Genetics of idiopathic disseminated bronchiectasis

Bronchiectasis is an abnormal dilation of bronchi, consequent to the destruction of their walls. It is included in the category of obstructive pulmonary diseases, along with chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis. In approximately 50% of cases, bronchiectasis is associated with underlying conditions; in the remainder, known causes are not ascertainable (idiopathic bronchiectasis). A search for genetic determinants of this phenotype, with the cystic fibrosis gene as a candidate, has been performed by three independent groups. The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms. The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis. A few other genes have been investigated in idiopathic bronchiectasis, with negative results. Idiopathic bronchiectasis is, therefore, to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases (or CFTR-opathies), whose pathogenesis is influenced by environmental factors and other undetermined genes.     

Gastric Emptying and Dyspeptic Symptoms in Patients with Nonautoimmune Fundic Atrophic Gastritis

Our aim was to evaluate the relationship between gastric emptying and demographic, clinical, histological, and secretory features in patients with nonautoimmune fundic atrophic gastritis. Only 31% of 45 patients with fundic atrophic gastritis presented with achlorhydria. Scintigraphic gastric emptying of solids was delayed compared to healthy controls. Patients with achlorhydria showed gastric emptying rates lower than those with preserved acid secretion. Significant, but weak, correlations were observed between emptying rates and both peak acid output (Rs = 0.33) and serum gastrin levels (Rs = –0.36), but not with grading of mucosal atrophy. No symptom differences were observed between patients with or without achlorhydria, but a weak correlation was detected between peak acid output and the severity of epigastric pain (Rs = 0.40). In conclusion, patients with fundic atrophic gastritis present delayed gastric emptying that is weakly related to the reduction of the acid secretion and the raising of serum gastrin levels rather than to the severity of the atrophy.     

Correlations between exhaled nitric oxide levels,blood eosinophilia,and airway obstruction reversibility in childhood asthma are detectable only in atopic individuals

The aim of this study was to compare in atopic and nonatopic asthmatic children correlations between two inflammation parameters, i.e., blood eosinophilia and exhaled nitric oxide (FE(NO)), and pulmonary function values, at baseline and after beta(2)-adrenergic bronchodilators. Ninety-two steroid-naive asthmatic children were evaluated: 26 were skin prick test- and RAST-negative (nonatopic subjects), whereas 66 were atopic, 15 being sensitized only to house dust mites (monosensitized) and 51 to mites and to at least one other class of allergens (polysensitized). Baseline spirometric values (FEV(1) and FEF(25-75%)) were similar in atopic and nonatopic groups (P > 0.1, each comparison). However, when compared to nonatopic subjects, atopic children showed a significantly higher degree of blood eosinophilia (3.0% and 6.7% white blood cell count, respectively; P = 0.0001) and higher FE(NO) levels (6.8 ppb and 16.0 ppb, respectively; P = 0.0001). While a positive correlation between FE(NO) levels and blood eosinophilia was observed in atopic children (r = 0.25, P = 0.041), no correlations between these two inflammation parameters and baseline pulmonary function values were demonstrated in any of the asthmatic groups. Inhalation of a beta(2)-agonist drug induced in the two asthmatic populations similar improvements in FEV(1) and FEF(25-75%) and no changes in FE(NO) levels or blood eosinophilia. However, only in atopic children positive correlations were found between percent variation in FEV(1) (delta%FEV(1)) and FE(NO) levels (r = 0.35, P = 0.006) or blood eosinophilia (r = 0.26, P = 0.04). Within the atopic group, no differences were found between mono- and polysensitized individuals in all parameters evaluated. Thus only in atopic children did parameters of inflammation correlate with airway obstruction reversibility.     

Impact of carotid intima-media thickening on risk stratification in elderly hypertensives

BACKGROUND: It has been shown that aging and arterial hypertension are both associated with an increased prevalence of carotid structural abnormalities, such as intima-media (IM) thickening or plaques, which are a powerful independent predictor of cardiovascular (CV) events. We investigated the impact of carotid IM thickening in profiling the absolute CV risk stratification according the 1999 World Health Organization/International Society of Hypertension (WHO/ISH) guidelines in elderly hypertensive patients. METHODS: Two hundred and thirty untreated elderly patients (>65 years) referred to our outpatient hospital clinic were included in the study. They underwent the following procedures: (i) medical history, physical examination and clinic blood pressure measurement; (ii) routine blood chemistry and urine analysis; (iii) electrocardiogram. The risk was initially stratified according to the routine procedures indicated by WHO/ISH guidelines and subsequently reassessed by adding the results of carotid ultrasonography (IM thickening as diffuse IM thickness >0.9 and <1.3 mm). RESULTS: According to routine classification 56% (=129) were medium-risk patients, 29% (n = 67) high-risk and 15% (n = 34) very-high-risk patients. The overall prevalence of carotid IM thickening was 54% (49% in medium-risk vs 60% in high or very high-risk patients, p < 0.05). A marked change in risk stratification was observed when IM thickening was taken in consideration: medium-risk patients decreased to 29% and high-risk rose to 56% (p < 0.01). CONCLUSIONS: Ultrasound assessment of large artery damage is extremely useful for a more accurate estimate of global CV risk in elderly hypertensives, because stratification based on diagnostic routine procedures can underestimate the overall risk in a large fraction of medium-risk subjects.     

Does sports activity enhance the risk of sudden death in adolescents and young adults?

OBJECTIVES: We sought to assess the risk of sudden death (SD) in both male and female athletes age 12 to 35 years. BACKGROUND: Little is known about the risk of SD in adolescents and young adults engaged in sports. METHODS: We did a 21-year prospective cohort study of all young people of the Veneto Region of Italy. From 1979 to 1999, the total population of adolescents and young adults averaged 1,386,600 (692,100 males and 694,500 females), of which 112,790 (90,690 males and 22,100 females) were competitive athletes. An analysis by gender of risk of SD and underlying pathologic substrates was performed in the athletic and non-athletic populations. RESULTS: There were 300 cases of SD, producing an overall cohort incidence rate of 1 in 100,000 persons per year. Fifty-five SDs occurred among athletes (2.3 in 100,000 per year) and 245 among non-athletes (0.9 in 100,000 per year), with an estimated relative risk (RR) of 2.5 (95% confidence interval [CI] 1.8 to 3.4; p < 0.0001). The RR of SD among athletes versus non-athletes was 1.95 (CI 1.3 to 2.6; p = 0.0001) for males and 2.00 (CI 0.6 to 4.9; p = 0.15) for females. The higher risk of SD in athletes was strongly related to underlying cardiovascular diseases such as congenital coronary artery anomaly (RR 79, CI 10 to 3,564; p < 0.0001), arrhythmogenic right ventricular cardiomyopathy (RR 5.4, CI 2.5 to 11.2; p < 0.0001), and premature coronary artery disease (RR 2.6, CI 1.2 to 5.1; p = 0.008). CONCLUSIONS: Sports activity in adolescents and young adults was associated with an increased risk of SD, both in males and females. Sports, per se, was not a cause of the enhanced mortality, but it triggered SD in those athletes who were affected by cardiovascular conditions predisposing to life-threatening ventricular arrhythmias during physical exercise.     

Adrenergic mechanisms and remodeling of subcutaneous small resistance arteries in humans

BACKGROUND: Vascular structural alterations in small resistance arteries of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. In fact, no difference in the smooth muscle cell volume (CV) between normotensive subjects (NT) and essential hypertensive patients was observed. However, experimental models of hypertension with chronic infusion of agonists of adrenergic receptors were characterized by the presence of smooth muscle cell hypertrophy or hyperplasia. Recently, we have observed the presence of vascular smooth muscle cell hypertrophy in patients with renovascular hypertension. OBJECTIVE: The aim of the study to investigate the structural characteristics of subcutaneous small resistance arteries of NT, of EH, and of patients with phaeochromocytoma (Phaeo). PATIENTS AND METHODS: Thirty Phaeo, 30 NT and 30 EH were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small resistance arteries (relaxed diameter 160-280 microm) were dissected and mounted on a micromyograph and the media : lumen ratio was calculated. In nine Phaeo, nine NT and 13 EH the cell volume was measured by an unbiased stereological principle, the 'disector' method.RESULTS No difference in smooth muscle cell volume was observed between groups. However, inward remodeling in Phaeo was less marked than in EH, although the increase in media : lumen ratio was similar compared with NT. However, the lack of changes in media cross-sectional area, compared with NT, suggest that there has been little hypertrophy, the changes observed thus being eutrophic. CONCLUSIONS: Our data show, based on a reasonably large sample, that a pronounced activation of the adrenergic system is not associated with vascular smooth muscle cell hypertrophy or hyperplasia in humans. It is therefore possible that adrenergic mechanisms may have a relevant role in the development of eutrophic remodeling in small vessels.     

Relation between lung function and RBC distribution width in a population-based study

STUDY OBJECTIVES: Pulmonary function is dependent not only on smoking, but also on nutritional status. Since an increased RBC distribution width (RDW) has been associated with nutritional deficiencies, we postulated that RDW has an inverse relation to pulmonary function. The purpose of this study was to test this hypothesis. DESIGN AND SETTING: A cross-sectional study was conducted of a random sample of the general population in western New York. PARTICIPANTS: A total of 1,616 subjects of both genders who were aged 35 to 79 years and were free of respiratory disease. INTERVENTIONS: None. MEASUREMENTS: Pulmonary function was assessed from FEV(1), FVC, height, body weight, total pack-years of smoking, smoking status, hemoglobin concentration, and hematologic indexes, eosinophil count, education, and blood levels of retinol, beta-cryptoxanthin, and vitamin E. RESULTS: We found a direct relation between RDW and the number of pack-years of smoking and smoking status, and an inverse relation between FEV(1) and FVC with RDW, even when potentially confounding variables such as smoking were taken into account. When the variability of FEV(1) due to smoking was used for comparison, an additional 27% of that variability in FEV(1) was explained by variations in antioxidant vitamin levels, and another 24% by RDW. CONCLUSIONS: The results confirmed our hypothesis that there is an inverse relation between RDW and pulmonary function, and raise the possibility that RDW may be a biomarker for as-yet unidentified nutrients that affect pulmonary function.     

Influence of left ventricular mass,uremia and hypertension on vagal tachycardic reserve

BACKGROUND: Left ventricular (LV) hypertrophy, arterial hypertension and end-stage renal disease (ESRD) are associated with deranged cardiac parasympathetic regulation and increased cardiovascular risk. These conditions often co-exist but little is known about the relative contribution of LV mass, arterial blood pressure and ESRD to impaired cardiac vagal tone.We evaluated the vagal tachycardic reserve (VTR) in subjects with normal renal function (age 58.4 +/- 6.6 years, n = 19) and in patients under chronic hemodialysis (HD) (age 62.6 +/- 13.2 years, n = 30) having wide ranges of LV mass and blood pressure. METHODS: VTR was estimated from the tachycardic response to atropine (15 microg/kg intravenously) administered during a dipyridamole-atropine stress-echo test performed as part of the diagnostic work-up for identification of inducible myocardial ischemia. LV hypertrophy (defined as LV mass index > 125 g/m2 in both genders) was present in 20 HD patients and in nine control patients. Only patients free of inducible myocardial ischemia were included in the study. RESULTS: The atropine-mediated tachycardia was: (i) significantly smaller in HD patients than in control patients (34.7 +/- 7.6 versus 60.8 +/- 10.5 beats/min, P < 0.01); (ii) independently and inversely related to LV mass (multiple regression; partial coefficients, -0.139 in HD patients and -0.382 in controls, both P < 0.01) and to mean blood pressure (-0.171 in HD patients and -0.268 in controls, both P < 0.01). CONCLUSIONS: LV mass is the strongest (inverse) determinant of VTR. Blood pressure as well as the patient's renal status are also independent correlates of VTR, and the concomitance of LV hypertrophy and ESRD exacerbates the impairment of VTR.     

Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin

BACKGROUND: It is debated whether in patients with chronic heart failure (CHF), aspirin may contrast the clinical benefits of angiotensin-converting enzyme inhibitors (ACEIs). Two major unresolved issues in patients with CHF are whether these agents together can affect mortality and whether the interaction is related with the dose of aspirin. We aimed at exploring these possibilities. METHODS: We evaluated more than 4000 hospitalizations with a principal discharge diagnosis of CHF from January 10, 1990, to December 31, 1999. The final analysis was restricted to 344 patients taking ACEIs who satisfied the selection criteria, in whom reliable information was available concerning drug therapy during follow-up. In these patients, treatment included no aspirin in 235 (group 1), a low dose (< or =160 mg) in 45 (group 2), and a high dose (> or = 325 mg) in 64 (group 3). RESULTS: During a mean follow-up of 37.6 months, there were 84 (36%) deaths in group 1, 15 (33%) in group 2, and 35 (55%) in group 3. By the Kaplan-Meier approach, survival was similar in groups 1 and 2, and significantly (P =.009) worse in group 3 compared with groups 1 and 2. After adjusting for potential confounding factors (including treatment, cause of heart disease, age, smoking, and diabetes mellitus), a time-dependent multivariate Cox proportional hazards regression analysis showed that the combination of high-dose aspirin with an ACEI was independently associated with the risk of death (hazard ratio, 1.03; P =.01) and that the combination of low-dose aspirin with an ACEI was not (hazard ratio, 1.02; P =.18). CONCLUSION: These results support the possibility that in some patients with CHF who are taking an ACEI, a dose-related effect of aspirin may adversely affect survival.     

Continuous absence of metaphase-defined cytogenetic abnormalities,especially of chromosome 13 and hypodiploidy,ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.