A Case of Multivessel Coronary Artery Disease and Anomalous Origin of the Right Coronary Artery With a Malignant Course Presenting With Non-exertional Chest Discomfort and Brugada Phenocopy.

Coronary artery anomalies (CAAs) are an uncommon cause of chest pain in the younger population. Misdiagnosis can be detrimental and lead to sudden cardiac deaths. We present a 62-year-old male with a past medical history significant for chest pain history with a workup in 2001 presumed to be non-cardiac in origin from bronchial asthma. He presented from a Micronesian Island for the evaluation of non-exertional chest discomfort. Further workup showed a Brugada type I pattern on ECG and ST wave depressions on anterolateral and inferior leads with associated AVR elevation on exercise stress testing. Further ischemic workup with coronary angiography revealed right dominant circulation with three-vessel coronary artery disease (CAD), including mid-left anterior descending (LAD) artery chronic total occlusion (CTO) with the right to left collaterals, left circumflex, and right coronary artery (RCA) with the accompanied anomalous origin of RCA. The patient underwent surgical correction of the anomalous RCA and coronary artery bypass grafting for the multi-vessel CAD. CAAs are usually found incidentally during ischemic workups similar to this case. Patients with CAAs can be managed conservatively with caution regarding physical activity. However, high-risk patients will warrant surgical treatment to avoid sudden cardiac death. The diagnosis of CAAs can be challenging and prone to misdiagnosis and maltreatment. It may be beneficial to pursue this in younger patients with ischemia-like symptoms. Further studies should be performed to identify the true incidence and guide medical practitioners regarding the risks, costs, and benefits of diagnosing and surgically treating CAAs in the general population.

Effect of Low-Level Er: YAG (2940 nm) laser irradiation on the photobiomodulation of mitogen-activated protein kinase cellular signaling pathway of rodent cementoblasts.

BACKGROUNDS: Dental avulsion due to trauma, especially in young patients, is a worldwide problem, requiring tooth replacement. Delayed replantation could cause tooth loss when the cementum is severely damaged. A small number of studies has reported that photobiomodulation (PBM) therapy using Er: YAG laser irradiation activates cellular signaling responses in different cell types, resulting in a variety of favorable biological effects. The aim of this in vitro study was to evaluate the potential biostimulatory effect of low-level Er: YAG laser irradiation on the biological responses of cultured mouse cementoblasts (OCCM-30), including the mitogen-activated protein kinases (MAPKs). METHODS: OCCM-30 cells were exposed to 2940 nm Er: YAG laser irradiation for 15 s at 0.34 W (pulse duration of 100 or 1000 µs, 17 mJ/pulse) at energy densities of 1 or 2 J/cm2. Irradiated and non-irradiated OCCM-30 cells were tested for migration (Scratch assay), proliferation (MTS assay) and functional differentiation (Alizarin Red S assay). Lumican (Lum) and Fibromodulin (Fmod) gene expression, and activation of MAPKs, were assessed by RT-PCR and Western blotting, respectively. RESULTS: Low-level Er: YAG laser irradiation at 2 J/cm2 and pulse duration of 1000 µs resulted in the highest migration rate and proliferation. Moreover, the pulse duration irradiation of 100 µs increased Lum expression. Fmod expression was increased after 1000 µs pulse duration laser stimulation. Low-level Er: YAG laser irradiation increased the mineralization of OCCM-30 cells after 7 days and activated ERK1/2, P38 and JNK signaling. CONCLUSIONS: Low-level Er: YAG laser irradiation induces OCCM-30 cell migration, proliferation and differentiation, and activates the MAPK signaling pathway.

Fibroelastic Tissue Ring Causing ECMO Catheter Obstruction: An Unusual Complication of Avalon Elite Catheter Insertion.

The Avalon Elite catheter (Maquet Cardiopulmonary, Rastatt, Germany) is a bicaval catheter for single-site cannulation that can be used in the initiation of venovenous extracorporeal membrane oxygenation (ECMO) or as a transition from venoarterial ECMO. We report a unique complication of tissue obstructing the outflow aperture during insertion. (Level of Difficulty: Advanced.).

The prostate health index selectively identifies clinically significant prostate cancer.

PURPOSE: The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S., Europe and Australia. We investigate whether phi improves specificity for detecting clinically significant prostate cancer and can help reduce prostate cancer over diagnosis. MATERIALS AND METHODS: From a multicenter prospective trial we identified 658 men age 50 years or older with prostate specific antigen 4 to 10 ng/ml and normal digital rectal examination who underwent prostate biopsy. In this population we compared the performance of prostate specific antigen, % free prostate specific antigen, [-2]proPSA and phi to predict biopsy results and, specifically, the presence of clinically significant prostate cancer using multiple criteria. RESULTS: The Prostate Health Index was significantly higher in men with Gleason 7 or greater and "Epstein significant" cancer. On receiver operating characteristic analysis phi had the highest AUC for overall prostate cancer (AUCs phi 0.708, percent free prostate specific antigen 0.648, [-2]proPSA 0.550 and prostate specific antigen 0.516), Gleason 7 or greater (AUCs phi 0.707, percent free prostate specific antigen 0.661, [-2]proPSA 0.558, prostate specific antigen 0.551) and significant prostate cancer (AUCs phi 0.698, percent free prostate specific antigen 0.654, [-2]proPSA 0.550, prostate specific antigen 0.549). At the 90% sensitivity cut point for phi (a score less than 28.6) 30.1% of patients could have been spared an unnecessary biopsy for benign disease or insignificant prostate cancer compared to 21.7% using percent free prostate specific antigen. CONCLUSIONS: The new phi test outperforms its individual components of total, free and [-2]proPSA for the identification of clinically significant prostate cancer. Phi may be useful as part of a multivariable approach to reduce prostate biopsies and over diagnosis.

Prospective multicenter evaluation of the Beckman Coulter Prostate Health Index using WHO calibration.

PURPOSE: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers. MATERIALS AND METHODS: Prostate specific antigen, percent free prostate specific antigen and [-2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([-2]proPSA/free prostate specific antigen) × PSA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values. RESULTS: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p <0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration. CONCLUSIONS: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone.

Multi-center analytical performance evaluation of the Access Hybritech® p2PSA immunoassay.

BACKGROUND: Total PSA assays measure both complexed and non-complexed forms of PSA while free PSA assays only measure non-complexed forms. Free PSA is a mixture of isoforms including immature PSA (proPSA) with retained portions of the leader sequence (e.g. [-7], [-4], and [-2]proPSA) and nicked forms (BPSA). ProPSA isoforms in male sera have been associated with prostate cancer. This study characterized the analytical performance of a chemiluminescent immunoassay for [-2]proPSA. METHODS: The Access Hybritech p2PSA assay is a sandwich immunoassay using an anti-[-2]proPSA monoclonal antibody attached to paramagnetic beads and an anti-PSA monoclonal antibody conjugated to alkaline phosphatase calibrated with recombinant [-2]proPSA. Analytical studies including sensitivity (CLSI EP17-A) and imprecision (CLSI EP5-A2) were performed. RESULTS: The Access Hybritech p2PSA assay for [-2]proPSA had a dynamic range of 0.5 to 5000 pg/ml. The total CV of the assay was <7% for [-2]proPSA concentrations between 20 and 1000 pg/ml. The LOB was 0.50 pg/ml, LOD 0.69 pg/ml, and LOQ 3.23 pg/ml (20% CV). There was no hook effect up to 15,000 pg/ml. There was a <5% difference between calibrator and reagent lots and no interference from normal serum constituents. CONCLUSIONS: The Access Hybritech p2PSA assay is a robust immunoassay for the measurement of serum [-2]proPSA.

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range.

PURPOSE: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. MATERIALS AND METHODS: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. RESULTS: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. CONCLUSIONS: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness.

BACKGROUND: The free prostate-specific antigen (PSA) isoform, [-2]proPSA, has been shown to be associated with prostate cancer. The study objective was to characterize the clinical utility of serum [-2]proPSA for prostate cancer detection and assess its association with aggressive disease. METHODS: From among 669 subjects in a prospective prostate cancer detection study at four National Cancer Institute Early Detection Research Network clinical validation centers, 566 were eligible. Serum PSA, free PSA, and [-2]proPSA were measured (Beckman Coulter Access 2 Analyzer). RESULTS: Two hundred and forty-five (43%) of the 566 participants had prostate cancer on biopsy. At 70% specificity, the sensitivity of %[-2]proPSA ([-2]proPSA/fPSA) was 54% [95% confidence interval (CI), 48-61%; null hypothesis, 40%]. Including %[-2]proPSA in a multivariate prediction model incorporating PSA and %fPSA improved the performance (P<0.01). In the 2 to 4 ng/mL PSA range, %[-2]proPSA outperformed %fPSA (receiver operator characteristic-areas under the curve, 0.73 versus 0.61; P=0.01). At 80% sensitivity, %[-2]proPSA had significantly higher specificity (51.6%; 95% CI, 41.2-61.8%) than PSA (29.9%; 95% CI, 21.0-40.0%) and %fPSA (28.9%; 95% CI, 20.1-39.0%). In the 2 to 10 ng/mL PSA range, a multivariate model had significant improvement (area under the curve, 0.76) over individual PSA forms (P<0.01 to <0.0001). At 80% sensitivity, the specificity of %[-2]proPSA (44.9%; 95% CI, 38.4-51.5%) was significantly higher than PSA (30.8%; 95% CI, 24.9-37.1%) and relatively higher than %fPSA (34.6%; 95% CI, 28.5-41.4%). %[-2]proPSA increased with increasing Gleason score (P<0.001) and was higher in aggressive cancers (P=0.03). CONCLUSIONS: In this prospective study, %[-2]proPSA showed potential clinical utility for improving prostate cancer detection and was related to the risk of aggressive disease. IMPACT: The addition of %[-2]proPSA could affect the early detection of prostate cancer.

Effects of immunomodulatory and organism-associated molecules on the permeability of an in vitro blood-brain barrier model to amphotericin B and fluconazole.

Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P < or = 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P < or = 0.04). TNF-alpha and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P < or = 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-alpha decreased tight-junction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1beta, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-alpha and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.

[Cost-utility analysis of insulin pumps compared to multiple daily doses of insulin in patients with type 1 diabetes mellitus in Spain]. / Análisis coste-utilidad de las bombas de insulina frente a múltiples dosis diarias en pacientes con diabetes mellitus tipo 1 en españa.

BACKGROUND: The use of continuous subcutaneous insulin infusion (CSII) for treating Type I diabetes mellitus (DM1) has been related to better metabolic control compared it to daily multiple insulin injections (DMI) and thus to a lowering of the related costs. However, this therapy is now being used to a lesser extent due, at least partially, to the higher initial cost of purchase. This study is aimed at estimating the clinical and economic consequences of using CSII as compared to DMI by means of a cost-utility analysis. METHODS: A mathematical simulation model was adapted using nationwide clinical and economic data to simulate the long-term clinical and economic consequences for a DM1 patient. The time horizon was the patient's lifetime, including only direct healthcare costs and updating both costs and benefits at an annual 3% rate. RESULTS: In the basecase, the patients treated using CSII gained 0.890 years (p < 0.05) and 0.852 QALYs (p < 0.05). CSII treatment gives rise to an incremental average cost of 25,523 Euro (p < 0.05) per patient treated, which gave us an incremental cost- utility ratio of 29,947 Euro-QALY [CI 95% (29,519; 30,375)]. CONCLUSIONS: The improvement in the glucose control among those patients treated using CSII was related to an overall lower cost in the handling of DM1 patients, which was found to have a favourable cost-utility ratio in comparison to conventional MDI treatment.

Análisis coste-utilidad de las bombas de insulina frente a múltiples dosis diarias en pacientes con diabetes mellitus tipo 1 en España / Cost-utility analysis of insulin pumps compared to multiple daily doses of insulin in patients with type 1 diabetes mellitus in Spain

Fundamento: El uso de bombas de infusión continua de insulina(BICI) para la diabetes mellitus tipo 1 (DM1) se ha relacionadocon un mejor control metabólico al compararlo con las múltiplesdosis de insulina (MDI). Este mejor control puede traducirse en unadisminución de las complicaciones asociadas a la DM1 y por lo tantouna reducción de los costes asociados. Sin embargo el uso de estaterapia ha quedado mermado, al menos en parte, debido a su mayorcoste inicial de adquisición. El objetivo del presente estudio fue estimarlas consecuencias clínicas y económicas del uso de BICI frentea MDI a través de un análisis de coste-utilidad.Métodos: Se adaptó un modelo matemático de simulación queemplea datos clínicos y económicos de ámbito nacional, para simularlas consecuencias clínicas y económicas a largo plazo de unpaciente con DM1. El horizonte temporal fue el de toda la vida delpaciente, incluyendo sólo costes directos sanitarios, y actualizandotanto costes como beneficios a una tasa del 3% anual.Resultados: En el caso base los pacientes tratados con BICIexperimentaron una ganancia de vida de 0,890 años (p<0,05) y 0,852AVACs (p<0,05). El tratamiento con BICI produce un coste medioincremental de 25.523 ? (p<0,05) por paciente tratado, lo que noscondujo a un ratio coste- utilidad incremental de 29.947 ?/AVAC [IC95% (29.519, 30.375)].Conclusiones: La mejora en el control glucémico en pacientescon BICI se asoció a una reducción del coste global del manejo depacientes con DM1, y resultó tener una relación coste-utilidad favorableal compararla con el tratamiento convencional MDI(AU)

Background: The use of continuous subcutaneous insulin infusion(CSII) for treating Type I diabetes mellitus (DM1) has beenrelated to better metabolic control compared it to daily multipleinsulin injections (DMI) and thus to a lowering of the related costs.However, this therapy is now being used to a lesser extent due, atleast partially, to the higher initial cost of purchase. This study isaimed at estimating the clinical and economic consequences ofusing CSII as compared to DMI by means of a cost-utility analysis.Methods: A mathematical simulation model was adapted usingnationwide clinical and economic data to simulate the long-term clinicaland economic consequences for a DM1 patient. The time horizonwas the patient's lifetime, including only direct healthcare costsand updating both costs and benefits at an annual 3% rate.Results: In the basecase, the patients treated using CSII gained0.890 years (p<0.05) and 0.852 QALYs (p<0.05). CSII treatmentgives rise to an incremental average cost of 25,523 ? (p<0.05) perpatient treated, which gave us an incremental cost- utility ratio of29,947 ?/QALY [CI 95% (29,519; 30,375)].Conclusions: The improvement in the glucose control amongthose patients treated using CSII was related to an overall lower costin the handling of DM1 patients, which was found to have a favourablecost-utility ratio in comparison to conventional MDI treatment(AU)