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Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease., This work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).

Both metabolic syndrome (MetS) and N-amino terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) confer increased risk of cardiovascular diseases (CVD). We assessed if NT-proBNP levels were greater in people with uncomplicated MetS, who had neither CVD/chronic kidney disease (CKD) nor diabetes, as compared with subjects who met none of the defining criteria of the MetS.A case-cohort study from the non-diabetic population-based Casale Monferrato study was performed, after exclusion of all subjects with established CVD, CKD [estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m(2)], and CRP values ≥3 mg/L. Cases (n = 161) with MetS were compared with all subjects within the cohort (n = 124) who were completely free of any component of the MetS. Serum NT-proBNP was centrally measured by immunoenzymatic assay.NT-proBNP levels were significantly higher in cases than in control subjects [35.4 (15.5-98.2) vs 24.4 (11.7-49.6) pg/mL, p = 0.014]. In logistic regression analysis, compared with NT-proBNP values in the lower quartiles (≤49.64 pg/mL), higher values conferred odds ratio 4.17 (1.30-13.44) of having the MetS, independently of age, sex, microalbuminuria, CRP, eGFR, and central obesity. This association was evident even after the exclusion of hypertensive subjects. Further adjustment for log-HOMA and diastolic blood pressure did not modify the strength of the association, while central obesity was a negative confounder.Compared with people without any component of the MetS, those with uncomplicated MetS, who had neither CVD/CKD nor diabetes, had increased NT-proBNP values, even if they were normotensive and although absolute values were still in the low range. The insulin resistance state did not mediate this association, while central obesity was a negative confounder.

Chromogranin A (CgA) is the neuroendocrine (NE) marker most frequently employed in detecting NE differentiation in prostate cancer patients, either at the tissue level or in the general circulation.We compared the two commercially CgA assay kits in detecting NE differentiation, in benign hyperplasia (BPH) or prostate cancer (PC) patients (pts). 170 pts with BPH, 107 with BPH+inflammation, and 136 PC pts entered the study. CgA was measured in each patient with the immunoradiometric assay (IRMA) and with the enzyme-linked immunoabsorbent assay (ELISA).A moderate relationship was found between CgA measured with IRMA and ELISA in the whole population (Spearman's R=0.65, p0.05), in BPH pts (R=0.76, p0.05), in BPH+inflammation pts (R=0.53, p0.05) and in PC pts (R=0.60, p0.05). Twenty-two out of 62 pts (35.4%) with elevated ELISA CgA did not have increased IRMA CgA; by contrast, 21/61 pts (34.4%) with elevated IRMA CgA were not recognized as abnormal by the ELISA kit.CgA measured by the two assays provided a significant discordance rate, suggesting that the two kits might elicit different information.

Two years after being diagnosed with ulcerative colitis, a 57-year-old man taking oral mesalamine experienced severe respiratory distress due to left lung pleuropneumonitis. Eight months later, severe respiratory distress recurred due to right lung pneumonitis. Extraintestinal manifestations of inflammatory bowel disease or mesalamine-induced pulmonary injury were considered in the differential diagnosis, which was complicated by a history of aseptic meningitis and evidence of an ongoing autoimmune response. The implications of the case are discussed.

No studies about correlation between post-operative half-life of tumor markers and prognosis in lung cancer exist in literature. The aim of our study was to determine the half-life of CEA, TPA, NSE and CYFRA 21-1 in postoperative period after surgery of bronchogenic carcinoma, and to correlate it with the prognosis and survival of the patients.From March 1997 to March 1998, 35 patients with bronchogenic carcinoma were studied (29 males and 6 females, mean age 64.9 years, range 51-77 and 61.0 years, range 52-77 respectively). The mean follow-up for males was 125.70 days (from 30 to 198) after surgery and for females 125.79 days (from 30 to 180). CEA and NSE were tested by immunoenzymatic automated method, whereas TPA and CYFRA 21-1 were assayed by immunoradiometric techniques. For each patient both the dismission curve and the half-life of considered markers were calculated during follow-up.A statistically significant difference was found for preoperative values of TPA (p = 0.027) and CYFRA 21-1 (p = 0.025) between SqCLC and adenocarcinoma. The preoperative levels of markers were higher in patients who would develop a relapse, even if statistical significance was not reached. CEA half-life was of 1.4 days, while in patients with a history of relapse or metastatic spreading was 4.5 days. No differences were revealed concerning CYFRA 21-1 between the two groups.Seriate determination of some markers (CEA and TPA in particular) during postoperative follow-up after surgery for bronchogenic carcinomas can be a useful prognostic tool. Longer follow-up would provide additional informations in order to determine individual predictive threshold between poor and good prognosis.

To evaluate the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after administrations of enrofloxacin in sheep.Crossover study performed by i.v. and i.m. administrations of 2.5 mg of enrofloxacin/kg of body weight to 2 groups of 3 sheep. After a 15-day resting period, the drug administration was repeated, using the alternative route.6 clinically normal Massese sheep of either sex.Blood samples were collected at suitable intervals over a 24-hour period, and plasma concentrations of enrofloxacin and its main metabolite ciprofloxacin were determined by a high-performance liquid chromatography method. Pharmacokinetic variables for both substances after i.v. and i.m. enrofloxacin administrations were calculated by use of statistical moments and were analyzed, using a crossover ANOVA.After i.v. administration of enrofloxacin, a rapid distribution phase was followed by a slower elimination phase. When the same dose was administered IM, enrofloxacin was rapidly and almost completely absorbed, with bioavailability of 85%. After 24 hours, the mean plasma concentration of ciprofloxacin was similar to that of the parent drug.The large volume of distribution indicates that enrofloxacin is widely distributed in the body of sheep. The fraction of enrofloxacin metabolized to ciprofloxacin (35 and 55% for i.v. and i.m. administrations, respectively) suggests that, in this species, the antimicrobial activity of enrofloxacin could be attributable, at least in part, to its main metabolite ciprofloxacin.i.v. or i.m. administration of 2.5 mg of enrofloxacin/kg provides plasma concentrations higher than mean inhibitory concentration for most pathogens in sheep.

An endothelin urinary hyperexcretion, which is not counterbalanced by an adequate increase in cGMP biosynthesis, was previously detected in some patients with IgA Nephropathy (IgAN). Since this imbalance might potentiate local ET1-mediated hemodynamics effects, 9 IgAN patients with an increased (or = 0.1) urinary ET1/cGMP ratio (group 1) and 5 IgAN patients with comparable renal function and reduced ET1/cGMP ratio (group 2) were given standard doses of isosorbide 5 mononitrate (as a nitric oxide source). Blood nitric oxide (NO) levels, as detected by electron paramagnetic resonance, significantly increased after isosorbide administration (p0.01) and decreased after drug discontinuation in both groups. Nitric oxide levels were significantly related with those of the effective renal plasma flow (p0.02), but not with the glomerular filtration rate. Proteinuria levels significantly decreased after drug administration (p0.009) in group 1 and returned to baseline levels thereafter, except two cases showing persisting low levels. Values of filtration fraction in the same group decreased after iso5M administration (p0.02 compared to basal levels). These results may possibly be related to the counterbalancing effects of nitric oxide on endothelin-mediated mesangial contraction.

Twenty-eight patients with small cell lung cancer were treated with high dose 4'-epidoxorubicin (EDX). Fifteen patients underwent EDX monotherapy (cumulative dose: 800 mg/m2) while 13 were treated with EDX (cumulative dose: 660 mg/m2) associated with cyclophosphamide, etoposide and cisplatin. A 2D-echo was performed in basal condition, after the third and sixth dose and 2 months after the end of the therapy. In the patients without cardiovascular disease (n = 19) left ventricular end-diastolic volume (EDV), end systolic volume (ESV) and ejection fraction (EF) were unchanged. The patients with coronary artery disease (n = 5) showed a statistically significant decrease in EF with an increase of ESV. All patients with systemic hypertension (n = 4) showed a significant reduction of EF and a significant increase of ESV and EDV.

We studied differences in the glucose metabolism, lipid pattern and apolipoprotein A and B after one month of combined hemodialysis-hemoperfusion (HD-HP) in eight regular maintenance hemodialysis (HD) patients. After one month of HD-HP predialytic serum creatinine and phosphate were lower than during the preceding HD period; the lipidic pattern and apolipoproteins were unchanged. A single HD-HP session significantly reduced triglycerides; this does not occur during HD. Postdialytic changes of all other lipoprotein metabolism parameters are identical in the two techniques. As regards glucose metabolism, after one month of regular HD-HP treatment glycemic curves during the intravenous glucose tolerance test (IVGTT) were perfectly matched with those in HD. However, insulin production was lower, with a reduction of the insulin resistance index. Differences did not reach statistical significance. The Authors infer that activated charcoal, even though it achieves better blood purification in uremia, may be unable to remove specific substances which hamper some key enzyme activities of the carbohydrate and lipid metabolism.

The distinction between fibrotic and viable myocardium is a key issue in patients with coronary artery disease and left ventricular dysfunction. Metabolic imaging with positron emission tomography (PET) and labeled tracers, along with the study of myocardial perfusion, is now available to identify hibernating myocardium. However, PET imaging of myocardial metabolism is a high-cost and time-consuming technique, and requires an on-site cyclotron. The aim of this study is to test the reliability of dobutamine echocardiography (DE) compared with PET imaging, for the identification of hibernating myocardium. In 16 patients, scheduled for myocardial revascularization, left ventricular shapes were divided in eight segments both for echocardiographic and nuclear study evaluation. All patients underwent a technetium 99m MIBI single-photon emission tomography stress-rest study of perfusion, a fluorine-18-labeled deoxyglucose (FDG(/PET study of metabolism, and a DE test (baseline, at a 5 micrograms/kg/min infusion of dobutamine for 8 minutes and at a 10 micrograms/kg/min dose for additional 8 minutes). Neither myocardial ischemia nor arrhythmia occurred during the DE test. Baseline echocardiograms showed 90 segments with wall motion abnormalities: wall motion impairment was decreased or reversed in 33 of 90 segments; it remained unchanged in 57 of 90 segments. In 32 of 33 segments considered viable on the basis of DE and in 21 of 57 segments with unchanged kinesis, some degree of FDG was detected. Thus, sensitivity and specificity of DE compared with nuclear studies was 60% and 97% respectively. Moreover, a good correlation and agreement (kappa = 0.51) between DE and the presence of FDG were found. We conclude that DE is a safe and reliable test for the screening of hibernating myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naive and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.

Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.

Aldosterone-producing adenomas (APA) are a frequent cause of secondary hypertension characterized by autonomous hypersecretion of aldosterone. However, the molecular mechanisms involved in adrenal tumorigenesis and deregulated aldosterone secretion are currently unknown. To identify putative functional genes, a transcriptional screening was performed on 8 APA and 3 normal adrenals (NA) using oligonucleotide microarrays. Data were next validated on an expanded set of samples by real-time PCR (APA, n=19; NA, n=10). The epidermal growth factor–like teratocarcinoma-derived growth factor-1 (TDGF-1) was upregulated in APA compared with NA (14.7-fold and 21.4-fold by microarray and real-time PCR, respectively). In vitro studies and Western blot analysis using the NCI H295R adrenocortical cell line showed that TDGF-1 increased Akt phosphorylation on Thr308 and Ser473, consistent with activation of phosphatidylinositol 3-kinase/Akt signaling, and also demonstrated a concomitant inactivation of the Akt substrate glycogen synthesis kinase-3β via Ser9 phosphorylation. Furthermore, TDGF-1 mediated a 3.8±0.4-fold increase in aldosterone secretion (n=4) that was specifically blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nmol/L) and LY294002 (20 μmol/L). Finally, TDGF-1 protected H295R cells from apoptosis induced by staurosporine, causing a decrease in caspase-3 activity, a reduction in the inactivation of poly(ADP-ribose) polymerase, and an inhibition of DNA fragmentation, detected by the TUNEL reaction and fluorescence microscopy that was blocked by LY294002. Taken together, our data suggest that TDGF-1, which is significantly upregulated in APA and mediates aldosterone hypersecretion and deregulated growth in adrenocortical cells in vitro, may represent a key player in the development and pathophysiology of primary aldosteronism.

Background.Impairedproteinanabolismandinsulinresistance are characteristic features of maintenance haemodialysis patients. We have used a randomised, matched-paired, double-blind, placebo-controlled experimental design to determine the capability of intravenous L-carnitine supplementation to modify insulin resistance and protein catabolism in non-diabetic patients with end-stage renal disease (ESRD) undergoing chronic haemodialysis treatment. Methods. L-carnitine (20 mg·kg −1 )( n = 9) or placebo (n = 10) were given intravenously at the end of seven consecutive dialysis sessions. Whole-body protein and glucose metabolism were assessed on interdialytic days by the L[1- 13 C]leucine and the [2,2- 2 H2]glucose kinetic models in the postabsorptive state and during euglicemic hyperinsulinemic clamp studies at baseline and at the end of the treatment period. Results. L-carnitine supplementation was associated with lower (P < 0.05) rates of leucine oxidation (−11 ± 12%) and appearance from proteolysis (−6 ± 2%) during the clampstudiesthanafterplacebosupplementation.Therates of glucose appearance in the postabsorptive state did not change significantly in the patients receiving L-carnitine treatment. Insulin-mediated glucose disappearance was improved by L-carnitine only in those patients (n = 5) (+18 ± 3%,P

The relationships between rest conditions of myocardial asynergy, response to dobutamine administration, perfusion and glucose metabolism were examined in 12 patients with chronic coronary artery disease and left ventricular dysfunction. We evaluated (1) rest and stress myocardial perfusion by 99 Tc m -methoxyisobutylisonitrile (MIBI) and single photon emission tomography (SPET), (2) rest myocardial segmental wall motion by trans-thoracic echocardiography and low-dose dobutamine, and (3) myocardial metabolism by [ 18 F]-2-fluoro-2-deoxy-D-gyucose ( 18 FDG) and positron emission tomography (PET), in the fasting state. The analysis was carried out on 16 left ventricular myocardial segments. The SPET studies were analysed semi-quantitatively by normalization to the peak activity. Wall motion was assessed by a visual score. An 18 FDG index was determined as the tissue/blood pool radioactivity ratio in each segment. The results showed: (1) remarkably good agreement between the number of dobutamine responsive segments and 18 FDG positive segments among those that were only moderately hypoperfused and hypokinetic; (2) a smaller number of dobutamine responsive segments than 18 FDG positive segments among those that were hypoperfused and akinetic; and (3) the presence of 18 FDG in 50% of the segments that were severely hypoperfused and akinetic or dyskinetic and without improvement with dobutamine. These results indicate that in severely hypoperfused and akinetic or dyskinetic segments, trans-thoracic echocardiography under inotropic stimulation provides little additional information compared with that obtained with rest echocardiography and perfusion studies; the assessment of 18 FDG uptake provides information that is complementary to that obtained by perfusion assessment, rest and dobutamine trans-thoracic echocardiography.