Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer

Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC.

Facteurs associés à l’alliance thérapeutique chez les patients ayant des troubles psychotiques

Rapport de stage présenté à la Faculté des études supérieures en vue de l’obtention du grade de maîtrise en science (M. Sc.) en criminologie, option cheminement avec stage en intervention

Clinical and demographic differences between sexually violent predators and other commitment types in a state forensic hospital

Sexual offenders who are involuntarily civilly committed to a secure state hospital as Sexually Violent Predators (SVPs) appear to differ significantly from other current patient populations. Demographically, SVPs are older and more predominantly Caucasian than other patients. They are less frequently psychotic than patients committed under other state statutes such as those found incompetent to stand trial, not guilty by reason of insanity and mentally ill prison transfers. Another salient dimension which distinguishes SVPs is the degree of psychopathy observed in these patients. As a group, SVPs display only slightly higher levels of psychopathy than other patient groups as measured by the revised Psychopathy Checklist. Yet when considered by offender type, rapists are found to have significantly higher average psychopathy scores than other patients, while child molesters are assessed as having lower average psychopathy scores than most other patient commitment categories.

Characteristics of Mentally Disordered Youth Referred to a Forensic Satellite Clinic for Violence Risk Assessment: A Case Control Study

There is a lack of appropriate services to manage youth with comorbid mental health problems and violence risks. To address this gap, we implemented a forensic satellite clinic in a youth mental health service. This paper characterises offending histories among 45 young patients referred to the clinic, and compares them with matched clinical controls (n = 45). Levels of prior risk taking and aggression were prominent among referred patients. Forensic cases and controls did not differ on demographic and clinical variables, with the exception of psychiatric inpatient admissions, which were higher among referred patients. Group differences were observed for prior offending variables (e.g., physical aggression), which were significantly higher among referred patients than controls. Findings suggest that referrals were made to the clinic based on challenging and aggressive behaviour rather than specific clinical characteristics. The role of specialist assessment, treatment and management of violence risks in youth mental health services are discussed.

Intensive case management for high-risk patients with first-episode psychosis: service model and outcomes

Background : The first episode of psychosis is a crucial period when early intervention can alter the trajectory of the young person's ongoing mental health and general functioning. After an investigation into completed suicides in the Early Psychosis Prevention and Intervention Centre (EPPIC) programme, the intensive case management subprogramme was developed in 2003 to provide assertive outreach to young people having a first episode of psychosis who are at high risk owing to risk to self or others, disengagement, or suboptimal recovery. We report intensive case management model development, characterise the target cohort, and report on outcomes compared with EPPIC treatment as usual.

Methods : Inclusion criteria, staff support, referral pathways, clinical review processes, models of engagement and care, and risk management protocols are described. We compared 120 consecutive referrals with 50 EPPIC treatment as usual patients (age 15–24 years) in a naturalistic stratified quasi-experimental real-world design. Key performance indicators of service use plus engagement and suicide attempts were compared between EPPIC treatment as usual and intensive case management, and psychosocial and clinical measures were compared between intensive case management referral and discharge.

Findings : Referrals were predominately unemployed males with low levels of functioning and educational attainment. They were characterised by a family history of mental illness, migration and early separation, with substantial trauma, history of violence, and forensic attention. Intensive case management improved psychopathology and psychosocial outcomes in high-risk patients and reduced risk ratings, admissions, bed days, and crisis contacts.

Interpretation : Characterisation of intensive case management patients validated the clinical research focus and identified a first episode of psychosis high-risk subgroup. In a real-world study, implementation of an intensive case management stream within a well-established first episode of psychosis service showed significant improvement in key service outcomes. Further analysis is needed to determine cost savings and effects on psychosocial outcomes. Targeting intensive case management services to high-risk patients with unmet needs should reduce the distress associated with pathways to care for patients, their families, and the community.

The Evidence of the Rugoscopy Effectiveness as a Human Identification Method in Patients Submitted to Rapid Palatal Expansion

The objective of this study was to demonstrate the effectiveness of rugoscopy as a human identification method, even when the patient is submitted to rapid palatal expansion, which in theory would introduce doubt. With this intent, the Rugoscopic Identity was obtained for each subject using the classification formula proposed by Santos based on the intra-oral casts made before and after treatment from patients who were subjected to palatal expansion. The casts were labeled with the patients' initials and randomly arranged for studying. The palatine rugae kept the same patterns in every case studied. The technical error of the intra-evaluator measurement provided a confidence interval of 95%, making rugoscopy a reliable identification method for patients who were submitted to rapid palatal expansion, because even in the presence of intra-oral changes owing to the use of palatal expanders, the palatine rugae retained the biological and technical requirements for the human identification process. © 2012 American Academy of Forensic Sciences.

Strangulation signs: initial correlation of MRI, MSCT, and forensic neck findings

PURPOSE: To evaluate multislice spiral computed tomography (MSCT) and magnetic resonance imaging (MRI) findings in hanging and manual strangulation cases and compare them with forensic autopsy results. MATERIALS AND METHODS: Postmortem MSCT and MRI of nine persons who died from hanging or manual strangulation were performed. The neck findings were compared with those discovered during forensic autopsy. In addition, two living patients underwent imaging and clinical examination following severe manual strangulation and near-hanging, respectively. For evaluation, the findings were divided into "primary" (strangulation mark and subcutaneous desiccation (i.e., soft-tissue thinning as a result of tissue fluids being driven out by mechanical compression) in hanging, and subcutaneous and intramuscular hemorrhage in manual strangulation) and "collateral" signs. The Wilcoxon two-tailed test was used for statistical analysis of the lymph node and salivary gland findings. RESULTS: In hanging, the primary and most frequent collateral signs were revealed by imaging. In manual strangulation, the primary findings were accurately depicted, with the exception of one slight hemorrhage. Apart from a vocal cord hemorrhage, all frequent collateral signs could be diagnosed radiologically. Traumatic lymph node hemorrhage (P = 0.031) was found in all of the manual strangulation cases. CONCLUSION: MSCT and MRI revealed strangulation signs concordantly with forensic pathology findings. Imaging offers a great potential for the forensic examination of lesions due to strangulation in both clinical and postmortem settings.

A study of outcomes measures in forensic mental health

Outcomes measures, which is the measurement of effectiveness of interventions and services has been propelled onto the health service agenda since the introduction of the internal market in the 1990s. It arose as a result of the escalating cost of inpatient care, the need to identify what interventions work and in what situations, and the desire for effective information by service users enabled by the consumerist agenda introduced by Working for Patients white paper. The research reported in this thesis is an assessment of the readiness of the forensic mental health service to measure outcomes of interventions. The research examines the type, prevalence and scope of use of outcomes measures, and further seeks a consensus of views of key stakeholders on the priority areas for future development. It discusses the theoretical basis for defining health and advocates the argument that the present focus on measuring effectiveness of care is misdirected without the input of users, particularly patients in their care, drawing together the views of the many stakeholders who have an interest in the provision of care in the service. The research further draws on the theory of structuration to demonstrate the degree to which a duality of action, which is necessary for the development, and use of outcomes measures is in place within the service. Consequently, it highlights some of the hurdles that need to be surmounted before effective measurement of health gain can be developed in the field of study. It concludes by advancing the view that outcomes research can enable practitioners to better understand the relationship between the illness of the patient and the efficacy of treatment. This understanding it is argued would contribute to improving dialogue between the health care practitioner and the patient, and further providing the information necessary for moving away from untested assumptions, which are numerous in the field about the superiority of one treatment approach over another.

Comparison of medical and forensic profiling potential of volatile biomarkers from different biological specimens from individuals and across populations

There is limited scientific knowledge on the composition of human odor from different biological specimens and the effect that physiological and psychological health conditions could have on them. There is currently no direct comparison of the volatile organic compounds (VOCs) emanating from different biological specimens collected from healthy individuals as well as individuals with certain diagnosed medical conditions. Therefore the question of matching VOCs present in human odor across various biological samples and across health statuses remains unanswered. The main purpose of this study was to use analytical instrumental methods to compare the VOCs from different biological specimens from the same individual and to compare the populations evaluated in this project. The goals of this study were to utilize headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME-GC/MS) to evaluate its potential for profiling VOCs from specimens collected using standard forensic and medical methods over three different populations: healthy group with no diagnosed medical or psychological condition, one group with diagnosed type 2 diabetes, and one group with diagnosed major depressive disorder. The pre-treatment methods of collection materials developed for the study allowed for the removal of targeted VOCs from the sampling kits prior to sampling, extraction and analysis. Optimized SPME-GC/MS conditions has been demonstrated to be capable of sampling, identifying and differentiating the VOCs present in the five biological specimens collected from different subjects and yielded excellent detection limits for the VOCs from buccal swab, breath, blood, and urine with average limits of detection of 8.3 ng. Visual, Spearman rank correlation, and PCA comparisons of the most abundant and frequent VOCs from each specimen demonstrated that each specimen has characteristic VOCs that allow them to be differentiated for both healthy and diseased individuals. Preliminary comparisons of VOC profiles of healthy individuals, patients with type 2 diabetes, and patients with major depressive disorder revealed compounds that could be used as potential biomarkers to differentiate between healthy and diseased individuals. Finally, a human biological specimen compound database has been created compiling the volatile compounds present in the emanations of human hand odor, oral fluids, breath, blood, and urine.

The Scored Patient-Generated Subjective Global Assessment (PG-SGA) and its Association with Quality of Life in Ambulatory Patients Receiving Radiotherapy

OBJECTIVE: To evaluate the scored Patient-generated Subjective Global Assessment (PG-SGA) tool as an outcome measure in clinical nutrition practice and determine its association with quality of life (QoL). DESIGN: A prospective 4 week study assessing the nutritional status and QoL of ambulatory patients receiving radiation therapy to the head, neck, rectal or abdominal area. SETTING: Australian radiation oncology facilities. SUBJECTS: Sixty cancer patients aged 24-85 y. INTERVENTION: Scored PG-SGA questionnaire, subjective global assessment (SGA), QoL (EORTC QLQ-C30 version 3). RESULTS: According to SGA, 65.0% (39) of subjects were well-nourished, 28.3% (17) moderately or suspected of being malnourished and 6.7% (4) severely malnourished. PG-SGA score and global QoL were correlated (r=-0.66, P<0.001) at baseline. There was a decrease in nutritional status according to PG-SGA score (P<0.001) and SGA (P<0.001); and a decrease in global QoL (P<0.001) after 4 weeks of radiotherapy. There was a linear trend for change in PG-SGA score (P<0.001) and change in global QoL (P=0.003) between those patients who improved (5%) maintained (56.7%) or deteriorated (33.3%) in nutritional status according to SGA. There was a correlation between change in PG-SGA score and change in QoL after 4 weeks of radiotherapy (r=-0.55, P<0.001). Regression analysis determined that 26% of the variation of change in QoL was explained by change in PG-SGA (P=0.001). CONCLUSION: The scored PG-SGA is a nutrition assessment tool that identifies malnutrition in ambulatory oncology patients receiving radiotherapy and can be used to predict the magnitude of change in QoL.