Long-Term Effects of Safinamide on Dyskinesia in Mid- to Late-Stage Parkinson's Disease: A Post-Hoc Analysis.

BACKGROUND: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of safinamide on dyskinesia may be related to severity of dyskinesia at baseline. OBJECTIVE: This post-hoc analysis further characterized the effects of safinamide on dyskinesia in mid- to late-stage PD patients. METHODS: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between safinamide and placebo were evaluated using the Wilcoxon rank-sum test. RESULTS: For the overall treated population (with or without baseline dyskinesia), safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. CONCLUSIONS: While no statistically significant difference in mean DRS scores was seen between safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of safinamide on dyskinesia. These results may be related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation.

Seasonal changes on microbial metabolism and biomass in the euphotic layer of Sicilian Channel.

As a part of a wider project on fisheries ecology, several biological and environmental parameters were monitored during two oceanographic cruises (BANSIC 2012 and NOVESAR 2013) in the Sicily Channel, which connects the Western and Eastern Mediterranean basins. The prokaryotic abundances and biomass as well as hydrolysis rates on organic matter were investigated in the euphotic layer of a retention area for fish larval stages including anchovy (Engraulis encrasicolus, Linnaeus, 1758) with the aim to investigate the different biogeochemical signatures in two seasonal conditions. The environmental parameters, particulate organic carbon and nitrogen together with heterotrophic production were also measured. Results showed significant increases for most of the studied parameters with increasing temperature during summer. This had effects on the Carbon cycle and recycling of nutrients; in fact total prokaryotic abundance and biomass, as well as carbon hydrolyzed by two enzymes (Leucine aminopeptidase and ß-glucosidase), increased significantly during summer. Conversely Alkaline phosphatase activity, Chlorophyll concentration and Oxygen increased during winter. The same environmental parameters affected also the presence of fish eggs. Moreover high percentages of free enzymes (i.e., enzymes not associated with cells) were measured, accounting for percentages variable from 12 to 95 % of the total enzymatic activity, with values generally higher in summer than in winter. In this oligotrophic environment, the prokaryotic biomass was supported by the C hydrolyzed by enzymatic activities. The ratio between the hydrolyzed C and prokaryotic biomass was higher in winter than in summer, indicating that alkaline phosphatase activity contribute to an efficient incorporation of C into biomass in winter.

Seasonal dynamics of prokaryotic abundance and activities in relation to environmental parameters in a transitional aquatic ecosystem (Cape Peloro, Italy).

This study examines the effects of temporal changes on microbial parameters in a brackish aquatic ecosystem. To this aim, the abundances of prokaryotes and vibrios together with the rates of enzymatic hydrolysis of proteins by leucine aminopeptidase (LAP), polysaccharides by ß-glucosidase (GLU) and organic phosphates by alkaline phosphatase (AP), heterotrophic prokaryotic production (HPP), respiration (R), were seasonally investigated, during a 2-year period in the coastal area of Cape Peloro (Messina, Italy), constituted by two brackish lakes (Faro and Ganzirri). In addition, physical and chemical parameters (temperature, salinity, nutrients) and particulate organic carbon and nitrogen (POC, PN) were measured. The influence of multiple factors on prokaryotic abundances and activities was analysed. The results showed that Cape Peloro area is characterised by high seasonal variability of the microbial parameters that is higher than the spatial one. Combined changes in particulate matter and temperature (T), could explain the variability in vibrios abundance, GLU and R activities in both lakes, indicating a direct stimulation of the warm season on the heterotrophic prokaryotic metabolism. Positive correlations between T (from 13.3 to 29.6 °C) and HPP, LAP, AP, POC, PN are also observed in Ganzirri Lake. Moreover, the trophic status index and most of the microbial parameters show significant seasonal differences. This study demonstrates that vibrios abundance and microbial activities are responsive to the spatial and seasonal changes of examined area. The combined effects of temperature and trophic conditions on the microbial parameters lead us to suggest their use as potential indicators of the prokaryotic response to climate changes in temperate brackish areas.

Enzymatic activities and prokaryotic abundance in relation to organic matter along a West-East Mediterranean transect (TRANSMED cruise).

The distribution of extracellular enzymatic activities (EEA) [leucine aminopeptidase (LAP), ß-glucosidase (GLU), alkaline phosphatase (AP)], as well as that of prokaryotic abundance (PA) and biomass (PB), dissolved organic carbon (DOC), particulate organic carbon and particulate total nitrogen (POC, PTN), was determined in the epi-, meso-, and bathypelagic waters of the Mediterranean Sea along a West-East transect and at one Atlantic station located outside the Strait of Gibraltar. This study represents a synoptical evaluation of the microbial metabolism during early summer. Decreasing trends with depth were observed for most of the parameters (PA, PB, AP, DOC, POC, PTN). Significant differences between the western and eastern basins of the Mediterranean Sea were found, displaying higher rates of LAP and GLU and lower C/N ratios more in the eastern than in the western areas. Conversely, in the epipelagic layer, PA and PB were found to be higher in the western than in the eastern basins. PB was significantly related to DOC concentration (all data, n = 145, r = 0.53, P < 0.01), while significant correlations of EEA with POC and PTN were found in the epipelagic layer, indicating an active response of microbial metabolism to organic substrates. Specific enzyme activities normalized to cell abundance pointed out high values of LAP and GLU in the bathypelagic layer, especially in the eastern basin, while cell-specific AP was high in the epi- and bathypelagic zone of the eastern basin indicating a rapid regeneration of inorganic P for both prokaryotes and phytoplankton needs. Low activity and abundance characterized the Atlantic station, while opposite trends of these parameters were observed along the Mediterranean transect, showing the uncoupling between abundance and activity data. In the east Mediterranean Sea, decomposition processes increased probably in response to mesoscale structures which lead to organic matter downwelling.

Leptin-based glycopeptide induces weight loss and simultaneously restores fertility in animal models.

AIM: To design, manufacture and test a second generation leptin receptor (ObR) agonist glycopeptide derivative. The major drawback to current experimental therapies involving leptin protein is the appearance of treatment resistance. Our novel peptidomimetic was tested for efficacy and lack of resistance induction in rodent models of obesity and appetite reduction. METHODS: The glycopeptide containing two additional non-proteinogenic amino acids was synthesized by standard solid-phase methods. Normal mice were fed with peanuts until their blood laboratory data and liver histology showed typical signs of obesity but not diabetes. The mice were treated with the peptidomimetic at 0.02, 0.1 or 0.5 mg/kg/day intraperitoneally side-by-side with 0.1 mg/kg/day leptin for 11 days. After termination of the assay, the blood cholesterol and glucose amounts were measured, the liver fat content was visualized and quantified and the remaining mice returned to normal diet and were allowed to mate. In parallel experiments normal rats were treated intranasally with the glycopeptide at 0.1 mg/kg/day for 10 days. RESULTS: The 12-residue glycosylated leptin-based peptidomimetic E1/6-amino-hexanoic acid (Aca) was designed to target a principal leptin/ObR-binding interface. E1/Aca induced leptin effects in ObR-positive cell lines at picomolar concentrations and readily crossed the blood-brain barrier (BBB) following intraperitoneal administration. The peptide initiated typical leptin-dependent signal transduction pathways both in the presence and absence of leptin protein. The peptide also reduced weight gain in mice fed with high-fat peanut diet in a dose-dependent manner. Obese mice receiving peptide E1/Aca at a 0.5 mg/kg/day dose lost weight, corresponding to a net 6.5% total body weight loss, while similar mice treated with leptin protein did not. Upon cessation of the weight loss treatment, several obesity-related pathologies (i.e. abnormal metabolic profile and liver histology as well as infertility) normalized in peptide-, but not leptin-treated, mice. Peptide E1/Aca added intranasally to growing normal rats decelerated normal weight gain corresponding to a net 6.8% net total body weight loss with statistical significance. CONCLUSIONS: No resistance induction to peptide E1/Aca or toxicity in either obese or healthy rodents was observed, indicating the potential for widespread utility of the peptidomimetic in the treatment of leptin-deficiency disorders. We provide additional proof for the hypothesis that difficulties in current leptin therapies reside at the BBB penetration stage, and we document that by either glycosylation or intranasal peptide administration we can overcome this limitation.

Founder mutations in BRCA1 and BRCA2 genes.

BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance.

Microplankton respiration (ETS) in two areas of the Northern Adriatic (Mediterranean Sea).

Respiratory rates in two areas of the North Adriatic Sea were studied in the context of a PRISMA II Project, with the aim of quantifying the oxidative processes occurring in the frontal system caused by strong riverine discharge. In the northern area, higher respiratory rates and seasonal variations occurred with respect to the southern area. On average, respiratory activity sustained the oxidation of 66.9 nM C h(-1) inside the front and 24.4 nM C h(-1) outside the front. In conclusion, organic matter oxidation inside the front resulted 2.7 times higher than outside the front. Oxidative metabolism in the Northern Adriatic Sea appears mainly governed by river inputs.

Detection of intracranial metastases: a multicenter, intrapatient comparison of gadobenate dimeglumine-enhanced MRI with routinely used contrast agents at equal dosage.

RATIONALE AND OBJECTIVES: To compare gadobenate dimeglumine (MultiHance) with other commercially available MRI contrast agents for the detection of intracranial metastases. METHODS: A retrospective assessment was performed on MR images from 22 patients enrolled in a prior phase II clinical trial of gadobenate dimeglumine. Each patient underwent two examinations: a first examination with one of three "comparator" agents (gadopentetate dimeglumine, gadodiamide, and gadoterate meglumine) at a dosage of either 0.1 or 0.2 mmol/kg, and then a similar examination with gadobenate dimeglumine at equal dosage. All images were evaluated randomly for lesion number and location in unpaired and then paired fashion by two independent, masked neuroradiologists. A third assessor performed quantitative assessments on the available complete sets of digitally recorded images (10 cases). RESULTS: The findings for the comparator agents were pooled. Sensitivity for lesion detection with gadobenate dimeglumine (93%-100%) was markedly superior to that of comparator-enhanced examinations (65%-73%). The increase of lesion-to-brain contrast of the main lesion was consistently greater with gadobenate dimeglumine than with comparator agents relative to unenhanced contrast (+43% vs. +27%). CONCLUSIONS: Gadobenate dimeglumine proved to be a more efficacious agent than comparator contrast agents for the detection of intracranial metastatic lesions: superior efficacy was noted by both reviewers for total lesion count as well as for sensitivity and positive predictive value for lesion detection. The higher relaxivity of gadobenate dimeglumine might explain the superior sensitivity of gadobenate dimeglumine-enhanced MRI for the detection of central nervous system metastases.

Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals.

Mechanistic studies regarding the action of gadobenate dimeglumine (Gd-BOPTA/Dimeg; MultiHance) in animals are presented, and the relevance of the results to protocols for MR imaging of the liver are discussed. Gd-BOPTA/Dimeg maintains all the characteristics of an extracellular contrast agent, but owing to a weak affinity for serum albumin, provides in these applications stronger signal intensities than contrast agents without such affinity at the same dose. This property can be taken advantage of for dynamic liver imaging. A unique property of Gd-BOPTA/Dimeg is that the contrast effective ion, Gd-BOPTA2-, enters hepatocytes selectively and reversibly through the sinusoidal plasma membrane using transport mechanisms other than the organic anion transport polypeptide. In a rate-limiting step, the ion is excreted by the multispecific organic anion transporter into the bile. The increase in liver distribution space of Gd-BOPTA2-, as compared to that of purely extracellular contrast agents, is identified as the principal mechanism of normal parenchymal signal enhancement. Microviscosity effects inside hepatocytes add to the relaxation effectiveness of Gd-BOPTA2-, while its presence in the bile and an affinity for intracellular macromolecules play subordinate roles only. Gd-BOPTA2- persists in hepatocytes beyond the times characteristic of dynamic imaging, providing delayed-phase contrast between normal hepatocytes and tumor cells. As a result, the conspicuity of small focal lesions and thus their detection is improved. Additionally, Gd-BOPTA/Dimeg allows sites of abscesses and systemically damaged tissue to be distinguished from healthy liver. Taken together these mechanistically-supported properties qualify the product as a versatile general MR contrast agent with added merits in liver imaging.

Microbial respiratory activity in the euphotic zone of the Mediterranean Sea.

Microplankton respiration in the euphotic zone in the Central Mediterranean Sea was calculated by ETS activity measurements. Distribution of ETSa in the studied area appeared homogeneous and comparable with previous data measured in the Mediterranean Sea. A typical ETSa value for euphotic Mediterranean waters of 0.14 meq O2 h-1 m-3 was calculated. The investigated area supports a metabolic CO2 production of 70 g C m-2 y-1. When compared with regional productivity, the respiration budget in the euphotic zone accounted for 22% of carbon fixed. ETSa appeared a useful assay for the study of evolutive history of the water masses in the Mediterranean Sea.

Structural differences of the microbial community in two sites of the Terra Nova Bay (Ross Sea, Antarctica): a statistical analysis.

The microbial community structure was investigated in a one month survey at two sampling stations located in the Terra Nova Bay (Antarctica). The microbial assemblage was studied by direct counts with epifluorescent microscopy (picoplankton and picophytoplankton), fractionated adenosine-triphosphate, lipopolysaccarides and bacterial growth on cultural medium. The results underwent the Spearman rank correlation and the principal component analysis together with other environmental parameters (temperature, salinity, nutrient salts and chlorophyll a) with the aim of revealing differences in the microbial community structure between the in-shore and off-shore sites.