Signal transduction pathways involved in intestinal salt and water secretion

This thesis describes some novel aspects of the regulation of salt and water secretion in the intestinal epithelium. This process is not unique for the intestine, but a common and necessary function of many other organs, including the stomach (gastric juice), kidney (urine), sweatglands (sweat), gallbladder (bile), testis, some endocrine glands and the lungs. Also most of the transport systems involved are not uniquely expressed in the intestine but shared by a variety of other salt transporting epithelia; this is exemplified by the generalized exocrinopathy seen in cystic fibrosis (CF), a genetic disease characterized by a mutation in a cr channel protein (designated CFTR) commonly expressed in epithelial tissues [Riordan et a!., 1990; Kartner et a!., 1991; Anderson et al, 1991 a; Bear eta!., 1992]. Some characteristics of ion transport regulation, however, are exclusively found in intestinal epithelium. These include: i) the pseudohormonal action of microbial enterotoxins (e.g. cholera toxin, heat labile and heat stable Escherichia coli toxin) on intestinal salt and water transport, resulting in secretory diarrhoea (SD) and dehydration: SD is still a major cause of morbidity and mortality among children in the developing countries [Guerrant, 1985]; ii) the role of cGMP and a cGMP-dependent protein kinase as intracellular mediators of intestinal ion secretion [DeJonge, 1981; DeJonge and Lohman, 1985; DeJonge and Rao, 1990]; iii) the presence of G-protein-activated phospholipase C at the brush border membrane, despite the absence of G-protein-coupled hormone receptors at this subcellular region [Vaandrager et a!., 1990]; iv) the CF defect in cholinergic/Ca2 • -mediated activation of intestinal cr secretion [De Jonge et a!., 1987; Berschneider et a!., 1988; De Jonge et a!., 1989], in sharp contrast to the normal Ca2 • -linked cr channel activation observed in most other CF-affected epithelia (airway [Boucher eta!., 1989; Wagner eta!., 1991], sweat gland [Sato and Sato, 1984]). This and some other unique aspects of intestinal signal transduction described in this thesis, render the study of ion transport regulation in the intestine especially rewarding

Economic Benefits of Intensive Insulin Therapy in Critically Ill Patients: The Targeted Insulin Therapy to Improve Hospital Outcomes (TRIUMPH) Project

OBJECTIVE—The purpose of this study was to analyze the economic outcomes of a clinical program implemented to achieve strict glycemic control with intensive insulin therapy in patients admitted to the intensive care unit (ICU)

Compilation of analyses of risks and measures, deliverable 8.2 of the H2020 project SafetyCube

This deliverable provides information on how the information on road safety risks and measures that has been collected within SafetyCube, is processed, stored and made available to users through the SafetyCube Decision Support System (DSS) [...continues]

From planning the port/city to planning the port-city : exploring the economic interface in European port cities

In last three decades, planning agencies of most ports have institutionally evolved into a (semi-) independent port authority. The rationale behind this process is that port authorities are able to react more quickly to changing logistical and spatial preferences of maritime firms, hence increasing the competitiveness of ports. Although these dedicated port authorities have proven to be largely successful, new economic, social, and environmental challenges are quickly catching up on these port governance models, and particularly leads to (spatial) policy ‘conflicts’ between port and city. This chapter starts by assessing this conflict and argue that the conflict is partly a result of dominant—often also academic—spatial representations of the port city as two separate entities. To escape this divisive conception of contemporary port cities, this chapter presents a relational visualisation method that is able to analyse the economic interface between port and city. Based on our results, we reflect back on our proposition and argue that the core challenge today for researchers and policy makers is acknowledging the bias of port/city, being arguably a self-fulfilling prophecy. Hence, we turn the idea of (planning the) port/city conflicts into planning the port-city’s strengths and weaknesses

Car drivers' road safety performance. A benchmark across 32 countries

The road safety performance of a country and the success of policy measures can be measured and monitored in different ways. In addition to the traditional road safety indicators based on the number of fatalities or injured people in road traffic crashes, complementary road safety performance indicators can be used in relation to vehicles, infrastructure, or road users' behaviour. The last-mentioned can be based on data from roadside surveys or from questionnaire surveys. However, results of such surveys are seldom comparable across countries due to differences in aims, scope, or methodology. This paper is based on the second edition of the E-Survey of Road Users' Attitudes (ESRA), an online survey carried out in 2018, and includes data from more than 35,000 road users across 32 countries. The objective is to present the main results of the ESRA survey regarding the four most important risky driving behaviours in traffic: driving under the influence (alcohol/drugs), speeding, mobile phone use while driving, and fatigued driving. The paper explores several aspects related to these behaviours as car driver, such as the self-declared behaviours, acceptability and risk perception, support for policy measures, and opinions on traffic rules and penalties. Results show that despite the high perception of risk and low acceptability of all the risky driving behaviours analysed, there is still a high percentage of car drivers who engage in risky behaviours in traffic in all the regions analysed. Speeding and the use of a mobile phone while driving were the most frequent self-declared behaviours. On the other hand, driving under the influence of alcohol or drugs was the least declared behaviour. Most respondents support policy measures to restrict risky behaviour in traffic and believe that traffic rules are not being checked regularly enough, and should be stricter. The ESRA survey proved to be a valuable source of information to understand the causes underlying road traffic crashes. It offers a unique database and provides policy makers and researchers with valuable insights into public perception of road safety

The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression

Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P1B-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process