Maximal Androgen Ablation: A Review

Primary management of advanced (stage D) adenocarcinoma of the prostate is androgen ablation. Since this principle was discovered in the early 1940s, therapeutic alternatives and progress have centered around different ways to obtain castrate levels of androgens. The role of adrenal androgens in supporting prostate or prostatic cancer growth has been debated for decades and until recently was believed to be minimal. In the 1980s the concept of maximum androgen suppression, involving both the testes and adrenal glands, was reintroduced with some investigators claiming exceptional results. We review studies that have examined this concept, with emphasis on the largest trial which was carried out by the National Cancer Institute

Analysing business processes to manage and resolve strategic issues in a manufacturing business

This paper demonstrates the value of applying heuristics to knowledge systems of business processes in a manufacturing company to resolve strategic issues and enable the attainment of strategic business goals. The manufacturing company was losing market share through not being able to get its new products to market quickly enough. The research illustrates the &lsquo;location&rsquo; and use of information systems in a manufacturing context. The researchers collected the specific business process knowledge in the company and developed a knowledge management system and then applied heuristics to the &lsquo;AS IS&rsquo; manufacturing process to determine better models of manufacturing that would enable faster to market product development and thus enable better strategic alignment between company expectations and realisation of market share. The paper highlights the strategic use of information systems as a means of directly solving business problems.<br /

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation

This work is supported by the UK Engineering Physical Sciences Research Council (EPSRC).A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided “point-and-transfect” user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits.Publisher PDFPeer reviewe

Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established

Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 µg 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes

Assessing quality of life in men with clinically localized prostate cancer: Development of a new instrument for use in multiple settings

Background : Quality of life in prostate cancer patients with clinically localized disease has become the focus of increasing attention over the past decade. However, few instruments have been developed and validated to assess quality of life specifically in this patient population. Objective : The purpose of this investigation was to create a comprehensive, multi-scale quality of life instrument that can be tailored to the needs of the clinician/investigator in multiple settings. Design , subjects , and measures : Patients diagnosed with clinically localized prostate cancer were mailed a questionnaire consisting of new and previously validated quality of life items and ancillary scales. Data from returned questionnaires were analyzed and used to create a multi-scale instrument that assesses the effects of treatment and disease on urinary, sexual, and bowel domains, supplemented by a scale assessing anxiety over disease course/effectiveness of treatment. The instrument was then mailed to a second sample of prostate cancer patients once and then again two weeks later to assess test–retest reliability. To assess feasibility in clinical settings, the instrument was self-administered to a third patient sample during a urology clinic visit. Results : All scales exhibited good internal consistency and test–retest reliability, convergent and discriminant validity, and significant correlations with disease specific, generic health-related, and global measures of quality of life. Men with greater physiologic impairment reported more limitations in role activities and more bother. Scales were also able to differentiate patients undergoing different therapies. All scales exhibited negligible correlations with a measure of socially desirable responding. Additionally, the instrument proved feasible when used as a self-administered questionnaire in a clinical setting. Conclusions : The current instrument possesses brief multi-item scales that can be successfully self-administered in multiple settings. The instrument is flexible, relatively quick, psychometrically reliable and valid, and permits a more comprehensive assessment of patients' quality of life.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43571/1/11136_2004_Article_282460.pd

Low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir

Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 106 plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 102 pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 104 pfu gave an infection that was intermediate between those of the 106 pfu and 102 pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (106 pfu) and low (102 pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines