Writing waveguides inside monolithic crystalline silicon with nanosecond laser pulses.

Direct three-dimensional (3D) laser writing of waveguides is highly advanced in a wide range of bandgap materials, but has no equivalent in silicon so far. We show that nanosecond laser single-pass irradiation is capable of producing channel micro-modifications deep into crystalline silicon. With an appropriate shot overlap, a relative change of the refractive index exceeding 10-3 is obtained without apparent nonuniformity at the micrometer scale. Despite the remaining challenge of propagation losses, we show that the created structures form, to the best of our knowledge, the first laser-written waveguides in the bulk of monolithic silicon samples. This paves the way toward the capability of producing 3D architectures for the rapidly growing field of silicon photonics.

Accessing Extreme Spatiotemporal Localization of High-Power Laser Radiation through Transformation Optics and Scalar Wave Equations.

Although tightly focused intense ultrashort laser pulses are used in many applications from nano-processing to warm dense matter physics, their nonparaxial propagation implies the use of numerical simulations with vectorial wave equations or exact Maxwell solvers that have serious limitations and thus have hindered progress in this important field up to now. Here we present an elegant and robust solution that allows one to map the problem on one that can be addressed by simple scalar wave equations. The solution is based on a transformation optics approach and its validity is demonstrated in both the linear and the nonlinear regime. Our solution allows accessing challenging problems of extreme spatiotemporal localization of high power laser radiation that remain almost unexplored theoretically until now.

Quantitative-phase microscopy of nanosecond laser-induced micro-modifications inside silicon.

Laser-induced permanent modification inside silicon has been recently demonstrated by using tightly focused nanosecond sources at a 1550 nm wavelength. We have developed a quantitative-phase microscope operating in the near-infrared domain to characterize the laser-induced modifications deep into silicon. By varying the number of applied laser pulses and the energy, we observe porous and densified regions in the focal region. The observed changes are associated with refractive index variations |Δn| exceeding 10-3, enough to envision the laser writing of optical functionalities inside silicon.

ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation.

Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFß-Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7-expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas.

Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase.

The first successful preparation of mono- and disubstituted 3,7-dihydroxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the resultant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobromo- and dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophosphatase with IC50 values in the low-micromolar range. The results are discussed in the context of the recently described novel mode of inhibition of the enzyme by 3,7-dihydroxytropolones.

Selective mechanism-based inactivation of peptidylglycine alpha-hydroxylating monooxygenase in serum and heart atrium vs. brain.

Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyses the rate-limiting step in the post-translational activation of substance P, among other neuropeptides, from its glycine-extended precursor. Comparative kinetic studies were performed, using trans-styrylacetic acid or trans-styrylthioacetic acid as known mechanism-based inhibitors, of PHM isolated from rat, horse or human blood serum. Distinctive species differences with respect to PHM inactivation were observed: the efficiency of inactivation decreased in the order of horse >> rat > human. Trans-styrylacetic acid was more active than its thioether derivative. Moreover, we studied the differential sensitivity towards mechanism-based inactivation, of soluble PHM from rat blood serum and rat brain by trans-styrylacetic acid or benzylhydrazine, as well as the membrane-associated enzymes from rat brain and heart atrium. For the heart atrium membrane PHM or the soluble PHM from blood serum, inactivation rate constants k(inact)/K(I) of approximately 100 M(-1)sec(-1) were found with trans-styrylacetic acid. However, neither of the two tested compounds, at 100 microM or 12 mM, respectively, could inactivate the soluble or membranous PHMs from rat brain during a 15-min pre-incubation period. Instead, under conditions of reversible inhibition, trans-styrylacetic acid competitively inhibited the soluble or membrane-associated brain PHM with inhibition constants K(I) = 0.6 microM and 1.0 microM, respectively. Organ-selective, time-dependent inactivation of PHM with compounds of the above types might be an important pharmacological tool to control peripheral neuropeptide activation.

Resistance to beta-lactams in Enterobacteriaceae: distribution of phenotypes related to beta-lactamase production.

Phenotypes of susceptibility to amoxycillin (Amo), ticarcillin (Tic), cephalothin (Ctn) were determined in 1366 isolates of Enterobacteriaceae by disk method and beta-lactamases were identified in 243 strains belonging to different phenotypes of amoxycillin-resistant strains. AmoR TicR CtnS strains (25%) were penicillinase producers and all of them were susceptible to the combination amoxycillin/clavulanic acid (Amo/CA) and ticarcillin/clavulanic acid (Tic/CA). Amo1/R TicS CtnR strains (12%) were cephalosporinase producers and resistance to Amo/CA was observed, except for Proteus vulgaris. AmoR TicR CtnR strains (18%) often produced two beta-lactamases (penicillinase and cephalosporinase) and they were resistant to Amo/CA; in this group, susceptibility to Tic/CA depends on the nature and the amount of the beta-lactamase produced, except for Serratia marcescens for which antibiotic resistance is probably due to other mechanisms. Tic/CA resistance was mainly found in Serratia marcescens (41%) and Enterobacter cloacae (36%).

[In vitro comparative study of piperacillin-aminoglycosides combinations against Enterococci and Enterobacteriaceae]. / Etude comparative in vitro d'associations pipéracilline-aminosides face aux entérocoques et aux entérobactéries.

The hundred and ninety-two combinations were tested against 17 strains chosen from the results of MIC determination (disc method): 5 enterococci exhibiting low level resistance (r) or high level resistance (R) to streptomycin (S) and gentamicin (G): 2 strains Sr Gr, 2 strains SR Gr and 1 strain Sr GR; 12 enterobacteria chosen for their resistance phenotypes to beta-lactams and aminoglycosides and because they are the most frequent clinical isolates: 2 strains Amos Tics Ctns (group 1), 4 strains AmoR Tics CtnR (gr. II), 4 strains AmoR TicR Ctns (gr. III) and 2 strains AmoR TicR CtnR (gr. IV). MIC and MBC were assessed for the 17 strains (Mueller Hinton broth). Combinations were carried out by a checkerboard micromethod. FBC index was calculated for each combination. Against enterococci the 50 combinations were: piperacillin versus ampicillin + aminoglycosides (streptomycin, tobramycin, amikacin, gentamicin, netilmicin). Against enterobacteria piperacillin was combined with different aminoglycosides depending on their resistance phenotypes. These combinations were compared with ticarcillin or mezlocillin or cefotaxime + aminoglycosides (total number 142). The species studied produced different results: with the enterococci Gr synergistic effects (FBC = 0.62-0.75) were rare; additive and indifferent effects were predominant. With the GR strain some antagonistic effects were observed. With the enterobacteria, in groups I and II synergistic effects were frequent and almost equivalent regardless of the beta-lactam chosen. In groups III and IV (TicR) piperacillin MICs were greater than or equal to 128 mg/l and mezlocillin MICs greater than 512 mg/l; the synergistic effects were significant (FBC from 0.25 to 0.62). beta-lactam + amikacin or netilmicin, and especially piperacillin + amikacin, were found to have the most frequent synergistic effects upon the strains tested. Mezlocillin combinations cannot be used clinically; the use of piperacillin combinations requires further discussion. On the other hand, cefotaxime + aminoglycosides combinations are active against those TicR strains.

[In vitro effect of piperacillin on aerobic bacteria. Variations according to the phenotypes of resistance to beta-lactam antibiotics]. / Activité in vitro de la pipéracilline sur les bactéries aérobies. Variations selon les phénotypes de résistance aux bêta-lactamines.

In a first study the MICs of piperacillin (PIP), mezlocillin (MEZ), azlocillin (AZL), carbenicillin (CARB) and ticarcillin (TIC) against 563 strains of aerobic bacteria were compared. The MIC50 of PIP against E. coli and P. mirabilis was 0.5 to 1 mg/l, that is equal to those of MEZ and TIC but 2 or 3 times lower than those of AZL and CAR. The MIC50 of PIP and MEZ against Klebsiella, a species that is naturally resistant to TIC and CAR, was 4 mg/l. Enterobacter, Serratia and Citrobacter showed two populations of strains: the first was sensitive to the five penicillins tested (MIC50 of PIP: 1 to 2 mg/l); the second was resistant to all of them. PIP and AZL were more active (MIC50 8 mg/l) against Ps. aeruginosa than MEZ, TIC and CAR. All five penicillins had limited activity against Acinetobacter (MIC50 less than 16 mg/l). PIP, MEZ and AZL were more active than TIC and CAR against enterococci. In a second study, the activity of PIP was evaluated by standard sensitivity tests on 4993 strains of enterobacteria, Ps. aeruginosa and Acinetobacter classified according to their phenotype of resistance to beta-lactam antibiotics. PIP was regularly active against enterobacteria and Ps. aeruginosa strains devoid of acquired resistance. The activity of PIP was significantly reduced against enterobacteria strains with a phenotype suggesting induced penicillinase production. However, the inhibition zone diameters, although reduced, remained within what is now considered the sensitivity range (notably with E. coli and Proteus spp), which raises the problem of in vitro tests interpretation. PIP was active against E. coli strains with a "cephalosporinase" phenotype, but inactive against cefotaxime resistant strains of: Enterobacter, Citrobacter and Serratia. The activity of PIP on CAR-resistant Ps. aeruginosa strains was significantly reduced, but the inhibition zone diameter in one quarter of them was still within limits of sensitivity.

Kinetic studies with myo-inositol monophosphatase from bovine brain.

The kinetic properties of myo-inositol monophosphatase with different substrates were examined with respect to inhibition by fluoride, activation or inhibition by metal ions, pH profiles, and solvent isotope effects. F- is a competitive inhibitor versus 2'-AMP and glycerol 2-phosphate, but noncompetitive (Kis = Kii) versus DL-inositol 1-phosphate, all with Ki values of approximately 45 microM. Activation by Mg2+ follows sigmoid kinetics with Hill constants around 1.9, and random binding of substrate and metal ion. At high concentrations, Mg2+ acts as an uncompetitive inhibitor (Ki = 4.0 mM with DL-inositol 1-phosphate at pH 8.0 and 37 degrees C). Activation and inhibition constants, and consequently the optimal concentration of Mg2+, vary considerably with substrate structure and pH. Uncompetitive inhibition by Li+ and Mg2+ is mutually exclusive, suggesting a common binding site. Lithium binding decreases at low pH with a pK value of 6.4, and at high pH with a pK of 8.9, whereas magnesium inhibition depends on deprotonation with a pK of 8.3. The pH dependence of V suggests that two groups with pK values around 6.5 have to be deprotonated for catalysis. Solvent isotope effects on V and V/Km are greater than 2 and 1, respectively, regardless of the substrate, and proton inventories are linear. These results are consistent with a model where low concentrations of Mg2+ activate the enzyme by stabilizing the pentacoordinate phosphate intermediate. Li+ as well as Mg2+ at inhibiting concentrations bind to an additional site in the enzyme-substrate complex. Hydrolysis of the phosphate ester is rate limiting and facilitated by acid-base catalysis.

Purification and properties of myo-inositol-1-phosphatase from bovine brain.

myo-Inositol-1-phosphatase from bovine brain was purified over 2000-fold. The native enzyme has a Mr of 59,000, and on SDS/polyacrylamide-gel electrophoresis the subunit Mr was 31,000. Thus the native enzyme is a dimer of two apparently identical subunits. The enzyme, purified to a specific activity of more than 300 units/mg of protein (1 unit of enzyme activity corresponds to the release of 1 mumol of Pi/h at 37 degrees C), catalysed the hydrolysis of a variety of phosphorylated compounds, the best one, in terms of V/Km, being D-myo-inositol 1-phosphate. Kinetic constants of compounds tested, including both isomers of glycerophosphate and two deoxy forms of beta-glycerophosphate, were measured. They show the importance of the two hydroxyl groups which are adjacent to the phosphate in myo-inositol 1-phosphate. With a wide variety of substrates Li+ was found to be an uncompetitive inhibitor whose Ki varied with substrate structure.

The in-vitro activity of cefodizime: a review.

For Enterobacteriaceae, MIC50s and MIC90s of cefodizime (mg/l), respectively, were as follows, for naturally non-beta-lactamase-producing species: Escherichia coli 0.12 and 0.5, Salmonella spp. and Shigella spp. 0.25 and 0.5, Proteus mirabilis 0.016 and 0.03; for chromosomal penicillinase-producing species. Klebsiella spp. 0.25 and 64, and for chromosomal cephalosporinase-producing species. Enterobacter cloacae 1 and 64, Citrobacter freundii 1 and 128, Serratia marcescens 2 and 8: indole-positive Proteus spp. 0.06 and 0.5; and Providencia stuartii 0.5 and 1. The activity of cefodizime was not modified by plasmid-mediated penicillinase-producing strains but cefodizime was inactive against cephalosporinase hyper-producing strains and against expanded broad-spectrum beta-lactamase-producing strains. Cefodizime was noticeably less active against Pseudomonas aeruginosa and Acinetobacter baumannii with MICs ranging from 32 to more than 128 mg/l. Haemophilus spp. and Neisseria gonorrhoeae, regardless of beta-lactamase producing status, as well as N. meningitidis, were highly susceptible (MIC50s and MIC90s less than or equal to 0.008 mg/l). Cefodizime was moderately active against methicillin-susceptible staphylococci (MIC50 and MIC90 8 mg/l) but failed to inhibit methicillin-resistant strains. Enterococci were generally resistant: Streptococcus pyogenes and Str. pneumoniae were inhibited by low concentrations (MIC50 and MIC90 0.12 and 0.5 mg/l). A fairly wide range of MICs was found for anaerobes, with lower values for Clostridium perfringens (MIC50 and MIC90 0.5 and 1 mg/l) than for Bacteroides fragilis (8- greater than 128 mg/l). These results show that cefodizime has similar properties to other third generation cephalosporins and suggest that cefodizime would find a role in the management of hospital infections.

DNA unwinding enzyme II of Escherichia coli. 1. Purification and characterization of the ATPase activity.

A DNA-stimulated ATP-gamma-phosphohydrolase of molecular weight 75000 was purified from Escherichia coli cells. The ATPase, a globular molecule (identical probably with an ATPase described previously by Richet and Kohiyama in 1976) shows specificity for adenine nucleotides, it prefers single-stranded DNA as the cofactor, it exhibits a complicated mode of response to variations of the cofacter concentration and it is devoid of nuclease activity. Preparations derived from rep3 mutant cells yield widely varying amounts of an apparently normal ATPase.

[Comparative bactericidal activity of beta-lactam-aminoglycoside combinations against Pseudomonas aeruginosa]. / Activité bactéricide comparée des associations bêta-lactamines-aminosides sur Pseudomonas aeruginosa.

The effects of combining each of 10 beta-lactamins (carbenicillin, ticarcillin, piperacillin, azlocillin, cefotaxime, moxalactam, ceftriaxone, cefoperazone, ceftazidime, cefsulodin) with 6 aminoglycosides were studied in vitro against two strains of Pseudomonas aeruginosa. The bactericidal activity was tested by two methods: solid medium technique of "cellophane transfer" and "checkerboard" method (broth-dilution micromethod partly automatic). No single antagonism was observed. Concerning new penicillins, the percentage of synergy is increasing from carbenicillin, to ticarcillin, to azlocillin and finally to piperacillin. For recent cephalosporins, the most synergistic combinations are obtained with ceftriaxone, cefoperazone and ceftazidime. If aminoglycosides associations are considered, there is a good activity whichever antibiotic chosen, with a higher level for streptomycin and lower one for tobramycin. Dibekacin combinations, also tested by the checkerboard method, are particularly synergistic with azlocillin and piperacillin for new penicillins, and equally well with ceftriaxone for recent cephalosporins.

[Qualitative and quantitative analysis of the residual hand flora after hygienic-type washing with a soap and a foaming antiseptic solution]. / Etude qualitative et quantitative de la flore résiduelle des mains après lavage de type "hygiénique" avec un savon et une solution antiseptique moussante.

Activity of a liquid soap and of a 4% povidone iodine detergent solution on hand skin flora after application for one minute ("hygienic type" handwashing) was studied. Samples were taken using a "bag" washing method. Total aerobic flora was determined quantitatively. Transient flora (Gram negative bacilli and mannitol positive Staphylococci) was determined both quantitatively and qualitatively. 54 determinations were performed (29 with liquid soap and 25 with povidone iodine) on 17 volunteers of the staff of the hospital bacteriology laboratory. After application of liquid soap, total flora, i.e. 10(6) bacteria per hand, was not reduced and the number of mannitol positive Staphylococci was increased. With povidone iodine, the reduction in total flora was 0.2-0.3 log 10 and the number of mannitol positive Staphylococci was decreased. With both products, Gram negative bacilli were eliminated in 60% of cases and greatly reduced in the remainder.

[Piperacillin-amikacin combinations: killing curves]. / Associations pipéracilline-amikacine: cinétique de bactéricidie.

Bactericidal activity as a function of time of piperacillin (PIP) and amikacin (AKN) alone and in combination was evaluated by killing curves technique on 23 clinical isolates: E. coli (6), K. pneumoniae (5), E. cloacae (6) and P. aeruginosa (6), for which the minimal inhibitory concentrations ranges of piperacillin were 0.25 to 64 mg/l and of amikacin 1 to 8 mg/l. For each species, the strains were chosen according to the most frequent phenotypes: beta-lactams susceptible, penicillinase (Pase), cephalosporinase (Case) and Pase + Case producers. Killing curves were carried out with the following concentrations (mg/l): piperacillin (2, 16, 64); amikacin (4, 8, 16); piperacillin (2) + amikacin (4); piperacillin (16) + amikacin (8); piperacillin (64) + amikacin (16). Antibiotic concentrations corresponded to pharmacokinetics and/or to critical values of piperacillin and amikacin. Bactericidal activity was defined as a 4 log 10 decrease in CFU/ml between 2 and 24 hours. When piperacillin (64) was combined with amikacin (16), the bactericidal effects were nearly the same as those with amikacin alone. But piperacillin (16) + amikacin (8) combination had bactericidal effect for the majority of strains (21/23) and it prevented for some of them the bacterial regrowth observed with amikacin alone at the same concentration. A bactericidal activity without regrowth (until the 24th hour) was obtained for 9 strains; 2 susceptible E. coli, 3 K. pneumoniae (chromosomal Pase producer) and 4 cefotaxime susceptible E. cloacae, with low dose combination piperacillin (2) + amikacin (4). Finally, only combinations piperacillin (64) + amikacin (16) or piperacillin (16) + amikacin (8) had bactericidal activity on 2 Ticarcillin-resistant P. aeruginosa, the two antibiotics being separatedly bacteriostatic.(ABSTRACT TRUNCATED AT 250 WORDS)

[In vitro effect of ceftriaxone on hospital bacteria. Line of regression and critical values]. / Activité de la ceftriaxone in vitro sur des bactéries hospitalières. Droite de régression et valeurs critiques.

Antimicrobial activity of ceftriaxone, a new third generation cephalosporin, against hospital isolates was investigated. 312 strains belonging to the most commonly recovered species were studied using the following methods: agar diffusion (disk antibiotic testing), agar dilution (determination of MIC) and dilution in a liquid medium with subculture to agar plates (determination of MBC). Except for a few Citrobacter strains and rare Serratia strains, all Enterobacteriaceae tested proved highly susceptible, with MICs less than or equal to 1 mg/l and mode MICs ranging from 0.003 mg/l (Proteus) to 0.25 mg/l (Enterobacter). MICs ranged from 16 to 32 mg/l for Acinetobacter (mode MICs: 16 mg/l) and 16 to greater than or equal to 128 for Pseudomonas (mode MIC greater than or equal to 128 mg/l). Methicillin-susceptible staphylococci were moderately susceptible to ceftriaxone (MIC: 2 to 8 mg/l) whereas methicillin-resistant staphylococci and enterococci were resistant (MIC greater than or equal to 64 mg/l). Bactericidal activity was excellent: MBC/MIC less than or equal to 2 (except for a few Serratia strains). A correlation curve was established. Given the high serum concentrations of ceftriaxone (achieved with the usual maximal dosage) and its unusually extended half-life (7 to 8 h), the following cutoff concentrations can be proposed: C less than or equal to 4 mg/l, corresponding to greater than or equal to 20 mm: susceptible bacteria C greater than 32 mg/l, corresponding to less than 15 mm: resistant bacteria.

[In-vitro activity of cefonicid on hospital bacteria. Regression line and proposal for critical values]. / Activité du céfonicid in vitro sur des bactéries hospitalières. Droite de régression et proposition de valeurs critiques.

Antimicrobial activity of cefonicid, a new second generation cephalosporin, against 315 hospital isolates (4th trimester 1984) was investigated. E. coli and Proteus mirabilis were the most susceptible species. All E. coli strains except one were inhibited at 8 mg/l (modal MIC: 0.5); MICs of all indole + Proteus were 8 mg/l (modal MIC: 0.06). Another group was moderately susceptible: MICs of Klebsiella and Citrobacter ranged from 0.12 to 128 mg/l, but MICs of 50% of these strains were less than or equal to 4 mg/l; MIC was less than or equal to 8 mg/l for 75% of indole + Proteus and Providencia strains; tested Proteus vulgaris were especially resistant (MICs greater than 128 mg/l). Most Enterobacter and Serratia strains showed little susceptibility (modal MIC for both species greater than or equal to 128 mg/l). MICs of all tested Pseudomonas aeruginosa strains were greater than 128 mg/l. 20 of the 24 tested Acinetobacter strains had a MIC of greater than or equal to 128 mg/l. For Staphylococcus aureus, 88% of methicillin-sensitive strains were inhibited by concentrations of 2 to 4 mg/l whereas methicillin-resistant strains were resistant to cefonicid (75%: MIC greater than 64 mg/l). Enterococci were resistant to cefonicid. A correlation curve was established (Enterobacteria and Staphylococci). On the basis of cefonicid's pharmacokinetic characteristics, critical concentrations are proposed.