Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

The evolution of a state-wide continuing education programme for allied health professionals

Allied health professionals require continuing education (CE) to maintain and improve competencies and standards of care. Research suggests that professional access to CE in rural areas can be difficult.

This article uses an action research framework to describe the development and implementation of a CE programme for allied health professionals in a rural area in Australia, and its subsequent evolution into a state-wide programme. To evaluate programme relevance, attendance and perceived clinical relevance, physiotherapists (n = 75) in southwest Victoria were surveyed 1year after commencement of a CE programme. A secondary outcome was the perceived effect on clinical practice.

More than two-thirds (68.6%) of physiotherapists attended at least one workshop, 57.2% attended four or more sessions and 22.9% attended at least one of the two conducted courses over the period. In addition, 20% of the physiotherapists perceived that attending the programme had a large positive effect on their therapeutic skills, whereas 68.6% reported some effect. From a regional CE programme for physiotherapists the programme evolved into a state-wide programme for 22 allied health professions.

Supervisors are central to work characteristics affecting nurse outcomes

Purpose: To examine the predictive capability of the demand-control-support (DCS) model, augmented by organizational justice variables, on attitudinal- and health-related outcomes for nurses caring for elderly patients.

Design: The study is based on a cross-sectional survey design and involved 168 nurses working with elderly patients in facilities of a medium to large Australian organization.

Method: Participants were asked to complete a questionnaire consisting of scales designed for measuring independent (e.g., demand, control, support, organizational justice) and dependent (e.g., job satisfaction, organizational commitment, wellbeing and psychological distress) variables. Multiple regression analyses were undertaken to identify significant predictors of the outcome variables.

Findings: The DCS model explains the largest amount of variance across both the attitudinal and health outcomes with 27% of job satisfaction and 49% of organizational commitment, and 33% of psychological distress and 35% of wellbeing, respectively. Additional variance was explained by the justice variables for job satisfaction (5%), organizational commitment (4%), and psychological distress (23%).

Conclusions: Using organizational justice variables to augment the DCS model was valuable in better understanding the work conditions experienced by nurses caring for elderly patients. Inclusion of curvilinear effects added clarity to the potentially artifactual nature of certain interaction variables.

Clinical Relevance: The results indicated practical implications for managers of nurses caring for elderly patients in terms of developing and maintaining levels of job control, support, and fairness, as well as monitoring levels of job demands. The results particularly show the importance of nurses' immediate supervisors.

COPD results in a reduction in UCP3 long mRNA and UCP3 protein content in types I and IIa skeletal muscle fibers.

Purpose: Findings recently have shown coupling protein-3 (UCP3) content to be decreased in the skeletal muscle of patients with chronic obstructive pulmonary disease (COPD). Uncoupling protein-3 mRNA exists as two isoforms: long (UCP3L) and short (UCP3S). The UCP3 protein is expressed the least in oxidative and the most in glycolytic muscle fibers. Levels of UCP3 have been associated positively with intramyocellular triglyceride (IMTG) contents in conditions of altered fatty acid metabolism. As a source for muscle free fatty acid metabolism, IMTG is decreased in COPD. The current study completely characterized all the parameters of UCP3 expression (ie, UCP3L and UCP3S mRNA expression in whole muscle samples) and UCP3 protein content as well as IMTG content in the different fiber types in patients with COPD and healthy control subjects.

Methods: Using real-time polymerase chain reaction, UCP3 gene expression was quantified. Skeletal muscle fiber type and UCP3 protein and IMTG content were measured using immunofluorescence and Oil red oil staining, respectively.

Results: The findings showed that UCP3L mRNA expression was 44% lower (P < .005) in the patients with COPD than in the control subjects, whereas the UCP3S mRNA content was similar in the two groups. As compared with control subjects, UCP3 protein content was decreased by 89% and 83% and the IMTG content by 64% and 54%, respectively, in types I and IIa fibers (P < .0167) of patients with COPD, whereas they were unchanged in IIx fibers.

Conclusions: The reduced UCP3 and IMTG content in the more oxidative fibers may be linked to the altered muscle fatty acid metabolism associated with COPD. Further studies are required to determine the exact role and clinical relevance of the reduced UCP3 content in patients with COPD.

Origins of inflated responsibility in obsessive compulsive disorder

The pivotal role of inflated responsibility beliefs in the maintenance and treatment of obsessive-compulsive disorder (OCD) has been clearly demonstrated (Rachman, 1993; Salkovskis, 1998; Shafran, 1997; van Oppen & Arntz, 1994). Yet little is known about the origins of these beliefs, their contribution to a sense of inflated responsibility or the symptoms of OCD, or the contribution of personality to inflated responsibility and to OCD, The aims of this thesis were to investigate a model of the inter-relationships among the personality dimensions of neuroticism and psychoticism, inflated responsibility and OCD, and the origins of inflated responsibility to inflated responsibility and to OCD. In order to achieve these aims, a scale was developed to assess the origins of inflated responsibility based upon the five pathways proposed by Salkovskis, Shafran, Rachman, and Freeston (1999) and the additional domains of guilt, vigilance and thought-action fusion (Shafran, Thordarson, & Rachman, 1996; Shafran, Watkins & Charman, 1996; Tallis, 1994). Eighty-four participants with OCD (age M = 43.36) and 74 control participants (age M =37.14) volunteered to participate in the two studies of this thesis. The aim of Study 1 was to develop and validate a measure of the Origins of Inflated Responsibility (OIR). The results of the first study yielded a 25-ttem scale, the Origins of Inflated Responsibility Questionnaire (OIRQ) with five independent factors: responsibility, strictness, protection from responsibility, critical incidents, and peer blame which demonstrated both internal reliability and temporal stability over a 2-week period. In Study 2, participants also completed the Responsibility Attitudes Scale (Salkovskis, Wroe, Gledhill, Morrison, Forrester, Richards, ct al. (2000) (a measure of inflated responsibility), the Padua Inventory (Sanavio, 1988) (to measure of the symptoms of OCD)y and the Eysenck Personality Inventory-Revised (Eysenck & Eysenck, 1991). Multivariatc Analysis of Variance revealed that the OCD group scored higher on all variables than the control group except for strictness where the groups were not different, and psychoticism where the OCD group scored lower. A series of Multiple Regression analyses revealed that both group and the OIR contributed to inflated responsibility (R2 = .56). When all variables, OIR, inflated responsibility and neuroticism were entered as predictors of OCD, 60% of the variance in OCD was explained however, 49% of the variance was shared by the independent variables suggesting the presence of some underlying construct. Structural Equation Modelling, where all the constructs in the model were examined simultaneously, revealed that neuroticism contributed to the OIR, inflated responsibility and OCD. The OIR were also significant predictors of inflated responsibility and indirectly through inflated responsibility predictive of OCD. The OIR also directly predicted OCD and when the total effects are considered, their contribution was greater than the total effect for inflated responsibility alone. The results of these studies provide good support for the origins of inflated responsibility proposed by Salkovskis et al. (1999), as measured by the OIRQ developed for use in the current thesis. The results also support the contribution of inflated responsibility and neuroticism, as well as the OIR, to OCD, The large amount of variance shared by the OIR, inflated responsibility and neuroticism suggest that there might be some underlying construct, perhaps of a biopsychosocial nature, that requires further investigation for its role in the onset and maintenance of OCD. The clinical relevance of these findings is discussed in terms of early prevention strategies and interventions.

Variation in age and physical status prior to total knee and hip replacement surgery : a comparison of centers in Australia and Europe

Objective : To investigate whether variation exists in the preoperative age, pain, stiffness, and physical function of people undergoing total knee replacement (TKR) and total hip replacement (THR) at several centers in Australia and Europe.
Methods : Individual Western Ontario and McMaster Universities Osteoarthritis Index data (range 0-100, where 0 = best and 100 = worst) collected within 6 weeks prior to primary TKR and THR were extracted from 16 centers (n = 2,835) according to specified eligibility criteria. Analysis of covariance was used to evaluate differences in pain, stiffness, and physical function between centers, with adjustment for age and sex.
Results : There was marked variation in the age of people undergoing surgery between the centers (TKR mean age 67-73 years; F[6,1004] = 4.21, P < 0.01, and THR mean age 63-72 years; F[14,1807] = 7.27, P < 0.01). Large differences in preoperative status were observed between centers, most notably for pain (TKR adjusted mean pain 52.5-61.1; F[6,1002] = 4.26, P < 0.01, and THR adjusted mean pain 49.2-65.7; F[14,1802] = 8.44, P < 0.01) and physical function (TKR adjusted mean function 52.7-61.4; F[6,1002] = 5.27, P < 0.01, and THR adjusted mean function 53.3-71.0; F[14,1802] = 6.71, P < 0.01). Large effect sizes (up to 0.98) reflect the magnitude of variation between centers and highlight the clinical relevance of these findings.
Conclusion : The large variations in age and preoperative status indicate substantial differences in the timing of joint replacement across the centers studied, with potential for compromised surgical outcomes due to premature or delayed surgery. Possible contributing factors include patient preferences, the absence of concrete indications for surgery, and the capacity of the health care systems.

Factors influencing the relationship between sexual abuse and academic achievement

This study examined factors expected to influence the relationship between sexual abuse and academic achievement in an adolescent inpatient psychiatric population. It was found that sexual abuse combined with either low intelligence, substance abuse, internalising behaviour problems or externalising behaviour problems predicted poor academic achievement. The supporting portfolio aims to discuss the proposed relationship between attachment and adolescent depression, highlighting the clinical relevance of this body of research with four cases of adolescent depression.

Factors influencing the impact of secondary exposure to trauma

The research found significant relationships between secondary exposure to client trauma and symptoms associated with secondary traumatic stress and vicarious trauma in a sample of community mental health clinicians. The research supports developmental conceptualisations of the relationships between these constructs and burnout, and identifies potential individual vulnerability and protective factors. The portfolio explores the impact of childhood maltreatment from an attachment theory perspective. Four clinical cases are presented illustrating the clinical relevance of the impact of childhood maltreatment and attachment disturbance, and the complexities associated with current attachment classification systems and differential diagnosis.

Do high-risk medicines alerts influence practice?

Background: Medicine-related adverse events are prevalent, costly and mostly preventable. The High Risk Medicines Working Party (Victoria) developed and distributed three highrisk medicines alerts – wrong route of administration of oral medicines, subcutaneous insulin and unfractionated heparin – and accompanying audit tools in 2008 and 2009.
Aims: To determine the impact of the three high-risk medicines alerts on Victorian health services; to assess the clinical relevance and utility of the audit tools; to identify barriers to implementing recommendations; and to obtain feedback and suggestions for future alert topics.
Method: A cross-sectional survey was undertaken from 6 to 31 July 2009 using an online questionnaire. The questionnaire was distributed to 90 metropolitan, regional and rural public health services in Victoria and approximately 200 members of the Quality Use of Medicines Network (Victoria).
Results: Most of the 90 respondents were pharmacists (53%) and nurses (31%). 53 (59%) respondents reported making changes as a result of receiving the high-risk medicines alerts – 21 (40%) concerned the wrong route of administration, 12 (23%) subcutaneous insulin and 7 (13%) unfractionated heparin. Barriers to implementation included time constraints, inadequate staff and resources, excessive paperwork and competing priorities. A minority of respondents indicated some alerts were not relevant to small rural services. Suggestions for
improving the audit tools included making them less labour intensive, enabling electronic responses and ensuring their distribution is coordinated with other medicine-related tools.
Conclusion: High-risk medicines alerts and the accompanying audit tools facilitated change but there were some barriers to their implementation, such as time and resource constraints. Not all alerts and audit tools were relevant to all health services.

Time for a change : applying the Good Lives Model of rehabilitation to a high-risk violent offender

In this article we operationalise the theoretical concepts of the Good Lives Model (GLM) of offender rehabilitation by providing a step-by-step framework for assessment, formulation, treatment planning, and monitoring with a high-risk violent offender residing in the community. The case study illustrates how the GLM can be applied to complement and enhance traditional Risk-Management interventions and shows how the GLM's clinical relevance extends from sex offending to broader offending typologies.

Multipurpose disinfecting solutions and their interactions with a silicone hydrogel lens

Purpose: To assess the compatibility of a new silicone hydrogel lens, asmofilcon A (with four multipurpose disinfecting solutions: OPTIFREE RepleniSH, ReNu MultiPlus, Solo-Care Aqua and MeniCare Soft). Ocular responses and subjective responses were monitored with each lens-care system combination.

Methods: The study was conducted as a prospective, bilateral, clinical trial with a single-masked investigator, and randomized cross-over design with four phases, (one for each care system). Each study phase comprised of two consecutive days of lens wear where the lenses were inserted on day 1 directly from the blister-packs and worn for over 8 hr, then inserted on day 2 after overnight disinfection with one of the study lens care systems. Twenty-five adapted soft contact lens wearers who were able to wear their habitual lenses comfortably for more than 12 hr were recruited.

Results: There were statistically significant differences in corneal staining found for all the lens-care systems when comparing the results of day 1 (from the blister pack) with day 2 (following care system use) (P < 0.05). ReNu MultiPlus solution had the highest grade for corneal staining at the 2-hr time point on day 2 which then decreased by 6 hr (P < 0.05). There was no difference between the lens care systems and the rating of subjective comfort over either of the two days. The rating of dryness and burning sensations were only slightly increased at 6 hr for all lens care systems except ReNu MultiPlus where burning was highest on insertion (P < 0.05).

Conclusion: Corneal staining observed in this study does not seem to have been related to the presence of polyhexamethylene biguanide (0.0001% wv) that was present in three of the four care systems. Only one care system (ReNu MultiPlus) demonstrated an associated level of corneal staining that was statistically significant; however, this was not considered to be of clinical relevance. These results suggest that using this novel surface-treated silicone hydrogel lens may result in less lens and lens care-related interactions.

Validation of the professional practice environment scale in Australian general practice

Purpose: To validate the Professional Practice Environment Scale (PPE) in Australian general practice. Methods: The PPE was modified slightly for appropriateness for the practice setting and administered to a sample of 342 Australian general practice nurses via an online survey tool. The factor structure of the 38-item PPE was examined using principal components analysis with Varimax rotation. Findings: An eight-factor solution accounted for 71.6% of the variance. Low factor loading (<0.3) or cross-component loadings were detected in eight items. A comparison of Cronbach's alpha values demonstrated little change in the deletion of eight items from four of the eight related components. Conclusions: Findings demonstrated that a 30-item version of the PPE was reliable and valid for use to assess the professional practice environment of nurses working in Australian general practice. Clinical Relevance: A tool to measure the professional practice environment in general practice is important as it will assist in monitoring the impact of the work environment on the recruitment, retention, and satisfaction of nurses in this setting.

Adult attachment insecurities are associated with obsessive compulsive disorder

Objectives.  Obsessive compulsive disorder (OCD) is one of the most disabling and highly prevalent anxiety disorders (ADs). Current cognitive models of OCD implicate views about the self and world in the maintenance of the disorder. However, little research has focused on issues that may lead to vulnerability to such views. In particular, a person's attachment insecurities (attachment anxiety, avoidance) may be important risk factors increasing the likelihood of such non-adaptive perceptions (Doron & Kyrios, 2005).

Design.  Participants meeting criteria for OCD were compared with cohorts meeting criteria for other ADs and healthy controls on a range of measures including adult attachment, OC symptoms, cognitions, and mood.

Methods.  Diagnosis of the clinical groups was established using the Anxiety Disorders Interview Schedule for DSM-IV (Brown, Di Nardo, & Barlow, 1994). The clinical relevance of attachment insecurities was ascertained by comparing their prevalence in an OCD sample (N= 30), an ADs sample (N= 20), and a community sample (N= 32). Results.  Attachment anxiety was significantly higher in individuals with OCD, even when controlling for depression.

Conclusions.  Addressing attachment anxiety in individuals presenting with OCD may be important for enhancing therapeutic outcomes. However, findings are based on cross-sectional data that preclude conclusions relating to causal influence.

Are material safety data sheets (MSDS) useful in the diagnosis and management of occupational contact dermatitis?

This study assesses both the success of medical practitioners in accessing hazardous substances' information from product manufacturers and the accuracy and clinical usefulness of Material Safety Data Sheets (MSDS) presented by workers with suspected occupational contact dermatitis (OCD). 00 consecutively presented MSDS were collected from 42 workers attending an occupational dermatology clinic. Product manufacturers were contacted to verify ingredients. MSDS were evaluated for compliance with the Australian criteria for listing of OCD relevant information (sensitizers present at a concentration > or =1%, irritants present at a concentration > or =20%), and for clinical usefulness. All sensitizers were checked for clinical relevance to the worker's dermatitis. Manufacturers supplied product constituents for 77/100 MSDS. 58 MSDS satisfied the Australian standard. 57/58 MSDS were deemed clinically useful. Irritants were listed for 19/23 MSDS and sensitizers were listed for 30/68 MSDS (P = 0.001). 3 MSDS contained sensitizers, which were clinically relevant to the presenting worker's dermatitis, 1 appropriately listed, 1 present at > or =1% but not listed, and 1 present at <1% in the product and therefore, not required to be listed. Sensitizers are frequently omitted from MSDS and clinicians are often unsuccessful in obtaining crucial information from manufacturers. MSDS are inadequate for the protection and diagnosis of workers with suspected OCD.

Statin use and risk of depression: a Swedish national cohort study

Background : Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n¿=¿4,607,990).MethodsNational register data for adults ¿40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.ResultsUse of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR¿=¿0.92, 95% CI, 0.89-0.96; p¿<¿0.001). Simvastatin had a protective effect (OR¿=¿0.93, 95% CI, 0.89-0.97; p¿=¿0.001), whereas atorvastatin was associated with increased risk of depression (OR¿=¿1.11, 95% CI, 1.01-1.22; p¿=¿0.032). There was a stepwise decrease in odds ratio with increasing age (OR¿¿¿40 years¿=¿0.95, OR¿¿¿50 years¿=¿0.91, OR¿¿¿60 years¿=¿0.85, OR¿¿¿70 years¿=¿0.81).ConclusionsThe use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.