Biodegradable polymeric micro/nano-structures with intrinsic antifouling/antimicrobial properties: relevance in damaged skin and other biomedical applications

Bacterial colonization of implanted biomedical devices is the main cause of healthcare-associated infections, estimated to be 8.8 million per year in Europe. Many infections originate from damaged skin, which lets microorganisms exploit injuries and surgical accesses as passageways to reach the implant site and inner organs. Therefore, an effective treatment of skin damage is highly desirable for the success of many biomaterial-related surgical procedures. Due to gained resistance to antibiotics, new antibacterial treatments are becoming vital to control nosocomial infections arising as surgical and post-surgical complications. Surface coatings can avoid biofouling and bacterial colonization thanks to biomaterial inherent properties (e.g., super hydrophobicity), specifically without using drugs, which may cause bacterial resistance. The focus of this review is to highlight the emerging role of degradable polymeric micro- and nano-structures that show intrinsic antifouling and antimicrobial properties, with a special outlook towards biomedical applications dealing with skin and skin damage. The intrinsic properties owned by the biomaterials encompass three main categories: (1) physical–mechanical, (2) chemical, and (3) electrostatic. Clinical relevance in ear prostheses and breast implants is reported. Collecting and discussing the updated outcomes in this field would help the development of better performing biomaterial-based antimicrobial strategies, which are useful to prevent infections

Hybridisation Schemes for Communication Satellite Payload Configuration Optimisation

International audienceThe increasing complexity of current telecommunication satellite payloads has made their manual management a difficult and error prone task. As a consequence, efficient optimisation techniques are re- quired to help engineers to configure the payload. Recent works focusing on exact approaches faced scalability issues while metaheuristics provided unsatisfactory solution quality. This work therefore proposes three hybridisation schemes that combine both metaheuristics and an exact method. We focus on the initial configuration problem case and we consider as objective to minimise the length of the longest channel path. Experimental results on realistic payload sizes demonstrate the advantage of those approaches in terms of efficiency within a strict operational time constraint of ten minutes on a single CPU core

Spin-up of low mass classical bulges in barred galaxies

Secular evolution is one of the key routes through which galaxies evolve along the Hubble sequence. Not only the disk undergoes morphological and kinematic changes, but also a preexisting classical bulge may be dynamically changed by the secular processes driven primarily by the bar. We study the influence of a growing bar on the dynamical evolution of a low mass classical bulge such as might be present in galaxies like the Milky Way. Using self-consistent high resolution {\it N}-body simulations, we study how an initially isotropic non-rotating small classical bulge absorbs angular momentum emitted by the bar. The basic mechanism of this angular momentum exchange is through resonances and a considerable fraction of the angular momentum is channeled through Lagrange point (-1:1) and ILR (2:1) orbits. In the phase of rapid dynamical growth, also retrograde non-resonant orbits absorb significant angular momentum. As a result of this angular momentum gain, the initially non-rotating classical bulge transforms into a fast rotating, radially anisotropic and triaxial object, embedded in the similarly fast rotating boxy bulge formed from the disk. Towards the end of the evolution, the classical bulge develops cylindrical rotation. By that time, its inner regions host a "classical bulge-bar" whose distinct kinematics could serve as direct observational evidence for the secular evolution in the galaxy. Some implications of these results are discussed briefly.Comment: 15 pages, 16 figures, accepted for publication by MNRA

An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity

Macrophage migration inhibitory factor (MIF) is a major proinflammatory cytokine that has been increasingly implicated in the pathogenesis of several inflammatory, autoimmune, infectious and oncogenic diseases. Accumulating evidence suggests that the tautomerase activity of MIF plays a role in modulating some of its intra- and extra-cellular activities. Therefore, the identification and development of small-molecule inhibitors targeting the catalytic activity of MIF has emerged as an attractive and viable therapeutic strategy to attenuate its function in health and disease. Herein we report a novel virtual screening protocol for the discovery of new inhibitors of MIF's tautomerase activity. Our protocol takes into account the flexibility and dynamics of the catalytic site by coupling molecular dynamics (MD) simulations aimed at modeling the protein's flexibility in solution to (i) docking with FlexX, or (ii) docking with FlexX and pharmacophoric filtering with Unity. In addition, we applied in parallel a standalone docking using the new version of Surflex software. The three approaches were used to screen the ChemBridge chemical library and the inhibitory activity of the top-ranked 333 compound obtained from each approach (1000 compound in total) was assessed in vitro using the tautomerase assay. This biochemical validation process resulted in the identification of 12 novel MIF inhibitors corresponding to a 1.2% hit rate. Six of these hits came from Surflex docking; two from FlexX docking with MD simulations and four hits were identified with MDS and pharmacophore filtering with minimal overlap between the hits from each approach. Six hits were identified with IC50 values lower than 10 microM (three hits with IC50 lower than 1 microM); four were shown to be suicide inhibitors and act via covalent modification of the N-terminal catalytic residues Pro1. One additional inhibitor, N-phenyl-N-1,3,4-thiadiazol-2-yl-thiourea, (IC50=300 nM) was obtained from FlexX docking combined to pharmacophoric filtering on one of the eight MD structures. These results demonstrate the power of integrative in silico approaches in the discovery of new modulator of MIF's tautomerase activity. The chemical diversity and mode of action of these compounds suggest that they could be used as molecular probes to elucidate the functions and biology of MIF and as lead candidates in drug developments of anti-MIF drugs

Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically localized prostate cancer

The aim of the present study was to evaluate how serum testosterone level (T) can affect urinary continence and erectile function in patients undergoing radical prostatectomy (RP). We included 257 patients with clinically localized prostate cancer, those who had filled out preoperative quality of life questionnaires (University of California, Los Angeles Prostate Cancer Index, International Index of Erectile Function (IIEF)), and those who had T and total PSA sampled the day before surgery. We calculated correlations between T and age, body mass index (BMI), PSA, urinary function or bother (UF, UB) and sexual function or bother (SF, SB) and IIEF-5 in the whole population and in sub-populations with normal (⩾10.4 nmol l−1) and low (<10.4 ng ml−1) T using Pearson's and Spearman's correlation coefficients. We evaluated differences in these parameters between patients with low and normal T using the unpaired samples t-test and Mann–Whitney test, and finally the correlation between UF and SF, UB and SB, and between PSA and T in the overall population, and separately in patients with low and normal T using the Pearson's correlation coefficient. Mean preoperative T was 13.5 nmol l−1 and 23.7% of patients presented a low T. Mean age, mean BMI and mean preoperative total PSA at RP were 64.3 years, 25.9 kg m−2 and 9.0 ng ml−1, respectively. BMI was negatively correlated with T in the overall population (r=−0.266; P=0.02); moreover, patients with normal T presented lower BMI compared with patients with low T (25.7 vs 27.6: P=0.02). We found a significant correlation between SF scores and T in patients with normal T (r=0.1777: P=0.05). SF was significantly higher in patients with normal T compared with those with low T (74.8 vs 64.8: P=0.05). Furthermore, UF and UB were significantly correlated with SF (r=0.2544: P<0.01) and SB (r=0.2512: P=0.01), respectively, in men with normal T. Serum T was significantly correlated with PSA in men with low T (r=0.3874: P=0.0029), whereas this correlation was missed in the whole population and in men with normal T. The correlation between preoperative PSA and T in men with low T is in agreement with the ‘saturation' model proposed by Morgentaler. The correlation between basal T and preoperative erectile function and urinary continence underlines the importance of assessing T before RP

No More Free Drug Samples?

Susan Chimonas and Jerome Kassirer argue that giving out “free” drug samples is not effective in improving drug access for the indigent, does not promote rational drug use, and raises the cost of care

The influence of diabetes mellitus on the spectrum of uropathogens and the antimicrobial resistance in elderly adult patients with urinary tract infection

BACKGROUND: The role of Diabetes mellitus (DM) in the etiology and in the antimicrobial resistance of uropathogens in patients with urinary tract infection has not been well clarified. For this reason we have evaluated the spectrum of uropathogens and the profile of antibiotic resistance in both diabetic and non diabetic patients with asymptomatic urinary tract infection (UTI). METHODS: Urinary isolates and their patterns of susceptibility to the antimicrobials were evaluated in 346 diabetics (229 females and 117 males) and 975 non diabetics (679 females and 296 males) who were screened for significant bacteriuria (≥10(5 )CFU/mL urine). The mean age of diabetic and non diabetic patients was respectively 73.7 yrs ± 15 S.D. and 72.7 ± 24 (p = NS). RESULTS: Most of our patients had asymptomatic UTI. The most frequent causative organisms of bacteriuria in females with and without DM were respectively : E. coli 54.1% vs 58.2% (p = NS), Enterococcus spp 8.3% vs 6.5% (p = NS), Pseudomonas spp 3.9 vs 4.7% (p = NS). The most frequent organisms in diabetic and non diabetic males were respectively E. coli 32.5% vs 31.4% (p = NS), Enterococcus spp 9.4% vs 14.5% (p = NS), Pseudomonas spp 8.5% vs 17.2% (p = <0.02). A similar isolation rate of E. coli, Enterococcus spp and Pseudomonas spp was also observed in patients with indwelling bladder catheter with and without DM. No significant differences in resistance rates to ampicillin, nitrofurantoin, cotrimoxazole and ciprofloxacin of E. coli and Enteroccus spp were observed between diabetic and non diabetic patients. CONCLUSION: In our series of patients with asymptomatic UTI (mostly hospital acquired), diabetes mellitus per se does not seem to influence the isolation rate of different uropathogens and their susceptibility patterns to antimicrobials

The relationship of serum and salivary cortisol levels to male sexual dysfunction as measured by the International Index of Erectile Function

To evaluate the biomarkers of sexual function, we investigated the relationship between questionnaire responses and biological hormones such as testosterone (T) and cortisol (F) in serum and saliva. The study population included 105 men aged 30–72 years (mean: 49±4.5, median: 49). Levels of all serum hormones (Total-T, Free-T, Bioavailable-T, Total-F and Bioavailable-F) and salivary hormones (Saliva-T and Saliva-F) were measured directly by liquid chromatography/tandem mass spectrometry. The International Index of Erectile Function (IIEF) was used as a questionnaire to evaluate sexual dysfunction. Free-T and Bioavailable-T showed significant inverse correlations with age (P<0.01). In the group not taking antidepressants, the levels of Bioavailable-F and Saliva-F showed significant inverse correlations with a portion of the IIEF score (P<0.05). However, reductions in Bioavailable-T and Saliva-T showed no association with the IIEF score. In the group taking antidepressants, these hormone levels showed no correlation with IIEF

Human Intestinal Cells Modulate Conjugational Transfer of Multidrug Resistance Plasmids between Clinical Escherichia coli Isolates.

Bacterial conjugation in the human gut microbiota is believed to play a major role in the dissemination of antibiotic resistance genes and virulence plasmids. However, the modulation of bacterial conjugation by the human host remains poorly understood and there is a need for controlled systems to study this process. We established an in vitro co-culture system to study the interaction between human intestinal cells and bacteria. We show that the conjugation efficiency of a plasmid encoding an extended spectrum beta-lactamase is reduced when clinical isolates of Escherichia coli are co-cultured with human intestinal cells. We show that filtered media from co-cultures contain a factor that reduces conjugation efficiency. Protease treatment of the filtered media eliminates this inhibition of conjugation. This data suggests that a peptide or protein based factor is secreted on the apical side of the intestinal cells exposed to bacteria leading to a two-fold reduction in conjugation efficiency. These results show that human gut epithelial cells can modulate bacterial conjugation and may have relevance to gene exchange in the gut

"Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

<p>Abstract</p> <p>Background</p> <p>This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC).</p> <p>Methods</p> <p>Simon two-step design: delta 20% (p₀50%, p₁70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m², days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m²plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m², days 8, 22; every 4 weeks.</p> <p>Results</p> <p>Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m². ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%.</p> <p>Conclusion</p> <p>Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered.</p> <p>Trial registration</p> <p>Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34</p