Oleuropein aglycone stabilizes the monomeric \u3b1-synuclein and favours the growth of non-toxic aggregates

\u3b1-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD); its deposits are found as amyloid fibrils in Lewy bodies and Lewy neurites, the histopathological hallmarks of PD. Amyloid fibrillation is a progressive polymerization path starting from peptide/protein misfolding and proceeding through the transient growth of oligomeric intermediates widely considered as the most toxic species. Consequently, a promising approach of intervention against PD might be preventing \u3b1-synuclein build-up, misfolding and aggregation. A possible strategy involves the use of small molecules able to slow down the aggregation process or to alter oligomer conformation favouring the growth of non-pathogenic species. Here, we show that oleuropein aglycone (OleA), the main olive oil polyphenol, exhibits anti-amyloidogenic power in vitro by interacting with, and stabilizing, \u3b1-synuclein monomers thus hampering the growth of on-pathway oligomers and favouring the growth of stable and harmless aggregates with no tendency to evolve into other cytotoxic amyloids. We investigated the molecular basis of such interference by both biophysical techniques and limited proteolysis; aggregate morphology was monitored by electron microscopy. We also found that OleA reduces the cytotoxicity of \u3b1-synuclein aggregates by hindering their binding to cell membrane components and preventing the resulting oxidative damage to cells

Non-motor symptoms burden in motor-fluctuating patients with Parkinson's disease may be alleviated by safinamide: the VALE-SAFI study

parkinson's disease (PD) is characterized by motor symptoms often experienced in concomitance with non-motor symptoms (NMS), such as depression, apathy, pain, sleep disorders, and urinary dysfunction. the present study aimed to explore the effect of safinamide treatment on NMS and quality of life in motor-fluctuating PD patients. VALE-SAFI is an observational single-centre study performed in fluctuating PD patients starting safinamide treatment and followed for 6 months. the effects of safinamide on NMS, sleep, fatigue, depression and pain were assessed through validated sales. changes in the scales from baseline to the 6-month follow-up visit were analysed. 60 PD patients (66.67% males) were enrolled at baseline, and 45 patients completed the 6-month follow-up. PD patients improved motor symptoms at follow-up, with the significant reduction of motor fluctuations. the global score of the NMS Scale significantly decreased between baseline and the follow-up. regarding pain domains, patients reported a significant improvement in discolouration and oedema/swelling. further, a significant improvement was observed from baseline to follow-up in sleep quality measured through the pittsburgh sleep quality Index, while no changes were documented in daytime sleepiness. no differences were found in depression and fatigue between baseline and follow-up. finally, the patient's perception of the impact of PD on functioning and well-being decreased from baseline to follow-up. the present findings confirmed the beneficial effect of safinamide on both motor and non-motor symptoms, also improving the quality of life of PD patients. furthermore, these data support the positive effects of safinamide on pain and mood, as well as on sleep quality and continuity

Testing the performance of the imputation of MHC region in large datasets when using different reference panels

The major histocompatibility complex (MHC) contains a group of genes (~260 genes in ~4Mb) involved in several inflammatory disorders and immune response including the HLA-C gene. So far, the IPD-IMGT/HLA database reports more than 4000 different HLA-C alleles. Given the highly polymorphic nature of the gene, GWAS generally don’t study or study only a small subset of polymorphic sites of the region. Imputation procedures may help in gaining additional information on this region. However, the successful imputation of the MHC region would require a reference panel with detailed information. The main goal of this study is to investigate whether imputation procedures using appropriate reference panels may effectively increase the number of polymorphic sites of the MHC region for association with complex traits. We studied the MHC region imputation performances using 3 different reference panels (Michigan and TOPMed imputation servers): TOPMed-r2, 1000 Genomes (Phase3, v5), and the novel four-digit multi-ethnic HLA panel (v1, 2021). Here, 5 datasets with more than 1000 individuals each underwent imputation. We then focused on the imputation results of the MHC region that surround the HLA-C gene (hg19: 31234948-31241032). Imputation reported a different number of markers for the different reference panels: 482 in 1000G, 365 in TOPMed, and 1272 in HLA-panel. Of note, the HLA panels gave a higher number of imputed markers than the others. We then selected the 104 common markers imputed by all the 3 reference panels. Moreover, 162 markers were found only by 1000G panel, 194 by TOPMed, and 998 by the HLA-panel. The first preliminary comparisons showed a high concordance value for the genotype calling by the 3 different reference sets. The efficiency of the imputation was measured by the R-squared (R2) values stratifying the markers into 3 groups according to the minor allele frequency (MAF). The 104 common markers showed high R2 values (>0.96). As expected, in the other marker groups, the R2 mean values were lower for markers with MAF<0.1 (>0.65 in 1000G, 0.15-0.20 in TOPMed, >0.40 in HLA panel). In conclusion, imputation-based procedures with dedicated HLA panels can produce much more high-quality information than other general purpose reference panels for the MHC region

Dissection of HLA-C gene region to investigate its association with complex traits

The genomic region of HLA gene cluster (6p21.3) contains several highly polymorphic genes involved in the immune response and therefore, they have been previously associated to several immune and inflammatory disorders. For the present study we investigated more than 3500 known alleles of HLA-C gene (from IPD-IMGT/HLA database, genomic sequences) that are grouped into 14 serogroups (e.g., C*01:02:01:01). All the sequences have been aligned against the human genome reference sequence (both versions; hg19 and hg38). Overall, the HLA-C gene (length ~3000 bp) contains more than 1500 SNPs. We used a clustering approach to understand how the alleles are evolutionarily connected. According to the clustering analysis we observed that sequences of the same serogroup cluster together more often than sequences of other serogroups, even if with several exceptions. This confirms that alleles of the same serogroup share strong identity in their sequence. Interestingly, as general rule, we observed that the main tree presents two branches, containing each a similar structure (relative distance between serogroups). Of note, the sequences of C*07 and C*17 serogroups belonged to one of the two branches only, whereas the sequences of C*06 and C*12 serogroups were observed in the alternative branch of the tree. We are now studying what are the main features that characterize the two branches. Moreover, the study will go on by investigating the association of the HLA-C serogroup SNP-based alleles with kidney related disease (INCIPE study) and Alzheimer’s disease (NIAGADS database) in large cohorts of individuals

Prevalence of Klebsiella pneumoniae strains producing carbapenemases and increase of resistance to colistin in an Italian teaching hospital from January 2012 To December 2014

The aim of this study was to characterize the spread of carbapenemase-producing Klebsiella pneumoniae (CPKP) in a tertiary level hospital using ongoing active surveillance with rectal swab cultures. Furthermore, this study analyzed the presence of CPKP in the clinical samples (CS) of a single patient as well as the evolution of Colistin-sensitive strains (CoS) to Colistin-resistant strains (CoR)

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

The present study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n = 480) and in controls (n = 823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR = 1.11, 95% CI: 0.88-1.40, p = 0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p = 1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies

In vitro evaluation of antibiotics' combinations for empirical therapy of suspected methicillin resistant Staphylococcus aureus severe respiratory infections

<p>Abstract</p> <p>Background</p> <p>Methicillin resistant <it>Staphylococcus aureus </it>(MRSA) is an increasingly common cause of nosocomial infections, causing severe morbidity and mortality worldwide, and accounting in some hospitals for more than 50% of all <it>S. aureus </it>diseases. Treatment of infections caused by resistant bacterial pathogens mainly relies on two therapeutic modalities: development of new antimicrobials and use of combinations of available antibiotics.</p> <p>Combinations of antibiotics used in the empiric treatment of infections with suspected methicillin resistant <it>Staphylococcus aureus </it>etiology were investigated.</p> <p>Methods</p> <p>Double (vancomycin or teicoplanin with either levofloxacin or cefotaxime) and triple (vancomycin or teicoplanin + levofloxacin + one among amikacin, ceftazidime, cefepime, imipenem, piperacillin/tazobactam) combinations were evaluated by means of checkerboard assay and time kill curves. Mutational rates of single and combined drugs at antimicrobial concentrations equal to the resistance breakpoints were also calculated.</p> <p>Results</p> <p>Vancomycin or teicoplanin + levofloxacin showed synergy in 16/50 and in 9/50 strains respectively, while vancomycin or teicoplanin + cefotaxime resulted synergic for 43/50 and 23/50 strains, respectively. Triple combinations, involving teicoplanin, levofloxacin and ceftazidime or piperacillin/tazobactam gave synergy in 20/25 strains. Teicoplanin + levofloxacin gave synergy in triple combinations more frequently than vancomycin + levofloxacin.</p> <p>For single antibiotics, mutational frequencies ranged between 10^-5and <10^-9for levofloxacin, cefotaxime, amikacin and imipenem, and <10^-9for vancomycin and teicoplanin. When tested in combinations, mutational frequencies fell below 10^-9for all the combinations.</p> <p>Conclusion</p> <p><it>In vitro </it>evidence of synergy between glycopeptides, fluoroquinolones (levofloxacin) and β-lactams and of reduction of mutational frequencies by combinations are suggestive for a potential role in empirical therapy of severe pneumonia with suspected MRSA etiology.</p

GBA variants in REM sleep behavior disorder: a multicenter study

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration