Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines : targets for therapy

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor—plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride {[Au(DPPE)2]Cl}, CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rhl23), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-S1a was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.

Productivity and time use during occupational therapy and nutrition/dietetics clinical education : a cohort study

Background: Currently in the Australian higher education sector higher productivity from allied health clinical education placements are a contested issue. This paper will report results of a study that investigated output changes associated with occupational therapy and nutrition/dietetics clinical education placements in Queensland, Australia. Supervisors’ and students’ time use during placements and how this changes for supervisors compared to when students are not present in the workplace is also presented. Methodology/Principal Findings: A cohort design was used with students from four Queensland universities, and their supervisors employed by Queensland Health. There was an increasing trend in the number of occasions of service delivered when the students were present, and a statistically significant increase in the daily mean length of occasions of service delivered during the placement compared to pre-placement levels. For project-based placements that were not directly involved in patient care, supervisors’ project activity time decreased during placements, with students undertaking considerably more time in project activities. Conclusions/Significance: A novel method for estimating productivity and time use changes during clinical education programs for allied health disciplines has been applied. During clinical education placements there was a net increase in outputs, suggesting supervisors engage in longer consultations with patients for the purpose of training students, while maintaining patient numbers. Other activities are reduced. This paper is the first time these data have been shown and form a good basis for future assessments of the economic impact of student placements for allied health disciplines.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

Development and review of vignettes representing older people with cognitive impairment

This paper describes a process undertaken to develop and review five clinical vignettes to be used in geriatric nursing educational research. The purpose of this process was to provide valid depictions of delirium and its subtypes and distinguish delirium from dementia. Five vignettes depicting hospital bedside interactions between nursing staff, family, and an older patient who displayed signs of one of the following conditions: delirium (hyper and hypo-active types respectively), dementia, or delirium (both types) superimposed on dementia were constructed. Vignette accuracy and reliability was established using a multistage process that culminated in formal review by a group of ten international nursing and medical delirium experts. The final five vignettes accurately depicted the given scenario as agreed by the experts and were at an appropriate level of simplicity and clarity. Given the increased interest in vignettes for both nursing research and educational purposes, the described method of vignette development and review has the ability to assist other vignette developers in creating reliable representations of their desired clinical scenarios.

ASAP ECMO : antibiotic, sedative and analgesic pharmacokinetics during extracorporeal membrane oxygenation : a multi-centre study to optimise drug therapy during ECMO

BACKGROUND: Given the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO. METHODS: This is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO. DISCUSSION: The evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure

Social cognitive mediators of the effect of the MobileMums intervention on physical activity

Objective To explore whether improvements in physical activity following the MobileMums intervention were mediated by changes in Social Cognitive Theory (SCT) constructs targeted in the intervention (barrier self efficacy, goal setting skills, outcome expectancy, social support, and perceived environmental opportunity for exercise). This paper also examined if the mediating constructs differed between initial (baseline to 6 weeks) and overall (baseline to 13 weeks) changes in physical activity. Methods Secondary analysis of data from a randomized controlled trial involving 88 postnatal women (<12 months postpartum). Participants were randomized to receive either the 12-week MobileMums intervention or a minimal-contact control condition. Physical activity and proposed mediators were assessed by self-report at baseline, 6 weeks, and 13 weeks. Walking for Exercise frequency was assessed using the Australian Women's Activity Survey and frequency of moderate-to-vigorous physical activity (MVPA) was assessed using a single-item question. Results Initial improvements in goal-setting skills mediated the relationship between experimental condition and initial changes in MVPA, αβ (95% CI) = 0.23(0.01, 0.59), and Walking for Exercise, αβ (95% CI) = 0.34(0.06, 0.73). Initial improvements in barrier self efficacy mediated the relationship between experimental condition and initial change in MVPA, αβ (95% CI) = 0.36(0.12, 0.65), but not Walking for Exercise. None of the SCT outcomes significantly mediated the relationship between experimental condition and overall (baseline to 13 weeks) change in frequency of MVPA or Walking for Exercise. Conclusion Future interventions with postnatal women using SCT should target barrier self-efficacy and goal setting skills in order to increase physical activity. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

How do older adults respond to Active Australia physical activity questions? Lessons from cognitive interviews

The aim of this study was to examine older adults’ understanding and interpretation of a validated questionnaire for physical activity surveillance, the Active Australia Survey (AAS). To address this aim, cognitive interviewing techniques were used during face-to-face semi-structured interviews with 44 adults aged 65-89 years. Qualitative data analysis revealed that participants were confused with questionnaire phrasing, misunderstood the scope of activities to include in answers, and misunderstood the time frame of activities to report. They also struggled to accurately estimate the frequency and duration of their activities. Our findings suggest that AAS questions may be interpreted differently by older adults than intended by survey developers. Findings also suggest that older adults use a range of methods for calculating PA frequency and duration. The issues revealed in this study may be useful for adapting AAS for use in older community-dwelling adults.

Outcomes following inpatient rehabilitation : a seven year perspective

Introduction: Improving physical and cognitive functioning is a key objective of multi-disciplinary inpatient geriatric rehabilitation. Outcomes relevant to minimum functional ability required for older adults to successfully participate in the community have been reported. However, there has been little investigation reporting outcomes of older inpatients receiving multi-disciplinary rehabilitation being discharged home from geriatric rehabilitation units. This study aims to investigate characteristics and physical and cognitive outcomes of this cohort. Method: The Princess Alexandra Hospital Geriatric and Rehabilitation Unit is the largest rehabilitation unit in Queensland. Multidisciplinary health professionals enter admission and discharge functional and clinical outcomes along with demographic information into a purpose designed database for all patients. Data collected between 2005 and 2011 was analysed using descriptive statistics. Results: During the seven-year period, 4120 patients were admitted for rehabilitation; 2126 (52%) were female, mean age of 74 years (Standard Deviation 14). Primary reasons for admission were for reconditioning post medical illness or surgical admission (n = 1285, 31%), and 30% (n = 1233) admitted for orthopaedic reasons. Of these orthopaedic admissions, 6.6% (n = 82) were for elective surgery, and 46% (n = 565) were for fractured neck-of-femurs. 76% (n = 3130) of patients were discharged home, 13% (n = 552) to residential care facilities and 10% (n = 430) were discharged to an alternative hospital setting or passed away during their admission. Mean length of stay was 44 days (SD 39) Preliminary analysis of FIM outcomes shows a mean motor score of 53 (SD = 19) on admission which significantly improved to 71 (SD = 18) by discharge. There was no change on FIM cognitive score (28 (SD7) vs 29 (SD 6). Conclusion: Geriatric patients have significant functional limitations even on discharge from inpatient rehabilitation; though overall cognition is relatively intact. Orthopaedic conditions and general deconditioning from medical/surgical admissions are the main reasons for admission. The majority of people receiving rehabilitation are discharged home.

Sensory imagery in craving : from cognitive psychology to new treatments for addiction

Sensory imagery is a powerful tool for inducing craving because it is a key component of the cognitive system that underpins human motivation. The role of sensory imagery in motivation is explained by Elaborated Intrusion (EI) theory. Imagery plays an important role in motivation because it conveys the emotional qualities of the desired event, mimicking anticipated pleasure or relief, and continual elaboration of the imagery ensures that the target stays in mind. We argue that craving is a conscious state, intervening between unconscious triggers and consumption, and summarise evidence that interfering with sensory imagery can weaken cravings. We argue that treatments for addiction can be enhanced by the application of EI theory to maintain motivation, and assist in the management of craving in high-risk situations.

Elaborated intrusion theory : a cognitive-emotional theory of food craving

A clear understanding of the cognitive-emotional processes underpinning desires to overconsume foods and adopt sedentary lifestyles can inform the development of more effective interventions to promote healthy eating and physical activity. The Elaborated Intrusion Theory of Desires offers a framework that can help in this endeavor through its emphases on the roles of intrusive thoughts and elaboration of multisensory imagery. There is now substantial evidence that tasks that compete for limited working memory resources with food-related imagery can reduce desires to eat that food, and that positive imagery can promote functional behavior. Meditation mindfulness can also short-circuit elaboration of dysfunctional cognition. Functional Decision Making is an approach that applies laboratory-based research on desire, to provide a motivational intervention to establish and entrench behavior changes, so healthy eating and physical activity become everyday habits.

Effect of mobile phone-based psychotherapy in suicide prevention : a randomized controlled trial in Sri Lanka

We conducted a randomized controlled trial to test whether a Brief Mobile Treatment (BMT) intervention could improve outcomes relative to usual care among suicide attempters. The intervention included training in problem solving therapy, meditation, a brief intervention to increase social support as well as advice on alcohol and other drugs, and mobile phone follow-up. The effect of the intervention was measured in terms of a reduction in suicidal ideation, depression and self-harm at Baseline, six and 12 months. A wait-list control group received usual care. A total of 68 participants was recruited from a Sri Lankan hospital following a suicide attempt. Participants who received the intervention were found to achieve significant improvements in reducing suicidal ideation and depression than those receiving usual care. The BMT group also experienced a significant improvement of social support when compared to the control group. However, the BMT group did not demonstrate a significant effect in reducing actual self-harm and most substance use, and differential effects on alcohol use were restricted to men. Although the present study was limited in revealing which component of the intervention was more effective in preventing suicide, it showed its efficacy in reducing suicide as a whole.

Response to “Topical agent therapy for prevention and treatment of radiodermatitis : a meta-analysis”

To the Editor; It was with interest that I read the recent article by Zhang et al. published in Supportive Care in Cancer [1]. This paper highlighted the importance of radiodermatitis (RD) being an unresolved and distressing clinical issue in patients with cancer undergoing radiation therapy. However, I am concerned with a number of clinical and methodological issues within this paper: (i) the clinical and operational definition of prophylaxis and treatment of RD; (ii) the accuracy of the identification of trials; and (iii) the appropriateness of the conduct of the meta-analyses...