Examining the significance of arginine vasopressin release to elucidate the often multifactorial etiology of hypotonic hyponatremia: A novel criterion.

Clinical hyponatremia guidelines, protocols and flowcharts are a convenient means for clinicians to quickly establish an etiological diagnosis for hyponatremia, and facilitate its often complex analysis. Unfortunately, they often erroneously attribute multifactorial hyponatremia to a single cause, which is potentially dangerous. In this manuscript, a novel criterion is proposed to quickly determine the physiological relevance of non-osmotic arginine vasopressin (AVP) release, and to add nuance to hyponatremia analysis. While analyzing hypotonic hyponatremia, it is imperative to not only verify whether or not a certain degree of inappropriate AVP release is present, but also to ascertain whether it-in itself-could sufficiently explain the observed hyponatremia, as these two are not always synonymous. Using well-known concepts from renal physiology to combine the electrolyte-free water balance and solute-free water balance, a novel physiological criterion is derived mathematically to easily distinguish three common hyponatremia scenarios, and to further elucidate the underlying etiology. The derived criterion can hopefully facilitate the clinician's and physiologist's interpretation of plasma and urine parameters in a patient presenting with hyponatremia, and warn against the important clinical pitfall of attributing hyponatremia too readily to a single cause.

A novel clinical nomogram for the evaluation of disorders of plasma osmolality.

Disorders of water and sodium homeostasis in the human body-or dysnatraemias-are frequently encountered in clinical practice, but their analysis is often complex and their management is often troublesome. For many clinicians, it remains challenging to correctly interpret all relevant biochemical parameters involved in the analysis of dysnatraemia, especially when a rapid 'bedside' evaluation is required to initiate treatment. By mathematically deriving the relationship between plasma osmolality and urine osmolality under physiological circumstances, we were able to propose a novel and clinically useful nomogram for the rapid evaluation of disorders of plasma osmolality. We believe that the presented osmolality nomogram could be a transparent and clinically useful tool for the quick evaluation of disorders of the water and sodium balance in patients.

Correction: Comparing the Voets equation and the Adrogue-Madias equation for predicting the plasma sodium response to intravenous fluid therapy in SIADH patients.

[This corrects the article DOI: 10.1371/journal.pone.0245499.].

Comparing the Voets equation and the Adrogue-Madias equation for predicting the plasma sodium response to intravenous fluid therapy in SIADH patients.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hypotonic hyponatremia. In our previous work, we have derived a novel model (Voets equation) that can be used by clinicians to predict the effect of crystalloid intravenous fluid therapy on the plasma sodium concentration in SIADH. METHODS: In this retrospective chart review, the predictive accuracy of the Voets equation and the Adrogue-Madias equation for the plasma sodium response to crystalloid infusate was compared for fifteen plasma sodium response measurements (n = 15) in twelve SIADH patients. The medical records of these patients were accessed anonymously and none of the authors were their treating physicians. The Pearson correlation coefficient r and corresponding p-value were calculated for the predictions by the Voets model compared to the measured plasma sodium response and for the predictions by the Adrogue-Madias model compared to the measured plasma sodium response. RESULTS AND CONCLUSION: The presented results show that the Voets model (r = 0.94, p < 0.001) predicted the aforementioned plasma sodium response significantly more accurately than the Adrogue-Madias model (r = 0.49, p = 0.07) in SIADH patients and could therefore be a clinically useful addition to the existing prediction models.

Understanding dysnatremia.

Dysnatremia-either hyponatremia or hypernatremia-is frequently encountered in the clinical practice and often poses a diagnostic and therapeutic challenge for physicians. Despite their frequent occurrence, disorders of the water and sodium balance in the human body have puzzled many physicians over the years and often remain elusive for those lacking experience in their interpretation and management. In this article, we derive a transparent governing equation that can be used by clinicians to describe how a change in relevant physiological parameters will affect the plasma sodium concentration. As opposed to many existing models, our model takes both input and output into account, and integrates osmolarity and tonicity. Our governing equation should be considered a means for clinicians to get a better qualitative understanding of the relationship between the plasma sodium concentration and the variables that influence it for a wide range of scenarios.

A quantitative approach to intravenous fluid therapy in the syndrome of inappropriate antidiuretic hormone secretion.

BACKGROUND: A wide range of interesting mathematical models has been derived to predict the effect of intravenous fluid therapy on the serum sodium concentration (most notably the Adrogué-Madias equation), but unfortunately, these models cannot be applied to patients with disorders characterized by aberrant antidiuretic hormone (ADH) release, such as the syndrome of inappropriate ADH secretion (SIADH). The use of intravenous fluids in these patients should prompt caution, as the inability of the kidneys to properly dilute the urine can easily result in deterioration of hyponatremia. METHODS: In this report, a transparent and clinically applicable equation is derived that can be used to calculate the estimated effect of different types and volumes of crystalloid infusate on the serum sodium concentration in SIADH patients. As a "proof of concept", we discuss five SIADH patient cases from our clinic. Alternatively, our mathematical model can be used to determine the infusate volume that is required to produce a certain desired change in the serum sodium concentration in SIADH patients. CONCLUSION: The presented model facilitates rational intravenous fluid therapy in SIADH patients, and provides a valuable addition to existing prediction models.

Central line-associated bloodstream infections and catheter dwell-time: A theoretical foundation for a rule of thumb.

Many clinicians know from experience and medical epidemiological literature that the risk of central line-associated bloodstream infections (CLABSI) increases rapidly with a prolonged catheter dwell-time, but how this infection risk increases over time remains obscure. In this manuscript, a clinically useful rule of thumb is derived, stating that the risk of CLABSI increases in a quadratic fashion with the increase in catheter dwell-time. The proposed rule of thumb could be considered a quick and effortless clinical tool to rationally predict the pattern of CLABSI risk with an increasing catheter dwell-time.

Extracellular volume depletion and resultant hypotonic hyponatremia: A novel translational approach.

Although several methods currently exist to determine that a person is hypovolemic, it often remains very challenging to accurately estimate the effective circulating volume or amount of intravascular volume depletion in a non-controlled setting. This depletion of intravascular volume can have many causes and is frequently accompanied by hypotonic hyponatremia as a result of hypovolemia-induced release of arginine vasopressin (AVP) from the posterior pituitary gland. Here, we derive a novel, comprehensible equation that provides a theoretical insight into the complex interrelationship between the degree of isotonic volume depletion and the resultant change in plasma sodium concentration. We believe that the presented model can prove to be a valuable tool for the analysis of fluid and electrolyte imbalances.

On the antigen-antibody interaction: A thermodynamic consideration.

Despite its relevance to many biomedical fields, relatively little effort has been put into a comprehensible quantitative description of the effect of reaction temperature on the interaction between antigens and their antibodies. In this article, a novel, straightforward mathematical model is proposed, which aims to describe the effect of temperature on antigen-antibody kinetics. The model proposed in this article could hopefully provide clinicians, immunologists, and biochemists with an improved insight into the kinetic effect of fluctuations in reaction temperature on antigen-antibody-dependent processes and therefore into the kinetics of the humoral adaptive immune response.

Serum cardiac troponin I analysis to determine the excessiveness of exercise intensity: A novel equation.

Physical exertion is often promoted because of its beneficial health effects. This only holds true, however, as long as the optimal exercise intensity is not exceeded. If physical exertion becomes too strenuous or prolonged, cardiac injury or dysfunction may occur. Consequently, a significant elevation of the serum concentration of the sensitive and specific cardiac biomarker troponin I can be observed. In this article, we present the derivation of a novel equation that can be used to evaluate to what extent the intensity of conducted endurance exercise was excessive, based on a post-exercise assessment of serum cardiac troponin I. This is convenient, as exercise intensity is difficult for an athlete to quantify accurately and the currently used heart rate indices can be affected by various physiological and environmental factors. Serum cardiac troponin I, on the other hand, is a post-hoc parameter that directly reflects the actual effects on the myocardium and may therefore be a promising alternative. To our knowledge, this is the first method to determine relative exercise intensity in retrospect. We therefore believe that this equation can serve as a potentially valuable tool to objectively evaluate the benefits or harmful effects of physical exertion.

[Non-transferrin-bound iron: a promising biomarker in iron overload disorders]. / 'Non-transferrin-bound iron': een veelbelovende biomarker bij ijzerstapelingsziekten.

Iron overload disorders are common and, if left untreated, severe systemic diseases that can have both genetic and acquired causes. Hereditary haemochromatosis, ß-thalassaemia, myelodysplastic syndromes and sickle cell disease are among the most important examples. Iron that is not bound to transferrin, haem or ferritin (non-transferrin-bound iron, NTBI) seems to play a key role in the pathophysiology of these disorders. NTBI is a heterogeneous group of potentially toxic iron complexes in plasma which are generated almost exclusively under pathological conditions. Cellular uptake of NTBI contributes to its toxicity and is mediated by several organ-specific transporters and receptors. NTBI-induced toxicity is the result of oxidative damage to various macromolecules by reactive oxygen species (ROS). In the near future, we hypothesize that NTBI will have important implications for both diagnosis and treatment of iron overload disorders. However, before NTBI can be applied to patient care, the currently available assays need further clinical and analytical validation.

Opposing influences of glucocorticoids and interleukin-1beta on the secretion of growth hormone and ACTH in the rat in vivo: role of hypothalamic annexin 1.

1. This study exploited established immunoneutralization protocols and an N-terminal annexin 1 peptide (annexin 1(Ac2 - 26)) to advance our knowledge of the role of annexin 1 as a mediator of acute glucocorticoid action in the rat neuroendocrine system in vivo. 2. Rats were treated with corticosterone (500 microg kg(-1), i.p.) or annexin 1(Ac2 - 26) (0.1 - 10 ng rat(-1), i.c.v.) and 75 min later with interleukin 1beta (IL-1beta, 10 ng rat(-1), i.c.v. or 500 microg kg(-1), i.p). Blood was collected 1 h later for hormone immunoassay. Where appropriate, anti-annexin 1 polyclonal antiserum (pAb) was administered subcutaneously or centrally prior to the steroid challenge. 3. Corticosterone did not affect the resting plasma corticotrophin (ACTH) concentration but suppressed the hypersecretion of ACTH induced by IL-1beta (i.p. or i.c.v.). Its actions were quenched by anti-annexin 1 pAb (s.c. or i.c.v) and mimicked by annexin 1(Ac2 - 26). 4. By contrast, corticosterone provoked an increase in serum growth hormone (GH) which was ablated by central but not peripheral administration of anti-annexin 1 pAb. IL-1beta (i.c.v. or i.p.) did not affect basal GH but, when given centrally but not peripherally, it abolished the corticosterone-induced hypersecretion of GH. Annexin 1(Ac2 - 26) (i.c.v.) also produced an increase in serum GH which was prevented by central injection of IL-1beta. 5. The results support the hypothesis that the acute regulatory actions of glucocorticoids on hypothalamo-pituitary-adrenocortical function require annexin 1. They also provide novel evidence that the positive influence of the steroids on GH secretion evident within this timeframe is effected centrally via an annexin 1-dependent mechanism which is antagonized by IL-1beta.

Annexin 1 (lipocortin 1) mediates the glucocorticoid inhibition of cyclic adenosine 3',5'-monophosphate-stimulated prolactin secretion.

Our previous studies have identified a role for annexin 1 (also called lipocortin 1) in the regulatory actions of glucocorticoids (GCs) on the release of PRL from the rat anterior pituitary gland. In the present study we used antisense and immunoneutralization strategies to extend this work. Exposure of rat anterior pituitary tissue to corticosterone (1 nM) or dexamethasone (100 nM) in vitro induced 1) de novo annexin 1 synthesis and 2) translocation of the protein from intracellular to pericellular sites. Both responses were prevented by the inclusion in the medium of an annexin 1 antisense oligodeoxynucleotide (ODN; 50 nM), but not by the corresponding sense and scrambled ODN sequences. Unlike the GCs, 17beta-estradiol, testosterone, and aldosterone (1 nM) had no effect on either the synthesis or the cellular disposition of annexin 1; moreover, none of the steroids or ODNs tested influenced the expression of annexin 5, a protein closely related to annexin 1. The increases in PRL release induced in vitro by drugs that signal via cAMP/protein kinase A [vasoactive intestinal polypeptide (10 nM), forskolin (100 microM), 8-bromo-cAMP (0.1 microM)] or phospholipase C (TRH, 10 nM) were attenuated by preincubation of the pituitary tissue with either corticosterone (1 nM) or dexamethasone (100 nM). The inhibitory actions of the steroids on the secretory responses to vasoactive intestinal polypeptide, forskolin, and 8-bromo-cAMP were specifically quenched by inclusion in the medium of the annexin 1 antisense ODN (50 nM) or a neutralizing antiannexin 1 monoclonal antibody (antiannexin 1 mAb, diluted 1:15,000). By contrast, the ability of the GCs to suppress the TRH-induced increase in PRL release was unaffected by both the annexin 1 antisense ODN and the antiannexin 1 mAb. In vivo, interleukin-1beta (10 ng, intracerebroventricularly) produced a significant increase in the serum PRL concentration (P < 0.01), which was prevented by pretreatment of the rats with corticosterone (100 microg/100 g BW, sc). The inhibitory actions of the steroid were specifically abrogated by peripheral administration of an antiannexin 1 antiserum (200 microl, sc); by contrast, when the antiserum was given centrally (3 microl, intracerebroventricularly), it was without effect. These results support our premise that annexin contributes to the regulatory actions of GCs on PRL secretion and suggest that it acts at point distal to the formation of cAMP.

Blockade of the classical pathway of protein secretion does not affect the cellular exportation of lipocortin 1.

The mechanism by which lipocortin 1 (LC1) is extruded from cells in the brain and periphery in response to a glucocorticoid challenge is unknown. This study examined the influence of three inhibitors of the classical endoplasmic reticulum-Golgi pathway of protein secretion on the dexamethasone-induced (0.1 microM, 2-3 h) cellular exportation of LC1 in vitro in brain (cortex, hippocampus, hypothalamus), anterior pituitary tissue and peritoneal macrophages. In all instances, the steroid-induced exportation of LC1 was unaffected by brefeldin A (1.4 microM), monensin (10 microM) and nocodazole (3.3 microM); however, these drugs readily blocked the release of corticotrophin from pituitary tissue. These data suggest that LC1 is exported by a mechanism distinct from the classical pathway of protein secretion.

Glucocorticoids modulate the cellular disposition of lipocortin 1 in the rat brain in vivo and in vitro.

The role of glucocorticoids in the regulation of lipocortin 1 (LC1) mRNA/protein expression in the brain is uncertain. This study has examined the influence of dexamethasone on the disposition of LC1 protein in various central and peripheral tissues in the rat. LC1 was readily detectable in all tissues studied by Western blot analysis. Exposure to dexamethasone in vitro (0.1 microM, 3 h) or in vivo (20 micrograms/100 g i.p., 24 h before autopsy) had no discernible effects on intracellular LC1 levels but increased the amount of LC1 attached to the outer surface of cells (pericellular LC1) in cortex, hippocampus, hypothalamus, pituitary gland and peritoneal macrophages (in vitro only). The results suggest that in central tissues, as in the periphery, glucocorticoids promote the translocation of LC1 from intracellular to pericellular sites.

Activation of the HPA axis by immune insults: roles and interactions of cytokines, eicosanoids, glucocorticoids.

It is now well established that challenges to the immune system (e.g., infection, inflammation) initiate diverse changes in neuroendocrine function, the most overt of which is activation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The glucocorticoids that are released as a consequence fulfill a vital role in the maintenance of homeostasis that is effected in part through their ability to quench the immune/inflammatory response and thereby prevent them accelerating to a point where they become hazardous to the host. This article discusses the putative mechanisms by which immune insults stimulate the HPA axis, with particular reference to the roles and interactions of the interleukins, eicosanoids and glucocorticoids.