A canine gait analysis protocol for back movement assessment in german shepherd dogs

Objective-To design and test a motion analysis protocol for the gait analysis of adult German Shepherd (GS) dogs with a focus in the analyses of their back movements. Animals-Eight clinically healthy adult large-sized GS dogs (age, 4 ± 1.3 years; weight, 38.8 ± 4.2 kg). Procedures-A six-camera stereo-photogrammetric system and two force platforms were used for data acquisition. Experimental acquisition sessions consisted of static and gait trials. During gait trials, each dog walked along a 6 m long walkway at self-selected speed and a total of six gait cycles were recorded. Results-Grand mean and standard deviation of ground reaction forces of fore and hind limbs are reported. Spatial-temporal parameters averaged over gait cycles and subjects, their mean, standard deviation and coefficient of variance are analyzed. Joint kinematics for the hip, stifle and tarsal joints and their average range of motion (ROM) values, and their 95% Confidence Interval (CI) values of kinematics curves are reported. Conclusions and Clinical Relevance-This study provides normative data of healthy GS dogs to form a preliminary basis in the analysis of the spatial-temporal parameters, kinematics and kinetics during quadrupedal stance posture and gait. Also, a new back movement protocol enabling a multi-segment back model is provided. Results show that the proposed gait analysis protocol may become a useful and objective tool for the evaluation of canine treatment with special focus on the back movement

a therapeutic strategy for cystic fibrosis

The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained therapeutic effect. We have developed a self-assembling nanocomplex formulation for siRNA delivery to the airways that consists of a liposome (DOTMA/DOPE; L), an epithelial targeting peptide (P) and siRNA (R). LPR formulations were assessed for their ability to silence expression of the transcript of the gene encoding the α-subunit of the sodium channel ENaC in cell lines and primary epithelial cells, in submerged cultures or grown in air-liquid interface conditions. LPRs, containing 50 nM or 100 nM siRNA, showed high levels of silencing, particularly in primary airway epithelial cells. When nebulised these nanocomplexes still retained their biophysical properties and transfection efficiencies. The silencing ability was determined at protein level by confocal microscopy and western blotting. In vivo data demonstrated that these nanoparticles had the ability to silence expression of the α-ENaC subunit gene. In conclusion, these findings show that LPRs can modulate the activity of ENaC and this approach might be promising as co-adjuvant therapy for cystic fibrosis

A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

Cytotoxic drugs for patients with breast cancer in the era of targeted treatment: Back to the future?

Background: Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC). Materials and methods: Medline searches were conducted for English language studies using the term =MBC= and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011. Results: Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials. Conclusion: Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity

DInSAR Analysis and Analytical Modeling of Mount Etna Displacements: The December 2018 Volcano‐Tectonic Crisis

We investigate the 24–27 December 2018 eruption of Mount Etna occurred from fissures located on the volcano eastern flank and accompanied by a seismic swarm, which was triggered by the magma intrusion and continued for weeks after the end of the eruption. Moreover, this swarm involved some of the shallow volcano‐tectonic structures located on the Mount Etna flanks and culminated on 26 December with the strongest event (ML 4.8), occurred along the Fiandaca Fault. In this work, we analyze seismological data and Sentinel‐1 Differential Interferometric Synthetic Aperture Radar (DInSAR) measurements, the latter inverted through analytical modeling. Our results suggest that a dike source intruded, promoting the opening of the eruptive fissures fed by a shallower dike. Moreover, our findings indicate that the activation of faults in different sectors of the volcano may be considered as a response to accommodate the deformations induced by the magma volumes injection.Published5817-58275V. Processi eruttivi e post-eruttiviJCR Journa

Genetic susceptibility variants for lung cancer: Replication study and assessment as expression quantitative trait loci

Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes

Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Background. The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase 2 dose-finding study of rostafuroxin, a digitoxygenin deivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. Methods. OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24 h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). Results. Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P=0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P=0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P=0.03) for systolic office BP; 0.70 mm Hg (P=0.08) for diastolic office BP; 0.36 mm Hg (P=0.49) for 24-h systolic BP; and 0.05 mm Hg (P=0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤=0.028), but carry-over effects were not significant (P≥=0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. Conclusions. In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. Trial Registration: NCT00415038 http://www.clinicaltrials.gov)