The influence of wear paths produced by hip replacement patients during normal walking on wear rates

Variation in wear paths is known to greatly affect wear rates in vitro, with multidirectional paths producing much greater wear than unidirectional paths. This study investigated the relationship between multidirectional motion at the hip joint, as measured by aspect ratio, sliding distance, and wear rate for 164 hip replacements. Kinematic input from three-dimensional gait analysis was used to determine the wear paths. Activity cycles were determined for a subgroup of 100 patients using a pedometer study, and the relationship between annual sliding distance and wear rate was analyzed. Poor correlations were found between both aspect ratio and sliding distance and wear rate for the larger group and between annual sliding distance and wear rate for the subgroup. However, patients who experienced a wear rate <0.08 mm/year showed a strong positive correlation between the combination of sliding distance, activity levels, and aspect ratio and wear rate (adjusted r2?=?55.4%). This group may represent those patients who experience conditions that most closely match those that prevail in simulator and laboratory tests. Although the shape of wear paths, their sliding distance, and the number of articulation cycles at the hip joint affect wear rates in simulator studies, this relationship was not seen in this clinical study. Other factors such as lubrication, loading conditions and roughness of the femoral head may influence the wear rate.

Age-specific reproductive investment in female burying beetles: independent effects of state and risk of death

1.How much should an individual invest in reproduction as it grows older? Answering this question involves determining whether individuals measure their age as the time left for future reproduction or as the rate of deterioration in their state. Theory suggests that in the former case individuals should increase their allocation of resources to reproduction as opportunities for future breeding dwindle, and terminally invest when they breed for the last time. In the latter case they should reduce their investment in reproduction with age, either through adaptive reproductive restraint or as a passive by-product of senescence.
2.Here we present the results of experiments on female burying beetles, Nicrophorus vespilloides, in which we independently manipulated the perceived risk of death (by activating the immune system) and the extent of deterioration in state (by changing age of first reproduction and/or prior investment in reproduction).
3.We found that the risk of death and state each independently influenced the extent of reproductive investment. Specifically, we found a state-dependent decline in reproductive investment as females grew older that could be attributed to both adaptive reproductive restraint and senescence. A perceived increase in the risk of death, induced by activation of the immune system, caused females to switch from a strategy of reproductive restraint to terminal investment. Nevertheless, absolute reproductive investment was lower in older females, indicating constraints of senescence.
4.Our results show that a decline in reproductive investment with age does not necessarily constitute evidence of reproductive senescence but can also result from adaptive reproductive restraint.
5.Our results further suggest that the extent of reproductive investment is dependent on several different intrinsic cues and that the particular blend of cues available at any given age can yield very different patterns of investment. Perhaps this explains why age-related reproductive investment patterns seen in nature are so diverse.

Comment on “Electron transport through correlated molecules computed using the time-independent Wigner function: Two critical tests”

The many-electron-correlated scattering (MECS) approach to quantum electronic transport was investigated in the linear-response regime [I. Bâldea and H. Köppel, Phys. Rev. B 78, 115315 (2008). The authors suggest, based on numerical calculations, that the manner in which the method imposes boundary conditions is unable to reproduce the well-known phenomena of conductance quantization. We introduce an analytical model and demonstrate that conductance quantization is correctly obtained using open system boundary conditions within the MECS approach.

The Ectocarpus genome and the independent evolution of multicellularity in brown algae

Brown algae (Phaeophyceae) are complex photosynthetic organisms with a very different evolutionary history to green plants, to which they are only distantly related(1). These seaweeds are the dominant species in rocky coastal ecosystems and they exhibit many interesting adaptations to these, often harsh, environments. Brown algae are also one of only a small number of eukaryotic lineages that have evolved complex multicellularity (Fig. 1). We report the 214 million base pair (Mbp) genome sequence of the filamentous seaweed Ectocarpus siliculosus (Dillwyn) Lyngbye, a model organism for brown algae(2-5), closely related to the kelps(6,7) (Fig. 1). Genome features such as the presence of an extended set of light-harvesting and pigment biosynthesis genes and new metabolic processes such as halide metabolism help explain the ability of this organism to cope with the highly variable tidal environment. The evolution of multicellularity in this lineage is correlated with the presence of a rich array of signal transduction genes. Of particular interest is the presence of a family of receptor kinases, as the independent evolution of related molecules has been linked with the emergence of multicellularity in both the animal and green plant lineages. The Ectocarpus genome sequence represents an important step towards developing this organism as a model species, providing the possibility to combine genomic and genetic(2) approaches to explore these and other(4,5) aspects of brown algal biology further.

Sperm DNA damage measured by the alkaline Comet assay as an independent predictor of male infertility and in vitro fertilization success

Objective: To evaluate sperm DNA fragmentation and semen parameters to diagnose male factor infertility and predict pregnancy after IVF.
Design: Prospective study.
Setting: Academic research laboratory.
Patient(s): Seventy-five couples undergoing IVF and 28 fertile donors.
Intervention(s): Sperm DNA fragmentation was measured by the alkaline Comet assay in semen and sperm after density gradient centrifugation (DGC). Binary logistic regression was used to analyze odds ratios (OR) and relative risks (RR) for IVF outcomes.
Main Outcome Measure(s): Semen parameters and sperm DNA fragmentation in semen and DGC sperm compared with fertilization rates, embryo quality, and pregnancy.
Result(s): Men with sperm DNA fragmentation at more than a diagnostic threshold of 25% had a high risk of infertility (OR: 117.33, 95% confidence interval [CI]: 12.72–2,731.84, RR: 8.75). Fertilization rates and embryo quality decreased as sperm DNA fragmentation increased in semen and DGC sperm. The risk of failure to achieve a pregnancy increased when sperm DNA fragmentation exceeded a prognostic threshold value of 52% for semen (OR: 76.00, CI: 8.69–1,714.44, RR: 4.75) and 42% for DGC sperm (OR: 24.18, CI: 2.89–522.34, RR: 2.16).
Conclusion(s): Sperm DNA testing by the alkaline Comet assay is useful for both diagnosis of male factor infertility and prediction of IVF outcome.

Inhibition of histone deacetylase 2 increases apoptosis and p21(Cip1/WAF1) expression, independent of histone deacetylase 1

Histone deacetylases ( HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21(Cip1/WAF1) expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK

Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 associated x protein/BCL-2 antagonist killer (BAX/BAK) consistent with its on-target pharmacodynamics, simultaneous silencing of both BAX and BAK did not abolish acute toxicity or loss of clonogenicity. This is despite complete inhibition of apoptosis. Obatoclax dramatically reduced viability without inducing loss of plasma membrane integrity. This was associated with rapid processing of light chain-3 (LC3) and reduction of S6 kinase phosphorylation, consistent with autophagy. Dramatic ultrastructural vacuolation, not typical of autophagy, was also induced. Silencing of beclin-1 failed to prevent LC3 processing, whereas knockout of autophagy-related (Atg) 7 abolished LC3 processing but failed to prevent obatoclax-induced loss of clonogenicity or ultrastructural changes. siRNA silencing of Atg7 in BAX/BAK knockout mouse embryonic fibroblasts did not prevent obatoclax-induced loss of viability. Cells selected for obatoclax resistance evaded apoptosis independent of changes in BCL-2 family expression and displayed reduced LC3 processing. In summary, obatoclax exhibits BAX- and BAK-dependent and -independent mechanisms of toxicity and activation of autophagy. Mechanisms other than autophagy and apoptosis are blocked in obatoclax resistant cells and contribute significantly to obatoclax's anticancer efficacy. Cell Death and Disease (2010) 1, e108; doi:10.1038/cddis.2010.86; published online 16 December 2010

PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The back 2 activity trial: education and advice versus education and advice plus a structured walking programme for chronic low back pain.:education and advice versus education and advice plus a structured walking programme for chronic low back pain

BACKGROUND: Current evidence supports the use of exercise-based treatment for chronic low back pain that encourages the patient to assume an active role in their recovery. Walking has been shown it to be an acceptable type of exercise with a low risk of injury. However, it is not known whether structured physical activity programmes are any more effective than giving advice to remain active.

METHODS/DESIGN: The proposed study will test the feasibility of using a pedometer-driven walking programme, as an adjunct to a standard education and advice session in participants with chronic low back pain. Fifty adult participants will be recruited via a number of different sources. Baseline outcome measures including self reported function; objective physical activity levels; fear-avoidance beliefs and health-related quality of life will be recorded. Eligible participants will be randomly allocated under strict, double blind conditions to one of two treatments groups. Participants in group A will receive a single education and advice session with a physiotherapist based on the content of the 'Back Book'. Participants in group B will receive the same education and advice session. In addition, they will also receive a graded pedometer-driven walking programme prescribed by the physiotherapist. Follow up outcomes will be recorded by the same researcher, who will remain blinded to group allocation, at eight weeks and six months post randomisation. A qualitative exploration of participants' perception of walking will also be examined by use of focus groups at the end of the intervention. As a feasibility study, treatment effects will be represented by point estimates and confidence intervals. The assessment of participant satisfaction will be tabulated, as will adherence levels and any recorded difficulties or adverse events experienced by the participants or therapists. This information will be used to modify the planned interventions to be used in a larger randomised controlled trial.

DISCUSSION: This paper describes the rationale and design of a study which will test the feasibility of using a structured, pedometer-driven walking programme in participants with chronic low back pain.

TRIAL REGISTRATION: [ISRCTN67030896].

Glycoprotein VI/Fc receptor gamma chain-independent tyrosine phosphorylation and activation of murine platelets by collagen

We have investigated the ability of collagen to induce signalling and functional responses in suspensions of murine platelets deficient in the FcRgamma (Fc receptor gamma) chain, which lack the collagen receptor GPVI (glycoprotein VI). In the absence of the FcRgamma chain, collagen induced a unique pattern of tyrosine phosphorylation which was potentiated by the thromboxane analogue U46619. Immunoprecipitation studies indicated that neither collagen alone nor the combination of collagen plus U46619 induced phosphorylation of the GPVI-regulated proteins Syk and SLP76 (Src homology 2-containing leucocyte protein of 76 kDa). A low level of tyrosine phosphorylation of phospholipase Cgamma2 was observed, which was increased in the presence of U46619, although the degree of phosphorylation remained well below that observed in wild-type platelets (similar to 10%). By contrast, collagen-induced phosphorylation of the adapter ADAP (adhesion- and degranulation-promoting adapter protein) was substantially potentiated by U46619 to levels equivalent to those observed in wild-type platelets. Collagen plus U46619 also induced significant phosphorylation of FAK (focal adhesion kinase). The functional significance of collagen-induced non-GPVI signals was highlighted by the ability of U46619 and collagen to induce the secretion of ATP in FcRgamma chain-deficient platelets, even though neither agonist was effective alone. Protein tyrosine phosphorylation and the release of ATP were abolished by the anti(alpha2 integrin) antibodies Ha1/29 and HMalpha2, but not by blockade of alphaIIbbeta3. These results illustrate a novel mechanism of platelet activation by collagen which is independent of the GPVI-FcRgamma chain complex, and is facilitated by binding of collagen to integrin alpha2beta1.