Mechanical Forces Impair Alveolar Ion Transport Processes – A Putative Mechanism Contributing to the Formation of Pulmonary Edema

The aim of this chapter is to highlight the importance of transepithelial ion transport processes for lung function in general and to focus on the impact of mechanical forces on pulmonary ion transport in particular. Linking mechanical forces with pulmonary ion transport derives from the fact that the lung is a dynamic organ as well as from several studies providing evidence that the amount of mechanical forces as used during artificial ventilation correlates with mortality rates in patients with respiratory failure such as ALI (acute lung injury) and ARDS (acute respiratory distress syndrome) (ARDS Network Investigators, 2000). In these patients the formation of pulmonary edema is a characteristic symptom (Frank and Matthay, 2003; Ricard et al., 2003) and the basic rationale behind this is, that mechanical perturbations cause epithelial leakage in response to mechanically induced damage of the epithelial layer. This damage is suggested to be a major cause for the formation of pulmonary edema as well as the inability to reabsorb the edema fluid. However, little is known whether or not mechanical forces may directly interfere with pulmonary ion transport processes and this represents a putative mechanism that facilitates the formation of pulmonary edema – in addition to damages of the epithelial layer

‘Policing Schools’ Strategies: A Review of the Evaluation Evidence

Background: Schools experience a wide range of crime and disorder, victimizing students and staff, and undermining attempts to create a safe and orderly environment for student learning. Police have long established programs with schools, but there has been no systematic review of evaluations of these programs, outside of police-led prevention classroom curriculum programs such as D.A.R.E.     Purpose: This paper documents a systematic search to identify experimental and quasi-experimental evaluations that assess the effectiveness of non-educational policing strategies and programs in schools.     Setting: Included studies took place in or around K-12 schools in the United States, Canada, and the United Kingdom.   Intervention: Studies were included if they reported on a specific school-based strategy that heavily involved police and did not exclusively involve the police teaching a curriculum or program such as Drug Abuse Resistance Education (D.A.R.E.).   Research Design:  Systematic review of experimental or quasi-experimental evaluations   Data Collection and Analysis: Only those impact studies that used experimental or quasi-experimental design, had at least one outcome measure of school crime or disorder, and were available through December 2009 were eligible.  Electronic searches and other methods were used to identify published and unpublished evaluation reports.       Findings: The searches identified a total of eleven quasi-experimental studies. Ten of the eleven studies would likely have received a “3” on the Maryland Scientific Methods Rating Scale, a common approach to classifying studies on the basis of internal validity.  If evidence rating criteria from the U.S. Department of Education’s What Works Clearinghouse (WWC) were applied, only one study would likely receive a grade of “Level 2” evidence (acceptable with reservations) and the other ten studies would likely not meet WWC evidence screening criteria.   Keywords: systematic review; police and schools; crime prevention&nbsp

Why Do We have to Move Fluid to be Able to Breathe?

The ability to breathe air represents a fundamental step in vertebrate evolution that was accompanied by several anatomical and physiological adaptations. The morphology of the air-blood barrier is highly conserved within air-breathing vertebrates. It is formed by three different plies, which are represented by the alveolar epithelium, the basal lamina, and the endothelial layer. Besides these conserved morphological elements, another common feature of vertebrate lungs is that they contain a certain amount of fluid that covers the alveolar epithelium. The volume and composition of the alveolar fluid is regulated by transepithelial ion transport mechanisms expressed in alveolar epithelial cells. These transport mechanisms have been reviewed extensively. Therefore, the present review focuses on the properties and functional significance of the alveolar fluid. How does the fluid enter the alveoli? What is the fate of the fluid in the alveoli? What is the function of the alveolar fluid in the lungs? The review highlights the importance of the alveolar fluid, its volume and its composition. Maintenance of the fluid volume and composition within certain limits is critical to facilitate gas exchange. We propose that the alveolar fluid is an essential element of the air-blood barrier. Therefore, it is appropriate to refer to this barrier as being formed by four plies, namely (1) the thin fluid layer covering the apical membrane of the epithelial cells, (2) the epithelial cell layer, (3) the basal membrane, and (4) the endothelial cells

Amiloride-Sensitive Sodium Channels and Pulmonary Edema

The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed

A gyorsított gyógyszer engedélyezési gyakorlat klinikai farmakológiai háttere, etikai és egészséggazdasági dilemmái

A gyorsított gyógyszer engedélyezési eljárások a súlyos, életet veszélyeztető betegségek kezelésére kifejlesztett gyógyszerek piacra jutását átlagosan 3-4 évvel rövidítik meg. A gyorsított eljárással forgalomba hozott szerek többsége egyben árva gyógyszernek is minősül, melyek fejlesztése és forgalmazása jelentős anyagi, tudományos és adminisztratív támogatást élvez. Ilyen módon a két gyógyszerfejlesztést támogató program társadalmi következményei szorosan összefonódnak. Az utóbbi években a gyorsított engedélyezési eljárást és az árva gyógyszer minősítést az esetek többségében a genetikailag azonosított ritka onkológiai betegségek esetén veszik igénybe a gyártók. A gyorsított eljárások elbírálása általában köztes végpontokon alapszik, melyek gyakran nem korrelálnak a végső kimenetellel. További gond, hogy a gyártók gyakran lassan vagy egyáltalán nem végzik el a végleges forgalomba hozatalhoz szükséges vizsgálatokat. Ilyen módon sokszor kiemelkedően drága, de nem kellően kivizsgált gyógyszerek is bekerülnek, illetve gyakran hosszabb ideig is az egészségügyi ellátásban maradnak. Komoly etikai és gazdasági gondot jelent, hogy a gyorsított eljárással forgalmazott gyógyszerek egy része nem eredményez klinikai hasznot, viszont jelentős anyagi megterhelést jelent a társadalom számára. | Accelerated drug approval procedures decrease the marketing access of drugs developed for treating severe, life-threatening diseases by 3-4 years. The majority of drugs marketed following accelerated ap- proval gets also orphan drug designation, whose de- velopment and marketing enjoy significant material, scientific and administrative support from the society. In this way the social effects of the two programs sup- porting drug development become tightly interconnec- ted. Medicines which can be used for the treatment of rare diseases can receive orphan designation. All orphan drugs might be eligible for accelerated approval. In recent years, drug producers have taken advantage of the accelerated approval process and orphan drug designation more frequently for genetically identified rare oncologic diseases. In many cases the evaluation of accelerated approvals is based on surrogate end- points, which frequently do not correlate well with the final outcome of the disease. It is a further problem that the producers perform often slowly or not at all the tri- als needed for the final marketing approval of these me- dicines. Consequently, many outstandingly expensive and not satisfactorily evaluated drugs reach, and rema- in for prolonged time in the health care system. It is an increasing ethical and economical concern that se- veral drugs approved by accelerated approach do not provide clinical benefit, but cause significant financial burden for the society

The Characteristics and Experiences of Beginning Teachers in Seven Northeast and Islands Region States and Nationally

How do East Coast teachers differ from teachers nationwide? Based on results from a recent survey of teachers, this report looks at the characteristics of beginning teachers to find out what makes them different or similar.The study's researchers define beginning teachers as those with five or less years of teaching experience at the time of the staffing survey.Here's what you'll find in this report:How beginning teachers are supported through professional developmentTeachers' overall sense of preparedness for teachingCharacteristics of teachers' classrooms and schoolsVariables related to teachers' preparation and workplace supports that are associated with their perceptions of preparedness, effectiveness, and retentionThe Regional Educational Laboratory Northeast and Islands at WestEd prepared this report

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

Background and Purpose Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown. Experimental Approach Transepithelial short circuit currents (ISC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca2+]i were studied on freshly dissociated mouse tracheal epithelial cells. Key Results Apical application of the nAChR agonist nicotine transiently increased ISC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. α‐Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A‐85380 (α4β2 and α3β4) increased ISC. The antagonists dihydro‐β‐erythroidine (α4β2, α3β2, α4β4 and α3β4), α‐conotoxin MII (α3β2) and α‐conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine‐ and epibatidine‐induced currents were unaltered in β2−/−mice, but in β4−/− mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca2+‐ATPase inhibitor) or the ryanodine receptor antagonists JTV‐519 and dantrolene there was a reduction in the nicotine‐effect, indicating involvement of Ca2+ release from intracellular stores. Additionally, the PKA inhibitor H‐89 and the TMEM16A (Ca2+‐activated chloride channel) inhibitor T16Ainh‐A01 significantly reduced the nicotine‐effect. Conclusion and Implications α3β4 nAChRs are responsible for the nicotine‐induced current changes via Ca2+ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A