Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model.

Therapies capable of decelerating, or perhaps even halting, neurodegeneration in Parkinson's disease (PD) remain elusive. Clinical trials of PD gene therapy testing the delivery of neurotrophic factors, such as the glial cell-line derived neurotrophic factor (GDNF), have been largely ineffective due to poor vector distribution throughout the diseased regions in the brain. In addition, current delivery strategies involve invasive procedures that obviate the inclusion of early stage patients who are most likely to benefit from GDNF-based gene therapy. Here, we introduce a two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF transgene expression in the brain following systemic administration. MR image-guided FUS allows circulating gene vectors to partition into the brain tissue by noninvasive and transient opening of the blood-brain barrier (BBB) within the areas where FUS is applied. Once beyond the BBB, BPN provide widespread and uniform GDNF expression throughout the targeted brain tissue. After only a single treatment, our strategy led to therapeutically relevant levels of GDNF protein content in the FUS-targeted regions in the striatum of the 6-OHDA-induced rat model of PD, which lasted at least up to 10 weeks. Importantly, our strategy restored both dopamine levels and dopaminergic neuron density and reversed behavioral indicators of PD-associated motor dysfunction with no evidence of local or systemic toxicity. Our combinatorial approach overcomes limitations of current delivery strategies, thereby potentially providing a novel means to treat PD.

Exploring reflective 'critical incident' documentation of professionalism lapses in a medical undergraduate setting.

BACKGROUND: Measuring professionalism in undergraduate medical students is a difficult process, and no one method has currently emerged as the definitive means of assessment in this field. Student skills in reflection have been shown to be highly important in the development of professional behaviours. By studying student reflections on lapses in professional judgement, recorded as 'critical incidents', it is possible to explore themes which are significant for the development of professional behaviour in an undergraduate setting. METHODS: We examined critical incident reporting combined with optional written student reflection as a method for exploring professionalism in undergraduate medical students. 228 students split between Year 1 and 2 of one academic year of undergraduate medicine were studied retrospectively and a grounded theory approach to analysis was employed. RESULTS: This year generated 16 critical incident reports and corresponding student reflections, all of which were considered. In addition to identifying the nature of the critical incidents, 3 principal themes emerged. These were the impact and consequences of the report having been made, student reactions to the events (both positive and negative), and student responses regarding future actions. CONCLUSION: This study indicates that unprofessional behaviour can be identified and challenged by both the faculty and the students involved, and suggests that positive behavioural changes might be made with the aim of preventing future occurrences. We provide a low cost approach of measuring and recording professional behaviour.

Utility of biomarkers in the differential diagnosis of heart failure in older people: findings from the heart failure in care homes (HFinCH) diagnostic accuracy study.

BACKGROUND: The performance of biomarkers for heart failure (HF) in older residents in long-term care is poorly understood and has not differentiated between left ventricular systolic dysfunction (LVSD) and HF with preserved ejection fraction (HFpEF). METHODS: This is the first diagnostic accuracy study in this population to assess the differential diagnostic performance and acceptability of a range of biomarkers against a clinical diagnosis using portable echocardiography. A total of 405 residents, aged 65-100 years (mean 84.2), in 33 UK long-term care facilities were enrolled between April 2009 and June 2010. RESULTS: For undifferentiated HF, BNP or NT-proBNP were adequate rule-out tests but would miss one in three cases (BNP: sensitivity 67%, NPV 86%, cut-off 115 pg/ml; NT-proBNP: sensitivity 62%, NPV 87%, cut-off 760 pg/ml). Using higher test cut-offs, both biomarkers were more adequate tests of LVSD, but would still miss one in four cases (BNP: sensitivity 76%, NPV 97%, cut-off 145 pg/ml; NT-proBNP: sensitivity 73%, NPV 97%, cut-off 1000 pg/ml). At these thresholds one third of subjects would test positive and require an echocardiogram. Applying a stricter 'rule out' threshold (sensitivity 90%), only one in 10 cases would be missed, but two thirds of subjects would require further investigation. Biomarkers were less useful for HFpEF (BNP: sensitivity 63%, specificity 61%, cut-off 110 pg/ml; NT-proBNP: sensitivity 68%, specificity 56%, cut-off 477 pg/ml). Novel biomarkers (Copeptin, MR-proADM, and MR-proANP) and common signs and symptoms had little diagnostic utility. CONCLUSIONS: No test, individually or in combination, adequately balanced case finding and rule-out for heart failure in this population; currently, in-situ echocardiography provides the only adequate diagnostic assessment. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN19781227.

Endoscopic removal of multiple duodenum foreign bodies: An unusual occurrence.

Deliberate single foreign body ingestion is a scenario that many gastroenterologists commonly see in psychiatric units and prisons. However, multiple foreign body ingestions, especially located in the duodenum, provide the endoscopist with unique challenges for management and treatment. Although most foreign objects pass spontaneously, one should have a low threshold of intervention for multiple objects, especially those that are wide, sharp and at risk of perforation. Diagnosis is typically made when there is a history of ingestion coupled with corresponding radiographic verification. The symptoms tend to be non-specific although some patients are able to delineate where the discomfort level is, correlating with the site of impaction. Most foreign bodies pass spontaneously; however when multiple sharp objects are ingested, the gastroenterologist should perform endoscopic procedures to minimize the risks of bowel perforation. We describe here a successful case of multiple ingested foreign bodies retrieved across the C-loop of the duodenum and the pharynges-esophageal curve via endoscopy and review the literature of multiple foreign body ingestion.