Pharmacokinetic profile of bisphosphonates in the treatment of metabolic bone disorders

The pharmacokinetic profile of bisphosphonates is complex and depends on their potency in inhibiting bone resorption through their cellular effects and on the physicochemical action related to the interaction of these compounds with bone matrix. Amino-substituted bisphosphonates exert a more potent cellular effect on osteoclast via the inhibition of the mevalonate pathway, whereas non-nitrogen containing compounds exert a weaker effect deriving from the induction of intracellular metabolites in osteoclasts. For nitrogen-containing bisphosphonates there is a correlation between in vitro potency of inhibition of a specific enzyme, farnesyl pyrophosphate synthase, and their antiresorptive potency in vivo. Besides these effects on osteoclasts, bisphosphonates may in part mediate indirectly their antiresoprtive activity through several effects on osteoblasts and osteocytes. Different binding affinities of bisphopshonates to hydroxyapatite depend on both side chains structures and may explain how these drugs reach bone cells and exert their prolonged action in terms of adsorption and desorption processes. Clinical and animalmodels derived data indicate that agents with high anti-resorptive potency, favourable bone binding characteristics and good tolerability can be used with long between-dose intervals to optimize therapeutic outcome

Multifocal diffusion of a KPC-3 producing ST512 K. pneumoniae clone in Northern Italy

Sequence Type 258 (ST258) together with its allelic single- and double-locus variants have mostly been associated with the dissemination of KPC-producing Klebsiella pneumoniae in Europe. A total of 56 nonreplicate K. pneumoniae isolates with decreased carbapenem-susceptibility, collected at 7 different hospitals located in Northern Italy were investigated for the occurrence of blaKPC-type genes. PCR and sequencing results highlighted the presence of blaKPC-2 or blaKPC-3 determinants in 10/56 and 5/56 cases respectively. Here we describe the intra- and inter-hospital spread in Northern Italy of a K. pneumoniae ST512 clone harboring the blaKPC-3 gene

Effect of a gelatin-based edible coating containing cellulose nanocrystals (CNC) on the quality and nutrient retention of fresh strawberries during storage

Strawberry is a non-climacteric fruit with a very short postharvest shelf-life. Loss of quality in this fruit is mostly due to its relatively high metabolic activity and sensitivity to fungal decay, meanly grey mold (Botrytis cinerea). In this study, the ability of gelatin coatings containing cellulose nanocrystals (CNC) to extend the shelf-life of strawberry fruit (Fragaria ananassa) over 8 days were studied. The filmogenic solution was obtained by the hydration of 5 g of gelatin (GEL) in 100 mL of distillated water containing different amounts of CNC dispersion (10 mg CNC/g of GEL or 50 mg of CNC/g of GEL) for 1 hour at room temperature. After this period, the solution was heated to 70 ºC and maintained at this temperature for 10 minutes. The plasticizer (glycerol) (10g/100g of the GEL) was then added with constant, gentle stirring in order to avoid forming air bubbles and also to avoid gelatin denaturation until complete homogenization. Strawberries (purchased at the local market) were immersed in the filmogenic solution for 1 minute and after coated were dried at 15 ºC by 24 hours. The strawberries were then kept under refrigeration and characterized in terms of their properties (weight loss, ascorbic acid content, titratable acidity, water content). The results have shown that samples covered with GEL/CNC had a significant improvement in its shelflife. For instance, for the control sample (without coating) the weight loss after 8 days of storage was around 65%, while covered samples loss in the range of 31-36%. Edible coating was also effective in the retention of ascorbic acid (AA) in the strawberries, while control sample presented a fast decay in the AA content, covered samples showed a slow decay in the AA concentration. Moreover, the use of GEL/CNC edible coating had an antimicrobial effect in the fruitsPostprint (published version

High-dose benzodiazepine use and QTc interval prolongation, a latent class analysis study

Benzodiazepine (BDZ) addiction is a widespread and multifaceted phenomenon. For many patients, especially females, the concomitant use of other drugs also increases their risk of QTc prolongation, possibly leading to complications such as seizures and even sudden death. However, the relationship between BDZ use and QTc prolongation is currently unclear. The present study aims to examine patterns of polysubstance use among a sample of Italian adults with BDZ dependence in relation with their QTc prolongation risk. We used Latent Class Analysis (LCA) on data collected from 251 inpatients of the Addiction Medicine Unit in Verona to group patients into three classes according to their substance use and their QTc prolongation risk. Results showed no significant relationship between QTc prolongation and BDZ use in any of the classes considered. We conclude that BDZs, even if used long-term and at high dosages, can be considered safe in terms of cardiovascular complications for patients

Multicenter prospective study on the prevalence of colistin resistance in escherichia coli: Relevance of mcr-1-positive clinical isolates in Lombardy, Northern Italy

Background: The emergence of the plasmid-mediated colistin resistance mechanism in Escherichia coli has raised concern among public health experts as colistin is a last-line antimicrobial resort. The primary aim of the study was to investigate the prevalence of this resistance trait in E. coli isolates circulating in the Lombardy region, Northern Italy. The presence of mcr-type genes and their genetic relationship were also studied. Materials and methods: A prospective study was performed during a 4-month period (May to August, 2016) in six acute care Hospitals. Consecutive nonduplicate clinical isolates of E. coli from any type of clinical specimen, with the exception of rectal swabs, were included in the study. Isolates that exhibited MIC values for colistin >2 mg/L were further investigated. Bacterial identification was obtained by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Amplification of mcr-type genes (-1 to -5 variants) and microarray analysis were accomplished. Repetitive sequence-based PCR (Rep-PCR) and multilocus sequence typing (MLST) analysis were used for genotyping. Results: Overall, 3,902 consecutive E. coli isolates (2,342 from outpatients, 1,560 from inpatients) were evaluated during the study period. Of them, 18/3,902 (0.5%), collected from 4/6 centers, showed resistance to colistin. These isolates were mostly obtained from urine of both outpatients (n=12) and inpatients (n=6). Colistin MIC values ranged from 4 to 8 mg/L. The mcr-1 gene was detected in 10/18 isolates (7 from outpatients, 3 from inpatients). Rep-PCR and MLST analysis revealed the presence of nine different clusters. Further mcr-type genes were not detected. Conclusion: Resistance to colistin in E. coli clinical isolates appears low in our geographic area. With regard to mcr-1-positive isolates, they accounted for approximately 50% of colistin-resistant E. coli isolates, thus representing a relevant resistance mechanism in this context. Although overall limited, the presence of mcr-1 determinant in our region should not be ignored and great concern should be given to the continuous surveillance

Dideoxynucleoside HIV reverse transcriptase inhibitors and drug-related hepatotoxicity: a case report

This report regards the case of a 43 year-old HIV-positive woman who developed an episode of serious transaminase elevation during stavudine-including antiretroviral therapy. Diagnostic assessment ruled out hepatitis virus co-infection, alcohol abuse besides other possible causes of liver damage. No signs of lactic acidosis were present. Liver biopsy showed portal inflammatory infiltrate, spotty necrosis, vacuoles of macro- and micro-vesicular steatosis, acidophil and foamy hepatocytes degeneration with organelles clumping, poorly formed Mallory bodies and neutrophil granulocytes attraction (satellitosis). A dramatic improvement in liver function tests occurred when stavudine was discontinued and a new antiretroviral regimen with different nucleoside reverse transcriptase inhibitors was used. The importance of considering hepatotoxicity as an adverse event of HAART including stavudine, even in absence of other signs of mitochondrial toxicity should therefore be underlined. Liver biopsy may provide further important information regarding patients with severe transaminase elevation, for a better understanding of the etiology of liver damage

A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection