Abstract The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes ...the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4 , a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap , while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Mechanical loading is an anabolic stimulus that increases bone mass, and thus a promising method to counteract osteoporosis-related bone loss. The mechanism of this anabolism remains ...unclear, and needs to be established for both cortical and cancellous envelopes individually. We hypothesized that cortical and cancellous bone display different gene expression profiles at baseline and in response to mechanical loading. To test this hypothesis, the left tibiae of 10-week-old female C57Bl/6 mice were subjected to one session of axial tibial compression (9 N, 1200 cycles, 4 Hz triangle waveform) and euthanized 3 and 24 h following loading. The right limb served as the contralateral control. We performed RNA-seq on marrow-free metaphyseal samples from the cortical shell and the cancellous core to determine differential gene expression at baseline (control limb) and in response to load. Differential expression was verified with qPCR. Cortical and cancellous bone exhibited distinctly different transcriptional profiles basally and in response to mechanical loading. More genes were differentially expressed with loading at 24 h with more genes downregulated at 24 h than at 3 h in both tissues. Enhanced Wnt signaling dominated the response in cortical bone at 3 and 24 h, but in cancellous bone only at 3 h. In cancellous bone at 24 h many muscle-related genes were downregulated. These findings reveal key differences between cortical and cancellous genetic regulation in response to mechanical loading. Future studies at different time points and multiple loading sessions will add to our knowledge of cortical and cancellous mechanotransduction with the potential to identify new targets for mouse genetic knockout studies and drugs to treat osteoporosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Objectives This paper summarises the findings of a national audit of mastectomy and breast reconstruction surgery carried out in England. It describes patterns of treatment, and the clinical ...and patient-reported quality of life outcomes associated with these types of procedure. Design Prospective cohort study. Setting All 150 National Health Service hospital groups (NHS trusts) in England that provided mastectomy or breast reconstruction surgery, along with six NHS trusts in Wales and Scotland and 114 independent hospitals. Participants Women aged 16 years and over undergoing mastectomy with or without immediate breast reconstruction, or primary delayed breast reconstruction, between 1st January 2008 and 31st March 2009. Main outcome measures Reconstructive utilisation, post-operative complications and sequelae, and patient-reported satisfaction and quality of life. Results Overall, 21% of the 16,485 women who had mastectomy underwent immediate reconstruction. However, the proportion varied between regions from 9% to 43% ( p < 0.001). Levels of patient satisfaction with information, choice and the quality of care were high. The proportion of women who experienced local complications was 10.30% (95% CI 9.78–10.84) for mastectomy surgery, ranged from 11.02% (9.31–12.92) to 18.24% (14.80–22.10) for different immediate reconstructive procedures, and from 5.00% (2.76–8.25) to 19.86% (16.21–23.94) for types of delayed reconstruction. Breast appearance and overall well-being scores reported 18 months after surgery were higher among women having immediate breast reconstruction compared to mastectomy only. Postoperative outcomes were similar across providers.. Conclusions The Audit found women were highly satisfied with their peri-operative care, with hospital providers achieving similar outcomes. English providers should examine how to reduce the variation in rates of immediate reconstruction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Non‐technical summary The force developed by a single fibre in frog muscles is transmitted laterally to the muscle surface with little or no loss. To demonstrate this phenomenon in mammals, a ‘yoke’ ...apparatus was developed that attached to the surface of whole, parallel‐fibred muscles and permitted measurements of the lateral transmission of forces. We then demonstrated that for wild‐type mice and rats longitudinal and lateral transmission of forces in muscles were not different. In contrast, for skeletal muscles of dystrophic mice and very old rats, in which the dystrophin‐associated glycoprotein complex (DGC) of fibres was disrupted, the forces transmitted laterally were impaired severely. We conclude that during contractions of skeletal muscles, an intact DGC is essential for the lateral transmission of force and disruptions of the DGC lead to sarcomere instability and contraction‐induced injury.
The dystrophin–glycoprotein complex (DGC) provides an essential link from the muscle fibre cytoskeleton to the extracellular matrix. In dystrophic humans and mdx mice, mutations in the dystrophin gene disrupt the structure of the DGC causing severe damage to muscle fibres. In frog muscles, transmission of force laterally from an activated fibre to the muscle surface occurs without attenuation, but lateral transmission of force has not been demonstrated in mammalian muscles. A unique ‘yoke’ apparatus was developed that attached to the epimysium of muscles midway between the tendons and enabled the measurement of lateral force. We now report that in muscles of young wild‐type (WT) mice and rats, compared over a wide range of longitudinal forces, forces transmitted laterally showed little or no decrement. In contrast, for muscles of mdx mice and very old rats, forces transmitted laterally were impaired severely. Muscles of both mdx mice and very old rats showed major reductions in the expression of dystrophin. We conclude that during contractions, forces developed by skeletal muscles of young WT mice and rats are transmitted laterally from fibre to fibre through the DGC without decrement. In contrast, in muscles of dystrophic or very old animals, disruptions in DGC structure and function impair lateral transmission of force causing instability and increased susceptibility of fibres to contraction‐induced injury.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction
Mastectomy patients’ satisfaction with reconstructive options has not been examined.
Methods
A national study measured 18‐month satisfaction with reconstructive options and collected ...case‐mix and reconstructive offer and uptake data on breast cancer patients having mastectomy with or without immediate reconstruction (IR) in England between January 2008 and March 2009. Multivariable logistic regression examined the relationship between satisfaction, age, IR offer and uptake, and clinical suitability.
Results
Of 4796 patients, 1889 were not offered IR, 1489 declined an offer and 1418 underwent it. Women not offered IR were more likely older, obese or smokers and had higher ASA grades, ECOG scores, tumour burdens and adjuvant chemotherapy and radiotherapy likelihoods (9% of lowest suitability group offered IR; 81% in highest suitability group). 83.7% were satisfied with their reconstructive options, varying significantly by IR offer and uptake (76.1% for those not offered IR; 85.8% for those who declined IR; 91.7% following IR). Older women and women deemed more suitable for IR were more often satisfied (p‐values <0.001).
Conclusions
Satisfaction varied by offer and uptake status, age and suitability score. Clinicians should target equity for women deemed unsuitable by exploring their needs and desired outcomes, standardising operative fitness assessments and utilising shared decision‐making aids.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objectives
To identify areas of agreement and disagreement in the implementation of multi‐parametric magnetic resonance imaging (mpMRI) of the prostate in the diagnostic pathway.
Materials and ...Methods
Fifteen UK experts in prostate mpMRI and/or prostate cancer management across the UK (involving nine NHS centres to provide for geographical spread) participated in a consensus meeting following the Research and Development Corporation and University of California‐Los Angeles (UCLA‐RAND) Appropriateness Method, and were moderated by an independent chair. The experts considered 354 items pertaining to who can request an mpMRI, prostate mpMRI protocol, reporting guidelines, training, quality assurance (QA) and patient management based on mpMRI levels of suspicion for cancer. Each item was rated for agreement on a 9‐point scale. A panel median score of ≥7 constituted ‘agreement’ for an item; for an item to reach ‘consensus’, a panel majority scoring was required.
Results
Consensus was reached on 59% of items (208/354); these were used to provide recommendations for the implementation of prostate mpMRI in the UK. Key findings include prostate mpMRI requests should be made in consultation with the urological team; mpMRI scanners should undergo QA checks to guarantee consistently high diagnostic quality scans; scans should only be reported by trained and experienced radiologists to ensure that men with unsuspicious prostate mpMRI might consider avoiding an immediate biopsy.
Conclusions
Our consensus statements demonstrate a set of criteria that are required for the practical dissemination of consistently high‐quality prostate mpMRI as a diagnostic test before biopsy in men at risk.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Estrogen receptor-alpha (ERα) regulates bone mass and is implicated in bone tissue's response to mechanical loading. The effects of ERα deletion in mice depend on sex, anatomical location, and the ...cellular stage at which ERα is removed. Few studies have investigated the effect of age on the role of ERα in skeletal maintenance and functional adaptation. We previously demonstrated that bone mass and adaptation to loading were altered in growing 10-week-old female and male mice lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO). Here our goal was to determine the effects of ERα and mechanical loading in skeletally-mature adult mice. We subjected 26-week-old skeletally-mature adult pOC-ERαKO and littermate control (LC) mice of both sexes to two weeks of in vivo cyclic tibial loading. ERα deletion in male mice did not alter bone mass or the response to loading. Adult female pOC-ERαKO mice had reduced cancellous and cortical bone mass and increased adaptation to high-magnitude mechanical loading compared to LC mice. Thus, ERα deletion from mature osteoblasts reduced the bone mass and increased the mechanoadaptation of adult female but not male mice. Additionally, compared to our previous work in young mice, adult female mice had greatly reduced mechanoadaptation and adult male mice retained most of their mechanoadaptation with age.
•Lower bone mass in adult female pOC-ERαKO mice than littermate controls•High magnitude loading more anabolic in adult female pOC-ERαKO than LC mice•Loading response reduced in adult female mice versus young, even at high magnitude•No effect of ERα deletion on phenotype or response to loading in adult male mice•Adult male mice retained loading response with age better than females
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Flexor tendinitis is a common and debilitating injury of elite and recreational athletes. Healing may be improved through intratendinous injection of insulin-like growth factor-I (IGF-I), which has ...been shown in vitro to stimulate mitogenesis and enhance tendon matrix production. This study investigated the effects of intratendinous injection of IGF-I on tendon healing in an equine model of flexor tendinitis. Collagenase-induced lesions were created in the tensile region of the
flexor digitorum superficialis tendon of both forelimbs of eight horses. Treated tendons were injected with 2 μg rhIGF-I intralesionally every other day for 10 injections, while controls received 0.9% NaCl. Tendon fiber deposition and organization were evaluated serially using ultrasonography throughout the 8 week trial period. Following euthanasia, the tendons were harvested and DNA, hydroxyproline, and glycosaminoglycan content determined, mechanical strength and stiffness evaluated, gene expression and spatial arrangement of collagen types I and III assessed by northern blot and in situ hybridization, and tendon fiber architecture assessed by polarized light microscopy. Local soft tissue swelling was reduced in the IGF-I treated limbs. Similarly, lesion size in IGF-I treated tendons was smaller 3 and 4 weeks after initiation of treatment. Cell proliferation and collagen content of the IGF-I treated tendons were increased compared to controls. Mechanically, IGF-I treated tendons showed a trend toward increased stiffness compared to saline treated controls. Considered together with the decreased soft tissue swelling and improved sonographic healing, these data support the potential use of intralesional IGF-I for treatment of debilitating tendon injuries.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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