Vincenzo Carnovale

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

OBJECTIVES The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). BACKGROUND Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. METHODS We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). RESULTS In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05). CONCLUSIONS Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Ischemic threshold and myocardial stunning in the aging heart.

The aging heart appears to be more susceptible to ischemia-reperfusion injury than the adult heart. There is no evidence of an age-related difference in the threshold of myocardial ischemia and myocardial stunning. We studied the effects on mechanical, hemodynamic, and metabolic parameters of graded reduction of coronary perfusion pressure from 66 to 29 mmHg in isolated and perfused hearts from adult and senescent rats. Cardiac function was also assessed during recovery following ischemic period. In both adult and senescent hearts developed pressure and +dP/dt linearly decreased and end-diastolic pressure linearly increased with decreasing perfusion pressure. However, all mechanical parameters were more severely impaired in senescent than in adult hearts at 37 mmHg and 29 mmHg perfusion pressure, respectively (p < 0.01 vs. adult). At 29 mmHg, in both adult and senescent hearts lactate production similarly increased whereas creatine kinase leakage did not differ from controls. Developed pressure recovered more slowly in senescent than in adult hearts (p < 0.001) in the absence of cellular damage and in the presence of restoration of coronary flow. Lactate production observed at the same step of coronary perfusion pressure suggests that the ischemic threshold is similar in adult and senescent hearts. The slow recovery of myocardial contractility after the ischemic period observed in senescent hearts suggests an age-related increase in myocardial stunning.

Neurotoxicity induced by Cefepime in a very old hemodialysis patient

Neurotoxicity is an unusual complication of cephalosporin therapy. Only few cases of neurotoxicity induced by Cefepime have been described and probably the frequency of Cefepime-induced status epilepticus is underestimated. We report a case of an 82 year-old male, ESRD patient on chronic hemodialysis program affected by pneumonia, who received a treatment with intravenous Cefepime (1 g/day) and developed a seizure 4 days after the starting antibiotic therapy. Cefepime-induced neurotoxicity was suspected and its administration was immediately discontinued. In order to increase Cefepime clearance a hemodialysis session was urgently started and an improvement of his conscious level was observed. On the following day, after a second hemodialysis session his clinical condition and the status of neurotoxicity were completely recovered. The patient was discharged from the hospital in stable clinical condition one week later. At variance with the cases previously reported, the daily dose of Cefepime administrated to our patient was 50% lower and respected drug prescription dosage. Thus, we speculate on the hypothesis that advanced age of our patient and metabolic encephalopathy induced by chronic uremia made him more sensitive to the neurotoxicity induced by the drug. In conclusion, our case suggests that, in very old patients on long-term hemodialysis, it should be considered, to avoid neurotoxicity, to monitor the clinical neurological status, to use Cefepime at lower dosage than that allowed in patients with severe renal impairment (1 g/day) and, when possible, to evaluate Cefepime plasma levels. However, in these patients, other agents of the same class should be considered such as Cefotaxime and Ceftriaxone which are characterized by both an hepatic and renal excretion. In alternative to cephalosporins, antibiotics with the same action spectrum in the absence of neurological toxicity (i.e. Meropenem) should be recommended.

A New Method to Improve the Clinical Evaluation of Cystic Fibrosis Patients by Mucus Viscoelastic Properties

In cystic fibrosis (CF) patients airways mucus shows an increased viscoelasticity due to the concentration of high molecular weight components. Such mucus thickening eventually leads to bacterial overgrowth and prevents mucus clearance. The altered rheological behavior of mucus results in chronic lung infection and inflammation, which causes most of the cases of morbidity and mortality, although the cystic fibrosis complications affect other organs as well. Here, we present a quantitative study on the correlation between cystic fibrosis mucus viscoelasticity and patients clinical status. In particular, a new diagnostic parameter based on the correlation between CF sputum viscoelastic properties and the severity of the disease, expressed in terms of FEV1 and bacterial colonization, was developed. By using principal component analysis, we show that the types of colonization and FEV1 classes are significantly correlated to the elastic modulus, and that the latter can be used for CF severity classification with a high predictive efficiency (88%). The data presented here show that the elastic modulus of airways mucus, given the high predictive efficiency, could be used as a new clinical parameter in the prognostic evaluation of cystic fibrosis.

Clinical expression of patients with the D1152H CFTR mutation

BACKGROUND Discordant results were reported on the clinical expression of subjects bearing the D1152H CFTR mutation, and also for the small number of cases reported so far. METHODS A retrospective review of clinical, genetic and biochemical data was performed from individuals homozygous or compound heterozygous for the D1152H mutation followed in 12 Italian cystic fibrosis (CF) centers. RESULTS 89 subjects carrying at least D1152H on one allele were identified. 7 homozygous patients had very mild clinical expression. Over half of the 74 subjects compound heterozygous for D1152H and a I-II-III class mutation had borderline or pathological sweat test and respiratory or gastrointestinal symptoms; one third had pulmonary bacteria colonization and 10/74 cases had complications (i.e. diabetes, allergic bronchopulmonary aspergillosis, and hemoptysis). However, their clinical expression was less severe as compared to a group of CF patients homozygous for the F508del mutation. Finally, 8 subjects compound heterozygous for D1152H and a IV-V class mutation showed very mild disease. CONCLUSIONS The natural history of subjects bearing the D1152H mutation is widely heterogeneous and is influenced by the mutation in trans.

Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis☆ , ☆☆

BACKGROUND In cystic fibrosis (CF) the defective CF transmembrane conductance regulator protein may be responsible for the impaired transport of glutathione (GSH), the first line defense of the lung against oxidative stress. The aim of this single-blind, randomized, placebo-controlled trial was to evaluate the effect of inhaled GSH in patients with CF. METHODS 54 adult and 51 pediatric patients were randomized to receive inhaled GSH or placebo twice daily for 12 months. RESULTS Twelve month treatment with inhaled GSH did not achieve our predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients. CONCLUSIONS Inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01450267; URL: www.clinicaltrialsgov.

Raman spectroscopy as a new tool for early detection of bacteria in patients with cystic fibrosis

Respiratory infections represent a major threat for people affected by cystic fibrosis, leading to pulmonary deterioration and lung transplantation as a therapeutic option for end-stage patients. A fast and correct identification of pathogens in airway fluid of these patients is crucial to establish appropriate therapies, to prevent cross-infections and, ultimately, to preserve lung function. In this study, we used Raman spectroscopy to reveal bacteria in the sputa of patients such as Pseudomonas aeruginosa and Staphylococcus aureus, which are among the earliest and the most frequent bacteria affecting cystic fibrosis patients. We found that Raman analysis, combined with principal component analysis, is able to provide a correct identification of these bacteria, with a global accuracy higher than 95%. Interestingly, bacterial identification is performed by analysing patients’ sputa as a whole, avoiding, therefore, time-consuming procedures involving bacterial isolation or even bacterial cultures. This study suggests that Raman spectroscopy could be a suitable candidate for the development of innovative and non-invasive procedures for a fast and reliable identification of respiratory infections in cystic fibrosis patients.

Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

Background The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. Objectives To describe the genotype–phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles. Methods We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. Results The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I–II mutation. Their CFTR activity on NEC was comparable with patients with two class I–II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I–II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV–V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I–II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I–II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3–36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I–II mutation had mild CF or CFTR-RD (gating activity: 18.5–19.0%). Conclusions The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction.

Reduced absorption and enhanced synthesis of cholesterol in patients with cystic fibrosis: a preliminary study of plasma sterols.

Abstract Background: Low cholesterol is typically observed in the plasma of patients with cystic fibrosis (CF) contrasting with the subcellular accumulation of cholesterol demonstrated in CF cells and in mice models. However, the homeostasis of cholesterol has not been well investigated in patients with CF. Methods: We studied the plasma of 26 patients with CF and 33 unaffected controls campesterol and β-sitosterol as markers of intestinal absorption and lathosterol as a marker of de novo cholesterol biosynthesis by gas chromatography (GC-FID and GC-MS). Results: Plasma campesterol and β-sitosterol results were significantly (p=0.01) lower while plasma lathosterol was significantly higher (p=0.001) in patients with CF as compared to control subjects. Plasma cholesterol results were significantly lower (p=0.01) in CF patients. Conclusions: Our data suggest that the impaired intestinal absorption of exogenous sterols in patients with CF stimulates the endogenous synthesis of cholesterol, but the levels of total cholesterol in plasma remain lower. This may be due to the CFTR dysfunction that reduces cholesterol blood excretion causing the accumulation of cholesterol in liver cells and in other tissues contributing to trigger CF chronic inflammation.

51 Inhaled GSH tolerability in patients with cystic fibrosis (CF)

Objectives: Oxidative stress biomarkers as reactive oxygen species are induced by the sustained activation of neutrophils and other CF-derived defects in the lung of CF patients. Observed defects include an impaired glutathione (GSH) metabolism. Its supplementation may counterbalance the oxidative stress. A randomized, single blind controlled trial of inhaled GSH versus placebo (NCT01450267) is underway in order to evaluate the effect of GSH in cohort of CF patients. We report preliminary data on tolerability to GSH in a pediatric subset of enrolled patients. Methods: 48 CF patients (F 23, age M±DS 13.53 yrs), in regular follow up at the Regional Pediatric CF Center of Naples, were enrolled for RCT. The main inclusion criteria were: CF diagnosis by sweat test and/or two CF causing mutations, age of patients >6 yrs, FEV1% >40% of the predicted value, negative culture for Burkholderia cepacia. Spirometry was performed before and 10 and 60 minutes after GSH inhalation test (10mg/kg, maximum dosage 600mg/dose) in order to assess tolerability. Conclusions: No patients showed a decrease in FEV1% >15% after GSH inhalation as defined in the study design. A statistically significant increase was observed for FEF25−75% after 10 and 60 minutes from inhalation (FEF25−75 M±DS: T0 71.64±33.35 VS T10 76.37±36.73; p< 0.02 and T0 71.64±33.35 VS T60: 80.26±35.25; p< 0.0001) and for FEV1% after 60 minutes from inhalation (FEV1 M±DS: T0 97.90±21.03 VS T60 100.01±19.42; p< 0.01). No side effects were reported. On the basis of these preliminary results we are currently evaluating the efficacy of inhaled GSH on pulmonary function and inflammatory markers within a 12 months therapy.