Claudins in lung diseases

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development

Renal salt wasting and chronic dehydration in claudin-7-deficient mice

Claudin-7, a member of the claudin family, is highly expressed in distal nephrons of kidneys and has been reported to be involved in the regulation of paracellular Cl− permeability in cell cultures. To investigate the role of claudin-7 in vivo, we generated claudin-7 knockout mice (Cln7−/−) by the gene-targeting deletion method. Here we report that Cln7−/− mice were born viable, but died within 12 days after birth. Cln7−/− mice showed severe salt wasting, chronic dehydration, and growth retardation. We found that urine Na+, Cl−, and K+ were significantly increased in Cln7−/− mice compared with that of Cln7+/+ mice. Blood urea nitrogen and hematocrit were also significantly higher in Cln7−/− mice. The wrinkled skin was evident when Cln7−/− mice were ∼1 wk old, indicating that they suffered from chronic fluid loss. Transepidermal water loss measurements showed no difference between Cln7+/+ and Cln7−/− skin, suggesting that there was no transepidermal water barrier defect in Cln7−/− mice. Claudin-7 deletion resulted in the dramatic increase of aldosterone synthase mRNA level as early as 2 days after birth. The significant increases of epithelial Na+ channel α, Na+-Cl− cotransporter, and aquaporin 2 mRNA levels revealed a compensatory response to the loss of electrolytes and fluid in Cln7−/− mice. Na+-K+-ATPase α1 expression level was also greatly increased in distal convoluted tubules and collecting ducts where claudin-7 is normally expressed. Our study demonstrates that claudin-7 is essential for NaCl homeostasis in distal nephrons, and the paracellular ion transport pathway plays indispensable roles in keeping ionic balance in kidneys

Randomization to randomization probability: Estimating treatment effects under actual conditions of use

Blinded randomized controlled trials (RCT) require participants to be uncertain if they are receiving a treatment or placebo. Although uncertainty is ideal for isolating the treatment effect from all other potential effects, it is poorly suited for estimating the treatment effect under actual conditions of intended use—when individuals are certain that they are receiving a treatment. We propose an experimental design, Randomization to Randomization Probabilities (R2R), which significantly improves estimates of treatment effects under actual conditions of use by manipulating participant expectations about receiving treatment. In the R2R design, participants are first randomized to a value, π, denoting their probability of receiving treatment (vs placebo). Subjects are then told their value of π and randomized to either treatment or placebo with probabilities π and 1-π, respectively. Analysis of the treatment effect includes statistical controls for π (necessary for causal inference) and typically a π-by-treatment interaction. Random assignment of subjects to π and disclosure of its value to subjects manipulates subject expectations about receiving the treatment without deception. This method offers a better treatment effect estimate under actual conditions of use than does a conventional RCT. Design properties, guidelines for power analyses, and limitations of the approach are discussed. We illustrate the design by implementing an RCT of caffeine effects on mood and vigilance and show that some of the actual effects of caffeine differ by the expectation that one is receiving the active drug

L'architettura ecclesiastica medievale nelle campagne venete

Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health-care policies, future research and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance