The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo.

HT61 is a small quinolone-derived compound previously demonstrated to exhibit bactericidal activity against gram-positive bacteria including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). When combined with the classical antibiotics and antiseptics neomycin, gentamicin, mupirocin and chlorhexidine, HT61 demonstrated synergistic bactericidal activity against both MSSA and MRSA infections in vitro. In this study, we investigated the individual antimicrobial activity of HT61 alongside its capability to potentiate the efficacy of tobramycin against both a tobramycin sensitive laboratory reference strain (PAO1) and tobramycin resistant clinical isolates (RP73, NN2) of the gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa). Using broth microdilution methods, the MICs of HT61 were assessed against all strains, as well as the effect of HT61 in combination with tobramycin using both the chequerboard method and bacterial time-kill assays. A murine model of pulmonary infection was also used to evaluate the combination therapy of tobramycin and HT61 in vivo. In these studies, we demonstrated significant synergism between HT61 and tobramycin against the tobramycin resistant P. aeruginosa strains RP73 and NN2, whilst an additive/intermediate effect was observed for P. aeruginosa strain PA01 which was further confirmed using bacterial time kill analysis. In addition, the enhancement of tobramycin by HT61 was also evident in in vitro assays of biofilm eradication. Finally, in vivo studies revealed analogous effects to those observed in vitro with HT61 significantly reducing bacterial load when administered in combination with tobramycin against each of the three P. aeruginosa strains at the highest tested dose (10 mg/kg).

Frequency modulated hybrid photonic crystal laser by thermal tuning.

We demonstrate frequency modulation (FM) in an external cavity (EC) III-V/silicon laser, comprising a reflective semiconductor optical amplifier (RSOA) and a silicon nitride (SiN) waveguide vertically coupled to a 2D silicon photonic crystal (PhC) cavity. The PhC cavity acts as a tunable narrowband reflector giving wavelength selectivity. The FM was achieved by thermo-optical modulation of the reflector via a p-n junction. Single-mode operation was ensured by the short cavity length, overlapping only one longitudinal laser mode with the reflector. We investigate the effect of reflector modulation theoretically and experimentally and predict a substantial tracking of the resonator by the laser frequency with very small intensity modulation (IM).

Experimental electric field visualisation of multi-mode dynamics in a short cavity swept laser designed for OCT applications.

An experimental study into the modal dynamics of a short cavity, fast frequency-swept laser is presented. This commercially available external cavity swept source is designed for use in optical coherence tomography (OCT) applications and displays a number of dynamic lasing regimes during the course of the wavelength sweep. Interferometric full electric field reconstruction is employed, allowing for measurement of the laser operation in a time-resolved, single-shot manner. Recovery of both the phase and intensity of the laser output across the entire sweep enables direct visualization of the laser instantaneous optical spectrum. The electric field reconstruction technique reveals the presence of multi-mode dynamics, including coherent mode-locked pulses. During the main part of the imaging sweep, the laser is found to operate in a second harmonic sliding frequency mode-locking regime. Examination of the modal evolution of this coherent regime reveals evidence of previously unobserved frequency switching dynamics.

Direct experimental measurement of single-mode and mode-hopping dynamics in frequency swept lasers.

A time-resolved study is presented of the single-mode and mode-switching dynamics observed in swept source vertical cavity surfing emitting lasers and swept wavelength short external cavity lasers. A self-delayed interferometric technique is used to experimentally measure the phase and intensity of these frequency swept lasers, allowing direct examination of the modal dynamics. Visualisation of the instantaneous optical spectrum reveals mode-hop free single mode lasing in the case of the vertical cavity laser, with a tuning rate of 6.3 GHz/ns. More complex mode-switching behaviour occurs in the external cavity laser, with the mode-hopping dynamics found to be dominated by the deterministic movement of the spectral filter. Evidence of transient multi-mode operation and mode-pulling is also presented.

Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is mediated via the P2Y1 and P2Y14 receptors in mice.

Platelet activation occurs during host defence and in various inflammatory disorders. In animal models of infection and inflammation, experimental depletion of platelets leads to significantly reduced leukocyte recruitment and impaired clearance of pathogens from the lung. It is now appreciated that purinergic receptor activation is required for leukocyte activation, motility and adhesion, and platelet interactions with leukocytes can be modulated by purinergic stimulation of platelets. Here, we have investigated the role of platelet P2Y1, P2Y12, P2Y14, and P2X1 receptors on leukocyte recruitment and chemotaxis. Mice were administered either vehicle controls or selective P2Y1, P2Y12, P2Y14, or P2X1 antagonists intravenously before intranasal administration of lipopolysaccharide (LPS) to investigate the effect of these drugs on pulmonary leukocyte recruitment, peripheral platelet counts, bleeding times, and ex vivo platelet aggregation. Separately, platelets were incubated with P2Y1, P2Y12, P2X1 antagonists, or P2Y14 agonists to assess effects on platelet-induced neutrophil chemotaxis in vitro. Pulmonary neutrophil recruitment induced by intranasal LPS administration was inhibited in mice administered either with P2Y1 or P2Y14 antagonists, but not with P2Y12 or P2X1 antagonists. Furthermore, the administration of either a P2Y1 or a P2Y14 antagonist reversed the incidence of peripheral thrombocytopaenia associated with LPS exposure. Bleeding times were significantly increased in mice administered P2Y1, P2Y12, or P2X1 antagonists, whilst ex vivo platelet aggregation to ADP was significantly reduced. These haemostatic responses remained unaltered following antagonism of P2Y14. In vitro chemotaxis assays revealed direct antagonism of platelet P2Y1, but not P2Y12 or P2X1 receptors suppressed platelet-dependent neutrophil motility towards Macrophage derived chemokine (MDC, CCL22). Furthermore, the stimulation of platelets with selective P2Y14 agonists (UDP-glucose, MRS2690) resulted in significant platelet-dependent neutrophil chemotaxis. These results reveal a role for P2Y1 and P2Y14 activation of platelets following exposure to LPS, whilst haemostatic indices were unaffected by inhibition of platelet function with the P2Y14 antagonist in response to LPS.

Single shot, time-resolved measurement of the coherence properties of OCT swept source lasers.

A novel, time-resolved interferometric technique is presented that allows the reconstruction of the complex electric field output of a swept source laser in a single-shot measurement. The power of the technique is demonstrated by examining a short cavity swept source designed for optical coherence tomography (OCT) applications with a spectral width of over 100 nm. The novel analysis allows a time-resolved real-time characterization of the roll-off, optical spectrum, linewidth, and coherence properties of a dynamic, rapidly swept laser source.

Dynamics of a short cavity swept source OCT laser.

We investigate the behaviour of a short cavity swept source laser with an intra cavity swept filter both experimentally and theoretically. We characterise the behaviour of the device with real-time intensity measurements using a fast digital oscilloscope, showing several distinct regimes, most notably regions of mode-hopping, frequency sliding mode-locking and chaos. A delay differential equation model is proposed that shows close agreement with the experimental results. The model is also used to determine important quantities such as the minimum and maximum sweep speeds for the mode-locking regime. It is also shown that by varying the filter width the maximum sweep speed can be increased but at a cost of increasing the instantaneous linewidth. The consequent impacts on optical coherence tomography applications are analysed.

Dynamics of Fourier domain mode-locked lasers.

An analysis of the dynamical features in the output of a Fourier Domain Mode Locked laser is presented. An experimental study of the wavelength sweep-direction asymmetry in the output of such devices is undertaken. A mathematical model based on a set of delay differential equations is developed and shown to agree well with experiment.

Dynamics of living polymers.

We study theoretically the dynamics of living polymers which can add and subtract monomer units at their live chain ends. The classic example is ionic living polymerization. In equilibrium, a delicate balance is maintained in which each initiated chain has a very small negative average growth rate ("velocity") just sufficient to negate the effect of growth rate fluctuations. This leads to an exponential molecular weight distribution (MWD) with mean N. After a small perturbation of relative amplitude epsilon, e.g. a small temperature jump, this balance is destroyed: the velocity acquires a boost greatly exceeding its tiny equilibrium value. For epsilon > epsilonc approximately equal to 1/N(1/2) the response has 3 stages: (1) Coherent chain growth or shrinkage, leaving a highly non-linear hole or peak in the MWD at small chain lengths. During this episode, lasting time tau(fast) approximately N, the MWD's first moment and monomer concentration m relax very close to equilibrium. (2) Hole-filling (or peak decay) after tau(fill) approximately epsilon2N2. The absence or surfeit of small chains is erased. (3) Global MWD shape relaxation after tau(slow) approximately N2. By this time second and higher MWD moments have relaxed. During episodes (2) and (3) the fast variables (N, m) are enslaved to the slowly varying number of free initiators (chains of zero length). Thus fast variables are quasi-statically fine-tuned to equilibrium. The outstanding feature of these dynamics is their ultrasensitivity: despite the perturbation's linearity, the response is non-linear until the late episode (3). For very small perturbations, epsilon < epsilonc, response remains non-linear but with a less dramatic peak or hole during episode (1). Our predictions are in agreement with viscosity measurements on the most widely studied system, alpha-methylstyrene.

Irreversible adsorption from dilute polymer solutions.

We study irreversible polymer adsorption from dilute solutions theoretically. Universal features of the resultant non-equilibrium layers are predicted. Two broad cases are considered, distinguished by the magnitude of the local monomer-surface sticking rate Q: chemisorption (very small Q) and physisorption (large Q). Early stages of layer formation entail single-chain adsorption. While single-chain physisorption times tau ads are typically micro- to milli-seconds, for chemisorbing chains of N units we find experimentally accessible times tau ads=Q(-1)N(3/5), ranging from seconds to hours. We establish 3 chemisorption universality classes, determined by a critical contact exponent: zipping, accelerated zipping and homogeneous collapse. For dilute solutions, the mechanism is accelerated zipping: zipping propagates outwards from the first attachment, accelerated by occasional formation of large loops which nucleate further zipping. This leads to a transient distribution omega(s) approximately s(-7/5) of loop lengths s up to a maximum size smax approximately (Qt)(5/3) after time t. By times of order tau ads the entire chain is adsorbed. The outcome of the single-chain adsorption episode is a monolayer of fully collapsed chains. Having only a few vacant sites to adsorb onto, late-arriving chains form a diffuse outer layer. In a simple picture we find for both chemisorption and physisorption a final loop distribution Omega(s) approximately s(-11/5) and density profile c(z) approximately z(-4/3) whose forms are the same as for equilibrium layers. In contrast to equilibrium layers, however, the statistical properties of a given chain depend on its adsorption time; the outer layer contains many classes of chain, each characterized by a different fraction of adsorbed monomers f. Consistent with strong physisorption experiments, we find the f values follow a distribution P(f) approximately f(-4/5).

Interfacial reactions: mixed order kinetics and segregation effects

We study A-B reaction kinetics at a fixed interface separating A and B bulks. Initially, the number of reactions R(t) approximately tn(infinity)(A)n(infinity)(B) is second order in the far-field densities n(infinity)(A), n(infinity)(B). First order kinetics, governed by diffusion from the dilute bulk, onset at long times: R(t) approximately x(t)n(infinity)(A), where x(t) approximately t(1/z) is the rms molecular displacement. Below a critical dimension, d0) leads to anomalous decay of interfacial densities. Numerical simulations for z = 2 support the theory.

Coronary angioplasty in New Zealand 1995-1998: a report from the National Coronary Angioplasty Registry.

AIMS: To report coronary angioplasty data collected by the New Zealand Coronary Angioplasty Registry from 1995-1998. METHOD: Information on all patients undergoing attempted coronary angioplasty in eight New Zealand institutions was recorded on datasheets at the time of, or soon after, the procedure. These were forwarded to the registry at Green Lane Hospital. RESULTS: Over the four-year period, 8395 angioplasty procedures were performed by 26 cardiologists in eight coronary interventional facilities, with a procedural success rate of 94%. Procedural numbers grew steadily, with 55% more coronary angioplasties performed in 1998 than in 1995 (p = 0.02). The New Zealand national angioplasty rate, which rose from 459/million population in 1995 to 684/million in 1998, remains lower than that of Australia and Western European countries. Excluding those that underwent angioplasty for acute myocardial infarction, the number of peri-procedural deaths was similar, with six in 1995 and four in 1998 (p = 0.30), and the requirement for emergency bypass surgery fell from 22 cases in 1995 to three in 1998 (p < 0.001). The use of stents increased dramatically, with 85% of patients receiving a stent in 1998, compared with 23% in 1995 (370% increase, p < 0.001). This was associated with a reduction in the number of patients requiring repeat percutaneous interventions for restenosis (10.7% in 1995 to 6.4% in 1998, p < 0.001). CONCLUSION: There has been a steady growth in the numbers of patients with coronary artery disease treated by coronary angioplasty, and in the number treated by intracoronary stents from 1995 to 1998. The need for urgent coronary bypass surgery has fallen. Continued submission of complete and accurate data to the coronary angioplasty registry is vital for ongoing audit.

Preliminary experience with the V-flex plus coronary stent: immediate and one-month clinical outcome.

Procedural and 1-month outcome data following implantation of the V-Flex Plus stent in our first 54 consecutive patients (35 male; mean age, 62 years) are described. Sixty-four stents were implanted for 60 mainly complex lesions; 48% were left anterior descending; 20%, circumflex; 27%, right coronary artery; and 5%, saphenous vein graft. The Indication for stenting was elective in half of the patients and for a suboptimal result or as a bailout procedure in the other half. The stents were deployed at a mean of 12 atm (range, 6-18) and postdilatated to a mean of 15 atm (range, 8-20). Pre- and postdilatation balloon sizes were 2.96 +/- 0.57 mm and 3.16 +/- 0.34 mm, respectively. The procedural success rate was 98%. There were no deaths or Q-wave myocardial infarctions. One patient suffered a non-Q-wave myocardial infarction and another developed a femoral false aneurysm. At 1-month follow-up, there were no additional events, in particular no revascularization procedures. Eighty-nine percent of patients were free of angina. Implantation of the V-Flex Plus stent is safe and effective with an excellent early success rate comparable to that of published randomized trials and registries of carefully selected patients.

Introduction of the Multilink stent into routine angioplasty practice: early angiographic and clinical outcome.

To assess the early outcome of implantation of the Multilink stent in everyday angioplasty practice, we prospectively collected procedural and 1-mo follow-up data on the first 126 patients (93 male, mean age 61+/-9 yr) in 3 centers. One hundred and seventy-four stents were implanted for 134 lesions: left anterior descending artery in 46%, circumflex in 20%, right coronary artery in 31%, and protected left main in 3%. The indication was elective in 56%, a suboptimal result in 43%, and bailout in 1%. Stents were deployed at 10.8+/-1.9 atmospheres and postdilated to 15.7+/-2.4 atmospheres. There were 115 patients who received ticlopidine and aspirin, 10 received aspirin alone, and 1 received warfarin and aspirin following the procedure. The reference diameter increased from 3.02+/-0.44 mm pre- to 3.13+/-0.43 mm postprocedure, with the minimal luminal diameter increasing from 0.82+/-0.47 to 2.86+/-0.45 mm (diameter stenosis 73% pre- and 9% postprocedure). The procedural success rate was 93.7%. There were no deaths, 1 (0.8%) Q- and 5 (4.0%) non-Q-wave myocardial infarctions, 3 (2.4%) emergency bypass operations, and 1 (0.8%) repeat angioplasty during the hospital admission (median stay, 1 day). There were 2 (1.6%) cases of subacute stent thrombosis. At 1-mo follow-up there were no additional events, with 88% of patients remaining free of angina. Implantation of the Multilink stent is safe and effective in everyday angioplasty practice, with a complication rate comparable to those of published trials of carefully selected patients.