The condensin complex is required for proper spindle assembly and chromosome segregation in Xenopus egg extracts.

Chromosome condensation is required for the physical resolution and segregation of sister chromatids during cell division, but the precise role of higher order chromatin structure in mitotic chromosome functions is unclear. Here, we address the role of the major condensation machinery, the condensin complex, in spindle assembly and function in Xenopus laevis egg extracts. Immunodepletion of condensin inhibited microtubule growth and organization around chromosomes, reducing the percentage of sperm nuclei capable of forming spindles, and causing dramatic defects in anaphase chromosome segregation. Although the motor CENP-E was recruited to kinetochores pulled poleward during anaphase, the disorganized chromosome mass was not resolved. Inhibition of condensin function during anaphase also inhibited chromosome segregation, indicating its continuous requirement. Spindle assembly around DNA-coated beads in the absence of kinetochores was also impaired upon condensin inhibition. These results support an important role for condensin in establishing chromosomal architecture necessary for proper spindle assembly and chromosome segregation

The influence of the strength of bone on the deformation of acetabular shells : a laboratory experiment in cadavers

Date of Acceptance: 24/08/2014 ©2015 The British Editorial Society of Bone & Joint Surgery. The authors would like to thank N. Taylor (3D Measurement Company) for his work with regard to data acquisition and processing of experimental data. We would also like to thank Dr A. Blain of Newcastle University for performing the statistical analysis The research was supported by the NIHR Newcastle Biomedical Research Centre. The authors P. Dold, M. Flohr and R. Preuss are employed by Ceramtec GmbH. Martin Bone received a salary from the joint fund. The author or one or more of the authors have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by G. Scott and first proof edited by J. Scott.Peer reviewedPostprin

Influence of body mass index (BMI) on functional improvements at 3 years following total knee replacement: a retrospective cohort study

Background The number of patients presenting for total knee replacement who are classified as obese is increasing. The functional benefits of performing TKR in these patients are unclear. Aim To assess the influence pre-operative body mass index has upon knee specific function, general health status and patient satisfaction at 3 years following total knee replacement. Design Retrospective comparative cohort study using prospectively collected data from an institutional arthroplasty register. Methods 1367 patients were assessed using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and Medical Outcomes Trust Short Form-36 (SF-36) scores supplemented by a validated measure of satisfaction pre-operatively and subsequently at 1,2 and 3 year post-operatively. Comparisons were made by dividing the cohort into 4 groups based on body mass index (BMI) 18.5–25.0 kg/m2 (n?=?253);>25.0–30.0 kg/m2 (n?=?559);>30.0?35.0 kg/m2 (n?=?373);>35.0 kg/m2 (n?=?182). Results Despite lower pre-operative, 1 and 3 year WOMAC and SF-36 scores patients with the highest BMIs >35.0 kg/m2 experienced similar improvements to patients with a ‘normal‘ BMI (18.5–25.0 kg/m2) at 1 year (Difference in WOMAC improvement?=?0.0 (95%CI ?5.2 to 5.2), p?=?1.00) and this improvement was sustained at up to 3 years (Difference in 1 year to 3 year improvement?=?2.2 (95%CI: ?2.1 to 6.5), p?=?1.00). This effect was also observed for the SF-36 mental and physical component scores. Despite equivalent functional improvements levels of satisfaction in the >35.0 kg/m2 group were lower than for any other BMI group (>35.0 kg/m2?=?84.6% satisfied versus 18.5–5.0 kg/m2?=?93.3% satisfied,p?=?0.01) as was the proportion of patients who stated they would have the operation again (>35.0 kg/m2?=?69.6% versus 18.5–25.0 kg/m2?=?82.2%,p?=?0.01). Conclusion Obese and morbidly obese patients gain as much functional benefit from total knee replacement as patients with lesser body mass indexes. This benefit is maintained for up to 3 years following surgery. However, these patients are less satisfied with their knee replacement and almost a third would not have the operation again

Conventional versus highly cross-linked polyethylene in primary total knee replacement : a comparison of revision rates using data from the National Joint Registry for England, Wales, and Northern Ireland

There is evidence to support the use of highly cross-linked polyethylene (HXLPE) in patients undergoing total hip arthroplasty. However, the benefits for those undergoing total knee arthroplasty are uncertain, with conflicting reports based on previous cohort analyses. The purpose of the present study was to compare the revision rates following primary total knee arthroplasty with use of HXLPE as compared with conventional polyethylene (CPE) using data from the National Joint Registry (NJR) for England, Wales and Northern Ireland. We performed a retrospective analysis of primary total knee arthroplasties recorded in the NJR from 2003 to 2014. Cobalt-chromium (CoCr)-CPE and CoCr-HXLPE bearing surfaces were compared using all-cause revision, aseptic revision, and septic revision as end points. Survival analyses were conducted using rates per 100 years observed, Kaplan-Meier survival estimates, and Cox regression hazard ratios (HRs) adjusted for age, sex, American Society of Anesthesiologists (ASA) classification, body mass index (BMI), lead surgeon grade, and implant constraint. Secondary analyses compared the most commonly used HXLPEs (Zimmer Prolong, DePuy XLK, and Stryker X3) against CPE for the 3 most common total knee arthroplasty systems (NexGen, PFC Sigma, and Triathlon). In the present study of 550,658 total knee arthroplasties, the unadjusted aseptic revision rates were significantly lower following procedures performed with CPE (n = 513,744) as compared with those performed with HXLPE total knee replacements (n = 36,914) (0.29 [95% confidence interval (CI), 0.28 to 0.30] compared to 0.38 [95% CI, 0.35 to 0.42], p 35 kg/m, the "second-generation" Stryker X3 HXLPE demonstrated significantly better survival than its respective CPE, with CPE having an HR of 2.6 (95% CI, 1.2 to 5.9) (p = 0.02). Alternative bearings are marketed as having improved wear properties over traditional CoCr-CPE. This registry-based analysis demonstrated no overall survival benefit of HXLPE after a maximum duration of follow-up of 12 years. Because of their increased cost, the routine use of HXLPE bearings may not be justified. However, they may have a role in specific "higher demand" groups such as patients 35 kg/m. Therapeutic Level III. See Instructions for Authors for a complete list of levels of evidence

The effect of aspirin and low-molecular-weight heparin on venous thromboembolism after knee replacement: a non-randomised comparison using National Joint Registry Data.

We compared thromboembolic events, major haemorrhage and death after knee replacement in patients receiving either aspirin or low-molecular-weight heparin (LMWH). Data from the National Joint Registry for England and Wales were linked to an administrative database of hospital admissions in the English National Health Service. A total of 156,798 patients between April 2003 and September 2008 were included and followed for 90 days. Multivariable risk modelling was used to estimate odds ratios adjusted for baseline risk factors (AOR). An AOR < 1 indicates that risk rates are lower with LMWH than with aspirin. In all, 36,159 patients (23.1%) were prescribed aspirin and 120,639 patients (76.9%) were prescribed LMWH. We found no statistically significant differences between the aspirin and LMWH groups in the rate of pulmonary embolism (0.49% vs 0.45%, AOR 0.88 (95% confidence interval (CI) 0.74 to 1.05); p = 0.16), 90-day mortality (0.39% vs 0.45%, AOR 1.13 (95% CI 0.94 to 1.37); p = 0.19) or major haemorrhage (0.37% vs 0.39%, AOR 1.01 (95% CI 0.83 to 1.22); p = 0.94). There was a significantly greater likelihood of needing to return to theatre in the aspirin group (0.26% vs 0.19%, AOR 0.73 (95% CI 0.58 to 0.94); p = 0.01). Between patients receiving LMWH or aspirin there was only a small difference in the risk of pulmonary embolism, 90-day mortality and major haemorrhage. These results should be considered when the existing guidelines for thromboprophylaxis after knee replacement are reviewed

Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis

OBJECTIVE: Joint fibrosis affects many synovial joints (including hip, knee and shoulder) causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease. Here we tested the hypothesis that joint fibrosis and other soft tissue fibrotic conditions are also associated with telomere length. PATIENTS AND METHODS: 5,200 participants in the TwinsUK registry had data on telomere length (measured by qPCR) and the traits of interest (hip and knee stiffness, total joint replacement (TJR, hip or knee) and fibrotic conditions (Dupuytren's disease, frozen shoulder). RESULTS: Multivariable logistic regression analyses showed a significant association between telomere length and fibrotic conditions (hip stiffness, knee stiffness and frozen shoulder, p = ≤0.002) even after taking age into account. No association was found between TJR and telomere length. CONCLUSION: These findings suggest that defects in telomere repair contribute to joint fibrosis, and that fibrosis shares a common mechanistic pathway in different organs. Therapeutic strategies to combat telomere shortening may offer novel treatments for fibrotic joint disease

Microinjections of acetaldehyde or salsolinol into the posterior ventral tegmental area increase dopamine release in the nucleus accumbens shell

BACKGROUND: Published findings indicate that acetaldehyde (ACD; the first metabolite of ethanol [EtOH]) and salsolinol (SAL; formed through the nonenzymatic condensation of ACD and dopamine [DA]) can be formed following EtOH consumption. Both ACD and SAL exhibit reinforcing properties within the posterior ventral tegmental area (pVTA) and both exhibit an inverted "U-shaped" dose-response curve. The current study was undertaken to examine the dose-response effects of microinjections of ACD or SAL into the pVTA on DA efflux in the nucleus accumbens shell (AcbSh). METHODS: For the first experiment, separate groups of male Wistar rats received pulse microinjections of artificial cerebrospinal fluid (aCSF) or 12-, 23-, or 90-μM ACD into the pVTA, while extracellular DA levels were concurrently measured in the AcbSh. The second experiment was similarly conducted, except rats were given microinjections of aCSF or 0.03-, 0.3-, 1.0-, or 3.0-μM SAL, while extracellular levels of DA were measured in the AcbSh. RESULTS: Both ACD and SAL produced a dose-dependent inverted "U-shaped" response on DA release in the AcbSh, with 23-μM ACD (200% baseline) and 0.3-μM SAL (300% baseline) producing maximal peak responses with higher concentrations of ACD (90 μM) and SAL (3.0 μM) producing significantly lower DA efflux. CONCLUSIONS: The findings from the current study indicate that local application of intermediate concentrations of ACD and SAL stimulated DA neurons in the pVTA, whereas higher concentrations may be having secondary effects within the pVTA that inhibit DA neuronal activity. The present results parallel the studies on the reinforcing effects of ACD and SAL in the pVTA and support the idea that the reinforcing effects of ACD and SAL within the pVTA are mediated by activating DA neurons

Cocaine influences alcohol-seeking behavior and relapse drinking in alcohol-preferring (P) rats

BACKGROUND: The results of several studies suggest that there may be common neurocircuits regulating drug-seeking behaviors. Common biological pathways regulating drug-seeking would explain the phenomenon that seeking for 1 drug can be enhanced by exposure to another drug of abuse. The objective of this study was to assess the time course effects of acute cocaine administration on ethanol (EtOH) seeking and relapse. METHODS: Alcohol-preferring (P) rats were allowed to self-administer 15% EtOH and water. EtOH-seeking was assessed through the use of the Pavlovian spontaneous recovery (PSR) model, while EtOH-relapse drinking was assessed through the use of the alcohol-deprivation effect. RESULTS: Cocaine (0, 1, or 10 mg/kg), injected immediately, 30 minutes, or 4 hours prior to the first PSR testing session, dose-dependently increased responding on the EtOH lever compared to extinction responses and responding by saline controls. Under relapse conditions, cocaine given immediately prior to the relapse session had no effect (1 mg/kg) or reduced responding (10 mg/kg). In contrast, cocaine given 4 hours prior to the relapse session markedly enhanced EtOH responding compared to saline. CONCLUSIONS: The enhanced expression of EtOH-seeking and EtOH-relapse behaviors may be a result of a priming effect of cocaine on neuronal circuits mediating these behaviors. The effect of cocaine on EtOH-relapse drinking is indicative of the complex interactions that can occur between drugs of abuse; production of conflicting behaviors (immediate), and priming of relapse/seeking (4-hour delay)