A genetic score for the prediction of beta-thalassemia severity

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.−158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R²=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions.     

Centronuclear myopathies: genotype–phenotype correlation and frequency of defined genetic forms in an Italian cohort

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype–phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four ‘canonical’ genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood–adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.     

人工流产术后口服达英-35的临床应用研究

目的采用人工流产术后口服短效避孕药（达英-35）的方法,研究达英-35对人流术后避孕效果及减少人流术后并发症的疗效。方法随机选取行人工流产的早孕（〈10孕周）健康妇女300例,分为观察组和对照组各150例,观察组于人流术后口服达英-35,对照组采用除口服避孕药外的其他避孕方式,观察两组术后出血情况、子宫恢复情况、避孕效果及并发症发生情况。结果观察组患者人流术后阴道出血持续时间少于对照组（P〈0.01）,术后恢复情况优于对照组,且并发症发生率较对照组显著减少（P〈0.01）。结论人流术后口服达英-35避孕效果好,不良反应小,可促进子宫恢复,治疗手段简单、经济,可减少人流术后并发症,具有广阔的临床应用价值,值得进一步研究并推广应用。     

Radiation dose reduction with application of non-linear adaptive filters for abdominal CT

AIM:To evaluate the effect of non-linear adaptive filters (NLAF) on abdominal computed tomography (CT) images acquired at different radiation dose levels.METHODS:Nineteen patients (mean age 61.6 ± 7.9 years,M:F=8:11) gave informed consent for an Institutional Review Board approved prospective study involving acquisition of 4 additional image series (200,150,100,50 mAs and 120 kVp) on a 64 slice multidetector row CT scanner over an identical 10 cm length in the abdomen.The CT images acquired at 150,100 and 50 mAs were processed with the NLAF.Two radiologists reviewed unprocessed and processed images for image quality in a blinded randomized manner.CT dose index volume,dose length product,patient weight,transverse diameters,objective noise and CT numbers wererecorded.Data were analyzed using Analysis of Variance and Wilcoxon signed rank test.RESULTS:Of the 31 lesions detected in abdominal CT images,28 lesions were less than 1 cm in size.Subjective image noise was graded as unacceptable in unprocessed images at 50 and 100 mAs,and in NLAF processed images at 50 mAs only.In NLAF processed images,objective image noise was decreased by 21% (14.4 ± 4/18.2 ± 4.9) at 150 mAs,28.3% (15.7 ± 5.6/21.9 ± 4) at 100 mAs and by 39.4% (18.8 ± 9/30.4 ± 9.2) at 50 mAs compared to unprocessed images acquired at respective radiation dose levels.At 100 mAs the visibility of smaller structures improved from suboptimal in unprocessed images to excellent in NLAF processed images,whereas diagnostic confidence was respectively improved from probably confident to fully confident.CONCLUSION:NLAF lowers image noise,improves the visibility of small structures and maintains lesion conspicuity at down to 100 mAs for abdominal CT.     

Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients.

BACKGROUND: Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican, RAD) is currently in clinical development to address this issue. METHODS: The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus. RESULTS: Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n = 44) or placebo (n = 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 10-19%); however, between-subject variability ranged from 34 to 60% for AUC and C(max). CONCLUSIONS: These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.     

Bioavailability of bromhexine tablets and preliminary pharmacokinetics in humans

The absorption of bromhexine from Bromhexin tablets 8 mg, DAK has been compared with that from Bisolvon® tablets 8 mg, Boehringer Ingelheim, in a two-way complete crossover study. Four tablets of each of the two bromhexine products, corresponding to a single dose of 32 mg of bromhexine hydrochloride (77.6 μmol), was administered to each of the 10 volunteers. The plasma concentration was followed over the 4-hour period following each administration. By means of Pratt's test for paired data no statistically significant difference (p > 0.10) between the two products was found with respect to maximum plasma concentration (89 and 84nmol.l^?1, respectively), the times for their occurrence (1.3 and 1.0h, respectively), and the area under the plasma concentration-time curves (140 and 132 nmol.l^?1.h, respectively). It is concluded that Bromhexin, DAK and Bisolvon® are bioequivalent. Provisional pharmacokinetic data for bromhexine, after oral administration, in man were obtained. The first-pass effect and the biological half-life were estimated by combining plasma and 30 h urine data from four of the volunteers. The first-pass effect was estimated to be c. 75 per cent, the biological half-life to be c. 6 h, and c. 0.1 per cent of the dose was found as unmetabolized bromhexine in the urine. The data indicate that the pharmacokinetics of bromhexine may be described as a two-compartment open model.