A novel mutation in the pendrin gene associated with Pendred's syndrome

OBJECTIVE: Pendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level. PATIENTS: Thirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome. MEASUREMENTS: Exons 2-21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis. RESULTS: The index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G --> A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine-deficient area. CONCLUSIONS: We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.     

Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.

OBJECTIVES: The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality. BACKGROUND: Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts. METHODS: We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores. RESULTS: The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p < 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, p < 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-, 4.5-, 6.4-, 9.2-, 10.4-, and 12.5-fold for scores of 11 to 100, 101 to 299, 300 to 399, 400 to 699, 700 to 999, and >1,000, respectively (p < 0.0001), when compared with a score of 0. Ten-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of >1,000 (p < 0.0001). CONCLUSIONS: This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.     

Effect of an antiserotoninergic drug, metergoline, on the ACTH and cortisol response to insulin hypoglycemia and lysine-vasopressin in man.

The effect of metergoline, a specific antiserotoninergic drug, on ACTH secretion was investigated in 29 normal volunteers and in 4 patients with increased ACTH production (3 with Addison's disease, 1 with Cushing's disease). In 15 normal subjects, a 4-day treatment with 10 mg daily of metergoline significantly blunted the ACTH response to insulin hypoglycemia. Mean peak ACTH values before and after treatment were, respectively, 333 +/- 39.2 (SE) and 235 +/- 38.8 pg/ml (P less than 0.05). The corresponding values of plasma cortisol were 29.6 +/- 2.96 and 20.5 +/- 2.67 mug/100 ml (P less than 0.05). In contrast, metergoline failed to affect the ACTH response to lysine-vasopressin (LVP) administered iv (8 subjects studied) and im (6 subjects studied). In 3 patients suffering from Addison's disease, an appreciable although not statistically significant lowering of the plasma ACTH levels was noted during metergoline administration. The mean pre- and post-treatment values of plasma ACTH in these patients were, respectively, 1116 +/- 192.2 and 666 +/- 100.8 pg/ml, 4240 +/- 50.0 and 3398 +/- 368.0 pg/ml, and 431 +/- 44.0 and 352 +/- 23.9 pg/ml. In one patient with Cushing's disease caused by a pituitary adenoma, metergoline did not appreciably modify plasma ACTH levels. Taken together, these results lend support to the concept of a physiological stimulating effect of serotonin on ACTH secretion. Moreover, they are compatible with the view that serotonin exerts its action chiefly at the hypothalamic level while LVP promotes ACTH release by a primary action on the pituitary.     

Prognostic value of coronary artery calcium screening in asymptomatic smokers and non-smokers.

AIMS: To determine the extent and prognostic significance of coronary artery calcium in asymptomatic smokers and non-smokers. Population data are available on the prognostic impact of smoking on atherosclerotic imaging measurements of the carotid and peripheral arteries. Limited data are available on the impact of cigarette smoking on the prognostic value of coronary calcium. METHODS AND RESULTS: A referred patient registry of 10,377 asymptomatic individuals (40% were current smokers) was followed for death from all-causes at 5 years. Univariable and multivariable Cox proportional hazard models were calculated to estimate time to all-cause mortality. Cumulative 5-year survival was 96.9 and 98.4% for smokers when compared with non-smokers (P < 0.0001). Using a stratified Cox proportional hazards survival analysis, survival for non-smokers ranged from 99.7 to 89.6% with calcium score of 0-10 and >1000 (P < 0.0001). In comparison, smokers had survival rates ranging from 99.5 to 81.4% for calcium score of 0-10 to >1000 (P < 0.0001). When further evaluating the effect of age on prognosis by coronary calcium, there was an additive relationship between age and calcium that was exacerbated with smoking, resulting in higher relative risk ratios for older smokers with coronary calcium (P < 0.0001). For smokers <50 years of age, a calcium score >1000 was associated with a relative risk ratio that was elevated 8.9-fold (P = 0.029). Thus, resulting in an expected reduction in life expectancy of 4.8 years for smokers <50 years of age with a calcium score >400 (P < 0.0001). CONCLUSION: The prognostic value of coronary artery calcium scoring was accurate in identifying a high-risk cohort of asymptomatic smokers and non-smokers. Young smokers with high-risk calcium scores have a four- to nine-fold increased risk of dying when compared with similarly aged non-smokers. When prospectively applied, evidence of a high-risk calcium score may be useful in educating patients as to their expected risk of dying over the next 5 years.     

Family members and health professionals’ perspectives on future life planning of ageing people with Down syndrome: a qualitative study

Abstract

Objectives: To address the way in which primary caregivers of people over 45 with Down syndrome describe daily life activities and context and foresee their future.

Methods: Thirteen family members and 15 health professionals participated to four focus groups. Meaningful concepts were identified and linked to the International Classification of Functioning, Disability and Health using established linking rules.

Results: A total of 258 relevant concepts were identified and linked to 75 categories of the classification: 38 were from activity and participation and 17 from environmental factors domains. The most commonly reported issues were mental functions (b117-intellectual functions and b152-emotional functions), community life activities (d910-community life and d920-recreation and leisure) and environmental factors (e310-support of immediate family, e355-support from health professionals and e555-associations and organizational services).

Conclusions: Information on the daily life and health of ageing people with Down syndrome is important to plan social and health care interventions tailored to deal with problems that they may encounter in older age. Considering the interaction between health and environment and maintaining a continuity of daily routines were reported as the most relevant topics for managing daily lives of persons with Down syndrome in older ages.

• Implications for rehabilitation

• Pay more attention to the interaction between environmental factors and health condition in ageing people with Down syndrome.

• Information about the life contest are important in order to plan present and future social–health care interventions.

• Future planning for people with Down syndrome is a great concern for family members.

     

Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders.

BACKGROUND: Vascular calcification and low bone turnover with a relatively low parathyroid hormone (PTH) often coexist in diabetic patients undergoing haemodialysis. Since calcium salts (CaS) are used extensively as primary phosphate binders and have been associated with progressive vascular calcification, we studied the effects of CaS on coronary arteries and parathyroid activity in incident haemodialysis diabetic patients. METHODS: We measured the change in coronary artery calcium scores (CACS) with sequential electron beam computed tomography (EBCT) in 64 diabetic and 45 non-diabetic patients, randomized to CaS or sevelamer within 90 days of starting haemodialysis. CACS measurements were repeated after 6, 12 and 18 months. Serum intact PTH (iPTH), calcium and phosphorus were serially tested. RESULTS: During the study period, serum phosphate was similar in diabetic and non-diabetic patients. Serum calcium levels were similar at baseline (2.3+/-0.25 mmol/l for both) and increased significantly with CaS treatment (P<0.05) both in diabetic and non-diabetic patients but not with sevelamer. Diabetic patients treated with CaS showed a significantly greater CACS progression than sevelamer-treated patients (median increase 177 vs 27; P=0.05). During follow-up, diabetic patients receiving CaS were significantly more likely to develop serum iPTH values<16 pmol/l than diabetic patients treated with sevelamer (33% vs 6%, P=0.005) and had a lower mean iPTH level (24+/-16 vs 31+/-14 pmol/l; P=0.038). CONCLUSIONS: The management of hyperphosphataemia with CaS in haemodialysis diabetic patients is associated with a significantly greater progression of CACS than with sevelamer. These effects are accompanied by iPTH changes suggestive of low bone turnover.     

Analysis of reboxetine, a novel antidepressant drug, in pharmaceutical tablets by capillary electrophoresis and derivative spectrophotometry.

The recent antidepressant drug reboxetine was quantified in pharmaceutical tablets by derivative spectrophotometry and capillary zone electrophoresis. The feasible sample pretreatment consists of a single extraction with a pH 2.5 phosphate buffer, centrifugation and dilution. For the spectrophotometric assay, the fourth derivative of the absorbance was used which gave satisfactory results in terms of accuracy (mean recovery 99.7%) and precision (mean RSD 3.4%). The electrophoretic experiments were carried out using the shortest effective length of the capillary (8.5 cm) in order to obtain a very rapid separation of reboxetine and dibenzepine used as the internal standard. Using a pH 2.5, 50 mM phosphate buffer as the background electrolyte, each analysis lasted less than 2.5 min. Accuracy (101.3%) and precision (1.5%) were very good.     

Role of noninvasive imaging in asymptomatic high-risk patients

Conclusions  CACS is highly predictive of major CVD events, independent of traditional risk factors including the FRS, body mass index, family history of premature CVD, and high-sensitivity C-reactive protein.36 A synthesis of available prognostic evidence reveals that patients with an intermediate FRS and a high-risk CAC score are at CVD risk-equivalent status with annual event rates of 2% or higher. This evidence is consistent with a multimarker approach for risk assessment that includes compounding novel and traditional risk factors to identify higher-risk subsets of patients. Another example of compounding risk is the combination of CT and SPECT markers. In those patients with high-risk subclinical disease, the frequency of inducible ischemia with SPECT is substantially increased. Nearly one quarter of patients with a high-risk CAC score will have ischemia on SPECT imaging. Thus it is anticipated that upcoming appropriateness criteria and guidelines may be more supportive of the use of CACS as a screening tool for risk assessment indications in asymptomatic individuals37,38 and that this evidence may translate into reimbursement for subclinical disease screening.39 It is hoped that strategies aimed at the detection of subclinical atherosclerosis may result in further reductions in CVD mortality rates, saving thousands of lives and reducing the economic burden of obstructive coronary disease.     

Determination of catecholamines in human plasma by high-performance liquid chromatography with electrochemical detection.

In the present study, assays were improved for the determination of catecholamines in human plasma. High-performance liquid chromatography with electrochemical detection was employed for quantitative analysis. The influence of various parameters on chromatographic performance, such as the composition and the pH of the mobile phase, and the detection potential, was investigated. An accurate solid-phase extraction procedure, after catecholamine complexation with diphenylborate, was developed. The efficiency yield for all catecholamines was in the range 92-98%. Relative standard deviation values for repeatability and for intermediate precision were less than 2% and 3%, respectively, for all three analytes.