Throwing workload and injury risk in elite cricketers.

OBJECTIVE: To investigate the risk between throwing workload and upper limb injury in elite cricketers. DESIGN: Prospective cohort study. SETTING: Elite Australian cricket. PARTICIPANTS: 28 adult male cricketers aged 18-32 years. ASSESSMENT OF RISK FACTORS: Daily throwing workload and injury were prospectively monitored over the 2007-2008 cricket season. Risk ratios (RRs) were calculated to describe the association between throwing workload and injury. MAIN OUTCOME MEASUREMENT: Upper limb injury associated with throwing. RESULTS: Seven (25%) players sustained an injury during the season. Injured players threw approximately 40 more throws/week (p=0.004) and 12.5 more throws per throwing day (p=0.061) than uninjured players. Players were at a significantly increased risk of injury if they completed more than 75 throws/week (RR=1.73, 95% CI=1.03 to 2.92), and there was a trend towards an increased risk if they completed more than 40 throws per throwing day (RR=1.41, 95% CI=0.88 to 2.26). Injured players also completed more throws and had more throwing days (and consequently less rest days) in the week before injury, as compared with the rest of their season preceding that point. CONCLUSION: An increased throwing workload is a risk factor for the development of upper limb injury in elite cricketers. Investigation of the kinematics of throwing in elite cricketers would complement this study, and further research is required to develop detailed throwing workload guidelines for cricketers across a range of ages.

Preferences for outcomes of treatment for rectal cancer: patient and clinician utilities and their application in an interactive computer-based decision aid.

PURPOSE: To quantify the importance that patients and clinicians assign to specific quality-of-life outcomes associated with the treatment of rectal cancer and to demonstrate a clinical application of these data in a computer-based multidimension decision aid (Annalisa). METHODS: For patients, a researcher-administered questionnaire using the time trade-off method was used to quantify the importance of nine outcomes. Information was ascertained from clinicians by use of a self-administered questionnaire. Responses were ranked and compared between groups. Mean values for each outcome were entered into Annalisa. RESULTS: Overall, 103 patients, 87 colorectal surgeons, 97 medical oncologists, and 80 radiation oncologists participated. For all groups, local cancer recurrence in the pelvis and fecal incontinence (mean utility scores 0.53 and 0.57, respectively) were the two outcomes to most avoid. In Annalisa, the "best fit" treatment for patients and surgeons was a low anterior resection with postoperative chemotherapy, whereas for medical and radiation oncologists the best-fit treatment was surgery alone. CONCLUSION: Local recurrence and fecal incontinence are considered the worst outcomes by patients and clinicians alike, but values for other outcomes vary. Decision aids that incorporate patients' individual values with evidence-based data hold considerable potential to optimize treatment decision-making.

The reliability of musculoskeletal screening tests used in cricket.

OBJECTIVES: To determine the inter- and intra-observer reliability of a field-based musculoskeletal screening protocol used to measure potential injury risk factors in cricket fast bowlers. DESIGN: Test-retest reliability study. SETTING: High performance Australian cricket. PARTICIPANTS: Ten volunteers. Two sports physiotherapists conducted the testing. MAIN OUTCOME MEASURES: Participants completed the following tests: knee extension; modified Thomas test (hip extension and abduction); hip internal and external rotation; combined elevation; ankle dorsiflexion lunge; bridging hold; prone four point hold; and calf heel raises. METHODS: For each of the tests, the participants were tested by each physiotherapist twice, and the inter- and intra-observer reliability were concurrently assessed. RESULTS: The inter-observer reliability of the tests was generally poor, with only four of the ten tests having an intraclass correlation coefficient (ICC) greater than 0.80 (range of ICCs 0.27-0.99). The intra-observer reliability of the tests was considerably higher, with nine tests having an ICC greater than 0.80 (range of ICCs 0.56-0.99). CONCLUSIONS: With the exception of the bridging hold, all tests would be considered acceptable where only one observer was conducting the testing. However, only the ankle dorsiflexion lunge, combined elevation test, calf heel raise test and prone four point hold have acceptable reliability when there are multiple physiotherapists recording measurements.

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo.

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K(i) = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of beta-N-acetylglucosaminidases.

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of beta-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human beta-hexosaminidase, as well as two bacterial beta-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency.

Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise.

O-GlcNAcase catalyzes the cleavage of beta-O-linked 2-acetamido-2-deoxy-beta-d-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-alpha-d-glucopyranoso[2,1-d]-Delta2'-thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal beta-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise.

Determining the intra- and inter-observer reliability of screening tools used in sports injury research.

Sports injury etiological studies explore the relationships between potential injury risk factors and injury outcomes. The ability of such studies to clearly identify intrinsic risk factors for sports injury depends on the accuracy of their measurement. Measurements need to be reproducible over time and repeatable by different observers, as well as within a given individual. The importance of the reliability of pre-participation screening protocols and other clinical assessment tools has been identified in a number of published studies. However, a review of these studies indicates that a variety of statistical techniques have been used to calculate intra- and inter-observer reliability. While the intra-class correlation coefficient (ICC) is the most often cited measure, a range of statistical approaches to estimating ICCs have been used. It is therefore difficult to determine which statistical method is most appropriate in the context of measuring intrinsic risk factors in sports injury research. This paper summarises a statistical method for the concurrent assessment of intra- and inter-observer reliability and presents an argument for why this approach should be adopted by sports injury researchers using screening protocols that collect continuous data.

Inhibition of O-GlcNAcase by a gluco-configured nagstatin and a PUGNAc-imidazole hybrid inhibitor.

Synthesis of a PUGNAc-imidazole hybrid and its characterization as an inhibitor of human O-GlcNAcase through enzyme kinetics and X-ray structural analysis.

Structure of the manganese superoxide dismutase from Deinococcus radiodurans in two crystal forms.

The structure of the manganese superoxide dismutase (Mn-SOD; DR1279) from Deinococcus radiodurans has been determined in two different crystal forms. Both crystal forms are monoclinic with space group P2(1). Form I has unit-cell parameters a = 44.28, b = 83.21, c = 59.52 angstroms, beta = 110.18 degrees and contains a homodimer in the asymmetric unit, with structure refinement (R = 16.8%, R(free) = 23.6%) carried out using data to d(min) = 2.2 angstroms. Form II has unit-cell parameters a = 43.57, b = 87.10, c = 116.42 angstroms, beta = 92.1 degrees and an asymmetric unit containing two Mn-SOD homodimers; structure refinement was effected to a resolution of 2.0 angstroms (R = 17.2%, R(free) = 22.3%). The resulting structures are compared with that of Mn-SOD from Escherichia coli, with which they are shown to be essentially isostructural.

Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity.

O-GlcNAc is an abundant post-translational modification of serine and threonine residues of nucleocytoplasmic proteins. This modification, found only within higher eukaryotes, is a dynamic modification that is often reciprocal to phosphorylation. In a manner analogous to phosphatases, a glycoside hydrolase termed O-GlcNAcase cleaves O-GlcNAc from modified proteins. Enzymes with high sequence similarity to human O-GlcNAcase are also found in human pathogens and symbionts. We report the three-dimensional structure of O-GlcNAcase from the human gut symbiont Bacteroides thetaiotaomicron both in its native form and in complex with a mimic of the reaction intermediate. Mutagenesis and kinetics studies show that the bacterial enzyme, very similarly to its human counterpart, operates via an unusual 'substrate-assisted' catalytic mechanism, which will inform the rational design of enzyme inhibitors.