Giuseppe Di Maria

Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma

BACKGROUND Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma. METHODS The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants. FINDINGS The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine. INTERPRETATION The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.

Early treatment with noninvasive positive pressure ventilation prolongs survival in Amyotrophic Lateral Sclerosis patients with nocturnal respiratory insufficiency

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.AimTo assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV.MethodsWe investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant.ResultsIncreased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001).ConclusionThis report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS.

Allergic susceptibility associated with diesel exhaust particle exposure: clear as mud

Abstract Exposure to elevated levels of particulate air pollution from motor vehicles is frequently associated with increased morbidity and mortality from cardiovascular conditions, lung cancer, and nonmalignant respiratory illnesses (e.g., asthma, bronchitis, respiratory tract infections). It appears, however, that less attention has been paid to the potential role of road traffic fumes in the induction of allergic conditions. Laboratory studies in humans and animals have shown that particulate toxic pollutants—particularly diesel exhaust particulates—can enhance allergic inflammation and can induce allergic immune responses. Most of these immune responses are mediated by the carbon core of diesel exhaust particulates. Polyaromatic hydrocarbons (e.g., anthracene, fluoranthene, pyrene, phenanthrene) are major chemical components of diesel exhaust particulates, and they have enhanced the production of immunoglobulin E. Although several large epidemiological studies have demonstrated a strong association between exposure to motor vehicle traffic emissions and allergic symptoms and reduced lung function, the evidence for the development of allergic sensitization from diesel exhaust particulates is less abundant than for the aforementioned associations. Recent comparisons of the prevalence of hay fever, as well as positive skin-prick tests, between citizens of former West and East Germany and between Hong Kong and China civilians, have demonstrated marked differences. Crucial variations in the level of particulate air pollution from motor vehicles in these countries may account for the observed increased prevalence of atopy. Although road-traffic pollution from automobile exhausts may be a risk factor for atopic sensitization, the evidence in support of this view remains conflictive. Some investigators have reported a clear association between the prevalence of allergy and road-traffic-related air pollution, whereas such a difference was not observed in other studies. Most discrepancies have been related to important variations in study design and methodology. In addition, inasmuch as exposure to ambient particles differs substantially in worldwide urban environments, perhaps qualitative—rather than quantitative—variations in particulate air pollution at different locations account for differences in the prevalence and/or severity of respiratory allergies.

Increased prevalence of cardiac arrhythmias and transient episodes of myocardial ischemia in hypertensives with left ventricular hypertrophy but without clinical history of coronary heart disease.

To evaluate the behavior of cardiac arrhythmias (CA) and transient episodes of myocardial ischemia (TEMI), in relation to the circadian pattern of blood pressure in patients suffering from arterial hypertension, with or without echocardiographically ascertained left ventricular hypertrophy (LVH), we studied 128 patients, 87 men (M) and 41 women (F), aging from 21 to 76 years, subdivided into two groups: Group I, including 66 patients with LVH (45 M and 21 F; mean age of 53.7 +/- 9.1 years; Group II, including 62 patients without LVH (42 M and 20 F; mean age of 49.7 +/- 9.5 years). Office blood pressure (OBP) as well as nighttime ambulatory blood pressure (ABP) were higher in patients with LVH (P < .05 and P < .01). CA were present in a higher number of patients of Group I (P < .001): premature supraventricular beats (PSVB) 22.7 v 4.8%, supraventricular couplets (SVC) 36.4 v 16.1%, supraventricular tachycardia runs (SVT runs) 27.3 v 12.9%, ventricular ectopic beats (VEB) 25.6 v 8.0%, ventricular couplets (VC) 30.3 v 12.9%, ventricular tachycardia runs (VT runs) 12.1 v 3.2%. The absolute number of ectopic beats was also significantly higher in patients of Group I. Ventricular arrhythmias were significantly related to ASBP (r = 0.83, P < .01), to ADBP (r = 0.74, P < .01) and to heart rate (r = 0.87, P < .01) in patients of Group I. TEMI were more frequent in patients of Group I (73 v 41 episodes, 39.39% v 25.8% of patients, P < .01) and were related to ABP peaks. In fact, in both groups of patients all TEMI without heart rate increase and most TEMI with heart rate increase were registered between 6:00 and midnight, hours in which ABP values were higher. We conclude that hypertensives with LVH, but without clinical history of coronary heart disease, have a higher prevalence of ventricular arrhythmias and of transient episodes of myocardial ischemia in relation to the circadian pattern of ABP.

Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD

The main complaint of patients with chronic obstructive pulmonary disease (COPD) is shortness of breath with exercise, that is usually progressive. The principal mechanism that explains this symptom is the development of lung hyperinflation (LH) which is defined by an increase of functional residual capacity (FRC) above predicted values. Patients with COPD may develop static LH (sLH) because of destruction of pulmonary parenchyma and loss of elastic recoil. In addition, dynamic LH (dLH) develops when patients with COPD breathe in before achieving a full exhalation and, as a consequence, air is trapped within the lungs with each further breath. Dynamic LH may also occur at rest but it becomes clinically relevant during exercise and exacerbation. Lung hyperinflation may have an impact beyond the lungs and the effects of LH on cardiovascular function have been extensively analysed. The importance of LH makes its identification and measurement crucial. The demonstration of LH in COPD leads to the adoption of strategies to minimise its impact on the daily activities of patients. Several strategies reduce the impact of LH; the use of long-acting bronchodilators has been shown to reduce LH and improve exercise capacity. Non pharmacologic interventions have also been demonstrated to be useful. This article describes the pathophysiology of LH, its impact on the lungs and beyond and reviews the strategies that improve LH in COPD.

Obstructive sleep apnoea syndrome and its management

Obstructive sleep apnoea (OSA) is a common disorder characterized by repetitive episodes of nocturnal breathing cessation due to upper airway collapse. OSA causes severe symptoms, such as excessive daytime somnolence, and is associated with a significant cardiovascular morbidity and mortality. Different treatment options are now available for an effective management of this disease. After more than three decades from its first use, continuous positive airway pressure (CPAP) is still recognized as the gold standard treatment. Nasal CPAP (nCPAP) is highly effective in controlling symptoms, improving quality of life and reducing the clinical sequelae of sleep apnoea. Other positive airway pressure modalities are available for patients intolerant to CPAP or requiring high levels of positive pressure. Mandibular advancement devices, particularly if custom made, are effective in mild to moderate OSA and provide a viable alternative for patients intolerant to CPAP therapy. The role of surgery remains controversial. Uvulopalatopharyngoplasty is a well established procedure and can be considered when treatment with CPAP has failed, whereas maxillar-mandibular surgery can be suggested to patients with a craniofacial malformation. A number of minimally invasive procedures to treat snoring are currently under evaluation. Weight loss improves symptoms and morbidity in all patients with obesity and bariatric surgery is an option in severe obesity. A multidisciplinary approach is necessary for an accurate management of the disease.

Project PriMo: Sharing principles and practices of bronchodilator therapy monitoring in COPD A consensus initiative for optimizing therapeutic appropriateness among Italian specialists

BACKGROUND Even after publication of the 2011 update of GOLD report, some fundamental questions in the management of COPD are still open and this may weaken the applicability of these guidelines in everyday clinical practice. OBJECTIVE To assess the level of consensus amongst Italian respirologists on different topics related to diagnosis, monitoring and role of bronchodilator therapy in COPD, by using the Delphi technique. METHODS A Delphi study was undertaken between July and November 2011, when two questionnaires were consecutively sent to a panel of experts to be answered anonymously. After each round, the data were aggregated at group level of question topics and structured feedback was given to the panel. RESULTS A first-round questionnaire was sent to 208 pulmonologists randomly selected from different Italian regions. The 132 respondents (63% of those initially selected) were from northern (53%), central (19%) and southern (28%) Italy. A second-round questionnaire was sent to all the first-round respondents, and a response was received from 110 of them (83%). The main topics that reached the pre-defined cut off for consensus (67% or more) were: a) bronchodilator therapy with long-acting bronchodilators could be beneficial in patients with airflow limitation even in the absence of symptoms, b) in patients not fully controlled with one long-acting bronchodilator, maximizing bronchodilation (i.e. adding another bronchodilator with a different mechanism of action) is the preferable option; and c) the use of inhaled corticosteroids (ICSs) as add on therapy should be considered in severe patients with frequent exacerbations. CONCLUSIONS Italian specialists agree on several aspects of the diagnosis and treatment of COPD and expert opinion could support everyday decision process in the management of COPD.

Effect of 8-iso-prostaglandin F2α on acetylcholine release from parasympathetic nerves in guinea pig airways

Abstract 8-Iso-prostaglandin F 2α is present in increased amounts in airway inflammation. 8-Iso-prostaglandin F 2α constricts the airways via the activation of thromboxane A 2 receptors. However, thromboxane A 2 receptors are also present pre-junctionally on cholinergic nerve terminals innervating guinea pig trachea. We have demonstrated that 8-iso-prostaglandin F 2α inhibited electrical field stimulation-evoked [ 3 H]acetylcholine release in a concentration-dependent manner, an effect that was not inhibited by the selective thromboxane A 2 receptor antagonist {4( Z )-6-[(2,4,5cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid} (ICI 192,605). These data suggest that 8-iso-prostaglandin F 2α inhibits acetylcholine release through a receptor distinct from the thromboxane A 2 receptor and provides evidence that isoprostanes may have a ‘dual’ role as both beneficial and deleterious mediators in airway disease.

Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases: preliminary experience

Cytoreductive surgery and hyperthermic-intraoperative-intrapleural-chemotherapy (HITHOC) is a known approach for malignant pleural diseases (MPD). This study was started to clarify the role of cytoreductive surgery and HITHOC in MPD. Criteria of inclusion were early-stage disease in malignant pleural mesothelioma (MPM), young age, good condition and selected stage-M1a lung cancer. Six patients with MPM and two patients with lung cancer were enrolled. After surgical debulking, intrapleural cisplatin was administered for 60 min at 42.5°C. Wedge, rib resection and repaired diaphragm were added in three, one and one patient, respectively. Morbidity, toxicity and mortality was nil. Hospital stay was 8 days. Mean survival is 13.6 months. This experience confirms that cytoreductive surgery and HITHOC is a good option in the treatment of MPD. A randomized controlled trial is necessary.

A retrospective study on acute health effects due to volcanic ash exposure during the eruption of Mount Etna (Sicily) in 2002.

BackgroundMount Etna, located in the eastern part of Sicily (Italy), is the highest and most active volcano in Europe. During the sustained eruption that occurred in October-November 2002 huge amounts of volcanic ash fell on a densely populated area south-east of Mount Etna in Catania province. The volcanic ash fall caused extensive damage to infrastructure utilities and distress in the exposed population. This retrospective study evaluates whether or not there was an association between ash fall and acute health effects in exposed local communities.MethodsWe collected the number and type of visits to the emergency department (ED) for diseases that could be related to volcanic ash exposure in public hospitals of the Province of Catania between October 20 and November 7, 2002. We compared the magnitude of differences in ED visits between the ash exposure period in 2002 and the same period of the previous year 2001.ResultsWe observed a significant increase of ED visits for acute respiratory and cardiovascular diseases, and ocular disturbances during the ash exposure time period.ConclusionsThere was a positive association between exposure to volcanic ash from the 2002 eruption of Mount Etna and acute health effects in the Catania residents. This study documents the need for public health preparedness and response initiatives to protect nearby populations from exposure to ash fall from future eruptions of Mount Etna.