An analog study was devised to examine perceived differences between psychiatrists and psychologists in providing expert testimony on the insanity defense. The effects of issue involvement and initial attitude were also assessed. Subjects who had been exposed to the differences in training between the professionals were used. In a pilot investigation, subjects were exposed to identical testimony from a defense expert identified either as a psychiatrist or psychologist. Medical bias, as measured by the tendency to concur with the expert recommendations and endorse attitudes consistent with the M.D., was confirmed. This finding was especially strong among pro insanity defense subjects with low issue involvement. The failure to find a similar pattern among anti-insanity defense subjects with low issue involvement was thought to be an artifact of the absence of opposing testimony. The overall failure of highly involved anti insanity defense subjects to reach verdicts consistent with their initial attitudes, was also thought to result from the lack of opposing testimony. The primary study was designed to clarify the findings of the pilot investigation and to approximate a more authentic court situation by including an opposing expert. Witness credentials were manipulated while testimony remained constant. Some subjects were exposed to the Ph.D. for the defense and M.D. for prosecution and others to the M.D. for the defense and Ph.D. for the prosecution. Medical bias was evident in this study, again measured by the tendency to follow the recommendations of the M.D. and endorse attitudes consistent with those recommendations. Additionally, subjects tended to evaluate the psychiatrist more favorably than the psychologist. Subjects with low issue involvement were more susceptible to the influence of the medical expert. Highly issue involved subjects maintained their initial attitudes. Attitudes, issue involvement and credentials seemed to affect memory for facts of the case. In some instances, initial attitudes became stronger when mock jurors were exposed to the opposing view (polarization). Implications and limits of these findings were explored.

The present research examined the ability of a group of objective and subjective social indicators to discriminate between respondents who were community mental health center clients and those who were community residents with no history of contact with mental health professionals. Previous research had suggested that objective social indicators were inadequate both for assessing well-being and for assessing mental health needs. Thus, the purpose of this project was to provide initial data on the relative efficacy of objective and subjective social indicators in discriminating those who needed mental health services from those who did not. In addition, the goal was to determine the ability of a combined group subjective and objective indicators to discriminate between those who needed mental health services and those who did not. Teams of trained undergraduates administered questionnaires containing questions regarding demographic variables, recent stressful life events, social supports, daily activities, and quality of life (domain satisfaction). Community mental health center clients appearing for the first time in East Tucson, Arizona were designated as those in need of mental health services (clinic). East Tucson community residents reporting no history of contact with mental health professionals were designated as those who were not in need of mental health services (community). Results indicate that discriminant function analysis using only demographic variables was able to correctly classify 85.7 percent of these respondents as belonging to either the community or clinic group. Using quality of life variables, 85.2 percent of these respondents were correctly classified. By combining one demographic variable, one recent stressful life event, and three quality of life items, a discriminant function analysis correctly classified 93.1 percent of these respondents as either clinic or community. Results of discriminant function analyses with a cross-validation sample support these results. The overall results are viewed as preliminary but suggestive of the potential utility of combining objective and subjective indicators for predicting mental health needs. The results are discussed in terms of their implications for preventive approaches to mental health in light of the limitations of defining need on the basis of utilization of services.

No description available.

No description available.

N-Methyl-D-aspartate (NMDA) receptors are critically involved in synaptic transmission, neural development and various forms of neuronal plasticity including long-term potentiation (LTP) and long-term depression (LTD). They are also involved in the production of neuronal damage following excessive activation by glutamate released as a result of hypoxia or ischaemia. Each heteromeric receptor includes one or two NRl subunits, at least two of the four NR2A-D subunits and less usually the NR3AJB subunits. This study demonstrates that the putative NR2B subunit-containing NMDA receptor antagonist Ro 25-6981 potentiates the effects ofNMDA on rat hippocampal slices. The NR2A subunit antagonist PEAQX blocks the effects of NMDA alone and the potentiated response following Ro 25-6981 application. Furthermore, Ro 25-6981 was not neuroprotective as reported previously but unexpectedly precipitated excitotoxicity. The potentiating effect of Ro 25-6981 required around 20 minutes to become apparent, took a further 30 minutes to reach its maximum effect and was irreversible. It was not prevented by staurosporine (a broad-spectrum protein kinase inhibitor), okadaic acid (a potent inhibitor of the serine/threonine protein phosphatases types 1 and 2A) or anisomycin (a protein synthesis inhibitor). However, the potentiation was prevented by cyclosporin A (an inhibitor of Ca2+/calmodulin-dependent phosphatase 2B [calcineurin]). The results indicate that in an intact neuronal network, NR2B subunits tonically gate NR2A subunit-containing receptor function by a negative coupling mechanism involving ca1cineurin activation. NMDA receptor-dependent LTP induced by high frequency stimulation was prevented by PEAQX, an NR2A antagonist. Ro 25-6981 was unable to prevent L TP induction but was associated with a marginal reduction in the magnitude of LTP induced. There is evidence for the binding of homoquinolinic acid to an NMDAinsensitive novel binding site in the brain. This study investigated the pharmacology of homoquinolinate on the evoked field excitatory synaptic potential (fEPSP) recorded from the CAl area of rat hippocampal slices. Two NMDA receptor agonists, quinolinic acid 150/lM and homoquinolinic acid 2.5/lM, caused an approximately 50% inhibition of fEPSP slope. Paired-pulse studies suggested there might be a presynaptic component to this action that is independent of presynaptic adenosine Al receptor activation. The broad-spectrum EAA antagonist kynurenic acid and the NMDA receptor blockers 2-amino-5-phosphonopentanoic acid and dizocilpine could prevent the inhibition of fEPSP slope. None of these antagonists revealed any other NMDA-insensitive activity of homoquinolinic acid. The use of 2-carboxy-3-carboxymethylquinoline (CCMQ) to displace the reported NMDA-insensitive binding had no effect on either baseline fEPSP slope or the depression caused by homoquinolinic acid. It was also apparent that responses to homoquinolinic acid were blocked completely by the NR2A subunit-selective antagonist PEAQX, but not by the NR2B subunit-selective blocker Ro 25-6981. It was concluded that the novel binding site for homoquinolinic acid does not affect synaptic potentials in the hippocampus and that homoquinolinic acid appears to be a selective agonist at NMDA receptors that include the NR2A subunit. Although the NR2B agonist site may be maximally activated under normal conditions and therefore it is not possible to observe any additional effects upon fEPSP slope. This study next investigated the negative coupling between NR2B and NR2A subunit-containing receptors, combining the NR2A1B subunit selective agonist HQA with the NR2B and NR2A selective antagonists Ro 25-6981 and PEAQX. The negative coupling observed previously with applications of NMDA was also seen using HQA and QA. The potentiation of responses to HQA by Ro 25-6981 application was also associated with an enhancement of paired-pulse interactions. The subsequent application of PEAQX was able to block both the depression of fEPSP slope and the associated enhancement of paired-pulse interactions. The presence of a presynaptic element during applications of HQA alone and potentiated responses alike and the blockade of these effects by PEAQX suggests the NR2A subunit-containing NMDA receptor is responsible for the presynaptic effects acting either directly at presynaptic sites or indirectly at postsynaptic sites leading to the raising of a retrograde signal. The NR2B subunit in both its activated and antagonised state was associated with enhancements in paired-pulse interactions which suggest that it is not able to modulate directly the presynaptic element. However, whilst paired-pulse interactions are generally accepted to he presynaptic phenomena, it does not follow that postsynaptic effects cannot influence the appearance of changes in these interactions in field recordings. The absence of any observable difference between HQA, QA and NMDA results suggests that the NR2D subunit is not obviously involved in these processes.

Guillian-Barré Syndrome (GBS) is the world’s leading cause of neuromuscular paralysis occurring in serologically and pathogenically distinct forms. GBS is believed to have an autoimmune basis, where antibodies raised during antecedent infections (eg Campylobacter jejuni) cross-react with self antigens, exemplifying the process of molecular mimicry. These self-antigens are gangliosides, which are glycolipid structures enriched in peripheral nerve in specific membrane compartments termed lipid rafts. To date, successful murine models of anti-GD1a and anti-Gq1b ganglioside mediated neuropathy exist. Clinical evidence supports the involvement of anti-GM1 antibodies in nerve injury, however generation of anti-GM1 antibody mediated neuropathy models remain an enigma, and to date, the only successful model is based in Japanese rabbits. This thesis aims to address the controversies surrounding anti-GM1 antibody mediated neuropathy by utilising a panel of anti-GM1 antibodies of differing specificity, and explores how the stereometric interactions of GM1 with lipid raft species underpin the pathogenic potential of these antibodies.

One hundred and nine generalised anxiety disorder (GAD) patients, referred by their General Practitioners to a clinical psychology primary care service, were assigned to either Cognitive, Behavioural, Cognitive-behavioural, Placebo or Waiting List conditions. `Stress Control' large group therapy combined didactic therapy with a workshop model and emphasised the aim of turning patients into their own `therapists' in order to enable them to deal with present and future problems. Patients were thus encouraged to view Stress Control as an `evening class' rather than `group therapy'. Measures of treatment process and outcome were obtained mainly from self-report instruments. Follow-up data were collected at six months post-treatment. At post-therapy, all active therapy conditions and, against expectation, the Placebo condition had shown significant time within treatment group change. The active therapy conditions, and to a lesser extent, the Placebo condition, were significantly different to the Waiting List condition, which, overall showed no evidence of improvement. At follow-up the active therapy condition generally enhanced therapy gains while the placebo condition maintained therapy gains. Process measures did not, with the exception of self-statement change, differentiate between the groups. Noted variable response in the main analyses was somewhat explained by various sub-group analyses. There appeared to be little benefit in dividing patients into those who experienced panic and those who did not. There was some evidence that `matching' patients to therapy, i.e. cognitive responders to cognitive therapy was of value at post-therapy although differences generally disappeared at follow-up. Synchronous change was associated with enhanced performance. Finally, attempts to predict response to Stress Control by a comparison of responders and non-responders were attempted and the results assessed in terms of clinical as opposed to statistical significance. The results of the present study are discussed with reference to other treatment outcome studies and an attempt to produce a model to account for the similar effects found across treatment conditions. The implications of these findings and some suggestions for future research for GAD and other diagnostic categories are discussed.

Osteoarthritis (OA), depression and anxiety are common problems in primary care. OA coexisting with depressive and/or anxiety symptoms has detrimental consequences to the individual. To inform recognition and management of these important problems in primary care a better understanding of their coexistence is needed. A systematic review with meta-analysis was undertaken to determine the prevalence of depression and anxiety in adults with OA/joint pain in the community. Elevated anxiety symptoms were more common (45%) than depression symptoms (24%) in persons with OA joint pain. Sources of between study variance include methods of ascertainment and geographical location. A review of measurement properties of several recommended patient-reported depression and anxiety measures found evidence to support properties in some populations, but some critical properties warrant investigation in adults with OA in the community. A secondary data analysis was conducted for older consecutive primary care patients with musculoskeletal pain recruited to a cohort (n=443) of the PROGnostic Research study. Latent Class Growth Analyses identified clusters of individuals who exhibited different trajectories of anxiety and depression symptoms over a 12-month period: three anxiety and two depression symptom trajectories. In total, 56% and 63% of participants experienced persistent anxiety and depression symptoms respectively for at least 12 months. Pain characteristics and coping strategies were the most prominent risk factors for persistent anxiety and depression symptoms. With the aim of identifying individuals with sub- threshold persistent anxiety and depression symptoms, characteristics predisposing to symptoms persistence may be considered. A medical records review found that only half of all older musculoskeletal patients with persistent anxiety and depression symptoms have their mental health problems detected by their GP. Frequent consulters and those with more severe anxiety were more likely to be detected. This reinforces the need to recognise and manage OA coexisting with depression and/or anxiety by patients and health professionals alike.

The cerebellum receives information from the hindlimbs through several populations of spinocerebellar tract neurons. Although the role of these neurons has been established in electrophysiological experiments, the relative contribution of afferent fibres and central neurons to their input, their organization and mechanisms of control of transmission has only been estimated approximately so far. The present study aimed to investigate the input properties of four populations of spinocerebellar tract neurons: dorsal spinocerebellar tract neurons located in Clarke´s column (ccDSCT) and in the dorsal horn (dhDSCT) and ventral spinocerebellar tract (VSCT) neurons including spinal border (SB) neurons. There were three major aims: (1) to investigate the excitatory inputs to four types of spinocerebellar tract neurons in the cat and rat thoraco-lumbar spinal cord; (2) to analyze the inhibitory inputs to four types of spinocerebellar tract neurons in the cat and rat thoraco-lumbar spinal cord; (3) to determine the origin of excitatory and inhibitory inputs to four types of spinocerebellar tract neurons in the cat and rat thoraco-lumbar spinal cord. Two series of experiments were carried out. In the first series of experiments in cats, spinocerebellar tract neurons were identified electrophysiologically and labelled intracellularly with rhodamine-dextran and Neurobiotin. In the second series of experiments in rats, cells were labelled by retrograde transport of b-subunit of Cholera toxin (CTb) from the cerebellum. In addition, to address the third aim, reticulospinal (RetS) and corticospinal (CS) terminals were identified by anterograde transport of CTb from the caudal medulla and hindlimb sensory motor cortex respectively in rats along with labelling of spinocerebellar tract neurons by retrograde injection of Fluorogold in the cerebellum. Following this, immunohistochemistry was carried out. The first aim was achieved by utilizing the difference in the immunohistochemistry of glutamatergic terminals of peripheral afferents and of central neurons with vesicular glutamate transporters, VGLUT1 or VGLUT2, respectively. All SB neurons with dominating inhibitory input from the periphery possessed very few VGLUT1 contacts and remarkably higher numbers of VGLUT2 contacts. In VSCT neurons with excitatory primary afferent input, the number of VGLUT1 contacts was relatively high although VGLUT2 contacts likewise dominated. In contrast, DSCT neurons were associated with numerous VGLUT1 contacts; ccDSCT neurons with strong input from group I afferents had higher density of VGLUT1 contacts than dhDSCT neurons with major input from group II and cutaneous afferents. In order to fulfill the second aim, quantification of contacts formed by inhibitory axon terminals on spinocerebellar tract neurons along with excitatory terminals was carried out. Inhibitory axon terminals were characterised as either GABAergic, glycinergic or both GABAergic/glycinergic by using antibodies against vesicular GABA transporter (VGAT), glutamic acid decarboxylase (GAD) and gephyrin. Similarly, excitatory terminals were characterised by using combination of VGLUT1 and 2. The comparison revealed the presence of much higher proportions of inhibitory than excitatory contacts on SB neurons but similar proportions were found on VSCT, ccDSCT and dhDSCT neurons. In all types of cell, the majority of inhibitory terminals were glycinergic. The density of contacts was higher on somata and proximal in comparison with distal dendrites of SB and VSCT neurons but more evenly distributed in ccDSCT and dhDSCT neurons. To achieve the third aim, a series of immunohistochemical reactions was performed to characterize contacts that originate from proprioceptors, different types of interneurons and descending RetS and CS pathways. Among the four populations of spinocerebellar tract neurons, ccDSCT neurons had the highest proportion of contacts formed by VGLUT1 terminals double labeled with parvalbumin (PV) which indicated that majority of direct excitatory sensory inputs to ccDSCT neurons are derived from proprioceptors. A small proportion of excitatory and inhibitory contacts on these neurons originated from Calbindin/ Calretinin/ PV expressing neurons. Quantitative analysis revealed that SB and VSCT neurons have significantly higher numbers of appositions from VGLUT2 expressing RetS axon terminals than DSCT neurons. A small proportion of the RetS contacts on these neurons were VGAT positive. In contrast, DSCT neurons had higher numbers of appositions made by CS axon terminals in comparison to SB and VSCT neurons. The present findings provide a new basis for understanding the organization and functional connectivity of four populations of spinocerebellar tract neurons and strengthen previous indications of their functional differentiation. SB and VSCT neurons principally receive inputs from spinal and supraspinal neurons although direct input from primary afferents is also stronger in VSCT neurons. DSCT neurons have major direct input from primary afferents and also to some extent from the CS pathway but monosynaptic inputs from proprioceptors dominated in ccDSCT neurons and dhDSCT neurons have mixed proprioceptive and low threshold cutaneous afferent input.

In studies on the pathophysiology of the autoimmune neuropathy, Miller Fisher syndrome (MFS), monoclonal antibodies to the disialosyl epitopes on GQ1b, GT1a and GD3 gangliosides have been produced. Antibodies to these complex gangliosides are thought to be crucial in the pathogenesis of MFS. These antibodies have recently been shown to produce complement dependent, glial and/or neuronal injury at mouse neuromuscular junctions (NMJs). Three antibodies (EG1, LB1 and R24) were identified as producing selective terminal Schwann cell (TSC) injury whilst sparing neuronal membranes at NMJs in BALB/c and C57BL/6 mouse strains in a dose dependent manner. These changes occur in the absence of observable acute physiological or morphological changes to the nerve terminal, suggesting that TSC injury or loss has no major short-term influence on synapse function. Having compared the suitability of two common ex vivo muscle preparations for use in characterisation studies, TSC selective antibodies were compared, and EG1 was identified as most suitable for further investigations on the role of the TSC in mammalian NMJ function and as a possible disease target in MFS. The effect of this antibody when combined with normal human serum as a source of complement in ex vivo hemidiaphragm preparations was independent of complement regulators DAF1 and CD59a. Cell specific promoter sequences have been used to produce a mouse line that expresses green-fluorescent protein (GFP) in TSCs, and cyan-fluorescent protein (CFP) in axons (CK mouse). Live imaging techniques were used to study the acute and chronic effects of EG1 mAb mediated, complement dependent glial injury in this system. It is shown that TSC injury is characterised by loss of GFP staining, occurring within 20 minutes of complement exposure. Repopulation of the NMJs with GFP-positive cell bodies is first evident at day 2. The origin of these returning Schwann cells is discussed, and three possible sources are considered – the last myelinating Schwann cell, non-myelinating Schwann cells lying more proximally in the peripheral nervous system, and muscle stem cells. At day 7, the number of GFP-positive cell bodies seen at the NMJ is higher (7-12 per NMJ) than prior to antibody exposure (3-5 per NMJ). This process of enhanced repopulation is not dependent on an intact axon as it is retained following axotomy. At 3 months, minor remodelling of the NMJ is seen, and is more pronounced at one year. Repeat antibody exposure within 48 hours does not injure returning processes, or delay repopulation. Instead, extra-junctional TSC processes are formed, with associated axon sprouts in the absence of gross terminal axon injury. Anti-GQ1b containing serum from a MFS patient is shown to induce murine TSC death in a similar manner to murine monoclonal antibodies described previously. This suggests that TSCs are a potential new disease target in human disease if the ganglioside profile of mouse and human TSCs is equivalent. Ganglioside distribution and antibody binding are examined on a series of human muscles. These studies demonstrate for the first time that components of the human NMJ are potentially susceptible to anti-ganglioside antibody mediated injury, by virtue of their ganglioside profile. This study suggests that TSCs may be a previously unrecognised site of immune-mediated nerve injury. It also describes a new technique for observing chronic TSC injury and recovery in an in vivo mouse model system, which could be used for human disease modelling.