A rapid, sensitive and specific method to quantify diclofenac in human plasma using indomethacin as the internal standard (IS) is described. Samples were extracted using protein precipitation ...protocol and analyzed by high performance liquid chromatography coupled to ultraviolet detection at 276 nm. Chromatography was performed isocratically with a run time of 8.0 min and the retention time observed for diclofenac and IS was 6.0 and 7.0 min, respectively. The calibration curve was linear over the range 50 - 4,000 ng/ml (r2 > 0.9995). The mean recovery of diclofenac ranged from 88.76 to 99.14% and the limit of quantification was 50 ng/ml. Intrabatch precision and accuracy (%CV) of the method ranged from 0.86 to 7.60%, and 99.34 to 103.8%, respectively. Interbatch precision (%CV) and accuracy ranged from 0.26 to 11.4%, and 92.00 to 105.34%, respectively. This HPLC method was used to determine the relative pharmacokinetics of two diclofenac-cholestyramine 140 mg capsule formulations. The study was conducted using an open, randomized and crossover design with a 1-week washout interval. A single 140 mg dose (equivalent to 70 mg of diclofenac) of each formulation was administered to 26 healthy volunteers (13 males and 13 females) and blood samples were obtained over 12-h interval. The geometric mean of diclofenac-cholestyramine/Flotac ratio was 90.53% for AUC0-12 and 100.22% for Cmax. Since the 90% CI for Cmax and AUCs ratios were all inside the 80 - 125% interval, it was concluded that the diclofenac-cholestyramine test formulation is bioequivalent to Flotac regarding both the rate and the extent of absorption.
Background Endoscopic submucosal dissection (ESD) has revolutionized the resection of GI superficial neoplasms, but adoption in Western countries is significantly delayed. Objective To evaluate a ...stepwise colorectal endoscopic submucosal dissection (ESD) learning and operative training protocol. Design Prospective study in the Western setting. Setting This study took place in a nonacademic hospital with one endoscopist expert in therapeutic endoscopy but novice in ESD. Patients Indications for ESD were superficial neoplasms 20 mm and larger without ulcerations or fibrosis. Intervention Training consisted of 5 unsupervised ESDs on isolated stomach, an observation period at an ESD expert Japanese center, 1 supervised ESD on isolated stomach, and retraining on 1 rectal ESD under supervision. The operative training on patients was performed without supervision moving from the rectum to the colon according to the competence achieved. Main Outcome Measurements Competence was defined as an 80% en bloc resection rate plus a statistically significant reduction in operating time per square centimeter. Learning curves were calculated based on consecutive blocks of 5 procedures. Results From February 2009 to February 2012, 30 rectal and 30 colonic ESDs were performed. The rectal ESD learning curve showed that the en bloc resection rate was 80% after 5 procedures ( P = not significant); the operating time per square centimeter significantly decreased after 20 procedures ( P = .0079); perforation occurred in 1 patient. The colonic ESD learning curve showed that the en bloc resection rate was 80% after 20 procedures ( P = not significant); the operating time per square centimeter significantly decreased after 20 procedures ( P = .031); perforations occurred in 2 patients. Limitations Single-center design. Conclusions A minimal intensive training seems sufficient for endoscopists expert in therapeutic procedures to take up ESD in a not overly arduous incremental method with separate and sequential learning curves for the rectum and colon.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses.
This study sought ...to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers.
Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.
Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers.
Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease carrying a risk of sudden death. Information about the clinical features during childhood and the age at ...disease onset is scanty.
The aim of the study was to describe the ARVC phenotype as its initial clinical manifestation in a pediatric population (<18 years) with desmosomal gene mutations.
Fifty-three ARVC desmosomal gene mutation carriers (mean age 12.3 ± 3.9 years) were investigated by electrocardiogram (ECG), signal-averaged ECG, 24-hour Holter, echocardiogram, and contrast-enhanced cardiac magnetic resonance (CMR).
None of the children ≤10 years old fulfilled the 1994 criteria, as opposed to six (33%) aged 11–14 years and eight aged >14 years (42%). At the end of follow-up (9 ± 7 years), 21 (40%) fulfilled the 1994 diagnostic criteria (mean age 16 ± 4 years). By using the 2010 criteria in subjects aged ≤18 years, 53% were unaffected, versus 62% by using the traditional criteria. More than two-thirds of affected subjects had moderate-severe forms of the disease. Contrast-enhanced CMR was performed in 21 (40%); of 13 unaffected gene mutation carriers, six showed ARVC morphological and/or tissue abnormalities.
In pediatric ARVC mutation carriers, a diagnosis was achieved in 40% of cases, confirming that the disease usually develops during adolescence and young adulthood. The 2010 modified criteria seem to be more sensitive than the 1994 ones in identifying familial pediatric cases. Contrast-enhanced CMR can provide diagnostic information on gene mutation carriers not fulfilling either traditional or modified criteria. Management of asymptomatic gene mutation carriers remains the main clinical challenge.
Early repolarization (ER) is typically observed in highly trained athletes as a physiologic consequence of increased vagal tone. The variant of anterior (V1 to V3) ER characterized by “domed” ...ST-segment elevation and negative T wave raises problems of differential diagnosis with the “coved-type” electrocardiographic pattern seen in Brugada syndrome (BS). This study was designed to identify electrocardiographic criteria for distinguishing athlete's ER from BS. The study compared the electrocardiographic tracings of 61 healthy athletes (80% men, median age 23 ± 8 years), showing “domed” ST-segment elevation and negative T wave in leads V1 to V3, with those of 92 consecutive age- and sex-matched BS patients with a “coved-type” electrocardiographic pattern. The electrocardiographic analysis focused on the ST-segment elevation at J point (STJ ) and at 80 milliseconds after J point (ST80 ). Athletes had a lower maximum amplitude of STJ (1.46 ± 0.7 vs 3.25 ± 0.6 mm, p <0.001) and lower STJ /ST80 (0.8 ± 0.3 vs 1.6 ± 0.3, p <0.001). All patients (100%) with BS showed a downsloping ST-segment configuration (STJ /ST80 >1) versus only 2 (3%) athletes (p <0.001). An upsloping ST-segment configuration (STJ /ST80 <1) showed a sensitivity of 97%, a specificity of 100%, and a diagnostic accuracy of 98.7% for the diagnosis of ER. At multivariate analysis, STJ /ST80 ratio remained the only independent predictor for ER (odds ratio 87, 95% confidence interval 19 to 357, p <0.001). In conclusion, the STJ /ST80 ratio is a highly accurate electrocardiographic parameter for differential diagnosis between anterior ER of the athlete and BS. Our results may help in reducing the number of athletes who undergo expensive diagnostic workup or are unnecessarily disqualified from competition for changes that fall within the normal range of athlete's heart.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by progressive myocardial atrophy and fibrofatty replacement. Standard electrocardiograms (ECGs) and ...signal-averaged ECGs (SAECGs) were relatively low cost and repeatable diagnostic tools. In this study, ECGs and SAECGs of patients with ARVC were analyzed with the aim to assess the diagnostic capability of these noninvasive techniques. A total of 205 patients with ARVC were analyzed. ECGs were abnormal in 74% of patients and SAECGs were positive in 60%, with normal ECGs mostly related to mild forms of the disease. The most common electrocardiographic abnormalities were localized right QRS prolongation, poor r wave progression in the right precordial leads, incomplete right branch bundle block, prolonged S-wave upstroke in V1 to V3 , parietal block, ST-segment elevation in V1 to V3 , inversion of T waves beyond V2 , and epsilon wave. Low QRS voltages in the precordial leads were frequently present in all patients with ARVC compared with a group of 120 healthy subjects (p = 0.00001). T-wave inversion beyond V3 characterized subjects with severe right ventricular dilatation, whereas in subjects with left ventricular involvement, T-wave inversion in lateral leads was more commonly detected. Overall, the extent of electrocardiographic abnormalities was related to disease extent. In conclusion, abnormalities in ECGs and SAECGs were frequent in patients with ARVC and correlated with disease extent, even if a stereotypical electrocardiographic pattern did not exist. ECGs and SAECGs remain an important tool for the diagnosis and assessment of ARVC extent. Nonetheless, a normal ECG does not exclude the presence of the disease.
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