biocatalyst for 2-HEMA/PEGMA-initiated PDL ring-opening polymerizations at 70 °C for 48 h in toluene (1:2 w/v of monomers). Thus, 2-HEMA-terminated PPDL was synthesized in yields of ~80% and with &lt;2 mol % carboxyl-terminated PPDL from initiation by water. Similarly, PEGMA-terminated PPDL was prepared. The free radical polymerizations of the corresponding macromers were carried out with AIBN at 70 °C in toluene. Thermal analysis of 2-HEMA-co-b-PPDL and PEGMA-co-b-PPDL macromers showed them to be stable and highly crystalline (Tm from 80 to 90 °C). In PEGMA-co-b-PPDL macromers, X-ray diffraction measurements show that the ethylene oxide units of the PEG block crystallize in the PPDL lattice. The main change observed upon polymerization of the macromers is a decrease of crystallinity (by both DSC and X-ray measurements).

Immobilized Candida antarctica Lipase B (Novozyme-435) was studied for bulk polyesterifications of linear aliphatic hydroxyacids of variable chain length. The products formed were not fractionated by precipitation. The relative reactivity of the hydroxyacids was l6-hydroxyhexadecanoic acid ≈ 12-hydroxydodecanoic acid ≈ 10-hydroxydecanoic acid (DPavg ≅ 120, Mw/Mn ≤ 1.5, 48 h, 90 °C) > 6-hydroxyhexanoic acid (DPavg ≅ 80, Mw/Mn ≤ 1.5, 48 h, 90 °C). Remarkable improvements in molecular-weight buildup resulted from leaving water in the reaction. By 4 h, without application of vacuum, the DPavg for 12- and 16-carbon hydroxyacids was about 90. In contrast, with identical substrates and water removal, the DPavg at 4 h was about 23. Large differences in the molecular-weight build up of 12-hydroxydodecanoic acid were observed for catalyst concentrations (%-by-wt relative to monomer) of 0.1, 0.5, 1, and 10. Nevertheless, by 24 h, with 1% catalyst containing 0.1% lipase, poly(12-hydroxydodecanoic acid) with Mn 17 600 was formed. For 12-hydroxydodecanoic acid polymerization at 90 °C, the catalyst activity decreased by 7, 18, and 25% at reaction times of 4, 24, and 48 h, respectively. Furthermore, the retention of catalyst activity was invariable as a function of the substrates used.

Bulk condensation polymerizations of adipic acid and octanediol, catalyzed by Candida antartica Lipase B (CALB), were investigated. The polymers formed by 8 and 24 h polymerizations using CALB immobilized on Accurel and Lewatit had similar molecular weights (e.g., Mn at 24 h ≈15 000). CALB “free” of the immobilization resin was also active for the polymerization but, relative to its immobilized forms, gave slower chain growth (Mn ≈ 10 000 by 48 h). For all three catalyst systems at degree of polymerization (DP) ≥ 20, dispersity (Mw/Mn) was ≤1.5. Since random processes of step-growth condensation polymerizations give dispersity values ≥ 2, the dispersity of products obtained using CALB as the catalyst is believed to result from the unique chain length or mass selectivity of the lipase. Gel permeation chromatograms showed that between 15 min and 4 h chain growth occurred rapidly so that the fraction of product with Mp values > 2910 increased from 28 to 78%. At 70 °C the catalyst activity at 4 h remained unchanged but decreased by 15 and 21% at 24 and 48 h. Unexpectedly, an increase in the concentration of CALB on Lewatit from 0.1 to 1 wt % protein resulted in only a small increase in Mn (e.g., at 24 h, 14 500 vs 17 800). However, decrease in the percent protein to 0.5% had a large detrimental effect. Between 65 and 90 °C the polymerizations occurred with little dependence on the reaction temperature.

Copolymers of octanediol adipate and sorbitol adipate, P(OA-SA), copolymers of octanediol adipate and glycerol adipate, P(OA-GA), poly(octamethylene adipate), POA, and poly(sorbitol adipate), PSorA, were synthesized using immobilized Lipase B from Candida antarctica (Novozyme-435) as catalyst. The molecular weights and polydispersity indices of these polyesters were determined. The physical properties of these polyesters were investigated by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), wide-angle X-ray scattering (WAXS), and dynamic mechanical analysis (DMA). These polymers are semicrystalline except for PSorA, which is amorphous. With increasing sorbitol or glycerol content in the polyesters, both melting and crystallization temperatures decreased. The melting temperature depression is well described by Baur's equation for random copolymers where the second comonomer is completely excluded from the crystal phase of the crystallizable first monomer. Also, the melting enthalpy decreases, and WAXS measurements confirm that the degree of crystallinity decreases upon copolymerization with either sorbitol or glycerol. Furthermore, the crystal phase is that of POA.

Studies of the kinetics and mechanism of Candida antarctica Lipase B (CALB) catalyzed ε-caprolactone (ε-CL) polymerizations in toluene were performed. The kinetic plot of ln ([M]0/[M]t) vs time was carried out to 96% ε-CL conversion and Mn 11 970. The plot is linear (r² = 0.998), indicating that termination did not occur and the propagation rate is first order with respect to monomer concentration. Changes in the water (e.g., initiator) concentration did not change the polymerization rate but did change the number of chains [R−OH]. Thus, the polymerization is zero order with respect to [R−OH] and initiator concentration. A plot of ln kapp vs ln [enzyme] gave 0.7 as the reaction order of the enzyme concentration. The apparent activation energy for Novozyme-435 catalyzed ε-CL polymerization in toluene is 2.88 kcal mol^-1. This is well below 10.3 kcal mol^-1, the activation energy for aluminum alkoxide catalyzed ε-CL polymerization in toluene. Upward deviation from linearity for Mn vs fractional ε-CL conversion and decreases in the number of chains was accentuated by low enzyme water contents and high monomer conversion. These results are consistent with a competition between ring-opening chain-end propagation and chain growth by steplike polycondensations. CALB was irreversibly inhibited by modification with paraoxon at the lipase active site (Ser105). The modified enzyme was no longer active for the polymerization. This supports that the polymerizations studied herein occurred by catalysis at the active serine residue (Ser105) and not by other chemical or nonspecific protein-mediated processes.

The effects of substrates and solvent on polymer formation, number-average molecular weight (Mn), polydispersity, and end-group structure for lipase-catalyzed polycondensations were investigated. Diphenyl ether was found to be the preferred solvent for the polyesterification of adipic acid and 1,8-octanediol giving a Mn of 28 500 (48 h, 70 °C). The effect of varying the alkylene chain length of diols and diacids on the molecular weight distribution and the polymer end-group structure was assessed. A series of diacids (succinic, glutaric, adipic, and sebacic acid) and diols (1,4-butanediol, 1,6-hexanediol, and 1,8-octanediol) were polymerized in solution and in bulk. It was found that reactions involving monomers having longer alkylene chain lengths of diacids (sebacic and adipic acid) and diols (1,8-octanediol and 1,6-hexanediol) give a higher reactivity than reactions of shorter chain-length diacids (succinic and glutaric acid) and 1,4-butanediol. The bulk lipase-catalyzed condensation reactions were feasible, but the use of diphenyl ether gave higher Mn values (42 400 g/mol in 3 days at 70 °C). The polydispersity varied little over the conditions studied giving values ≤2. No specific trend with respect to end-group structure as a function of time was observed. At 70 °C, the retention of catalyst activity in the bulk was independent of substrate structure but was higher when reactions were conducted in diphenyl ether than in bulk.

Synchrotron infrared microspectroscopy (SIRMS) was used for the first time to image the distribution and secondary structure of an enzyme (lipase B from Candida antarctica, CALB) immobilized within a macroporous polymer matrix (poly(methyl methacrylate)) at 10 μm resolution. The beads of this catalyst (Novozyme435) were cut into thin sections (12 μm). SIRMS imaging of these thin sections revealed that the enzyme is localized in an external shell of the bead with a thickness of 80−100 μm. Also, the enzyme was unevenly distributed throughout this shell. Furthermore, by SIRMS-generated spectra, it was found that CALB secondary structure was not altered by immobilization. Unlike CALB, polystyrene molecules of similar molecular weight diffuse easily throughout Novozyme435 beads. Scanning electron micrograph (SEM) images of the Novozyme435 beads showed that the average pore size is 10 times larger than CALB or polystyrene molecules, implying that there is no physical barrier to enzyme or substrate diffusion throughout the bead. Thus, the difference between polystyrene and enzyme diffusivity suggests that protein−matrix and protein−protein interactions govern the distribution of the enzyme within the macroporous resin.

Syngeneic graft‐versus‐host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a short course of cyclosporin A (CsA) therapy. The disease is characterized by the development of a T helper cell type 1‐like cytokine response [interleukin (IL)‐12, interferon‐γ (IFN‐γ), and tumor necrosis factor α], and macrophage activation is central to development of the syndrome. It has been shown that nitric oxide (NO) participates significantly in the development of allogeneic GVHD. Studies were initiated to determine if NO participates in the pathology associated with SGVHD. Significant increases in inducible NO synthase (iNOS) mRNA and circulating NO were found in the tissues of SGVHD versus control animals. Treatment of SGVHD animals with the iNOS inhibitor aminoguanidine (AG) reversed the pathology associated with this disease. Furthermore, AG treatment reduced the production of IL‐12 and IFN‐γ mRNA in the colons of CsA‐treated mice. These studies demonstrate that NO participates in the pathological processes that are associated with the development of murine SGVHD.

Unusual copolymers were prepared by Candida antarctica Lipase B (Novozyme-435) catalyzed copolymerization of ω-pentadecalactone (PDL) with trimethylene carbonate (TMC). Atypical solid-state properties were revealed by thermogravimetric analysis, differential scanning calorimetry (DSC), and X-ray diffraction analyses. Thermal degradation of poly(PDL−TMC) occurs in two steps:  the first well above the degradation range of poly(TMC) and the other at a temperature (430 °C) comparable with that of poly(PDL) decomposition. Thermal stability of PDL−TMC copolymers increases with randomization of comonomer distribution. All poly(PDL−TMC) investigated are highly crystalline, even those with equimolar comonomer content and close-to-random distribution. This result indicates that PDL and TMC units cocrystallize. The copolymers show two melting processes:  the higher one at about 90 °C, i.e., close to poly(PDL) melting, and the other 30 °C lower. The relative intensity of the two phenomena changes with copolymer microstructure. The X-ray diffraction patterns of poly(PDL−TMC) are practically identical to that of poly(PDL) in the range 10° &lt; 2θ &lt; 80°. Significant differences appear in the low-angle region below 2θ = 10°, indicating in some copolymers the presence of crystals with higher periodicity than poly(PDL) along the chain direction. Comparison of DSC and X-ray results with copolymer microstructure shows that two crystal phases can develop in poly(PDL−TMC):  poly(PDL) crystals and&sbd;whenever a significant amount of heterodiads are present&sbd;another lower melting crystal phase, characterized by a larger fiber axis periodicity and possibly associated with crystallization of alternate PDL−TMC sequences.

The mono-terminal hydroxyl groups of polybutadiene of varying chain length were studied as sites for initiation of lactone ring-opening polymerization by lipase catalysis. Novozyme-435 (immobilized Candida antarctica lipase B) was an effective catalyst for this acylation. Monohydroxyl-terminated polybutadiene with Mn of 2.6, 10, and 19 kg/mol efficiently initiated ω-pentadecalactone (PDL) and ε-caprolactone (CL) polymerization in toluene at 55 °C to give polybutadiene-b-polypentadecalactone and polybutadiene-b-polycaprolactone, respectively. For example, monohydroxyl-terminated polybutadiene with Mn 2.6 kg/mol initiated PDL ring-opening polymerization (1:25, OH:PDL) and formed a product with Mn 9.6 kg/mol in 19 h with 17 mol % chains initiated by water and >90% initiator efficiency. This method circumvented previously published chemical methods that required a metal catalyst and strict exclusion of moisture. A fractionation method was developed to separate the oligomers and to reduce the homopolymer contamination in the diblock copolymer. In situ NMR experiments were used to monitor the initiation of CL ring-opening polymerization with PBD-OH. Characterization of polymer was performed using ¹H and ¹³C NMR spectroscopies and GPC.

Lipase-catalyzed intrachain transesterification reactions were studied in dry toluene (70 °C) using an immobilized form of Candida antarctica lipase B (Novozyme-435), poly(ε-caprolactone), PCL, and hexanol/water as competitive nucleophiles. In addition to NMR and GPC, MALDI−TOF MS was also used to determine product molecular weight and end group structure. Experiments were conducted to determine (i) whether lipases cleave at random or specific sites along a polyester substrate and (ii) how reaction parameters such as the molecular weight of the starting polyester, reaction time, and nucleophile concentration effect the structure of the products formed. For the ratio of CL units to hexanol (22/1 mol:mol) and parent PCL Mn 56 400, calculations based on integration of ¹H NMR spectra for the precipitated products showed that, after only 10 and 20 min reactions, about 60 and 70% of the PCL chains have terminal hexyl ester groups. Thus, transesterification reactions between PCL and hexanol occur rapidly. By 2 h, Novozyme-435 resolved the higher (A) and lower (B) molecular mass components of the starting polyester. This gave fraction A with Mn and polydisperity (Mw/Mn) of 122 000 and 1.44, respectively. The “mass-selective” transesterification is evident in the GPC traces within 10 min, giving a product with Mn and polydispersity of 1810 and 1.6 (population D). Thus, the lipase cleaves short chain segments with an average length of 16 units by an endo-type mechanism. From 10 min to 24 h, it appears that condensation reactions of population D occur to give fraction C (Mn = 4040, Mw/Mn = 1.8, Mpeak = 7240). The results of this work show how enzymatic transesterification reactions can be further developed to provide oligomers with well-defined length and end group structure.

The new monomer 1,2-O-isopropylidene-3-benzyloxy-pentofuranose-4,4‘-cyclic carbonate (IPPTC) was prepared. IPPTC has both a ketal-protected diol and a benzyl ether-protected hydroxyl. Thus, these two sets of hydroxyl groups can be independently deprotected to give IPPTC repeat units with one, two, or three free hydroxyl groups. Stannous octanoate at 130 °C was used for the copolymerization of [l]-LA with IPPTC. When fLA/fIPPTC was 91/9, the percent yield, Mn, and percent incorporation of IPPTC units were 78%, 77 800 g/mol, and 4 mol %, respectively. By the method of Fineman and Ross, the [l]-LA and IPPTC comonomer reactivity ratios were 8.6 and 0.51, respectively. Relative to poly([l]-LA), incorporation of IPPTC units into [l]-LA/IPPTC copolymers gave products that are lower melting (112 °C, 14 mol % IPPTC) and have higher thermal stabilities and higher glass transition temperatures (69 °C, 100 mol % IPPTC). The liberation of hydroxyl pendant groups by the selective removal of the benzyl ether, the ketal groups, or both was possible without substantial loss in the product molecular weight. The removal of the protecting groups of poly([l]-LA-co-4.0 mol % IPPTC) did not change the Tm value (160 °C) but did alter the copolymer crystallization kinetics and thermal stability.

Polymerizations of ε-CL catalyzed by Novozyme-435 (immobilized Lipase B from Candida antarctica) were studied at temperatures between 20 and 108 °C. The monomer conversion to polymer was remarkably rapid at ambient temperature. At 20 °C by 7 h, ε-CL conversion and product Mn were >97% and 17 800, respectively. Contrary to previous reports, the number of chains formed, as well as the product molecular weight, was almost identical for polymerizations at constant enzyme water content between 60 and 108 °C. Thus, differences in reaction temperature over a 48 °C range did not “free” water from “bound” states so that it could function for chain initiation. At 60 °C, variation in the enzyme water content from 0.6 to 1.9% increased the number of chains formed but did not change the polymerization propagation kinetics. Therefore, the enzyme water content and not the reaction temperature regulated the product molecular weight. In contrast, at 108 °C, an increase in the reaction water content from 0.6 to 1.8% increased both the number of chains and the polymerization propagation kinetics. Explanations for these differences in behavior as a function of temperature and water contents are discussed.

Abstract. The two-component system BvgAS positively controls transcription of the virulence genes of Bordetella pertussis and B. bronchiseptica, which include several genes for toxins and adhesins. On the other hand, the BvgAS system negatively controls the expression of a poorly characterized set of genes, the so-called virulence repressed (vrg) genes. To investigate the function of this group of genes and their relationship to virulence, we identified several novel vrg genes of B. bronchiseptica via the generation of transcriptional fusions with gfp (the ORF encoding Green Fluorescent Protein) by transposon mutagenesis. Expression of all of the vrg genes was enhanced under phenotype-modulating growth conditions and in phase variants, demonstrating that their transcription is indeed controlled by the BvgAS system. In addition, transcription of most of these new vrg genes was found to be affected by the growth phase of the bacteria, with maximal expression being observed in the late logarithmic or stationary phase. The majority of these genes encode putative metabolic functions involved in redox reactions and amino acid transport. Interestingly, several vrg genes of B. bronchiseptica are not expressed or have been lost in B. pertussis, indicating that, possibly as a consequence of its adaptation to a single host organism, many vrg genes of B. pertussis are gradually decaying.

Previously, we reported the horseradish peroxidase (HRP) mediated free radical polymerization of methyl methacrylate.1 The reaction medium was restricted to water/water-miscible co-solvent mixtures that solubilize both the monomer and enzyme. This paper describes HRP-mediated acrylamide polymerizations in aqueous medium with and without the addition of surfactants. Also, studies were conducted on polymerizations in concentrated emulsions using sorbitane monooleate as the surfactant. In aqueous medium, within 3 h, 98% yields of poly(acrylamide) were attained. By adding either anionic bis(2-ethylhexyl)sodium sulfosuccinate (AOT) or cationic cetyltrimethylammonium bromide (CTAB), the polymerization proceeded more rapidly so that within 60 and 75 min, respectively, 94% polymer yields were reached. When conducted in a concentrated emulsion formed with sodium monooleate, nearly quantitative yields resulted in 1.25 h. The weight average molecular weight (M_w) of the products ranged from 128 to 210 K and 106 to 154 K in aqueous medium and concentrated emulsions, respectively. In both of the above reaction systems, there was no apparent effect of the enzyme on the regulation of chain stereochemistry. The HRP-mediated polymerization of sodium acrylate conducted in aqueous medium gave poly(sodium acrylate) in yields up to 88% within 24 h with M_w ca. 119 K.

We report on the fabrication and structural characterization of coherently strained La2/3Ca1/3MnO3 (LCMO) thin films and La2/3Ca1/3MnO3/La2/3Ba1/3MnO3 (LCMO/LBMO) heterostructures on SrTiO3 substrates. The thin films grow in a layer-by-layer mode as verified by reflection high energy electron diffraction (RHEED) and atomic force microscopy (AFM). X-ray diffraction (XRD) reciprocal space mapping shows that the thin films match the substrate lattice constants leading to a strong tetragonal distortion of the lattice. Such (ultra)thin films and heterostructures are well suited for a systematic investigation of the influence of biaxial strain on the physical properties of doped manganites.

Epitaxial thin films of the bilayered perovskite La2—2xSr1+2xMn2O7 (x = 0.3, 0.4) have been grown by laser molecular beam epitaxy on NdGaO3 substrates. Magnetotransport measurements with the current in the ab-plane and along the c-axis direction showed an intrinsic c-axis tunneling magnetoresistance effect associated with nonlinear current-voltage-characteristics for the x = 0.3 compound. Besides the colossal magnetoresistance effect around the Curie temperature TC, at temperatures below about 40 K an additional high-field magnetoresistance was found most likely due to a strain and disorder induced re-entrant spin glass state in both the x = 0.3 and 0.4 compounds. Our experiments show that the substrate induced coherency strain in the high quality epitaxial films results in magnetotransport properties that show markedly different behavior from those of single crystals.

To assess cognitive and affective functioning in patients with essential tremor (ET).

Copolymerizations of ω-pentadecalactone (PDL) with trimethylene carbonate (TMC) were studied using chemical and enzyme catalysts. By using stannous octanoate, methylaluminoxane (MAO), or aluminum isopropoxide, copolymerizations of PDL with TMC with 1:1 feed ratio resulted in either homo-polyTMC or PDL/TMC block copolymers. These catalysts polymerize TMC more rapidly than PDL. A copolymerization catalyzed by MAO gave poly(TMC-co-16 mol % PDL) with Mn 26.4 × 10³g/mol and randomness numder (B) about 1.1. The sodium ethoxide-catalyzed copolymerization led to products with low Mn (&lt;6.8 × 10³) but nearly random sequence distribution. The copolymerization of PDL with TMC was also studied by using lipase catalysts. Of the six lipases evaluated for PDL/TMC copolymerizations in toluene at 70 °C, an immobilized form of lipase B from Candida antarctica (Novozyme-435) was preferred. Changing the PDL/TMC comonomer feed ratio from 1:10 to 10:1 (mol/mol) provided copolymers that ranged in Mn and PDL mol % from 7.3 × 10³ to 25.2 × 10³ and 28 to 88, respectively. In contrast to the chemical catalyst systems, Novozyme-435 catalysis showed that PDL was consumed more rapidly than TMC. Also, in contrast to most of the chemical catalysts, ¹H and ¹³C NMR analyses showed that the copolymers from Novozyme-435 catalysis were able to give a random distribution of the repeat units at extended reaction times. Furthermore, in contrast to TMC polymerization in the presence of preformed polyPDL with MAO, Novozyme-435 catalyzed polymerization led to random copolymers.