High versus low ultrafiltration rates during experimental peritoneal dialysis in rats: Acute effects on plasma volume and systemic haemodynamics

Introduction: Intradialytic hypotension is a common complication of haemodialysis, but uncommon in peritoneal dialysis (PD). This may be due to lower ultrafiltration rates in PD compared to haemodialysis, allowing for sufficient refilling of the blood plasma compartment from the interstitial volume, but the underlying mechanisms are unknown. Here we assessed plasma volume and hemodynamic alterations during experimental PD with high versus low ultrafiltration rates. Methods: Experiments were conducted in two groups of healthy Sprague-Dawley rats: one group with a high ultrafiltration rate ( N = 7) induced by 8.5% glucose and a low UF group ( N = 6; 1.5% glucose), with an initial assessment of the extracellular fluid volume, followed by 30 min PD with plasma volume measurements at baseline, 5, 10, 15 and 30 min. Mean arterial pressure, central venous pressure and heart rate were continuously monitored during the experiment. Results: No significant changes over time in plasma volume, mean arterial pressure or central venous pressure were detected during the course of the experiments, despite an ultrafiltration (UF) rate of 56 mL/h/kg in the high UF group. In the high UF group, a decrease in extracellular fluid volume of −7 mL (−10.7% (95% confidence interval: −13.8% to −7.6%)) was observed, in line with the average UF volume of 8.0 mL (standard deviation: 0.5 mL). Conclusion: Despite high UF rates, we found that plasma volumes were remarkably preserved in the present experiments, indicating effective refilling of the plasma compartment from interstitial tissues. Further studies should clarify which mechanisms preserve the plasma volume during high UF rates in PD.

Annual change in the extracellular fluid/intracellular fluid ratio and mortality in patients undergoing maintenance hemodialysis

We aimed to investigate whether annual change in the extracellular fluid to intracellular fluid (ΔECF/ICF) ratio can accurately predict mortality in hemodialysis patients. Totally, 247 hemodialysis patients were divided into two groups according to the median baseline ECF/ICF ratio of 0.563 and ΔECF/ICF ≥ 0% or < 0% during the first year, respectively. Thereafter, they were divided into four groups according to each cutoff point and were followed up for mortality assessment. The ECF/ICF ratio increased from 0.566 ± 0.177 to 0.595 ± 0.202 in the first year (P = 0.0016). During the 3.4-year median follow-up, 93 patients died (42 cardiovascular-specific causes). The baseline ECF/ICF ≥ 0.563 and ΔECF/ICF ≥ 0% were independently associated with all-cause mortality (adjusted hazard ratio [aHR] 4.55, 95% confidence interval [CI] 2.60–7.98 and aHR 8.11, 95% CI 3.47–18.96, respectively). The aHR for ECF/ICF ≥ 0.563 and ΔECF/ICF ≥ 0% vs. ECF/ICF < 0.563 and ΔECF/ICF < 0% was 73.49 (95% CI 9.45–571.69). For model discrimination, adding the ΔECF/ICF (0.859) alone and both the baseline ECF/ICF and ΔECF/ICF (0.903) to the established risk model (0.746) significantly improved the C-index. Similar results were obtained for cardiovascular mortality. In conclusion, the ΔECF/ICF ratio could not only predict all-cause and cardiovascular mortality but also improve predictability of mortality in hemodialysis patients.

Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the a and g subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange was required for terrestrial survival.

The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans

The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations.

TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells

Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer and play a role in the regulation of vascular functions, such as the blood coagulation-fibrinolytic system. When the monolayer is severely or repeatedly injured, platelets aggregate at the damaged site and release transforming growth factor (TGF)-β1 in large quantities from their α-granules. Cadmium is a heavy metal that is toxic to various organs, including the kidneys, bones, liver, and blood vessels. Our previous study showed that the expression level of Zrt/Irt-related protein 8 (ZIP8), a metal transporter that transports cadmium from the extracellular fluid into the cytosol, is a crucial factor in determining the sensitivity of vascular endothelial cells to cadmium cytotoxicity. In the present study, TGF-β1 was discovered to potentiate cadmium-induced cytotoxicity by increasing the intracellular accumulation of cadmium in cells. Additionally, TGF-β1 induced the expression of ZIP8 via the activin receptor-like kinase 5-Smad2/3 signaling pathways; Smad3-mediated induction of ZIP8 was associated with or without p38 mitogen-activated protein kinase (MAPK). These results suggest that the cytotoxicity of cadmium to vascular endothelial cells increases when damaged endothelial monolayers that are highly exposed to TGF-β1 are repaired.

A Breakthrough in Understanding the Pathogenesis of Molar Hypomineralisation: The Mineralisation-Poisoning Model

Popularly known as “chalky teeth”, molar hypomineralisation (MH) affects over 1-in-5 children worldwide, triggering massive amounts of suffering from toothache and rapid decay. MH stems from childhood illness and so offers a medical-prevention avenue for improving oral and paediatric health. With a cross-sector translational research and education network (The D3 Group; thed3group.org) now highlighting this global health opportunity, aetiological understanding is urgently needed to enable better awareness, management and eventual prevention of MH. Causation and pathogenesis of “chalky enamel spots” (i.e., demarcated opacities, the defining pathology of MH) remain unclear despite 100 years of investigation. However, recent biochemical studies provided a pathomechanistic breakthrough by explaining several hallmarks of chalky opacities for the first time. This article outlines these findings in context of previous understanding and provides a working model for future investigations. The proposed pathomechanism, termed “mineralisation poisoning”, involves localised exposure of immature enamel to serum albumin. Albumin binds to enamel-mineral crystals and blocks their growth, leading to chalky opacities with distinct borders. Being centred on extracellular fluid rather than enamel-forming cells as held by dogma, this localising pathomechanism invokes a new type of connection with childhood illness. These advances open a novel direction for research into pathogenesis and causation of MH, and offer prospects for better clinical management. Future research will require wide-ranging inputs that ideally should be coordinated through a worldwide translational network. We hope this breakthrough will ultimately lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay.

Delirium in Acute Poisoning with 1,4-Butanediol and Its Correction

Delirium complicating regular use of psychoactive substances remains one of the major issues of critical care, toxicology, and psychiatry. However, the pathogenetic mechanisms of delirium development in patients with 1,4-butanediol poisoning have been poorly studied until now.The aim of the study was to reveal specific patterns of delirium in patients with 1,4-butanediol poisoning as well as to study the changes in systemic hemodynamic parameters, respiratory function, and body fluid compartments during the treatment.Material and methods. The study was prospective and treatment-randomized. Forty-eight male patients aged 20 to 45 years with delirium and acute 1,4-butanediol poisoning were enrolled. Of them, 24 patients were administered with succinate-containing drug 40 ml daily, 24 patients received standard treatment without antihypoxic agents. We studied the evolution of delirium, changes in anaerobic metabolism parameters, systemic hemodynamics, respiratory function, and the volume of fluid compartments. Impedance measurement method adjusted for interference was used in the study.Results. At the «peak» of delirium (days 1–3), the hyperdynamic circulation, increased systemic arterial tone, stroke output, respiratory function parameters, and metabolic lactate acidosis were recorded. A decrease in total fluid volume and extracellular fluid volume was clearly observed during day 1 of intoxication delirium along with increased permeability of cell membranes. On day 3 of delirium, a decrease in intracellular fluid volume and increase in extracellular fluid volume were noted. After the cytoflavin administration, shorter delirium duration (7.5 [6; 8] days), more rapid correction of lactate acidosis, stabilization of respiratory parameters and stabilization of cell membrane permeability by day 5 were found. In the control group, delirium persisted for up to 14 [11; 15] days (z=-5.9; P=0.00011) with more frequent development of complications such as nosocomial pneumonia (χ2=8.4, P<0.001).Conclusion. The severity of delirium in acute poisoning with 1,4-butanediol was associated with metabolic lactate acidosis, changes in systemic hemodynamics and pulmonary function. A positive effect of adjunctive antihypoxic therapy with succinate-containing agent on cardio-respiratory parameters, cell membrane permeability, water balance due to elimination of tissue hypoxia and prompt switching to tissue aerobic metabolism has been found.

Blood-Brain Barrier Overview: Structural and Functional Correlation

The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain’s extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.

Lipid droplets as endogenous intracellular microlenses

Using a single biological element as a photonic component with well-defined features has become a new intriguing paradigm in biophotonics. Here we show that endogenous lipid droplets in the mature adipose cells can behave as fully biocompatible microlenses to strengthen the ability of microscopic imaging as well as detecting intra- and extracellular signals. By the assistance of biolenses made of the lipid droplets, enhanced fluorescence imaging of cytoskeleton, lysosomes, and adenoviruses has been achieved. At the same time, we demonstrated that the required excitation power can be reduced by up to 73%. The lipidic microlenses are finely manipulated by optical tweezers in order to address targets and perform their real-time imaging inside the cells. An efficient detecting of fluorescence signal of cancer cells in extracellular fluid was accomplished due to the focusing effect of incident light by the lipid droplets. The lipid droplets acting as endogenous intracellular microlenses open the intriguing route for a multifunctional biocompatible optics tool for biosensing, endoscopic imaging, and single-cell diagnosis.