Sistema a rilascio di farmaco basato su nanotubi di carbonio per lo sviluppo di neuro-interfacce innovative

Lo scopo di questo lavoro di tesi è la realizzazione di un’interfaccia neurale a rilascio di farmaco, basata sull’utilizzo di array di nanotubi di carbonio (CNT). La scelta dei nanotubi è dovuta alle caratteristiche elettriche, chimiche e di biocompatibilità che li rendono potenziali materiali per ristabilire intricate connessioni a livello neurale. Gli array di CNT sono strutture tridimensionali, in cui i nanotubi sono disposti verticalmente su un apposito substrato di silicio con una densità superficiale di circa 10^9 CNT/cm^2 . Esistono diversi lavori in letteratura che documentano l’utilizzo degli array di CNT per lo sviluppo di interfacce neurali. Recentemente è stato posto il problema dell’inglobamento di farmaci in tali matrici. Il sistema sviluppato, nell’ambito di tale studio, consiste di un array di nanotubi di carbonio, rivestito di un film sottile di PPy, un polimero conduttore, al fine di migliorare le caratteristiche meccaniche dei CNT ed evitare il fenomeno dello steaking Il sistema a rilascio di farmaco è realizzato tramite deposizione, sulla superficie dei CNT, di un film micrometrico di polimero, l’alginato, con all’interno intrappolata la proteina. La cinetica di rilascio è stata valutata tramite spettrofotometria. Infine l’interfaccia è stata validata in vitro utilizzando come linea cellulare i fibroblasti felini renali Crandell. Tali test hanno dimostrato l’efficacia del rilascio e l’attività della proteina rilasciata. L’analisi è stata condotta tramite microscopia in fluorescenza e microscopia a fascio ionico (FIB)

Beta-blokers in patients with cirrhosis and infection: don't blame too soon.

We found that PPI-users had a higher rate and BBs-users a lower rate of infections. The lower infection rate and better prognosis of BB-users can not be attributed, as suggested by Schiavon et al., to a higher proportion of variceal bleeding in this group; in fact, the large majority of patients hospitalized for bleeding were excluded from the study as they came to our ward already on systemic antibiotic treatment (which is usually started in the Emergency room) and this would have represented a confounding factor. Only few patients with variceal bleeding were included: they developed bleeding after enrolment and were equally distributed between those taking and not taking BBs. Following the recent debate about the ‘therapeutic window’ of BBs in cirrhotic patients (2–4), we were also interested in evaluating possible harmful effects of BBs in cirrhotic patients with infections. This was a secondary aim of our study and we certainly recognize that the study was underpowered for this purpose

Albumin infusion in cirrhotic patients with infections other than spontaneous bacterial peritonitis: End of the story?

Non-invasive assessment of liver fibrosis with impulse elastography: Comparison of Supersonic Shear Imaging with ARFI and FibroScan

A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients

Background: Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. Methods: This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. Results: We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (–37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). Conclusion: Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting. Keywords: profitability, diagnosis-related group, cost saving, antibiotic failur

Nano-oncology: clinical application for cancer therapy and future perspectives

Nano-oncology, the application of Nanomedicine to cancer diagnosis and treatment, has the potential to transform clinical oncology by enhancing the efficacy of cancer chemotherapy for a wide spectrum of invasive cancers. It achieves this by enabling novel drug delivery systems which target the tumour site with several functional molecules, including tumour-specific ligands, antibodies, cytotoxic agents, and imaging probes simultaneously thereby improving tumour response rates in addition to significant reduction of the systemic toxicity associated with current chemotherapy regimens. For this reason, nano-oncology is attracting considerable scientific interest and a growing investment by the global pharmaceutical industry. Several therapeutic nano-carriers have been approved for clinical use and others are undergoing phase II and III clinical trials. This paper describes the current approved formulations, such as liposomes and polymeric nanoparticles, and discusses the overall present status of nano-oncology as an emerging branch of nanomedicine and its future perspectives in cancer and therapy

Zinc oxide nanoparticles as selective killers of proliferating cells

Background: It has recently been demonstrated that zinc oxide nanoparticles (ZnO NPs) induce death of cancerous cells whilst having no cytotoxic effect on normal cells. However, there are several issues which need to be resolved before translation of zinc oxide nanoparticles into medical use, including lack of suitable biocompatible dispersion protocols and a better understanding being needed of the mechanism of their selective cytotoxic action. Methods: Nanoparticle dose affecting cell viability was evaluated in a model of proliferating cells both experimentally and mathematically. The key issue of selective toxicity of ZnO NPs toward proliferating cells was addressed by experiments using a biological model of noncancerous cells, ie, mesenchymal stem cells before and after cell differentiation to the osteogenic lineage. Results: In this paper, we report a biocompatible protocol for preparation of stable aqueous solutions of monodispersed zinc oxide nanoparticles. We found that the threshold of intracellular ZnO NP concentration required to induce cell death in proliferating cells is 0.4 ± 0.02 mM. Finally, flow cytometry analysis revealed that the threshold dose of zinc oxide nanoparticles was lethal to proliferating pluripotent mesenchymal stem cells but exhibited negligible cytotoxic effects to osteogenically differentiated mesenchymal stem cells. Conclusion: Results confirm the ZnO NP selective cytotoxic action on rapidly proliferating cells, whether benign or malignant

The spread of multi drug resistant infections is leading to an increase in the empirical antibiotic treatment failure in cirrhosis: a prospective survey

Background The spread of multi-resistant infections represents a continuously growing problem in cirrhosis,particularly in patients in contact with the healthcare environment. Aim Our prospective study aimed to analyze epidemiology, prevalence and risk factors of multiresistant infections, as well as the rate of failure of empirical antibiotic therapy in cirrhotic patients. Methods All consecutive cirrhotic patients hospitalized between 2008 and 2013 with a microbiologically-documented infection (MDI) were enrolled. Infections were classified as Community- Acquired (CA), Hospital-Acquired (HA) and Healthcare-Associated (HCA). Bacteria were classified as Multidrug-Resistant (MDR) if resistant to at least three antimicrobial classes, Extensively-Drug-Resistant (XDR) if only sensitive to one/two classes and Pandrug-Resistant (PDR) if resistant to all classes. Results One-hundred-twenty-four infections (15% CA, 52% HA, 33% HCA) were observed in 111 patients. Urinary tract infections, pneumonia and spontaneous bacterial peritonitis were the more frequent. Forty-seven percent of infections were caused by Gram-negative bacteria. Fifty-one percent of the isolates were multi-resistant to antibiotic therapy (76% MDR, 21% XDR, 3% PDR): the use of antibiotic prophylaxis (OR = 8.4; 95%CI = 1.03-76; P = 0,05) and current/recent contact with the healthcare-system (OR = 3.7; 95%CI = 1.05-13; P = 0.04) were selected as independent predictors. The failure of the empirical antibiotic therapy was progressively more frequent according to the degree of resistance. The therapy was inappropriate in the majority of HA and HCA infections. Conclusions Multi-resistant infections are increasing in hospitalized cirrhotic patients. A better knowledge of the epidemiological characteristics is important to improve the efficacy of empirical antibiotic therapy. The use of preventive measures aimed at reducing the spread of multi-resistant bacteria is also essential

Generation of magnetized olfactory ensheathing cells for regenerative studies in the central and peripheral nervous tissue

As olfactory receptor axons grow from the peripheral to the central nervous system (CNS) aided by olfactory ensheathing cells (OECs), the transplantation of OECs has been suggested as a plausible therapy for spinal cord lesions. The problem with this hypothesis is that OECs do not represent a single homogeneous entity, but, instead, a functionally heterogeneous population that exhibits a variety of responses, including adhesion and repulsion during cell-matrix interactions. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical gradients. In this paper, we report a system based on modified OECs carrying magnetic nanoparticles as a proof of concept experiment enabling specific studies aimed at exploring the potential of OECs in the treatment of spinal cord injuries. Our studies have confirmed that magnetized OECs (i) survive well without exhibiting stress-associated cellular responses; (ii) in vitro, their migration can be modulated by magnetic fields; and (iii) their transplantation in organotypic slices of spinal cord and peripheral nerve showed positive integration in the model. Altogether, these findings indicate the therapeutic potential of magnetized OECs for CNS injuries

Quantitative changes of nicotinic receptors in the hippocampus of dystrophin-deficient mice

Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of alpha 4, beta 2, and alpha 7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. the number of [H-3]-cytisine (alpha 4 beta 2) and [I-125]-alpha-bungarotoxin ([I-125]-alpha BGT, alpha 7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [H-3]-cytisine (48%) and [I-125]-alpha BGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [H-3]-cytisine binding in the hippocampus, but [I-125]-alpha BGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR alpha 4, beta 2, and alpha 7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients. (C) 2012 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Escola Paulista Med, Sect Nat Prod, Dept Pharmacol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, São Paulo, BrazilUniv Fed Santa Catarina, Dept Pharmacol, Neuropharmacol Lab, Florianopolis, SC, BrazilAmazon Biotechnol Ctr, Lab Pharmacol & Toxicol, Manaus, AM, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Nat Prod, Dept Pharmacol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, São Paulo, BrazilWeb of Scienc