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Mathematical Biosciences and... Oct 2023Human immunodeficiency virus (HIV) infection is a major public health concern with 1.2 million people living with HIV in the United States. The role of nutrition in...
Human immunodeficiency virus (HIV) infection is a major public health concern with 1.2 million people living with HIV in the United States. The role of nutrition in general, and albumin/globulin in particular in HIV progression has long been recognized. However, no mathematical models exist to describe the interplay between HIV and albumin/globulin. In this paper, we present a family of models of HIV and the two protein components albumin and globulin. We use albumin, globulin, viral load and target cell data from simian immunodeficiency virus (SIV)-infected monkeys to perform model selection on the family of models. We discover that the simplest model accurately and uniquely describes the data. The selection of the simplest model leads to the observation that albumin and globulin do not impact the infection rate of target cells by the virus and the clearance of the infected target cells by the immune system. Moreover, the recruitment of target cells and immune cells are modeled independently of globulin in the selected model. Mathematical analysis of the selected model reveals that the model has an infection-free equilibrium and a unique infected equilibrium when the immunological reproduction number is above one. The infection-free equilibrium is locally stable when the immunological reproduction number is below one, and unstable when the immunological reproduction number is greater than one. The infection equilibrium is locally stable whenever it exists. To determine the parameters of the best fitted model we perform structural and practical identifiability analysis. The structural identifiability analysis reveals that the model is identifiable when the immune cell infection rate is fixed at a value obtained from the literature. Practical identifiability reveals that only seven of the sixteen parameters are practically identifiable with the given data. Practical identifiability of parameters performed with synthetic data sampled a lot more frequently reveals that only two parameters are practically unidentifiable. We conclude that experiments that will improve the quality of the data can help improve the parameter estimates and lead to better understanding of the interplay of HIV and albumin-globulin metabolism.
Topics: Animals; Humans; HIV Infections; Models, Theoretical; Simian Immunodeficiency Virus; Albumins
PubMed: 38052613
DOI: 10.3934/mbe.2023865 -
Laboratory Investigation; a Journal of... Nov 1986Intradermal injections of killed Escherichia coli are known to cause a variety of pathophysiological changes in the microcirculation that facilitate the extravasation of...
Intradermal injections of killed Escherichia coli are known to cause a variety of pathophysiological changes in the microcirculation that facilitate the extravasation of plasma constituents into the interstitium. In an attempt to learn more of the factors that regulate the magnitude and duration of inflammatory edema, we have focused on the relationship between the extravasation of protein into the interstitium and the removal of extravascular protein from the lesion sites. Vascular permeability changes have been assessed by the local accumulation of systemically administered [131I] or [125I]-albumin and extravascular protein clearance measured by monitoring the disappearance of [125I]-albumin from the same sites. Radioactivity was quantitated with an external gamma-scintillation probe or by punching out the lesion sites in sacrificed animals and counting in a gamma-spectrometer. Scintillation probe measurements of the net accumulation of intravenously administered [125I]-albumin in E. coli-induced skin lesions revealed that the extravasation of albumin was greater than the clearance of protein from the same sites. Comparisons of the removal rates of albumin injected directly into the E. coli sites revealed that, despite increases in vascular permeability amounting to 170 to 700% of control values, the mobilization of deposited albumin was no greater than that from control tissues that received saline; in fact with high concentrations of E. coli (10(8) injected/site) the mobilization of protein from the lesions was significantly reduced. The systemic administration of 055:B5 endotoxin (0.3, 1.6, or 3.3 micrograms/kg) also suppressed the clearance of albumin from skin. In contrast to these results, 300 to 1500% increases in vascular permeability induced with other inflammatory stimuli including thermal injury, high concentrations of bovine serum albumin, or bradykinin, resulted in enhanced clearance of extravascular protein from lesion or injection sites. These experiments suggest that an inability to effectively mobilize extravascular protein from the inflammatory focus could be a major contributing factor in regulating edema in inflammatory reactions induced with E. coli and may possibly contribute to the edema associated with septicemia.
Topics: Albumins; Animals; Bradykinin; Burns; Capillary Permeability; Dermatitis; Edema; Endotoxins; Escherichia coli Infections; Extracellular Space; Inflammation; Rabbits; Skin; Sodium Iodide
PubMed: 3534449
DOI: No ID Found -
Journal of Artificial Organs : the... Dec 2022For designing and evaluating the dialyzer and investigating the optimal therapeutic conditions, in vitro studies bring us many useful findings. In hemodialysis, however,...
For designing and evaluating the dialyzer and investigating the optimal therapeutic conditions, in vitro studies bring us many useful findings. In hemodialysis, however, the membrane fouling due to protein molecules reduces solute removal performance. Therefore, we investigated a method for replicating the fouling in dialyzers in aqueous experiments. After the albumin solution was circulated in the test circuit with a dialyzer, a glutaraldehyde solution was pumped into the dialyzer to immobilize albumin on the hollow fiber membrane. Under various immobilization conditions, the permeability of creatinine and vitamin B was evaluated by dialysis experiments. The creatinine clearance after immobilization of albumin was decreased, suggesting pore plugging by our fouling replication method. The glutaraldehyde crosslinked albumin molecules that adhered them to the membrane firmly. Moreover, the degree of fouling may be controlled by changing the concentration of albumin solution and the volume of glutaraldehyde solution used for immobilization. Our fouling replication method was applied to three types of polyester polymer alloy (PEPA) dialyzers and one polysulfone (PSf) dialyzer. This method enables to evaluate the permeability of various dialyzers with fouling in vitro that will be of great help in collecting data for designing dialyzers.
Topics: Membranes, Artificial; Renal Dialysis; Creatinine; Glutaral; Albumins
PubMed: 35146587
DOI: 10.1007/s10047-022-01318-3 -
Nano Letters Jan 2024Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation...
Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation of senescent HSCs, exacerbating liver fibrosis. The activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for both senescence and the innate immune response. Additionally, the specific delivery to activated HSCs is hindered by their inaccessible anatomical location, capillarization of liver sinusoidal endothelial cells (LSECs), and loss of substance exchange. Herein, we propose an antifibrotic strategy that combines prosenescence with enhanced immune clearance through targeted delivery of manganese (a cGAS-STING stimulator) via albumin-mediated transcytosis, specifically aimed at inducing senescence and eliminating activated HSCs in liver fibrosis. Our findings demonstrate that only albumin efficiently transfers manganese to activated HSCs from LSECs via transcytosis compared to liposomes, resulting in significant antifibrotic effects in vivo while exhibiting negligible toxicity.
Topics: Humans; Hepatic Stellate Cells; Liver; Manganese; Endothelial Cells; Liver Cirrhosis; Albumins; Nucleotidyltransferases
PubMed: 38164915
DOI: 10.1021/acs.nanolett.3c03689 -
Therapeutic Apheresis and Dialysis :... Feb 2014Extracorporeal albumin dialysis as a measure to remove water soluble and protein bound toxins simultaneously has been shown to improve complications of liver failure....
Extracorporeal albumin dialysis as a measure to remove water soluble and protein bound toxins simultaneously has been shown to improve complications of liver failure. However, recent research suggests that only treatments associated with a measurable improvement of patient's albumin binding function by effective removal of albumin bound toxins leads to better survival. The aim of the present work was to develop a test platform for upcoming devices to evaluate long term effectiveness on toxin removal and improvement of patients' albumin binding capacity. The classical one compartment model consisting of a closed pool of toxin spiked plasma was combined with continuous infusion of water soluble and protein bound toxins mimicking physiological rebound rates reflected in the literature. The model was used to demonstrate the effect of stabilizer contamination of dialysate albumin on toxin clearance and albumin binding function. In comparison to the classical one compartment model, the two compartment model allows for long term effectiveness tests of liver assist devices not only for strongly albumin-bound, but also water-soluble molecules. The limitations of commercial albumin overloaded with caprylate ligands (5:1 molar ratio) were demonstrated by presenting a significant improvement of albumin binding function using 80 g deligandized albumin compared to no significant improvement using the standard 120 g albumin as dialysate. The new two compartment model allows for pre-clinical evaluation of new upcoming devices aiming for improvement of patients' albumin binding function as a measure for clinically meaningful extracorporeal detoxification of albumin-bound toxins.
Topics: Albumins; Caprylates; Dialysis Solutions; Humans; Ligands; Models, Biological; Renal Dialysis; Toxins, Biological
PubMed: 24499088
DOI: 10.1111/1744-9987.12025 -
European Journal of Internal Medicine Feb 2020To predict the 3-months mortality in permanently bedridden medical non-oncologic inpatients.
Three-month mortality in permanently bedridden medical non-oncologic patients. The BECLAP study (permanently BEdridden, creatinine CLearance, albumin, previous hospital admissions study).
OBJECTIVE
To predict the 3-months mortality in permanently bedridden medical non-oncologic inpatients.
PATIENTS AND METHODS
2788 consecutive patients admitted in 5 Italian Internal Medicine units from January 2016 through January 2017 were prospectively screened; 644 oncologic patients were excluded; 2144 non-oncologic patients (1021 female) were followed-up for mortality for 6 months. Main outcome was 3-months mortality in permanently bedridden inpatients with at least 2 of: creatinine clearance <35 ml/min; albumin < 2.5 g/dl; at least 2 hospital admissions in the previous 6 months. Advanced dementia and dysphagia were also recorded.
RESULTS
Mean age of the 2144 patients was 73.9 (SD, 14.9) years; 374 (17%) were permanently bedridden, 435 (20%) had a creatinine clearance <35 ml/min, 217 (10%) albumin <2,5 g/dl, 112 (5%) at least 2 hospital admissions in the previous 6 months. Seventy-seven (4%) patients were permanently bedridden with at least 2 of the above mentioned items, and 48 of them died within 3 months (62%) (p < 0.001;95% CI 51-73%). Regression coefficients of the variables associated with 3-months mortality in multivariate analysis in 998 patients of unit 1 (training cohort) were used to create a simple score, which was validated in the 1146 patients of the other units (validation cohort) and performed well in predicting the 3-months mortality (https://www.ejcrim.com/beclap/).
CONCLUSIONS
Approximately two out of three non-oncologic medical patients permanently bedridden having 2 of the abovementioned items are dead 3 months after index admission; a simple score including bedridden status, creatinine clearance, albumin, dysphagia, age and sex may help discuss management priorities.
Topics: Aged; Albumins; Creatinine; Female; Hospital Mortality; Hospitalization; Hospitals; Humans; Italy
PubMed: 31757579
DOI: 10.1016/j.ejim.2019.10.016 -
Xenobiotica; the Fate of Foreign... Feb 20181. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the...
1. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the influence of a binding to albumin (ALB) using an isolated perfused rat liver (IPRL) system; and (ii) to compare results of prediction algorithms with measured clearance rates. 2. The IPRL system and liver microsomes were used to determine the metabolic constants of BPA and NAP either in the presence or absence of ALB. In this study, the IPRL was used as proxy for the in vivo situation. Accordingly, diverse in vitro-to-in vivo and in vivo-to-in vivo extrapolations (IVIVEs) were made to predict CL of BPA determined in situ/in vivo with ALB from metabolic data determined without ALB by using different binding correction methods (i.e., direct and conventional scaling as well as a novel scaling considering an ALB-facilitated uptake mechanism). 3. The addition of ALB significantly influenced the liver kinetics of BPA and NAP either administered alone or in binary mixtures, which was reflected in the Michaelis-Menten constants. Analysis of concomitant exposures of BPA and NAP gave a fully competitive inhibition. Furthermore, the IVIVE method based on the ALB-facilitated uptake mechanism provided the most accurate predictions of CL as compared with the other IVIVE methods when the impact of ALB is considered. 4. Our findings support the notion that high binding to ALB reduces the biotransformation of BPA and NAP when administered alone or in mixtures in the IPRL system. However, the free drug concentration in liver in vivo is probably higher than expected since the IVIVE method based on a potential ALB-facilitated uptake mechanism is the most robust prediction method. Overall, this study should improve the physiologically-based pharmacokinetic (PBPK) modelling of chemical-drug interactions.
Topics: Albumins; Animals; Benzhydryl Compounds; Drug Interactions; Hepatocytes; Liver; Metabolic Clearance Rate; Microsomes, Liver; Naproxen; Phenols; Rats
PubMed: 28277163
DOI: 10.1080/00498254.2017.1294276 -
Critical Care (London, England) 2000The benefit of albumin administration in the critically ill patient is unproven. Epidemiological evidence suggests that there is an increase in death among patients with... (Review)
Review
The benefit of albumin administration in the critically ill patient is unproven. Epidemiological evidence suggests that there is an increase in death among patients with burns, hypoalbuminaemia, and hypotension treated with human albumin solution (HAS). In critical illness, hypoalbuminaemia is a result of transcapillary leak, decreased synthesis, large volume body fluid losses, and dilution caused by fluid resuscitation. When treating patients with hypoalbuminaemia, efforts must be centred around correction of the underlying disorder rather than reversal of hypoalbuminaemia. Problems with using albumin arise because it is an expensive blood product, and can result in systemic changes that include cardiovascular, haematological, renal, pulmonary, and immunological effects.
Topics: Albumins; Critical Illness; Evidence-Based Medicine; Humans; Infusions, Intravenous; Meta-Analysis as Topic; Metabolic Clearance Rate; Patient Selection; Practice Guidelines as Topic; Treatment Outcome
PubMed: 11211856
DOI: 10.1186/cc688 -
The Journal of Physiology Jan 2010Atrial natriuretic peptide (ANP) via its guanylyl cyclase-A (GC-A) receptor participates in regulation of arterial blood pressure and vascular volume. Previous studies...
Atrial natriuretic peptide (ANP) via its guanylyl cyclase-A (GC-A) receptor participates in regulation of arterial blood pressure and vascular volume. Previous studies demonstrated that concerted renal diuretic/natriuretic and endothelial permeability effects of ANP cooperate in intravascular volume regulation. We show that the microvascular endothelial contribution to the hypovolaemic action of ANP can be measured by the magnitude of the ANP-induced increase in blood-to-tissue albumin transport, measured as plasma albumin clearance corrected for intravascular volume change, relative to the corresponding increase in ANP-induced renal water excretion. We used a two-tracer method with isotopically labelled albumin to measure clearances in skin and skeletal muscle of: (i) C57BL6 mice; (ii) mice with endothelium-restricted deletion of GC-A (floxed GC-A x tie2-Cre: endothelial cell (EC) GC-A knockout (KO)); and (iii) control littermates (floxed GC-A mice with normal GC-A expression levels). Comparison of albumin clearances in hypervolaemic EC GC-A KO mice with normovolaemic littermates demonstrated that skeletal muscle albumin clearance with ANP treatment accounts for at most 30% of whole body clearance required for ANP to regulate plasma volume. Skin microcirculation responded to ANP similarly. Measurements of permeability to a high molecular mass contrast agent (35 kD Gadomer) by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enabled repeated measures in individual animals and confirmed small increases in muscle and skin microvascular permeability after ANP. These quantitative methods will enable further evaluation of the contribution of ANP-dependent microvascular beds (such as gastro-intestinal tract) to plasma volume regulation.
Topics: Albumins; Animals; Atrial Natriuretic Factor; Blood Pressure; Capillary Permeability; Female; Magnetic Resonance Imaging; Mice; Mice, Knockout; Microcirculation; Muscle, Skeletal; Plasma Volume; Receptors, Atrial Natriuretic Factor; Skin; Time Factors
PubMed: 19948658
DOI: 10.1113/jphysiol.2009.180463 -
Journal of Immunological Methods Oct 2015The lymphatic vessels are playing an important role in inflammation since they return extravasated fluid, proteins, and cells back into the circulation and regulate...
The lymphatic vessels are playing an important role in inflammation since they return extravasated fluid, proteins, and cells back into the circulation and regulate immune cell trafficking. The oral mucosa, including gingiva, is well supplied with lymphatic vessels and is frequently challenged with inflammatory insults. Lymphatic vessels in gingiva protect against periodontal disease development, but quantification of lymph flow in this area has so far never been performed, due to lack of reliable methods. Mice of FVB strain (n=17) were anesthetized with isoflurane and placed on a jaw retraction board allowing the mouth to be kept open and stable. Albumin conjugated with Alexa680-fluorochrome (with or without LPS from Porphyromonas gingivalis) was injected superficially in oral mucosa mesio-buccal to the left first molar in each mouse. 60 min post-injection the mouse was transferred to an OptixMX3 optical imager where the total fluorescence was measured in the posterior facial area. The measurements continued further every 60 min for 7h for each mouse. The mice were awake and active between measurements. The in vivo washout of Alexa680-albumin was calculated using the natural logarithm of the relative values creating a negative slope for each mouse. Statistical analysis of variance was performed. The injection and distribution site for tracer was verified with India ink and shown to be in the interstitium below the oral mucosal epithelium, in an area well supplied with initial lymphatic vessels. Washout of the tracer Alexa680-albumin was log-linear, and the basal lymph flow calculated from depot clearance averaged -0.28 ± 0.08%/min (n=8). The clearance was significantly faster (-0.30 ± 0.08%/min, n=9) in acutely inflamed oral mucosa (p=0.0326). We developed a method that can successfully quantify the lymph flow in oral mucosa in steady state conditions and under acute perturbation. By use of this method, new information about the lymphatic function in oral mucosa during physiological and pathological conditions can be achieved.
Topics: Albumins; Animals; Gingiva; Lymphatic Vessels; Mice; Mouth Mucosa; Optical Imaging
PubMed: 26141254
DOI: 10.1016/j.jim.2015.06.014