Evaluation of spin in reviews of biodegradable balloon spacers for massive irreparable rotator cuff tears.

HYPOTHESIS: Clinical studies are often at risk of spin, a form of bias where beneficial claims are overstated while negative findings are minimized or dismissed. Spin is often more problematic in abstracts given their brevity and can result in the misrepresentation of a study's actual findings. The goal of this study is to aggregate primary and secondary studies reporting the clinical outcomes of the use of subacromial balloon spacers in the treatment of massive irreparable rotator cuff tears to identify the incidence of spin and find any significant association with study design parameters. MATERIALS AND METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Independent searches were completed on 2 databases (PubMed and Embase) for primary studies, systematic and current concepts reviews, and meta-analyses and the results were compiled. Two authors independently screened the studies using a predetermined inclusion criteria and aggregated data including titles, publication journals and years, authors, study design, etc. Each study was independently assessed for the presence of 15 different types of spin. Statistical analysis was conducted to identify associations between study characteristics and spin. RESULTS: Twenty-nine studies met the inclusion criteria for our analysis, of which 10 were reviews or meta-analyses and 19 were primary studies. Spin was identified in every study except for 2 (27/29, 93.1%). Type 3 spin, "Selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention" and type 9 spin, "Conclusion claims the beneficial effect of the experimental treatment despite reporting bias" were most frequently noted in our study, both observed in 12/29 studies (41.4%). Date of publication, and adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses or "The International Prospective Register of Systematic Reviews" were study characteristics associated with a higher rate of certain types of spin. There was a statistically significant association between disclosure of external study funding source and the presence of spin type 4, but none of the other forms of spin. CONCLUSION: Spin is highly prevalent in the abstracts of primary studies, systematic reviews, and meta-analyses discussing the use of subacromial balloon spacer technology in the treatment of massive irreparable rotator cuff tears. Our findings revealed that spin in the abstract tended to favor the balloon spacer intervention. Further efforts are required in the future to mitigate spin within the abstracts of published manuscripts.

The impact of national holidays on postoperative radiotherapy of squamous cell carcinoma of the head and neck.

Background: Delays in starting postoperative radiotherapy (PORT) have been established as negative predictors for clinical outcomes in head and neck squamous cell carcinomas (HNSCC). Our study aimed to examine the effect of delays during PORT, and the impact of national holidays in Canada, a publicly funded system, on oncologic outcomes such as Overall Survival (OS) and Local Recurrence (LR). Methods: The provincial cancer registry was queried to obtain demographic, pathologic, and outcomes data from cancer patients treated for all squamous cell carcinomas of the head and neck region treated between January 1, 2007 and November 30, 2019. All extracted information was cross-referenced and supplemented by chart review of patient electronic medical records. Extracted data were analyzed for OS and LR, in the context of Canadian national holidays causing delays during PORT. Results: 1433 patients treated for HNSCCs were identified, of whom 338 were treated curatively with surgery followed by PORT. 68.6% of patients experienced at least one day of interruption during treatments due to holidays. LR was 15.4% and OS was 59.6% at 5 years. Treatment interruptions by holidays were predictive of local recurrence (HR, 2.38; 95% CI 1.17-4.83; p = 0.017). Patients that developed early recurrence prior to PORT had very poor oncologic outcomes. Conclusion: Our findings were consistent with previously published studies in limiting the interval between surgery and PORT. We identified the novel finding of paired holidays as a significant predictor in determining LR, suggesting the importance of modifying RT delivery schedules and timing.

What does degeneration at the cervicothoracic junction tell us? A kinematic MRI study of 93 individuals.

PURPOSE: Current decision-making in multilevel cervical fusion weighs the potential to protect adjacent levels and reduce reoperation risk by crossing the cervicothoracic junction (C7/T1) against increased operative time and risk of complication. Careful planning is required, and the planned distal and adjacent levels should be assessed for degenerative disc disease (DDD). This study assessed whether DDD at the cervicothoracic junction was associated with DDD, disc height, translational motion, or angular variation in the adjacent superior (C6/C7) or inferior (T1/T2) levels. METHODS: This study retrospectively analyzed 93 cases with kinematic MRI. Cases were randomly selected from a database with inclusion criteria being no prior spine surgery and images having sufficient quality for analysis. DDD was assessed using Pfirrmann classification. Vertebral body bone marrow lesions were assessed using Modic changes. Disc height was measured at the mid-disc in neutral and extension. Translational motion and angular variation were calculated by assessing translational or angular motion segment integrity respectively in flexion and extension. Statistical associations were assessed with scatterplots and Kendall's tau. RESULTS: DDD at C7/T1 was positively associated with DDD at C6/C7 (tau = 0.53, p < 0.01) and T1/T2 (tau = 0.58, p < 0.01), with greater disc height in neutral position at T1/T2 (tau = 0.22, p < 0.01), and with greater disc height in extended position at C7/T1 (tau = 0.17, p = 0.04) and at T1/T2 (tau = 0.21, p < 0.01). DDD at C7/T1 was negatively associated with angular variation at C6/C7 (tau = - 0.23, p < 0.01). No association was appreciated between DDD at C7/T1 and translational motion. CONCLUSION: The association of DDD at the cervicothoracic junction with DDD at the adjacent levels emphasizes the necessity for careful selection of the distal level in multilevel fusion in the distal cervical spine.

Timing of treatment in osteosarcoma: challenges and perspectives - a scoping review.

BACKGROUND: The timing of events in the management of osteosarcoma may be critical for patient survivorship; however, the prognostic value of factors such as onset of symptoms or initiation of therapy in these patients has not been studied. This study sought to review the literature reporting treatment of osteosarcoma to determine the utility of event timing as a prognostic indicator. Due to significant heterogeneity in the literature, this study was conducted as a scoping review to assess the current state of the literature, identify strengths and weaknesses in current reporting practices, and to propose avenues for future improvement. MAIN BODY: This review screened 312 peer-reviewed studies of osteosarcoma in any anatomic location published in an English journal for reporting of an event timing metric of any kind in a population of 6 or more. Thirty-seven studies met inclusion/exclusion criteria and were assessed for level of evidence, quality, and event timing metric. Reviewers also collated: publication year, population size, population age, tumor site, tumor type, surgical treatment, and adjuvant medical treatment. Extracted event timing data were further characterized using nine standardized categories to enable systematic analysis. The reporting of event timing in the treatment of osteosarcoma was incomplete and heterogenous. Only 37 of 312 (11.9%) screened studies reported event timing in any capacity. The period between patient-reported symptom initiation and definitive diagnosis was the most reported (17/37, 45.9%). Symptom duration was the second most reported period (10/37, 27.0%). Event timing was typically reported incidentally and was never rigorously incorporated into data analysis or discussion. No studies considered the impact of event timing on a primary outcome. The six largest studies were assessed in detail to identify pearls for future researchers. Notable shortcomings included the inadequate reporting of the definition of an event timing period and the pooling of patients into poorly defined timing groups. CONCLUSIONS: Inconsistent reporting of event timing in osteosarcoma treatment prevents the development of clinically useful conclusions despite evidence to suggest event timing is a useful prognostic indicator. Consensus guidelines are necessary to improve uniformity and utility in the reporting of event timing.

Evaluation of spin in systematic reviews and meta-analyses of superior capsular reconstruction.

BACKGROUND: Small, preliminary studies and the systematic reviews on superior capsular reconstruction (SCR) that collate data are at increased risk spin. This study's primary objective was to identify, describe, and account for the incidence of spin in systematic reviews of SCR. This study's secondary objective was to characterize the studies in which spin was identified to determine whether identifiable patterns of characteristics exist among studies with spin. METHODS: This study was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a predetermined protocol. A search was conducted on the PubMed and Embase databases for systematic reviews and meta-analyses on SCR. Screening and data extraction were conducted independently by 2 authors. Each included study's abstract was assessed for the presence of the 15 most common types of spin, with full texts reviewed during cases of disagreement or for clarification. General data that were extracted included study title, authors, publication year, journal, level of evidence, study design, funding source, reported adherence to PRISMA guidelines, preregistration of the study protocol, and primary and secondary outcome measures. Full texts were used in the assessment of study quality per AMSTAR 2. RESULTS: We identified 53 studies during our search, of which 17 met the inclusion criteria. At least 1 form of spin was observed in all 17 studies. The most common types of spin were type 5 ("The conclusion claims the beneficial effect of the experimental treatment despite a high risk of bias in primary studies") and type 9 ("Conclusion claims the beneficial effect of the experimental treatment despite reporting bias"), both of which were observed in 11 studies (11 of 17, 65%). A statistically significant association between lower level of evidence and type 5 ("The conclusion claims the beneficial effect of the experimental treatment despite a high risk of bias in primary studies") was observed (P = .0175). A statistically significant association was also found between more recent year of publication and the spin category misleading interpretation (P = .0398), and between lower AMSTAR 2 score and type 13 ("Failure to specify the direction of the effect when it favors the control intervention") (P = .0260). No other statistical associations between other study characteristics were observed. CONCLUSION: Spin is highly prevalent in abstracts of SCR systematic reviews and meta-analyses. An association was found between the presence of spin and lower level of evidence, year of publication, and AMSTAR 2 ratings.

Stereotactic radiotherapy as planned boost after definitive radiotherapy for head and neck cancers: Systematic review.

Management of locoregionally advanced head and neck cancers (HNCs) remains a challenge. Some groups have attempted to use stereotactic radiotherapy (SBRT) to deliver "boost" treatment following conventional radiotherapy to improve local control (LC) and overall survival (OS), while aiming for acceptable toxicities. Medline, EMBASE, and Cochrane Library databases were queried for SBRT as curative-intent planned boost in HNC after conventional radiotherapy. Individual studies were reviewed from inception until January 2021, extracting patient, treatment, and outcome data. Nine studies met inclusion criteria, representing 454 unique patients treated with curative intent across multiple head and neck sites with conventional radiotherapy. At 3 years, median LC was 92% (90%-98%), and median OS was 80% (75%-91%). Seven treatment-related grade 5 toxicities (1.5%) were reported. Despite acceptable LC and OS rates, there were severe treatment-related late toxicities. As such, SBRT boost should only be used in investigational settings until more data is available.

Stereotactic Radiation Therapy for De Novo Head and Neck Cancers: A Systematic Review and Meta-Analysis.

PURPOSE: Stereotactic body radiation therapy (SBRT) for de novo (previously untreated) head and neck cancers (HNCs) is increasingly being used in medically unfit patients. A systematic review of SBRT was conducted for previously untreated HNCs. METHODS AND MATERIALS: Medline (PubMed), excerpta medica database, and Cochrane Library databases were queried from inception until July 2020. Comparative outcome data were extracted where available up to 5 years. Results from random-effect models were presented in forest plots, with between-study heterogeneity evaluated by I2 statistics and Q-tests. RESULTS: Nine studies met inclusion criteria, representing 157 patients. Local control rates at 1, 2, and 3 years were as follows: 90.7% (95% confidence interval, 80.6%-95.6%), 81.8% (67.2%-90.7%), and 73.5% (40.4%-90.5%), respectively. Overall survival at 1, 2, and 3 years was 75.9% (75.1%-76.6%), 61.1% (60.3%-61.9%), and 50.0% (48.8%-51.4%), respectively. Late grade 3 to 4 toxicity rate was 3.3% (0.2%-10.2%), and late grade 5 toxicity rate was 0.1% (0.0%-1.0%). CONCLUSIONS: SBRT for de novo HNC is safe and effective in providing locoregional control, with acceptable toxicities in most subsites. This finding warrants broader validation to guide its scope.

Use of short roll C-arm computed tomography and fully automated 3D analysis tools to guide transcatheter aortic valve replacement.

Determination of the coplanar view is a critical component of transcatheter aortic valve replacement (TAVR). The safety and accuracy of a novel reduced angular range C-arm computed tomography (CACT) approach coupled with a fully automated 3D analysis tool package to predict the coplanar view in TAVR was evaluated. Fifty-seven patients with severe symptomatic aortic stenosis deemed prohibitive-risk for surgery and who underwent TAVR were enrolled. Patients were randomized 2:1 to CACT vs. angiography (control) in estimating the coplanar view. These approaches to determine the coplanar view were compared quantitatively. Radiation doses needed to determine the coplanar view were recorded for both the CACT and control patients. Use of CACT offered good agreement with the actual angiographic view utilized during TAVR in 34 out of 41 cases in which a CACT scan was performed (83 %). For these 34 cases, the mean angular magnitude difference, taking into account both oblique and cranial/caudal angulation, was 1.3° ± 0.4°, while the maximum difference was 7.3°. There were no significant differences in the mean total radiation dose delivered to patients between the CACT and control groups as measured by either dose area product (207.8 ± 15.2 Gy cm(2) vs. 186.1 ± 25.3 Gy cm(2), P = 0.47) or air kerma (1287.6 ± 117.7 mGy vs. 1098.9 ± 143.8 mGy, P = 0.32). Use of reduced-angular range CACT coupled with fully automated 3D analysis tools is a safe, practical, and feasible method by which to determine the optimal angiographic deployment view for guiding TAVR procedures.

Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.

Folylpolyglutamate synthase (FPGS) plays a critical role in intracellular folate homeostasis. FPGS-induced polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence FPGS modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression and aberrant DNA methylation is mechanistically linked cancer development. We investigated whether FPGS modulation would affect global and gene-specific promoter DNA methylation with consequent functional effects on gene expression profiles in HCT116 colon and MDA-MB-435 breast cancer cells. Although FPGS modulation altered global DNA methylation and DNA methyltransferases (DNMT) activity, the effects of FPGS modulation on global DNA methylation and DNMT activity could not be solely explained by intracellular folate concentrations and content of long-chain folylpolyglutamates, and it may be cell-specific. FPGS modulation influenced differential gene expression and promoter cytosine-guanine dinucleotide sequences (CpG) DNA methylation involved in cellular development, cell cycle, cell death and molecular transport. Some of the altered gene expression was associated with promoter CpG DNA methylation changes. In both the FPGS-overexpressed HCT116 and MDA-MB-435 cell lines, we identified several differentially expressed genes involved in folate biosynthesis and one-carbon metabolism, which might in part have contributed to the observed increased efficacy of 5-fluorouracil in response to FPGS overexpression. Our data suggest that FPGS modulation affects global and promoter CpG DNA methylation and expression of several genes involved in important biological pathways. The potential role of FPGS modulation in DNA methylation and its associated downstream functional effects warrants further studies.

Transfemoral Transcatheter Aortic Valve Replacement for Mixed Aortic Valve Disease in Child's Class C Liver Disease Prior to Orthotopic Liver Transplantation: A Case Report.

The American Association for the Study of Liver Diseases practice guidelines list severe cardiac disease as a contraindication to liver transplantation. Transcatheter aortic valve replacement has been shown to decrease all-cause mortality in patients with severe aortic stenosis who are not considered candidates for surgical aortic valve replacement. We report our experience of liver transplantation in a patient with severe aortic stenosis and moderate aortic insufficiency who underwent transcatheter aortic valve replacement with Child-Pugh Class C disease at a Model For End-Stage Liver Disease score of 29. The patient had a difficult post procedure course that was successfully medically managed. After liver transplantation the patient was discharged to home on postoperative day 11. The combination of cardiac disease and end stage liver disease is challenging but these patients can have a successful outcome despite very severe illness.

A Radiation Dose Reduction Technology to Improve Patient Safety During Cardiac Catheterization Interventions.

OBJECTIVES: A novel radiation dose reduction technology was evaluated in a cardiac catheterization laboratory during routine clinical care to determine if it could reduce radiation dose to patients undergoing coronary angiography and percutaneous coronary intervention. These results were compared to patients undergoing similar procedures in a cardiac catheterization laboratory without this technology. BACKGROUND: There is a safety priority in clinical care to reduce X-ray radiation dose to patients in order to lower the risk of deterministic and stochastic effects. Dose reduction technologies must be verified in clinical settings to prove if they reduce X-ray radiation dose and to what extent. METHODS: Radiation dose data and procedure characteristics of 268 consecutive patients were collected and analyzed from a cardiac catheterization laboratory with dose reduction technology installed (referred to as Lab A, n = 135) and from a cardiac catheterization laboratory without this technology (referred as Lab B, n = 133). RESULTS: For diagnostic procedures, the median total dose-area product in Lab A was reduced by 46% (P < 0.0001) compared to Lab B, with no differences in terms of body mass index (P = 0.180), total fluoroscopy times (P = 1), number of acquired images (P = 0.920), and contrast medium (P = 0.660). For interventional procedures, the median total dose-area product in Lab A was reduced by 34% (P = 0.015) compared to Lab B, with no differences in terms of body mass index (P = 0.665), total fluoroscopy times (P = 0.765), number of acquired images (P = 0.923), and contrast medium (P = 0.969). CONCLUSIONS: This new dose reduction technology significantly reduces X-ray radiation dose without affecting fluoroscopy time, number of images, and contrast medium used during diagnostic and interventional coronary procedures.

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.

γ-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways.

Removal of Impella® 2.5 while maintaining vascular access: a solution to a vascular quandary.

Cardiogenic shock (CS) in the setting of acute myocardial infarction is associated with high in-hospital mortality rates. Society guidelines provide a Class Ib recommendation for the use of hemodynamic support devices in patients with CS following ST-elevation myocardial infarction. Exchanging of hemodynamic support devices is often complicated by inability to maintain percutaneous vascular access upon device removal in the setting of anticoagulation. This report highlights one potential solution to the dilemma of maintaining vascular access following removal of an Impella® 2.5 mechanical support device to allow safe transition to a TandemHeart system in a patient with refractory CS.

Association of prior coronary artery bypass graft surgery with quality of care of patients with non-ST-segment elevation myocardial infarction: a report from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines.

BACKGROUND: The American College of Cardiology/American Health Association guidelines recommend both an early invasive strategy and administration of antiplatelet/anticoagulant therapy for high-risk patients in the absence of contraindications. Little is known about adherence to guideline recommendations in patients with prior coronary artery bypass graft (CABG) surgery presenting with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS: We analyzed 47,557 patients with NSTEMI in the 2007-2008 National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines. Treatment patterns were compared between patients with and without prior CABG surgery. Multivariable regression with generalized estimating equations evaluated the association between prior CABG and in-hospital outcomes. RESULTS: In this study, 8,790 NSTEMI patients (18.5%) had a history of CABG surgery. Prior CABG surgery was associated with a significantly lower adjusted likelihood of early cardiac catheterization (adjusted odds ratio [OR] 0.88, 95% CI 0.83-0.92), higher rates of short-term clopidogrel use (adjusted OR 1.08, 95% CI 1.02-1.14), and comparable use of anticoagulant therapy (adjusted OR 0.96, 95% CI 0.88-1.04). Adjusted risks of bleeding and in-hospital mortality did not differ significantly between the 2 groups (adjusted ORs 1.00, 95% CI 0.92-1.11 and 0.99, 95% CI 0.87-1.11, respectively). CONCLUSIONS: Patients with prior CABG surgery presenting with NSTEMI are often felt to be at high risk for adverse outcomes and therefore require aggressive treatment. Our study indicates that they are less likely to undergo guideline-recommended early cardiac catheterization but equally or more likely to receive guideline-recommended antiplatelet and anticoagulant therapy. This risk-treatment paradox, however, does not appear to negatively influence short-term clinical outcomes.

Clinical feasibility of a fully automated 3D reconstruction of rotational coronary X-ray angiograms.

BACKGROUND: Although fixed view x-ray angiography remains the primary technique for anatomic imaging of coronary artery disease, the known shortcomings of 2D projection imaging may limit accurate 3D vessel and lesion definition and characterization. A recently developed method to create 3D images of the coronary arteries uses x-ray projection images acquired during a 180 degrees C-arm rotation and continuous contrast injection followed by ECG-gated iterative reconstruction. This method shows promise for providing high-quality 3D reconstructions of the coronary arteries with no user interaction but requires clinical evaluation. METHODS AND RESULTS: The reconstruction strategy was evaluated by comparing the reconstructed 3D volumetric images with the 2D angiographic projection images from the same 23 patients to ascertain overall image quality, lesion visibility, and a comparison of 3D quantitative coronary analysis with 2D quantitative coronary analysis. The majority of the resulting 3D volume images were rated as having high image quality (66%) and provided the physician with additional clinical information such as complete visualization of bifurcations and unobtainable views of the coronary tree. True-positive lesion detection rates were high (90 to 100%), whereas false-positive detection rates were low (0 to 8.1%). Finally, 3D quantitative coronary analysis showed significant similarity with 2D quantitative coronary analysis in terms of lumen diameters and provided vessel segment length free from the errors of foreshortening. CONCLUSIONS: Fully automated reconstruction of rotational coronary x-ray angiograms is feasible, produces 3D volumetric images that overcome some of the limitations of standard 2D angiography, and is ready for further implementation and study in the clinical environment.

Percutaneous transcatheter closure of prosthetic mitral paravalvular leaks: are we there yet?

A potential complication of mitral valve replacement surgery is the development of a paravalvular leak (PVL). Percutaneous transcatheter closures of PVLs using a wide array of devices have been reported in the literature, although the procedural success rate of this approach remains variable. One major challenge of transcatheter mitral PVL closure lies in the ability to adequately visualize the area of interest to facilitate defect crossing and equipment selection. Furthermore, the current spectrum of devices available for off-label use in the closure of these unique defects remains limited. This review examines the current state of transcatheter prosthetic mitral PVL closure, describes our institution's experience using advanced imaging modalities for procedural guidance, and illustrates some of the limitations associated with using existing devices in transcatheter PVL closure.

Use of rapid prototyping in the care of patients with structural heart disease.

Advances in surgery, interventional techniques, and critical care have allowed more than 90% of children born with structural heart defects to survive into adulthood. In addition, advances in imaging technology continue to raise awareness of hemodynamically significant intracardiac shunt lesions in both adults and children. Adult cardiologists are now faced with the daunting task of caring for patients with complex structural heart lesions, a population subset that at one time was exclusively cared for by pediatric cardiologists and congenital heart disease specialists. Given the wide range of anatomic complexity present in patients with structural heart disease, the definition and anatomic clarification of their structural abnormalities through high-quality noninvasive imaging has become paramount. Current two-dimensional imaging techniques, however, remain limited in their ability to effectively illustrate the complex three-dimensional relationships present in structural heart disease. Rapid prototyping, a process by which three-dimensional digital surface models are converted into physical models, represents the next evolution in advanced image processing and may serve as a means to improve our understanding of the many forms of structural heart disease. Ultimately, the technology may be used to enhance the level of care provided to the growing number of patients with structural heart defects. We recently reviewed the novel cardiovascular application of rapid prototyping. This review examines the expanded applications of rapid prototyping in the care and treatment of adult patients with structural heart disease.

Induction of chemokines and chemokine receptors CCR2b and CCR4 in authentic human osteoclasts differentiated with RANKL and osteoclast like cells differentiated by MCP-1 and RANTES.

Chemokines MCP-1 and RANTES are induced when authentic bone resorbing human osteoclasts differentiate from monocyte precursors in vitro. In addition, MCP-1 and RANTES can stimulate the differentiation of cells with the visual appearance of osteoclasts, being multinuclear and positive for tartrate resistance acid phosphatase (TRAP +). We show here that MIP1alpha is also potently induced by RANKL during human osteoclast differentiation and that this chemokine also induces the formation of TRAP + multinucleated cells in the absence of RANKL. MIP1alpha was able to overcome the potent inhibition of GM-CSF on osteoclast differentiation, permitting the cells to pass through to TRAP + multinuclear cells, however these were unable to form resorption pits. Chemokine receptors CCR2b and CCR4 were potently induced by RANKL (12.6- and 49-fold, P = 4.0 x 10(-7) and 4.0 x 10(-8), respectively), while CCR1 and CCR5 were not regulated. Chemokine treatment in the absence of RANKL also induced MCP-1, RANTES and MIP1alpha. Unexpectedly, treatment with MCP-1 in the absence of RANKL resulted in 458-fold induction of CCR4 (P = 1.0 x 10(-10)), while RANTES treatment resulted in twofold repression (P = 1.0 x 10(-4)). Since CCR2b and CCR4 are MCP-1 receptors, these data support the existence of an MCP-1 autocrine loop in human osteoclasts differentiated using RANKL.

MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase, NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption.

MCP-1 (monocyte chemotactic protein-1) is a CC chemokine that is induced by receptor activator of NFkappaB ligand (RANKL) in human osteoclasts. In the absence of RANKL, treatment of human peripheral blood mononuclear cells with macrophage colony-stimulating factor and MCP-1 resulted in tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells that are positive for calcitonin receptor (CTR) and a number of other osteoclast markers, including nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). Although NFATc1 was strongly induced by MCP-1 and was observed in the nucleus, MCP-1 did not permit the formation of bone-resorbing osteoclasts, although these cells had the typical TRAP(+)/CTR(+) multinuclear phenotype of osteoclasts. Despite a similar appearance to osteoclasts, RANKL treatment was required in order for TRAP(+)/CTR(+) multinuclear cells to develop bone resorption activity. The lack of bone resorption was correlated with a deficiency in expression of certain genes related to bone resorption, such as cathepsin K and MMP9. Furthermore, calcitonin blocked the MCP-1-induced formation of TRAP(+)/CTR(+) multinuclear cells as well as blocking osteoclast bone resorption activity, indicating that calcitonin acts at two stages of osteoclast differentiation. Ablation of NFATc1 in mature osteoclasts did not prevent bone resorption activity, suggesting NFATc1 is involved in cell fusion events and not bone resorption. We propose that the MCP-1-induced TRAP(+)/CTR(+) multinuclear cells represent an arrested stage in osteoclast differentiation, after NFATc1 induction and cellular fusion but prior to the development of bone resorption activity.