Delineating pathological pathways in a chemically-induced mouse model of Gaucher disease

Great interest has been shown in understanding the pathology of Gaucher disease (GD), due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor, conduritol B-epoxide (CBE), is particularly attractive, although few systematic studies examining the effect of CBE on development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioral abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Transport capital formation and economic growth on Teesside, 1820- 50

Before 1850 economic growth on Teesside was associated with heavy investment in transport facilities which supported a rapid expansion of the region's coal shipping trade after 1830. The spread of railways throughout the region and the growth of the shipping trade encouraged an increase in the number of firms engaged in shipbuilding, iron manufacture, and engineering. New towns sprang into existence and old-established centres of industry, trade and commerce experienced an upsurge of activity as population grew in response to expanding local employment opportunities. Regional population inflow was particularly heavy in the 1830's. Economic growth during this period appears to have occurred within the framework of two long fluctuations in constructional activity, the first beginning in 1820 and reaching a peak in the early 1830's, and the second beginning in the years 1835-36, with the peak coming in 1840. The rapid economic growth experienced by the region is underlined by the sustained rise in the trend of investment activity throughout the period, so much so that even during the difficult years 1842-44, when the economy was severely depressed, the level of capital formation in the region was relatively well maintained. -from Autho

Society for Vascular Surgery Vascular Registry evaluation of stent cell design on carotid artery stenting outcomes

ObjectiveThe Society for Vascular Surgery (SVS) Vascular Registry (VR) collects data on outcomes of carotid endarterectomy and carotid artery stenting (CAS). The purpose of this study was to evaluate the impact of open vs closed cell stent design on the in-hospital and 30-day outcome of CAS.MethodsThe VR collects provider-reported data on patients using a Web-based database. Data were analyzed both in-hospital and at 30 days postprocedure. The primary outcome is combined death/stroke/myocardial infarction (MI).ResultsAs of October 14, 2009, there were 4337 CAS with discharge data and 2397 with 30-day data. Open cell stents (OPEN) were used in 3451 patients (79.6%), and closed cell stents (CLOSED) were used in 866 patients (20.4%). Baseline demographics showed no differences in age, gender, race, and ethnicity. However, the OPEN group had more patients with atherosclerosis (74.5% vs 67.4%; P = .0003) as the etiology of carotid artery disease. The OPEN group also had a higher prevalence of preprocedural stroke (25.8% vs 21.4%; P = .0079), chronic obstructive pulmonary disease (COPD; 21.0% vs 17.6%; P = .0277), cardiac arrhythmia (14.7% vs 11.4%; P = .0108), valvular heart disease (7.4% vs 3.7%; P < .0001), peripheral vascular disease (PVD; 40.0% vs 35.3%; P = .0109), and smoking history (59.0% vs 54.1%; P = .0085). There are no statistically significant differences in the in-hospital or 30-day outcomes between the OPEN and CLOSED patients. Further subgroup analyses demonstrated symptomatic patients had a higher event rate than the asymptomatic cohort in both the OPEN and CLOSED groups. Among symptomatic patients, the OPEN patients had a lower (0.43% vs 1.41%; P = .0349) rate of in-hospital mortality with no difference in stroke or transient ischemic attack (TIA). There were no differences in 30-day event rates. In asymptomatic patients, there were also no statistically significant differences between the OPEN and CLOSED groups. After risk adjustment, there remained no statistically significant differences between groups of the primary endpoint (death/stroke/MI) during in-hospital or 30 days.ConclusionIn-hospital and 30-day outcomes after CAS were not significantly influenced by stent cell design. Symptomatic patients had higher adverse event rates compared to the asymptomatic cohort. As there is no current evidence of differential outcome between the use of open and closed cell stents, physicians should continue to use approved stent platforms based on criteria other than stent cell design

The institutional legacy and the development of an Australian national innovation system

Institutions are the rules of the game that help to shape the long-term historical development of societies. They mediate human interaction and can be more or less formal (or tangible) in nature ranging from systems of government to common modes of behaviour. Most formal institutions can be distinguished as economic, social, political or cultural in nature although such distinctions are more difficult to make for informal institutions. What is certain is the pervasive impact of all types of institutions on a country’s multifaceted development. Thus, economic performance may be shaped as much by a nation’s legal system as by its trade policy