The CD46-Jagged1 interaction is critical for human TH1 immunity.

CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ (IFN-γ)-secreting effector T helper type 1 (T(H)1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4(+) T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate T(H)1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.

In Vitro Inflammatory Cell-Induced Corrosion Using a Lymphocyte and Macrophage Coculture.

BACKGROUND: Cobalt-chromium-molybdenum (CoCrMo) and titanium alloys have been used for orthopaedic implants for decades. However, recent evidence has shown that inflammatory cell-induced corrosion (ICIC) can damage these metal alloys. This study aimed to investigate the mechanisms of ICIC by coculturing macrophages with lymphocytes. We hypothesized that macrophages would be able to alter the surface oxide layer of CoCrMo and titanium alloy (Ti6Al4V) disks, with greater oxide layer damage occurring in groups with a coculture compared to a macrophage monoculture and in groups with inflammatory activators compared to nonactivated groups. METHODS: Murine macrophages were cultured on American Society for Testing and Materials F1537 CoCrMo and F136 Ti6Al4V disks for 30 days and activated with interferon gamma and lipopolysaccharide. Interferon gamma and lipopolysaccharide were added to the culture medium to simulate local inflammation. Macrophages were either cultured alone or in a coculture with T helper lymphocytes. After the 30-day experiment, scanning electron microscopy was used to examine the disk surfaces, and oxide levels were found using energy dispersive x-ray spectroscopy. RESULTS: Pitting features consistent with previous reports of ICIC were found on disks cultured with cells. Both CoCrMo and Ti6Al4V disks had significantly lower oxide levels in all groups with cells compared to control groups with no cells (P < .01). Additionally, CoCrMo disks had significantly lower oxide levels when cultured with activated macrophages and lymphocytes compared to nonactivated macrophages alone (P < .001), activated macrophages alone (P < .01), and nonactivated macrophages and lymphocytes (P < .05). No differences in the oxide levels were found among the Ti6Al4V groups. CONCLUSIONS: This study demonstrates the ability of macrophages to alter the surface chemistry of commonly used orthopaedic alloys. We found that the addition of lymphocytes and a simulated local inflammatory response may contribute to the ICIC of CoCrMo implants.

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

In-Vitro Cell-Induced Corrosion by Macrophages on Cobalt-Chromium-Molybdenum Alloy.

BACKGROUND: Patients have received cobalt-chromium-molybdenum (CoCrMo) implants for their joint replacement for decades. There have been reports of inflammatory cell-induced corrosion (ICIC) of these implants from retrieval studies. The goal of this study is to see if we could recreate ICIC in vitro and whether electrocautery damage to alloy surfaces may hasten this process. METHODS: Murine macrophages were cultured on CoCr disks with and without damage from a monopolar electrocautery. Culture medium was replaced every 12 hours and supernatant was collected every 4 days. After 30 days, cells were removed, counted, and digested. The metal concentrations in the supernatant and within cells were assessed using inductively coupled plasma spectrometry for comparison. RESULTS: The Co supernatant concentration was higher in the undamaged disks with activated macrophages. Higher concentrations of Co and Mo were found in the supernatant of the undamaged disks vs the electrocautery (EC) corrosion damaged disks. There was a significantly higher intracellular Co and Mo concentration with activated cells on CoCrMo disks vs the control group and no difference compared to EC damaged disk group. Scanning electron microscopy displayed microscopic pitting on the surfaces exposed to macrophages without EC damage. CONCLUSION: We found that macrophages could reproduce findings of ICIC pits on the surface of CoCrMo alloy and that the addition of EC damage to the surface did not increase the process. The clinical significance of these findings should be further investigated to determine if this could explain a small number of poor total knee arthroplasty reported outcomes.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Simvastatin loaded chitosan guided bone regeneration membranes stimulate bone healing.

BACKGROUND AND OBJECTIVE: Electrospun chitosan membranes (ESCM) modified with short-chain fatty acids have the ability to control the release of simvastatin (SMV), an anti-cholesterol drug with osteogenic potential, for guided bone regeneration (GBR) applications. This study evaluated in vivo osteogenic effects of rapid short release of SMV (4 weeks) vs long sustained release (8 weeks) from acetic anhydride (AA)-and hexanoic anhydride (HA)-modified ESCMs, respectively. METHODS: AA ESCMs loaded with 10 or 50 µg SMV and HA ESCMs loaded with 50 µg SMV were evaluated for biocompatibility and bone formation at 4 and 8 weeks, in 5 mm critical size rat calvarial defects, using histological evaluation and micro-CT analysis. RESULTS: No severe inflammatory response was noticed around the ESCMs. Less hydrophobic AA membranes showed signs of resorption by week 4 and were almost completely resorbed by week 8 whereas the more hydrophobic HA membranes resorbed slowly, remaining intact over 8 weeks. In micro-CT analysis, 10 µg SMV-loaded AA membranes did not show significant bone formation as compared to non-loaded AA membranes at either evaluation time points. 50 µg SMV-loaded AA membranes stimulated significantly more bone formation than non-loaded AA membranes by week 4 (%bone = 31.0 ± 5.9% (AA50) vs 18.5 ± 13.7% (AA0)) but showed no difference at week 8. HA membranes with 50 µg SMV showed significantly more bone formation as compared to corresponding non-loaded membranes by week 8 (%bone = 61.7 ± 8.9% (HA50) vs 33.9 ± 29.7% (HA0)), though such an effect was not significant at week 4. CONCLUSION: These results indicate that modified ESCMs may be used to control the release of SMV and promote bone healing in GBR applications.

Analysis of Wheeled Knee Walker Use following Foot and Ankle Surgery or Injury.

To determine patient satisfaction and safety with wheeled knee walkers, we performed a retrospective, observational, and descriptive study. Inclusion criteria were age ≥18 years, unilateral foot or ankle surgery, non-weightbearing status, and being given the option of using the knee walker. Surveys were sent to eligible patients, and chart review included only those patients who returned surveys. Primary endpoints were occurrence and frequency of falls. Secondary endpoints were patient demographics, comorbidities, knee walker characteristics, duration of use, and patient satisfaction. We also attempted to identify associations between falls and patient characteristics. Eighty participants, 51 females and 29 males, responded adequately to the survey. The mean age of respondents was 55.6 ± 13.0 years and their mean body mass index (BMI) was 30.2 ± 5.9 kg/m2. Most used a steerable, 4-wheeled knee walker. Almost half (46%) had no prior experience with any type of walking aids, and none had experience using a knee walker. Two thirds (66%) did not receive any instruction on usage of the knee walker. Thirty-four (43%) of the 80 respondents fell while using the knee walker; nearly two thirds (62%) of those who fell reported multiple falls. Sixteen (55%) of 29 males compared to 18 (36%) of 50 females reported falling (p = .097). There was no statistical association between falls and age, BMI, or number of comorbidities. Most respondents (91%) who fell still reported satisfaction with the knee walker. Nearly half (43%) experienced falling, and nearly two thirds (64%) of those who fell had multiple falls.

Prostate cancer cells enhance interleukin-15-mediated expansion of NK cells.

OBJECTIVES: To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra-tumoural administration in pre-clinical and clinical prostate cancer trials. MATERIALS AND METHODS: Lymphocytes isolated from normal donor blood were set up in co-cultures with either cancer or non-cancerous prostate cell lines, together with each of the cytokines interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-γ or IL-21 for a period of 7 days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co-culture. The role of the tumour-secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co-cultures was also investigated because of their effects on NK and CD8 T-cell activation. RESULTS: We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL-15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non-cancerous cell lines (PNT2 and WPMY-1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co-cultures with IL-15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL-15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells. CONCLUSIONS: Among a panel of NK cell-activating cytokines, IL-15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL-15 may be a good candidate for novel future intra-tumoural therapy of the disease.

Manuka honey modulates the release profile of a dHL-60 neutrophil model under anti-inflammatory stimulation.

Manuka honey, a wound treatment used to eradicate bacteria, resolve inflammation, and promote wound healing, is a current focus in the tissue engineering community as a tissue template additive. However, Manuka honey's effect on neutrophils during the inflammation-resolving phase has yet to be examined. This study investigates the effect of 0.5% and 3% Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes from a dHL-60 neutrophil model in the presence of anti-inflammatory stimuli (TGF-ß, IL-4, IL-4 +IL-13). We hypothesized that Manuka honey would reduce the output of pro-inflammatory signals and increase the release of anti-inflammatory signals. The results of this study indicate that 0.5% honey significantly increases the release of CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1ß, CCL20/MIP-3α, IL-4, IL-1ra, and FGF-13 while reducing Proteinase 3 release in the anti-inflammatory-stimulated models. However, 3% honey significantly increased the release of TNF-α and CXCL8/IL-8 while reducing the release of all other analytes. We replicated a subset of the most notable findings in primary human neutrophils, and the consistent results indicate that the HL-60 data are relevant to the performance of primary cells. These findings demonstrate the variable effects of Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes of this model of neutrophil anti-inflammatory activity. This study reinforces the importance of tailoring the concentration of Manuka honey in a wound or tissue template to elicit the desired effects during the inflammation-resolving phase of wound healing. Future in vivo investigation should be undertaken to translate these results to a physiologically-relevant wound environment.

Provisional best practices guidelines for the evaluation of bulbar dysfunction in amyotrophic lateral sclerosis.

INTRODUCTION: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. METHODS: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. DISCUSSION: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019.

Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in patients with amyotrophic lateral sclerosis: A quantitative speech analysis.

AIMS: A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS: Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS: The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.

Tobacco use predicts a more difficult episode of care after anatomic total shoulder arthroplasty.

BACKGROUND: In the current health care environment, it is becoming increasingly important to recognize risks factors that may affect a patient's postoperative outcome. To determine the potential impact of tobacco as a risk factor, we evaluated postoperative pain, narcotic use, length of stay, reoperations, and complications in the global 90-day episode of care for patients undergoing anatomic total shoulder arthroplasty (TSA) who were current tobacco users, former users, or nonusers. METHODS: Database search identified 163 patients with primary anatomic TSA done for glenohumeral arthritis; these were divided into 3 groups: current tobacco users (28), nonusers (88), and former users (47). All surgeries were done with the same technique and implants. RESULTS: Patients in the current tobacco use group had significantly higher visual analog scale scores preoperatively and at 12 weeks postoperatively than nonusers and former users. Mean improvement in visual analog scale scores was significantly less in current tobacco users. Cumulative oral morphine equivalent use at 12 weeks was significantly higher in current tobacco users than in nonusers and former users. The average oral morphine equivalent per day was also significantly higher in the current tobacco users than in nonusers and former users. There were no significant differences in length of stay or complications. CONCLUSIONS: Although length of stay, complication rates, hospital readmissions, and reoperation rates were not significantly different, tobacco users reported increased postoperative pain and narcotic use in the global period after TSA. Former tobacco users were found to have a postoperative course similar to that of nonusers, suggesting that discontinuation of tobacco use can improve a patient's episode of care performance after TSA.

Liposomal bupivacaine mixture has similar pain relief and significantly fewer complications at less cost compared with indwelling interscalene catheter in total elbow arthroplasty.

BACKGROUND: Postoperative pain control, short-term and long-term narcotic consumption, complication rates, and costs of indwelling interscalene catheter (ISC) were compared with a liposomal bupivacaine (LBC) mixture in patients undergoing primary total elbow arthroplasty. METHODS: Forty-four consecutive patients were identified, the first 28 with an ISC and the later 16 with intraoperative LBC injection that also included ketorolac and 0.5% bupivacaine. Medical records were reviewed for visual analog scale scores for pain, oral morphine equivalent (OME) use, complications, and facility charges. RESULTS: Average visual analog scale scores at 24 hours, 2 weeks, 6 weeks, and 12 weeks were not significantly different. Mean OME use was significantly greater in the LBC group at 24 hours but less at 12 weeks, although this difference was not statistically significant. Twelve anesthetic-related complications occurred in the ISC group (1 major and 11 minor); 10 patients (36%) had at least 1 complication. The major complication was respiratory failure requiring emergent tracheostomy. Minor complications included leaking pump/catheters, catheters inadvertently pulled out early, global hand paresthesias, forearm paresthesias, and pain at the catheter site. There were no anesthetic-related complications in the LBC group. The average charge for the LBC mixture was $327.10; charges for ISC, including equipment and anesthesia fees, were $1472.42. CONCLUSIONS: An LBC mixture provides similar pain relief with fewer complications at a lower cost than indwelling ISC after total elbow arthroplasty. Although the OME use in the LBC group was almost double that of the ISC group at 24 hours, there was no difference at later time points.

Five-year minimum clinical and radiographic outcomes of total shoulder arthroplasty using a hybrid glenoid component with a central porous titanium post.

BACKGROUND: To determine the effectiveness of hybrid glenoid components in reducing the frequency of glenoid component loosening, we evaluated clinical and radiographic outcomes at a minimum 5-year follow-up in 45 shoulders that underwent total shoulder arthroplasty (TSA) using a system with a central porous titanium post to augment the cemented peripheral pegs. METHODS: Function and pain were evaluated with the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment score, visual analog scale, active shoulder range of motion, and strength. Postoperative radiographs were analyzed for radiolucent lines, progressive loosening, and at-risk signs. RESULTS: The mean American Shoulder and Elbow Surgeons score improved from 40.4 to 83.7 (P < .0001) and the mean visual analog scale from 5.9 to 0.8 (P < .0001). Forward elevation improved from 113° to 151° (P < .001), internal rotation from 49° to 60° (P = .035), and mean external rotation from 36° to 50° (P = .0006). Radiographs showed glenoid component radiolucency in 29 shoulders. Radiolucencies were confined to the area under the glenoid faceplate in 6 and were only around the central post in 13. Nine TSAs (20%) demonstrated 2 or more columns of involvement but were not judged to be at-risk. One implant (2.2%) had glenoid component failure and was revised to a hemiarthroplasty. CONCLUSION: Anatomic TSA using a hybrid glenoid component with a central porous titanium post demonstrated a low rate of mechanical failure and a rate of radiolucent lines comparable to reports of all polyethylene implants. Further evaluations are needed to demonstrate the long-term durability of these implants and to determine the significance and fate of the radiolucent lines, particularly relative to the central post.

Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS.

Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity.

Reliability testing of the Larsen and Sharp classifications for rheumatoid arthritis of the elbow.

BACKGROUND: Two popular systems for classifying rheumatoid arthritis affecting the elbow are the Larsen and Sharp schemes. To our knowledge, no study has investigated the reliability of these 2 systems. We compared the intraobserver and interobserver agreement of the 2 systems to determine whether one is more reliable than the other. METHODS: The radiographs of 45 patients diagnosed with rheumatoid arthritis affecting the elbow were evaluated. Anteroposterior and lateral radiographs were deidentified and distributed to 6 evaluators (4 fellowship-trained upper extremity surgeons and 2 orthopedic trainees). Each evaluator graded all 45 radiographs according to the Larsen and Sharp scoring methods on 2 occasions, at least 2 weeks apart. RESULTS: Overall intraobserver reliability was 0.93 (95% confidence interval [CI], 0.90-0.95) for the Larsen system and 0.92 (95% CI, 0.86-0.96) for the Sharp classification, both indicating substantial agreement. Overall interobserver reliability was 0.70 (95% CI, 0.60-0.80) for the Larsen classification and 0.68 (95% CI, 0.54-0.81) for the Sharp system, both indicating good agreement. There were no significant differences in the intraobserver or interobserver reliability of the systems overall and no significant differences in reliability between attending surgeons and trainees for either classification system. CONCLUSION: The Larsen and Sharp systems both show substantial intraobserver reliability and good interobserver agreement for the radiographic classification of rheumatoid arthritis affecting the elbow. Differences in training level did not result in substantial variances in reliability for either system. We conclude that both systems can be reliably used to evaluate rheumatoid arthritis of the elbow by observers of varying training levels.

Liposomal Bupivacaine Mixture Has Similar Pain Relief and Significantly Fewer Complications at Less Cost Compared to Indwelling Interscalene Catheter in Total Shoulder Arthroplasty.

BACKGROUND: The efficacy and costs of indwelling interscalene catheter (ISC) and liposomal bupivacaine (LBC), with and without adjunctive medications, in patients with primary shoulder arthroplasty are a source of current debate. METHODS: In 214 arthroplasties, 156 patients had ISC and 58 had LBC injections that were mixed with morphine, ketorolac, and 0.5% bupivacaine with epinephrine. Charts were reviewed for visual analog scale pain scores, oral morphine equivalent (OME) usage, major complications, and costs. RESULTS: Visual analog scale scores were not significantly different at 24 hours or at 2, 6, and 12 weeks. Average OME consumption at 24 hours was significantly more with LBC, but was not significantly different at 12 weeks. Relative risk of a major complication was nearly 4 times higher with ISC than with LBC. The average cost for the LBC mixture was $289.04, and for ISC, including equipment and anesthesia fees, was $1559.42. CONCLUSION: The intraoperative LBC mixture provided equivalent pain relief with significantly fewer major complications and at markedly lower cost than ISC. LBC required almost twice as much OME to attain the same level of pain relief at 24 hours, but there was no significant difference in the cumulative amount of outpatient narcotic use.

Expression of two WFDC1/ps20 isoforms in prostate stromal cells induces paracrine apoptosis through regulation of PTGS2/COX-2.

BACKGROUND: WFDC1/Prostate stromal 20 (ps20) is a small secreted protein highly expressed within the prostate stroma. WFDC1/ps20 expression is frequently downregulated or lost in prostate cancer (PCa) and ps20 has demonstrated growth-suppressive functions in numerous tumour model systems, although the mechanisms of this phenomenon are not understood. METHODS: Ps20 was cloned and overexpressed in DU145, PC3, LNCaP and WPMY-1 cells. Cellular growth, cell cycle and apoptosis were characterised. WPMY-1 stromal cells expressing ps20 were characterised by transcriptome microarray and the function of WPMY-1 conditioned media on growth of PCa cell lines was assessed. RESULTS: Prostrate stromal 20 expression enhanced the proliferation of LNCaP cells, whereas stromal WPMY-1 cells were inhibited and underwent increased apoptosis. Prostrate stromal 20-expressing WPMY-1 cells secrete a potently proapoptotic conditioned media. Prostrate stromal 20 overexpression upregulates expression of cyclooxygenase-2 (COX-2) in LNCaP and WPMY-1 cells, and induces expression of a growth-suppressive phenotype, which inhibits proliferation of PCa cells by ps20-expressing WPMY-1 conditioned media. This growth suppression was subsequently shown to be dependent on COX-2 function. CONCLUSIONS: This work posits that expression of ps20 in the prostate stroma can regulate growth of epithelial and other tissues through the prostaglandin synthase pathway, and thereby restricts development and progression of neoplasms. This provides a rational for selective pressure against ps20 expression in tumour- associated stroma.

Younger patients report similar activity levels to older patients after reverse total shoulder arthroplasty.

BACKGROUND: Younger patients who have undergone reverse total shoulder arthroplasty (RTSA) are believed to have higher activity levels that place higher stresses across the prosthesis, increasing the risk of failure, but there is little information to support or refute this supposition. The purposes of this study were to define the patient-reported activity levels of patients younger than 65 years and older than 65 years who underwent RTSA and to evaluate any differences between the groups. METHODS: Forty-six patients who underwent primary RTSA answered a questionnaire regarding their activity levels. Data were categorized and tabulated according to pain, range of motion, strength, and activity level (low, medium, and high demand). Statistical analyses were performed using the Fisher exact test, χ(2) test, and independent t test. Differences with P < .05 were considered statistically significant. RESULTS: Seventeen patients younger than 65 years (mean age, 57.7 years) and 29 patients older than 65 years (mean age, 75.2 years) were included. No significant differences were found for range of motion, strength, or number of activities; 47% of younger patients and 44% of older patients reported high-demand activities (P = .64); 24% of younger patients and 37% of older patients reported medium-demand use (P = .30). Patients younger than 65 years were more likely to require narcotic pain medication (P = .03) and to have disability (P = .0001). CONCLUSION: These data provide initial evidence that commonly held concerns about higher activity levels among younger patients placing excessive demands on the RTSA prosthesis may not be as important as currently thought. Rather, patients seem to self-regulate their activities to minimize pain and maximize essential functions after surgery.

Reliability testing of two classification systems for osteoarthritis and post-traumatic arthritis of the elbow.

HYPOTHESIS AND BACKGROUND: The severity of elbow arthritis is one of many factors that surgeons must evaluate when considering treatment options for a given patient. Elbow surgeons have historically used the Broberg and Morrey (BM) and Hastings and Rettig (HR) classification systems to radiographically stage the severity of post-traumatic arthritis (PTA) and primary osteoarthritis (OA). We proposed to compare the intraobserver and interobserver reliability between systems for patients with either PTA or OA. METHODS: The radiographs of 45 patients were evaluated at least 2 weeks apart by 6 evaluators of different levels of training. Intraobserver and interobserver reliability were calculated by Spearman correlation coefficients with 95% confidence intervals. Agreement was considered almost perfect for coefficients >0.80 and substantial for coefficients of 0.61 to 0.80. RESULTS: In patients with both PTA and OA, intraobserver reliability and interobserver reliability were substantial, with no difference between classification systems. There were no significant differences in intraobserver or interobserver reliability between attending physicians and trainees for either classification system (all P > .10). The presence of fracture implants did not affect reliability in the BM system but did substantially worsen reliability in the HR system (intraobserver P = .04 and interobserver P = .001). CONCLUSIONS: The BM and HR classifications both showed substantial intraobserver and interobserver reliability for PTA and OA. Training level differences did not affect reliability for either system. Both trainees and fellowship-trained surgeons may easily and reliably apply each classification system to the evaluation of primary elbow OA and PTA, although the HR system was less reliable in the presence of fracture implants.