PARP-1 modulates amyloid beta peptide-induced neuronal damage.

Amyloid beta peptide (A beta) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with A beta(25-35) fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. A beta(25-35) induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following A beta(25-35) exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that A beta(25-35) induces DNA damage which in turn activates PARP-1. Challenge with A beta(25-35) is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, A beta(25-35) via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by A beta and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed

Swept-source OCT reduces the risk of axial length measurement errors in eyes with cataract and epiretinal membranes

Aims To compare the biometric data from partial coherence interferometry (PCI) and swept-source OCT (SS-OCT) in patients with age-related cataract and epiretinal membrane (ERM): ERM, ERM with foveoschisis and macular pseudohole. Methods 49 eyes of 49 subjects including 36 ERM, 9 ERM foveoschisis and 4 macular pseudohole were analysed to evaluate the axial length (AL) measurements and the presence of AL measurement errors, defined basing on the shape of the biometric output graphs and on the concordance of AL values between instruments. Eyes with ERM were divided in four stages according to OCT features (i.e. presence/absence of the foveal pit, presence of ectopic inner foveal layers, disrupted retinal layers). Results The devices provided similar mean AL measurements in all subgroups, with differences <0.1 mm in 41/49 cases (83.6%). AL measurement errors were observed in ERM stages 3 and 4, characterized by ectopic inner foveal layers, and were significantly more frequent with the PCI (8/17, 47%) as compared with the SS-OCT device (2/17, 12%), p = 0.02. The refractive prediction error in cases with AL measurement errors was significantly greater using the PCI compared to the SS-OCT device (p<0.05). Conclusion Both devices provide reliable biometric data in the majority of patients and can be used in the preoperative assessment of patients with age-related cataract and ERM. In eyes with ectopic inner foveal layers, attention should be paid as AL measurement and refractive prediction errors may occur, more frequently with the PCI device

Differences in osteoimmunological biomarkers predictive of psoriatic arthritis among a large Italian cohort of psoriatic patients

(1) Background: In literature it is reported that 20\u201330% of psoriatic patients evolve to psoriatic arthritis over time. Currently, no specific biochemical markers can either predict progression to psoriatic arthritis or response to therapies. This study aimed to identify osteoimmunological markers applicable to clinical practice, giving a quantitative tool for evaluating pathological status and, eventually, to provide prognostic support in diagnosis. (2) Methods: Soluble (serum) bone and cartilage markers were quantified in 50 patients with only psoriasis, 50 psoriatic patients with psoriatic arthritis, and 20 healthy controls by means of multiplex and enzyme-linked immunoassays. (3) Results: Differences in the concentrations of matrix metalloproteases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), receptor activator of nuclear factor kappa-B-ligand (RANK-L), procollagen type I N propeptide (PINP), C-terminal telopeptide of type I collagen (CTx-I), dickkopf-related protein 1 (DKK1), and sclerostin (SOST) distinguished healthy controls from psoriasis and psoriatic arthritis patients. We found that MMP2, MMP12, MMP13, TIMP2, and TIMP4 distinguished psoriasis from psoriatic arthritis patients undergoing a systemic treatment, with a good diagnostic accuracy (Area under the ROC Curve (AUC) > 0.7). Then, chitinase-3-like protein 1 (CHI3L1) and MMP10 distinguished psoriasis from psoriatic arthritis not undergoing systemic therapy and, in the presence of onychopathy, MMP8 levels were higher in psoriasis than in psoriatic arthritis. However, in these latter cases, the diagnostic accuracy of the identified biomarkers was low (0.5 < AUC < 0.7). (4) Conclusions. By highlighting never exploited differences, the wide osteoimmunological biomarkers panel provides a novel clue to the development of diagnostic paths in psoriasis and psoriasis-associated arthropathic disease

Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.

OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity

Plasma microRNA signature associated with skeletal muscle wasting in post‐menopausal osteoporotic women

Background: Skeletal muscle mass wasting almost invariably accompanies bone loss in elderly, and the coexistence of these two conditions depends on the tight endocrine crosstalk existing between the two organs, other than the biomechanical coupling. Since the current diagnostics limitation in this field, and given the progressive population aging, more effective tools are needed. The aim of this study was to identify circulating microRNAs (miRNAs) as potential biomarkers for muscle mass wasting in post-menopausal osteoporotic women. Methods: One hundred seventy-nine miRNAs were assayed by quantitative real-time polymerase chain reaction in plasma samples from 28 otherwise healthy post-menopausal osteoporotic women (73.4 ± 6.6 years old). The cohort was divided in tertiles based on appendicular skeletal muscle mass index (ASMMI) to better highlight the differences on skeletal muscle mass (first tertile: n = 9, ASMMI = 4.88 ± 0.40 kg·m-2 ; second tertile: n = 10, ASMMI = 5.73 ± 0.23 kg·m-2 ; third tertile: n = 9, ASMMI = 6.40 ± 0.22 kg·m-2 ). Receiver operating characteristic (ROC) curves were calculated to estimate the diagnostic potential of miRNAs. miRNAs displaying a statistically significant fold change ≥ ±1.5 and area under the curve (AUC) > 0.800 (P < 0.05) between the first and third tertiles were considered. A linear regression model was applied to estimate the association between miRNA expression and ASMMI in the whole population, adjusting for body mass index, age, total fat (measured by total-body dual-energy X-ray absorptiometry [DXA]) and bone mineral density (measured by femur DXA). Circulating levels of adipo-myokines were evaluated by bead-based immunofluorescent assays and enzyme-linked immunosorbent assays. Results: Five miRNAs (hsa-miR-221-3p, hsa-miR-374b-5p, hsa-miR-146a-5p, hsa-miR-126-5p and hsa-miR-425-5p) resulted down-regulated and two miRNAs (hsa-miR-145-5p and hsa-miR-25-3p) were up-regulated in the first tertile (relative-low ASMMI) compared with the third tertile (relative-high ASMMI) (fold change ≥ ±1.5; P-value < 0.05). All the corresponding ROC curves had AUC > 0.8 (P < 0.05). Two signatures hsa-miR-126-5p, hsa-miR-146a-5p and hsa-miR-425-5p; and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p and hsa-miR-25-3p showed the highest AUC, 0.914 (sensitivity = 77.78%; specificity = 100.00%) and 0.901 (sensitivity = 88.89%; specificity = 100.00%), respectively. Conclusions: In this study, we identified, for the first time, two miRNA signatures, hsa-miR-126-5p, hsa-miR-146a-5p and hsa-miR-425-5p; and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p and hsa-miR-25-3p, specifically associated with muscle mass wasting in post-menopausal osteoporotic women

Metformin overdose causes platelet mitochondrial dysfunction in humans

Introduction. We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in-vitro and ex-vivo. Methods. Human platelets were incubated for 72 h with saline or increasing dose of metformin (in-vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97\ub10.18 and lactate 16\ub17 mmol/l) due to accidental metformin intoxication (serum drug level 32\ub114 mg/l) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex-vivo experiments). Results. In-vitro, metformin dose-dependently increased lactate production (p<0.001), decreased respiratory chain complex I activity (p=0.009), mitochondrial membrane potential (p=0.003) and oxygen consumption (p<0.001) of human platelets. Ex-vivo, platelets taken from intoxicated patients had significantly lower complex I (p=0.045) and complex IV (p<0.001) activity compared to controls. Conclusions. Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in-vitro and, possibly, in-vivo. Trial registration. NCT 0094212

Vitrectomy in Small idiopathic MAcuLar hoLe (SMALL) study: Internal limiting membrane peeling versus no peeling

Purpose: To compare vitrectomy with and without internal limiting membrane (ILM) peeling in small idiopathic macular holes. Methods: Retrospective multicentre study including consecutive eyes with ≤250 μm idiopathic macular hole treated with vitrectomy. The primary outcome was hole closure rate. Best-corrected visual acuity (BCVA) change, closure patterns on optical coherence tomography, rates of external limiting membrane (ELM) and ellipsoid zone (EZ) recovery, and rate of complications were also investigated. Results: In total, 693 eyes were included. Hole closure rate was 98% in the peeling and 85% in the no-peeling group (p &lt; 0.001). At 12 months, mean BCVA change was 0.38 ± 0.22 logMAR in the peeling and 0.45 ± 0.21 logMAR in the no-peeling group (p = 0.02); 66% versus 80% of eyes had a U-shaped morphology, respectively; EZ recovery rate was 75% and 93%, respectively (p = 0.02). In the no-peeling group, eyes with a vitreomacular traction (VMT) showed a 96% closure rate, comparable to the peeling group (p = 0.40). The incidence of adverse events was similar except for dissociated optic nerve fibre layer (55% in the peeling vs. 9% in the no-peeling group, p &lt; 0.001). Conclusions: In small idiopathic macular holes, ILM peeling provides a higher closure rate compared to no-peeling; however, if a VMT is present closure rates are comparable. In closed macular holes, the no-peeling technique provides advantages in terms of visual outcome and anatomical recovery