Compliance, peritoneal dialysis and chronic kidney disease : lessons from the literature

Poor patient compliance with peritoneal dialysis (PD) has significant adverse effects on morbidity and mortality rates in individuals with chronic kidney disease (CKD). It also adds to the resource burdens of healthcare services and providers. This paper explores the notion of PD compliance in patients with CKD with reference to the relevant published literature. The analysis of the literature reveals that ‘PD compliance’ is a complex and challenging construct for both patients and health professionals. There is no universal definition of compliance that is widely adopted in practice and research, and therefore a lack of consensus on how to determine ‘compliant’ patient outcomes. There are also multiple and interconnected determinants of PD compliance that are context-bound, which healthcare professionals must be aware of, and which makes producing consensus of measuring PD compliance difficult. The complexity of the interventions required to produce even a modest improvement in PD compliance, which are described in this paper, are significant. Compliance with PD and other treatments for CKD is a multidimensional, context-bound concept, that to date has tended to efface the role and needs of the renal patient. We conclude the paper with the implications for contemporary practice.

The use of economic evaluation in CAM : an introductory framework

Background For CAM to feature prominently in health care decision-making there is a need to expand the evidence-base and to further incorporate economic evaluation into research priorities. In a world of scarce health care resources and an emphasis on efficiency and clinical efficacy, CAM, as indeed do all other treatments, requires rigorous evaluation to be considered in budget decision-making. Methods Economic evaluation provides the tools to measure the costs and health consequences of CAM interventions and thereby inform decision making. This article offers CAM researchers an introductory framework for understanding, undertaking and disseminating economic evaluation. The types of economic evaluation available for the study of CAM are discussed, and decision modelling is introduced as a method for economic evaluation with much potential for use in CAM. Two types of decision models are introduced, decision trees and Markov models, along with a worked example of how each method is used to examine costs and health consequences. This is followed by a discussion of how this information is used by decision makers. Conclusions Undoubtedly, economic evaluation methods form an important part of health care decision making. Without formal training it can seem a daunting task to consider economic evaluation, however, multidisciplinary teams provide an opportunity for health economists, CAM practitioners and other interested researchers, to work together to further develop the economic evaluation of CAM.

Potential of St John's Wort for the treatment of depression : the economic perspective

The burden of rising health care expenditures has created a demand for information regarding the clinical and economic outcomes associated with complementary and alternative medicines. Meta-analyses of randomized controlled trials have found Hypericum perforatum preparations to be superior to placebo and similarly effective as standard antidepressants in the acute treatment of mild to moderate depression. A clear advantage over antidepressants has been demonstrated in terms of the reduced frequency of adverse effects and lower treatment withdrawal rates, low rates of side effects and good compliance, key variables affecting the cost-effectiveness of a given form of therapy. The most important risk associated with use is potential interactions with other drugs, but this may be mitigated by using extracts with low hyperforin content. As the indirect costs of depression are greater than five times direct treatment costs, given the rising cost of pharmaceutical antidepressants, the comparatively low cost of Hypericum perforatum extract makes it worthy of consideration in the economic evaluation of mild to moderate depression treatments.

Effect of acupressure on thirst in hemodialysis patients

Background: Thirst and dry mouth are common among hemodialysis (HD) patients. This paper reports a study to evaluate the impact of an acupressure program on HD patients’ thirst and salivary flow rates. Methods: The acupressure program included placebo, followed by true acupressure each applied for 4 weeks. Twenty-eight patients (mean age 57.6, SD = 16.13 years) first received a sticker as placebo acupressure at two acupoints CV23 and TE17 three times a week for 4 weeks, and then received true acupressure in the same area for the next 4 weeks. Salivary flow rate and thirst intensity were measured at baseline, during and after treatment completion for both the placebo and true acupressure program. Results: The true acupressure program was associated with significantly increased salivary flow rate (0.09 ± 0.08 ml/min at baseline to 0.12 ± 0.08 ml/min after treatments completion, p = 0.04). The mean thirst intensity also improved from 4.21 ± 2.66 at baseline to 2.43 ± 2.32 (p = 0.008) after treatment completion in HD patients. There was no statistically significant difference in pre-post program salivary flow rate; however, significant improvement in thirst intensity scores was observed (p = 0.009) in the placebo acupressure program. Conclusion: This study provides preliminary evidence that acupressure may be effective in improving salivary flow rates and thirst intensity.

Best practice for prevention and treatment of cardiovascular disease through an equity lens : a review

Background: Despite declining rates of cardiovascular disease (CVD) mortality in developed countries, lower socioeconomic groups continue to experience a greater burden of the disease. There are now many evidence-based treatments and prevention strategies for the management of CVD and it is essential that their impact on the more disadvantaged group is understood if socioeconomic inequalities in CVD are to be reduced. Aims: To determine whether key interventions for CVD prevention and treatment are effective among lower socioeconomic groups, to describe barriers to their effectiveness and the potential or actual impact of these interventions on the socioeconomic gradient in CVD. Methods: Interventions were selected from four stages of the CVD continuum. These included smoking reduction strategies, absolute risk assessment, cardiac rehabilitation, secondary prevention medications, and heart failure self-management programmes. Electronic searches were conducted using terms for each intervention combined with terms for socioeconomic status (SES). Results: Only limited evidence was found for the effectiveness of the selected interventions among lower SES groups and there was little exploration of socioeconomic-related barriers to their uptake. Some broad themes and key messages were identified. In the majority of findings examined, it was clear that the underlying material, social and environmental factors associated with disadvantage are a significant barrier to the effectiveness of interventions. Conclusion: Opportunities to reduce socioeconomic inequalities occur at all stages of the CVD continuum. Despite this, current treatment and prevention strategies may be contributing to the widening socioeconomic-CVD gradient. Further research into the impact of best-practice interventions for CVD upon lower SES groups is required.

Population-based survival estimates for childhood cancer in Australia during the period 1997–2006

Background: This study provides the latest available relative survival data for Australian childhood cancer patients. Methods: Data from the population-based Australian Paediatric Cancer Registry were used to describe relative survival outcomes using the period method for 11 903 children diagnosed with cancer between 1983 and 2006 and prevalent at any time between 1997 and 2006. Results: The overall relative survival was 90.4% after 1 year, 79.5% after 5 years and 74.7% after 20 years. Where information onstage at diagnosis was available (lymphomas, neuroblastoma, renal tumours and rhabdomyosarcomas), survival was significantly poorer for more-advanced stage. Survival was lower among infants compared with other children for those diagnosed with leukaemia, tumours of the central nervous system and renal tumours but higher for neuroblastoma. Recent improvements in overall childhood cancer survival over time are mainly because of improvements among leukaemia patients. Conclusion: The high and improving survival prognosis for children diagnosed with cancer in Australia is consistent with various international estimates. However, a 5-year survival estimate of 79% still means that many children who are diagnosed with cancer will die within 5 years, whereas others have long-term health morbidities and complications associated with their treatments. It is hoped that continued developments in treatment protocols will result in further improvements in survival.

The ghrelin receptor isoforms (GHS-R1a and GHS-R1b) and GPR39 : an investigation into receptor dimerisation

Prostate cancer is the second most common cause of cancer-related deaths in Western males. Current diagnostic, prognostic and treatment approaches are not ideal and advanced metastatic prostate cancer is incurable. There is an urgent need for improved adjunctive therapies and markers for this disease. GPCRs are likely to play a significant role in the initiation and progression of prostate cancer. Over the last decade, it has emerged that G protein coupled receptors (GPCRs) are likely to function as homodimers and heterodimers. Heterodimerisation between GPCRs can result in the formation of novel pharmacological receptors with altered functional outcomes, and a number of GPCR heterodimers have been implicated in the pathogenesis of human disease. Importantly, novel GPCR heterodimers represent potential new targets for the development of more specific therapeutic drugs. Ghrelin is a 28 amino acid peptide hormone which has a unique n-octanoic acid post-translational modification. Ghrelin has a number of important physiological roles, including roles in appetite regulation and the stimulation of growth hormone release. The ghrelin receptor is the growth hormone secretagogue receptor type 1a, GHS-R1a, a seven transmembrane domain GPCR, and GHS-R1b is a C-terminally truncated isoform of the ghrelin receptor, consisting of five transmembrane domains. Growing evidence suggests that ghrelin and the ghrelin receptor isoforms, GHS-R1a and GHS-R1b, may have a role in the progression of a number of cancers, including prostate cancer. Previous studies by our research group have shown that the truncated ghrelin receptor isoform, GHS-R1b, is not expressed in normal prostate, however, it is expressed in prostate cancer. The altered expression of this truncated isoform may reflect a difference between a normal and cancerous state. A number of mutant GPCRs have been shown to regulate the function of their corresponding wild-type receptors. Therefore, we investigated the potential role of interactions between GHS-R1a and GHS-R1b, which are co-expressed in prostate cancer and aimed to investigate the function of this potentially new pharmacological receptor. In 2005, obestatin, a 23 amino acid C-terminally amidated peptide derived from preproghrelin was identified and was described as opposing the stimulating effects of ghrelin on appetite and food intake. GPR39, an orphan GPCR which is closely related to the ghrelin receptor, was identified as the endogenous receptor for obestatin. Recently, however, the ability of obestatin to oppose the effects of ghrelin on appetite and food intake has been questioned, and furthermore, it appears that GPR39 may in fact not be the obestatin receptor. The role of GPR39 in the prostate is of interest, however, as it is a zinc receptor. Zinc has a unique role in the biology of the prostate, where it is normally accumulated at high levels, and zinc accumulation is altered in the development of prostate malignancy. Ghrelin and zinc have important roles in prostate cancer and dimerisation of their receptors may have novel roles in malignant prostate cells. The aim of the current study, therefore, was to demonstrate the formation of GHS-R1a/GHS-R1b and GHS-R1a/GPR39 heterodimers and to investigate potential functions of these heterodimers in prostate cancer cell lines. To demonstrate dimerisation we first employed a classical co-immunoprecipitation technique. Using cells co-overexpressing FLAG- and Myc- tagged GHS-R1a, GHS-R1b and GPR39, we were able to co-immunoprecipitate these receptors. Significantly, however, the receptors formed high molecular weight aggregates. A number of questions have been raised over the propensity of GPCRs to aggregate during co-immunoprecipitation as a result of their hydrophobic nature and this may be misinterpreted as receptor dimerisation. As we observed significant receptor aggregation in this study, we used additional methods to confirm the specificity of these putative GPCR interactions. We used two different resonance energy transfer (RET) methods; bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), to investigate interactions between the ghrelin receptor isoforms and GPR39. RET is the transfer of energy from a donor fluorophore to an acceptor fluorophore when they are in close proximity, and RET methods are, therefore, applicable to the observation of specific protein-protein interactions. Extensive studies using the second generation bioluminescence resonance energy transfer (BRET2) technology were performed, however, a number of technical limitations were observed. The substrate used during BRET2 studies, coelenterazine 400a, has a low quantum yield and rapid signal decay. This study highlighted the requirement for the expression of donor and acceptor tagged receptors at high levels so that a BRET ratio can be determined. After performing a number of BRET2 experimental controls, our BRET2 data did not fit the predicted results for a specific interaction between these receptors. The interactions that we observed may in fact represent ‘bystander BRET’ resulting from high levels of expression, forcing the donor and acceptor into close proximity. Our FRET studies employed two different FRET techniques, acceptor photobleaching FRET and sensitised emission FRET measured by flow cytometry. We were unable to observe any significant FRET, or FRET values that were likely to result from specific receptor dimerisation between GHS-R1a, GHS-R1b and GPR39. While we were unable to conclusively demonstrate direct dimerisation between GHS-R1a, GHS-R1b and GPR39 using several methods, our findings do not exclude the possibility that these receptors interact. We aimed to investigate if co-expression of combinations of these receptors had functional effects in prostate cancers cells. It has previously been demonstrated that ghrelin stimulates cell proliferation in prostate cancer cell lines, through ERK1/2 activation, and GPR39 can stimulate ERK1/2 signalling in response to zinc treatments. Additionally, both GHS-R1a and GPR39 display a high level of constitutive signalling and these constitutively active receptors can attenuate apoptosis when overexpressed individually in some cell types. We, therefore, investigated ERK1/2 and AKT signalling and cell survival in prostate cancer the potential modulation of these functions by dimerisation between GHS-R1a, GHS-R1b and GPR39. Expression of these receptors in the PC-3 prostate cancer cell line, either alone or in combination, did not alter constitutive ERK1/2 or AKT signalling, basal apoptosis or tunicamycin-stimulated apoptosis, compared to controls. In summary, the potential interactions between the ghrelin receptor isoforms, GHS-R1a and GHS-R1b, and the related zinc receptor, GPR39, and the potential for functional outcomes in prostate cancer were investigated using a number of independent methods. We did not definitively demonstrate the formation of these dimers using a number of state of the art methods to directly demonstrate receptor-receptor interactions. We investigated a number of potential functions of GPR39 and GHS-R1a in the prostate and did not observe altered function in response to co-expression of these receptors. The technical questions raised by this study highlight the requirement for the application of extensive controls when using current methods for the demonstration of GPCR dimerisation. Similar findings in this field reflect the current controversy surrounding the investigation of GPCR dimerisation. Although GHS-R1a/GHS-R1b or GHS-R1a/GPR39 heterodimerisation was not clearly demonstrated, this study provides a basis for future investigations of these receptors in prostate cancer. Additionally, the results presented in this study and growing evidence in the literature highlight the requirement for an extensive understanding of the experimental method and the performance of a range of controls to avoid the spurious interpretation of data gained from artificial expression systems. The future development of more robust techniques for investigating GPCR dimerisation is clearly required and will enable us to elucidate whether GHS-R1a, GHS-R1b and GPR39 form physiologically relevant dimers.

Corneal confocal microscopy : a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE: The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies. ---------- RESEARCH DESIGN AND METHODS: A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM). ---------- RESULTS: Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm2 with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm2 with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74). ---------- CONCLUSIONS: CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity. Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal. In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.

Identification of factors contributing to recurrence of venous leg ulcers

Background and Significance Venous leg ulcers are a significant cause of chronic ill-health for 1–3% of those aged over 60 years, increasing in incidence with age. The condition is difficult and costly to heal, consuming 1–2.5% of total health budgets in developed countries and up to 50% of community nursing time. Unfortunately after healing, there is a recurrence rate of 60 to 70%, frequently within the first 12 months after heaing. Although some risk factors associated with higher recurrence rates have been identified (e.g. prolonged ulcer duration, deep vein thrombosis), in general there is limited evidence on treatments to effectively prevent recurrence. Patients are generally advised to undertake activities which aim to improve the impaired venous return (e.g. compression therapy, leg elevation, exercise). However, only compression therapy has some evidence to support its effectiveness in prevention and problems with adherence to this strategy are well documented. Aim The aim of this research was to identify factors associated with recurrence by determining relationships between recurrence and demographic factors, health, physical activity, psychosocial factors and self-care activities to prevent recurrence. Methods Two studies were undertaken: a retrospective study of participants diagnosed with a venous leg ulcer which healed 12 to 36 months prior to the study (n=122); and a prospective longitudinal study of participants recruited as their ulcer healed and data collected for 12 months following healing (n=80). Data were collected from medical records on demographics, medical history and ulcer history and treatments; and from self-report questionnaires on physical activity, nutrition, psychosocial measures, ulcer history, compression and other self-care activities. Follow-up data for the prospective study were collected every three months for 12 months after healing. For the retrospective study, a logistic regression model determined the independent influences of variables on recurrence. For the prospective study, median time to recurrence was calculated using the Kaplan-Meier method and a Cox proportional-hazards regression model was used to adjust for potential confounders and determine effects of preventive strategies and psychosocial factors on recurrence. Results In total, 68% of participants in the retrospective study and 44% of participants in the prospective study suffered a recurrence. After mutual adjustment for all variables in multivariable regression models, leg elevation, compression therapy, self efficacy and physical activity were found to be consistently related to recurrence in both studies. In the retrospective study, leg elevation, wearing Class 2 or 3 compression hosiery, the level of physical activity, cardiac disease and self efficacy scores remained significantly associated (p<0.05) with recurrence. The model was significant (p <0.001); with a R2 equivalent of 0.62. Examination of relationships between psychosocial factors and adherence to wearing compression hosiery found wearing compression hosiery was significantly positively associated with participants’ knowledge of the cause of their condition (p=0.002), higher self-efficacy scores (p=0.026) and lower depression scores (p=0.009). Analysis of data from the prospective study found there were 35 recurrences (44%) in the 12 months following healing and median time to recurrence was 27 weeks. After adjustment for potential confounders, a Cox proportional hazards regression model found that at least an hour/day of leg elevation, six or more days/week in Class 2 (20–25mmHg) or 3 (30–40mmHg) compression hosiery, higher social support scale scores and higher General Self-Efficacy scores remained significantly associated (p<0.05) with a lower risk of recurrence, while male gender and a history of DVT remained significant risk factors for recurrence. Overall the model was significant (p <0.001); with an R2 equivalent 0.72. Conclusions The high rates of recurrence found in the studies highlight the urgent need for further information in this area to support development of effective strategies for prevention. Overall, results indicate leg elevation, physical activity, compression hosiery and strategies to improve self-efficacy are likely to prevent recurrence. In addition, optimal management of depression and strategies to improve patient knowledge and self-efficacy may positively influence adherence to compression therapy. This research provides important information for development of strategies to prevent recurrence of venous leg ulcers, with the potential to improve health and decrease health care costs in this population.

Paradigm shifters : tricksters and cultural science

This paper seeks to link anthropological and economic treatments of the process of innovation and change, not only within a given ‘complex system’ (e.g. a cosmology; an industry) but also between systems (e.g. cultural and economic systems; but also divine and human systems). The role of the ‘Go-Between’ is considered, both in the anthropological figure of the Trickster (Hyde 1998) and in the Schumpeterian entrepreneur. Both figures parlay appetite (economic wants) into meaning (cultural signs). Both practice a form of creativity based on deception, ‘creative destruction’; renewal by disruption and needs-must adaptation. The disciplinary purpose of the paper is to try to bridge two otherwise disconnected domains – cultural studies and evolutionary economics – by showing that the traditional methods of the humanities (e.g. anthropological, textual and historical analysis) have explanatory force in the context of economic actions and complex-system evolutionary dynamics. The objective is to understand creative innovation as a general cultural attribute rather than one restricted only to accredited experts such as artists; thus to theorise creativity as a form of emergence for dynamic adaptive systems. In this context, change is led by ‘paradigm shifters’ – tricksters and entrepreneurs who create new meanings out of the clash of difference, including the clash of mutually untranslatable communication systems (language, media, culture).

The role of assisted self-help in services for alcohol-related disorders

Potentially harmful substance use is common, but many affected people do not receive treatment. Brief face-to-face treatments show impact, as do strategies to assist self-help remotely, by using bibliotherapies, computers or mobile phones. Remotely delivered treatments offer more sustained and multifaceted support than brief interventions, and they show a substantial cost advantage as users increase in number. They may also build skills, confidence and treatment fidelity in providers who use them in sessions. Engagement and retention remain challenges, but electronic treatments show promise in engaging younger populations. Recruitment may be assisted by integration with community campaigns or brief opportunistic interventions. However, routine use of assisted self-help by standard services faces significant challenges. Strategies to optimize adoption are discussed. ----- ----- Research Highlights: ► Many people with risky or problematic drinking do not currently receive treatment. ► Assisted self-help has a significant impact and can be delivered at low cost. ► Maximal effects from assisted self-help require engagement of potential users. ► Marketing campaigns and integration into existing service models may assist.

Implementing low intensity CBT in case management of clients with severe mental illness

In a previous chapter (Dean and Kavanagh, Chapter 37), the authors made a case for applying low intensity (LI) cognitive behaviour therapy (CBT) to people with serious mental illness (SMI). As in other populations, LI CBT interventions typically deal with circumscribed problems or behaviours. LI CBT retains an emphasis on self-management, has restricted content and segment length, and does not necessarily require extensive CBT training. In applying these interventions to SMI, adjustments may be needed to address cognitive and symptomatic difficulties often faced by these groups. What may take a single session in a less affected population may require several sessions or a thematic application of the strategy within case management. In some cases, the LI CBT may begin to appear more like a high-intensity (HI) intervention, albeit simple and with many LI CBT characteristics still retained. So, if goal setting were introduced in one or two sessions, it could clearly be seen as an LI intervention. When applied to several different situations and across many sessions, it may be indistinguishable from a simple HI treatment, even if it retains the same format and is effectively applied by a practitioner with limited CBT training. ----- ----- In some ways, LI CBT should be well suited to case management of patients with SMI. treating staff typically have heavy workloads, and find it difficult to apply time-consuming treatments (Singh et al. 2003). LI CBT may allow provision of support to greater numbers of service users, and allow staff to spend more time on those who need intensive and sustained support. However, the introduction of any change in practice has to address significant challenges, and LI CBT is no exception. ----- ----- Many of the issues that we face in applying LI CBT to routine case management in a mnetal health service and their potential solutions are essentially the same as in a range of other problem domains (Turner and Sanders 2006)- and, indeed, are similar to those in any adoption of innovation (Rogers 2003). Over the last 20 years, several commentators have described barriers to implementing evidence-based innovations in mental health services (Corrigan et al. 1992; Deane et al. 2006; Kavanagh et al. 1993). The aim of the current chapter is to present a cognitive behavioural conceptualisation of problems and potential solutions for dissemination of LI CBT.

Brief motivational interviewing for depression and anxiety

Motivational interviewing (MI)can be applied as a brief, low intensity (LI) intervention of 1-4 individualised sessions (typically 45-60 minutes in duration), including screening, assessment feedback, and psycho-education. MI is a client-centred, directive therapeutic style that enhances readiness for change by helping clients explore and resolve ambivalence (Miller and Rollnick 2002). A summary of the key components of brief MI interventions is provided in Table 16.1. There is a well-established evidence base for MI in the treatment of substance misuse (particularly alcohol misuse; Moyer et al. 2002), as well as a growing evidence for the use of MI in the treatment of other mental disorders (e.g. depression, PTSD, OCD), as well as suicidality and physical health problems (Hettema et al. 2005). Brief MI intervention can be delivered as a standalone treatment or as a motivational prelude to pharmacological and/or other psychological treatments (Hettema et al. 2005). MI has been used as an accompaniment to cognitive behavioural therapy (CBT) in the treatment of both depression and anxiety for resolving ambivalence about change and developing strategies for responding to resistance (e.g. treatment attendance, homework/medication compliance; Arkowitz et al. 2008a, 2008b). This chapter will describe how to apply brief MI interventions to the treatment of depression and anxiety as applied to the case of Megan (see Box 16.1) along with some of the challenges and potential solutions to applying MI in practice.

Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.

Mesenchymal stem cells

Cell based therapies as they apply to tissue engineering and regenerative medicine, require cells capable of self renewal and differentiation, and a prerequisite is to be able to prepare an effective dose of ex vivo expanded cells for autologous transplants. The in vivo identification of a source of physiologically relevant cell types suitable for cell therapies therefore figures as an integral part of tissue engineering. Stem cells serve as a reserve for biological repair, having the potential to differentiate into a number of specialised cell types within the body; they therefore represent the most useful candidates for cell based therapies. The primary goal of stem cell research is to produce cells that are both patient specific, as well as having properties suitable for the specific conditions for which they are intended to remedy. From a purely scientific perspective, stem cells allow scientists to gain a deeper understanding of developmental biology and regenerative therapies. Stem cells have acquired a number of uses for applications in regenerative medicine, immunotherapy, gene therapy, but it is in the area of tissue engineering that they generate most excitement, primarily as a result of their capacity for self-renewal and pluripotency. A unique feature of stem cells is their ability to maintain an uncommitted quiescent state in vivo and then, once triggered by conditions such as disease, injury or natural wear or tear, serve as a reservoir and natural support system to replenish lost cells. Although these cells retain the plasticity to differentiate into various tissues, being able to control this differentiation process is still one of the biggest challenges facing stem cell research. In an effort to harness the potential of these cells a number of studies have been conducted using both embryonic/foetal and adult stem cells. The use of embryonic stem cells (ESC) have been hampered by strong ethical and political concerns, this despite their perceived versatility due to their pluripotency. Ethical issues aside, other concerns raised with ESCs relates to the possibility of tumorigenesis, immune rejection and complications with immunosuppressive therapies, all of which adds layers of complications to the application ESC in research and which has led to the search for alternative sources for stem cells. The adult tissues in higher organisms harbours cells, termed adult stem cells, and these cells are reminiscent of unprogrammed stem cells. A number of sources of adult stem cells have been described. Bone marrow is by far the most accessible source of two potent populations of adult stem cells, namely haematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (BMSCs). Autologously harvested adult stem cells can, in contrast to embryonic stem cells, readily be used in autografts, since immune rejection is not an issue; and their use in scientific research has not attracted the ethical concerns which have been the case with embryonic stem cells. The major limitation to their use, however, is the fact that adult stem cells are exceedingly rare in most tissues. This fact makes identifying and isolating these cells problematic; bone marrow being perhaps the only notable exception. Unlike the case of HSCs, there are as yet no rigorous criteria for characterizing MSCs. Changing acuity about the pluripotency of MSCs in recent studies has expanded their potential application; however, the underlying molecular pathways which impart the features distinctive to MSCs remain elusive. Furthermore, the sparse in vivo distribution of these cells imposes a clear limitation to their study in vitro. Also, when MSCs are cultured in vitro, there is a loss of the in vivo microenvironment, resulting in a progressive decline in proliferation potential and multipotentiality. This is further exacerbated with increased passage numbers in culture, characterized by the onset of senescence related changes. As a consequence, it is necessary to establish protocols for generating large numbers of MSCs but without affecting their differentiation potential. MSCs are capable of differentiating into mesenchymal tissue lineages, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Recent findings indicate that adult bone marrow may also contain cells that can differentiate into the mature, nonhematopoietic cells of a number of tissues, including cells of the liver, kidney, lung, skin, gastrointestinal tract, and myocytes of heart and skeletal muscle. MSCs can readily be expanded in vitro and can be genetically modified by viral vectors and be induced to differentiate into specific cell lineages by changing the microenvironment–properties which makes these cells ideal vehicles for cellular gene therapy. MSCs can also exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways, and this property allows them to overcome the issue of immune rejection. Despite the many attractive features associated with MSCs, there are still many hurdles to overcome before these cells are readily available for use in clinical applications. The main concern relates to in vivo characterization and identification of MSCs. The lack of a universal biomarker, sparse in vivo distribution, and a steady age related decline in their numbers, makes it an obvious need to decipher the reprogramming pathways and critical molecular players which govern the characteristics unique to MSCs. This book presents a comprehensive insight into the biology of adult stem cells and their utility in current regeneration therapies. The adult stem cell populations reviewed in this book include bone marrow derived MSCs, adipose derived stem cells (ASCs), umbilical cord blood stem cells, and placental stem cells. The features such as MSC circulation and trafficking, neuroprotective properties, and the nurturing roles and differentiation potential of multiple lineages have been discussed in details. In terms of therapeutic applications, the strengths of MSCs have been presented and their roles in disease treatments such as osteoarthritis, Huntington’s disease, periodontal regeneration, and pancreatic islet transplantation have been discussed. An analysis comparing osteoblast differentiation of umbilical cord blood stem cells and MSCs has been reviewed, as has a comparison of human placental stem cells and ASCs, in terms of isolation, identification and therapeutic applications of ASC in bone, cartilage regeneration, as well as myocardial regeneration. It is my sincere hope that this book will update the reader as to the research progress of MSC biology and potential use of these cells in clinical applications. It will be the best reward to all contributors of this book, if their efforts herein may in some way help the readers in any part of their study, research, and career development.