Disease trends over time and CD4+CCR5+ T-cells expansion predict carotid atherosclerosis development in patients with systemic lupus erythematosus.

BACKGROUND AND AIM: Patients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study. METHODS AND RESULTS: Clinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 ± 9 years; 14.4 ± 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4+CCR5+; CD4+CXCR3+; CD4+HLADR+; CD4+CD45RA+RO-, CD4+CD45RO+RA- and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4+CCR5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients. CONCLUSION: Serial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression.

Asthma management among allergists in Italy: results from a survey.

BACKGROUND: In Europe more than 50% of asthmatic treated patients have not well-controlled asthma. Asthma affects about 2.5 million of patients in Italy. AIMS AND OBJECTIVES: The present survey aims at investigating how Italian allergists approach asthmatic patients, in order to highlight pitfalls and unmet needs concerning real-life asthma management. METHODS: An anonymous 16 item web questionnaire was available (April-October 2015) to all allergists who visited the web site of SIAAIC (Società Italiana di Allergologia, Asma Immunologia Clinica). Those who wished to give their contribution had the opportunity to answer about epidemiology, risk factors, treatment approaches, and adherence to therapy. RESULTS: One hundred and seventy four allergists answered the survey. 54% of them reported up to 10 patient visits per week and 35.3% between 10 and 30. The most frequent reasons of follow up visits are routine check-up (56.5% of allergists), and worsening of symptoms (41% of allergists). Nocturnal apnoeas, gastro-esophageal reflux and obesity are the most important comorbidities/risk factors of poorly controlled asthma. Bronchial hyper-responsiveness, increased NO levels and reduced exercise tolerance are the most important indicators of asthma severity. Concerning therapy, ICS combined with LABA is the treatment of choice suitable for the majority of patients. A rapid onset of action and a flexible ICS dosage are indicated as the optimal characteristics for achieving the therapeutic goals. Poor adherence to therapy is an important reason for symptom worsening for the majority of allergists. Complex dosage regimens and economic aspects are considered the most important factors impacting on adherence. CONCLUSIONS: Allergists are involved in the management of asthma, regularly seeing their patients. Co-morbidities are frequent in asthmatic patients and may impact negatively on disease control, thus identifying patients who need a more careful and strict monitoring. Airway hyper-responsiveness to methacholine challenge test and nitric oxide are considered important indicators of asthma severity. The combination of LABA and inhaled steroids is considered the treatment of choice for most asthmatic patients, in keeping with broad evidence indicating that the combination therapy is more effective and rapid in gaining asthma control than inhaled corticosteroids alone. Adherence to medication regimens is considered of essence to achieve the therapeutic goals.

The role of T and B cells in human atherosclerosis and atherothrombosis.

Far from being merely a passive cholesterol accumulation within the arterial wall, the development of atherosclerosis is currently known to imply both inflammation and immune effector mechanisms. Adaptive immunity has been implicated in the process of disease initiation and progression interwined with traditional cardiovascular risk factors. Although the body of knowledge regarding the correlation between atherosclerosis and immunity in humans is growing rapidly, a relevant proportion of it derives from studies carried out in animal models of cardiovascular disease (CVD). However, while the mouse is a well-suited model, the results obtained therein are not fully transferrable to the human setting due to intrinsic genomic and environmental differences. In the present review, we will discuss mainly human findings, obtained either by examination of post-mortem and surgical atherosclerotic material or through the analysis of the immunological profile of peripheral blood cells. In particular, we will discuss the findings supporting a pro-atherogenic role of T cell subsets, such as effector memory T cells or the potential protective function of regulatory T cells. Recent studies suggest that traditional T cell-driven B2 cell responses appear to be atherogenic, while innate B1 cells appear to exert a protective action through the secretion of naturally occurring antibodies. The insights into the immune pathogenesis of atherosclerosis can provide new targets in the quest for novel therapeutic targets to abate CVD morbidity and mortality.

Asthma management among different specialists: results from a national Italian survey.

In Europe more than 50% of asthmatic treated patients have a not well-controlled asthma. The present survey aims at investigating how different specialists approach asthmatic patients. A web anonymous questionnaire was randomly administered to 604 General Practitioners (GPs), 241 Pneumologists and 131 Allergists. It concerned: epidemiology, diagnostic workup, follow-up and risk factors, treatment and future risk. A general agreement emerges about asthma diagnostic work-up. All categories are aware of the impact of comorbidities on asthma. LABA/inhaled steroids combination is considered the first choice treatment. Surprisingly, depot steroids and long-acting beta2 agonists (LABA) alone are still prescribed by GPs. Concerning monitoring tools, Allergists rely on inflammation biomarkers, whereas reduction of rescue medication is more relevant for GPs. Asthma Control Test (ACT) is considered time consuming by more than 50% of all physicians and is not known by most of GPs. Adherence is considered a crucial problem in asthma management. All categories seem to have a good knowledge about asthma. The cultural background may account for mild differences in asthma control tools and treatment options. GPs have a pivotal role in discriminating patients who need specific assessment by specialists. It is thus important that GPs and specialists share common tools for recognizing and managing those patients.

Implementation of GOLD consensus report in real life: results from the Velletri-Lariano (VELA) cohort.

BACKGROUND: COPD is one of the leading causes of morbidity and mortality. Pharmacotherapy improves quality of life and reduces exacerbations although low adherence with prescribed treatments may represent a barrier to optimal disease management. The first objective of this paper is to report the distribution of COPD patients according to GOLD categories, in a sample of patients from a cohort study in an area of the Latium region in Italy. The second objective is to evaluate the agreement between the distributions of severity obtained from the HCPs and the experts included in the study board (Board). METHODS: COPD patients were given a card to collect demographic and clinical data at baseline. Information in those cards was independently evaluated by HCPs and Board to include each patient into one of the four GOLD categories. RESULTS: In a sample of 187 stable COPD patients, 59% male, mean age 70 year, the distribution of GOLD categories according to the Board was: 6% A, 34% B, 2% C, and 58% D. A discrepancy in GOLD classification was observed between the study board and field-based HCPs, regarding more than 50% of the patients, with a clear trend to underestimate the frequency of patients in D level (21%) and to overestimate the frequency in C level (21%). CONCLUSIONS: These results describe for the first time the distribution of COPD patients in an Italian cohort according to the GOLD categories, with the highest frequencies in levels B and D. The misclassification from HCPs may impact the therapeutic approach and the clinical outcomes.

AN INTERNATIONAL COOPERATION BY USING AN ALL-ENCOMPASSING PASSIVE RADON MONITOR.

The recently developed radon film-badge makes it possible to measure radon indoors, in soil, in water and/or in aqueous media (e.g. mud). As a result of its wide response linearity, this monitor has been successfully used to measure radon in-water with concentrations from 10 to ~10 000 Bq/L. By exploiting the unique characteristics of this badge, a mini-survey has been carried out by Health Canada in which radon in water was measured from 12 private wells, as well as in tap water originating from the Ottawa River. Due to the widespread interest of different laboratories in using these passive monitors, laboratories were provided with plastic films to construct their own badges by using in-house CR-39 detectors. Monitors were then irradiated by a known radon concentration at the National Institute of Radiation Metrology (ENEA)'s radon chamber and sent back to each laboratory for processing and counting. Even though these laboratories have been using different etching- and counting-procedures, the film-badge responses varied only within ~12%.

L-type calcium channels are modified in rat hippocampus by short-term experimental ischemia.

Increasing evidence suggests a role for calcium ions in the pathophysiology of ischemic brain damage. The major mechanism allowing calcium entry from the extracellular compartment is the opening of voltage-operated calcium channels. In this line, we have explored the hypothesis that the characteristics of central L-type voltage-dependent calcium channels, labeled by the dihydropyridine ligand 3H-PN 200-110, may be modified by experimental ischemia. The results show that short-term mild ischemia, produced in the rat by 1 h of right carotid ligation, induces an increase in the number of 3H-PN 200-110 binding sites in the hippocampus ipsilateral to the side of carotid occlusion, accompanied by an increase in the dissociation constant value, whereas no changes in the kinetic parameters of the binding were observed in the other areas examined, i.e., the cortex and the striatum. The changes in hippocampus are transient: 96 h after the occlusion, binding parameters return to the control range. The modifications of the binding characteristics in the hippocampus may be related to alterations of Ca2+ fluxes through L-type calcium channels.

Microcirculation and neurotransmitter metabolism in the pathophysiology of brain ischaemia. A role for calcium.

Calcium is an essential component in a multitude of cellular processes, ranging from muscle contraction to cell division, and hormone and neurotransmitter release. Disruption of calcium homeostasis at the neuronal level, which occurs in pathological events such as ischaemia, causes a series of biological reactions that ultimately lead to cell death. Furthermore, calcium-triggered events may influence vascular activity, causing spasm at the level of the major vessels and inducing changes in the permeability of the blood-brain barrier. Thus, knowledge of the biochemical events involved in the initiation and progression of cell injury occurring in acute cerebrovascular events may have important implications for possible strategies of pharmacological intervention such as calcium entry blockade.

Stereoisomers of BAY K 8644 show opposite activities in the normal and ischaemic rat heart. A comparison with nifedipine.

The effects of the stereoisomers and the racemate of the calcium agonist BAY K 8644 and the calcium antagonist nifedipine were studied on the Langendorff-perfused rat heart, subjected to 30 min of global ischaemia. The results show that (-)- and (+/-)-BAY K 8644 induced a strong positive inotropic effect at 100 and 1000 nmol/l and a vasoconstricting effect which was most prominent at 1 and 10 nmol/l, respectively. At higher concentrations the flow reduction was inverted to a flow increase, closely related to the positive inotropic activity. The inotropic status induced by the agonist before the onset of ischaemia was reflected in an accelerated development of the diastolic contracture during ischaemia. During the reperfusion, a complex triphasic effect on the recovery was found, in which probably positive inotropism, vasoconstriction, metabolic and mechanical factors are involved. The (+)-enantiomer of BAY K 8644 behaved as a weak calcium antagonist showing merely vasodilatation, which accelerated the recovery from the ischaemic contracture at reperfusion. The calcium antagonistic, vasodilating effects of the (+)-enantiomer were expressed in the racemate only during the reperfusion phase, where it took an intermediate position between the effects of the (-)- and (+)-enantiomer. In contrast, nifedipine, at negative inotropic - energy saving - concentrations, diminished the height and delayed the development of the energy deprivation-induced left ventricular diastolic contracture during ischaemia. The time needed for recovery from the contracture during reperfusion was significantly shortened already at a 100 times lower, vasodilating concentration of nifedipine.

Protection by verapamil and nifedipine against ischaemia-induced loss of [3H]-(+)-PN 200-110 binding sites in the rat heart.

We have studied the effects of 60 min global ischaemia and 30 min of subsequent reperfusion on the binding of [3H]-(+)-PN 200-110 and [3H]-(-)-devapamil (desmethoxyverapamil or D888) in rat heart membranes. The hearts were perfused in the Langendorff-mode and pretreated with 1 mumol/l verapamil, 30 nmol/l and 1 mumol/l nifedipine. After 60 min of global ischaemia in the absence of drugs, we found a reduction of [3H]-(+)-PN 200-110 binding sites, without changes in the equilibrium dissociation binding constant (Kd). After the subsequent reperfusion maximum specific binding (Bmax) was further reduced, whereas the Kd remained constant. [3H]-devapamil binding sites were influenced to a lower extend and showed only a decrease in Bmax at reperfusion. Pretreatment with 1 mumol/l verapamil completely prevented the changes which were observed for [3H]-(+)-PN 200-110. Pretreatment with a low, vasodilating concentration (30 nmol/l) of nifedipine displayed selective protection against the extra reduction in Bmax which was observed during reperfusion. It is concluded that calcium antagonists show protection against the ischaemia-induced loss of dihydropyridine binding sites in relation to their negative inotropic, energy-saving activity. Furthermore, nifedipine at low, vasodilating but not negative inotropic concentrations protects against further reperfusion-induced injury, which protection may be related to an improved flow during reperfusion.

The aging brain: protein phosphorylation as a target of changes in neuronal function.

There is evidence that senescence affects neurotransmission at different levels. In particular, this review summarizes the studies on age-dependent modifications in protein phosphorylation, which represents the final pathway in the action of transmitters and hormones at neuronal level. Cyclic AMP-dependent protein kinase and protein kinase C have been reported to be modified during aging in various cerebral areas; the changes may involve either enzyme activity or substrate availability. These findings can be related to the alterations in neurotransmitter function and synaptic efficiency observed in the senescent brain. The activity of the other types of protein kinases (tyrosine-, cGMP-, calcium/calmodulin-dependent) during aging needs to be explored. An emerging point is the role of protein phosphorylation in the transfer of membrane signals to the nucleus, for the activation or disactivation of specific genes responsible for long-term neuronal events. Along this view, alterations in protein kinase pathway during senescence would ultimately affect gene expression, resulting in long term modifications of cell function. The reviewed literature opens the perspective of restoring some of the deficits associated with senescence by modulating protein phosphorylation pathway.

beta-Adrenergic receptors in brain microvessels of diabetic rats.

A significant decrease in the number of beta-adrenergic receptors was observed in cerebral microvessels of fatty (fa/fa) and streptozotocin-induced diabetic rats, without receptor affinity changes. These results suggest that alterations of central adrenergic regulation of small vessels may be involved in brain microvasculature disturbances that occur with diabetes.

[Vascular and neuronal mechanisms of calcium antagonists. Significance in neurological therapy]. / Meccanismi vascolari e neuronali dei calcio-antagonisti. Significato in terapia neurologica.

Calcium-channel entry blockers are drugs with different chemical properties and a common pharmacological characteristic. Calcium is very important in many physiological mechanisms and could be involved in neuronal damage following cerebral ischemia. Thus, calcium-channel blockers agents could be of interest in medical treatment of cerebrovascular diseases, headache and subarachnoid hemorrhage. Calcium-channel blockers seem to have a direct protective role against neuronal ischemic damage and/or a direct action on cerebral vessels. Some clinical experiences have suggested a protective role of nimodipine in the prevention of ischemic complications related to cerebral vasospasm after subarachnoid hemorrhage.

The influence of clay mineralogy on the mobility of radiocaesium in upland soils of NW Italy.

137Cs extraction experiments were performed on 14 contaminated soils from NW Italy with different characteristics and mineralogical composition. Solutions of HCl (pH = 0.5) and buffered EDTA/ammonium acetate (Lakanen solution) were used to assess bioavailability. The results show that less than 2% of 137Cs is available for leaching and/or root uptake. Even within a complex natural system it was possible to identify the amount of swelling clays (vermiculite + smectite) as the main control on Cs mobility under acidic conditions. The ammonium ion appears to be effective in desorbing Cs and its role is briefly discussed in terms of crystal chemistry. The relevance of mineralogy in assessing soil vulnerability is underlined.

Comparison of different methods for the assessment of the environmental gamma dose.

Four different techniques for the assessment of environmental gamma dose are discussed and compared: high pressure ionisation chamber (Reuter-Stokes type), TLD dosemeters (GR-200), in situ gamma ray spectrometry and dose evaluation from the activity concentration of radionuclides in the soil. Soil samples gathered from a field near Turin (North-West Italy) have been analysed with a p-type HPGe, and their radionuclide concentrations have been used to evaluate the dose at I m above the soil surface. At the same location the dose rate was evaluated with the in situ gamma ray spectrometry (with a portable n-type HPGe) and with the ionisation chamber and the TLD dosemeters. The contribution of cosmic rays was added to the dose rate calculated from the soil samples and the in situ gamma spectrometry. The results obtained with these four techniques agree well within 20%.

Variations of the isotopic ratios of uranium in environmental samples containing traces of depleted uranium: theoretical and experimental aspects.

The possibility of using conventional analysis, such as gamma spectrometry and alpha spectrometry, for the detection of traces of depleted uranium (DU) in environmental samples has been investigated. The expected values have been compared with the experimental results obtained by using mollusc samples gathered in the Adriatic Sea. The analysis has shown that it is possible to detect DU. if the percentage composition is about 20% depleted uranium and 80% natural uranium, for a sample containing 10 Bq x kg(-1) of 238U. The possibility of extending this approach to samples with any given uranium concentration is investigated.

Gamma dose rate calculation and mapping of piemonte (North-West Italy) from gamma spectrometry soil data.

In this study the air gamma dose rate map of Piemonte, a region in the North-West of Italy, was produced from gamma spectrometry soil data. Soil samples collected in 110 different sites of Piemonte were analysed with Hyperpure Germanium (HPGe) detectors (30% relative efficiency), which allow the evaluation of the activity concentrations of natural radionuclides and (137)Cs. Then, using the available mathematical models, the gamma absorbed dose rate in air due to radionuclides was calculated. The contribution of the cosmic radiation to the total absorbed dose rate, which depend on the site altitude was also evaluated and added to the soil contribution. Finally, the map of the whole region was obtained by fitting the dose rate values of the different sites with kriging algorithms.

A simple approach to measure the radon equilibrium factor F from air filter gross beta counting.

The internal alpha dose assessment (ICRP 65, 1994) depends on the value of the equilibrium factor F. This parameter is generally not measured and a mean conventional value ranging between 0.4 and 0.6 is assumed, possibly leading to a significant bias in the dose assessments. In this paper, a method for the measurement of F is reported, based on the total aerosol sampling on filters and immediate gross beta counting of 214Pb and 214Bi activities. Measurements are interpreted according to a Raabe-Wrenn and Jacobi simplified room model, leading to an estimate of the individual airborne activities of short-lived radon daughters, the removal parameter and the equilibrium factor. The method was laboratory tested and validated and it is being qualified by field surveys in different indoor environmental conditions.

Outdoor radon concentration measurements: some correlation with major urban pollutants.

Air pollutants concentration in the urban air strongly depends on the properties of the planetary boundary layer (the lower region of the atmosphere), roughly up to 1 km from Earth's surface. Radioactive radon gas has been recognised by various authors as a valuable natural tracer of transport and dispersion within this layer. To achieve a better comprehension of the urban pollution dynamic in the town of Alessandria, situated in the Po Valley in the north-west of Italy, a system for continuous measurement of radon concentration in outdoor air was experimented. This paper presents the first results obtained: the hourly trend of radon concentration in the diurnal course during different seasons and its correlation with the concentration of the major urban pollutants.