Sports Imaging of Team Handball Injuries.

Team handball is a fast high-scoring indoor contact sport with > 20 million registered players who are organized in > 150 federations worldwide. The combination of complex and unique biomechanics of handball throwing, permitted body tackles and blocks, and illegal fouls contribute to team handball ranging among the four athletic sports that carry the highest risks of injury. The categories include a broad range of acute and overuse injuries that most commonly occur in the shoulder, knee, and ankle. In concert with sports medicine, physicians, surgeons, physical therapists, and radiologists consult in the care of handball players through the appropriate use and expert interpretations of radiography, ultrasonography, CT, and MRI studies to facilitate diagnosis, characterization, and healing of a broad spectrum of acute, complex, concomitant, chronic, and overuse injuries. This article is based on published data and the author team's cumulative experience in playing and caring for handball players in Denmark, Sweden, Norway, Germany, Switzerland, and Spain. The article reviews and illustrates the spectrum of common handball injuries and highlights the contributions of sports imaging for diagnosis and management.

Design and Synthesis of 2,3- trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters.

Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2 S,3 R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor ( Ki = 0.61 µM) over GluN1/GluN2B-D ( Ki = 2.7-62 µM).

Biocide Runoff from Building Facades: Degradation Kinetics in Soil.

Biocides are common additives in building materials. In-can and film preservatives in polymer-resin render and paint, as well as wood preservatives are used to protect facade materials from microbial spoilage. Biocides leach from the facade material with driving rain, leading to highly polluted runoff water (up to several mg L-1 biocides) being infiltrated into the soil surrounding houses. In the present study the degradation rates in soil of 11 biocides used for the protection of building materials were determined in laboratory microcosms. The results show that some biocides are degraded rapidly in soil (e.g., isothiazolinones: T1/2 < 10 days) while others displayed higher persistence (e.g., terbutryn, triazoles: T1/2 ≫ 120 days). In addition, mass balances of terbutryn and octylisothiazolinone were determined, including nine (terbutryn) and seven (octylisothiazolinone) degradation products, respectively. The terbutryn mass balance could be closed over the entire study period of 120 days and showed that relative persistent metabolites were formed, while the mass balances for octylisothiazolinone could not be closed. Octylisothiazolinone degradation products did not accumulate over time suggesting that the missing fraction was mineralized. Microtox-tests revealed that degradation products were less toxic toward the bacterium Aliivibrio fischeri than their parent compounds. Rain is mobilizing these biocides from the facades and transports them to the surrounding soils; thus, rainfall events control how often new input to the soil occurs. Time intervals between rainfall events in Northern Europe are shorter than degradation half-lives even for many rapidly degraded biocides. Consequently, residues of some biocides are likely to be continuously present due to repeated input and most biocides can be considered as "pseudo-persistent"-contaminants in this context. This was verified by (sub)urban soil screening, where concentrations of up to 0.1 µg g-1 were detected for parent compounds as well as terbutryn degradation products in soils below biocide treated facades.

New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype†1 (EAAT1) Inhibitors UCPH-101 and UCPH-102.

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism.

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 µM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B.

The membrane bound enzyme monoamine oxidase exist in two splice variants designated A and B (MAO-A and MAO-B) and are key players in the oxidative metabolism of monoamines in mammalians. Despite their importance and being a prevalent target for the development of inhibitors as drugs, no systematic study of substrate specificity has been reported. In this study we present a systematic study of the MAO-A and MAO-B substrate specificity profile by probing two series of phenethylamine analogs. Km and kcat values were determined for four N-alkyl analogs 2-5 and four aryl halide analogs 6-9 at MAO-A and MAO-B. A following in silico study disclosed a new adjacent compartment to the MAO-B substrate pocket defined by amino acids Tyr188, Tyr435, Tyr398, Thr399, Cys172 and Gly434. This new insight is important for the understanding of the substrate specificity of the MAO-B enzyme and will be relevant for future drug design within the field of monoamines.

Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors.

Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d-amino acids in the P3 position. Cbz-D-Phe-Phe-Arg-bk (33) was found to be the best candidate with a potency of K(i)=8µM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l-Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.

Rational design, synthesis and pharmacological evaluation of the (2R)- and (2S)-stereoisomers of 3-(2-carboxypyrrolidinyl)-2-methyl acetic acid as ligands for the ionotropic glutamate receptors.

In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM2081. Pharmacological evaluation of the two stereoisomers revealed that one stereoisomer showed a subtype selectivity profile with low micromolar affinity for GluK1 and GluK3 and a 10- to 15-fold lower affinity for GluK2. The other stereoisomer displayed full selectivity for the KA over AMPA and NMDA receptors (GluK1-3: 0.39, 0.51 and 0.099 µM, respectively).

Palladium-catalyzed alpha-arylation of tetramic acids.

A mild, racemization-free, palladium-catalyzed alpha-arylation of tetramic acids (2,4-pyrrolidinediones) has been developed. Various amino acid-derived tetramic acids were cleanly arylated by treatment with 2 mol % of Pd(OAc)(2), 4 mol % of a sterically demanding biaryl phosphine, 2.3 equiv of K(2)CO(3) or K(3)PO(4), and aryl chlorides, bromides, or triflates in THF. With conventional heating, conversions >95% could be attained after 1 h at 80 degrees C, whereas microwave-induced heating led to much shorter reaction times (5 min at 110 degrees C). The electron density of the aryl electrophile had no effect on their reactivity: both electron-rich and electron-poor aryl chlorides and bromides or triflates led to good yields. Ortho-substituted aryl halides and heteroaryl halides, however, did not undergo the title reaction.

Improved fructan accumulation in perennial ryegrass transformed with the onion fructosyltransferase genes 1-SST and 6G-FFT.

Carbohydrate limitation has been identified as a main cause of inefficient nitrogen use in ruminant animals, which feed mainly on fresh forage, hay and silage. This inefficiency results in suboptimal meat and milk productivity. One important molecular breeding strategy is to improve the nutritional value of ryegrass (Lolium perenne) by increasing the fructan content through expression of heterologous fructan biosynthetic genes. We developed perennial ryegrass lines expressing sucrose:sucrose 1-fructosyltransferase and fructan:fructan 6G-fructosyltransferase genes from onion (Allium cepa) which exhibited up to a 3-fold increased fructan content. Further, the high fructan content was stable during the growth period, whereas the fructan content in an elite variety, marketed as a high sugar variety, dropped rapidly after reaching its maximum and subsequently remained low.

Photoperiodic regulation of flowering in perennial ryegrass involving a CONSTANS -like homolog.

Photoperiod and vernalization are the two key environmental factors of the floral induction of perennial ryegrass (Lolium perenne L.). Transition from vegetative to reproductive growth will only occur after an extended vernalization period, followed by an increase in day length and temperature. Here we report on the isolation and characterization of a L. perenne gene (LpCO ) that is homologous to CONSTANS , and which is tightly coupled to the floral inductive long day signal. Like other monocot CO-like proteins, the LpCO contains a zinc finger domain with a non-conserved B-Box2. Although the B-Box2 has been demonstrated to be essential for the function of the Arabidopsis CO (AtCO), LpCO is able to complement the Arabidopsis co-2 mutant, and ectopic expression in Arabidopsis wild type leads to early flowering. The LpCO transcript exhibits diurnal oscillations and is expressed at higher levels during long days.

Expression of a 434:VP16 chimeric activator leads to high-level activation of gene expression in stable transformants of Arabidopsis.

The performance of an expression system based on a fusion of the bacteriophage 434-repressor to the VP16 activation domain of Herpes simplex virus type 1 (434:VP16) was tested after stable integration into Arabidopsis. A special feature of this system was the use of the monocot maize ubiquitin1 and rice actin1 promoters to drive the expression of the 434:VP16 activator and 434-repressor, respectively. Our results demonstrate that the maize ubiquitin1 and the rice actin1 promoters, each of which contain introns, are active in Arabidopsis and can be used to express genes in this dicot species. Activation of gene expression after co-integration of the activator and reporter cassettes into the same genomic locus resulted in a higher activation level (84-fold activation) compared to crossing individual lines expressing only the activator or the operator reporter cassette alone (9-fold activation). Increasing the number of operator elements in the reporter cassette from 1 to 4 increased the activation level in cross-activated lines to an average of 281-fold with one combination of parental lines giving a 900-fold activation. Simultaneous expression of the 434-repressor protein driven by the rice actin promoter resulted in a significant decrease in the 434:VP16 mediated reporter gene expression. Nevertheless, an overall induction via 434:VP16 was possible even in the presence of the 434-repressor protein. This feature is important for genes which need to be absolutely repressed except under activating conditions. To our knowledge this investigation is the first report on the use of the 434:VP16 chimeric activator in an expression system in stably transformed plant lines.