Novel Macrocyclic Amidinoureas: Potent Non-Azole Antifungals Active against Wild-Type and Resistant Candida Species.

Novel macrocyclic amidinourea derivatives 11, 18, and 25 were synthesized and evaluated as antifungal agents against wild-type and fluconazole resistant Candida species. Macrocyclic compounds 11 and 18 were synthesized through a convergent approach using as a key step a ring-closing metathesis macrocyclization reaction, whereas compounds 25 were obtained by our previously reported synthetic pathway. All the macrocyclic amidinoureas showed antifungal activity toward different Candida species higher or comparable to fluconazole and resulted highly active against fluconazole resistant Candida strains showing in many cases minimum inhibitory concentration values lower than voriconazole.

Recommended Practice for Accepting New Concrete Pavement Surfaces for Tire/Pavement Noise, March 2, 2011

This practice provides guidance and example specification language intended for use by Owner-Agencies in development of specific contract language when requiring the evaluation of tire/pavement noise for new concrete pavement surfaces. The overall sound intensity level is designated as the quality characteristic used for pay adjustment.

The Effect of Inoculum Size on Selection of In Vitro Resistance to Vancomycin, Daptomycin, and Linezolid in Methicillin-Resistant Staphylococcus aureus.

OBJECTIVES: The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) at high bacterial densities. The effect of three inoculum sizes on the selection of resistance to vancomycin, daptomycin, and linezolid was investigated in methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Low (10(4) CFU/ml), medium (10(6) CFU/ml), and high (10(8) CFU/ml) inocula of MRSA were exposed to twofold increasing concentrations of either drug during 15 days of cycling. MICs for low (MICL), medium (MICM), and high (MICH) inocula were determined daily. Conventional MICs were measured at days 1, 5, 10, and 15. Experiments were performed in triplicate. RESULTS: At the beginning of the experiment a small IE was observed for vancomycin (MICL=1 μg/ml, MICM=1-2 μg/ml, and MICH=2 μg/ml) and a significant IE for daptomycin (MICL=0.25 μg/ml, MICM=0.25-0.5 μg/ml, and MICH=2 μg/ml). Linezolid exhibited no IE at low and medium inocula (MICL=1 μg/ml and MICM=1-2 μg/ml), but with the high inoculum, concentrations up to 2,048 μg/ml did not fully inhibit visual growth. During cycling, increase of MIC was observed for all antibiotics. At day 15, MICL, MICM, and MICH of vancomycin were 2-4, 4-8, and 4-16 μg/ml and of daptomycin were 0.5-2, 8-128, and 64-256 μg/ml, respectively. MICL and MICM of linezolid were 1 and 2-4 μg/ml, respectively. Conventional MICs showed vancomycin and daptomycin selection of resistance since day 5 depending on the inocula. No selection of linezolid resistance was observed. CONCLUSIONS: Our results showed the importance of the inoculum size in the development of resistance. Measures aimed at lowering the inoculum at the site of infection should be used whenever possible in parallel to antimicrobial therapy.

Sub-inhibitory concentrations of vancomycin prevent quinolone-resistance in a penicillin-resistant isolate of Streptococcus pneumoniae.

BACKGROUND: The continuous spread of penicillin-resistant pneumococci represents a permanent threat in the treatment of pneumococcal infections, especially when strains show additional resistance to quinolones. The main objective of this study was to determine a treatment modality impeding the emergence of quinolone resistance. RESULTS: Exposure of a penicillin-resistant pneumococcus to increasing concentrations of trovafloxacin or ciprofloxacin selected for mutants resistant to these drugs. In the presence of sub-inhibitory concentrations of vancomycin, development of trovafloxacin-resistance and high-level ciprofloxacin-resistance were prevented. CONCLUSIONS: Considering the risk of quinolone-resistance in pneumococci, the observation might be of clinical importance.

Mutations in penicillin-binding protein (PBP) genes and in non-PBP genes during selection of penicillin-resistant Streptococcus gordonii.

Penicillin resistance in Streptococcus spp. involves multiple mutations in both penicillin-binding proteins (PBPs) and non-PBP genes. Here, we studied the development of penicillin resistance in the oral commensal Streptococcus gordonii. Cyclic exposure of bacteria to twofold-increasing penicillin concentrations selected for a progressive 250- to 500-fold MIC increase (from 0.008 to between 2 and 4 microg/ml). The major MIC increase (> or = 35-fold) was related to non-PBP mutations, whereas PBP mutations accounted only for a 4- to 8-fold additional increase. PBP mutations occurred in class B PBPs 2X and 2B, which carry a transpeptidase domain, but not in class A PBP 1A, 1B, or 2A, which carry an additional transglycosylase domain. Therefore, we tested whether inactivation of class A PBPs affected resistance development in spite of the absence of mutations. Deletion of PBP 1A or 2A profoundly slowed down resistance development but only moderately affected resistance in already highly resistant mutants (MIC = 2 to 4 microg/ml). Thus, class A PBPs might facilitate early development of resistance by stabilizing penicillin-altered peptidoglycan via transglycosylation, whereas they might be less indispensable in highly resistant mutants which have reestablished a penicillin-insensitive cell wall-building machinery. The contribution of PBP and non-PBP mutations alone could be individualized in DNA transformation. Both PBP and non-PBP mutations conferred some level of intrinsic resistance, but combining the mutations synergized them to ensure high-level resistance (> or = 2 microg/ml). The results underline the complexity of penicillin resistance development and suggest that inhibition of transglycosylase might be an as yet underestimated way to interfere with early resistance development.

Nanometer-scale oxidation of Si(100) surfaces by tapping mode atomic force microscopy

The nanometer¿scale oxidation of Si(100) surfaces in air is performed with an atomic force microscope working in tapping mode. Applying a positive voltage to the sample with respect to the tip, two kinds of modifications are induced on the sample: grown silicon oxide mounds less than 5 nm high and mounds higher than 10 nm (which are assumed to be gold depositions). The threshold voltage necessary to produce the modification is studied as a function of the average tip¿to¿sample distance.

Ab initio cluster-model study of the on-top chemisorption of F and Cl on Si(111) and Ge(111) surfaces

The interaction of atomic F and Cl with Si4H9 and Ge4H9 cluster models has been studied by using ab initio pseudopotentials and basis sets of increasing complexity. The results show that the effect of d orbitals is important in order to reproduce the experimental findings. However, the use of polarization functions in the atoms which are directly involved in the chemisorption bond leads to results which are very close to those obtained using extended basis sets. The local nature of the chemisorption bond is also interpreted by means of a Mulliken population analysis. For F-Si4H9 and Cl-Si4H9 the present results are in good agreement with previous ab initio all-electron calculations, and for the chemisorption of Cl on Si(111) and Ge(111) surfaces, good agreement is found with respect to the available experimental results as well as with previous slab calculations based on the local-density-functional formalism.

Chemisorption of group-III metals on the Si(111) and Ge(111) surfaces: An ab initio study

Chemisorption of group-III metal adatoms on Si(111) and Ge(111) has been studied through the ab initio Hartree-Fock method including nonempirical pseudopotentials and using cluster models to simulate the surface. Three different high-symmetry sites (atop, eclipsed, and open) have been considered by using X4H9, X4H7, and X6H9 (X=Si,Ge) cluster models. In a first step, ideal surface geometries have been used. Metal-induced reconstruction upon chemisorption has also been taken into account. Equilibrium distances, binding energies, and vibrational frequencies have been obtained and compared with available experimental data. From binding-energy considerations, the atop and eclipsed sites seem to be the most favorable ones and thus a coadsorption picture may be suggested. Group-III metals exhibit a similar behavior and the same is true for Si(111) and Ge(111) surfaces when chemisorption is considered.

Transcatheter renal denervation for the treatment of resistant arterial hypertension: the Swiss expert consensus.

Transcatheter (or percutaneous) renal denervation is a novel technique developed for the treatment of resistant hypertension. So far, only one randomised controlled trial has been published, which has shown a reduction of office blood pressure. The Swiss Society of Hypertension, the Swiss Society of Cardiology, The Swiss Society of Angiology and the Swiss Society of Interventional Radiology decided to establish recommendations to practicing physicians and specialists for good clinical practice. The eligibility of patients for transcatheter renal denervation needs (1.) confirmation of truly resistant hypertension, (2.) exclusion of secondary forms of hypertension, (3.) a multidisciplinary decision confirming the eligibility, (4.) facilities that guarantee procedural safety and (5.) a long-term follow-up of the patients, if possible in cooperation with a hypertension specialist. These steps are essential until long-term data on safety and efficacy are available.

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib.

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

How to Reduce Tire-Pavement Noise: Better Practices for Constructing and Texturing Concrete Pavement Surfaces, TPF-5(139), 2012

Concrete pavements can be designed and constructed to be as quiet as any other conventional pavement type in use today. This report provides an overview of how this can be done—and done consistently. In order to construct a quieter concrete pavement, the texture must have certain fundamental characteristics. While innovative equipment and techniques have shown promise for constructing quieter pavements in the future, quieter concrete pavements are routinely built today all across the United States using the following standard nominal concrete pavement textures: drag, longitudinal tining, diamond grinding, and even, to limited extent, transverse tining. This document is intended to serve as a guide that describes better practices for designing, constructing, and texturing quieter concrete pavements.

Very low prevalence of meticillin-resistant Staphylococcus aureus carrying the mecC gene in western Switzerland.

We report the first case of meticillin-resistant Staphylococcus aureus (MRSA) with the mecC gene in a patient in western Switzerland. After this first identification, a polymerase chain reaction protocol was established to investigate the occurrence of this new mecC gene in the population of this region. Enrichment broths were investigated from 1062 patients screened for MRSA, meticillin-susceptible Staphylococcus aureus isolates from clinical specimens from 475 patients, and 80 MRSA isolates (from 2005 to 2011) showing discrepancies between genotypic and phenotypic meticillin resistance. None was positive for mecC, suggesting that it is rare in the patient population of this region.

Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analog of glucagon-like peptide-1.

Glucagon-like peptide-1(7-37) (GLP-1) is the most potent insulinotropic hormone characterized thus far. Because its activity is preserved in non-insulin-dependent diabetes mellitus (NIDDM) patients, it is considered a potential new drug for the treatment of this disease. One limitation in its therapeutic use is a short half-life in vivo (5 minutes), due in part to a fast degradation by the endoprotease dipeptidylpeptidase IV (DPPIV). Recently, it was reported that GLP-1 became resistant to DPPIV when the alanine residue at position 8 was replaced by a glycine (GLP-1-Gly8). We report here that this change slightly decreased the affinity of the peptide for its receptor (IC50, 0.41 +/- 0.14 and 1.39 +/- 0.61 nmol/L for GLP-1 and GLP-1-Gly8, respectively) but did not change the efficiency to stimulate accumulation of intracellular cyclic adenosine monophosphate (cAMP) (EC50, 0.25 +/- 0.05 and 0.36 +/- 0.06 nmol/L for GLP-1 and GLP-1-Gly8, respectively). Second, we demonstrate for the first time that this mutant has an improved insulinotropic activity compared with the wild-type peptide when tested in vivo in an animal model of diabetes. A single injection of 0.1 nmol GLP-1-Gly8 in diabetic mice fed a high-fat diet can correct fasting hyperglycemia and glucose intolerance for several hours, whereas the activity of 1 nmol GLP-1 vanishes a few minutes after injection. These actions were correlated with increased insulin and decreased glucagon levels. Interestingly, normoglycemia was maintained over a period that was longer than the predicted peptide half-life, suggesting a yet undescribed long-term effect of GLP-1-Gly8. GLP-1-Gly8 thus has a markedly improved therapeutic potential compared with GLP-1, since it can be used at much lower doses and with a more flexible schedule of administration.