Biomedical subjects
Publications and source records attributed to Richard Porter.
A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.
Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog 4l. Robust in vivo efficacy of 4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.
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Bipolar disorder affects 1.6% of the population. The majority of the burden of illness for people with bipolar disorder is due to depression. Suicide rates for people with bipolar disorder are 15 times higher than in the general population, and the majority of these deaths occur during depressive episodes. More effective prevention of such depressive episodes is important. Lamotrigine is an anticonvulsant and a mood stabiliser that is more effective at preventing depressive relapses than most other mood stabilising drugs. Its use for this purpose has been recommended by English language treatment guidelines since 2002. Lamotrigine is approved for use in the prophylaxis of depression in bipolar disorder and for epilepsy. PHARMAC subsidises its use in treatment-resistant epilepsy (subject to a 'special authority' application) but not in bipolar disorder. The New Zealand Mental Health Strategy and the imminent New Zealand Suicide Strategy identify reducing suicide as a key goal. Among other initiatives, this requires effective treatment of bipolar depression, yet a treatment likely to support this is not currently subsidised.
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UNLABELLED: A case of localized anterior tooth surface loss (TSL) with an unusual aetiology is reported. Whilst suffering from a bout of acute depression and anxiety, a 29-year-old female caused significant trauma to her anterior dentition with a pair of fabric scissors. The presentation and management of this case is described. CLINICAL RELEVANCE: Although tooth surface loss is a common clinical finding in many patient groups, practitioners should be aware of possible unusual aetiologies which may be involved.
RATIONALE: Antagonists at the metabotropic glutamate 5 (mGlu5) receptor produce robust anxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working memory and spatial learning following intracerebroventricular administration. OBJECTIVES: The aim of this study is to compare the effect of the potent and selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent tests of cognition and anxiety. METHODS: MPEP was assessed in the following rodent tests, 60 min following oral administration: Geller--Seifter conflict, conditioned emotional response (CER), Vogel conflict, delayed match to position (DMTP) and Morris water maze. Diazepam was also tested as a comparator. RESULTS: MPEP had a significant anxiolytic effect, comparable in magnitude to diazepam, at 10--30 mg/kg in the two conflict and CER tasks. There was no effect of MPEP up to 30 mg/kg on working memory in the DMTP task, but at 100 mg/kg, there was a significant reduction in choice accuracy at the longest delay interval (24 s). MPEP (3--30 mg/kg) did not significantly impair spatial learning in the Morris water maze, although during the last probe trial, 30-mg/kg-treated rats were significantly less accurate than controls. In contrast, diazepam significantly impaired performance in both the DMTP and Morris water maze tests. Assessment of plasma and brain concentration of MPEP approximately 75 min following oral administration showed a dose linearity from 3 to 30 mg/kg and good brain penetration, i.e. a brain/plasma ratio of 3.1. CONCLUSIONS: Oral administration of the selective mGlu5 receptor antagonist MPEP induces a robust anxiolytic-like effect in rat conflict tests comparable to that seen with diazepam, but in contrast to diazepam, MPEP does not impair working memory or spatial learning at anxiolytic doses.
The preimplantation mammalian embryo from different species appears sensitive to the environment in which it develops, either in vitro or in vivo, for example, in response to culture conditions or maternal diet. This sensitivity may lead to long-term alterations in the characteristics of fetal and/or postnatal growth and phenotype, which have implications for clinical health and biotechnological applications. We review the breadth of environmental influences that may affect early embryos and their responses to such conditions along epigenetic, metabolic, cellular, and physiological directions. In addition, we evaluate how embryo environmental responses may influence developmental potential and phenotype during later gestation. We conclude that a complex of different mechanisms may operate to associate early embryo environment with future health.
STUDY DESIGN: The first case of scoliosis in an Orangutan spine is reported. OBJECTIVES: To study the nature of scoliosis in the spinal specimen, and to determine the etiologic significance to human idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Idiopathic scoliosis has not been observed in primates other than man. Previous studies highlighted the importance of erect posture in the development of idiopathic scoliosis in man. METHODS: A spinal model of an orangutan spine was studied in great detail to determine its nature. The methods used included plain radiographs, computed tomography scans, a three-dimensional plastic model using rapid prototyping, and dissection of the frozen specimen. RESULTS: Features similar to human idiopathic scoliosis were noted including a right-side curve, vertebral rotation to convexity, displacement of the spinal cord to the concavity, and an equal number of ribs on either side. No evidence of congenital anomaly was found. Atypical findings included male gender, a short curve, and kyphosis at the apex. CONCLUSIONS: Although scoliosis found in the orangutan has features similar to idiopathic scoliosis, there also are some dissimilar features, making this diagnosis unlikely. The features observed in this spine suggest that erect posture is important in the morphology of human idiopathic scoliosis.
We retrospectively studied the prevalence of the nasal carriage of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) on admission to a medical surgical intensive care unit (ICU). We also compared the intensive care survival of MSSA carriers with non-carriers. Records of 678 patients admitted over a 24-month period were retrospectively reviewed. Nasal swabs were taken from 565 patients on admission to the ICU. MSSA was isolated from the anterior nares of 126 (22%) patients, MRSA was isolated in 16 (3%) patients and 423 (75%) patients had no nasal carriage identified. MSSA carriers were more likely to have been admitted to the ICU after less than 24 h hospital stay (28% non-carriers, 44% MSSA carriers) and were significantly younger (mean age of 50 years) than non-carriers (mean age 55 years). The median survival (with confidence intervals (CI)) was 29 days (CI 14-44) in non-carriers, 16 days (CI 10-22) in MSSA carriers and 6 days (CI 4-8) for the MRSA carriers. This difference was significant when MSSA carriers were compared with non-carriers ( p=0.003). The ICU mortality was also significantly higher ( p=0.004) in MSSA carriers (88 of the 423 (21%) non-carriers and 40 of 126 (32%) MSSA carriers died prior to ICU discharge).
PURPOSE: Tripronucleate (3pn) development after conventional insemination (CONV) or ICSI was analyzed to estimate the rate of second polar body retention giving rise to 3pn formation. METHODS: Data from 453 consecutive IVF cycles were reviewed during a 6-month period. Mature oocytes were monitored in ICSI (n = 3195) and CONV (n = 2274) groups by fertilization assessment 16-18 h post-insemination. Ovulation induction protocols and in vitro culture conditions remained constant during the study interval. RESULTS: Normal (2pn) fertilization occurred in 74.2% and 70.5% for CONV and ICSI groups, respectively (p < 0.003). 1pn formation was observed in 4.5% of CONV oocytes, and 2.5% of ICSI oocytes (p < 0.001); 3pn formation was 8.1% in the CONV group, and 2.5% in the ICSI group (p < 0.0001). We observed 4pn formation in 0.4% of oocytes in the CONV group, but in only 0.04% of oocytes fertilized with ICSI (p < 0.007). Cellular degeneration occurred in 2.4% of oocytes inseminated conventionally, and in 3.5% of oocytes fertilized by ICSI (p = 0.02). Maternal age did not impact pronuclear status. CONCLUSIONS: We found the 3pn formation rate after ICSI to be approximately one-third that observed in the CONV group. Extrapolating the ICSI data to the CONV data, it may be inferred that 2.5% of 3pn development after CONV was due to second polar body retention. This suggests that 5.6% of CONV oocytes showed dispermic fertilization. Decreasing oocyte quality with increasing maternal age had no apparent influence on any of the fertilization outcomes.
OBJECTIVE: To introduce clinicians to the methodology and critical appraisal of randomized controlled trials (RCTs) in psychiatry. METHOD: The methodology of RCTs in psychiatry is discussed. Using a systematic approach to critical appraisal, a published RCT of treatments for severe depression is examined and evaluated. RESULTS AND CONCLUSIONS: The RCT appraised illustrates certain problematic areas in the methodology of trials in psychiatry. A detailed knowledge of methodology and critique of RCTs is essential in determining whether reported results will influence clinicians' practice.
OBJECTIVE: To discuss the extent to which the results of randomized controlled trials (RCTs) in psychiatry can be generalized to clinical practice. METHOD: Threats to internal and external validity in psychiatric RCTs are reviewed. RESULTS: Threats to internal validity increase the possibility of bias. Psychiatric RCTs have problems with small samples, arbitrary definitions of caseness, disparate definitions of outcome and high spontaneous recovery rates. Particular issues arise in psychotherapy RCTs. Threats to external validity reduce the extent to which the results of a RCT produce a correct basis for generalization to other circumstances. These include high rates of comorbidity and sub syndromal pathology in normal clinical practice, manual-based treatment protocols and varying definitions of successful treatment. CONCLUSIONS: Randomized controlled trials remain the most robust design to investigate the effectiveness of treatments. They should be applied to important clinical questions; and carried out, as far as possible, with typical patients in the clinical conditions in which the treatment is likely to be used.
Dysplastic epithelium at the resection margin after a cervical cone is known to predict persisting disease. We followed 702 women for 30 months after cervical excision to see which resection margin was predictive. The risk of persisting cytological abnormalities was doubled when CIN extended to the endocervical resection margin and was doubled when there was evidence of HPV. In contrast, disease at the ectocervical resection margin and the grade of CIN were not associated with a higher risk of residual disease.
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