Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed.

N-acetylcysteine for antioxidant therapy : pharmacology and clinical utility

Glutathione is an endogenous antioxidant and has a ubiquitous role in many of the body’s defences. Treatment with N -acetylcysteine (NAC) has been shown to increase levels of glutathione. NAC has been proposed as a treatment for several illnesses. Objectives : The efficacy and tolerability of NAC was examined across a range of conditions to evaluate the evidence supporting the use of NAC for each indication. Methods : A literature search was conducted using PubMed. Information was also collected from other online sources including the websites of the Therapeutic Goods Administration of Australia and the FDA. Results : Reports ranged from case studies to clinical trials. There is strong evidence to support the use of NAC for the treatment of paracetamol overdose and emerging evidence suggesting it has utility in psychiatric disorders, particularly schizophrenia and bipolar disorder. NAC is safe and well tolerated when administered orally but has documented risks with intravenous administration.

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

Protocol for the Hall Technique study: A trial to measure clinical effectiveness and cost-effectiveness of stainless steel crowns for dental caries restoration in primary molars in young children

BACKGROUND: The Hall Technique (HT) is a carious primary molar treatment that does not require local analgesia, carious tissue removal or tooth preparation. The carious lesions in carefully selected teeth are sealed with a stainless steel crown (preformed metal crown). The study aims are to determine the clinical effectiveness, acceptability and cost-effectiveness of the HT for management of carious lesions in young dental patients. METHODS/DESIGN: Children, aged 3-7years, with a primary molar tooth with a carious lesion extending no further than the middle third of dentine, with no signs or symptoms of pulp inflammation or infection, and attending one of three community agencies are recruited. Target sample size is 220. A control tooth with an intra-coronal restoration is sourced from the same mouth. The primary outcome is the period of time free from further treatment. The assessments are scheduled at 6, 12 and 24months. In addition to the clinical assessment, acceptability of the HT will be assessed via questionnaires among patients and their primary carers at baseline, 6, 12 and 24months. Cost-outcome description and cost-effectiveness analysis from healthcare provider and societal perspective will be conducted. DISCUSSION: The clinical effectiveness, acceptability and cost-effectiveness of the HT in the community dental setting will be evaluated. The results of this study will determine the implementation of HT in the management of dental caries in young children.

An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus.

Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.

Postoperative pulmonary dysfunction in adults after cardiac surgery with cardiopulmonary bypass: clinical significance and implications for practice

Postoperative pulmonary complications are the most frequent and significant contributor to morbidity, mortality, and costs associated with hospitalization. Interestingly, despite the prevalence of these complications in cardiac surgical patients, recognition, diagnosis, and management of this problem vary widely. In addition, little information is available on the continuum between routine postoperative pulmonary dysfunction and postoperative pulmonary complications. The course of events from pulmonary dysfunction associated with surgery to discharge from the hospital in cardiac patients is largely unexplored. In the absence of evidence-based practice guidelines for the care of cardiac surgical patients with postoperative pulmonary dysfunction, an understanding of the path ophysiological basis of the development of postoperative pulmonary complications is fundamental to enable clinicians to assess the value of current management interventions. Previous research on postoperative pulmonary dysfunction in adults undergoing cardiac surgery is reviewed, with an emphasis on the pathogenesis of this problem, implications for clinical nursing practice, and possibilities for future research.

The questioning skills of clinical teachers and preceptors: a comparative study

Aim of the study. The purpose of this study, conducted as partial requirement for a Master of Nursing Studies Degree, was to explore, describe and compare the level of questions asked by clinical teachers and preceptors.

Background. Questioning is one of many teaching/learning strategies thought to facilitate the development of critical thinking skills which are integral to nursing practice. As such the type and number of questions asked have implications for student learning. Currently in Melbourne, Australia, many undergraduate nursing degree courses utilize both clinical teachers and preceptors to facilitate student learning in the clinical setting.

Design. A comparative descriptive design was used. Participants were given three acute care patient scenarios involving an undergraduate nursing student, as part of a questionnaire, and asked to identify the questions they would ask the student in relation to the scenario.

Findings. Data revealed that the clinical teachers had considerably more years of experience in their role and higher academic qualifications than did the preceptors. The clinical teachers also asked a greater number of questions overall and more from the higher cognitive level. Despite this, the findings suggest that both clinical teachers and especially preceptors need to increase the number of higher level questions they ask.

Conclusions. Based on the findings of this study, it is evident that there is a need for further comparative studies into the questioning skills of clinical teachers and preceptors. Also, these two groups require education about the importance of higher level questioning for student learning as well as how to ask questions generally.

Clinical usefulness and feasibility of using Reality Orientation with patients who have dementia in acute care settings

Reality Orientation (RO) was developed as a strategy to assist people with dementia to improve their orientation and everyday function. Although its efficacy has been extensively studied in long-term care facilities, its effectiveness has rarely been examined in acute care settings. The aim of this review was to examine the studies cited in systematic reviews of RO to determine the potential clinical usefulness and the feasibility of using RO in acute care settings. Based on this information, the authors make recommendations for future research in this area. The feasibility of implementing RO in acute care poses challenges because of the short time a patient is in hospital and their ability to participate given their acute medical condition. Although the efficacy and feasibility of using RO in acute care settings have not been sufficiently examined, its potential to improve care should not be ignored. A comprehensive and rigorous study is necessary to investigate the usefulness of RO in the acute care setting and to help establish clinical guidelines for dementia care in the context of acute care nursing.

Almost there : empirical insights into clinical method and ethics courses in climbing the hill towards lawyers' professionalism

Results of a study into the relationships between values and ethical behaviour for early-career legal practitioners - effect of gender, clinical experience and prior ethics education - implications for ethics education in tertiary institutions and after admission to legal practice.

Clinical placement and rurality of career commencement : a pilot study

This article reports on a project that aimed to discover whether rural placement can influence new graduates to take up rural positions, and what factors play a role in the decision-making. This pilot study reports the findings from a pre-survey of students (n = 110) who completed a questionnaire at the end of their rural placement in the Greater Green Triangle region, Australia. Findings are compared with matched questionnaire responses for students who subsequently completed a post-survey after graduation and who commenced work (n = 28). Rural placement appears to be associated with commencing rural practice after graduation. More graduates with an urban home address commenced rural practice than graduates with a rural home address who started their careers in the city. Longer placements may sway those with a city background to start work in a rural area.

Mother–infant psychotherapy and perinatal psychiatry: current clinical practice and future directions

Objective: To explore trends in the practice of mother-infant psychotherapy among perinatal psychiatry clinicians based in Melbourne.Methods: A cross-sectional survey with a purpose designed self-report questionnaire was used to assess the attitudes and practices of 47 perinatal and infant psychiatry clinicians in their use and understanding of mother-infant psychotherapy.Results: Seventy per cent of clinicians in this field of psychotherapy who responded to the questionnaire subscribe to a psychodynamic model, although cognitive behavioural models are also used. The interventions were mostly used in conjunction with other interventions, would be more accurately described as 'parent-infant psychotherapy', and non-psychiatrists in the area tended to be more likely to be formally trained in psychotherapy, but only 4% were formally trained in specific mother-infant psychotherapy. There was a unanimous request for further clinical training in this area.Conclusions: The emerging field of perinatal psychiatry needs to develop coherent therapeutic models and conduct outcome trials on specific interventions. Specific trainings in these models, in assessment and in diagnostic frameworks are required to enhance clinical efficacy, for research and service development purposes.

Clinical supervision and symmetrical communication : towards a critical practice of supervision

The central argument of the thesis is that the dominant modes of the supervision of teaching are in need of critique and reconstruction. From a critical perspective, supervision is viewed as a political and ideological process enacted through asymmetrical relations and structures of communication. It is underpinned by a discourse of technocratic rationality and control Clinical supervision, a currently popular model of teacher supervision, has (despite its emancipatory origins) been accommodated by the dominant ideology and is employed as a hegemonic mechanism of evaluation, control and even dismissal of teachers. However, historical analysis reveals that teachers have contested and resisted authoritarianism and centralized control in favour of developing more democratic and participatory forms of professional development. In these moves can be found a rationale for a reconstruction of the theory and practice of clinical supervision around the concepts of symmetrical communication and critical pedagogy. The researcher engaged in a self-reflective study with a group of supervisors and teachers in N.S.W. schools to explore the possibilities and limitations of a critical and counter-hegemonic practice of supervision. The outcomes, in the form of three case studies, are analysed in terms of a dialectic of reconstruction and maintenance of the status quo. The evidence reveals that some of the research participants sought to reconstruct their supervisory relationships in ways which challenged the bureaucratic structures of their workplace. Others, however, rejected the emancipatory possibilities and resolved to maintain their traditional hierarchical relationship.

Cystic fibrosis in children of the eastern Arabian peninsula : a clinical, spatial and genetic study

Aim: The aim of this thesis is to describe the process by which the inherited disease, cystic fibrosis, (CF) was recognised as an important clinical entity in the United Arab Emirates (UAE) and the Sultanate of Oman (Oman). It examines the clinical presentation of the first patients and assesses their degree of severity. Further, it describes the first studies carried out to determine the underlying CF mutations associated with the disease in the UAE and Oman. An estimate is offered of the birth frequency of the condition. Overall, the cultural, geographical and historical aspect of the societies in which the disease occurs is stressed. Methods: An initial literature search was carried out using Medline of any literature pertaining to the Arab World and CF. this was read and classified into the relevance to Arabs in general, the Middle East and then specifically the Arab (Persian) Gulf societies. Thereafter, a clinic was established at Tawam Hospital, Al Ain, UAE, for children presenting With chronic respiratory disease that could serve as a national referral centre. It was run by the Author as a service of the Paediatric Department of the UAE University Medical School. I sent a letter to every Paediatrician working in the UAE informing them of our clinic and offering our services for the diagnosis and management of chronic respiratory disease in children. This was based on the author's experience as a respiratory paediatrician in Australia and New Zealand and as the Professor of Paediatrics in the UAE. No such service then existed in the UAE. Funding was sought to establish a research programme and develop a molecular genetics laboratory in the UAE Medical School. A series of successful research applications provided the grants to commence the investigations. Once a small number of children had been identified as having CF from those referred to the respiratory clinic, the initial project was to assess and report their clinical presentation. Following this an early start was made on the identification of the mutations responsible. Once these were established an attempt was made to estimate the frequency of the condition at birth. Additional clinical studies revolved around assessing the severity of the condition that was associated with the main mutations that were identified. A clinical comparison was made with those with the mutation AF508 and the other main mutation, despite the obvious limitation of small numbers then available. Radiological assessment was made to evaluate the progression of the disease. The final aspect of the study was to assess patients from Oman and compare their findings and mutations with the neighbouring UAE. Based on information gained hypotheses are proposed regarding the spread of the gene mutation by population drift. Thesis outline: A literature review is presented in the form of a critique on the disease and a resume of the relevant aspects of the genetics of CF. Additionally, facts about the two countries' geography and history are presented. Finally, knowledge about CF mutations and population origins from other areas is presented. The second main section deals with the clinical features of the disorder as it presents in the UAE. Molecular findings are then presented and details of the common mutation found in Bedouin Arabs. Hypotheses are then presented based on the information gathered. Results: CF is not a rare disease in the Arab children of the UAE and Oman. These findings refute previous reports of CF being a rare or non-existent disease in Arabs. The condition presents with a severe clinical picture, with early colonisation of the respiratory tract with staphylococcus, haemophilus and pseudomonas organisms, even with conventional CF management practices in place. The CF mutation S549R is prevalent in Arabs of Bedouin stock, while AF508 is found in those of Baluch origin. The former may be descendants of Arabs who left southern Arabia and travelled to the Trucial Coast at the time of the destruction of the great dam at Marib. The origins of this mutation may lie in the area that corresponds to the modern Republic of Yemen. The latter groups are descendants of those who came originally from Baluchistan. It is hypothesised also that the ancestral home of the AF508 mutation may be in the geographical area now known as Baluchistan, that spans three separate modern political territories. The evidence presented supports the concept that the S549R mutation may be associated with a severe, if not the severest, clinical pattern recognised. It equates with that seen with the homozygous AF508 genotype. The absence of an additional mutation in the promoter region accounts for the different clinical pattern seen in previously described patients. Conclusions: There needs to be a major awareness of the presence of CF as a severe clinical disease in the children of the Gulf States. The clinical presentation and findings support the concept of under recognition of the disease. Climatic conditions put the children at special risk of hyponatraemia and electrolyte imbalance. The absence of surviving adults with the disease suggests premature deaths have occurred, but the high fertility rates have maintained the gene pool for this recessive disorder.

Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia

Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy. The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient. The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.