A comparison of the effects of xenobiotics on hepatic haem metabolism

Hepatic microsomal cytochrome P-450 has previously been postulated to be an important factor in determining the rates of hepatic haem biosynthesis and biodegradation. The basis for this proposal is that the haem moiety of cytochrome P-450 appears to be in equilibrium between binding to apocytochrome P-450 and existing in some form in the central hepatic pool of haem concerned with the regulation of the haem metabolic pathways. Consequently, any change in the levels of hepatic cytochrome P-450 would be anticipated to affect the pathways of hepatic haem biosynthesis and biodegradation. At the onset of this project, relatively few chemical agents were known to destroy cytochrome P-450 (either by degradation of the haem moiety of, or dissociation of the haem moiety from hepatic microsomal cytochrome P-450) and to affect hepatic haem biosynthesis and/or haem biodegradation (e.g. AIA, Cs₂ and various metals). We thus attempted to further establish the relationship between the ability of compounds to affect hepatic cytochrome P-450 and to affect hepatic haem metabolism in vivo, using the three anaesthetic agents, fluroxene, halothane and trichloroethylene. During the preparation of this thesis, several other chemicals have been found which destroy cytochrome P-450 and affect hepatic haem metabolism (e.g. norethisterone, morphine). In addition to the above, it has been attempted to clarify the roles of the degradation of different forms of cytochrome P-450 and of the different mechanisms of destruction of cytochrome P-450 in the control of hepatic haem metabolism. The three anaesthetic agents, fluroxene, halothane and trichloroethylene were chosen for study since they destroy cytochrome P-450 by apparently different mechanisms. Both fluroxene and trichloroethylene specifically degrade the haem moiety of different forms of cytochrome P-450, but fluroxene converts the haem moiety of cytochrome P-450 to an N-substituted porphyrin, while TCE apparently degrades the haem into uncoloured products. In contrast, halothane appears to degrade the haem of cytochrome P-450 to uncoloured products as well as to facilitate the dissociation of haem from intact cytochrome P-450

The Characterisation of Pax3 Expressant Cells in Adult Peripheral Nerve

Pax3 has numerous integral functions in embryonic tissue morphogenesis and knowledge of its complex function in cells of adult tissue continues to unfold. Across a variety of adult tissue lineages, the role of Pax3 is principally linked to maintenance of the tissue’s resident stem/progenitor cell population. In adult peripheral nerves, Pax3 is reported to be expressed in nonmyelinating Schwann cells, however, little is known about the purpose of this expression. Based on the evidence of the role of Pax3 in other adult tissue stem and progenitor cells, it was hypothesised that the cells in adult peripheral nerve that express Pax3 may be peripheral glioblasts. Here, methods have been developed for identification and visualisation of Pax3 expressant cells in normal 60 day old mouse peripheral nerve that allowed morphological and phenotypic distinctions to be made between Pax3 expressing cells and other nonmyelinating Schwann cells. The distinctions described provide compelling support for a resident glioblast population in adult mouse peripheral nerve

Pax genes during neural development and their potential role in neuroregeneration

Pax genes encode a family of transcription factors that have long been recognised as obligate contributors to embryonic development of the CNS, with evidence obtained from various animal models illustrating phylogenetically conserved functions. Within the CNS, Pax genes play substantial roles in cellular and regional specification, proliferation, progenitor cell maintenance, anti-apoptosis and neural differentiation. This comprehensive review details the critical functions of those Pax genes involved in pre- and post-natal CNS development, provides possible molecular mechanisms by which Pax genes contribute to proliferation and differentiation of neuronal cells, and explains observed changes in Pax gene expression in response to neurotrauma in the mature animal. Knowledge of the ability of individual Pax genes to specify precise lineages within the CNS is beneficial for cell replacement strategies, particularly in the production of ‘‘designer’’ cells for the treatment of neurodegenerative disorders. The manipulation of stem or committed cells so that they express definitive Pax genes may indeed assist in the pursuit of the holy grail of regenerative medicine – that of CNS cell replacement therapies leading to functional repair. We explain here, however, that only the sophisticated and precise use of Pax genes will lead to a successful outcome

Tropomyosin autoantibodies associated with checkpoint inhibitor myositis

Background Treatment plan adherence is recognized as a worldwide health issue, particularly important in the management of cardiovascular patients. Healthcare professionals are the primary sources of information and support for people diagnosed with CVD and those who have experienced a cardiac event, yet we know little about how healthcare professionals contribute to the process of adherence to treatment plans that aim to prevent and/or reduce disease and adverse events. Qualitative evidence that explores factors that influence adherence to treatment plans is limited. Objective This systematic review identified and synthesised the best available evidence on factors that influence adherence to treatment plans among people living with cardiovascular disease. Design Systematic review and qualitative synthesis. Methods Data were collected from Medline, Web of Science, CINAHL, PsychINFO, Embase- Non-Medline, Scopus, Cochrane Library, ProQuest Central (Grey Literature). Pre-defined keywords and MeSH terms were used to identify qualitative methods English-language studies published between 2001 and 2018. Quality appraisal of each paper was completed using the JBI Critical Appraisal Checklist and two reviewers extracted the data independently. Results Twenty-two articles were included. Eight key themes were identified that related to facilitators and barriers to adherence to treatment plans. Facilitators were identified as engaging in exercise, having support and mentorship, lifestyle modification, and the perceived value of taking medication. Barriers were identified as a perceived lack of support, concerns about taking medication, and lack of engagement in exercise and lifestyle changes. Conclusions The findings highlight the factors that support adherence and healthcare professionals can build on also the areas that can be targeted to support and improve adherence to treatment plans. Nurses can play an important role in enhancing the provision of information pre hospital discharge and support in the community on taking medication, the value of physical activity and dietary changes

A Systematic Review and Meta-Analysis of Strength Training in Individuals With Multiple Sclerosis or Parkinson Disease

Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson diseaseormultiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%-83.2%) and multiple sclerosis (4.5%-36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electro-myography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis

Evaluation of a multi-marker immunomagnetic enrichment assay for the quantification of circulating melanoma cells

Background: Circulating melanoma cells (CMCs) are thought to be valuable in improving measures of prognosis in melanoma patients and may be a useful marker of residual disease to identify non-metastatic patients requiring adjuvant therapy. We investigated whether immunomagnetic enrichment targeting multiple markers allows more efficient enrichment of CMCs from patient peripheral blood than targeting a single marker. Furthermore, we aimed to determine whether the number of CMCs in patient blood was associated with disease stage.Methods: We captured CMCs by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271, both individually and in combination, by immunomagnetic enrichment. CMCs were enriched and quantified from the peripheral blood of 10 non-metastatic and 13 metastatic melanoma patients.Results: Targeting all markers in combination resulted in the enrichment of more CMCs than when any individual marker was targeted (p \u3c 0.001-0.028). Furthermore, when a combination of markers was targeted, a greater number of CMCs were enriched in metastatic patients compared with non-metastatic patients (p = 0.007).Conclusions: Our results demonstrated that a combination of markers should be targeted for optimal isolation of CMCs. In addition, there are significantly more CMCs in metastatic patients compared with non-metastatic patients and therefore quantification of CMCs may prove to be a useful marker of disease progression

Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service

Objective This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain. Method A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores. Results Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous. Conclusions MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients

Evaluation of a multi-marker immunomagnetic enrichment assay for the quantification of circulating melanoma cells

Background: Circulating melanoma cells (CMCs) are thought to be valuable in improving measures of prognosis in melanoma patients and may be a useful marker of residual disease to identify non-metastatic patients requiring adjuvant therapy. We investigated whether immunomagnetic enrichment targeting multiple markers allows more efficient enrichment of CMCs from patient peripheral blood than targeting a single marker. Furthermore, we aimed to determine whether the number of CMCs in patient blood was associated with disease stage.Methods: We captured CMCs by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271, both individually and in combination, by immunomagnetic enrichment. CMCs were enriched and quantified from the peripheral blood of 10 non-metastatic and 13 metastatic melanoma patients.Results: Targeting all markers in combination resulted in the enrichment of more CMCs than when any individual marker was targeted (p \u3c 0.001-0.028). Furthermore, when a combination of markers was targeted, a greater number of CMCs were enriched in metastatic patients compared with non-metastatic patients (p = 0.007).Conclusions: Our results demonstrated that a combination of markers should be targeted for optimal isolation of CMCs. In addition, there are significantly more CMCs in metastatic patients compared with non-metastatic patients and therefore quantification of CMCs may prove to be a useful marker of disease progression