Abstract The risk of revision following unicompartmental arthroplasty (UKA) is greater compared with primary total knee arthroplasty (TKA). Some surgeons report that UKA revision is straightforward ...with outcomes comparable to TKA. We reviewed all Oxford medial UKAs and TKAs performed at our institution over a five year period. Patient reported outcomes were compared between revised UKAs, successful UKAs and primary TKAs. Out of 546 Oxford medial UKAs, twenty-nine (5.3%) were revised at a mean of 25 months. The commonest indications for revision were aseptic loosening and progression of osteoarthritis. Ten patients (34%) required augments, stemmed implants or bone grafts. Outcomes following revision were poorer than those following successful UKA and primary TKA, and were a consequence of poor pre-operative function rather than the complexity of surgery.
Plants produce a variety of proteinase inhibitors (PIs) that have a major function in defense against insect herbivores. In turn, insects have developed strategies to minimize the effect of dietary ...PIs on digestion. We have discovered that Helicoverpa larvae that survive consumption of a multidomain serine PI from Nicotiana alata (NaPI) contain high levels of a chymotrypsin that is not inhibited by NaPI. Here we describe the isolation of this NaPI-resistant chymotrypsin and an NaPI-susceptible chymotrypsin from Helicoverpa larvae, together with their corresponding cDNAs. We investigated the mechanism of resistance by mutating selected positions of the NaPI-susceptible chymotrypsin using the corresponding amino acids of the NaPI-resistant chymotrypsin. Four critical residues that conferred resistance to NaPI were identified. Molecular modeling revealed that a Phe→Leu substitution at position 37 in the chymotrypsin results in the loss of important binding contacts with NaPI. Identification of the molecular mechanisms that contribute to PI resistance in insect digestive proteases will enable us to develop better inhibitors for the control of lepidopteran species that are major agricultural pests worldwide.
Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the ...development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.
The rising phase of the action potential in excitable cells is mediated by voltage-gated sodium channels (VGSCs), of which there are nine mammalian subtypes with distinct tissue distribution and ...biophysical properties. The involvement of certain VGSC subtypes in disease states such as pain and epilepsy highlights the need for agents that modulate VGSCs in a subtype-specific manner. Conotoxins from marine snails of the
Conus genus constitute a promising source of such modulators, since these peptide toxins have evolved to become selective for various membrane receptors, ion channels and transporters in excitable cells. This review covers the structure and function of three classes of conopeptides that modulate VGSCs: the pore-blocking μ-conotoxins, the δ-conotoxins which delay or inhibit VGSC inactivation, and the μO-conotoxins which inhibit VGSC Na
+ conductance independent of the tetrodotoxin binding site. Some of these toxins have potential therapeutic and research applications, in particular the μO-conotoxins, which may develop into potential drug leads for the treatment of pain states.
We propose a surface ion trap design incorporating microwave control electrodes for near-field single-qubit control. The electrodes are arranged so as to provide arbitrary frequency, amplitude and ...polarization control of the microwave field in one trap zone, whilst a similar set of electrodes is used to null the residual microwave field in a neighbouring zone. The geometry is chosen to reduce the residual field to the 0.5 % level without nulling fields; with nulling, the crosstalk may be kept close to the 0.01 % level for realistic microwave amplitude and phase drift. Using standard photolithography and electroplating techniques, we have fabricated a proof-of-principle electrode array with two trapping zones. We discuss requirements for the microwave drive system and prospects for scalability to a large 2-D trap array.
Several macrocyclic peptides (∼30 amino acids), with diverse biological activities, have been isolated from the Rubiaceae and Violaceae plant families over recent years. We have significantly ...expanded the range of known macrocyclic peptides with the discovery of 16 novel peptides from extracts of
Viola hederaceae,
Viola odorata and
Oldenlandia affinis. The
Viola plants had not previously been examined for these peptides and thus represent novel species in which these unusual macrocyclic peptides are produced. Further, we have determined the three-dimensional structure of one of these novel peptides, cycloviolacin O1, using
1H NMR spectroscopy. The structure consists of a distorted triple-stranded β-sheet and a cystine-knot arrangement of the disulfide bonds. This structure is similar to kalata B1 and circulin A, the only two macrocyclic peptides for which a structure was available, suggesting that despite the sequence variation throughout the peptides they form a family in which the overall fold is conserved. We refer to these peptides as the cyclotide family and their embedded topology as the cyclic cystine knot (CCK) motif. The unique cyclic and knotted nature of these molecules makes them a fascinating example of topologically complex proteins. Examination of the sequences reveals they can be separated into two subfamilies, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularization of the backbone. The second subfamily contains a backbone twist due to a
cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip. Here we define the structural features of the two apparent subfamilies of the CCK peptides which may be significant for the likely defense related role of these peptides within plants.
Most mammalian defensins are cationic peptides of 29-42 amino acids long, stabilized by three disulfide bonds. However, recently Tang et al. (1999, Science 286, 498-502) reported the isolation of a ...new defensin type found in the leukocytes of rhesus macaques. In contrast to all the other defensins found so far, rhesus theta defensin-1 (RTD-1) is composed of just 18 amino acids with the backbone cyclized through peptide bonds. Antibacterial activities of both the native cyclic peptide and a linear form were examined, showing that the cyclic form was 3-fold more active than the open chain analogue Tang et al. (1999) Science 286, 498-502. To elucidate the three-dimensional structure of RTD-1 and its open chain analogue, both peptides were synthesized using solid-phase peptide synthesis and tert-butyloxycarbonyl chemistry. The structures of both peptides in aqueous solution were determined from two-dimensional (1)H NMR data recorded at 500 and 750 MHz. Structural constraints consisting of interproton distances and dihedral angles were used as input for simulated-annealing calculations and water refinement with the program CNS. RTD-1 and its open chain analogue oRTD-1 adopt very similar structures in water. Both comprise an extended beta-hairpin structure with turns at one or both ends. The turns are well defined within themselves and seem to be flexible with respect to the extended regions of the molecules. Although the two strands of the beta-sheet are connected by three disulfide bonds, this region displays a degree of flexibility. The structural similarity of RTD-1 and its open chain analogue oRTD-1, as well as their comparable degree of flexibility, support the theory that the additional charges at the termini of the open chain analogue rather than overall differences in structure or flexibility are the cause for oRTD-1's lower antimicrobial activity. In contrast to numerous other antimicrobial peptides, RTD-1 does not display any amphiphilic character, even though surface models of RTD-1 exhibit a certain clustering of positive charges. Some amide protons of RTD-1 that should be solvent-exposed in monomeric beta-sheet structures show low-temperature coefficients, suggesting the possible presence of weak intermolecular hydrogen bonds.
We present patient outcomes following surgical excision of primary wrist ganglia over a 5 year period. Patients (48 of 59; 81%) responded to a questionnaire by post or telephone, with a mean time to ...follow-up of 44 (range 21–77) months. There was a statistically significant reduction in all reported symptoms, including pain, paraesthesia, weakness, stiffness, and cosmesis. The recurrence rate was 8%. In total, 98% of patients were satisfied or very satisfied with treatment. Surgical excision of primary wrist ganglia may have advantages over aspiration and reassurance alone, particularly in reducing recurrence and hastening resolution of symptoms.
Conotoxins are small disulfide rich peptides from the venoms of marine cone snails. They target specific nicotinic acetylcholine receptor (nAChR) subtypes with high affinity and potency and are ...therefore valuable as neuropharmacological probes and potential drug leads. This article gives a general overview of the chemical and biological features of alpha-conotoxins, including their pharmacology, binding interactions and structure. A detailed analysis of recently reported three-dimensional structures from members of different subfamilies of the alpha-conotoxins, including those with 3/5, 4/3, 4/6 and 4/7 spacings of their two intracysteine loops is given. The structures are generally well defined and represent useful frameworks for the display of amino acid residues to target molecules.
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