Mechanistic comparison between spinal and trigeminal neuropathic pain

Chronic neuropathic pain is resistant to classical analgesics and is characterised by allodynia, hyperalgesia and spontaneous pain. Pain associated with damage to the trigeminal nerve may be particularly persistent lasting twice as long as that in the spinal nerves, which possibly reflects differences between trigeminal and spinal mechanisms of synaptic plasticity. Neuropathic sensitisation occurs at the first synapses in the dorsal horn of the spinal cord and in the trigeminal spinal complex. The NMDA glutamate receptor plays a key role in this process. It is known to bind to adapter proteins, such as the membrane-associated guanylate kinases (MAGUKs including PSD-95, SAP-102, SAP-97, and Chapsyn-110), linking the receptor to a complex of signalling, anchoring, docking, and scaffolding proteins. One of these adapter proteins, PSD-95, has previously been shown by this laboratory to be crucial in the development of neuropathic pain in the spinal cord.For this study, we used rodent models of chronic constriction injury of sciatic or trigeminal nerve to investigate the electrophysiological responsiveness of single neurones to mechanical stimuli. This strategy allowed comparison of the degree of sensitisation in the two areas. We also examined changes in expression of NMDA receptor subunits and MAGUK proteins.Our results show a marked facilitation of responsiveness in thermal and mechanical behavioural reflexes in both spinal and trigeminal neuropathic pain models. Electrophysiological experiments indicated an increase in responsiveness of individual neurons to mechanical stimulation in spinal neuropathic animals but this increase was not as pronounced in trigeminal neuropathic animals. Further differences in electrophysiological response characteristics to various peripheral sensory stimuli between spinal and trigeminal neurons were shown in normal animals and following nerve injury. That is, neurons from neuropathic animals show a marked post-stimulus discharge response (PSDR). The length of discharge was an average of 8333 ±1610 action potentials from spinal cord neurons and 46390 ± 16026 action potentials for trigeminal neurons, whilst the mean threshold force for eliciting a PSDR for spinal neurons was 2.1 fold that for trigeminal neurons.Trigeminal neurons were also tested for responses to von Frey filaments both before and after a brief brush or cold stimulus applied to the face, ipsilateral to injury. Using ix this protocol for before and after brush stimulation, 14 neurons from trigeminal neuropathic animals were tested. Of these, 7 neurons showed an increased initial response to low (4g) and high (15g) forces after the brush stimulus compared to that before (4g force: 12.2 spikes per second ± 0.9 before and 24.3 spikes per second ± 2.9 after. 15g force 19.6 spikes per second ± 5.8 before and 26.8 spikes per second ± 7.0 after. Conditioning stimuli experiments were not carried out in spinal cord preparation animals due to time constraints.Biochemical experiments revealed that changes in expression of some NMDA receptor subunits, as well as associated MAGUK proteins, differed between spinal and trigeminal neuropathic animals, and within different regions of the trigeminal complex itself. A reduction in NR1 expression in the spinal cord ipsilateral to CCI compared with the contralateral side a mean reduction of 27%, was shown, whilst no change in NR1 expression was seen in any of the trigeminal regions investigated. Differential injury-induced changes were also seen in NMDA R-interacting proteins. PSD-95 shows no change in expression in regions of the trigeminal complex following CCI, but does increase in expression ipsilateral to nerve injury in the spinal cord, a mean increase of 140% compared to the contralateral side. The rise in NR2B subunit and PSD-95 protein expression at a time concomitant with the development of neuropathic pain behaviours is consistent with previous reports showing the necessity for an intact NR2B-PSD-95 complex for the development of neuropathic behaviours in PSD-95 mutant mice (Garry et al, 2003). Furthermore, Chapsyn-110/PSD-93 which shows no demonstrable change in expression in the spinal cord exhibits a marked 40% decrease in ipsilateral expression in the trigeminal caudalis compared to the contralateral side following CCI.We further investigated the potential role of proteins such as persyn (known to influence cytoskeletal network integrity) and a-synuclein (implicated in cell death), which may particularly influence the development, duration or recovery from neuropathic pain. We investigated the role of persyn and a-synuclein proteins in neuropathic pain, using two null-expression mutant mouse strains. However, no substantial differences were observed between the reflex behavioural responses of these mutant animals and wild type animals following nerve injury.In conclusion, this study provides evidence for mechanistic differences in neuropathic sensitisation between trigeminal and spinal regions. These differences may lead to targets for improved therapeutic treatment of intractable pain states

Lightweight energy absorbing structures for crashworthy design

PhD ThesisThe application of lightweight composite materials into the rail industry requires a stepwise approach to ensure rail vehicle designs can make optimal use of the inherent properties of each material. Traditionally, materials such as steel and aluminium have been used in railway rolling stock to achieve the energy absorption and structural resistance demanded by European rail standards. Adopting composite materials in primary structural roles requires an innovative design approach which makes the best use of the available space within the rolling stock design such that impact energies and loads are accommodated in a managed and predictable manner. This thesis describes the innovative design of a rail driver’s cab to meet crashworthiness and structural requirements using lightweight, cost-effective composite materials. This takes the application of composite materials in the rail industry beyond the current state-of-the-art and delivers design solutions which are readily applicable across rolling stock categories. An overview of crashworthiness with respect to the rail industry is presented, suitable composite materials for incorporation into rolling stock designs are identified and a methodology to reconfigure and enhance the space available within rail vehicles to meet energy absorption requirements is provided. To realise the application of composite materials, this body of work describes the pioneering application of aluminium honeycomb to deliver unique solutions for rail vehicle energy absorbers, as well as detailing the use of lightweight composite materials to react the structural loads into the cab and carbody. To prove the capability of the design it is supported by finite element analysis and the construction of a full-scale prototype cab which culminated in the successful filing of two patents to protect the intellectual property of the resulting design.The European Commission whose Framework 6 funded project “De-Light” (Contract Number 031483) forms the basis of this work

Improving the effectiveness of age-abundance indicators in the management of fisheries in Queensland, Australia

The development of fishery indicators is a crucial undertaking as it ultimately provides evidence to stakeholders about the status of fished species such as population size and survival rates. In Queensland, as in many other parts of the world, age-abundance indicators (e.g. fish catch rate and/or age composition data) are traditionally used as the evidence basis because they provide information on species life history traits as well as on changes in fishing pressures and population sizes. Often, however, the accuracy of the information from age-abundance indicators can be limited due to missing or biased data. Consequently, improved statistical methods are required to enhance the accuracy, precision and decision-support value of age-abundance indicators

Optical methods of acoustic detection

This thesis details the experimental investigation of a fibre Bragg gratings (FBG) as to its suitability as a point ultrasonic sensor for medical applications, the FBG being interrogated by a low-coherence psuedo-heterodyne technique. The noise-limited pressure resolution of the FBG sensor was found to be 4.5kPa/√Hz at a frequency of 1.911 MHz. The ability of the FBG sensor to accurately determine the spatial field profile from a focussed ultrasonic transducer was also investigated and compared with results obtained from a commercially available piezoelectric hydrophone. Ultrasonic shielding materials on the bare optical fibre were also experimentally investigated in an attempt to provide a more localised grating response to the ultrasonic field. The ultrasonic response of low-finesse Fabry-Perot cavities based around 50pm thick polymer films was also investigated as a potential alternative to the use of fibre Bragg gratings, the cavity being interrogated by a low-coherence interferometric heterodyne technique. The noise-limited pressure resolution for a low-finesse Fabry-Perot cavity based on a 50pm thick polyethylene teraphthalate film was found to be 72 Pa/√Hz at an ultrasonic frequency of 1.911 MHz and 11 Pa/√Hz at 612 kHz. The ability of this cavity sensor to spatially resolve the ultrasonic field profile was also examined experimentally. Finally, the use of in-fibre Er3+ FBG based lasers as acoustic sensors in the frequency range 200Hz- 20 kHz was examined experimentally using a heterodyne interferometric interrogation method to assess the potential of these devices as highly sensitive acoustic sensors for military applications. The noise limited pressure resolution of the most sensitive fibre laser was found to be 4 x 1O$^{-3}$ Pa/√Hz over a frequency range of 4-6 kHz. An array of 4 distributed feedback fibre lasers was constructed and two separate methods of demultiplexing the laser array were compared and contrasted. The limiting system noise sources were also measured where possible

How Do Psychiatrists Apply the Minimum Clinically Important Difference to Assess Patient Responses to Treatment?

Symptom report scales are used in clinical practice to monitor patient outcomes. Using them permits the definition of a minimum clinically important difference (MCID) beyond which a patient may be judged as having responded to treatment. Despite recommendations that clinicians routinely use MCIDs in clinical practice, statisticians disagree about how MCIDs should be used to evaluate individual patient outcomes and responses to treatment. To address this issue, we asked how clinicians actually use MCIDs to evaluate patient outcomes in response to treatment. Sixty-eight psychiatrists made judgments about whether hypothetical patients had responded to treatment based on their pre- and posttreatment change scores on the widely used Positive and Negative Syndrome Scale. Psychiatrists were provided with the scale’s MCID on which to base their judgments. Our secondary objective was to assess whether knowledge of the patient’s genotype influenced psychiatrists’ responder judgments. Thus, psychiatrists were also informed of whether patients possessed a genotype indicating hyperresponsiveness to treatment. While many psychiatrists appropriately used the MCID, others accepted a far lower posttreatment change as indicative of a response to treatment. When psychiatrists accepted a lower posttreatment change than the MCID, they were less confident in such judgments compared to when a patient’s posttreatment change exceeded the scale’s MCID. Psychiatrists were also less likely to identify patients as responders to treatment if they possessed a hyperresponsiveness genotype. Clinicians should recognize that when judging patient responses to treatment, they often tolerate lower response thresholds than warranted. At least some conflate their judgments with information, such as the patient’s genotype, that is irrelevant to a post hoc response-to-treatment assessment. Consequently, clinicians may be at risk of persisting with treatments that have failed to demonstrate patient benefits

The role of inflammation in subventricular zone cancer

The adult subventricular zone (SVZ) stem cell niche has proven vital for discovering neurodevelopmental mechanisms and holds great potential in medicine for neurodegenerative diseases. Yet the SVZ holds a dark side - it can become tumorigenic. Glioblastomas can arise from the SVZ via cancer stem cells (CSCs). Glioblastoma and other brain cancers often have dismal prognoses since they are resistant to treatment. In this review we argue that the SVZ is susceptible to cancer because it contains stem cells, migratory progenitors and unusual inflammation. Theoretically, SVZ stem cells can convert to CSCs more readily than can postmitotic neural cells. Additionally, the robust long-distance migration of SVZ progenitors can be subverted upon tumorigenesis to an infiltrative phenotype. There is evidence that the SVZ, even in health, exhibits chronic low-grade cellular and molecular inflammation. Its inflammatory response to brain injuries and disease differs from that of other brain regions. We hypothesize that the SVZ inflammatory environment can predispose cells to novel mutations and exacerbate cancer phenotypes. This can be studied in animal models in which human mutations related to cancer are knocked into the SVZ to induce tumorigenesis and the CSC immune interactions that precede full-blown cancer. Importantly inflammation can be pharmacologically modulated providing an avenue to brain cancer management and treatment. The SVZ is accessible by virtue of its location surrounding the lateral ventricles and CSCs in the SVZ can be targeted with a variety of pharmacotherapies. Thus, the SVZ can yield aggressive tumors but can be targeted via several strategies

Clozapine-induced liver injury and pleural effusion

Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs