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.

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Cities around the world are struggling to access additional water supplies to support their continued growth because their freshwater sources are becoming exhausted. Half of all cities with populations greater than 100,000 are located in water-scarce basins, and in these basins agricultural water consumption accounts for more than 90% of all freshwater depletions. In this paper we review the water development histories of four major cities: Adelaide, Phoenix, San Antonio and San Diego. We identify a similar pattern of water development in these cities, which begins with the exhaustion of local surface and groundwater supplies, continues with importation of water from other basins, and then turns to recycling of wastewater or stormwater, or desalination of either seawater or brackish groundwater. Demand management through water conservation has mitigated, to varying degrees, the timing of water-system expansions and the extent to which cities rely on new sources of supply. This typical water development pattern in cities is undesirable from a sustainability perspective, as it is usually associated with serious ecological and social impacts as well as sub-optimal cost effectiveness. We highlight case examples and opportunities to invest in water conservation measures, particularly through urban-rural partnerships under which cities work with farmers to implement irrigation conservation measures, thereby freeing up water for ecological restoration and use by cities.

BackgroundThe 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).MethodsThis 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.ResultsFor 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.ConclusionsNo 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 RegistrationControlled-Trials.com ISRCTN19781227