Can the use of an inclinometer improve the positioning of the acetabular component in total hip arthroplasty?

Aims: Accurate placement of the acetabular component is essential in total hip arthroplasty (THA). The purpose of this study was to determine if the ability to achieve inclination of the acetabular component within the 'safe-zone' of 30° to 50° could be improved with the use of an inclinometer. Patients and Methods: We reviewed 167 primary THAs performed by a single surgeon over a period of 14 months. Procedures were performed at two institutions: an inpatient hospital, where an inclinometer was used (inclinometer group); and an ambulatory centre, where an inclinometer was not used as it could not be adequately sterilized (control group). We excluded 47 patients with a body mass index (BMI) of > 40 kg/m2, age of > 68 years, or a surgical indication other than osteoarthritis whose treatment could not be undertaken in the ambulatory centre. There were thus 120 patients in the study, 68 in the inclinometer group and 52 in the control group. The inclination angles of the acetabular component were measured from de-identified plain radiographs by two blinded investigators who were not involved in the surgery. The effect of the use of the inclinometer on the inclination angle was determined using multivariate regression analysis. Results: The mean inclination angle for the THAs in the inclinometer group was 42.9° (95% confidence interval (CI) 41.7° to 44.0°; range 29.0° to 63.8°) and 46.5° (95% CI 45.2° to 47.7°; range 32.8° to 63.2°) in the control group (p < 0.001). Regression analysis identified a 9.1% difference in inclination due to the use of an inclinometer (p < 0.001), and THAs performed without the inclinometer were three times more likely to result in inclination angles of > 50° (odds ratio (OR) 2.8, p = 0.036). The correlation coefficient for the interobserver reliability of the measurement of the two investigators was 0.95 (95% CI 0.93 to 0.97). Conclusion: The use of a simple inclinometer resulted in a significant reduction in the number of outliers compared with a freehand technique. Cite this article: Bone Joint J 2018;100-B:862-6.

Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft-tissue sarcomas.

Background: Prediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management. Methods: A code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n = 124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n = 67) and matching frozen and FFPE samples (n = 45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated. Results: CINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI: 1.23-6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared with FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI: 1.25-15.72). Conclusion: CINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind®) in routine clinical practice on FFPE blocks to predict metastatic outcome.

Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature.

AIMS: Instability remains a challenging problem in both primary and revision total hip arthroplasty (THA). Dual mobility components confer increased stability, but there are concerns about the unique complications associated with these designs, as well as the long-term survivorship. MATERIALS AND METHODS: We performed a systematic review of all English language articles dealing with dual mobility THAs published between 2007 and 2016 in the MEDLINE and Embase electronic databases. A total of 54 articles met inclusion criteria for the final analysis of primary and revision dual mobility THAs and dual mobility THAs used in the treatment of fractures of the femoral neck. We analysed the survivorship and rates of aseptic loosening and of intraprosthetic and extra-articular dislocation. RESULTS: For the 10 783 primary dual mobility THAs, the incidence of aseptic loosening was 1.3% (142 hips); the rate of intraprosthetic dislocation was 1.1% (122 hips) and the incidence of extra-articular dislocation was 0.46% (41 hips). The overall survivorship of the acetabular component and the dual mobility components was 98.0%, with all-cause revision as the endpoint at a mean follow-up of 8.5 years (2 to 16.5). For the 3008 revision dual mobility THAs, the rate of aseptic acetabular loosening was 1.4% (29 hips); the rate of intraprosthetic dislocation was 0.3% (eight hips) and the rate of extra-articular dislocation was 2.2% (67 hips). The survivorship of the acatabular and dual mobility components was 96.6% at a mean of 5.4 years (2 to 8). For the 554 dual mobility THAs which were undertaken in patients with a fracture of the femoral neck, the rate of intraprosthetic dislocation was 0.18% (one hip), the rate of extra-articular dislocation was 2.3% (13 hips) and there was one aseptic loosening. The survivorship was 97.8% at a mean of 1.3 years (0.75 to 2). CONCLUSION: Dual mobility articulations are a viable alternative to traditional bearing surfaces, with low rates of instability and good overall survivorship in primary and revision THAs, and in those undertaken in patients with a fracture of the femoral neck. The incidence of intraprosthetic dislocation is low and limited mainly to earlier designs. High-quality, prospective, comparative studies are needed to evaluate further the use of dual mobility components in THA. Cite this article: Bone Joint J 2018;100-B:11-19.

Effects of preoperative dexamethasone on postoperative pain, nausea, vomiting and respiratory function in women undergoing conservative breast surgery for cancer: Results of a controlled clinical trial.

The objective was to evaluate whether preoperative administration of dexamethasone improved postoperative nausea and vomiting (PONV), pain and respiratory function tests in women undergoing conservative surgery for breast cancer. This was a controlled clinical trial conducted between June 2013 and October 2014. Eighty patients were evaluated. Patients received a preoperative dose of 8 mg of dexamethasone (n = 40) or placebo (n = 40). The data on PONV and pain intensity was obtained and forced spirometry tests were performed, 1 hr before and at 1, 6, 12 and 24 hr after surgery. Any use of additional analgesic/antiemetic drugs was recorded. Patients were followed until 30 days after surgery for any surgical or medical complications. The pain intensity was lower in the treatment group for all periods; PONV was lower at 6, 12 and 24 hr; Additional analgesics/antiemetics were required less frequently (all p < .05). Both groups exhibited a restrictive ventilatory pattern immediately after surgery, which was reversed in the following hours. However, spirometric values were higher in the dexamethasone group. There were no pulmonary or metabolic complications after surgery. Our conclusions were that dexamethasone significantly reduced the incidences of PONV, pain and improved respiratory parameters, and reduced the need for additional postoperative analgesic and antiemetic drugs.

Do higher-volume hospitals provide better value in revision hip and knee arthroplasty?

AIMS: The purpose of this study is to determine if higher volume hospitals have lower costs in revision hip and knee arthroplasty. MATERIALS AND METHODS: We questioned the Centres for Medicare and Medicaid Services (CMS) Inpatient Charge Data and identified 789 hospitals performing a total of 29 580 revision arthroplasties in 2014. Centres were dichotomised into high-volume (performing over 50 revision cases per year) and low-volume. Mean total hospital-specific charges and inpatient payments were obtained from the database and stratified based on Diagnosis Related Group (DRG) codes. Patient satisfaction scores were obtained from the multiyear CMS Hospital Compare database. RESULTS: High-volume hospitals comprised 178 (30%) of the total but performed 15 068 (51%) of all revision cases, including 509 of 522 (98%) of the most complex DRG 466 cases. While high-volume hospitals had higher Medicare inpatient payments for DRG 467 ($21 458 versus $20 632, p = 0.038) and DRG 468 ($17 003 versus $16 120, p = 0.011), there was no difference in hospital specific charges between the groups. Higher-volume facilities had a better CMS hospital star rating (3.63 versus 3.35, p < 0.001). When controlling for hospital geographic and demographic factors, high-volume revision hospitals are less likely to be in the upper quartile of inpatient Medicare costs for DRG 467 (odds ratio (OR) 0.593, 95% confidence intervals (CI) 0.374 to 0.941, p = 0.026) and DRG 468 (OR 0.451, 95% CI 0.297 to 0.687, p < 0.001). CONCLUSION: While a high-volume hospital is less likely to be a high cost outlier, the higher mean Medicare reimbursements at these facilities may be due to increased case complexity. Further study should focus on measures for cost savings in revision total joint arthroplasties. Cite this article: Bone Joint J 2017;99-B:1611-17.

maLPA1-null mice as an endophenotype of anxious depression.

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.

Body weight changes after adjuvant chemotherapy of patients with breast cancer: results of a Mexican cohort study.

Weight gain is observed in breast cancer patients receiving chemotherapy and is a well-known complication. Several factors that contributing to weight gain have been identified. However, there is a lack of information about factors associated with weight changes following adjuvant chemotherapy. A retrospective cohort of 200 pre- and post-menopausal Mexican patients treated for breast cancer was made. Anthropometric variables were measured before/after treatment. Biomarkers, cellular differentiation and chemotherapy were similar between groups. Weight gain occurred in 85.6% of pre-menopausal and 72.6% of post-menopausal women (p = .03). At the end of chemotherapy, weight and body mass index (BMI) did not differ significantly between pre-menopausal (69.3 ± 12.6 kg; 26.6 ± 4.8 kg/m2 ) and post-menopausal women (69.5 ± 10.9 kg; 27.3 ± 4.4 kg/m2 ) (p = .91 and 0.34). Dexamethasone doses were higher in pre-menopausal (85.7 ± 39.1 g) than post-menopausal patients (79.2 ± 22.5 g; p = .13). Weight loss was observed in 9.2% of pre-menopausal and 20.2% of post-menopausal patients (p = .04). A multivariate analysis revealed that age (OR = 2.7; 95% CI = 1.26-5.79; p = .01), menopausal status (OR = 2.29; 95% CI = 1.09-4.80; p = .03), dexamethasone dosage (OR = 2.1; 95% CI = 1.04-4.23; p = .03) and daily caloric intake (OR = 2.3; 95% CI = 1.12-5.10; p = .02) were independent variables that inducted weight gain. Pre- and post-menopausal women gained weight, but more pre-menopausal patients showed gain. An effort should be made to administer lower steroid doses to reduce weight gain.

Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells.

TDP-43 is aggregated in patients with ALS and FLTD through mechanisms still incompletely understood. Since aggregation in the cytosol is most probably responsible for the delocalization and loss of proper RNA-binding function of TDP-43 in the nucleus, interception of the formation of aggregates may represent a useful therapeutic option. In this study, we investigated the relative importance of the N-terminal and C-terminal moieties of TDP-43 in the aggregation process and the weight of each of the six cysteine residues in determining unfolding and aggregation of the different domains. We report that cytoplasmic inclusions formed by WT and mutant TDP-43 in motor neuron-like NSC34 cells are redox-sensitive only in part, and contain at least two components, i.e. oligomers and large aggregates, that are made of different molecular species. The two N-terminal cysteine residues contribute to the seeding for the first step in oligomerization, which is then accomplished by mechanisms depending on the four cysteines in the RNA-recognition motifs. Cysteine-independent large aggregates contain unfolded isoforms of the protein, held together by unspecific hydrophobic interactions. Interestingly, truncated isoforms are entrapped exclusively in oligomers. Ab initio modeling of TDP-43 structure, molecular dynamics and molecular docking analysis indicate a differential accessibility of cysteine residues that contributes to aggregation propensity. We propose a model of TDP-43 aggregation involving cysteine-dependent and cysteine-independent stages that may constitute a starting point to devise strategies counteracting the formation of inclusions in TDP-43 proteinopathies.

Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.

Data in support of Gallium (Ga(3+)) antibacterial activities to counteract E. coli and S. epidermidis biofilm formation onto pro-osteointegrative titanium surfaces.

This paper contains original data supporting the antibacterial activities of Gallium (Ga(3+))-doped pro-osteointegrative titanium alloys, obtained via Anodic Spark Deposition (ASD), as described in "The effect of silver or gallium doped titanium against the multidrug resistant Acinetobacter baumannii" (Cochis et al. 2016) [1]. In this article we included an indirect cytocompatibility evaluation towards Saos2 human osteoblasts and extended the microbial evaluation of the Ga(3+) enriched titanium surfaces against the biofilm former Escherichia coli and Staphylococcus epidermidis strains. Cell viability was assayed by the Alamar Blue test, while bacterial viability was evaluated by the metabolic colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Finally biofilm morphology was analyzed by Scanning Electron Microscopy (SEM). Data regarding Ga(3+) activity were compared to Silver.

The surgical approach for revision total knee arthroplasty.

A key to the success of revision total knee arthroplasty (TKA) is a safe surgical approach using an exposure that minimises complications. In most patients, a medial parapatellar arthrotomy with complete synovectomy is sufficient. If additional exposure is needed, a quadriceps snip performed through the quadriceps tendon often provides the additional exposure required. It is simple to perform and does not alter the post-operative rehabilitative protocol. In rare cases, in which additional exposure is needed, or when removal of a cemented long-stemmed tibial component is required, a tibial tubercle osteotomy (TTO) may be used. Given the risk of post-operative extensor lag, a V-Y quadricepsplasty is rarely indicated and usually considered only if TTO is not possible.

[Risk of Developing Clinical Symptomatically Postmeniscectomy Bone Marrow Edema]. / Risiko des Auftretens eines klinisch symptomatischen Knochenmarködems nach arthroskopischer Meniskusteilresektion.

BACKGROUND: Bone marrow edema (BME) of the knee is often seen in MRI and has several different underlying pathologies. The correlation between disorders of the knee joint and a BME is not fully understood yet. Persistent or progressive postoperative pain and/or functional impairment after arthroscopic partial meniscectomy is still a common phenomenon in many patients. The aim of this prospective clinical trial was to find a correlation between the typical postoperative disorders and BME in MRI and to identify possible therapeutic consequences. PATIENTS, MATERIAL AND METHODS: 150 consecutive patients with preoperatively diagnosed meniscus defects and without any previous operation and no BME underwent arthroscopic partial meniscectomy. A two- to three-day resting period was established postoperatively. The patients then rapidly returned to full weight bearing. No crutches were used. As a standard analgetic, we used diclofenac 50 mg three times a day for three days. Clinical control and removal of the sutures was performed on day 8 postoperatively. The patients' pain status was controlled by using the IKDC score and the Visual Analogue Scale (VAS) before and six weeks after surgery. Six weeks after the surgical intervention, the patients underwent a standardized physical examination and, if there was ongoing functional impairment or discomfort of the knee, a new MRI was performed. However, if patients showed signs or severe discomfort prior to the end of the six-week observation period an MRI was scheduled earlier. RESULTS: Postoperatively 11 of the 150 patients (7,3 %) developed progressive discomfort with pain during stress and also by night. A postoperative BME in the MRI was seen in all 11 symptomatic patients (100 %). We saw a significant correlation to women older than 70 years (p < 0.05). The VAS score six weeks after arthroscopy was significant reduced in the group without any clinical symptoms (2.63 ± 2.83 after arthroscopy and 4.27 ± 2.36 MW ± SEM before arthroscopy) compared to the group with proven BME (5.09 ± 2.74 before arthroscopy and 5.27 ± 2.57 MW ± SEM after arthroscopy; p < 0.05). The IKDC score was significantly enhanced in the clinical asymptomatic group: 58.1 ± 10.53 in comparison to the patients with proven BME, with 35.32 ± 13.2 MW ± SEM (p < 0.05). CONCLUSION: Patients with clinical symptomatic BME showed a significantly higher VAS score and a significantly lower IKDC score postoperatively. Therefore, in patients with postoperative discomfort, a prompt MRI should be performed and, if a BME is proven, further therapy should be modified.

[Evaluation of the quality control of anticoagulation in patients with atrial fibrillation in a Primary Health Care Area of Madrid]. / Evaluación de la calidad del control de la anticoagulación en los pacientes con fibrilación auricular en Atención Primaria en la zona noroeste de Madrid.

OBJECTIVE: To calculate the time in therapeutic range (TTR), as well as the scores on the CHADS2 scale in anticoagulated patients with non-valvular atrial fibrillation, attending the Primary Care Health Centre of Aravaca. LOCATION: Basic health area of Aravaca (Madrid). DESIGN: Retrospective observational study. PARTICIPANTS: The Community of Madrid provides a list of patients with non-valvular atrial fibrillation and on anticoagulant therapy in the centre. Excluding those with less than 8 INRs, who began treatment after January 2011, interrupted by inter-current treatment or had cancer or coagulopathy. The study period is from 1 January 2012 to 1 January 2013. MAIN MEASUREMENTS: The TTR (fraction of INRs in range) was the primary endpoint. The score was also calculated on the CHADS2 scale. RESULTS: A value of 56.28% TTR (59.5-53.1) was obtained from a sample of 963 INRs. Just over half (52%) of patients had a TTR<60%. There were 65 patients with a mean age of 80±7.5 years. The distribution of risk factors for the CHADS2 scale was: Heart failure 18.5%; hypertension 80%; diabetes 29.2%, and embolic events 18.5%. CONCLUSION: The results of our sample TTR is suboptimal (<60%), which implies an increased risk for embolic episodes and increased likelihood of bleeding. We need to incorporate into our clinical practice an objective measure of the quality of anticoagulation in order to identify poorly controlled patients and introduce corrective measures.

Role of Merlin/NF2 inactivation in tumor biology.

Merlin (Moesin-ezrin-radixin-like protein, also known as schwannomin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. Loss of function mutations or deletions in NF2 cause neurofibromatosis type 2 (NF2), a multiple tumor forming disease of the nervous system. NF2 is characterized by the development of bilateral vestibular schwannomas. Patients with NF2 can also develop schwannomas on other cranial and peripheral nerves, as well as meningiomas and ependymomas. The only potential treatment is surgery/radiosurgery, which often results in loss of function of the involved nerve. There is an urgent need for chemotherapies that slow or eliminate tumors and prevent their formation in NF2 patients. Interestingly NF2 mutations and merlin inactivation also occur in spontaneous schwannomas and meningiomas, as well as other types of cancer including mesothelioma, glioma multiforme, breast, colorectal, skin, clear cell renal cell carcinoma, hepatic and prostate cancer. Except for malignant mesotheliomas, the role of NF2 mutation or inactivation has not received much attention in cancer, and NF2 might be relevant for prognosis and future chemotherapeutic approaches. This review discusses the influence of merlin loss of function in NF2-related tumors and common human cancers. We also discuss the NF2 gene status and merlin signaling pathways affected in the different tumor types and the molecular mechanisms that lead to tumorigenesis, progression and pharmacological resistance.

Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways.

Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.

The CT20 peptide causes detachment and death of metastatic breast cancer cells by promoting mitochondrial aggregation and cytoskeletal disruption.

Metastasis accounts for most deaths from breast cancer, driving the need for new therapeutics that can impede disease progression. Rationally designed peptides that take advantage of cancer-specific differences in cellular physiology are an emerging technology that offer promise as a treatment for metastatic breast cancer. We developed CT20p, a hydrophobic peptide based on the C terminus of Bax that exhibits similarities with antimicrobial peptides, and previously reported that CT20p has unique cytotoxic actions independent of full-length Bax. In this study, we identified the intracellular actions of CT20p which precede cancer cell-specific detachment and death. Previously, we found that CT20p migrated in the heavy membrane fractions of cancer cell lysates. Here, using MDA-MB-231 breast cancer cells, we demonstrated that CT20p localizes to the mitochondria, leading to fusion-like aggregation and mitochondrial membrane hyperpolarization. As a result, the distribution and movement of mitochondria in CT20p-treated MDA-MB-231 cells was markedly impaired, particularly in cell protrusions. In contrast, CT20p did not associate with the mitochondria of normal breast epithelial MCF-10A cells, causing little change in the mitochondrial membrane potential, morphology or localization. In MDA-MB-231 cells, CT20p triggered cell detachment that was preceded by decreased levels of α5ß1 integrins and reduced F-actin polymerization. Using folate-targeted nanoparticles to encapsulate and deliver CT20p to murine tumors, we achieved significant tumor regression within days of peptide treatment. These results suggest that CT20p has application in the treatment of metastatic disease as a cancer-specific therapeutic peptide that perturbs mitochondrial morphology and movement ultimately culminating in disruption of the actin cytoskeleton, cell detachment, and loss of cell viability.

What do we know about taper corrosion in total hip arthroplasty?

Mechanically assisted crevice corrosion (MACC) at metal/metal modular junctions in which at least one of the components is fabricated from cobalt-chromium alloy, has reemerged as a potential clinically significant complication in total hip arthroplasty. The clinical manifestation of MACC may include the development of an adverse local tissue reaction (ALTR), similar to what has been described in association with metal-on-metal bearing total hip and resurfacing arthroplasty. The clinical presentation of MACC-associated ALTRs may include pain and possibly late recurrent dislocations. Abnormal metal artifact reduction sequence magnetic resonance images and elevated serum metal levels (cobalt elevations out of proportion to chromium elevations) can be helpful in the diagnosis of these MACC-associated ALTRs.

LIM domain kinases as potential therapeutic targets for neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene that encodes a tumor-suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss-of-function is associated with increased activity of Rac and p21-activated kinases (PAKs) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates the actin severing and depolymerizing activity of cofilin. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2(ΔEx2)) exhibited increased levels of LIMK1, LIMK2 and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared with wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared with normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2(ΔEx2) MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5 decreased the viability of Nf2(ΔEx2) MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2(ΔEx2) MSCs. The decreased viability of Nf2(ΔEx2) MSCs was not due to caspase-dependent or -independent apoptosis, but rather due to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrests cells in early mitosis by decreasing aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency.

The two-stage standard in revision total hip replacement.

Two-stage exchange remains the gold standard for treatment of peri-prosthetic joint infection after total hip replacement (THR). In the first stage, all components and associated cement if present are removed, an aggressive debridement is undertaken including a complete synovectomy, and an antibiotic-loaded cement spacer is put in place. Patients are then treated with six weeks of parenteral antibiotics, followed by an 'antibiotic free period' to help ensure the infection has been eradicated. If the clinical evaluation and serum inflammatory markers suggest the infection has resolved, then the second stage can be completed, which involves removal of the cement spacer, repeat debridement, and placement of a new THR.