Effects of NK-4 in a Transgenic Mouse Model of Alzheimer's Disease

Beta-amyloid (Aβ) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and molecules that can prevent pathways of Aβ toxicity may be potential therapeutic agents for treatment of AD. We have previously reported that NK-4, a cyanine photosensitizing dye, displays neurotrophic and antioxidant activities. In this study, we report the effects of NK-4 on the toxicity of Aβ and on cognitive function and Aβ concentration in a transgenic mouse model of AD (Tg2576). In vitro, NK-4 effectively protected neuronal cells from toxicity induced by Aβ. In addition, it displayed profound inhibitory activities on Aβ fibril formation. In vivo, Tg2576 mice received an intraperitoneal injection at 100 or 500 µg/kg of NK-4 once a day, five times a week for 9 months. Administration of NK-4 to the mice attenuated impairment of recognition memory, associative memory, and learning ability, as assessed by a novel object recognition test, a passive avoidance test, and a water maze test, respectively. NK-4 decreased the brain Aβ concentration while increasing the plasma amyloid level in a dose-dependent manner. NK-4 also improved memory impairments of ICR mice induced by direct intracerebroventricular administration of Aβ. These lines of evidence suggest that NK-4 may affect multiple pathways of amyloid pathogenesis and could be useful for treatment of AD

Parental origin of sequence variants associated with complex diseases

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldEffects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.info:eu-repo/grantAgreement/EC/FP7/21807

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Height seasonal oscillations and long-term trends from a combination of GPS, gravity and InSAR data

A fundamental development of the next coming years shall be the definition and the implementation of a high-accuracy and space-time continuous observation system for monitoring Earth\u2019s surface deformation. The IAG project GGOS (Global Geodetic Observing System) will be the geodetic contribution to such a realization. A detailed knowledge of the crustal deformation is a key element to achieve a thorough comprehension of how the solid Earth responds to deformational forces and for an improved understanding of the seismogenetic cycle. We have studied and applied a combined observational strategy for monitoring and reliably identifying both seasonal and log-term crustal movements, namely height variations/changes. The strategy adopted is based on a multidisciplinary approach that combines the information provided by GPS, InSAR and terrestrial gravimetry. The results of these different techniques are compared and combined in a study on land subsidence in the southeastern Po Plain and the northern Adriatic coast, in Italy

Monitoring Crustal Deformation by Continuous Gravity and GPS Observations

At Medicina, near Bologna, Italy, a superconducting gravimeter, periodically controlled by absolute gravity observations, is acquiring continuous data series since the beginning of measurements in October 1996. A permanent GPS receiver was also installed at the station and is providing continuous observations since mid 1996. The time series are about 8 years long and they constitute, together with a remarkable ensemble of environmental parameters, a unique data set. The results of the gravity data analysis are interpreted to separate seasonal oscillations from a long-term trend and are compared with the height variations estimated by means of GPS. Noticeable seasonal oscillations are present both in the gravity and GPS time series and they were modeled by accounting for atmospheric, hydrological and non-tidal oceanic effects. Interannual variability is observed. A mean seasonal model derived by stacking of the observations is computed both for the gravity and GPS data series and it is compared with that obtained from the models. A moderate long-term trend has been identified in gravity, which is confirmed by the GPS height variations

A combined GPS and Gravity analysis to study the effect of environmental parameters

Geodetic in-situ observations are always effected by environmental parameters like atmosphere, ocean and hydrology. It is often criticised that seasonal effects accounted for global network analysis do not significantly improve the resulting parameters. In a local case study at Medicina, space geodetic (GPS and VLBI) and gravity observations (SCG and FG5) are used together with environmental observations and models to provide significant information both on the seasonal fluctuation as well as on the linear and non-linear long-term trend in height. Models of seasonal height and gravity components have been achieved by accounting for loading and mass effects, by atmosphere, non tidal ocean and the local hydrology. This last component shows to be a major contribution of the seasonal variations not only in terms of loading and mass variations but also for soil consolidation effects induced by water table decrease / increase on the clayey soil in Medicina. The local hydrology is an important component to understand the seasonal effects but it is difficult and / or expensive to get sufficient information at the observation sites. It will be demonstrated that regional and global information on hydrology, the Hydrological Balance and GRACE results used as input can satisfactory replace locally observed environmental data. The experiment carried out in Medicina demonstrates that only the combined reduction of the effect of environmental parameters will improve the overall analysis. Rigorously applied it allows to study linear and non-linear long-term station variations. There is a high probability that the consequent consideration of environmental parameters will have positiv effects on the long-term evolution of the global reference frame

Observing and assessing non-tidal ocean loading using ocean, continuous GPS and gravity data in the Adriatic area

The effect of nontidal ocean loading (NTOL) is observed in the height series of four permanent GPS stations in the northern Adriatic. A validation of the ECCO model is performed by comparing model estimates of sea-level anomalies from tide-gauges with TOPEX/ POSEIDON data, and ECCO model estimates of bottom pressure with those derived from temperature and salinity observations. The amplitudes of theECCO sea-level anomaly are found to be 1.4 times smaller than observations; bottom pressure is 2 times smaller. Using a Green’s functions approach to determine elastic deformations, the ECCO ocean bottom pressure is used to estimate surface displacements at the GPS sites. Model results were compared with the height series and with the observed NTOL effect. The height series and the predicted NTOL are highly correlated at all four stations. The analysis performed on superconducting gravimeter data at the Medicina station also shows high correlation

Vertical Crustal Movements and Sea-level Changes in the Northern Adriatic

The Department of Physics of the University of Bologna (UNIBO), the Consorzio Venezia Nuova, sole agent of the Magistrato alle Acque di Venezia for the managemente of the Venice lagoon environment (MAV), the Italian National Agency for Environmental Protection and Technical Services (APAT), have recently started joint projects to determine and study vertical crustal movements and sea-level fluctuations in the northern Adriatic area where the natural subsidence has been enhanced by anthropogenic components during last century. The combination of the permanent GPS stations belonging to UNIBO and of those of the MAV and APAT constitutes a basic network for the study of land subsidence in the northern Adriatic. We have studied and applied a combined observational strategy for monitoring and reliably identifying both seasonal and log-term crustal movements, namely height variations/changes. The strategy adopted is based on a multidisciplinary approach that combines the information provided by GPS, InSAR and terrestrial and space gravimetry. The results of these different techniques are compared and combined in a study on land subsidence in the southeastern Po Plain and the northern Adriatic coast, in Italy. The sea-level time series of the Marina di Ravenna, Venice and Trieste tide gauge stations are compared to the Topex/Poseidon satellite altimetry sea-level elevation and to the GPS height and InSAR long-term trends at the same stations