Proteoglycan 4 reduces friction more than other synovial fluid components for both cartilage-cartilage and cartilage-metal articulation.

OBJECTIVE: The clinical success of focal metallic resurfacing implants depends largely on the friction between implant and opposing cartilage. Therefore, the present study determines the lubricating ability of the synovial fluid components hyaluronic acid (HA), proteoglycan 4 (PRG4) and a surface-active phospholipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC), on the articulation between cartilage and a Cobalt Chromium Molybdenum (CoCrMo) implant surface, compared with two cartilage surfaces. METHODS: A ring-on-disk geometry was used to perform repeated friction measurements at physiologically relevant velocities (6 and 60 mm/s) using lubricants with an increasing number of components present. Shear measurements were performed in order to evaluate the viscosity. To ensure that it is clinically relevant to explore the effect of these components, the presence of PRG4 in synovial fluid obtained from primary and revision knee and hip implant surgeries was examined. RESULTS: PRG4 in the presence of HA was found to significantly reduce the coefficient of friction for both cartilage-cartilage and cartilage-CoCrMo interface. This is relevant, as it was also demonstrated that PRG4 is still present at the time of revision surgeries. The addition of POPC had no effect for either configurations. HA increased the viscosity of the lubricating fluid by one order of magnitude, while PRG4 and POPC had no effect. CONCLUSION: The present study demonstrates the importance of selecting the appropriate lubrication solution to evaluate implant materials with biotribology tests. Because PRG4 is a key component for reducing friction between cartilage and an opposing surface, developing coatings which bind PRG4 is recommended for cartilage resurfacing implants.

An Operational Perspective of The Changing Prosthetics & Orthotics Landscape.

Leading the growth of a private prosthetic and orthotic (P&O) practice, as clinician and founder, I developed a unique perspective of this rapidly changing profession. Many positive influences from my early career shaped my vison toward an innovative practice model, as well as the need to elevate the standard of care through education and the use of outcome measures. As the practice model expanded, advancements were made in electronic health records (EHR), best-in-class outsource fabrication, and clinical research. To better support clinicians and patients served, an organizational structure with an executive team was built. The practice model achieved operational efficiency through documenting best practices, developing a hiring and onboarding process, and establishing key performance indicators aligned with quality clinical care. As a regional clinical care organization, the practice model seized an opportunity to reach more patients through a partnership that brought the optimal strategic and cultural fit. Bringing our innovative P&O practice model together with expertise in lean facility design, scanning, fabrication, sensor technology, product development and clinical care experience from around the world, we can advance care standards and improve the patient experience in exciting new ways.

Wear testing of crosslinked polyethylene: wear rate variability and microbial contamination.

The wear performance of two types of crosslinked polyethylene (Marathon™ and XLK™, DePuy Synthes Inc., Warsaw, IN) was evaluated in a pin-on-disc wear tester, a hip wear simulator, and a knee wear simulator. Sodium azide was used as the microbial inhibitor in the calf serum-based lubricant. In the pin-on-disc wear tester, the Marathon wear rate of 5.33±0.54mm(3)/Mc was significantly lower (p=0.002) than the wear rate of 6.43±0.60mm(3)/Mc for XLK. Inversely, the Marathon wear rate of 15.07±1.03mm(3)/Mc from the hip wear simulator was 2.2-times greater than the XLK wear rate of 6.71±1.03mm(3)/Mc from the knee wear simulator. Differences in implant design, conformity, GUR type, and kinematic test conditions were suggested to account for the difference between the wear rates generated in the different types of wear testing apparati. In all wear tests, sodium azide was ineffective at inhibiting microbial growth in the lubricant. Eight different organisms were identified in the lubricant samples from the wear tests, which suggested the necessity of using an alternative, more effective microbial inhibitor. Careful sample preparation and thorough cleaning has shown to improve the consistency of the wear results. The wear rates generated in the hip and knee wear simulators closely reflected the wear behaviour of Marathon and XLK reported in published data that were tested under similar conditions.

Performance assessment of femoral knee components made from cobalt-chromium alloy and oxidized zirconium.

BACKGROUND: The surface characteristics of the femoral component affect polyethylene wear in modular total knee replacements. In the present retrieval study, the surface characteristics of cobalt-chromium (CoCr) alloy and oxidized zirconium (OxZr) femoral components were assessed and compared. METHODS: Twenty-six retrieved CoCr alloy femoral components were matched with twenty-six retrieved OxZr femoral components for implantation period, body-mass index, patient gender, implant type, and polyethylene insert thickness. The surface damage on the retrieved femoral components was evaluated using a semi-quantitative assessment method, scanning electron microscopy, and contact profilometry. RESULTS: The retrieved CoCr alloy femoral components showed less posterior surface gouging than OxZr femoral components; however, at a higher magnification, the grooving damage features on the retrieved CoCr alloy femoral components confirmed an abrasive wear mechanism. The surface roughness values Rp, Rpm, and Rpk for the retrieved CoCr alloy femoral components were found to be significantly higher than those of the retrieved OxZr femoral components (p≤0.031). The surface roughness values were higher on the medial condyles than on the lateral condyles of the retrieved CoCr alloy femoral components; such a difference was not observed on the retrieved OxZr femoral components. CONCLUSIONS: The surface roughness of CoCr alloy femoral components increased while the surface roughness of the OxZr femoral components remained unchanged after in vivo service. Therefore, the OxZr femoral components' resistance to abrasive wear may enable lower polyethylene wear and ensure long-term durability in vivo. LEVEL OF EVIDENCE: Level IV.

Fatal cardiomyopathy after revision total hip replacement for fracture of a ceramic liner.

Symptomatic cobalt toxicity from a failed total hip replacement is a rare but devastating complication. It has been reported following revision of fractured ceramic components, as well as in patients with failed metal-on-metal articulations. Potential clinical findings include fatigue, weakness, hypothyroidism, cardiomyopathy, polycythaemia, visual and hearing impairment, cognitive dysfunction, and neuropathy. We report a case of an otherwise healthy 46-year-old patient, who developed progressively worsening symptoms of cobalt toxicity beginning approximately six months following synovectomy and revision of a fractured ceramic-on-ceramic total hip replacement to a metal-on-polyethylene bearing. The whole blood cobalt levels peaked at 6521 µg/l. The patient died from cobalt-induced cardiomyopathy. Implant retrieval analysis confirmed a loss of 28.3 g mass of the cobalt-chromium femoral head as a result of severe abrasive wear by ceramic particles embedded in the revision polyethylene liner. Autopsy findings were consistent with heavy metal-induced cardiomyopathy.We recommend using new ceramics at revision to minimise the risk of wear-related cobalt toxicity following breakage of ceramic components.

Commissioning of a displacement-controlled knee wear simulator and exploration of some issues related to the lubricant.

A six-station displacement-controlled knee simulator with separately controlled left (L) and right (R) banks (three wear implants per bank) was commissioned for a total of three million cycles (Mc) following ISO 14243-3. A commissioning protocol was applied to compare the polyethylene wear among the six wear stations by exchanging the implants between wear stations. Changes in lubricant characteristics during wear testing, such as polypeptide degradation, low-molecular-weight polypeptide concentration, and possible microbial contamination were also assessed. The total mean wear rate for the implants was 23.60 +/- 1.96 mm3/Mc and this was of a similar magnitude to the mean wear rate for the same implant tested under similar conditions by DePuy Orthopaedics Inc. (Warsaw, IN). Repeated run-in wear was observed when the implants were exchanged between wear stations, suggesting that implants should be subjected to the same wear station throughout the duration of a wear test. The total polypeptide degradation for the implants measured 30.53 +/- 3.96 percent; the low-molecular-weight polypeptide concentration of the "used" lubricant for implants (0.131 +/- 0.012 g/L) was 3.3 times greater than the mean polypeptide concentration of the fresh, "unused" lubricant (0.039 +/- 0.004 g/L). This increase in low-molecular weight polypeptide concentration was suggested to be attributable to protein shear in the articulation of the implant, the circulation of the lubricant, and some proteolytic activity. Sodium azide was ineffective in maintaining a sterile environment for wear testing as a single, highly motile Gram-negative micro-organism was identified in the lubricant from wear tests.

Mass gain behaviour of tibial polyethylene inserts during soak testing.

Fluid adsorption and the associated mass gain behaviour in tibial inserts of total knee replacements was investigated in polyethylene (PE) manufactured from extruded GUR 1050 resin. Repeatedly removing the PE inserts from the soak fluid for gravimetric assessment (including cleaning, desiccation, and weighing) increased the mass gain. Soaking PE inserts for 46 days or 92 days seemed to give about the same mass gain. PE inserts that were soaked at 37 degrees C gained more mass than PE inserts soaked at room-temperature. Gas-plasma sterilized PE inserts gained less mass than gamma-in-air sterilized PE inserts. No statistically significant differences were detected in mass gain between PE inserts that were of 10mm and 14mm thickness. The mass gain of PE inserts was higher in protein-rich soak fluid compared with low-ion distilled water. Prior to knee simulator wear testing, tibial PE inserts should be conditioned in the same medium and under the same test conditions (gravimetric assessment frequency, fluid protein content, and fluid temperature). This approach would help improve the accuracy and precision of the gravimetrically determined PE wear rate during knee simulator wear testing.

Delamination wear on two retrieved polyethylene inserts after gamma sterilization in nitrogen.

Two self-aligning mobile bearing knee replacements (SAL-1) with gamma-in-nitrogen sterilized polyethylene inserts were revised due to instability after 6.3 years and after 14.2 years in vivo in two patients. The predominant damage features were burnishing, cracking, and delamination and were observed on the proximal bearing surface of the retrieved polyethylene inserts. This suggested an association with sub-surface fatigue, perhaps initiated by in vivo oxidative degradation which was confirmed by developing a sub-surface white band in one insert. The damage features observed on the distal bearing surface of the polyethylene inserts suggested both an adhesive wear mechanism and an abrasive wear mechanism. The titanium-nitrite coated, titanium-alloy tibial tray was severely worn in one case and possibly contributed to third-body abrasive wear at the distal surface interface. We suggest to carefully follow-up patients who received this type of mobile bearing knee system.

Biochemical comparisons of osteoarthritic human synovial fluid with calf sera used in knee simulator wear testing.

Osteoarthritic human synovial fluid was obtained from the knees of 20 patients and was compared with four different calf sera solutions frequently used as lubricants in knee simulator wear testing. Assuming that the fluid after arthroplasty was the same as the fluid in patients with osteoarthritis, the total protein concentration, protein constituent fractions, osmolality, trace element concentrations, and the thermal stability obtained via differential scanning calorimetry were determined. Human synovial fluid, with an average total protein concentration of 34 g/L, was significantly different from all undiluted calf sera. However, alpha-calf serum and iron-supplemented alpha-calf serum were closest in protein constituent fractions (albumin, alpha-1-globulin, alpha-2-globulin, ss-globulin, and gamma-globulin) to human synovial fluid. Diluting calf sera with low-ion distilled water to a total protein concentration of 17 g/L (as recommended by ISO 14243) produced non-clinically relevant total protein concentration and osmolality levels. Performing the same dilution of iron-supplemented alpha-calf serum with phosphate-buffered saline solution and 1.5 g/L hyaluronic acid produced an artificial lubricant with both a clinically relevant level of osmolality and clinically relevant thermal stability as seen in human synovial fluid from patients with osteoarthritis. The present study suggested that alpha-calf serum, phosphate-buffered saline solution and hyaluronic acid were essential constituents of an artificial lubricant to mimic the major biochemical properties of human synovial fluid for simulator wear testing of total knee replacements.

Evaluation of artificial neural networks for the prediction of pathologic stage in prostate carcinoma.

BACKGROUND: Currently, the standard for predicting pathologic stage from information available at the time of prostate biopsy is the "Partin nomograms" that were derived using logistic regression analysis. The authors retrospectively reviewed a large series of men with clinically localized prostate carcinoma who underwent staging pelvic lymphadenectomy and radical retropubic prostatectomy. They then utilized pathologic and clinical data at the time of prostate biopsy to develop and test an artificial neural network (ANN) to predict the final pathologic stage for this group of men. They then compared the results of ANN with the previous nomograms. METHODS: Five thousand seven hundred forty-four men were treated at the authors' institution from 1985 to 1998. An ANN was developed using two randomly selected training and validation sets for predicting pathologic stage. Input variables included age, preoperative serum prostate specific antigen level, clinical TNM (tumor, lymph node, and metastasis) classification, and Gleason score from the biopsy specimen. Outcomes included organ confinement and lymph node involvement status. RESULTS: The ANN was slightly superior to the nomograms in predicting pathologic stage, such as organ confinement and lymph node involvement status. CONCLUSIONS: In predicting organ confinement and lymph node involvement status, ANN was more accurate and had a larger area under ROC than the nomograms based on the logistic regression method. Artificial neural network models can be developed and used to better predict final pathologic stage when preoperative pathologic and clinical features are known.

The problem of cutoff levels in a screened population: appropriateness of informing screenees about their risk of having prostate carcinoma.

BACKGROUND: Transrectal prostate biopsy decisions often have been based on absolute cutoff values for total and free prostate-specific antigen (PSA). The authors decided that it would be more appropriate to develop risk profiles for the individual patient to allow him to decide whether to undergo a prostate biopsy. METHODS: To develop risk profiles, the authors first used multivariate logistic regression analysis to analyze 2054 males who were part of the Tyrol (Austria) PSA Screening Project. Second, artificial neural network (ANN) analyses were performed using data from 3474 males who also were part of the Tyrol PSA Screening Project and who had undergone prostate biopsy. These analyses were compared with standard cutoff levels of specificity for the detection of prostate carcinoma. RESULTS: To the authors' knowledge, this was the first time that multivariate logistic regression analysis was used to decide whether to perform prostate biopsies based on risk profiles rather than on single cutoff levels. For the detection of prostate carcinoma, at sensitivity levels of 90--95%, the ANN was 150--200% more specific than the standard cutoff points. For screened volunteers with total PSA levels below 4 ng/mL, ANN showed a lower cancer predictive ability in comparison with volunteers with total PSA levels above 4 ng/mL. However, the ANN was approximately 150--200% more specific than the standard cutoff levels in both groups. CONCLUSIONS: At high sensitivity levels, ANN increased the specificity for prostate carcinoma detection in a PSA-based screened population. The improvement in specificity between standard cutoff levels and ANN ranged between 150--200% and was not affected by the presence of benign prostatic hyperplasia or prostatitis.

Neural network and regression predictions of 5-year survival after colon carcinoma treatment.

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) for patients with colon carcinoma was used to develop several artificial neural network and regression-based models. These models were designed to predict the likelihood of 5-year survival after primary treatment for colon carcinoma. METHODS: Two modeling methods were used in the study. Artificial neural networks were used to select the more important variables from the NCDB database and model 5-year survival. A standard parametric logistic regression also was used to model survival and the two methods compared on a prospective set of patients not used in model development. RESULTS: The neural network yielded a receiver operating characteristic (ROC) area of 87.6%. At a sensitivity to mortality of 95% the specificity was 41%. The logistic regression yielded a ROC area of 82% and at a sensitivity to mortality of 95% gave a specificity of 27%. CONCLUSIONS: The neural network found a strong pattern in the database predictive of 5-year survival status. The logistic regression produced somewhat less accurate, but good, results.

Introduction to artificial neural networks for physicians: taking the lid off the black box.

BACKGROUND: Over the past 5 years, a steady stream of publications has discussed the use of artificial neural networks (ANNs) for urologic and other medical applications. The pace of this research has increased recently, and deployed products based on this technology are now appearing. Before these tools can be widely accepted by clinicians and researchers, a deeper level of understanding of ANNs is necessary. This article attempts to lay some of the groundwork needed to facilitate this familiarity. METHODS: A short discussion of neural network history is included for background. This is followed by an in-depth discussion of how and why ANNs work. This discussion includes the relationship between ANNs and statistical regression. An investigation of issues associated with neural networks follows, applicable to both general and urologic-specific applications. RESULTS: Neural networks are computer models that have been studied extensively for over 50 years, with prostate cancer applications since 1994. From a biological viewpoint, ANNs are artificial analogues of data structures that exist in nervous systems. From a numeric viewpoint, ANNs are matrices of numbers whose values comprise knowledge that is distilled from historic databases. Many types of neural networks are analogous to well-known statistical methods. CONCLUSIONS: ANNs are complex numeric constructs, but no more complex than similar statistical methods. However, several issues associated with neural network derivation demand that developers apply rigorous engineering practices in their studies.

Neural network analysis of the prediction of cancer recurrence following debulking laparotomy and chemotherapy in stages III and IV ovarian cancer.

An artificial neural network (ANN) has been developed to predict the presence or absence of cancer following debulking laparotomy and chemotherapy in patients with stages III and IV ovarian cancer. The presence or absence of a residual gross tumor or microscopic disease was determined by a second-look laparotomy. The ANN was trained and tested using detailed operative findings and related surgical procedures associated with the debulking surgery. The ANN predictive results were compared with linear and logistic regression. The ANN significantly outperformed both logistic and linear regression analyses, but additional cases are needed to validate the network.

Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth.

We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth. alpha(1)-adrenergic agonist-induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator-activated receptor-alpha (PPARalpha) response element. Ventricular pressure overload studies in mice, together with PPARalpha overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPARalpha gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPARalpha is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.

The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism.

The postnatal mammalian heart uses mitochondrial fatty acid oxidation (FAO) as the chief source of energy to meet the high energy demands necessary for pump function. Flux through the cardiac FAO pathway is tightly controlled in accordance with energy demands dictated by diverse physiologic and dietary conditions. In this report, we demonstrate that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO. In response to the metabolic stress imposed by pharmacologic inhibition of mitochondrial long-chain fatty acid import with etomoxir, PPARa serves as a molecular 'lipostat' factor by inducing the expression of target genes involved in fatty acid utilization including enzymes involved in mitochondrial and peroxisomal beta-oxidation pathways. In mice lacking PPARalpha (PPARalpha-/- mice), etomoxir precipitates a cardiac phenotype characterized by myocyte lipid accumulation. Surprisingly, this metabolic regulatory response is influenced by gender as demonstrated by the observation that male PPARalpha-/- mice are more susceptible to the metabolic stress compared to female animals. These results identify an important role for PPARalpha in the control of cardiac lipid metabolism.

Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a B-precursor immunophenotype: the Pediatric Oncology Group experience.

Five pediatric patients are described with acute lymphoblastic leukemia (ALL) who at presentation had clinical findings suggestive of B cell ALL and lymphoblasts with FAB L3 morphology and the characteristic t(8;14)(q24;q32). However, the leukemia cells of all five patients failed to express surface immunoglobulin (sIg) and kappa or lambda light chains. Based on initial immunophenotyping results consistent with B-precursor ALL, four of these cases were initially treated with conventional ALL chemotherapy. These four patients were switched to B cell ALL treatment protocols once cytogenetic results became available revealing the 8;14 translocation. The fifth case was treated with B cell ALL therapy from the outset. Four of the five patients are in complete remission at 64, 36, 29 and 13 months from diagnosis. One patient relapsed and died 6 months after initial presentation. These five unusual cases with clinical B cell ALL, the t(8;14), and FAB L3 morphology, but negative sIg, demonstrate the importance of careful and multidisciplinary evaluation of leukemic cells with morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha.

To explore the gene regulatory mechanisms involved in the metabolic control of cardiac fatty acid oxidative flux, the expression of muscle-type carnitine palmitoyltransferase I (M-CPT I) was characterized in primary cardiac myocytes in culture following exposure to the long-chain mono-unsaturated fatty acid, oleate. Oleate induced steady-state levels of M-CPT I mRNA 4.5-fold. The transcription of a plasmid construct containing the human M-CPT I gene promoter region fused to a luciferase gene reporter transfected into cardiac myocytes, was induced over 20-fold by long-chain fatty acid in a concentration-dependent and fatty acyl-chain length-specific manner. The M-CPT I gene promoter fatty acid response element (FARE-1) was localized to a hexameric repeat sequence located between 775 and 763 base pairs upstream of the initiator codon. Cotransfection experiments with expression vectors for the peroxisome proliferator-activated receptor alpha (PPARalpha) demonstrated that FARE-1 is a PPARalpha response element capable of conferring oleate-mediated transcriptional activation to homologous or heterologous promoters. Electrophoretic mobility shift assays demonstrated that PPARalpha bound FARE-1 with the retinoid X receptor alpha. The expression of M-CPT I in hearts of mice null for PPARalpha was approximately 50% lower than levels in wild-type controls. Moreover, a PPARalpha activator did not induce cardiac expression of the M-CPT I gene in the PPARalpha null mice. These results demonstrate that long-chain fatty acids regulate the transcription of a gene encoding a pivotal enzyme in the mitochondrial fatty acid uptake pathway in cardiac myocytes and define a role for PPARalpha in the control of myocardial lipid metabolism.