On model and data requirements for determining the bioavailability of oral therapeutic agents: application to gut absorption of thyroid hormones

1979 ◽  
Vol 236 (3) ◽  
pp. R137-R141 ◽  
Author(s):  
J. J. DiStefano ◽  
P. H. Mak
Keyword(s):  
Model Development ◽  
Whole Body ◽  
Optimal Dosage ◽  
Human Gut ◽  
Identifiability Analysis ◽  
Dosage Regimens ◽  
Pool Model ◽  
Oral Therapeutic ◽  
Data Requirements ◽  
Percent Absorption

A two-pool model is proposed as a first approximation of the dynamics of thyroid hormone dissolution and absorption in the human gut. It is shown that this model, or any more complex one of the same process, must be imbedded in a larger whole-body model for the purpose of quantifying its parameters. Parameter identification experiments are designed with the aid of identifiability analysis and a complete quantification is obtained, for both triiodothyronine (T3) and thyroxine (T4) absorption, using kinetic data obtained from the literature. The average percent absorption of oral dosages calculated from the model for T3 (95.8%) and for T4 (49.3%) are exceptionally close to reported measured values. Other data not used in model development also serve to validate the results, for use in applications not demanding greater physiological detail, such as for determining the bioavailability of orally administered hormones, or for the "inverse problem," computing optimal dosage regimens for hormone therapy.

scholarly journals Detection and Segmentation of Pelvic Bones Metastases in MRI Images for Patients With Prostate Cancer Based on Deep Learning

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiang Liu ◽  
Chao Han ◽  
Yingpu Cui ◽  
Tingting Xie ◽  
Xiaodong Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Deep Learning ◽  
Bone Metastases ◽  
Model Development ◽  
Whole Body ◽  
Pelvic Bone ◽  
Skeletal Metastases ◽  
Dice Similarity Coefficient ◽  
Patient Level ◽  
Lesion Level

ObjectiveTo establish and evaluate the 3D U-Net model for automated segmentation and detection of pelvic bone metastases in patients with prostate cancer (PCa) using diffusion-weighted imaging (DWI) and T1 weighted imaging (T1WI) images.MethodsThe model consisted of two 3D U-Net algorithms. A total of 859 patients with clinically suspected or confirmed PCa between January 2017 and December 2020 were enrolled for the first 3D U-Net development of pelvic bony structure segmentation. Then, 334 PCa patients were selected for the model development of bone metastases segmentation. Additionally, 63 patients from January to May 2021 were recruited for the external evaluation of the network. The network was developed using DWI and T1WI images as input. Dice similarity coefficient (DSC), volumetric similarity (VS), and Hausdorff distance (HD) were used to evaluate the segmentation performance. Sensitivity, specificity, and area under the curve (AUC) were used to evaluate the detection performance at the patient level; recall, precision, and F1-score were assessed at the lesion level.ResultsThe pelvic bony structures segmentation on DWI and T1WI images had mean DSC and VS values above 0.85, and the HD values were <15 mm. In the testing set, the AUC of the metastases detection at the patient level were 0.85 and 0.80 on DWI and T1WI images. At the lesion level, the F1-score achieved 87.6% and 87.8% concerning metastases detection on DWI and T1WI images, respectively. In the external dataset, the AUC of the model for M-staging was 0.94 and 0.89 on DWI and T1WI images.ConclusionThe deep learning-based 3D U-Net network yields accurate detection and segmentation of pelvic bone metastases for PCa patients on DWI and T1WI images, which lays a foundation for the whole-body skeletal metastases assessment.

Calcium Metabolism Evaluated by 47Ca kinetics: Estimation of Dermal Calcium Loss

1983 ◽  
Vol 65 (4) ◽  
pp. 415-422 ◽  
Author(s):  
P. Charles ◽  
F. Taagehøj Jensen ◽  
L. Mosekilde ◽  
H. Hvid Hansen
Keyword(s):  
Primary Hyperparathyroidism ◽  
Specific Radioactivity ◽  
Medullary Carcinoma ◽  
Whole Body ◽  
Control Group ◽  
Intestinal Bypass ◽  
Calcium Balance ◽  
Whole Body Counter ◽  
Pool Model ◽  
Calcium Loss

1. Seventy-seven calcium balance and 47Ca turnover studies were performed in normal volunteers (n = 15) and in patients with osteoporosis (n = 12), primary hyperparathyroidism (n = 8), osteogenesis imperfecta (n = 5), medullary carcinoma of the thyroid (n = 4), thyrotoxicosis (n = 2) and intestinal bypass for obesity (n = 11). 2. After intravenous injection of 20 μCi of 47Ca two retention curves of 47Ca were obtained: R1(t) directly measured on a whole-body counter and R2(t) calculated from the cumulated daily excretions of 47Ca in urine and faeces. The data were fitted to a modification of the continuously expanding exchangeable calcium pool model. 3. Dermal calcium loss was estimated from the serum 47Ca specific radioactivity curve and the constantly increasing difference between the two retention curves. The median dermal calcium loss in 77 studies was 1.50 mmol 24 h−1 1.73 m−2 (range 0.13-4.60). 4. The dermal calcium loss might be overestimated by redistribution of tracer or by eventual insufficient collection of urine and faeces. The possible influences of these errors have been evaluated. 5. Patients with primary hyperparathyroidism had a greater (P < 0.02) dermal calcium loss (2.64 mmol; range 0.80–4.50) than a control group (1.38 mmol; range 1.25–2.34).

Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa

2003 ◽  
Vol 285 (2) ◽  
pp. G266-G273 ◽  
Author(s):  
Moïse Coëffier ◽  
Sophie Claeyssens ◽  
Bernadette Hecketsweiler ◽  
Alain Lavoinne ◽  
Philippe Ducrotté ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Cathepsin D ◽  
Mrna Level ◽  
Mass Spectrometry Analysis ◽  
Whole Body ◽  
Synthesis Rate ◽  
Mrna Levels ◽  
Human Gut ◽  
Mucosal Protein

Effects of glutamine on whole body and intestinal protein synthesis and on intestinal proteolysis were assessed in humans. Two groups of healthy volunteers received in a random order enteral glutamine (0.8 mmol·kg body wt-1·h-1) compared either to saline or isonitrogenous amino acids. Intravenous [2H5]phenylalanine and [13C]leucine were simultaneously infused. After gas chromatography-mass spectrometry analysis, whole body protein turnover was estimated from traced plasma amino acid fluxes and the fractional synthesis rate (FSR) of gut mucosal protein was calculated from protein and intracellular phenylalanine and leucine enrichments in duodenal biopsies. mRNA levels for ubiquitin, cathepsin D, and m-calpain were analyzed in biopsies by RT-PCR. Glutamine significantly increased mucosal protein FSR compared with saline. Glutamine and amino acids had similar effects on FSR. The mRNA level for ubiquitin was significantly decreased after glutamine infusion compared with saline and amino acids, whereas cathepsin D and m-calpain mRNA levels were not affected. Enteral glutamine stimulates mucosal protein synthesis and may attenuate ubiquitin-dependent proteolysis and thus improve protein balance in human gut.

Three weeks of caloric restriction alters protein metabolism in normal-weight, young men

2005 ◽  
Vol 289 (3) ◽  
pp. E446-E455 ◽  
Author(s):  
Anne L. Friedlander ◽  
Barry Braun ◽  
Margaret Pollack ◽  
Jay R. MacDonald ◽  
Charles S. Fulco ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Lean Mass ◽  
Nitrogen Balance ◽  
Exercise Performance ◽  
Young Men ◽  
Normal Weight ◽  
Peak Oxygen Consumption ◽  
Whole Body ◽  
Aerobic Performance ◽  
Pool Model

The effects of prolonged caloric restriction (CR) on protein kinetics in lean subjects has not been investigated previously. The purpose of this study was to test the hypotheses that 21 days of CR in lean subjects would 1) result in significant losses of lean mass despite a suppression in leucine turnover and oxidation and 2) negatively impact exercise performance. Nine young, normal-weight men [23 ± 5 y, 78.6 ± 5.7 kg, peak oxygen consumption (V̇o2 peak) 45.2 ± 7.3 ml·kg−1·min−1, mean ± SD] were underfed by 40% of the calories required to maintain body weight for 21 days and lost 3.8 ± 0.3 kg body wt and 2.0 ± 0.4 kg lean mass. Protein intake was kept at 1.2 g·kg−1·day−1. Leucine kinetics were measured using α-ketoisocaproic acid reciprocal pool model in the postabsorptive state during rest and 50 min of exercise (EX) at 50% of V̇o2 peak. Body composition, basal metabolic rate (BMR), and exercise performance were measured throughout the intervention. At rest, leucine flux (≈131 μmol·kg−1·h−1) and oxidation (Rox; ≈19 μmol·kg−1·h−1) did not differ pre- and post-CR. During EX, leucine flux (129 ± 6 vs. 121 ± 6) and Rox (54 ± 6 vs. 46 ± 8) were lower after CR than they were pre-CR. Nitrogen balance was negative throughout the intervention (≈3.0g N/day), and BMR declined from 1,898 ± 262 to 1,670 ± 203 kcal/day. Aerobic performance (V̇o2 peak, endurance cycling) was not impacted by CR, but arm flexion endurance decreased by 20%. In conclusion, 3 wk of caloric restriction reduced leucine flux and Rox during exercise in normal-weight young men. However, despite negative nitrogen balance and loss of lean mass, whole body exercise performance was well maintained in response to CR.

Validity of segmental bioelectrical impedance analysis for estimating fat-free mass in children including overweight individuals

2017 ◽  
Vol 42 (2) ◽  
pp. 157-165 ◽  
Author(s):  
Megumi Ohta ◽  
Taishi Midorikawa ◽  
Yuki Hikihara ◽  
Yoshihisa Masuo ◽  
Shizuo Sakamoto ◽  
...  
Keyword(s):  
Bioelectrical Impedance Analysis ◽  
Cross Validation ◽  
Model Development ◽  
Bioelectrical Impedance ◽  
Impedance Analysis ◽  
Whole Body ◽  
Body Segments ◽  
Significant Difference ◽  
Development Group ◽  
Segmental Bioelectrical Impedance

This study examined the validity of segmental bioelectrical impedance (BI) analysis for predicting the fat-free masses (FFMs) of whole-body and body segments in children including overweight individuals. The FFM and impedance (Z) values of arms, trunk, legs, and whole body were determined using a dual-energy X-ray absorptiometry and segmental BI analyses, respectively, in 149 boys and girls aged 6 to 12 years, who were divided into model-development (n = 74), cross-validation (n = 35), and overweight (n = 40) groups. Simple regression analysis was applied to (length)2/Z (BI index) for each of the whole-body and 3 segments to develop the prediction equations of the measured FFM of the related body part. In the model-development group, the BI index of each of the 3 segments and whole body was significantly correlated to the measured FFM (R2 = 0.867–0.932, standard error of estimation = 0.18–1.44 kg (5.9%–8.7%)). There was no significant difference between the measured and predicted FFM values without systematic error. The application of each equation derived in the model-development group to the cross-validation and overweight groups did not produce significant differences between the measured and predicted FFM values and systematic errors, with an exception that the arm FFM in the overweight group was overestimated. Segmental bioelectrical impedance analysis is useful for predicting the FFM of each of whole-body and body segments in children including overweight individuals, although the application for estimating arm FFM in overweight individuals requires a certain modification.

Dosage Regimens of Intranasal Aerosolized Surfactant on Otitis Media with Effusion in an Animal Model

2001 ◽  
Vol 124 (4) ◽  
pp. 388-393 ◽  
Author(s):  
Natarajan Venkatayan ◽  
Patricia E. Connelly ◽  
Alan J. Mautone ◽  
Yolanda L. Troublefield ◽  
Sujana S. Chandrasekhar
Keyword(s):  
Otitis Media ◽  
Saline Solution ◽  
Otitis Media With Effusion ◽  
Synthetic Surfactant ◽  
Dose Inhaler ◽  
Optimal Dosage ◽  
Metered Dose Inhaler ◽  
Once Daily ◽  
Dosage Regimens ◽  
Metered Dose

OBJECTIVE: To determine optimal dosage regimens of intranasal metered dose aerosolized surfactant with and without other medications in the treatment of otitis media with effusion (OME). STUDY DESIGN: Resolution of experimental OME in gerbils was determined based on otomicroscopy and tympanometry. Experimental intranasal drugs were: surfactant, surfactant with betamethasone, surfactant with phenylephrine, and a normal saline solution placebo. Medications were administered once or twice daily via a metered dose inhaler. RESULTS: For twice-daily dosing, mean days to OME resolution were 8.5 for the aerosolized surfactant, 6.3 for the surfactant with betamethasone, 18.7 for the surfactant with phenylephrine, and 16 each for control and placebo. Resolution with the once-daily dosage was longer for all conditions. Results were comparable using tympanometry. CONCLUSION: OME resolved faster than the natural course when treated with intranasal surfactant with and without steroids. Twice-daily dosing was statistically superior. SIGNIFICANCE: This study reiterates the effectiveness of OME treatment with an aerosolized synthetic surfactant with and without steroids and establishes a superior twice-daily dosage schedule.

scholarly journals NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0243010
Author(s):  
Einat Nissim-Eliraz ◽  
Eilam Nir ◽  
Noga Marsiano ◽  
Simcha Yagel ◽  
Nahum Y. Shpigel
Keyword(s):  
Steady State ◽  
Epithelial Cells ◽  
Temporal Dynamics ◽  
Whole Body ◽  
Central Component ◽  
Reporter System ◽  
Human Gut ◽  
Nf Kappa B ◽  
Bowel Diseases ◽  
Epithelial Cell Layer

The single-epithelial cell layer of the gut mucosa serves as an essential barrier between the host and luminal microflora and plays a major role in innate immunity against invading pathogens. Nuclear factor kB (NF-κB), a central component of the cellular signaling machinery, regulates immune response and inflammation. NF-κB proteins are activated by signaling pathways downstream to microbial recognition receptors and cytokines receptors. Highly regulated NF-κB activity in intestinal epithelial cells (IEC) is essential for normal gut homeostasis; dysregulated activity has been linked to a number of disease states, including inflammatory bowel diseases (IBD) such as Crohn’s Disease (CD). Our aim was to visualize and quantify spatial and temporal dynamics of NF-κB activity in steady state and inflamed human gut. Lentivirus technology was used to transduce the IEC of human gut xenografts in SCID mice with a NF-κB luminescence reporter system. NF-κB signaling was visualized and quantified using low resolution, intravital imaging of the whole body and high resolution, immunofluorescence microscopic imaging of the tissues. We show that NF-κB is activated in select subset of IEC with low “leaky” NF-κB activity. These unique inflammatory epithelial cells are clustered in the gut into discrete hotspots of NF-κB activity that are visible in steady state and selectively activated by systemic LPS and human TNFα or luminal bacteria. The presence of inflammatory hotspots in the normal and inflamed gut might explain the patchy mucosal lesions characterizing CD and thus could have important implications for diagnosis and therapy.

Influence of protein intake on whole body and splanchnic leucine kinetics in humans

1997 ◽  
Vol 272 (4) ◽  
pp. E584-E591 ◽  
Author(s):  
M. Cayol ◽  
Y. Boirie ◽  
F. Rambourdin ◽  
J. Prugnaud ◽  
P. Gachon ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Intake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
The Body ◽  
Whole Body ◽  
Body Protein ◽  
Leucine Kinetics ◽  
Protein X ◽  
Pool Model

The influence of the protein content of the meal on protein turnover was investigated in the splanchnic bed and in the remaining parts of the body in humans. Two groups of five subjects consumed every 20 min a liquid formula providing either 1.5 g protein x kg(-1) x day(-1) (P) or no protein (PF). L-[1-(13)C]leucine and L-[5,5,5-(2)H3]leucine were administered by vein and gut, respectively. An open two-pool model was developed to calculate leucine kinetics in both compartments, with the assumption that the enrichment of the tracers incorporated into very low density lipoprotein apolipoprotein B100 at isotopic steady state could reflect the leucine labeling in the splanchnic region. Nonsplanchnic uptake and release of leucine were not significantly different in the two groups. Within the splanchnic area, leucine uptake was 2.1 times higher in the P than in the PF group (P < 0.01), whereas leucine release was reduced but not significantly (-19%) in the P group compared with the PF group. Moreover, data derived from this model showed that protein intake induced an increase in whole body protein synthesis and no change in whole body protein breakdown. Albumin synthesis, as well as its contribution to whole body protein synthesis, was significantly enhanced by protein intake.

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