Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another

Banishment in Public Housing: Testing an Evolution of Broken Windows

Banishment policies grant police the authority to formally ban individuals from entering public housing and arrest them for trespassing if they violate the ban. Despite its widespread use and the social consequences resulting from it, an empirical evaluation of the effectiveness of banishment has not been performed. Understanding banishment enforcement is an evolution of broken windows policing, this study explores how effective bans are at reducing crime in public housing. We analyze crime data, spanning the years 2001–2012, from six public housing communities and 13 surrounding communities in one southeastern U.S. city. Using Arellano-Bond dynamic panel models, we investigate whether or not issuing bans predicts reductions in property and violent crimes as well as increases in drug and trespass arrests in public housing. We find that this brand of broken windows policing does reduce crime, albeit relatively small reductions and only for property crime, while resulting in an increase in trespass arrests. Given our findings that these policies have only a modest impact on property crime, yet produce relatively larger increases in arrests for minor offenses in communities of color, and ultimately have no significant impact on violent crime, it will be important for police, communities, and policy makers to discuss whether the returns are worth the potential costs

The senior universities students in Portugal and Brazil

Given the growth in the number of senior universities in Portugal and Brazil, we think it is important to know the audience which frequents these institutions, their motivations, the health impact and whether there are significant differences between the two countries. The authors have created a survey that was applied in person in Portugal and the State of Goiás in Brazil. With this study, it was possible to trace the profile of the students who attend the Senior Universities (US or U3A) in Portugal and universities open to Seniors (UNATI) in Brazil. We also added a study on volunteer teachers in the Portuguese US. We now know that are essentially women, aged 60-75 years and of all social and educational levels. As for the motives are essentially the conviviality, get active and learn. No significant differences were found between the two countries, in groups and in the motivations, with exception to the marital status and the number of courses attendedinfo:eu-repo/semantics/publishedVersio

Micropolis: A Virtual City for Water Distribution System Research Applications

For security reasons, cities keep their water distribution system data confidential. This data includes geographic layout of pipes, tanks, pumps, wells, buildings, and demands. While the secrecy of water system data is crucial, it poses a difficulty for research on water distribution systems as results can not be publicized. Therefore, a library of virtual water distribution systems can be an important research tool for comparative development of many analytical methods. A “virtual city” has been developed, including a comprehensive water distribution system, as a first entry into such a library. “Micropolis” is a virtual city of 5000 residents fully described in both geographic information systems (GIS) and EPANet hydraulic model frameworks. To simulate realism of infrastructure, a developmental timeline spanning 130 years was described, and this timeline is manifested in items such as pipe material, diameter, and topology. Examples of using the virtual city for simulations of contaminant spread are presented, and future applications will include fire flow and water auditing. The data digital files describing Micropolis are available from the authors for others’ use. It is hoped that other virtual cities will follow for the use of the research community.Dr. Roger Smit

Growing Aesthetics Into the Biowall

Aesthetic Considerations for Biowall Design & Operation A Biowall is a plant-based filter used to improve Indoor Air Quality (IAQ) in a residence. This area of research leverages NASA’s 30 years of experience on plant filtration capabilities. A result of that research is NASA’s Top 10 Air Filtering Plant list. These plants are identified for their ability to remove carbon based and Volatile Organic Compound (VOC) contaminants from the air; non-toxicity to human plant owners; ease of growth; and expected lifespan. In addition to improving IAQ, a Biowall has a unique and important role in the aesthetics of the space where it is located. A Biowall is a technology that brings nature indoors and enhances overall sustainability. If the Biowall does not have a pleasant appearance, nobody is going to want one. This research targeted both aesthetics and functionality in a conditional plant growth study within a fully operational Biowall in a home. The goal was to identify which plants grow well within the 0artificial, low nutrient environment and document how to care for these plants. The result was a toolbox of known air filtering plants that can thrive in the Biowall environment, while also making eye-pleasing arrangements with the plant filtration trays. This knowledge will aid in the commercialization of the concept

Occupational stress management from the perspective of the area of program evaluation

O objetivo deste artigo é apresentar procedimentos para implementar e avaliar programas de manejo de estresse ocupacional focados no indivíduo, fundamentando-se na literatura das áreas de psicologia da saúde ocupacional e de avaliação de programas. São abordados o planejamento da intervenção, sua implementação e avaliação, com base no ciclo da pesquisa em ciências sociais, cujas etapas compreendem a avaliação de necessidades, busca de base teórica, definição de objetivos, variáveis, instrumentos, delineamento, participantes, procedimentos, implementação do programa e coleta de dados, análise e interpretação de resultados, divulgação dos resultados e formulação de novas questões. São discutidas perspectivas futuras para a área de avaliação de programas e possíveis ganhos resultantes de alianças entre este campo e o campo de intervenções em manejo de estresse ocupacional.The aim of this article is to present procedures to implement and evaluate individual focused occupational stress management interventions, based on literature of the area of occupational health psychology and program evaluation. Intervention, implementation and evaluation planning are discussed, based on the social science research cycle, which stages include needs evaluation, search of theoretical basis, definition of goals, variables, instruments, design, participants, procedures, program implementation and data collection, analysis and results interpretation, publishing results and formulation of new questions. Future perspectives for program evaluation and possible gains resulted from the alliance between this area and occupational stress management interventions are discussed

Analyzing risk and uncertainty for improving water distribution system security from malevolent water supply contamination events

Previous efforts to apply risk analysis for water distribution systems (WDS) have not typically included explicit hydraulic simulations in their methodologies. A risk classification scheme is here employed for identifying vulnerable WDS components subject to an intentional water contamination event. A Monte Carlo simulation is conducted including uncertain stochastic diurnal demand patterns, seasonal demand, initial storage tank levels, time of day of contamination initiation, duration of contamination event, and contaminant quantity. An investigation is conducted on exposure sensitivities to the stochastic inputs and on mitigation measures for contaminant exposure reduction. Mitigation measures include topological modifications to the existing pipe network, valve installation, and an emergency purging system. Findings show that reasonable uncertainties in model inputs produce high variability in exposure levels. It is also shown that exposure level distributions experience noticeable sensitivities to population clusters within the contaminant spread area. The significant uncertainty in exposure patterns leads to greater resources needed for more effective mitigation

Microcrystals promote cystogenesis and exacerbate autosomal dominant polycystic kidney disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder affecting approximately 2.5 million people worldwide. It is the number one, life-threatening monogenic disorder known, caused by mutations in either the Pkd1 or Pkd2 genes resulting in numerous fluid-filled cysts within the kidneys. ADPKD presents in the 2nd decade of life and presents with progressive renal decline and eventually to end stage renal disease (ESRD) in the 5th to 6th decade of life for half of all patients. Currently no treatments exist to ameliorate or cure ADPKD, creating a large financial burden on both the health care system, the patient, and their care-givers. Treatment options once patients reach ESRD are limited to dialysis and kidney transplant. Since the discovery of the genetic link to ADPKD, there has been intense research to understand what role the Pkd1/2 genes play in the formation of cysts and the progression of ADPKD. The slow progression of ADPKD and the difference in disease severity between individuals implies that there may be environmental factors acting as causative agents in promoting cyst formation. Animal models of ADPKD appear to be more susceptible to cyst formation following injury with nephrotoxic chemicals, ischemia, and partial or total unilateral nephrectomy. These data demonstrate that the injured state is a driver of cyst formation once Pkd1/2 have been mutated, but these experimental approaches are not representative of normal environmental injuries to the kidney. The focus of my research is to elucidate an environmental agent that can promote cystogenesis in an otherwise healthy individual. The kidney is responsible for filtering solutes from the blood which include ions and molecules that under the right circumstances can form precipitates in the urinary filtrate. It is our hypothesis that the endogenous kidney injury in ADPKD patients results via the precipitation of microcrystals and the inappropriate response to crystal clearance. The kidney is producing sub-clinical microcrystals daily that are excreted into the urine without incident. Individuals with ADPKD may be unable to respond appropriately in the clearance of these small crystals. Previously, our lab has shown that ADPKD cyst lining epithelial cells exhibit increased levels of mTOR and STAT3 activity. This same activation of mTOR and STAT3 can be seen following calcium oxalate crystal deposition in both wild-type mice and rats. In addition to the increase in STAT3 and mTOR activity, there is a concomitant increase in tubule dilation. This dilation persists until crystals are no longer detected in kidneys along with a cessation of mTOR and STAT3 activity. Additionally, we demonstrate that the Han:SPRD and pck rat models of PKD exhibit an exacerbated renal phenotype following an increase in kidney microcrystals. Cyst number and cystic index increase following crystal deposition demonstrating that the mechanism of cystogenesis is crystal dependent. The discovery that crystals act as a trigger for cyst formation is an important step in elucidating the causal mechanism of cystogenesis in ADPKD and a critical step in creating effective preventative and palliative strategies