Empirically validated interventions for adult disorders

The movement toward evidence-based practice in psychology and medicine should offer few problems in cognitive-behavior therapies because it is consistent with the principles by which they have been developed and disseminated. However, the criteria for assessing empirical status, including the heavy emphasis on manualized treatments, need close examination. A possible outcome of the evidence-based movement would be to focus on the application of manualized treatments in both training and clinical practice; problems with that approach are discussed. Commitment to evidence-based treatment should also include comparisons between psychological and pharmacological interventions, so that rational health care decisions can be made. Psychologists should not be afraid of following the evidence, even when it supports treatments that are not cognitive-behavioral in stated orientation. Such results should be taken as an opportunity for theoretical development and new empirical inquiry rather than be a cause for concern.

Tesofensine : a novel potent weight loss medicine

Background: The incidence of obesity is increasing; this is of major concern, as obesity is associated with cardiovascular disease, stroke, type 2 diabetes, respiratory tract disease, and cancer. Objectives/methods: This evaluation is of a Phase II clinical trial with tesofensine in obese subjects. Results: After 26 weeks, tesofensine caused a significant weight loss, and may have a higher maximal ability to reduce weight than the presently available anti-obesity agents. However, tesofensine also increased blood pressure and heart rate, and may increase psychiatric disorders. Conclusions: It is encouraging that tesofensine 0.5 mg may cause almost double the weight loss observed with sibutramine or rimonabant. As tesofensine and sibutramine have similar pharmacological profiles, it would be of interest to compare the weight loss with tesofensine in a head-to-head clinical trial with sibutramine, to properly assess their comparative potency. Also, as teso fensine 0.5 mg increases heart rate, as well as increasing the incidence of adverse effects such as nausea, drug mouth, flatulence, insomnia, and depressed mode, its tolerability needs to be further evaluated in large Phase III clinical trials.

Translation of addictions science into practice : update and future directions.

Recent advances in the understanding of the genetic, neurochemical, behavioral and cultural underpinnings of addiction have led to rapid advances in the understanding of addiction as a disease. In fact, advances in basic science and the development of new pharmacological and behavioral therapies associated with them are appearing faster than can be assimilated not only by clinical researchers but practitioners and policy makers as well. Translation of science-based addictions knowledge into improved prevention, assessment and treatment, and communication of these changes to researchers and practitioners are significant challenges to the field. The general aim of this book is to summarize current and potential linkages between advances in addiction science and innovations in clinical practice. Whilst this book is primarily focused on translation, it also encompasses some scientific advances that are relevant to dissemination, and the book is itself a tool for disseminating innovative thinking. The goal is to generate interest in application opportunities from both recent research and theoretical advances.

Schizophrenia : an overview and practical handbook

Schizophrenia is a serious mental disorder currently undergoing a renaissance of scientific interest. This book summarizes current knowledge and details some of the recent developments. Divided into three sections, it presents an overview of the disorder, including its features, social impact and aetiology; reviews methods of assessing the symptoms and disabilities of schizophrenia and examining the sufferer's social environment; and discusses a range of interventions, from pharmacological treatment to skill training for individuals and families. Issues that arise in planning services for sufferers and their families are also reviewed. All of the chapters focus on clinical practice and many include guides to assessment and practice. This handbook should be particularly useful in training health professionals in psychiatric/mental health services and general practice. It also aims to offer practitioners and researchers a comprehensive update on schizophrenia that is both easy to read and practical in its focus.

Management of comorbidity

Comorbidity of substance use disorders and mental disorders is very common, and there is substantial heterogeneity within subgroups in terms of both their characteristics and the nature of causal relationships between the disorders. Assessment and management strategies need to deal with both the size of the problem across the community and its severe impact in some subgroups, including those with psychosis. At this stage, the research base from which we can derive recommendations is very narrow, but it does offer a foundation for preliminary conclusions. This chapter reviews the current evidence and makes some suggestions for assessment and for both psychological and pharmacological management.

The efficacy of an augmented virtual reality system to alleviate pain in children undergoing burns dressing changes : a randomised controlled trial

In children, the pain and anxiety associated with acute burn dressing changes can be severe, with drug treatment alone frequently proving to be inadequate. Virtual reality (VR) systems have been successfully trialled in limited numbers of adult and paediatric burn patients. Augmented reality (AR) differs from VR in that it overlays virtual images onto the physical world, instead of creating a complete virtual world. This prospective randomised controlled trial investigated the use of AR as an adjunct to analgesia and sedation in children with acute burns. Forty-two children (30 male and 12 female), with an age range of 3–14 years (median age 9 years) and a total burn surface area ranging from 1 to 16% were randomised into a treatment (AR) arm and a control (basic cognitive therapy) arm after administration of analgesia and/or sedation. Pain scores, pulse rates (PR), respiratory rates (RR) and oxygen saturations (SaO2) were recorded pre-procedurally, at 10 min intervals and post-procedurally. Parents were also asked to grade their child's overall pain score for the dressing change. Mean pain scores were significantly lower (p = 0.0060) in the AR group compared to the control group, as were parental pain assessment scores (p = 0.015). Respiratory and pulse rates showed significant changes over time within groups, however, these were not significantly different between the two study groups. Oxygen saturation did not differ significantly over time or between the two study groups. This trial shows that augmented reality is a useful adjunct to pharmacological analgesia.

Effectiveness of community-based nonpharmacological interventions for early-stage dementia : conclusions and recommendations

In 2007, a comprehensive review of the extant research on nonpharmacological interventions for persons with early-stage dementia was conducted. More than 150 research reports, centered on six major domains, were included: early-stage support groups, cognitive training and enhancement programs, exercise programs, exemplar programs, health promotion programs, and “other” programs not fitting into previous categories. Theories of neural regeneration and plasticity were most often used to support the tested interventions. Recommendations for practice, research, and health policy are outlined, including evidence-based, nonpharmacological treatment protocols for persons with mild cognitive impairment and early-stage dementia. A tested, community-based, multimodal treatment program is also described. Overall, findings identify well-supported nonpharmacological treatments for persons with early-stage dementia and implications for a national health care agenda to optimize outcomes for this growing population of older adults.

Translation of addictions science into practice

Recent advances in the understanding of the genetic, neurochemical, behavioral and cultural underpinnings of addiction have led to rapid advances in the understanding of addiction as a disease. In fact, advances in basic science and the development of new pharmacological and behavioral therapies associated with them are appearing faster than can be assimilated not only by clinical researchers but practitioners and policy makers as well. Translation of science-based addictions knowledge into improved prevention, assessment and treatment, and communication of these changes to researchers and practitioners are significant challenges to the field. The general aim of this book is to summarize current and potential linkages between advances in addiction science and innovations in clinical practice. Whilst this book is primarily focused on translation, it also encompasses some scientific advances that are relevant to dissemination, and the book is itself a tool for disseminating innovative thinking. The goal is to generate interest in application opportunities from both recent research and theoretical advances.

The p38 mitogen-activated protein kinase regulates interleukin-1beta-induced IL-8 expression via an effect on the IL-8 promoter in intestinal epithelial cells

Several lines of evidence implicate the p38 mitogen-activated protein kinase (p38 MAPK) in the proinflammatory response to bacterial agents and cytokines. Equally, the transcription factor, nuclear factor (NF)-kappaB, is recognized to be a critical determinant of the inflammatory response in intestinal epithelial cells (IECs). However, the precise inter-relationship between the activation of p38 MAPK and activation of the transcription factor NF-kappaB in the intestinal epithelial cell (IEC) system, remains unknown. Here we show that interleukin (IL)-1beta activates all three MAPKs in Caco-2 cells. The production of IL-8 and monocyte chemotactic protein 1 (MCP-1) was attenuated by 50% when these cells were preincubated with the p38 MAPK inhibitor, SB 203580. Further investigation of the NF-kappaB signalling system revealed that the inhibitory effect was independent of the phosphorylation and degradation of IkappaBalpha, the binding partner of NF-kappaB. This effect was also independent of the DNA binding of the p65 Rel A subunit, as well as transactivation, determined by an NF-kappaB luciferase construct, using both SB 203580 and dominant-negative p38 MAPK. Evaluation of IL-8 and MCP-1 RNA messages by reverse transcription-polymerase chain reaction (RT-PCR) revealed that the inhibitory effect of SB 203580 was associated with a reduction in this parameter. Using an IL-8-luciferase promoter construct, an effect of p38 upon its activation by both pharmacological and dominant-negative p38 construct co-transfection was demonstrated. It is concluded that p38 MAPK influences the expression of chemokines in intestinal epithelial cells, through an effect upon the activation of the chemokine promoter, and does not directly involve the activation of the transcription factor NF-kappaB

Efficacy of a progressive walking program and glucosamine sulphate supplementation on osteoarthritic symptoms of the hip and knee: a feasibility trial

Introduction: Management of osteoarthritis (OA) includes the use of non-pharmacological and pharmacological therapies. Although walking is commonly recommended for reducing pain and increasing physical function in people with OA, glucosamine sulphate has also been used to alleviate pain and slow the progression of OA. This study evaluated the effects of a progressive walking program and glucosamine sulphate intake on OA symptoms and physical activity participation in people with mild to moderate hip or knee OA. Methods: Thirty-six low active participants (aged 42 to 73 years) were provided with 1500 mg glucosamine sulphate per day for 6 weeks, after which they began a 12-week progressive walking program, while continuing to take glucosamine. They were randomized to walk 3 or 5 days per week and given a pedometer to monitor step counts. For both groups, step level of walking was gradually increased to 3000 steps/day during the first 6 weeks of walking, and to 6000 steps/day for the next 6 weeks. Primary outcomes included physical activity levels, physical function (self-paced step test), and the WOMAC Osteoarthritis Index for pain, stiffness and physical function. Assessments were conducted at baseline and at 6-, 12-, 18-, and 24-week follow-ups. The Mann Whitney Test was used to examine differences in outcome measures between groups at each assessment, and the Wilcoxon Signed Ranks Test was used to examine differences in outcome measures between assessments. Results: During the first 6 weeks of the study (glucosamine supplementation only), physical activity levels, physical function, and total WOMAC scores improved (P<0.05). Between the start of the walking program (Week 6) and the final follow-up (Week 24), further improvements were seen in these outcomes (P<0.05) although most improvements were seen between Weeks 6 and 12. No significant differences were found between walking groups. Conclusions: In people with hip or knee OA, walking a minimum of 3000 steps (~30 minutes), at least 3 days/week, in combination with glucosamine sulphate, may reduce OA symptoms. A more robust study with a larger sample is needed to support these preliminary findings. Trial Registration: Australian Clinical Trials Registry ACTRN012607000159459.

Cochrane review summary for cancer nursing : drug therapy for cancer-related fatigue

Cancer-related fatigue (CRF) is one of themost debilitating symptoms in patients with cancer. It is prevalent at the time of diagnosis and during and after antineoplastic treatment and in patients with advanced disease. The multifactorial and complex nature of CRF makes it challenging for health professionals to identify a clear underlying mechanism and manage this symptom effectively. Often, the management plan for CRF (whether pharmacological or nonpharmacological) can be further complicated by the coexistence of other symptoms. This systematic review1 is therefore important in informing health professionals on the effectiveness of pharmacological management for CRF.

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation (reviewed Kaumann and Molenaar, 2008). Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site (Baker et al 2002) and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Our aim was to investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 or (-)-isoprenaline in the absence or presence of (-)-bupranolol. _______________________________________________________________________ (-)-CGP 12177 (-)-Bupranolol affinity (pKB) pEC50 vs (-)-CGP 12177 vs (-)-isoprenaline _______________________________________________________________________ β1AR 8.00 ± 0.11 (11) 7.23 ± 0.23 (5) 9.52 ± 0.28 (5) β2AR (high density) 9.24 ± 0.14 (5) 9.82 ± 0.52 (8) xPaulxxxxxxx β2AR (low density) no effect β1(β2TMV)AR 8.86 ± 0.10 (15) 8.06 ± 0.17 (8) 9.08 ± 0.22 (6) β1(V230I)AR 9.07 ± 0.07 (10) 7.64 ± 0.12 (8) 9.36 ± 0.28 (9) β1(R222Q)AR 8.09 ± 0.29 (6) 7.33 ± 0.23 (5) 9.36 ± 0.08 (6) β1(V230A)AR 7.59 ± 0.09 (6) 7.32 ± 0.24 (4) 8.62 ± 0.18 (5) _______________________________________________________________________ The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR) but not β2AR. The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol at β1AR and mutants was higher when determined with (-)-isoprenaline than with (-)-CGP 12177. The affinity of (-)-bupranolol determined against (-)-CGP 12177 was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion V230 of the β1AR contributes in part to the low affinity binding site of β1AR. Baker JG, Hall IP, Hill SJ (2002). Pharmacological characterization of CGP12177 at the human β2-adrenoceptor. Br J Pharmacol 137, 400−408 Kaumann AJ, Molenaar P (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther 118, 303-336

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.

Insulin-like growth factor-i : vitronectin complex-induced changes in gene expression effect breast cell survival and migration

Recent studies have demonstrated that IGF-I associates with VN through IGF-binding proteins (IGFBP) which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment and migration. Since IGFs play important roles in transformation and progression of breast tumours, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of PI3-K/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and PI3-K pathways confirms that both pathways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue (\[L24]\[A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of ECM and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.

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.