Targeting cancer with a lupus autoantibody

Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair–deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents.

The impact of prolonged hyperinsulinaemia on glucose transport in equine skeletal muscle and digital lamellae

REASONS FOR PERFORMING STUDY An increased incidence of metabolic disease in horses has led to heightened recognition of the pathological consequences of insulin resistance (IR). Laminitis, failure of the weight-bearing digital lamellae, is an important consequence. Altered trafficking of specialised glucose transporters (GLUTs) responsible for glucose uptake, are central to the dysregulation of glucose metabolism and may play a role in laminitis pathophysiology. OBJECTIVES We hypothesised that prolonged hyperinsulinaemia alters the regulation of glucose transport in insulin-sensitive tissue and digital lamellae. Our objectives were to compare the relative protein expression of major GLUT isoforms in striated muscle and digital lamellae in healthy horses and during hyperinsulinaemia. STUDY DESIGN Randomised, controlled study. METHODS Prolonged hyperinsulinaemia and lamellar damage were induced by a prolonged-euglycaemic hyperinsulinaemic clamp (p-EHC) or a prolonged-glucose infusion (p-GI) and results were compared to electrolyte-treated controls. GLUT protein expression was examined with immunoblotting. RESULTS Lamellar tissue contained more GLUT1 protein than skeletal muscle (p = 0.002) and less GLUT4 than the heart (p = 0.037). During marked hyperinsulinaemia and acute laminitis (induced by the p-EHC), GLUT1 protein expression was decreased in skeletal muscle (p = 0.029) but unchanged in the lamellae, while novel GLUTs (8; 12) were increased in the lamellae (p = 0.03), but not skeletal muscle. However, moderate hyperinsulinaemia and subclinical laminitis (induced by the p-GI) did not cause differential GLUT protein expression in the lamellae vs. control horses. CONCLUSIONS The results suggest that lamellar tissue functions independently of insulin and that IR may not be an essential component of laminitis aetiology. Marked differences in GLUT expression exist between insulin-sensitive and insulin-independent tissues during metabolic dysfunction in horses. The different expression profiles of novel GLUTs during acute and subclinical laminitis may be important to disease pathophysiology and require further investigation.

The impact of diabetic ketoacidosis and age on behavior six months post-diagnosis in children with type 1 diabetes

Objectives: Children with type 1 diabetes mellitus (DM1) may be at increased risk of psychosocial and adjustment difficulties. We examined behavioral outcomes six months post-diagnosis in a group of children with newly diagnosed DM1. Methods: This study formed part of a larger longitudinal project examining pathophysiology and neuropsychological outcomes in diabetic patients with or without diabetic ketoacidosis (DKA). Participants were 61 children (mean age 11.8 years, SD 2.7 years) who presented with a new diagnosis of DM1 at the Royal Children’s Hospital, Melbourne. Twenty-three (11 female) presented in DKA and 38 (14 female) without DKA. Parents completed the behavior assessment system for children, second edition six months post-diagnosis. Results: There was a non-linear relationship between age and behavior. Internalising problems (i.e. anxiety depression, withdrawal) peaked in the transition from childhood to adolescence; children aged 10–13 years had elevated rates relative to the normal population (t = 2.55, P = 0.018). There was a non-significant trend for children under 10 to display internalising problems (P = 0.052), but rates were not elevated in children over 13 (P = 0.538). Externalising problems were not significantly elevated in any age group. Interestingly, children who presented in DKA were at lower risk of internalising problems than children without DKA (t = 3.83, P < 0.001). There was no effect of DKA on externalising behaviors. Conclusions: Children transitioning from childhood to adolescence are at significant risk for developing internalising problems such as anxiety and lowered mood after diagnosis of DM1. Somewhat counter-intuitively, parents of children presenting in DKA reported fewer internalising symptoms than parents of children without DKA. These results highlight the importance of monitoring and supporting psychosocial adjustment in newly diagnosed children even when they seem physically well.

A loss of bioscience knowledge in nursing students

Background: Knowledge of the human biosciences is fundamental to the development of competent nurse practitioners (Smales, 2010) with the requisite knowledge and skills, necessary for high quality patient care and good patient outcomes (Logan and Angel, 2011). Many of these students study bioscience units which cover topics in anatomy, physiology, pathophysiology and microbiology. Studies of science recall in general and medical education, report up to 33% loss of knowledge in the first year which declines to 50% in the subsequent year (Custers, 2010). Objectives: The objectives were to test the recall of bioscience knowledge by nursing students and to ascertain their perceptions of the testing. Questions explored: What would the results be for multiple choice questions in fundamental microbiology and gastrointestinal anatomy and physiology (A&P) undertaken by nursing students 4, 9 and 16 months after their first bioscience exam on these topics? Would pre-warning the students of a microbiology quiz and not a gastrointestinal A&P quiz affect the findings? How would the students respond to the testing when surveyed? Recall results: The nursing students performed better in the final exam on gastrointestinal A&P than on fundamental microbiology. There was an approximate 20% loss in knowledge of gastrointestinal A&P after 4 months and this did not change significantly over the next 12 months. Although there was an improved performance in microbiology quizzes after 4 months, there was no significant difference in results over the next 12 months. Survey results: More than 50% of students thought the testing helped them focus for the lectures and made them aware they had some pre-knowledge of the lecture topics. Discussion: Although there was a loss of knowledge of gastrointestinal A&P, it appears that warning the students about the microbiology quiz may have helped their recall. The majority of students valued the testing as a useful learning exercise. References: Custers, E. J. F. M. (2010). Long-term retention of basic science knowledge: a review study. Advances in Health Science Education, 15, 109-128. Smales, K. (2010). Learning and applying biosciences to clinical practice in nursing. Nursing Standard, 24(33), 35-39. Logan, P.A., & Angel, L. (2011). Nursing as a scientific undertaking and the intersection with science in undergraduate studies: implications for nursing management. Journal of Nursing Management, 19(3), 407-417.

Development of an electronic role-play assessment initiative in bioscience for nursing students

Devising authentic assessments for subjects with large enrolments is a challenge. This study describes an electronic role-play assessment for approximately 600 first-year nursing students to learn and apply pathophysiology (bioscience) concepts to nursing practice. Students used Microsoft Office PowerPoint® to prepare electronic role-plays both between a nurse and patient, and between two nurses, thus simulating workplace scenarios. Student feedback demonstrated that respondents found this assessment useful for learning pathophysiology, and for applying pathophysiology to a nursing clinical setting. This electronic presentation circumvented issues associated with a traditional oral presentation such as embarrassment and logistics of scheduling groups, and rated well with students of non-English speaking background. The electronic role-play assessment initiative encouraged students to apply their bioscience knowledge to a clinical setting, and allowed students to conceptualise the importance of bioscience within both the nursing degree and the profession.

Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility

Objective There is evidence that folate metabolism has a role in migraine pathophysiology, particularly in the migraine with aura subtype. In this study we investigate whether two non-synonymous single nucleotide polymorphisms (SNPs), rs1950902 (C401T; R134K) and rs2236225 (G1958A; R653Q), in MTHDF1 are associated with migraine in an Australian case-control population. Background Increased plasma levels of homocysteine (HCy), one of the metabolites produced in the folate pathway, has been found to be a risk factor for migraine. There is also a genetic link, as a common polymorphism (C667T) that reduces the catalytic activity of MTHFR, the enzyme that catalyses the formation of HCy, is associated with an increase in risk of the migraine with aura (MA) subtype. MTHFD1 is a crucial multifunctional enzyme that catalyses three separate reactions of the folate pathway and therefore variants in MTHFD1 may also influence migraine susceptibility. Methods The R134K and R653Q variants in MTHFD1 were genotyped in an Australian cohort of 520 unrelated migraineurs (162 were diagnosed with migraine without aura [MO] and 358 with MA) and 520 matched controls. Data were analysed for association with migraine and for interaction with the MTHFR C667T polymorphism. Results We find no significant differences in genotype or allele frequencies for either SNP between migraineurs and controls, or when either MO or MA cases were compared to controls. In addition these MTHFD1 polymorphisms did not appear to influence the risk of MA conferred by the MTHFR 667T allele. Conclusions We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population. However, as folate metabolism appears to be important in migraine, particularly with respect to the aura component, future studies using high throughput methods to expand the number of SNPs in folate-related genes genotyped and investigation of interactions between SNPs may be justified.

Development of an online role-play assessment initiative for nursing students in their bioscience studies

Devising assessment tasks for large units that embrace academic goals of authenticity and assessment variety can be a challenge. We developed an online Role-Play Assessment Initiative for first year nursing students in bioscience. Students responded to a case study by preparing two role-play dialogues: as a nurse with the patient, and between two nurses. The aims were to assess whether the students could: 1) understand the underlying disease process (pathophysiology) and relate it to clinical practice; 2) use language appropriate for lay and medical conversation; and 3) apply information using active learning. We conducted a student survey using quantitative questions (Likert scale: 1=strongly disagree to 5=strongly agree), and qualitative questions. 65 completed surveys were received. 80% of respondents agreed (includes agree or strongly agree) that it was a useful way to learn and understand pathophysiology of the case study. 86% agreed that it was useful to apply pathophysiology from lectures to a clinical setting. Overall, students found it enjoyable, which is beneficial for enhanced student engagement, and agreed that it allowed them to work well in a group (74% and 85%, respectively). Most qualitative suggestions for improvement related to group work, despite the encouraging response to group work in quantitative questions. Most positive comments surrounded different communication with a nurse compared with a patient. These results demonstrate that students developed deeper understanding of pathophysiology through active learning and were able to expand their nursing career skills during the role-play. Learning using role-play to simulate the workforce has fostered active learning.

Reduced motor facilitation during action observation in schizophrenia : a mirror neuron deficit?

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.

Review of the long-term disability associated with hip fractures

Objectives To determine the proportion of hip fracture patients who experience long-term disability and to re-estimate the resulting burden of disease associated with hip fractures in Australia in 2003. Methods A literature review of the functional outcome following a hip fracture (keywords: morbidity, treatment outcome, disability, quality of life, recovery of function, hip fractures, and femoral neck fractures) was carried out using PubMed and Ovid MEDLINE. Results A range of scales and outcome measures are used to evaluate recovery following a hip fracture. Based on the available evidence on restrictions in activities of daily living, 29% of hip fracture cases in the elderly do not reach their pre-fracture levels 1 year post-fracture. Those who do recover tend to reach their pre-fracture levels of functioning at around 6 months. These new assumptions result in 8251 years lived with disability for hip fractures in Australia in 2003, a 4.5-fold increase compared with the previous calculation based on Global Burden of Disease assumptions that only 5% of hip fractures lead to long-term disability and that the duration of short-term disability is just 51 days. Conclusions The original assumptions used in burden of disease studies grossly underestimate the long-term disability from hip fractures. The long-term consequences of other injuries may similarly have been underestimated and need to be re-examined. This has important implications for modelling the cost-effectiveness of preventive interventions where disability-adjusted life years are used as a measure of health outcome.

Wheeze, asthma diagnosis and medication use : a national adult survey in a developing country

Background As relatively little is known about adult wheeze and asthma in developing countries, this study aimed to determine the predictors of wheeze, asthma diagnosis, and current treatment in a national survey of South African adults. Methods A stratified national probability sample of households was drawn and all adults (>14 years) in the selected households were interviewed. Outcomes of interest were recent wheeze, asthma diagnosis, and current use of asthma medication. Predictors of interest were sex, age, household asset index, education, racial group, urban residence, medical insurance, domestic exposure to smoky fuels, occupational exposure, smoking, body mass index, and past tuberculosis. Results A total of 5671 men and 8155 women were studied. Although recent wheeze was reported by 14.4% of men and 17.6% of women and asthma diagnosis by 3.7% of men and 3.8% of women, women were less likely than men to be on current treatment (OR 0.6; 95% confidence interval (CI) 0.5 to 0.8). A history of tuberculosis was an independent predictor of both recent wheeze (OR 3.4; 95% CI 2.5 to 4.7) and asthma diagnosis (OR 2.2; 95% CI 1.5 to 3.2), as was occupational exposure (wheeze: OR 1.8; 95% CI 1.5 to 2.0; asthma diagnosis: OR 1.9; 95% CI 1.4 to 2.4). Smoking was associated with wheeze but not asthma diagnosis. Obesity showed an association with wheeze only in younger women. Both wheeze and asthma diagnosis were more prevalent in those with less education but had no association with the asset index. Independently, having medical insurance was associated with a higher prevalence of diagnosis. Conclusions Some of the findings may be to due to reporting bias and heterogeneity of the categories wheeze and asthma diagnosis, which may overlap with post tuberculous airways obstruction and chronic obstructive pulmonary disease due to smoking and occupational exposures. The results underline the importance of controlling tuberculosis and occupational exposures as well as smoking in reducing chronic respiratory morbidity. Validation of the asthma questionnaire in this setting and research into the pathophysiology of post tuberculous airways obstruction are also needed.

Indigenous health issues in Australia

This adaptation of Understanding Pathophysiology by Huether and McCance builds on the strengths of the US edition while tailoring it to the specific needs of Australia and New Zealand undergraduate nursing students.

In vitro microenvironments to study breast cancer bone colonisation

Bone metastasis occurs frequently in patients with advanced breast cancer and is a major cause of morbidity and mortality in these patients. In order to advance current therapies, the mechanisms leading to the formation of bone metastases and their pathophysiology have to be better understood. Several in vitro models have been developed for systematic studies of interactions between breast cancer cells and the bone microenvironment. Such models can provide insights into the molecular basis of bone metastatic colonisation and also may provide a useful platform to design more physiologically relevant drug testing assays. This review describes different in vitro approaches and discusses their advantages and disadvantages.