Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

Temperature stabilization, ocean heat uptake and radiative forcing overshoot profiles

Political leaders in numerous nations argue for an upper limit of the global average surface temperature of 2 K above the pre-industrial level, in order to attempt to avoid the most serious impacts of climate change. This paper analyzes what this limit implies in terms of radiative forcing, emissions pathways and abatement costs, for a range of assumptions on rate of ocean heat uptake and climate sensitivity. The primary aim is to analyze the importance of ocean heat uptake for radiative forcing pathways that temporarily overshoot the long-run stabilization forcing, yet keep the temperature increase at or below the 2 K limit. In order to generate such pathways, an integrated climate-economy model, MiMiC, is used, in which the emissions pathways generated represent the least-cost solution of stabilizing the global average surface temperature at 2 K above the pre-industrial level. We find that the level of overshoot can be substantial. For example, the level of overshoot in radiative forcing in 2100 ranges from about 0.2 to 1 W/m2, where the value depends strongly and positively on the effective diffusivity of heat in the oceans. Measured in relative terms, the level of radiative forcing overshoot above its longrun equilibrium level in 2100 is 20% to 60% for high values of climate sensitivity (i.e., about 4.5 K) and 8% to 30% for low values of climate sensitivity (i.e., about 2 K). In addition, for cases in which the radiative forcing level can be directly stabilized at the equilibrium level associated with a specific climate sensitivity and the 2 K limit, the net present value abatement cost is roughly cut by half if overshoot pathways are considered instead of stabilization of radiative forcing at the equilibrium level without an overshoot

Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus

Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments

The Gut Microbiome and Cirrhosis: Basic Aspects

In this chapter the basic aspects helping to understand the microbiome in terms of quantity, diversity, complexity, function, and interaction with the host are discussed. First the nomenclature, definitions of taxa, and measures of diversity as well as methods to unravel this kingdom are outlined. A brief summary on its physiological relevance for general health and the functions exerted specifically by the microbiome is presented. Differences in the composition of the microbiome along the gastrointestinal tract and across the gut wall and its interindividual variations, enterotypes, and stability are highlighted. The reader will be familiarized with all different modulators impacting on the microbiome, namely, intrinsic and extrinsic factors. Intrinsic factors include gastrointestinal secretions (gastric acid, bile, pancreatic juice, mucus), antimicrobial peptides, motility, enteric nervous system, and host genotype. Extrinsic factors are mainly dietary choices, hygiene, stress, alcohol consumption, exercise, and medications. The second part of the chapter focuses on quantitative and qualitative changes in microbiome in liver cirrhosis. The mechanisms contributing to dysbiosis, small intestinal bacterial overgrowth, and bacterial translocation are delineated underscoring their role for the liver-gut axis

Contribution of Neutrophils to Acute Lung Injury

Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI

Common surgical procedures in pilonidal sinus disease: A meta-analysis, merged data analysis, and comprehensive study on recurrence

Abstract We systematically searched available databases. We reviewed 6,143 studies published from 1833 to 2017. Reports in English, French, German, Italian, and Spanish were considered, as were publications in other languages if definitive treatment and recurrence at specific follow-up times were described in an English abstract. We assessed data in the manner of a meta-analysis of RCTs; further we assessed non-RCTs in the manner of a merged data analysis. In the RCT analysis including 11,730 patients, Limberg & Dufourmentel operations were associated with low recurrence of 0.6% (95%CI 0.3–0.9%) 12 months and 1.8% (95%CI 1.1–2.4%) respectively 24 months postoperatively. Analysing 89,583 patients from RCTs and non-RCTs, the Karydakis & Bascom approaches were associated with recurrence of only 0.2% (95%CI 0.1–0.3%) 12 months and 0.6% (95%CI 0.5–0.8%) 24 months postoperatively. Primary midline closure exhibited long-term recurrence up to 67.9% (95%CI 53.3–82.4%) 240 months post-surgery. For most procedures, only a few RCTs without long term follow up data exist, but substitute data from numerous non-RCTs are available. Recurrence in PSD is highly dependent on surgical procedure and by follow-up time; both must be considered when drawing conclusions regarding the efficacy of a procedure