Biomechanical comparison of standing posture and during trot between German shepherd and Labrador retriever dogs.

It is widely accepted that canine breeds stand and move differently. The prevalence of various musculoskeletal disorders such as hip and elbow dysplasia is also different between breeds. German shepherd dog (GSD) and Labrador retriever dog (LRD) are two large breeds with different conformations that have high prevalence of these disorders. This study quantifies the movement and standing posture of twelve healthy GSDs and twelve healthy LRDs to identify biomechanical similarities and differences that may be linked to sub-optimal hip and elbow mechanics. A pressure walkway and a motion capture system obtained measures of kinetics, kinematics and conformation during standing and trot. During standing, LRDs carry a greater percentage of the weight on the forelimbs (69%±5% vs. GSDs: 62%±2%, p<0.001) and their body Centre of Pressure (CoP) is located more cranially (p<0.001). GSDs had a greater pelvic tilt (79°±8 vs. 66°±9°, p = 0.004), more flexed stifles (44°±9° vs. LRDs: 34°±10°, p<0.05) and hocks (58°±11° vs. 26°±9°, p<0.01) and more extended hips (-10°±11° vs. 30°±12°, p<0.001). During trot, the GSDs' CoP had a longer anterior-posterior trajectory (151%±22% vs. LRDs: 93%±25% of the withers height, p<0.001). Stride parameters and loading of limbs were similar when normalised to the size and weight of the dog, respectively. The LRDs had a more extended thoracolumbar angle (p<0.001) and a less flexed lumbosacral angle (p<0.05). The LRDs' hip remained flexed during trot whereas the GSDs' hip joint was less flexed during swing (p<0.001) and more extended in late stance and early swing (p<0.001). In conclusion, the LRDs and GSDs differ in the way they stand and move and this would result in different loading pattern of the joints. Further investigation is required to determine the extent to which biomechanical differences are linked to musculoskeletal problems presented clinically.

Simulated activities of daily living do not replicate functional upper limb movement or reduce movement variability.

Kinematic assessments of the upper limb during activities of daily living (ADLs) are used as an objective measure of upper limb function. The implementation of ADLs varies between studies; whilst some make use of props and define a functional target, others use simplified tasks to simulate the movements in ADLs. Simulated tasks have been used as an attempt to reduce the large movement variability associated with the upper limb. However, it is not known whether simulated tasks replicate the movements required to complete ADLs or reduce movement variability. The aim of this study is to evaluate the use of simulated tasks in upper limb assessments in comparison to functional movements. Therefore answering the following questions: Do simulated tasks replicate the movements required of the upper limb to perform functional activities? Do simulated tasks reduce intra- and inter-subject movement variability? Fourteen participants were asked to perform five functional tasks (eat, wash, retrieve from shelf, comb and perineal care) using two approaches: a functional and a simulated approach. Joint rotations were measured using an optoelectronic system. Differences in movement and movement variability between functional and simulated tasks were evaluated for the thorax, shoulder, elbow/forearm and wrist rotations. Simulated tasks did not accurately replicate the movements required for ADLs and there were minimal differences in movement variability between the two approaches. The study recommends the use of functional tasks with props for future assessments of the upper limb.

Shoulder Bone Geometry Affects the Active and Passive Axial Rotational Range of the Glenohumeral Joint.

BACKGROUND: The range of motion of the glenohumeral joint varies substantially among individuals and is dependent on humeral position. How variation in shape of the humerus and scapula affects shoulder axial range of motion at various positions has not been established. PURPOSE: To quantify variation in the shape of the glenohumeral joint and investigate whether the scapula and humerus geometries affect the axial rotational range of the glenohumeral joint. STUDY DESIGN: Descriptive laboratory study. METHODS: The range of active and passive internal-external rotation of the glenohumeral joint was quantified for 10 asymptomatic participants with optical motion tracking at 60º, 90º, and 120º humeral elevations in the coronal, scapular, and sagittal planes. Bone geometrical parameters were acquired from shoulder magnetic resonance image scans, and correlations between geometrical parameters and maximum internal and external rotations were investigated. Three-dimensional participant-specific models of the humerus and scapula were used to identify collisions between bones at the end of range. RESULTS: Maximum internal and external rotations of the glenohumeral joint were correlated to geometric parameters and were limited by bony collisions. Generally, the active axial rotational range was greater with increased articular cartilage and glenoid curvature, while a shorter acromion resulted in greater passive range. Greater internal rotation was correlated with a greater glenoid depth and curvature in the scapular plane ( r = 0.76, P < .01, at 60° of elevation), a greater subacromial depth in the coronal plane ( r = 0.74, P < .01, at 90° of elevation), and a greater articular cartilage curvature in the sagittal plane ( r = 0.75, P < .01, at 90° of elevation). At higher humeral elevations, a greater subacromial depth and shorter acromion allowed a greater range of motion. CONCLUSION: The study strongly suggests that specific bony constraints restrict the maximum internal and external rotations achieved in active and passive glenohumeral movement. CLINICAL RELEVANCE: This study identifies bony constraints that limit the range of motion of the glenohumeral joint. This information can be used to predict full range of motion and set patient-specific rehabilitation targets for those recovering from shoulder disorders. It can improve positioning and choice of shoulder implants during preoperative planning by considering points of collision that could limit range of motion.

Assessment of the glenohumeral joint's active and passive axial rotational range.

BACKGROUND: Assessment of the range of axial rotation of the glenohumeral joint will improve understanding of shoulder function, with applications in shoulder rehabilitation and sports medicine. However, there is currently no complete description of motion of the joint. The study aimed to develop a reliable protocol to quantify the internal and external axial rotations of the glenohumeral joint during active and passive motion at multiple humeral positions. METHODS: Optical motion tracking was used to collect kinematic data from 20 healthy subjects. The humerus was positioned at 60°, 90°, and 120° of humerothoracic elevation in the coronal, scapular, and sagittal planes. Internal and external rotations were measured at each position for active and passive motion, where intrasubject standard deviations were used to assess variations in internal-external rotations. RESULTS: The protocol showed intrasubject variability in the axial rotational range of <5° for active and passive rotations at all humeral positions. Maximum internal rotation was shown to be dependent on humeral position, where a reduced range was measured in the sagittal plane (P < .001) and at 120° elevations (P < .001). Conversely, maximum external rotations were not affected by humeral position. CONCLUSION: The results describe normal ranges of internal-external rotation of the glenohumeral joint at multiple humeral positions. The protocol's low variability means that it could be used to test whether shoulder pathologic conditions lead to changes in axial rotational range at specific humeral positions.

Discovery of AZD3199, An Inhaled Ultralong Acting ß2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.

Finite element analysis of thermal and acoustic processes during laser tattoo removal.

BACKGROUND AND OBJECTIVE: Q-switched laser therapy is commonly used for the removal of tattoos. However, despite ever increasing demand for this intervention, a better understanding of the mechanisms that result in pigment reduction is required in order to optimise outcomes and reduce the number of treatment episodes. STUDY DESIGN: A finite element analysis computer simulation was developed to model the fragmentation response of ink granules during irradiation of a professional black tattoo using a Q-switched Nd:YAG laser. Thermal and acoustic mechanisms were considered, allowing the optimal laser settings to be predicted throughout the course of treatment. Changes in the thermal properties of the ink during heating were taken into account to improve the reliability of the results obtained. RESULTS: The simulated results are in close agreement with clinical observations. Thermal fragmentation was shown to be the dominant mechanism in pigment reduction when using a 6 nanoseconds pulse at 1,064 nm. In order to provide maximum clearance whilst maintaining acceptable levels of tissue thermal damage, later treatments were shown to benefit from higher fluence levels than initial treatments. Larger spot diameters were also preferable throughout the course of treatment. CONCLUSIONS: The results from the simulation build upon previous work carried out in the field, applying ink thermal coefficients which vary with temperature for the first time. These results compliment clinical knowledge, suggesting that a proactive increase in fluence during a course of treatments is likely to improve the response to laser therapy.

Determination of the thermal and physical properties of black tattoo ink using compound analysis.

Despite the widespread use of laser therapy in the removal of tattoos, comparatively little is known about its mechanism of action. There is a need for an improved understanding of the composition and thermal properties of the tattoo ink in order that simulations of laser therapy may be better informed and treatment parameters optimised. Scanning electron microscopy and time-of-flight secondary ion mass spectrometry identified that the relative proportions of the constituent compounds of the ink likely to exist in vivo are the following: carbon black pigment (89 %), carvacrol (5 %), eugenol (2 %), hexenol (3 %) and propylene glycol (1 %). Chemical compound property tables identify that changes in phase of these compounds lead to a considerable reduction in the density and thermal conductivity of the ink and an increase in its specific heat as temperature increases. These temperature-dependent values of density, thermal conductivity and specific heat are substantially different to the constant values, derived from water or graphite at a fixed temperature, which have been applied in the simulations of laser therapy as previously described in the literature. Accordingly, the thermal properties of black tattoo ink described in this study provide valuable information that may be used to improve simulations of tattoo laser therapy.

Design-driven LO: the discovery of new ultra long acting dibasic ß2-adrenoceptor agonists.

Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.

Design driven HtL: The discovery and synthesis of new high efficacy ß2-agonists.

The design and synthesis of a new series of high efficacy ß(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ß(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ß(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

The asymmetric Maitland-Japp reaction and its application to the construction of the C1-C19 bis-pyran unit of phorboxazole B.

The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and the C1-C19 bis-pyran unit was formed in an impressive 10.4% yield.

Non-basic ligands for aminergic GPCRs: the discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders.

Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.

A Brønsted acid mediated cascade enone synthesis from aldehydes containing a tethered propargylsilane.

MeSO3H effects the intramolecular allenylation of a series of aldehydes 1 to provide allenyl alcohol product 3 as a single diastereoisomer. Cyclization proceeds rapidly at -78 degrees C. However, when the reaction is performed at room temperature, aldehyde 1 provides enone product 7 instead. A mechanism for the formation of this product is proposed in which the initially formed allenyl alcohol 3 undergoes dehydration to provide an allyl carbocation, which is trapped with water, thereby installing the enone.

8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABA A receptor.

8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.

Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines.

The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.

4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia.

Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.