Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981.

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

Three-dimensional optoacoustic imaging of nailfold capillaries in systemic sclerosis and its potential for disease differentiation using deep learning.

The autoimmune disease systemic sclerosis (SSc) causes microvascular changes that can be easily observed cutaneously at the finger nailfold. Optoacoustic imaging (OAI), a combination of optical and ultrasound imaging, specifically raster-scanning optoacoustic mesoscopy (RSOM), offers a non-invasive high-resolution 3D visualization of capillaries allowing for a better view of microvascular changes and an extraction of volumetric measures. In this study, nailfold capillaries of patients with SSc and healthy controls are imaged and compared with each other for the first time using OAI. The nailfolds of 23 patients with SSc and 19 controls were imaged using RSOM. The acquired images were qualitatively compared to images from state-of-the-art imaging tools for SSc, dermoscopy and high magnification capillaroscopy. The vascular volume in the nailfold capillaries were computed from the RSOM images. The vascular volumes differ significantly between both cohorts (0.216 ± 0.085 mm3 and 0.337 ± 0.110 mm3; p < 0.0005). In addition, an artificial neural network was trained to automatically differentiate nailfold images from both cohorts to further assess whether OAI is sensitive enough to visualize anatomical differences in the capillaries between the two cohorts. Using transfer learning, the model classifies images with an area under the ROC curve of 0.897, and a sensitivity of 0.783 and specificity of 0.895. In conclusion, this study demonstrates the capabilities of RSOM as an imaging tool for SSc and establishes it as a modality that facilitates more in-depth studies into the disease mechanisms and progression.

Flattop laser irradiance profile for stimulation of cutaneous nociceptors.

OBJECTIVE: A nerve stimulator based on a CO2 laser has been developed for use in human pain research. A flattened irradiance profile was generated for safer and more uniform pain stimulation. The pain evoked by the flattened profile was compared to a TEM00 profile. BACKGROUND DATA: The CO2 laser normally operates in TEM00 mode. This is not ideal for thermal stimulation, since the beam will generate a temperature that has a peak in the center of the irradiance profile. This will result in non-uniform activation of nerve fibers. MATERIALS AND METHODS: A lens system has been designed to redistribute the energy of the beam to produce a flattened supergaussian irradiance profile for uniform heating of the skin. The lenses work by refracting the more intense central part of the beam towards the periphery. Psychophysical techniques were used to compare the pain evoked with a flattop irradiance profile and a TEM00 profile. RESULTS: It was found that the supergaussian beam evokes pain at a lower energy level than a TEM00 beam. CONCLUSION: A flattop irradiance profile is a safer source than a gaussian beam for evoking pain in human pain studies.

Time and frequency resolved XeCl laser-induced mechanical transients in otic capsule bone.

OBJECTIVE: This study identifies the presence of photoacoustic waves during excimer laser treatment of porcine otic capsule bone. BACKGROUND DATA: Pulsed ultraviolet lasers have been suggested for use in middle ear surgery due to their potential for fiberoptic delivery, decreased thermal trauma, and precise ablation characteristics. However, the short pulse width of excimer lasers (typically 10-150 ns) can create large thermoelastic stresses in the ablation specimen. MATERIALS AND METHODS: A XeCl (lambda = 308 nm, tau = 12 ns) excimer laser was used to ablate wafers of bone with energies of 90, 35, 13, 5, and 1.8 mJ/pulse. Custom high-frequency polyvinyldifluoride (PVDF) piezoelectric film transducers were fabricated and attached to the slices of bone. During ablation photoacoustic signals were amplified using a low-noise preamplifier and recorded on a digitizing oscilloscope. RESULTS: Photoacoustic waves were clearly identified. Stress wave amplitude increased with laser fluence. CONCLUSION: A laser fluence must be found that compromises between an increased ablation rate and increased stress wave amplitude. The acoustic power levels generated during ablation are below maximum exposure limits.

The effects of XeCl laser etching of Ni-Cr alloy on bond strengths to composite resin: a comparison with sandblasting procedures.

OBJECTIVES: The aim of this study was to determine the effect of laser surface treatment of Ni-Cr alloy on the tensile bond strength of a proprietary composite resin (Panavia 21) in comparison with a conventional sandblasting technique. METHODS: Eighty cylinders of Ni-Cr were randomly allocated into the following groups: Group I-sandblasting only; Group II-low laser fluence (3.0 J/cm(2)); Group III-medium laser fluence (4.0 J/cm(2)); Group IV-high laser fluence (4.9 J/cm(2)); Group V-sandblasting in combination with medium laser fluence (4.0 J/cm(2)). Specimens within groups were bonded into pairs with resin cement as per manufacturer's instructions. They were then de-bonded using a tensile test. RESULTS: The mean de-bond strengths (SD) were: Group I-13.1 (4.2)MPa; Group II-17.6 (5.8)MPa; Group III-25.7 (11.8)MPa; Group IV-22.6 (6.6)MPa; Group V-41.8 (13.2)MPa. A statistically significant improvement (Bonferroni, p<0.05) in bond strength was found for the specimens which had been both lased and sandblasted (Group V) compared to all other groups, including those which were only sandblasted. SIGNIFICANCE: Laser pre-treatment of Ni-Cr alloy increases bond strength to composite resin compared with sandblasting; laser pre-treatment in combination with sandblasting further increases the de-bond strengths.

Qualitative assessment of surface topography of XeCl laser etched Ni-Cr alloy.

OBJECTIVES: The aims of this study were to compare the mode of debonding (adhesive or cohesive) of laser-etched Ni-Cr alloy (Wiron 99) to a standard sandblasting technique, and to a combination of sandblasting and laser etching. The etched surfaces were examined using optical and electron microscopy techniques. METHODS: Five groups of randomly allocated Ni-Cr cylinders were prepared: Group I-sandblasted; Groups II-IV-laser etched at three fluences (3.0, 4.0 and 4.9 J/cm2), Group V-combination sandblasting and laser etching (4.0 J/cm2). Within groups specimens were bonded into pairs (N=8) with composite luting cement (Panavia 21) prior to tensile debonding. Optical and scanning electron microscopy were performed both prior to and following debonding. RESULTS: An oxide layer was observed on sample surfaces before surface preparation by lasing or abrasion. Sandblasting removed the oxidation layer, which low and medium laser fluences alone failed to fully ablate. The highest (4.9 J/cm2) laser fluence melted the surface of the Ni-Cr alloy, covering the oxidation layer. A combination of sandblasting and lasing at 4.0 J/cm2 allowed full removal of the surface oxidation layer due to abrasion, followed by roughening of the surface with the laser. This resulted in greater mean tensile debonding strengths [Murray, A, Attrill, D, Dickinson, M. Dent Mater, 2004, In press] and a tendency for cohesive rather than adhesive interface failures. Groups I-IV underwent partial adhesive failure at both surfaces. Group V, in the main, underwent cohesive failure with a layer of adhesive remaining on both surfaces. SIGNIFICANCE: Laser etching of Ni-Cr alloy in combination with sandblasting optimises bonding to composite luting agents, resulting in a high proportion of cohesive failures when compared to sandblasting or lasing alone.

Effect of target biological tissue and choice of light source on penetration depth and resolution in optical coherence tomography.

The effectiveness of an optical coherence tomography (OCT) system depends largely on the light source chosen. Published data on the optical properties of tissues are used to quantify the exponential attenuation of broadband light on transport through tissue. The effective attenuation coefficient is taken to be the sum of the absorption and scattering coefficients. This is used to demonstrate the effect on the spectra of a wide range of published OCT sources and the change in system resolution induced, and hence to comment on the suitability of different sources for OCT. The tissues studied include skin dermis, liver, and gallbladder. Sources at higher wavelengths are shown to be capable of high-resolution OCT imaging at greater depths. Titanium:sapphire lasers would be most suited for high-resolution OCT over comparatively shallow depths into tissue. For lower-resolution applications of OCT, a semiconductor optical amplifier and ytterbium fiber sources have better powers and bandwidths than superluminescent diodes. The resolution of OCT systems is not reduced significantly with imaging depth.

High-speed photography of plasma during excimer laser-tissue interaction.

During high fluence laser-tissue interaction, ablation of tissue occurs, debris is removed from the ablation site and is then ejected at high velocity. This debris may be observed as a combination of luminous plasma and non-luminous plume, both of which have the potential to shield the ablation site. This study examined the role of ablation debris in shielding the tissue and determined its effects on the ablation rate over a range of laser pulse energies, pulse repetition rates and pulse numbers for dentine; the velocity differences between hard and soft tissues were also examined. High-speed photography was carried out at up to 1 x 10(8) frames per second. A maximum velocity of 2.58 +/- 0.52 x 10(4) m s(-1) was recorded for dentine debris within the first 10 ns following ejection. The maximum duration of tissue shielding due to a single pulse, determined by attenuation of a probe beam, was found to be approximately 7 ms, approximately 80 micros of which was due to luminous plasma and the remainder due to the non-luminous plume.

Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD.

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

Pushing, pulling and twisting liquid crystal systems: exploring new directions with laser manipulation.

Optical tweezers are exciting tools with which to explore liquid crystal (LC) systems; the motion of particles held in laser traps through LCs is perhaps the only approach that allows a low Ericksen number regime to be accessed. This offers a new method of studying the microrheology associated with micrometre-sized particles suspended in LC media--and such hybrid systems are of increasing importance as novel soft-matter systems. This paper describes the microrheology experiments that are possible in nematic materials and discusses the sometimes unexpected results that ensue. It also presents observations made in the inverse system; micrometre-sized droplets of LC suspended in an isotropic medium.

Tissue ablation-rate measurements with a long-pulsed, fibre-deliverable 308 nm excimer laser.

This ablation rate study has been carried out with a fibre-deliverable, 308 nm, XeCl laser, producing long pulses of 200 ns as opposed to the usual 10-20 ns. This in-depth study aimed to evaluate the ablation rates for this longer pulse length. The effects on the ablation depth of dentine, enamel, soft tissue and bone were investigated ex vivo. Radiant exposure, number of pulses, pulse repetition rate and spot size were independently varied. For all tissues, ablation depth per pulse was found to increase, initially, linearly with radiant exposure. For both dentine and soft tissue a saturation radiant exposure was determined; thereafter the ablation rate decreased. The depth per pulse increased linearly with repetition rate but decreased logarithmically with both number of pulses and spot size. The ablation depth due to a 200 ns pulse is comparable to that caused by a 10-20 ns pulse but has the advantage of fibre delivery.

Lateralisation of nociceptive processing in the human brain: a functional magnetic resonance imaging study.

Nociceptive processing within the human brain takes place within two distinct and parallel systems: the lateral and medial pain systems. Current knowledge indicates that the lateral system is involved in processing the sensory-discriminative aspects of pain, and that the medial system is involved in processing the affective-motivational aspects of pain. Hemispheric differences in brain activation (lateralisation) during nociceptive processing were studied to further clarify the division of function between the lateral and medial pain systems. Hemispheric lateralisation was studied by applying painful CO(2) laser stimuli of 3-s duration sequentially to the left and right medial lower calves of five normal right-handed human subjects. The resultant brain activity was measured using 3-T functional magnetic resonance imaging, by determining significant changes in blood oxygen level dependent (BOLD) signal and applying a general linear modelling approach. Volumes of interest were defined for the primary and secondary somatosensory cortices (SI and SII), the insular cortex, and the thalamus, on individual subjects' high-resolution structural scans. Hemispheric lateralisation was quantified by comparing the level of activation between brain hemispheres within each volume of interest. In SII, no significant hemispheric difference in activation was detected. In the insula, activation was significantly greater in the left hemisphere than the right. In both SI and the thalamus, activation in response to painful stimulation was significantly greater in the hemisphere contralateral to the stimulus, which is consistent with these areas being involved in processing the sensory-discriminative aspects of pain.