High-salt diet causes osmotic gradients and hyperosmolality in skin without affecting interstitial fluid and lymph

The common notion is that the body Na+ is maintained within narrow limits for fluid and blood pressure homeostasis. Several studies have, however, shown that considerable amounts of Na+ can be retained or removed from the body without commensurate water loss and that the skin can serve as a major salt reservoir. Our own data from rats have suggested that the skin is hypertonic compared with plasma on salt storage and that this also applies to skin interstitial fluid. Even small electrolyte gradients between plasma and interstitial fluid would represent strong edema-generating forces. Because the water accumulation has been shown to be modest, we decided to reexamine with alternative methods in rats whether interstitial fluid is hypertonic during salt accumulation induced by high-salt diet (8% NaCl and 1% saline to drink) or deoxycorticosterone pellet implantation. These treatments resulted both in increased systemic blood pressure, skin salt, and water accumulation and in skin hyperosmolality. Interstitial fluid isolated from implanted wicks and lymph draining the skin was, however, isosmotic, and Na+ concentration in fluid isolated by centrifugation and in lymph was not different from plasma. Interestingly, by eluting layers of the skin, we could show that there was an osmolality and urea gradient from epidermis to dermis. Collectively, our data suggest that fluid leaving the skin as lymph is isosmotic to plasma but also that the skin can differentially control its own electrolyte microenvironment by creating local gradients that may be functionally important.acceptedVersio

Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat

We discovered high Na(+) and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2(-/-) animals exhibiting lower skin Na(+) and water levels than controls at birth, they retained ~ 30% higher Na(+) content in their pelts at the expense of K(+) thereafter. Hsd11b2(-/-) neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na(+) through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na(+) imbalance in the Hsd11b2(-/-) neonate leads to excess Na(+) storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na(+) uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na(+) plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney

Dauerhafte Studien über Natriumbilanz und deren Wichtigkeit für die Gesundheit

The steady-state theory of sodium homeostasis for maintenance of constant extracellular solute and fluid concentrations suggests that the body sodium (Na+) content is maintained steady by rapid adjustment of renal excretion to variable intakes. This theory derives from studies with short-term exposure to dietary extremes. We recently performed the reverse experiment in that we fixed sodium intake for weeks at three levels of sodium intake (salt 6 g/day, 9 g/day, 12 g/day) and collected all urine made. We capitalized on a simulated flight to Mars, in which we could control intake and output of all nutrients for months. We found weekly (circaseptan) patterns in sodium excretion that were inversely cross-correlated with aldosterone and directly to cortisol. Total-body sodium was not dependent on sodium intake either but instead exhibited far longer (≥ monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. We also tested the utility of 24 hour urinary sample to predict the actual salt intake. Due to inherent changing patterns in Na+ of retention and excretion and alterations in the body Na+ content that are uncoupled from body fluid and blood pressure homeostasis, every second 24 hour urinary sample failed to predict salt intake within a 3 g range of real intake. Our findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing sodium magnetic resonance imaging to pursue open questions on sodium balance in patients. In Berlin, we could expand this technique to a 7-Tesla platform with greater resolution. The findings may recast thinking about how homeostasis of internal environment composition is achieved and become beneficial to diagnostic and therapeutic strategies, for instance in hypertension and target-organ damage.Natrium-Homöostase soll einen Gleichgewichtszustand aufrechterhalten werden. Eine rasche Anpassung der Natriumausscheidung auf vermehrte oder verminderte Natriumzufuhr hält dabei den Natriumgehalt im Körper konstant. Diese Theorie basiert auf relativ kurzen Experimenten, in deren Verlauf massive Veränderungen in der Kochsalzzufuhr vorgenommen wurden. Wir konnten im Rahmen eines simulierten Marsfluges die Natrium-Homöostase unter konstanten Bedingungen von drei Kochsalzmengen (6, 9 und 12 Gramm/Tag) über Wochen an 10 normalen männlichen Probanden untersuchen. Alle anderen Diätbestandteile wurden über diese Zeit konstant gehalten. Wir entdeckten bei konstanter Natriumzufuhr wöchentliche (circaseptane) Rhythmuszyklen in der Natriumausscheidung, die invers mit Aldosteronausscheidung und direkt mit Kortisolausscheidung kreuzkorrelierten. Der Gesamtkörpergehalt an Natrium schwankte mit noch langfristiger infadianer Rhythmik (Periodendauer >30 Tage). Diese Schwankungen des Gesamtkörpernatriums traten ohne parallele Veränderungen von Gesamtkörperwasser, Körpergewicht oder Blutdruck auf. Wir testeten auch den prädiktiven Wert von 24-Stunden-Sammelurinproben zur Erfassung der täglichen Salzzufuhr. Aufgrund der infradianen Ausscheidungsrhythmen erfasst nur jede zweite 24-Stunden-Sammelurinprobe die tatsächliche Natriumaufnahme innerhalb eines 3-g Prädiktionsintervalls korrekt. Unsere Befunde zur Natriumspeicherung beim Menschen stimmen mit unseren Tierversuchsergebnissen überein. Auch passen sie zu unseren Natrium- Magnetresonanztomographischen Untersuchungen, die wir in Berlin auf 7-Tesla haben erweitern können. Unsere Befunde könnten jetzige Überlegungen hinsichtlich Kochsalzzufuhr, Bluthochdruck und Endorganschaden beeinflussen und zu besseren therapeutischen Strategien führen

Additional file 1 of COVID-19 vaccines effectiveness against symptomatic SARS-CoV-2 during Delta variant surge: a preliminary assessment from a case-control study in St. Petersburg, Russia

Additional file 1: Supplementary material with the results of sensitivity analysis

Additional file 1 of Vaccine effectiveness against referral to hospital after SARS-CoV-2 infection in St. Petersburg, Russia, during the Delta variant surge: a test-negative case-control study

Additional file 1: Figure A1. Vaccine effectiveness against referral to hospital, according to age. Figure A2. Probability of any lung injury, according to age and vaccination status. Figure A3. Vaccine effectiveness against any lung injury, according to age