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A chemoenzymatic approach for the synthesis of homoazasugars is described, utilizing an aldolase to catalyze the key asymmetric aldol addition reaction. This approach is illustrated by the synthesis of β-D-homomannonojirimycin (11) using D-fructose diphosphate (FDP) aldolase.

The next generation of semi-conductor devices will be manufactured using extreme ultraviolet lithography with a laser-produced plasma as a candidate 13.5nm light source. A primary challenge, particularly for metrology tools, is the stability and the brightness of the generated EUV at the intermediate focus. In the experimental facility at ETH a novel collecting system is studied to optimize brightness and stability, and to avoid contamination after the intermediate focus. Different experimental studies are shown to confirm the design's success for both the EUV beam quality and lack of contamination after the intermediate focus.

Two methods are presented for kinetic resolutions of compounds containing ester and sulfoxide functionalities (sulfinylalkanoates). In the first a crude lipase preparation from Pseudomonas sp. (K10) mediates enantioselective hydrolysis of these esters in an aqueous environment. The second method uses the same lipase preparation to promote enantioselective transestesterifications with alcohols in hexane

A chemoenzymatic approach for the synthesis of homoazasugars is described, utilizing an aldolase to catalyze the key asymmetric aldol addition reaction. This approach is illustrated by the synthesis of β-D-homomannonojirimycin (11) using D-fructose diphosphate (FDP) aldolase.

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD 50 ) and to estimate 50% lethal exposure concentrations relative to time (LCt 50 ) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD 50 and LCt 50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

The one-pot, microwave-assisted synthesis of 5-thia-4b,10-diaza-indeno[2,1-a]indene-5,5-dioxide (6) and 10H-11-thia-5,10a-diaza-benzo[b]fluorene-11,11-dioxide (7) from 1,2-phenylenediamine and 2-aminobenzylamine, respectively, is described. Generation of a sulfonamide through reaction of the appropriate diamine with 2-cyanobenzenesulfonyl chloride is followed by a multistep intramolecular transformation and subsequent elimination of ammonia to provide the corresponding tetracycle in good yield.

The leading candidate for the manufacture of next generation semi-conductor devices is extreme ultraviolet lithography, with laser-produced plasmas as a candidate 13.5nm light source. A primary challenge for continuous operation is elimination of the debris load on the collector, without compromising the radiation intensity at the intermediate focus. A novel combination of thermal management and debris mitigation is developed in order to reduce the deformation and degradation of collector optics. This patent-pending novel debris mitigation technique enables the continuous operation of the source. The paper shows atomic force microscope measurements of the collector surface deposition. The debris mitigation system run at 50% design operating condition gives 90% debris mitigation effectiveness. The average temperature of the cooled collector is 36.5°C at the design point, with a peak-to-peak difference of 0.8°C. The collector geometry, after being adapted to compensate the thermal deformation, yields a spot size of 30μm at IF. Computational simulations, using ETH's multi-scale computational tools, complement the presented experimental results.

The following three stereoisomers of castanospermine have been prepared: (1R,6R,7R,8S,8aR)-1,6,7,8-tetrahydroxyindolizidine (1), (1R,6S,7S,8S,8aR)-1,6,7,8-tetrahydroxyindolizidine (2), and (1R,6R,7S,8S,8aR)-1,6,7,8-tetrahydroxyindolizidine (3). Each of these compound was synthesized via asymmetric allylation of pentose derivatives with [(Z)-γ-(methoxyinethoxy)allyl]diisopinocampheylborane, an approach which is, in principle, suitable for preparations of a total of eight stereoisomers of castanospermine

Two methods are presented for kinetic resolutions of compounds containing ester and sulfoxide functionalities (sulfinylalkanoates). In the first a crude lipase preparation from Pseudomonas sp. (K10) mediates enantioselective hydrolysis of these esters in an aqueous environment. The second method uses the same lipase preparation to promote enantioselective transestesterifications with alcohols in hexane

This book provides an analysis of the law of targeting during an armed conflict; focusing on what is a lawful target, what is proportional collateral damage, and describing a process by which legal responsibility for targeting decisions can be assessed.

We discovered a structurally novel SCD (Delta9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta5 and Delta6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties.

Consistent numerical classification of protein secretion systems according to the outer membrane translocation mechanisms is crucial in diderm bacteria. The mycobacterial ESAT-6 secretion system (Ess), more generically defined as the WXG100 secretion system (Wss), is clearly dedicated to protein translocation across the cytoplasmic membrane. Though, naming this system a “T7SS” is quite premature as the existence, nature and specificity of a putative outer membrane translocon that would enable true protein secretion in mycobacteria remains completely unknown.

4-Chlorophenylsulfinylacetates of defined stereochemistry at sulfur were prepared from monochiral alcohols: compound 2 from (+)-menthol; 3 and 4 from (−)-8-phenylmenthol; 5 and 6 from (+)-trans-2-phenylcyclohexanol; and, 7 and 9 from (-)-10-dicyclohexylsulfamoyl-D-isoborneol. Reagents for which the sulfoxide asymmetry is matched with the inducing effect of the auxiliary give good diastereoselection in SPAC reactions affording γ-hydroxy-α,β-unsaturatod alcohols of high optical purity. Asymmetry at the sulfoxide has a greater effect than the auxiliaries on the stereochemical outcome of these reactions.

Factors that govern chemical and optical yields of methyl γ-hydroxy-α,β-unsaturated esters 1 formed in reactions of optically active sulfinylacetates 2 with aldehydes (the «SPAC» reaction) are defined. Racemic samples of these chirons (1) can be resolved via acylations mediated by crude preparations of the lipase Pseudomonas K-10 in organic solvents. Combinations of asymmetric SPAC reactions with these biocatalytic resolutions provide routes to highly optically active esters 1 in good yields. This methodology is applied in a completely asymmetric synthesis of (4S-cis)-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone (15), a cyclic derivative of (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA)

A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.

The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A2A receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A2A binding assay and an A1 selectivity assay. Selected examples exhibited excellent affinity for A2A and good selectivity versus the A1 receptor.

The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.

Extracellular proteins are a subject of intense interest because of their essential roles in bacterial lifestyles. However, several terms related to secretion are used confusingly in the literature, and this is a topical issue in genomics and proteomics. Defining a secreted protein as actively translocated via a secretion system, here, we put into perspective that homologous translocation systems can result in radically different subcellular localizations of a secreted protein. We propose using standardized nomenclature for secretion systems from type I to type VIII for Gram-negative bacteria only, whereas the terms 'Sec' (secretion), 'Tat' (twin-arginine translocation), 'FEA' (flagella export apparatus), 'FPE' (fimbrilin-protein exporter), 'holin' (hole forming) and 'Wss' (WXG100 secretion system) should be applied to translocation systems across the cytoplasmic membrane of both Gram-positive and Gram-negative bacteria. Finally, we discuss why the term 'exoproteome' should be favoured over 'secretome' when describing the subset of proteins present in the extracellular milieu.

The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.

(1S, 2R, 7R, 7aR)- 1,2,7-Trihydroxypyrrolizidine ( 1 ) is prepared by elaboration of an erythrose derivative ( 4 ) via an asymmetric allylation reaction; this approach promises to be widely applicable to syntheses of polyhydroxylated indolizidine and pyrrolizidine alkaloids.

γ-Hydroxy-α,β-unsaturated compounds ( 3 ) (SPAC creation products) are resolved via irreversible biocatalytic acylations; this process can be used in series with asymmetric SPAC reactions to improve optical purities.

Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC 50 value at 0.3 μM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7 ). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders.

Botulinum neurotoxin (BoNT) is a biological warfare threat. Protein antigens have been developed against the seven major BoNT serotypes for the development of a recombinant protein vaccine. This study is an evaluation of adsorption profiles for three of the recombinant protein antigens to aluminum salt adjuvants in the development of a trivalent vaccine against BoNT. Adsorption profiles were obtained over a range of protein concentrations. The results document that charge-charge interactions dominate the adsorption of antigen to adjuvant. Optimal conditions for adsorption were determined. However, potency studies and solution stability studies indicated the necessity of using aluminum hydroxide adjuvant at low pH. To improve the adsorption profiles to AlOH adjuvant, phosphate ions were introduced into the adsorption buffers. The resulting change in the adjuvant chemistry led to an improvement of adsorption of the BoNT antigens to aluminum hydroxide adjuvant while maintaining potency. Competitive adsorption profiles were also determined, and showed changes in maximum adsorption from mixed solutions compared to adsorption from individual protein solutions. The adsorption profiles for each protein varied due to differences in adsorption mechanism and affinity for the adjuvant surface. These results emphasize the importance of evaluating competitive adsorption in the development of multivalent vaccine products.

The discovery and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin (IP) receptor antagonists is described. Analogs disclosed showed high affinity for the IP receptor in human platelet membranes with IC50 values of 0.05–0.50 μM, demonstrated functional antagonism by inhibiting cAMP production in HEL cells with IC50 values of 0.016–0.070 μM, and exhibited significant selectivity versus other prostanoid receptors.

Information regarding the quality of autologous chondrocyte implantation repair is needed to determine whether the current autologous chondrocyte implantation surgical technology and the subsequent biologic repair processes are capable of reliably forming durable hyaline or hyaline-like cartilage in vivo. We report and analyze the properties and qualities of autologous chondrocyte implantation repairs. We evaluated 66 autologous chondrocyte implantation repairs in 57 patients, 55 of whom had histology, indentometry, and International Cartilage Repair Society repair scoring at reoperation for mechanical symptoms or pain. International Knee Documentation Committee scores were used to address clinical outcome. Maximum stiffness, normalized stiffness, and International Cartilage Repair Society repair scoring were higher for hyaline articular cartilage repairs compared with fibrocartilage, with no difference in clinical outcome. Reoperations revealed 32 macroscopically abnormal repairs (Group B) and 23 knees with normal-looking repairs in which symptoms leading to arthroscopy were accounted for by other joint disorders (Group A). In Group A, 65% of repairs were either hyaline or hyaline-like cartilage compared with 28% in Group B. Autologous chondrocyte repairs composed of fibrocartilage showed more morphologic abnormalities and became symptomatic earlier than hyaline or hyaline-like cartilage repairs. The hyaline articular cartilage repairs had biomechanical properties comparable to surrounding cartilage and superior to those associated with fibrocartilage repairs.

In a high-throughput screen of four million compounds from combinatorial libraries for small-molecule modulators of the chemokine receptor CXCR3, two classes of receptor agonists, based on tetrahydroisoquinoline and piperidinyl diazepanone templates, were identified. Several of these compounds stimulated calcium flux in HEK293 cells expressing the recombinant human CXCR3 receptor with efficacies and kinetics similar to those of native ligand CXCL11/I-TAC and stimulated chemotaxis of activated human T-cells. The agonist small molecules also inhibited binding of another CXCR3 ligand, CXCL10/IP-10, to the receptor. The response to small-molecule agonists was inhibited by a CXCR3-specific small-molecule antagonist previously identified within the same combinatorial compound collection but structurally unrelated to the agonists. Remarkably, while other, non-amino acid substituents were present in the majority of the library compounds screened, the agonists from both classes contained a positively charged amino acid component, with preference for Arg>Lys, as well as a hydrophobic component.

The p38 mitogen-activated protein (MAP) kinases are a family of serine/threonine protein kinases that play important roles in cellular responses to inflammation and external stress. Inhibitors of the p38 MAP kinase have shown promise for potential treatment of inflammatory disorders such as rheumatoid arthritis, acute coronary syndrome, psoriasis, and Crohn's disease. We identified a novel class of p38 inhibitors via high-throughput screening. PS200981 [3-(4-(1,4-diazepan-1-yl)-6-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a representative compound identified from screening a collection of combinatorial libraries, amounting to 2.1 million compounds, inhibits p38alpha kinase and the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor (TNF) alpha levels in cell media of human monocytes with IC50 values of 1 microM. The screening data revealed a preferred synthon, 3-amino-4-methyl benzamide, which is critical for the activity against p38. This synthon appeared almost exclusively in screening hits including PS200981, and slight variations of this synthon including 3-amino benzamide and 2-amino-4-methyl benzamide also contained in the library were inactive. PS200981 is equally potent against the alpha and beta forms of p38 but did not inhibit p38 gamma and is25-fold selective versus a panel of other kinases. PS200981 inhibited the LPS-induced increase in TNFalpha levels when administered at 30 mg/kg to mice. Selectivity and in vivo activity of this class of p38 inhibitors was further demonstrated by PS166276 [(R)-3-(4-(isobutyl(methyl)-amino)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a highly structurally related but more potent and less cytotoxic inhibitor, in several intracellular signaling assays, and in LPS-challenged mice. Overall, this novel class of p38 inhibitors is potent, active in vitro and in vivo, and is highly selective.

The process of reading conscripted by certain mid-Victorian novel is addressed. European tradition of Antipodes is described before discussing conscription process, then the discoveries and development of the early science of reading are compared and finally the implications of this reading process for the formation of British imperial subjectivity, and the continuing role of the tradition of 'the Antipodes' are discussed.

Purpose: Our purposes were to report the clinical outcome of autologous chondrocyte implantation (ACI) patients with graft hypertrophy compared with that of unoperated ACI patients and to longitudinally assess the effects of graft hypertrophy debridement. Methods: We divided 170 knee ACI patients with a minimum of 2 years' follow-up into groups according to the need for reoperation after ACI and the findings at surgery. Group A (n = 73) comprised patients who did not undergo reoperation, group B (n = 61) comprised patients who underwent reoperation and had findings unrelated to the repair, and group C (n = 36) comprised patients who underwent reoperation and had isolated graft hypertrophy. The International Knee Documentation Committee, modified Cincinnati knee rating, and Short Form 36 physical component scores for the 3 groups were compared. Of the repairs debrided because of graft hypertrophy, 41 were longitudinally assessed with arthroscopy or magnetic resonance imaging. Results: The mean follow-up was 42.2 months. Patch-related problems were seen in 73.7% of cases undergoing reoperation less than 2 years after implantation, whereas cartilage-related problems were the dominant finding more than 2 years after implantation (70.2%). Group A patients fared significantly better than group B or C patients with regard to all 3 parameters measured, with no difference between groups B and C. Longitudinal assessment of 41 hypertrophied repairs revealed 18 with signs of pathology after graft debridement. Conclusions: This study shows that reoperation is frequent after ACI and is associated with a less satisfying outcome. Furthermore, debridement of a hypertrophied ACI graft appears to be detrimental as shown by longitudinal assessment of repairs. Level of Evidence: Level IV, therapeutic case series.

A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.

To determine the efficacy of autologous chondrocyte implantation (ACI) in treating focal chondral defects of the knee, we reviewed the 2-year treatment outcome of ACI in 53 patients (72 lesions) through clinical evaluation, MRI, second-look arthroscopy and biopsies obtained. Improvement in mean subjective score from preoperative (37.6) to 12 months (56.4) and 24 (60.1) months post-ACI were observed. Knee function levels also improved [86% International Cartilage Repair Society (ICRS) III/IV to 66.6% I/II] from preoperative period to 24 months postimplantation. Objective IKDC score of A or B were observed in 88% preoperatively. This decreased to 67.9% at 3 months before improving to 92.5% at 12 months and 94.4% at 24 months post implantation. Transient deterioration in all these clinical scores was observed at 3 months before progressive improvement became evident. MRI studies demonstrated 75.3% with at least 50% defect fill, 46.3% with near normal signal, 68.1% with mild/no effusion and also 66.7% with mild/no underlying bone marrow oedema at 3 months. These values improved to 94.2%, 86.9%, 91.3% and 88.4%, respectively, at 12 months. At 24 months, further improvements to 97%, 97%, 95.6% and 92.6%, respectively, were observed. Second-look arthroscopy carried out in 22 knees (32 lesions) demonstrated all grafts to be normal/nearly normal based on the International Cartilage Repair Society (ICRS) visual repair assessment while core biopsies from 20 lesions demonstrated 13 grafts to have hyaline/hyaline-like tissue. Improvement in clinical and MRI findings obtained from second-look arthroscopy and core biopsies evaluated indicate that, at 24 months post-ACI, the resurfaced focal chondral defects of the knee remained intact and continued to function well.

A recombinant C-terminus heavy chain fragment from botulinum neurotoxin serotype E (BoNT/E) is proposed as a vaccine against the serotype E neurotoxin. This fragment, rBoNTE(Hc), was produced intracellular in Pichia pastoris GS115 by a three-step fermentation process, i.e., glycerol batch phase and a glycerol fed-batch phase to achieve high cell densities, followed by a methanol fed-batch induction phase. The rBoNTE(Hc) protein was puriWed from the soluble fraction of cell lysates using three ion-exchange chromatography steps (SP Sepharose Fast Flow, Q Sepharose Fast Flow, Sp Sepharose High Performance) and polished with a hydrophobic charge induction chromatography step (MEP HyperCel). Method development at the bench scale was achieved using 7– 380 mL columns and the process was performed at the pilot scale using 0.5–3.1 L columns in preparation for technology transfer to cGMP manufacturing. The puriWcation process resulted in greater than 98% pure rBoNTE(Hc) based on HPLC and yielded up to 1.01 g of rBoNTE(Hc)/kg cells at the bench scale and 580 mg vaccine/kg cells at the pilot scale. N-terminal sequencing showed that the puriWed rBoNTE(Hc) N-terminus is intact and was found to protect mice against a challenge of 1000 mouse intraperitoneal LD50’s of BoNT/E.

Powerlase has made significant steps forward in developing reliable and cost-effective, kilowatt-class laser modules with short pulse duration and small footprint, for use as EUV drivers. These characteristics in parallel to EUV target requirements are essential for the generation of 115W of in-band EUV power at the intermediate focus. These laser modules can be coupled to the EUV target by using our flexible spatial and temporal multiplexing approach in order to scale up the laser average power on target. The multiplexing method developed by Powerlase is modular and optimised for maximum EUV collection angle. To further this goal we are currently evaluating target materials such as xenon in various phases and forms and also have a programme in place to investigate suitable tin targets.

A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

Background: Simultaneous anterior and posterior ankle impingement has not been previously reported. We identified 62 patients with both anterior and posterior impingement and report the results of anterior arthroscopic and posterior open treatment. Methods: Between January, 1990, and December, 2003, 62 consecutive patients with symptoms and signs of both anterior and posterior impingement of the ankle were identified. Fifty-eight recorded a single injury or multiple ankle sprains. The most common mechanism of injury was inversion or plantarflexion. Initial conservative treatment failed in all patients and anterior arthroscopy and open posterior clearance were done. Followup averaged 11.4 months (up to 5 years). All patients showed posttraumatic synovitis at arthroscopy, and 48 had other arthroscopically-detected lesions, such as anterior tibial plafond lesions, ossicles, or soft-tissue impingement. The posterior arthrotomy revealed a bony cause for impingement in all but four patients, usually an os trigonum or a long posterior process of the talus. Results: Three patients had anterolateral tenderness after arthroscopy and three had tenderness of the posterior arthrotomy scar. There were no persistent neurologic complications. Fifty-eight patients were available for followup. Forty-seven (81%) had excellent or good outcomes, nine (15.5%) had fair outcomes, and two (3.5%) were graded as poor. Conclusion: Usually, anterior and posterior impingement occur separately; however, there are patients who have symptoms and signs of both anterior and posterior ankle impingement. A single inversion or plantarflexion mechanism of injury may be responsible for this syndrome, although it may also be caused by repetitive inversion injury. Combined anterior arthroscopic and posterior open treatment obtained good results with minimal complications and morbidity.

Laser milling of diverse materials has been demonstrated with short pulse lasers ranging from microsecond to femtosecond pulse durations, and with wavelengths from the far infrared to vacuum ultra-violet. In all cases a balance between quality, throughput and cost of ownership must be struck in order to determine commercial relevance. Latest generation Q-switched Diode Pumped Solid State Lasers offer the potential to enable the industrial uptake of laser milling for a wide variety of materials including aerospace alloys, thermal barrier coatings, tool steels, diamond and diamond substitutes. This paper will investigate these practical applications of laser milling with reference to comparative laser and non-laser processes.

Patellofemoral pain remains one of the most common musculoskeletal disorders encountered in orthopaedic practice. In this retrospective clinical study, 108 knees in 98 patients with patellofemoral pain due to malalignment were treated using a combined proximal and distal realignment technique. The results were evaluated at an average of 29.2 (1–9.2 years) months postoperatively. At final evaluation using the modified Trillat grading scale, good or excellent results were obtained in 88 (81.4%) of the knees treated. Second-look arthroscopy performed in 65 (60.2%) knees demonstrated good patellar tracking and Grade II articular changes were noted in 16 (14.8%) of the patellofemoral joints examined. Complications noted included anterior compartment syndrome with foot drop in one case and arthrofibrosis in another. We conclude that extensor realignment surgery with a combined proximal and distal realignment procedure is a reliable technique for patellofemoral pain secondary to malalignment.

Laser milling of a variety of substrates is investigated with the intention of achieving high quality material removal to create three-dimensional shapes in the material. A high power Q-switched Diode Pumped Solid State Nd:YAG Laser at 1064nm is used in all cases. Materials investigated include Nickel Superalloys, Thermal Barrier Coatings, Steels, Tungsten Carbide and Polycrystalline Diamond. Multi-layer substrates are also considered. The effects of laser intensity, plasma formation, pulse duration, material properties, and resulting removal rate, recast and surface finish are explored for this process. This paper defines the findings of this study within the context of commercial imperatives.

Heavy chain fragments of botulinum neurotoxin serotypes A and B are being developed as a bivalent vaccine for botulism. To potentiate the immune response, an aluminum containing adjuvant will be formulated with the two antigens. The adsorption mechanisms of each antigen to aluminum phosphate and aluminum hydroxide adjuvants were studied. The adsorption of the serotype A antigen to each adjuvant, and the serotype B antigen to aluminum phosphate adjuvant, is dependent on electrostatic attractive forces. The serotype A antigen is basic, and pretreatment with phosphate anions is required for favorable adsorption conditions to aluminum hydroxide adjuvant. In contrast, the serotype B antigen displays a high affinity to aluminum hydroxide adjuvant even when the two species possess the same charge. It is proposed that the serotype B antigen is adsorbed to aluminum hydroxide adjuvant by a ligand exchange mechanism.

We have reviewed 22 patients from a total of 135 treated by autologous chondrocyte implantation (ACI) who had undergone further surgery for pain in the knee and mechanical symptoms after a mean of 10.5 months. There were 31 grafted lesions. At operation the findings included lifting (24/31) and detachment (3/31) of periosteal patches for which arthroscopic shaving was performed. Chondroplasty was undertaken on two new lesions, another required an ACI and a further patient required trimming of a meniscus. The mechanical symptoms resolved within two weeks. At the last review, two to 14 months from reoperation; 68% had improved, and 86% had normal or nearly normal IKDC scores. Of the 31 lesions, 30 (97%) had normal or nearly normal visual repair scores. Biopsy showed good integration with subchondral bone and the marginal interface in all specimens, most of which showed hyaline or hyaline-like cartilage (70%). Troublesome mechanical symptoms required surgery in 13% of ACI-treated patients and were attributed to periosteal extrusion. Simple arthroscopic debridement was curative.

Publisher Summary Very valuable resources for the discovery of biologically active agents are encoded combinatorial libraries of small molecules. A binary encoding protocol employing electrophoric molecular tags (ECLiPSe technology) has been developed at Pharmacopeia. A series of quality control (QC) protocols to ensure the highest degree of library has also been put into practice. This protocol, sets of synthons are serially combined through split-and-pool or direct divide synthesis in tandem with the incorporation of binary sets of electrophoric tags on solid support. Quality control steps occur throughout the entire library construction pipeline. To ensure a successful library synthesis and production elution Extensive synthon profiling, rigorous analysis of QC compounds, final confirmation of library chemistry (library QA), and production-in-process-QC analysis are essential. Empirical information regarding overall fidelity and an indication of the performance of individual synthons is provided by both in-line and final library QA. The quality of large, encoded combinatorial libraries can be assessed by library QA, a powerful analytical protocol. Based on the combined application of tag decoding and single bead liquid chromatography/mass spectrometry (LC/MS), QA analysis would be virtually impossible to carry out without an encoding strategy due to redundant masses produced during split synthesis. The statistical theory and its application to library assessment are analogous to the accepted statistical sampling practices used in the industry to ascertain the quality of mass-produced material. The simplicity of tag reading and rapid acquisition of structure activity relationship (SAR) information is arguably the most significant advantage of encoding technology vs. other deconvolution techniques. Library QA serves to substantiate and enhance the value of nascent SAR obtainment from library screening.