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Development and Validation of a Simple Diagnostic Method to Detect Gain and Loss of Function Defects in Fibroblast Growth Factor-23.
Ramadan, AR, Shawar, SM, Alghamdi, MA
Hormone research in paediatrics. 2016;(1):45-52
Abstract
BACKGROUND Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates the homeostasis of phosphate and vitamin D. Three substitutions in the hormone are reported to cause autosomal dominant hypophosphatemic rickets and seven substitutions to cause autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC). Both disorders are rare in the general population and occur most often in the Eastern Mediterranean region and Africa. None of the mutations could be identified using standard restriction fragment length polymorphism. The only technique currently available to confirm the clinical diagnosis is DNA sequencing. METHODS Using a tri-primer ARMS-PCR, in vitro site-directed mutagenesis and DNA sequencing, we developed, verified and validated a rapid and reliable diagnostic test for the ten mutations in FGF23. RESULTS We generated a test for all ten mutations and confirmed each test by DNA sequencing. We increased the specificity of the test by introducing a mismatch at position -2 in the 3'-terminus of the reverse primer of the normal and the mutant sequences. Finally, using DNA sequencing, we validated the technique for FGF23/S129F substitution by testing samples from 80 individuals from two unrelated Arab families harboring HFTC. CONCLUSIONS This inexpensive and specific method could be adopted where DNA sequencing is not available or affordable.
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The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography.
Gottlieb, I, Miller, JM, Arbab-Zadeh, A, Dewey, M, Clouse, ME, Sara, L, Niinuma, H, Bush, DE, Paul, N, Vavere, AL, et al
Journal of the American College of Cardiology. 2010;(7):627-34
Abstract
OBJECTIVES This study was designed to evaluate whether the absence of coronary calcium could rule out >or=50% coronary stenosis or the need for revascularization. BACKGROUND The latest American Heart Association guidelines suggest that a calcium score (CS) of zero might exclude the need for coronary angiography among symptomatic patients. METHODS A substudy was made of the CORE64 (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors) multicenter trial comparing the diagnostic performance of 64-detector computed tomography to conventional angiography. Patients clinically referred for conventional angiography were asked to undergo a CS scan up to 30 days before. RESULTS In all, 291 patients were included, of whom 214 (73%) were male, and the mean age was 59.3 +/- 10.0 years. A total of 14 (5%) patients had low, 218 (75%) had intermediate, and 59 (20%) had high pre-test probability of obstructive coronary artery disease. The overall prevalence of >or=50% stenosis was 56%. A total of 72 patients had CS = 0, among whom 14 (19%) had at least 1 >or=50% stenosis. The overall sensitivity for CS = 0 to predict the absence of >or=50% stenosis was 45%, specificity was 91%, negative predictive value was 68%, and positive predictive value was 81%. Additionally, revascularization was performed in 9 (12.5%) CS = 0 patients within 30 days of the CS. From a total of 383 vessels without any coronary calcification, 47 (12%) presented with >or=50% stenosis; and from a total of 64 totally occluded vessels, 13 (20%) had no calcium. CONCLUSIONS The absence of coronary calcification does not exclude obstructive stenosis or the need for revascularization among patients with high enough suspicion of coronary artery disease to be referred for coronary angiography, in contrast with the published recommendations. Total coronary occlusion frequently occurs in the absence of any detectable calcification. (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218).
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Impact of calcification on diagnostic accuracy of 64-slice spiral computed tomography for detecting coronary artery disease: a single center experience.
Nazeri, I, Shahabi, P, Tehrai, M, Sharif-Kashani, B, Nazeri, A
Archives of Iranian medicine. 2010;(5):373-83
Abstract
BACKGROUND The main aim of our study was to investigate the influence of calcification on the accuracy of 64-slice computed tomography for identification of significant coronary artery disease. METHODS A contrast-enhanced 64-slice computed tomography was performed prior to invasive coronary angiography in 168 consecutive patients with suspected coronary artery disease. All coronary segments 1.5 mm or larger in diameter were evaluated for the presence or absence of significant coronary artery stenosis, defined as a diameter reduction of >50%. The patients were also ranked by total calcium score which was expressed in Agatston units and the impacts of calcification on diagnostic accuracy of 64-slice computed tomography were assessed. Results were compared with quantitative coronary angiography as the standard of reference. RESULTS The overall sensitivity, specificity, positive predictive value, and negative predictive value of 64-slice computed tomography for detection of significant stenosis were: by segments, 95%, 98%, 91%, and 99%, respectively; by patient, 98%, 97%, 96%, and 99%, respectively; and by artery, 94%, 93%, 91%, and 95%, respectively. In mild and moderate calcium scores (0-418 Agatston units), the sensitivity was 100%, specificity was 93%, positive predictive value was 97% and negative predictive value was 100%. Severe calcification (>419 Agatston units) reduced the sensitivity, specificity, positive, and negative predictive values of multi-slice computed tomography to 89%, 60%, 89%, and 60%, respectively. CONCLUSION Our study revealed that the 64-slice computed tomography is a highly accurate diagnostic modality for detecting hemodynamically significant coronary stenosis; however, severe calcification is considered as a shortcoming which limits the routine application of multi-slice computed tomography in daily practice.
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Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA).
Folsom, AR, Kronmal, RA, Detrano, RC, O'Leary, DH, Bild, DE, Bluemke, DA, Budoff, MJ, Liu, K, Shea, S, Szklo, M, et al
Archives of internal medicine. 2008;(12):1333-9
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BACKGROUND Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence. Our objective was to assess whether maximum carotid IMT or CAC (Agatston score) is the better predictor of incident CVD. METHODS A prospective cohort study of subjects aged 45 to 84 years in 4 ethnic groups, who were initially free of CVD (n = 6698) was performed, with standardized carotid IMT and CAC measures at baseline, in 6 field centers of the Multi-Ethnic Study of Atherosclerosis (MESA). The main outcome measure was the risk of incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up. RESULTS There were 222 CVD events during follow-up. Coronary artery calcium was associated more strongly than carotid IMT with the risk of incident CVD. After adjustment for each other (CAC score and IMT) and age, race, and sex [corrected], the hazard ratio of CVD increased 2.1-fold (95% confidence interval [CI], 1.8-2.5) for each 1-standard deviation (SD) increment of log-transformed CAC score, vs 1.3-fold (95% CI, 1.1-1.4) for each 1-SD increment of the maximum IMT. For coronary heart disease, the hazard ratios per 1-SD increment increased 2.5-fold (95% CI, 2.1-3.1) for CAC score and 1.2-fold (95% CI, 1.0-1.4) for IMT. A receiver operating characteristic curve analysis also suggested that CAC score was a better predictor of incident CVD than was IMT, with areas under the curve of 0.81 vs 0.78, respectively. CONCLUSION Although whether and how to clinically use bioimaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC score is a better predictor of subsequent CVD events than carotid IMT.
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Imaging of calcified coronary arteries with multislice computed tomography.
Wittlinger, T, Martinovic, I, Moosdorf, R, Moritz, A
Asian cardiovascular & thoracic annals. 2006;(4):321-7
Abstract
Reliable noninvasive detection of coronary artery disease is a prime goal in clinical cardiology. The aim of this study was to investigate the accuracy of multislice computed tomography in detecting coronary artery disease in correlation to the calcium score. Fifty patients with 61 stenoses > 50% and 41 occlusions underwent multislice computed tomography and conventional coronary angiography. Calcium scoring was calculated for the total coronary artery territory and patients were divided into 3 groups based on this score. Multislice computed tomography visualized 89% (365/500) of all coronary segments. The sensitivity and specificity for detection of stenoses > 50% or occlusion was 47%-92%, and 97%-100% for the calcium score. Forty of 500 segments were underestimated by multislice computed tomography, of which 39 were in the group with a calcium score > 400. Multislice computed tomography allows noninvasive angiographic evaluation of coronary artery disease with high diagnostic accuracy. However, the method strongly depends on the degree of vascular calcification and underestimates the degree of stenosis according to the calcium score. This new technology holds promise for noninvasive risk assessment in patients with known or suspected coronary artery disease.
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Medium-energy shock wave therapy in the treatment of rotator cuff calcifying tendinitis.
Moretti, B, Garofalo, R, Genco, S, Patella, V, Mouhsine, E
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2005;(5):405-10
Abstract
To evaluate the results of the treatment with medium-energy extracorporeal shock wave therapy (ESWT) in rotator cuff calcifying tendinitis. Fifty-four non-consecutive patients, who were referred to our institute for rotator cuff calcifying tendinitis, were managed with a standardized protocol in four sessions of medium-energy (0.11 mJ/mm2) ESWT administered with an electromagnetic lithotriptor. Pain was evaluated at the end of each session, functional state of shoulder was assessed at 1 and 6 months after the end of procedure. All patients underwent radiographs and sonography imaging. No systemic or local complications. Thirty-eight patients (70%) reported satisfactory functional results. Radiographs and sonographs showed a disappearance of calcium deposit in 29 patients (54%) and in 19 patients (35%) it appeared to be reduced more than a half. A correlation was found between residual calcium deposit and the clinical outcome, but some patients showed a reduced pain without modification of calcium deposit. These results were unmodified at 6 months follow-up. Our protocol of medium-energy ESWT provides good results overall about pain modulation.
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A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.
Cowell, SJ, Newby, DE, Prescott, RJ, Bloomfield, P, Reid, J, Northridge, DB, Boon, NA, ,
The New England journal of medicine. 2005;(23):2389-97
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BACKGROUND Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. METHODS In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. RESULTS Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). CONCLUSIONS Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis.
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The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.
Chertow, GM, Raggi, P, McCarthy, JT, Schulman, G, Silberzweig, J, Kuhlik, A, Goodman, WG, Boulay, A, Burke, SK, Toto, RD
American journal of nephrology. 2003;(5):307-14
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BACKGROUND We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated. METHODS To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year. RESULTS The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate -2.5 +/- 1.8 mg/dl vs. sevelamer -2.8 +/- 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium > or =10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 +/- 2.1 g/day - equivalent to 1.2 +/- 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 +/- 350, median change +20, p = 0.002) and aorta (mean change 181 +/- 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects. CONCLUSION Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.
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Continuous probabilistic prediction of angiographically significant coronary artery disease using electron beam tomography.
Budoff, MJ, Diamond, GA, Raggi, P, Arad, Y, Guerci, AD, Callister, TQ, Berman, D
Circulation. 2002;(15):1791-6
Abstract
BACKGROUND We sought to incorporate electron beam tomography-derived calcium scores in a model for prediction of angiographically significant coronary artery disease (CAD). Such a model could greatly facilitate clinical triage in symptomatic patients with no known CAD. METHODS AND RESULTS We examined 1851 patients with suspected CAD who underwent coronary angiography for clinical indications. An electron beam tomographic scan was performed in all patients. Total per-patient calcium scores and separate scores for the major coronary arteries were added to logistic regression models to calculate a posterior probability of the severity and extent of angiographic disease. These models were designed to be continuous, adjusted for age and sex, corrected for verification bias, and independently validated in terms of their incremental diagnostic accuracy. The overall sensitivity was 95%, and specificity was 66% for coronary calcium to predict obstructive disease on angiography. With calcium scores >20, >80, and >100, the sensitivity to predict stenosis decreased to 90%, 79%, and 76%, whereas the specificity increased to 58%, 72%, and 75%, respectively. The logistic regression model exhibited excellent discrimination (receiver operating characteristic curve area, 0.842+/-0.023) and calibration (chi2 goodness of fit, 8.95; P=0.442). CONCLUSIONS Electron beam tomographic calcium scanning provides incremental and independent power in predicting the severity and extent of angiographically significant CAD in symptomatic patients, in conjunction with pretest probability of disease. This algorithm is most useful when applied to an intermediate-risk population.
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[Detection of coronary calcinosis with multislice spiral computerized tomography: an alternative to electron beam tomography].
Knez, A, Becker, A, Becker, C, Leber, A, Boekstegers, P, Reiser, M, Steinbeck, G
Zeitschrift fur Kardiologie. 2002;(8):642-9
Abstract
Electron-beam CT (EBT) has been used for years as the gold standard to quantify coronary artery calcification as a marker of coronary atherosclerosis. With the introduction of Multi-Slice Spiral CT (MSCT) technology in 1999, EBT is now challenged in the determination of coronary calcium. The aim of this study was to determine the diagnostic accuracy of MSCT for the assessment of coronary calcium, comparing this new technique to EBT. The study population consisted of 54 male patients, aged 58 +/- 11 years with suspected coronary artery disease. For EBT, 40 axial slices (scan time = 100 ms, slice thickness = 3 mm) were acquired in one breath-hold (35 +/- 5 s) using an ECG-trigger at 80% of the RR interval. For MSCT, simultaneous acquisition of four axial slices (scan time = 250 ms, slice thickness = 2.5 mm) allowed the entire heart (40 slices) to be covered in one breath-hold (25 +/- 5 s) using a prospective ECG-trigger (R--450 ms). For quantification of coronary calcium the Agatston and the Volumetric calcium score (VCS) were applied. Mean Agatston score of the study group was calculated as 88 +/- 111 (median = 45), which is between the 25th and 75th age-corrected percentile of asymptomatic patients. For the Volumetric calcium score, number of lesions, calcium mass and density, no statistical difference was found between both imaging modalities. Agatston and Volumetric calcium score were statistically different between and within both scans. Mean variability of VCS of the two methods was calculated as 24% and was in the range of repeated EBT studies (14-44.9%). The Multi-Slice Spiral CT scanner is equivalent to EBT for the determination of coronary calcium and can, therefore, be used for calcium screening. Using a prospective ECG-trigger technique, the application of the Agatston method delivers statistically different results in comparison to EBT. With the application of the spiral mode technique, retrospective ECG-trigger and thinner slice thickness, further improvement in variability can be expected, thus allowing for follow-up studies to determine progression or regression of atherosclerosis with high accuracy.