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Research in women's health has revealed the difficulties female patients experience in their attempts to receive accurate medical diagnoses. Depression may be misdiagnosed in 30-50% of female patients. This difficulty is considerably enhanced when women have physical diseases characterized by symptoms that resemble a major depressive disorder. In addition, medical treatments may induce symptoms that are misdiagnosed as affective distress. Multiple causes contribute to an enhanced likelihood of misdiagnoses in women, including physicians' androcentrically orientated medical training and the two-to-one female-to-male ratio of depression treatment. The adverse consequences of incorrect diagnoses range from unnecessary expenditures of a woman's resources to potentially life-threatening medical conditions. Ironically, medical misdiagnoses of physical conditions may induce depressive reactions in female patients. A woman's age, sexual orientation, menstrual, occupational, and/or parental status represent potential areas of discrimination in diagnostic determinations. Suggestions are offered for improving the accuracy of health care providers' diagnoses in women. [ABSTRACT FROM AUTHOR]

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A . Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification., Methods: An in vitro SCN5A -Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function., Results: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak I Na density ( R 2 =0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic., Conclusions: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A -Brugada syndrome variants of uncertain significance., Competing Interests: Dr Glazer is a consultant for BioMarin Inc Victoria Parikh is a scientific advisory board member (Lexeo Therapeutics), clinical advisor (Constantiam Biosciences), and consultant (BioMarin Inc, viz.ai). Dr Parikh also receives research support from BioMarin, Inc. The other authors report no conflicts.

Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPL L isoform localizes to mitochondria, whereas PREPL S remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPL L is involved in mitochondrial homeostasis., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Defining functions for the full complement of proteins is a grand challenge in the post-genomic era and is essential for our understanding of basic biology and disease pathogenesis. In recent times, this endeavor has benefitted from a combination of modern large-scale and classical reductionist approaches-a process we refer to as "systems biochemistry"-that helps surmount traditional barriers to the characterization of poorly understood proteins. This strategy is proving to be particularly effective for mitochondria, whose well-defined proteome has enabled comprehensive analyses of the full mitochondrial system that can position understudied proteins for fruitful mechanistic investigations. Recent systems biochemistry approaches have accelerated the identification of new disease-related mitochondrial proteins and of long-sought "missing" proteins that fulfill key functions. Collectively, these studies are moving us toward a more complete understanding of mitochondrial activities and providing a molecular framework for the investigation of mitochondrial pathogenesis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The role of inflammation in tendinopathy has historically been a subject of significant controversy. Our primary aim was to determine whether inflammatory cell numbers were increased in painful human tendinopathy versus healthy control tendons. Our secondary aim was to assess whether the inflammatory cells had been linked with symptoms or disease stage., Methods: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. Only studies measuring inflammatory cells using specific markers in tissue from human patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by 2 independent researchers on review of abstracts or full-text using specific predetermined criteria. The search yielded 5 articles in total., Results: There were increased numbers of macrophages (4 studies) and mast cells (3 studies) in tendinopathic versus healthy control tissues. One study demonstrated increased numbers of T cells in tendinopathic tissue versus healthy control tendons. There were reduced numbers of T cells (1 study), macrophages (2 studies) and mast cells (2 studies) in torn tendon versus intact tendinopathic tissue., Conclusions: The existing evidence supports the hypothesis that increased numbers of inflammatory cells are present in pathological tendons. The lack of high-quality quantitative studies in this area demonstrates a clear need for future research to better understand the role of inflammation in tendinopathy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Ras converting enzyme 1 (Rce1) is an endoprotease that catalyzes processing of the C-terminus of Ras protein by removing -aaX from the CaaX motif. The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions. Ras is responsible for transmitting signals related to cell proliferation, cell cycle progression, and apoptosis. The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer. Ras, its effectors and regulators, and the enzymes that are involved in its maturation process are all targets for anti-cancer therapeutics. Key enzymes required for Ras maturation and localization are the farnesyltransferase (FTase), Rce1, and isoprenylcysteine carboxyl methyltransferase (ICMT). Among these proteins, the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been fully explored. Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics. Structure-activity relationship (SAR) analysis of a previously reported Rce1 inhibitor, NSC1011, has been performed to generate a new library of Rce1 inhibitors. The new inhibitors caused a reduction in Rce1 in vitro activity, exhibited low cell toxicity, and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression. Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor (FTI), which is significant because of the preponderance of K-Ras mutations in cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Glucocorticoids are generally used to relieve pain and/or inflammation in a wide variety of musculoskeletal disorders including osteoarthritis, inflammatory arthritis, tendinopathy and degenerative spine disease. Glucocorticoids reduce tendon derived cell proliferation in vitro and reduce extracellular matrix synthesis both in vitro and in vivo, in particular type I collagen synthesis. Glucocorticoids also appear to result in acute deleterious changes in healthy in vivo tendon including collagen necrosis, collagen disorganisation and inflammatory cell infiltration; while the overall effect of glucocorticoid administration on the mechanical properties of healthy in vivo tendon are generally negative. Overall the existing in vitro and in vivo evidence suggests that glucocorticoids should be used with caution in treating painful tendinopathy. Certainly a real need exists to follow up the long term clinical effects of glucocorticoid in treating tendinopathy, as there is currently a paucity of evidence in this area. However in this context while the short term benefits are clear, glucocorticoids remain a useful treatment option provided they are used in the right patients in sensible moderation.

It is known that extracellular glutamate concentrations are increased in tendinopathy but the effects of glutamate upon human tendon derived cells are unknown. The primary purpose was to investigate the effect of glutamate exposure on human tendon-derived cells in terms of viability, protein, and gene expression. The second purpose was to assess whether NMDAR antagonism would affect the response of tendon-derived cells to glutamate exposure. Human tendon-derived cells were obtained from supraspinatus tendon tissue obtained during rotator cuff repair (tendon tear derived cells) and from healthy hamstring tendon tissue (control cells). The in vitro impact of glutamate exposure and NMDAR antagonism (MK-801) was measured using the Alamar blue cell viability assay, immunocytochemistry, and quantitative real-time PCR. Glutamate reduced cell viability at 24 h in tendon tear derived cells but not in control cells at concentrations of 7.5 mM and above. Cell viability was significantly reduced after 72 h of 1.875 mM glutamate in both cell groups; this deleterious effect was attenuated by NMDAR antagonism with 10 µM MK-801. Both 24 and 72 h of 1.875 mM glutamate exposure reduced Type 1 alpha 1 collagen (COL1A1) and Type 3 alpha 1 collagen (COL3A1) gene expression, but increased Aggrecan gene expression. We propose that these effects of glutamate on tendon derived cells including reduced cell viability and altered matrix gene expression contribute to the pathogenesis of tendinopathy., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Introduction: The relationship between peripheral tissue characteristics and pain symptoms in soft tissue inflammation is poorly understood. The primary aim of this study was to determine immunohistochemical differences in tissue obtained from patients with persistent pain and patients who had become pain-free after surgical treatment for rotator cuff tendinopathy. The secondary aim was to investigate whether there would be differences in glutaminergic and inflammatory gene expression between disease-derived and healthy control cells in vitro., Methods: Supraspinatus tendon biopsies were obtained from nine patients with tendon pain before shoulder surgery and from nine further patients whose pain had resolved completely following shoulder surgery. Histological markers relating to the basic tendon characteristics, inflammation and glutaminergic signalling were quantified by immunohistochemical analysis. Gene expression of glutaminergic and inflammatory markers was determined in tenocyte explants derived from painful rotator cuff tendon tears in a separate cohort of patients and compared to that of explants from healthy control tendons. Dual labelling was performed to identify cell types expressing nociceptive neuromodulators., Results: Tendon samples from patients with persistent pain demonstrated increased levels of metabotropic glutamate receptor 2 (mGluR2), kainate receptor 1 (KA1), protein gene product 9.5 (PGP9.5), CD206 (macrophage marker) and CD45 (pan-leucocyte marker) versus pain-free controls (p <0.05). NMDAR1 co-localised with CD206-positive cells, whereas PGP9.5 and glutamate were predominantly expressed by resident tendon cells. These results were validated by in vitro increases in the expression of mGluR2, N-methyl-D-aspartate receptor (NMDAR1), KA1, CD45, CD206 and tumour necrosis factor alpha (TNF-α) genes (p <0.05) in disease-derived versus control cells., Conclusions: We conclude that differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of shoulder pain in rotator cuff tendinopathy, and that disease-derived cells exhibit a distinctly different neuro-inflammatory gene expression profile to healthy control cells.

The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration of UbiB kinase activity has remained elusive for unknown reasons. Here, we quantitatively define UbiB-specific sequence motifs and reveal their positions within the crystal structure of a UbiB protein, ADCK3. We find that multiple UbiB-specific features are poised to inhibit protein kinase activity, including an N-terminal domain that occupies the typical substrate binding pocket and a unique A-rich loop that limits ATP binding by establishing an unusual selectivity for ADP. A single alanine-to-glycine mutation of this loop flips this coenzyme selectivity and enables autophosphorylation but inhibits coenzyme Q biosynthesis in vivo, demonstrating functional relevance for this unique feature. Our work provides mechanistic insight into UbiB enzyme activity and establishes a molecular foundation for further investigation of how UbiB family proteins affect diseases and diverse biological pathways., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Glucocorticoid injection (GCI) and surgical rotator cuff repair are two widely used treatments for rotator cuff tendinopathy. Little is known about the way in which medical and surgical treatments affect the human rotator cuff tendon in vivo. We assessed the histological and immunohistochemical effects of these common treatments on the rotator cuff tendon., Study Design: Controlled laboratory study., Methods: Supraspinatus tendon biopsies were taken before and after treatment from 12 patients undergoing GCI and 8 patients undergoing surgical rotator cuff repair. All patients were symptomatic and none of the patients undergoing local GCI had full thickness tears of the rotator cuff. The tendon tissue was then analysed using histological techniques and immunohistochemistry., Results: There was a significant increase in nuclei count and vascularity after rotator cuff repair and not after GCI (both p=0.008). Hypoxia inducible factor 1α (HIF-1α) and cell proliferation were only increased after rotator cuff repair (both p=0.03) and not GCI. The ionotropic N-methyl-d-aspartate receptor 1 (NMDAR1) glutamate receptor was only increased after GCI and not rotator cuff repair (p=0.016). An increase in glutamate was seen in both groups following treatment (both p=0.04), while an increase in the receptor metabotropic glutamate receptor 7 (mGluR7) was only seen after rotator cuff repair (p=0.016)., Conclusions: The increases in cell proliferation, vascularity and HIF-1α after surgical rotator cuff repair appear consistent with a proliferative healing response, and these features are not seen after GCI. The increase in the glutamate receptor NMDAR1 after GCI raises concerns about the potential excitotoxic tendon damage that may result from this common treatment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. Sorcs1 belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from the trans-Golgi network (TGN) to the vacuole. Whole-body Sorcs1 KO mice, when made obese with the leptin(ob) mutation (ob/ob), developed diabetes. β Cells from these mice had a severe deficiency of secretory granules (SGs) and insulin. Interestingly, a single secretagogue challenge failed to consistently elicit an insulin secretory dysfunction. However, multiple challenges of the Sorcs1 KO ob/ob islets consistently revealed an insulin secretion defect. The luminal domain of SORCS1 (Lum-Sorcs1), when expressed in a β cell line, acted as a dominant-negative, leading to SG and insulin deficiency. Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Chronic exposure of islets from lean Sorcs1 KO mice to high glucose and palmitate depleted insulin content and evoked an insulin secretion defect. Thus, in metabolically stressed mice, Sorcs1 is important for SG replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Overexpression of full-length SORCS1 led to a 2-fold increase in SG content, suggesting that SORCS1 is sufficient to promote SG biogenesis.

Objective: Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells., Methods: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study., Results: Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies. The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of -0.67 (95% CI = 0.01 to -1.33) (data from 9 studies)., Conclusions: Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections., (© 2013 Elsevier Inc. All rights reserved.)

If a patient asks 'why does my shoulder hurt?' the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or 'nociception', (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.

Lysine acetylation is rapidly becoming established as a key post-translational modification for regulating mitochondrial metabolism. Nonetheless, distinguishing regulatory sites from among the thousands identified by mass spectrometry and elucidating how these modifications alter enzyme function remain primary challenges. Here, we performed multiplexed quantitative mass spectrometry to measure changes in the mouse liver mitochondrial acetylproteome in response to acute and chronic alterations in nutritional status, and integrated these data sets with our compendium of predicted Sirt3 targets. These analyses highlight a subset of mitochondrial proteins with dynamic acetylation sites, including acetyl-CoA acetyltransferase 1 (Acat1), an enzyme central to multiple metabolic pathways. We performed in vitro biochemistry and molecular modeling to demonstrate that acetylation of Acat1 decreases its activity by disrupting the binding of coenzyme A. Collectively, our data reveal an important new target of regulatory acetylation and provide a foundation for investigating the role of select mitochondrial protein acetylation sites in mediating acute and chronic metabolic transitions.

Background: The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients., Questions/purposes: The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms., Methods: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text., Results: Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain., Conclusions: The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process.

Background: The Jones fracture has been a topic of controversy ever since being first described by Sir Robert Jones himself in 1902. The aim of this review is to summarize the classification, management, outcome, and complications of this particular injury., Methods: The authors conducted a systematic review of the scientific literature regarding the Jones fracture., Results: There was no consistent approach to the Jones fracture classification. The rate of nonunion with nonoperative treatment is high in both acute and chronic cases. Surgical intervention reduces the incidence of nonunion, but the complication rate of surgery is high., Conclusions: Surgical intervention for the acute Jones fracture should be reserved for the athletic individual because there is a clear advantage in terms of time to return to sporting activity. Nonoperative treatment remains a viable alternative to surgery in all acute and delayed cases, providing there is no established nonunion and the patient is aware of the implications.

Purpose: Although originally designed for reconstruction after primary malignant bone tumour resection, modular endoprosthetic replacement (EPR) can be used in salvage surgery for complex periprosthetic fracture and failed internal fixation. The purpose of this study was to assess the functional outcome following EPR for failed internal fixation of the proximal femur., Methods: We assessed clinical and functional outcomes of using a modular tumour endoprosthesis to reconstruct the proximal femur following failed internal fixation in eight consecutive patients between 2001 and 2008., Results: There were four men and four women, with a mean age of 67.5 (range 50-79) years and a mean follow-up of 16.5 (6-36) months. All patients had failed internal fixation for traumatic proximal femoral fractures--four 31.A2.3, two 31.A3.1, two 31.A3.3 using the Arbeitsgemeinshaft für Osteosynthesefragen (AO) fracture classification. Mean time from the first attempted internal fixation to definitive EPR was 34 (6-102) months, and the median number of previous surgical procedures was two (1-11). Histology revealed infection (two cases), uninfected nonunion (five cases) and plasmocytoma (one case). The EPR was carried out as a one-stage procedure in six cases and a two-stage procedure in two cases. Mean postoperative Harris Hip Score was 71.4 (range 64-85). There were no surgical complications. One patient died as a result of systemic complications of myeloma several years following EPR., Conclusions: EPR is an effective salvage procedure for failed fixation of traumatic proximal femoral fractures. Immediate weightbearing and a good functional outcome can be expected in this difficult group of patients.