A double blind randomized controlled trial investigating efficacy and safety of varenicline for smoking cessation in patients with type 2 diabetes: study protocol.

Reducing exposure to cigarette smoke is an imperative for public health and for diabetic patients. Patients with diabetes who continue to smoke face challenges at quitting and the delivery of effective smoking cessation interventions is a major unmet need. The high-affinity α4ß2 nicotinic acetylcholine receptor partial agonist varenicline in combination with counseling is effective for smoking cessation, but evidence in patients with diabetes is limited. A clinical trial of varenicline targeted specifically at smokers with T2DM is warranted. This randomized, double blind, placebo-controlled trial will be the first study to test efficacy and safety of varenicline in smokers with type 2 diabetes mellitus (T2DM) over the course of 52 weeks. We hypothesize that varenicline treatment (1 mg BID, administered for 12 weeks) would increase quit rates, maintain smoking abstinence up to 1 year after treatment, and be well-tolerated in T2DM smokers intending to quit. Efficacy end points will include carbon monoxide-confirmed continuous abstinence rate (CAR) and 7-day point prevalence of abstinence. The results of this RCT will help inform medical/health authorities and physicians worldwide whether an optimally varenicline-treated cohort of T2DM patients who smoke will experience significant success rates, without significant side effects.Trial registration NCT01387425 ( https://clinicaltrials.gov/ct2/show/NCT01387425 ).

Unresolved Gamma-Ray Sky through its Angular Power Spectrum.

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15.

Investigating the Nature of Late-Time High-Energy GRB Emission Through Joint Fermi /Swift Observations.

We use joint observations by the Neil Gehrels Swift X-ray Telescope (XRT) and the Fermi Large Area Telescope (LAT) of gamma-ray burst (GRB) afterglows to investigate the nature of the long-lived high-energy emission observed by Fermi LAT. Joint broadband spectral modeling of XRT and LAT data reveal that LAT non-detections of bright X-ray afterglows are consistent with a cooling break in the inferred electron synchrotron spectrum below the LAT and/or XRT energy ranges. Such a break is sufficient to suppress the high-energy emission so as to be below the LAT detection threshold. By contrast, LAT-detected bursts are best fit by a synchrotron spectrum with a cooling break that lies either between or above the XRT and LAT energy ranges. We speculate that the primary difference between GRBs with LAT afterglow detections and the non-detected population may be in the type of circumstellar environment in which these bursts occur, with late-time LAT detections preferentially selecting GRBs that occur in low wind-like circumburst density profiles. Furthermore, we find no evidence of high-energy emission in the LAT-detected population significantly in excess of the flux expected from the electron synchrotron spectrum fit to the observed X-ray emission. The lack of excess emission at high energies could be due to a shocked external medium in which the energy density in the magnetic field is stronger than or comparable to that of the relativistic electrons behind the shock, precluding the production of a dominant synchrotron self-Compton (SSC) component in the LAT energy range. Alternatively, the peak of the SSC emission could be beyond the 0.1-100 GeV energy range considered for this analysis.

Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index.

BACKGROUND: Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II). OBJECTIVE: The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic ß-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest. METHODS: A comprehensive MEDLINE® search was performed using relevant key terms for PCOS and DM II. RESULTS: Insulin-induced hyperandrogenism could impair pancreatic ß-cell function, the SC abdominal adipocytes' lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance. CONCLUSIONS: Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data.

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10^{-3}. We take into account systematic effects that could mimic true anisotropies at this level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. The present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.

Search for Spectral Irregularities due to Photon-Axionlike-Particle Oscillations with the Fermi Large Area Telescope.

We report on the search for spectral irregularities induced by oscillations between photons and axionlike-particles (ALPs) in the γ-ray spectrum of NGC 1275, the central galaxy of the Perseus cluster. Using 6 years of Fermi Large Area Telescope data, we find no evidence for ALPs and exclude couplings above 5×10^{-12} GeV^{-1} for ALP masses 0.5≲m_{a}≲5 neV at 95% confidence. The limits are competitive with the sensitivity of planned laboratory experiments, and, together with other bounds, strongly constrain the possibility that ALPs can reduce the γ-ray opacity of the Universe.

Resolving the Extragalactic γ-Ray Background above 50 GeV with the Fermi Large Area Telescope.

The Fermi Large Area Telescope (LAT) Collaboration has recently released a catalog of 360 sources detected above 50 GeV (2FHL). This catalog was obtained using 80 months of data re-processed with Pass 8, the newest event-level analysis, which significantly improves the acceptance and angular resolution of the instrument. Most of the 2FHL sources at high Galactic latitude are blazars. Using detailed Monte Carlo simulations, we measure, for the first time, the source count distribution, dN/dS, of extragalactic γ-ray sources at E>50 GeV and find that it is compatible with a Euclidean distribution down to the lowest measured source flux in the 2FHL (∼8×10^{-12} ph cm^{-2} s^{-1}). We employ a one-point photon fluctuation analysis to constrain the behavior of dN/dS below the source detection threshold. Overall, the source count distribution is constrained over three decades in flux and found compatible with a broken power law with a break flux, S_{b}, in the range [8×10^{-12},1.5×10^{-11}] ph cm^{-2} s^{-1} and power-law indices below and above the break of α_{2}∈[1.60,1.75] and α_{1}=2.49±0.12, respectively. Integration of dN/dS shows that point sources account for at least 86_{-14}^{+16}% of the total extragalactic γ-ray background. The simple form of the derived source count distribution is consistent with a single population (i.e., blazars) dominating the source counts to the minimum flux explored by this analysis. We estimate the density of sources detectable in blind surveys that will be performed in the coming years by the Cherenkov Telescope Array.

Reproductive function in male patients with type 1 diabetes mellitus.

This study was undertaken to evaluate conventional and some of the main bio-functional spermatozoa parameters, serum gonadal hormones and didymo-epididymal ultrasound features in patients with type 1 diabetes mellitus (DM1). DM1 affects an increasing number of men of reproductive age. Diabetes may affect male reproduction by acting on the hypothalamic-pituitary-testicular axis, causing sexual dysfunction or disrupting male accessory gland function. However, data on spermatozoa parameters and other aspects of the reproductive function in these patients are scanty. Thirty-two patients with DM1 [27.0 (25.0-30.0 years)] and 20 age-matched fertile healthy men [28.0 (27.25-30.75 years)] were enrolled. Patients with diabetic neuropathy, other endocrine disorders or conditions known to alter spermatozoa parameters were excluded. Each subject underwent semen analysis, blood withdrawal for fasting and post-prandial glycaemia, hormonal analysis and didymo-epididymal ultrasound evaluation before and after ejaculation. Patients with DM1 had a lower percentage of spermatozoa with progressive motility [10.0 (7.0-12.75) vs. 45.0 (42.0-47.75) %; p < 0.01] and a higher percentage of spermatozoa with abnormal mitochondrial function than controls [47.0 (43.0-55.0) vs. 2.0 (1.0-5.0) %; p < 0.01]. Patients also had greater post-ejaculatory diameters of cephalic [11.5 (10.2-13.6) vs. 6.0 (4.0-7.0) mm; p < 0.01] and caudal epididymis [5.5 (4.00-7.55) vs. 3.0 (2.0-4.0) mm; p < 0.01] compared to controls, suggesting a lack of the physiological post-ejaculation epididymal shrinkage. Correlation analysis suggested that progressive motility was associated with fasting glucose (r = -0.68; p < 0.01). The other parameters did not show any significant difference. Patients with DM1 had a lower percentage of spermatozoa with progressive motility, impaired mitochondrial function and epididymal post-ejaculatory dysfunction. These findings may explain why patients with DM1 experience fertility disturbance. Larger multi-centric studies are necessary to confirm these results.

Alexithymia, more than depression, influences glycaemic control of type 2 diabetic patients.

PURPOSE: Psychiatric disorders could affect the patients' abilities to cope with diabetes. The objectives of this study were to assess the prevalence of depression and alexithymia among type 2 diabetic patients and investigate the possible correlations between these psychopathological phenomena and glycaemic control assessed through glycated hemoglobin (HbA1c). METHODS: All the patients were evaluated through 20-item Toronto Alexithymia Scale (TAS-20), Hamilton rating scale for depression and Quality of Life Index. HbA1c values, diabetes duration, therapy and socio-demographic characteristics were recorded. RESULTS: One hundred and twenty-eight patients (75 males and 53 female, mean age 64.7 ± 11.2 years) were enrolled. Alexithymic patients, compared to non-alexithymic ones, presented a significantly higher HbA1c (7.7 ± 1.5 vs. 7 ± 1.5, p = 0.016). No statistically significant difference was found when comparing the HbA1c of depressed versus non-depressed patients. Considering the raw values of HbA1c, the higher percentage was recorded among patients suffering from depression plus alexithymia (comorbidity group) followed by patients presenting alexithymia only, patients with neither depression nor alexithymia (control group) and, finally, those presenting depression only. The comorbidity group presented a significantly higher value of HbA1c (7.7 ± 1.2) than the control group (7 ± 1.6, p < 0.04) and the depressed patients (6.9 ± 1.3, p = 0.04). At the logistic regression, the HbA1c was found to be significantly associated only with alexithymia (TAS-20 total score) and insulin therapy. CONCLUSIONS: Alexithymia more than depression influences glycaemic control. When evaluating a diabetic patient, a rapid screening for psychopathological alterations would guarantee a more accurate management. The treatment of any associated psychiatric disorders would improve the patients' quality of life.

Balance control impairment induced after OKS in patients with vestibular migraine: an intercritical marker.

The aim of the study was to assess the effects of optokinetic stimulation (OKS) on vestibular postural control in migraine patients with recurrent vertigo. 15 patients with vestibular migraine (VM) were enrolled in a posturographic study in eyes open (OE) and eyes closed (CE) condition. The tests were performed between attacks of headache and vertigo at three different time: before, during, and 60 min after OKS. Data of patients with VM were compared with those obtained from two control groups matched for sex and age (15 for each group): (a) normal subjects not suffering from migraine without history of recurrent vertigo (N group); (b) subjects suffering from migraine with no history of recurrent vertigo (M group). Mean sway path velocity and sway area were analyzed. OKS increased the instability in all groups during the stimulus, and both the velocity and area values were higher in M and VM group. However, there was not significant difference between these two groups when stability was examined in OE condition before, during and after OKS stimulation. Conversely, in CE condition a significant greater instability was induced after OKS stimulation only in VM. In particular, post-stimulus values were significantly higher than the pre-stimulus one only in this group, while no significant difference was observed in other groups. A spatial analysis of the sway area evidenced that the instability induced by the OKS in VM group occurred along the direction of OKS. We suggest that this enhanced instability observed after OKS during the intercritical period may be considered an useful marker to support the diagnostic definition of VM in the absence of other vestibular signs.

Stage of change and motivation to healthy diet and habitual physical activity in type 2 diabetes.

Lifestyle changes to healthy diet (HD) and habitual physical activity (HPA) are recommended in type 2 diabetes mellitus (T2DM). Yet, for most people with diabetes, it may be difficult to start changing. We investigated the stage of change toward healthier lifestyles according to Prochaska's model, and the associated psychological factors in T2DM patients, as a prerequisite to improve strategies to implement behavior changes in the population. A total of 1,353 consecutive outpatients with T2DM attending 14 tertiary centers for diabetes treatment completed the validated EMME-3 questionnaire, consisting of two parallel sets of instruments to define the stage of change for HD and HPA, respectively. Logistic regression was used to determine the factors associated with stages that may hinder behavioral changes. A stage of change favoring progress to healthier behaviors was more common in the area of HD than in HPA, with higher scores in action and maintenance. Differences were observed in relation to gender, age and duration of disease. After adjustment for confounders, resistance to change toward HD was associated with higher body mass index (BMI) (odds ratio (OR) 1.05; 95 % confidence interval (CI) 1.02-1.08). Resistance to improve HPA also increased with BMI (OR 1.06; 95 % CI 1.03-1.10) and decreased with education level (OR 0.74; 95 % CI 0.64-0.92). Changing lifestyle, particularly in the area of HPA, is not perceived as an essential part of treatment by many subjects with T2DM. This evidence must be considered when planning behavioral programs, and specific interventions are needed to promote adherence to HPA.

Prevalence of male accessory gland inflammations/infections in patients with Type 2 diabetes mellitus.

BACKGROUND: MAGI is an acronym that identifies the "male accessory gland inflammations/infections", a potential cause of male infertility. Type 2 diabetes mellitus (DM2) prevalence is going to increase among men of reproductive age. Due to the high prevalence of these two conditions, we could suppose that they might appear together in the same patient. AIM: To evaluate MAGI prevalence in patients with DM2 in fertile age. SUBJECTS AND METHODS: A cross-sectional study carried out on patients with DM2 of fertile age. All patients underwent andrological evaluation for the identification of conventional MAGI diagnostic criteria. RESULTS: DM2 patients showed a frequency of MAGI about 43%, significantly lower (p<0.05) than in infertile patients of the same age without diabetes, which showed a MAGI overall frequency of 61%. Among examined diabetic patients the prevalence of MAGI did not significantly differ between patients attending for diabetes care problems (glycemic control) and patients with andrological disorders. Finally, no significant difference in seminal inflammatory signs frequency was detected between patients with DM2 and infertile patients without diabetes. Finally, the correlation analysis showed a significant direct correlation between duration of diabetes and glycemic control with the prevalence of MAGI. CONCLUSION: MAGI prevalence in DM2 is lower than the one detected in age-matched infertile non-diabetic patients, however, as in infertile patients, there is a high frequency of seminal inflammatory signs. Moreover, the observed prevalence among diabetic patients with diabetes care problems and diabetic patients with andrological problems is not statistically different.

The immunobiology of apotransferrin in type 1 diabetes.

The transferrin (Tf) family of iron binding proteins includes important endogenous modulators of the immune function that may modulate autoimmune diseases. To define more clearly the role of apotransferrin (apoTf) in type 1 diabetes we determined the impact of this protein on type 1 diabetes as investigated in islet cells, animal models and patient sera. First, we demonstrated that recombinant apoTf counteracts the cytokine-induced death of murine pancreatic islet cells. Secondly, human apoTf administration favourably influences the course of type 1 diabetes in animal models, resulting in protection against disease development that was associated with reduction of insulitis and reduced levels of proinflammatory cytokines. Finally, we confirmed that patients with newly diagnosed type 1 diabetes manifest significantly lower apoTf serum levels compared to healthy controls and patients with long-lasting disease. In conclusion, our data suggest the apoTf pivotal role in the perpetuation of type 1 diabetes pathology.

NAD(P)H oxidase p22(phox) polymorphism and cardiovascular function in amateur runners.

AIM: NAD(P)H system represents the major source of superoxide production at cardiovascular (CV) level. It has several genetic variants: in particular, the C242T polymorphism of its p22(phox) subunit is associated with a different oxidase activity, being the T allele related to a lower superoxide production. Although several authors investigated the protective effect of T allele in CV diseases, only few data are available on its functional role in physiological conditions. The aim of our study was to investigate the relationship between the p22(phox) C242T polymorphism and CV function in amateur runners. METHODS: Seventy-three male amateur runners were screened for CYBA polymorphism. CV analysis was performed by echocardiographic-Doppler examination and by PulsePen tonometer assessment. RESULTS: The genetic subgroups (CC and CT/TT) did not differ for VM O(2max) and cardiac dimension. Nevertheless, T carriers (n = 40) were characterized by a more efficient myocardial contraction and left ventricular (LV) filling, as evidenced by significant higher values of the midwall fractional shortening, systolic excursion of the tricuspid annular plane and of early/late diastolic wave velocities ratio and by a lower E wave deceleration time. Pulse wave velocity and augmentation index, parameters related to the arterial stiffness, were higher in CC subjects compared with CT/TT also when the analysis was adjusted for weight and diastolic pressure. CONCLUSION: In amateur runners, CYBA variants may influence both systolic and diastolic function and arterial stiffness. We suppose that the lower oxidative activity that characterizes 242T subjects may positively influence the excitation-contraction and arterial-ventricular coupling mechanisms, thus leading to a more efficient CV function.

Original evaluation of endothelial dysfunction in men with erectile dysfunction and metabolic syndrome.

We have recently demonstrated the diagnostic value of a new immunophenotype of blood endothelial progenitor cells (EPCs=CD45neg/CD34pos/CD144pos) and endothelial microparticles (EMPs=CD45neg/CD144pos/AnnexinVpos) in patients with arterial erectile dysfunction (ED) according to severity of cavernous arterial insufficiency evaluated through penile Doppler. The aim of this study was to evaluate both EPCs and EMPs in patients with arterial ED and metabolic syndrome (MetS), comparing these patients with another group of patients without MetS and ED and a third group with MetS but without ED. For this study 50 patients with arterial ED and MetS were selected (age: 55.0±3.0 years; range: 47-60). A group of age-matched (age: 54.0±2.0 years; range: 44-60) patients without arterial ED and MetS (n=30), and another group of age-matched (age: 57.0±4.0 years; range: 40-62) patients with MetS but without ED (n=20) represented the control groups. EPCs and EMPs were significantly higher in patients compared with other groups (P<0.01). Both EPCs and EMPs correlated positively with the age, body mass index, and score of international index of ED (version five items) and with the following cavernous artery indices: peak systolic velocity, acceleration time and intima-media thickness. Among control groups patients with MetS but without ED showed serum concentrations of EPCs and EMPs significantly higher (P<0.05) compared with patients without MetS and ED. Patients with arterial ED and MetS have higher EPCs and EMPs compared with patients with MetS but without ED and patients without MetS and ED.

Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients.

BACKGROUND: The aim of this study was to assess the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting late cardiotoxicity in patients treated with not-high-dose chemotherapy (NHDC), and to compare the predictive value of NT-proBNP and cardiac troponin I (cTnI). METHODS: In 71 patients undergoing NHDC with anthracyclines, NT-proBNP and cTnI levels were measured before and 24 h after each NHDC cycle. Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up. RESULTS: During NHDC, only NT-proBNP showed abnormal values. According to NT-proBNP behaviour, patients were divided into two groups: group A (n=50) with normal (n=23) or transiently elevated NT-proBNP levels (n=27), and group B (n=21) with persistently elevated NT-proBNP levels. At follow-up, LV impairment was significantly worse in group B than in group A. %Δ (baseline-peak) NT-proBNP was predictive of LV impairment at 3-, 6- and 12-month follow-up, with a cutoff of 36%. CONCLUSION: Serial measurements of NT-proBNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity.

Left ventricular surgical remodeling after the STICH trial.

Surgical treatment of anteroseptal scars has been, and still is, a challenging task for cardiac surgeons. Most patients are in heart failure and the infarcted areas can include different parts of the septum and the anterior wall. The core problem of ischemic congestive heart failure is the undue demand placed on the residual viable left ventricle myocardium. The surgical techniques used to correct the mismatch between contractile and asynergic areas differ, but the evolution of surgical techniques for left ventricular surgical remodeling (LVSR) is still a work in progress. The most popular one was proposed by Dor et al. in the 1980s and is still in general use. This technique addressed the problem of recovering a predictable volume but not necessarily the problem of rebuilding a physiologically conical shape. This anatomical aspect is becoming increasingly important, and the purpose of septal reshaping, as proposed by us in 2004, is more to recover a conical shape than to achieve volume reduction. Thus, we use the Dor operation only when septoapical scars are present. The need for a different surgical strategy is emphasized by the result of the STICH trial, which reports the data of 1000 patients randomized for coronary artery bypass grafting (CABG, n = 499) or CABG and LVSR (n = 501) and which failed to show any benefit of LVSR. However, the only surgical technique used was the classic Dor operation, where the purpose was to reestablish volume and not to recreate a physiological shape. This study, however, does not provide a definitive answer, as echocardiography results included only 212 patients in the CABG arm and 161 in the CABG and LVSR arm. Furthermore, previous myocardial infarction (MI) was not a prerequisite for study inclusion (13 % of patients in each group had no previous MI) and whether a previous MI was Q-wave or not was not specified. In conclusion, the long-term results after LVSR are satisfactory but appear to be better if a conical shape has been recreated. The role of preemptive surgery in selected cases and how to establish the limits of LVSR (grade of preoperative diastolic dysfunction, diastolic diameter, ventricular volumes, function of the remote zone, etc.) is still unclear. The impact of each individual treatment in the individual patient (medical treatment, CABG alone, CABG and LVSR) has still to be identified.

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17ß-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites.

NAD(P)H oxidase and pro-inflammatory response during maximal exercise: role of C242T polymorphism of the P22PHOX subunit.

Intense exercise induces a pro-inflammatory status through a mechanism involving the NAD(P)H oxidase system. We focused our attention on p22phox, a subunit of the NAD(P)H oxidase, and on its allelic polymorphism C242T, which is known to affect the functional activity of the enzyme. We investigated whether the p22phox C242T variants exhibit systemic effects in healthy subjects by analyzing the proinflammatory and cardiocirculatory responses to physical exercise in endurance athletes. The group of study consisted of 97 long distance runners, 37 +/- 4.4 yrs of age, with similar training history. The subjects underwent a maximal stress test during which both inflammatory and cardiopulmonary parameters were monitored. Our results demonstrate that T allele deeply influences the neutrophil activation in response to intense exercise, since T carriers were characterized by significantly lower release of myeloperoxidase (MPO), a classical leukocyte derived pro-inflammatory cytokine. In addition, the presence of T allele was associated with a higher cardiopulmonary efficiency as evidenced by a significantly lower Heart Rate (HR) at the peak of exercise and, when a dominant model was assumed, by a higher maximal oxygen uptake (VO2 max). On the other hand, no effects of 242T mutation on the plasmatic total antioxidant capacity (TAC) and on the cortisol responses to the physical exercise were detected. In conclusion, our data support a systemic role for p22phox C242T polymorphism that, modifying the intensity of the inflammatory response, can influence the cardiovascular adaptations elicited by aerobic training. These results contribute to support the hypothesis of a systemic effect for the C242T polymorphism and of its possible functional rebound in healthy subjects.