An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques, and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL) and hippocampus. The proteins were consistent with biochemical or pathological alterations in AD and have been central to further investigations of the disease. The present study focused on the identification of specific targets of protein S-glutathionylation in AD and control IPL by using a redox proteomics approach. For AD IPL, we identified deoxyhemoglobin, alpha-crystallin B, glyceraldehyde phosphate dehydrogenase (GAPDH), and alpha-enolase as significantly S-glutathionylated relative to these brain proteins in control IPL. GAPDH and alpha-enolase were also shown to have reduced activity in the AD IPL. This study demonstrates that specific proteins are sensitive to S-glutathionylation, which most likely is due to their sensitivity to cysteine oxidation initiated by the increase in oxidative stress in the AD brain.     

Treatment with pegylated interferon and ribavirin for hepatitis C virus-associated severe cryoglobulinemia in a liver/kidney transplant recipient

End-stage liver disease after hepatitis C virus (HCV) infection is the most common indication for liver transplantation, accounting for over 40% of liver transplants performed. Combined liver/kidney transplantation is being performed more frequently, in part because HCV infection may coexist with conditions that damage the kidney, such as diabetes and cryoglobulinemia. Unfortunately, HCV hepatitis and cryoglobulinemia may recur after liver transplantation and adversely affect graft and patient survival. In immunocompetent patients, interferon (IFN) and ribavirin (RBV) combination therapy is often able to control cryoglobulinemic syndrome. Very little data are available on liver transplant recipients, whereas IFN usually is not indicated in kidney transplant recipients because of early reports of steroid-induced rejection after its administration. Successful treatment of cryoglobulinemia with IFN/RBV in recipients of combined liver/kidney transplant has not been previously reported. We treated 1 recipient of a combined liver and kidney transplant with pegylated-IFN/RBV combination therapy. The patient developed HCV recurrence associated with cryoglobulinemia and severe cutaneous peripheral and neurologic manifestations. Treatment with pegylated-IFN-alpha2b and RBV for 12 months cured the cryoglobulinemic vasculitis and allowed the sustained eradication of HCV with no significant changes in kidney function.     

Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress

Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66(Shc) adaptor protein controls cellular responses to oxidative stress. Mice lacking p66(Shc) (p66(Shc-/-)) have increased resistance to ROS and prolonged life span. The present work was designed to investigate hyperglycemia-associated changes in endothelial function in a model of insulin-dependent diabetes mellitus p66(Shc-/-) mouse. p66(Shc-/-) and wild-type (WT) mice were injected with citrate buffer (control) or made diabetic by an i.p. injection of 200 mg of streptozotocin per kg of body weight. Streptozotocin-treated p66(Shc-/-) and WT mice showed a similar increase in blood glucose. However, significant differences arose with respect to endothelial dysfunction and oxidative stress. WT diabetic mice displayed marked impairment of endothelium-dependent relaxations, increased peroxynitrite (ONOO(-)) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66(Shc-/-) diabetic mice did not develop these high-glucose-mediated abnormalities. Furthermore, protein expression of the antioxidant enzyme heme oxygenase 1 and endothelial NO synthase were up-regulated in p66(Shc-/-) but not in WT mice. We report that p66(Shc-/-) mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66(Shc) adaptor protein is part of a signal transduction pathway relevant to hyperglycemia vascular damage and, hence, may represent a novel therapeutic target against diabetic vascular complications.     

Respiratory symptoms/diseases and environmental tobacco smoke (ETS) in never smoker Italian women

AIM: To study the relationship between respiratory/allergic disorders and chronic environmental tobacco smoke (ETS) exposure to husband or at workplace among non-smoking women of a general population in Italy. METHODS: Analyses regard 2195 married or employed women. Information was collected through a self-administered questionnaire. ETS exposure was validated by salivary cotinine. RESULTS: Exposure both to husband and at work resulted a significant risk factor for current dyspnoea (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.20-2.16), any shortness of breath at rest (OR 2.81, 95% CI 1.83-4.30), recent wheeze (OR 1.71, 95% CI 1.04-2.82), recent attacks of shortness of breath with wheeze (OR 1.85, 95% CI 1.05-3.26), asthma diagnosis/symptoms (OR 1.50, 95% CI 1.09-2.08), diagnosis of asthma or bronchitis/emphysema (obstructive lung diseases (OLD)) (OR 2.24, 95% CI 1.40-3.58), current cough/phlegm (OR 1.52, 95% CI 1.07-2.15), and rhino-conjunctivitis (OR 1.48, 95% CI 1.13-1.94). Exposure only at work yielded higher adjusted odds ratios for all health conditions, except for rhino-conjunctivitis. Overall, about 24% of shortness of breath at rest, 16% of dyspnoea, 17% of rhino-conjunctivitis, 12% of OLD, and 10% of asthma diagnosis/symptoms are attributable to the effect of exposures to both husband and at work. Twelve percent of shortness of breath at rest and 10% of rhino-conjunctivitis cases might be avoided by eliminating exposure only at work and only to husband, respectively. CONCLUSIONS: Lifetime ETS exposure, especially at work, is associated with respiratory symptoms/diseases, and it accounts for a sizeable proportion of such disorders. The combined effect of both exposures is higher than the separate effects.     

Reference equations for spirometry from a general population sample in central Italy

Aim of this study was to derive new lung function reference equations and compare the predicted values with those from three sets of existing reference equations: one derived from a Northern Italy population and the two others widely used in European (ECCS) and American (NHANES III) clinical practice. Reference equations for flow-volume curve indexes and VC were derived on 497 normal subjects, aged 8-74, from the epidemiological survey in Pisa, Central Italy (1991-1993). By applying natural cubic splines, one single smooth and continuous equation for the entire age range was provided for each index, separately by gender. Along with age and height, reference values also depended on BMI. Differences among the four reference equations for FEV(1), FVC, VC were quantified for average subjects. The magnitude largely varied over the age range in both genders, reaching up to half litre of air volume at specific ages. Age-gender-specific prevalence rates of airway obstruction, as defined by the ERS criterion, largely varied by applying the considered equations, the differences ranging from -3% to 28%. The observed discrepancies confirm that reference equations should be derived from a population most similar to that for which the equations are to be used and based on measurements obtained by the same instrument and testing procedures, in order to minimize technical variability in lung function both for clinical and epidemiological purposes.     

The urokinase-type plasminogen activator polymorphism PLAU_1 is a risk factor for APOE-epsilon4 non-carriers in the Italian Alzheimer's disease population and does not affect the plasma Abeta(1-42) level

Sporadic Alzheimer's disease (AD) is the most frequent form of dementia in the elderly. A non-conservative polymorphism in the urokinase-type plasminogen activator gene (PLAU_1=RS2227564) has been analyzed, but data are conflicting on whether it is a risk factor for AD. To clarify whether this genetic variant modifies AD risk in the Italian population, we ran a case-control association study on 192 AD and 126 age-matched controls. We did not find any association between PLAU_1 genotype and AD in the whole AD population, but when we stratified our sample by APOE-epsilon4 status, we found a significant association between PLAU_1 genotype (C/T+T/T) and APOE-epsilon4 negative AD subjects (p=0.02, chi(2)-test). The PLAU_1 genotype did not appear to affect the plasma Abeta42 concentration. Our data support a role for PLAU_1 as an independent genetic risk factor for AD in the Italian population for those subjects who do not have the APOE-epsilon4 allele.     

Pulmonary and sinusal changes in 45 patients with primary immunodeficiencies: computed tomography evaluation

OBJECTIVE: The aims of the study were 1) to identify and quantify pulmonary changes in subjects affected by agammaglobulinemia (AG), and common variable immunodeficiency (CVID) and 2) to assess the incidence, type, and degree of chronic sinusitis and their relation to pulmonary changes. METHODS: Forty-five patients affected by AG (18) and CVID (27) underwent computed tomography of lungs and paranasal sinuses. RESULTS: Of 45 patients, 26 (57.7%) had pulmonary changes, more frequent among CVID than AG patients (P = 0.37). Bronchiectases were detected in 7 of 12 AG and in 9 of 14 CVID; the difference is not statistically significant (P = 0.53). Computed tomographic findings of chronic sinusitis were detected in 41 of 45 patients. There was no statistically significant difference between AG and CVID patients. Bronchial and sinusal abnormalities did not correlate in 11 patients followed longitudinally. CONCLUSIONS: On computed tomography, the type and severity of lung lesions do not correlate either with the type of immunodeficiency or with the severity of the sinusal involvement.