Survival bias may explain the appearance of the obesity paradox in hip fracture patients.

Patients with low-energy hip fractures do not follow the obesity paradox as previously reported. In datasets where injury mechanism is not available, the use of age >50 years (as opposed to commonly used >65 years) as a surrogate for a low-energy hip fracture patients may be a more robust inclusion criterion. PURPOSE: In elderly patients with a hip fracture, limited data suggests that obese patients counterintuitively have improved survival compared to normal-weight patients. This "obesity paradox" may be the byproduct of selection bias. We hypothesized that the obesity paradox would not apply to elderly hip fracture patients. METHODS: The National Surgical Quality Improvement Project dataset identified 71,685 hip fracture patients ≥50 years-of-age with complete body mass index (BMI) data that underwent surgery. Patients were stratified into under and over 75-year-old cohorts (n=18,956 and 52,729, respectively). Within each age group, patients were stratified by BMI class and compared with respect to preoperative characteristics and 30-day mortality. Significant univariate characteristics (p<0.1) were included in multivariate analysis to determine the independent effect of obesity class on 30-day mortality (p<0.05). RESULTS: Multivariate analysis of <75-year-old patients with class-III obesity were more likely to die within 30-days than similarly aged normal-weight patients (OR 1.91, CI 1.06-3.42, p=0.030). Multivariate analysis of ≥75-year-old overweight (OR 0.69, CI 0.62-0.77, p<0.001), class-I obese (OR 0.62, CI 0.51-0.74, p<0.001), or class-II obese (OR=0.69, CI 0.50-0.95, p=0.022) patients were less likely to die within 30-days when compared to similarly aged normal-weight patients. CONCLUSIONS: Our data suggest that obesity is a risk factor for mortality in low-energy hip fracture patients, but the appearance of the "obesity paradox" in elderly hip fracture patients results from statistical bias that is only evident upon subgroup analysis.

Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty: a systematic review and meta-analysis.

Aims: The aim of this study was to assess the efficacy of non-selective and selective non-steroidal anti-inflammatory drugs (NSAIDs) in preventing heterotopic ossification (HO) after total hip arthroplasty (THA). Methods: A thorough and systematic literature search was conducted and 29 studies were found that met inclusion criteria. Data were extracted and statistical analysis was carried out generating forest plots. Results: Non-selective NSAIDs showed a significant decrease in the odds for forming HO after THA (odds ratio (OR) -1.35, confidence interval (CI) -1.83 to -0.86) when compared with placebo. Selective NSAIDs also showed a significant decrease in the odds for forming HO after THA when compared with placebo (OR -1.58, CI -2.41 to -0.75). When comparing non-selective NSAIDs with selective NSAIDs, there was no significant change in the odds for forming HO after THA (OR 0.22, CI -0.36 to 0.79). Conclusion: Our meta-analyses of all available data suggest that both non-selective and selective NSAIDs are effective HO prophylaxis and can be used routinely after THA for pain control as well as prevention of HO. Indomethacin may serve as the benchmark among non-selective NSAIDs and celecoxib among selective NSAIDs. There was no difference in the incidence of HO between non-selective and selective NSAIDs, allowing physicians to choose either based on the clinical scenario and patient-specific factors. Cite this article: Bone Joint J 2018;100-B:915-22.

Metal-on-metal total hip arthroplasty is not associated with cardiac disease.

AIMS: Many case reports and small studies have suggested that cobalt ions are a potential cause of cardiac complications, specifically cardiomyopathy, after metal-on-metal (MoM) total hip arthroplasty (THA). The impact of metal ions on the incidence of cardiac disease after MoM THA has not been evaluated in large studies. The aim of this study was to compare the rate of onset of new cardiac symptoms in patients who have undergone MoM THA with those who have undergone metal-on-polyethylene (MoP) THA. PATIENTS AND METHODS: Data were extracted from the Standard Analytics Files database for patients who underwent MoM THA between 2005 and 2012. Bearing surface was selected using International Classification of Diseases ninth revision codes. Patients with a minimum five-year follow-up were selected. An age and gender-matched cohort of patients who underwent MoP THA served as a comparison group. New diagnoses of cardiac disease were collected during the follow-up period. Comorbidities and demographics were identified and routine descriptive statistics were used. RESULTS: We identified 29 483 patients who underwent MoM THA and 24 175 matched patients who underwent MoP THA. Both groups had a mean Charlson comorbidity index score of 4. There were no statistically significant differences in 30 of 31 pre-existing comorbidities. Patients undergoing MoM THA had a slightly lower incidence of cardiac failure compared with those undergoing MoP THA at three years (6.60% versus 7.06%, odds ratio (OR) 0.93, 95% confidence interval (CI) 0.87 to 0.99) and four years (8.73% versus 9.49%, OR 0.91, 95% CI 0.86 to 0.97) postoperatively, with no difference in the incidence of new cardiac failure in between the groups at five years. There was no statistically significant difference in the incidence of arrhythmia, myocardial infarction and cardiomyopathy at any time between the two groups. CONCLUSION: MoM THA is not associated with cardiac complications. Initial reports may have represented individual instances of cardiac disease in patients with a failing MoM articulation rather than an emerging epidemiological trend. Cite this article: Bone Joint J 2018;100-B:28-32.

Radiographic scoring system for the evaluation of stability of cementless acetabular components in the presence of osteolysis.

AIMS: The stability of cementless acetabular components is an important factor for surgical planning in the treatment of patients with pelvic osteolysis after total hip arthroplasty (THA). However, the methods for determining the stability of the acetabular component from pre-operative radiographs remain controversial. Our aim was to develop a scoring system to help in the assessment of the stability of the acetabular component under these circumstances. PATIENTS AND METHODS: The new scoring system is based on the mechanism of failure of these components and the location of the osteolytic lesion, according to the DeLee and Charnley classification. Each zone is evaluated and scored separately. The sum of the individual scores from the three zones is reported as a total score with a maximum of 10 points. The study involved 96 revision procedures which were undertaken for wear or osteolysis in 91 patients between July 2002 and December 2012. Pre-operative anteroposterior pelvic radiographs and Judet views were reviewed. The stability of the acetabular component was confirmed intra-operatively. RESULTS: Intra-operatively, it was found that 64 components were well-fixed and 32 were loose. Mean total scores in the well-fixed and loose components were 2.9 (0 to 7) and 7.2 (1 to 10), respectively (p < 0.001). In hips with a low score (0 to 2), the component was only loose in one of 33 hips (3%). The incidence of loosening increased with increasing scores: in those with scores of 3 and 4, two of 19 components (10.5%) were loose; in hips with scores of 5 and 6, eight of 19 components (44.5%) were loose; in hips with scores of 7 or 8, 13 of 17 components (70.6%) were loose; and for hips with scores of 9 and 10, nine of nine components (100%) were loose. Receiver-operating-characteristic curve analysis demonstrated very good accuracy (area under the curve = 0.90, p < 0.001). The optimal cutoff point was a score of ≥ 5 with a sensitivity of 0.79, and a specificity of 0.87. CONCLUSION: There was a strong correlation between the scoring system and the probability of loosening of a cementless acetabular component. This scoring system provides a clinically useful tool for pre-operative planning, and the evaluation of the outcome of revision surgery for patients with loosening of a cementless acetabular component in the presence of osteolysis. Cite this article: Bone Joint J 2017;99-B:601-6.

Greater inadvertent muscle damage in direct anterior approach when compared with the direct superior approach for total hip arthroplasty.

AIMS: We wished to quantify the extent of soft-tissue damage sustained during minimally invasive total hip arthroplasty through the direct anterior (DA) and direct superior (DS) approaches. MATERIALS AND METHODS: In eight cadavers, the DA approach was performed on one side, and the DS approach on the other, a single brand of uncemented hip prosthesis was implanted by two surgeons, considered expert in their surgical approaches. Subsequent reflection of the gluteus maximus allowed the extent of muscle and tendon damage to be measured and the percentage damage to each anatomical structure to be calculated. RESULTS: The DA approach caused substantially greater damage to the gluteus minimus muscle and tendon when compared with the DS approach (t-test, p = 0.049 and 0.003, respectively). The tensor fascia lata and rectus femoris muscles were damaged only in the DA approach. There was no difference in the amount of damage to the gluteus medius muscle and tendon, piriformis tendon, obturator internus tendon, obturator externus tendon or quadratus femoris muscle between approaches. The posterior soft-tissue releases of the DA approach damaged the gluteus minimus muscle and tendon, piriformis tendon and obturator internus tendon. CONCLUSION: The DS approach caused less soft-tissue damage than the DA approach. However the clinical relevance is unknown. Further clinical outcome studies, radiographic evaluation of component position, gait analyses and serum biomarker levels are necessary to evaluate and corroborate the safety and efficacy of the DS approach. Cite this article: Bone Joint J 2016;98-B1036-42.

Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. DESIGN: Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. RESULTS: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. CONCLUSION: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

Revision total hip arthroplasty after removal of a fractured well-fixed extensively porous-coated femoral component using a trephine.

When fracture of an extensively porous-coated femoral component occurs, its removal at revision total hip arthroplasty (THA) may require a femoral osteotomy and the use of a trephine. The remaining cortical bone after using the trephine may develop thermally induced necrosis. A retrospective review identified 11 fractured, well-fixed, uncemented, extensively porous-coated femoral components requiring removal using a trephine with a minimum of two years of follow-up. The mean time to failure was 4.6 years (1.7 to 9.1, standard deviation (sd) 2.3). These were revised using a larger extensively porous coated component, fluted tapered modular component, a proximally coated modular component, or a proximal femoral replacement. The mean clinical follow-up after revision THA was 4.9 years (2 to 22, sd 3.1). The mean diameter of the femoral component increased from 12.7 mm (sd 1.9) to 16.2 mm (sd 3.4; p > 0.001). Two revision components had radiographic evidence of subsidence that remained radiographically stable at final follow-up. The most common post-operative complication was instability affecting six patients (54.5%) on at least one occasion. A total of four patients (36.4%) required further revision: three for instability and one for fracture of the revision component. There was no statistically significant difference in the mean Harris hip score before implant fracture (82.4; sd 18.3) and after trephine removal and revision THA (81.2; sd 14.8, p = 0.918). These findings suggest that removal of a fractured, well-fixed, uncemented, extensively porous-coated femoral component using a trephine does not compromise subsequent fixation at revision THA and the patient's pre-operative level of function can be restored. However, the loss of proximal bone stock before revision may be associated with a high rate of dislocation post-operatively.

Revision total hip arthroplasty in patients with extensive proximal femoral bone loss using a fluted tapered modular femoral component.

Revision total hip arthroplasty (THA) is challenging when there is severe loss of bone in the proximal femur. The purpose of this study was to evaluate the clinical and radiographic outcomes of revision THA in patients with severe proximal femoral bone loss treated with a fluted, tapered, modular femoral component. Between January 1998 and December 2004, 92 revision THAs were performed in 92 patients using a single fluted, tapered, modular femoral stem design. Pre-operative diagnoses included aseptic loosening, infection and peri-prosthetic fracture. Bone loss was categorised pre-operatively as Paprosky types III-IV, or Vancouver B3 in patients with a peri-prosthetic fracture. The mean clinical follow-up was 6.4 years (2 to 12). A total of 47 patients had peri-operative complications, 27 of whom required further surgery. However, most of these further operations involved retention of a well-fixed femoral stem, and 88/92 femoral components (97%) remained in situ. Of the four components requiring revision, three were revised for infection and were well fixed at the time of revision; only one (1%) was revised for aseptic loosening. The most common complications were post-operative instability (17 hips, 19%) and intra-operative femoral fracture during insertion of the stem (11 hips, 12%). Diaphyseal stress shielding was noted in 20 hips (22%). There were no fractures of the femoral component. At the final follow-up 78% of patients had minimal or no pain. Revision THA in patients with extensive proximal femoral bone loss using the Link MP fluted, tapered, modular stem led to a high rate of osseointegration of the stem at mid-term follow-up. Cite this article: Bone Joint J 2015; 97-B:312-17.

Total hip replacement in patients with Down syndrome and degenerative osteoarthritis of the hip.

Dysplasia of the hip, hypotonia, osteopenia, ligamentous laxity, and mental retardation increase the complexity of performing and managing patients with Down syndrome who require total hip replacement (THR). We identified 14 patients (six males, eight females, 21 hips) with Down syndrome and degenerative disease of the hip who underwent THR, with a minimum follow-up of two years from 1969 to 2009. In seven patients, bilateral THRs were performed while the rest had unilateral THRs. The mean clinical follow-up was 5.8 years (standard deviation (sd) 4.7; 2 to 17). The mean Harris hip score was 37.9 points (sd 7.8) pre-operatively and increased to 89.2 (sd 12.3) at final follow-up (p = 1x10(-9)). No patient suffered a post-operative dislocation. In three patients, four hips had revision THR for aseptic loosening at a mean follow-up of 7.7 years (sd 6.3; 3 to 17). This rate of revision THR was higher than expected. Our patients with Down syndrome benefitted clinically from THR at mid-term follow-up.

The cell cycle in steroid hormone regulated proliferation and differentiation.

Steroid hormones mediate pleiotropic cellular processes involved in metabolism, cellular proliferation, and differentiation. The ability of the cell to respond to its hormonal environment is transduced by nuclear receptors (NRs) that bind both hormone and DNA. Hence, NRs represent a link between the external hormonal milieu and the genes that control cell physiology. Therefore, understanding the effects of steroid hormones on proliferation and differentiation requires a knowledge of the cell cycle, the interaction of NRs at the level of transcription, and the potential areas of cross-talk between these two.

Cell-cycle dysregulation in breast cancer: breast cancer therapies targeting the cell cycle.

Breast cancer is the most commonly diagnosed cancer in American women. The underlying mechanisms that cause aberrant cell proliferation and tumor growth involve conserved pathways, which include components of the cell cycle machinery. Proto-oncogenes, growth factors, and steroids have been implicated in the pathogenesis of breast cancer. Surgery, local irradiation, and chemotherapy have been the mainstay of treatment for early and advanced stage disease. Potential targets for selective breast cancer therapy are herein reviewed. Improved understanding of the biology of breast cancer has led to more specific "targeted therapies" directed at biological processes that are selectively deregulated in the cancerous cells. Examples include tamoxifen for estrogen receptor positive tumors and imunoneutralizing antibodies such as trastuzumab for Her2/neu overexpressing tumors. Other novel anticancer agents such as paclitaxel, a microtubule binding molecule, and flavopiridol, a cyclin dependent kinase inhibitor, exert their anticancer effects by inhibiting cell cycle progression.

The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways.

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20-30% of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the beta-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of beta(1) and beta(3) integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide -54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3beta (GSK-3beta) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.

Cell-cycle dysregulation and the molecular mechanisms of prostate cancer.

Prostate cancer is the most common cause of non-cutaneous cancer in men and although frequently latent is the second commonest cause of death. Screening for the disease was historically based on symptoms of urethral obstruction, clinical examination of the prostate gland and serum measurements of prostate specific antigen. As prostate cancer growth in the early stages is enhanced by androgens, the mainstay of therapy has been androgen ablation by pharmaco-therapeutic or surgical means. The subsequent development of androgen therapy resistant prostate cancer in many patients, for whom therapeutic options remain limited, has led researchers to focus attention on understanding the molecular genetics of prostate cancer. The array of genetic abnormalities observed in prostate tumors, which include changes in components of the cell cycle, suggest the disease is quite heterogeneous and may require further sub-classification based on genetic markers. Such analyses may lead to identification of relevant new prognostic and therapeutic indicators. The advent of transgenic mouse models of prostate cancer may provide a critical tool for the implementation of rational genetic based therapeutics and alternate drug design.

Adenosine receptor mediates motility in human melanoma cells.

Cell motility is an essential component of tumor progression and metastasis. A number of factors, both autocrine and paracrine, have been found to influence cell motility. In the present study, adenosine and adenine nucleotides directly stimulated chemotaxis of A2058 melanoma cells in the absence of exogenous factors. Three adenosine receptor agonists stimulated motility in the melanoma cells and two adenosine receptor antagonists strongly inhibited the chemotactic response to both adenosine and AMP. The chemotactic stimulation by adenosine and AMP was pertussis toxin sensitive. Otherwise unresponsive Chinese hamster ovary cells which were transfected with the adenosine A1 receptor cDNA acquired the direct, pertussis toxin sensitive, chemotactic response to adenosine, and this response was inhibited by adenosine receptor antagonists. These findings demonstrate that adenosine and adenine nucleotides are capable of stimulating chemotaxis of tumor cells mediated through an adenosine receptor, probably of the A1 subtype. The possibility of antimetastatic therapies based on inhibition of adenosine receptor activity is raised.