2-component Models Research Articles

Study of risk factors for healthcare-associated infections in acute cardiac patients using categorical principal component analysis (CATPCA)

Using categorical principal component analysis, we aimed to determine the relationship between health care-associated infections (HAIs) and diagnostic categories (DCs) in patients with acute heart disease using data collected in the Spanish prospective ENVIN-HELICS intensive care registry over a 10-year period (2005–2015). A total of 69,876 admissions were included, of which 5597 developed HAIs. Two 2-component CATPCA models were developed. In the first model, all cases were included; the first component was determined by the duration of the invasive devices, the ICU stay, the APACHE II score and the HAIs; the second component was determined by the type of admission (medical or surgical) and by the DCs. No clear association between DCs and HAIs was found. Cronbach’s alpha was 0.899, and the variance accounted for (VAF) was 52.5%. The second model included only admissions that developed HAIs; the first component was determined by the duration of the invasive devices and the ICU stay; the second component was determined by the inflammatory response, the mortality in the ICU and the HAIs. Cronbach’s alpha value was 0.855, and VAF was 46.9%. These findings highlight the role of exposure to invasive devices in the development of HAIS in patients with acute heart disease.

2D vs 3D – Triple negative breast cancer spheroid formation induces quantitative heterogeneity of VEGF and PDGF receptor profiles and modulates cytosolic phosphorylation

Micro‐tumor spheres (MTS) have been considered a phenotypic intermediate between 2‐dimensional cell culture and tumor explants from living organisms. However, limited information exists for understanding membrane bound antigens of live cells in MTS. These antigens include several families of transmembrane proteins fundamental to signal transduction, cell communication, and adhesion processes and are thereby identified as key therapeutic targets in malignant cells. This study couples MTS cell culture and a high throughput method for live single cell receptoromic analysis, to compare MTS and monolayer cell surface densities of the PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 tumor angiogenesis regulating receptors on MDB‐MB‐231.Cumulatively, the average density of PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 in MTS is 1.7‐fold higher in tumor only MTS when compared to monolayer cells. When cells are analyzed on a cell‐by‐cell basis, 2‐component Gaussian mixture models predict means of high‐density and low‐density MTS sub‐populations within PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 frequency distributions. The high density to low density means show 3.9‐, 1.6‐, 1.1‐, and 3.2‐fold differences for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2, respectively. Finally, an analysis of MTS intracellular phosphorylation profiles preliminarily reveals attenuated phosphorylation, including reduced activation of the MAPK pathway, in MDA‐MB‐231 MTS simulated by a 20pg/mL VEGFA solution. Together, the current data suggests that MTS may provide a biologically relevant representation of breast cancer cells' VEGFR and PDGFR signaling axes through altering cell surface receptor density and heterogeneity. Our continued work will investigate the effects of varying VEGA concentrations on MTS signal transduction.Support or Funding InformationThis research was supported by NIEHS grant (T32 ES007326).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High temporal resolution gastric emptying breath tests in mice.

Gastric emptying is a complex physiological process regulating the division of a meal into smaller partitions for the small intestine. Disrupted gastric emptying contributes to digestive disease, yet current measures may not reflect different mechanisms by which the process can be altered. We have developed high temporal resolution solid and liquid gastric emptying breath tests in mice using [13 C]-octanoic acid and off axis- integrated cavity output spectroscopy (OA-ICOS). Stretched gamma variate and 2-component stretched gamma variate models fit measured breath excretion data. These assays detect acceleration and delay using pharmacological (7.5mg/kg atropine) or physiological (nutrients, cold exposure stress, diabetes) manipulations and remain stable over time. High temporal resolution resolved complex excretion curves with 2 components, which was more prevalent in mice with delayed gastric emptying following streptozotocin-induced diabetes. There were differences in the gastric emptying of Balb/c vs C57Bl6 mice, with slower gastric emptying and a greater occurrence of two-phase gastric emptying curves in the latter strain. Gastric emptying of C57Bl6 could be accelerated by halving the meal size, but with no effect on the occurrence of two-phase gastric emptying curves. A greater proportion of two-phase gastric emptying was induced in Balb/c mice with the administration of PYY (8-80nmol) 60min following meal ingestion. Collectively, these results demonstrate the utility of high temporal resolution gastric emptying assays. Two-phase gastric emptying is more prevalent than previously reported, likely involves intestinal feedback, but contributes little to the overall rate of gastric emptying.

Accuracy of aggregate 2- and 3-component models of body composition relative to 4-component for the measurement of changes in fat mass during weight loss in overweight and obese subjects.

The 4-component (4-C) model is the reference method to measure fat mass (FM). Simpler 2-component (2-C) models are widely used to assess FM. We hypothesised that an aggregate 2-C model may improve accuracy of FM assessment during weight loss (WL). One hundred and six overweight and obese men and women were enrolled in different WL programs (fasting, very low energy diet, low energy diet). Body density, bone mineral content, and total body water were measured. FM was calculated using 2-C, 3-C, and 4-C models. Aggregate equations for 2-C, 3-C, and 4-C models were calculated, with the aggregate 4-C model assumed as the reference method. The aggregate approach postulates that the average of the individual estimates obtained from each model is more accurate than the best single measurement. The average WL was -7.5 kg. The agreement between 3-C and 4-C models for FM change was excellent (R(2) = 0.99). The aggregate 2-C equation was more accurate than individual 2-C estimates in measuring changes in FM. The aggregate model was characterised by a lower measurement error at baseline and post-WL. The relationship between the aggregate 3-C and 4-C component models was highly linear (R(2) = 0.99), whereas a lower linearity was found for the aggregate 2-C and 4-C model (R(2) = 0.72). The aggregate 2-C model is characterised by a greater accuracy than commonly applied 2-C equations for the measurement of FM during WL in overweight and obese men and women.

Body composition assessed by the 4-component model and association with lung function in 6–12-y-old children with cystic fibrosis

Malnutrition is an indicator of a poor prognosis in patients with cystic fibrosis (CF). Previous body-composition (BC) studies in children with CF used 2-component models (2CMs) to assess fat mass (FM) and fat-free mass (FFM), but to our knowledge no study has used the gold-standard 4-component model (4CM), which allows for a more accurate evaluation of the nature of both elements. We measured BC by using the 4CM in 6-12-y-old children with CF to 1) compare findings with those of healthy, matched control children and reference data; 2) relate BC to lung spirometry [forced expired volume in 1 s (FEV₁)]; and 3) compare findings with those from more commonly used 2CM techniques. One hundred clinically stable children with CF (57% girls) aged 6-12 y were measured by using the 4CM. Children with CF underwent spirometry (FEV₁). Girls with CF had significantly less FM than did healthy girls, even after adjustment for height and pubertal status; boys with CF had higher body mass index SD scores than did healthy boys. FM in girls was positively associated with the FEV₁ percentage predicted. The 2CM FM was significantly different from the 4CM FM, with differences dependent on sex and condition, although most techniques identified a relation between FM and FEV₁ in girls. Although shorter than healthy children, boys with CF were heavier and had a BC within the normal range; however, girls with CF had lower FM than did healthy girls, and this was associated with poorer lung function. Given the worse prognosis in girls, this finding merits more attention. The reliability of 2CM techniques varied with sex and health status.

Perturbed dark energy: Classical scalar field versus tachyon

The evolution of scalar linear perturbations is studied in gauge-invariant approach for 2-component models with nonrelativistic matter and minimally coupled scalar fields, the potentials of which were constructed for either constant dark energy equation of state parameter $w$ or its adiabatic sound speed ${c}_{a}^{2}$ equal to zero. The numerical solutions show that such fields are almost smoothed out on subhorizon scales. However, they cause the scale dependent suppression of the nonrelativistic matter density perturbations and the decay of gravitational potential, which can be used for choice of the dark energy model. We discuss two types of the Lagrangian: classical and tachyonic ones. As our results show, the fields with $w=\mathrm{const}$ are almost indistinguishable, while for fields with ${c}_{a}^{2}=0$ the difference of dark energy effective sound speeds ${c}_{s}^{2}$, which is caused by the shape of Lagrangian, affects the evolution of perturbations significantly. We present also the transfer functions for both components.

Large-scale structure formation in cosmology with classical and tachyonic scalar fields

The evolution of scalar perturbations is studied for 2-component (non-relativistic matter and dark energy) cosmological models at the linear and non-linear stages. The dark energy is assumed to be the scalar field with either classical or tachyonic Lagrangian and constant equation-of-state parameter w. The fields and potentials were reconstructed for the set of cosmological parameters derived from observations. The comparison of the calculated within these models and observational large-scale structure characteristics is made. It is shown that for w = const such analysis can’t remove the existing degeneracy of the dark energy models.

Morphology of Large ZSM-5 Crystals Unraveled by Fluorescence Microscopy

Understanding the internal structure of ZSM-5 crystallites is essential for improving catalyst performance. In this work, a combination of fluorescence microscopy, AFM, SEM, and optical observations is employed to study intergrowth phenomena and pore accessibility in a set of five ZSM-5 samples with different crystal morphologies. An amine-functionalized perylene dye is used to probe acid sites on the external crystal surface, while DAMPI (4-(4-diethylaminostyryl)- N-methylpyridinium iodide) is used to map access to the straight channels in MFI from the outer surface. The use of these dyes is validated by studying the well-understood rounded-boat type ZSM-5 crystals. Next coffin-shaped ZSM-5 crystals are considered; we critically evaluate the seemingly conflicting 2-component and 3-component models that have been proposed to account for the hourglass structure in these crystals. The data prove that observation of an hourglass structure is essentially unrelated to a 90 degree rotation of the pyramidal crystal components under the (010) face. Hence, in perfectly formed coffin-shaped crystals, the straight channels can be accessed from (010). However, in other crystal batches, sections with a 90 degrees rotation can be found; they are indeed located inside the crystal sections under (010) but often only partially occupy these pyramidal components. In such a case, both straight and sinusoidal pores surface at the hexagonal face. The results largely support the 3-component model, but with the added notion that 90 degree rotated sections (as proposed in the 2-component model) are most likely to be formed inside the defect-rich, pyramidal crystal sections under the (010) faces.

Malnutrition and hypermetabolism in patients with liver cirrhosis

Clinical signs of protein-energy malnutrition (PEM) are frequently seen in cirrhotic patients and may be obvious at all clinical stages of liver disease and even in clinically stable situations (1). Malnutrition in cirrhotic patients is readily understood as a consequence of metabolic disturbances in combination with low spontaneous dietary intake (1). Because PEM is associated with clinical complications of cirrhosis, such as ascites, and because it increases mortality with and without liver transplantation (2, 3), its early identification and characterization are mandatory. However, PEM is frequently underdiagnosed in clinical practice. This is explained in part by the fact that water retention increases body weight and thus masks losses of body mass. There are also methodologic limitations: for example, standard 2-component models used for assessment of body composition cannot be used with confidence in cirrhotic patients because of great variability in the density and hydration of fat-free mass [FFM (4)]. In this issue of the Journal, Peng et al (5) addressed body composition as well as the metabolic and functional consequences of malnutrition in cirrhotic patients. This cross-sectional study is exceptional, because the authors have taken into account essential procedural issues relevant to establishing nutritional status and metabolism. The strengths of the study include a large population of 268 well-characterized, clinically stable patients and detailed measurements of body composition, muscle function, and resting energy expenditure (REE) obtained by using state-of-the-art technologies, including neutron activation and a 6-compartment model of body composition. Functional and metabolic data can thus be adjusted for tissue hydration to allow comparisons between individual subjects. Whereas the prevalence of overhydration varied between 40% and 84%, Peng et al found significant protein depletion in 51% of the patient group. Protein depletion was more likely in men than in women, for an unexplained effect of sex. The severity of PEM increased with progression of liver disease and was associated with reduced muscle strength. In addition, hypermetabolism that was independent of clinical data as well as of PEM was found in 15% of the patients. The limits of cross-sectional data became evident, because energy and protein intake also showed no association with PEM. Thus, further longitudinal studies are needed. The finding of significant protein depletion is in line with previous data (4, 6) suggesting that neutron activation and multicomponent models have high accuracy without loss of precision in their assessment of PEM in the cirrhotic patient. Because these methods are cumbersome and not available in clinical practice, simpler nutritional assessment schemes are required for clinical use. A global assessment scheme combining body mass index and midupper arm circumference with dietary intake data provided a reproducible and valid method for assessing nutritional status in patients with cirrhosis (7). However, only detailed body composition analysis, as was performed by Peng et al, identifies early and specific deficits that can provide a suitable basis for targeted interventions. The finding of a high prevalence of hypermetabolism extends our present knowledge on the variance of REE in cirrhosis. The prevalence of hypermetabolism was lower in the study of Peng et al than in 2 other comprehensive studies in this area (8, 9). These differences are explained in part by the use of different definitions of hypermetabolism. Peng et al (5) used predicted REE on the basis of FFM corrected for hydration, whereas others used standard body weight–based formulae such as Harris-Benedict or uncorrected FFM values, or both. Approximately 50% of the variance in REE in clinically stable cirrhosis patients was explained by FFM, irrespective of the method used to assess FFM and of a suitable correction for hydration (5, 8, 9). The data suggest that FFM is the major determinant of REE in cirrhosis. Although hypermetabolism is a frequent feature of cirrhosis, its cause is still unclear. Peng et al (5) found no association of hypermetabolism with sex, etiology, severity of disease, protein depletion, or the presence of ascites or tumor. There is indirect evidence that increased sympathetic nervous system activity, possibly due to disturbancies in liver circulation resulting in a hyperdynamic status, explains 25% of hypermetabolism in liver cirrhosis (8). More detailed body-composition analyses may provide further clues. One may speculate that the composition of FFM—ie, the relation between muscle and organ mass—varies in cirrhosis. The greater loss of muscle mass than of nonmuscle FFM results in a relative increase in the mass of “high-metabolic-rate” organs such as heart, brain, and kidneys, which increases the REE per kg FFM (10). This idea is supported by the finding that hypermetabolic patients tended to weigh less (5) and to suffer more frequently from malnutrition (8) than did normometabolic patients. The fact that functional liver mass is also reduced in cirrhosis adds to interindividual variances in metabolic data.

Two-component models are of limited value for the assessment of body composition in patients with cirrhosis

Most techniques for measuring body composition are based on 2-component models (2-CMs) and depend on assumptions relating to the constancy of the density (D(FFM)) and hydration fraction (HF(FFM)) of fat-free mass (FFM). The objectives were to determine whether these assumptions are systematically violated in patients with cirrhosis and to assess the validity of the estimates of body composition obtained in these patients by using 2-CM techniques. Body composition was assessed by using a 4-component model (4-CM), which was based on data obtained from densitometry, deuterium dilution, and dual-energy X-ray absorptiometry, in 20 patients with cirrhosis who had no evidence of fluid retention and in 20 pair-matched healthy control subjects. The results were compared with those obtained by using "reference" and "bedside" 2-CM techniques. The mean (+/-SD) D(FFM) was significantly lower in the patients with cirrhosis (1.091 +/- 0.008 compared with 1.100 +/- 0.006 kg/L; P < 0.001); no significant difference in HF(FFM) was observed between the patients and control subjects (74.5 +/- 2.6 compared with 73.5 +/- 2.1), although there was greater variability in the patients. Significant differences were observed in the body-composition variables obtained by using the "reference" 2-CM techniques compared with the 4-CM-the 95% limits of agreement in the patients with cirrhosis exceeded 5% body fat and 3 kg FFM; the corresponding values for the "bedside" 2-CM techniques were 11% body fat and 7.5 kg FFM. Assumptions relating to the constancy of the D(FFM) and HF(FFM) are violated in patients with cirrhosis. Thus, standard 2-CM techniques provide inaccurate body composition estimates in this patient population.

Four-component model of body composition in children: density and hydration of fat-free mass and comparison with simpler models

Body composition in children is generally measured by 2-component (2C) models, which are subject to error arising from variation in fat-free mass (FFM) composition. The 4-component (4C) model, which divides body weight into fat, water, mineral, and protein, can overcome these limitations. The aims of our study were to 1) describe 4C model data for children aged 8-12 y; 2) evaluate interindividual variability in the hydration, bone mineral content, and density of FFM; 3) evaluate the success with which 2C models and bedside techniques measure body composition in this age group with use of the 4C model as a reference. Dual-energy X-ray absorptiometry, underwater weighing, deuterium dilution, bioelectrical impedance analysis, and anthropometry were used to determine body composition in 30 children. The contribution of methodologic error to the observed variability in the hydration and density of FFM was evaluated by using propagation of error. Mean (+/-SD) FFM density and hydration were 1.0864+/-0.0074 kg/L and 75.3+/-2.2%, respectively, and were significantly different from adult values (P < 0.02). Relative to the 4C model, deuterium dilution and dual-energy X-ray absorptiometry showed no mean bias for fatness, whereas underwater weighing underestimated fatness (P < 0.025). Fatness determined by using skinfold-thickness and bioelectrical impedance analysis measurements along with published equations showed poor agreement with 4C model data. Biological variability and methodologic error contribute equally to the variability of FFM composition. Our findings have major implications for bedside prediction methods used for children, traditionally developed in relation to underwater weighing.

Body composition of spinal cord injured adults.

The prevalence of diseases associated with obesity, such as cardiovascular disease and diabetes mellitus, is higher in the spinal cord injury (SCI) population. Specifically, the mortality rate for cardiovascular disease is 228% higher in the SCI population. In addition, 100% of SCI individuals have osteoporosis in the paralysed extremities. These diseases are related to physical activity level, the level of the spinal cord lesion, and time post injury. Physically active SCI men and women have above-average fat mass (16 to 24% and 24 to 32%, respectively, compared with 15% for able-bodied men and 23% for able-bodied women), while sedentary SCI individuals have 'at-risk' levels of body fat (above 25% and 32%, respectively). The proportions and densities of the 3 main constituents comprising the fat-free body (mineral, protein and water) are altered following SCI. Bone mineral content decreases by 25 to 50%, and the magnitude of reduction is dependent on the level, completeness and duration of SCI. Because of denervation resulting in skeletal muscle atrophy, total body protein reduces by 30%, and total body water relative to bodyweight decreases by 15% following SCI. Indirect methods based on 2-component body composition models assume constant proportions and densities of mineral, protein, and water in the fat-free body. As a result, prediction equations based on 2-component models yield invalid estimates of fat and fat-free mass in the SCI population. Therefore, future research needs to directly quantify the proportions and densities of the constituents of the fat-free body in the SCI population relative to age, sex, physical activity level, level of the spinal cord lesion and time post injury, and to develop equations based on multicomponent body composition models.

Evaluation of body composition. Current issues.

In the selection of body composition field methods and prediction equations, exercise and health practitioners must consider their clients' demographics. Factors, such as age, gender, level of adiposity, physical activity and ethnicity influence the choice of method and equation. Also, it is important to evaluate the relative worth of prediction equations in terms of the criterion method used to derive reference measures of body composition for equation development. Given that hydrodensitometry, hydrometry and dual-energy x-ray absorptiometry are subject to measurement error and violation of basic assumptions underlying their use, none of these should be considered as a 'gold standard' method for in vivo body composition assessment. Reference methods, based on whole-body, 2-component body composition models, are limited, particularly for individuals whose fat-free body (FFB) density and hydration differ from values assumed for 2-component models. Use of field method prediction equations developed from 2-component model (Siri equation) reference measures of body composition will systematically underestimate relative body fatness of American Indian women, Black men and women, and Hispanic women because the average FFB density of these ethnic groups exceeds the assumed value (1.1 g/ml). Thus, some researchers have developed prediction equations based on multicomponent model estimates of body composition that take into account interindividual variability in the water, mineral, and protein content of the FFB. One multicomponent model approach adjusts body density (measured via hydrodensitometry) for total body water (measured by hydrometry) and/or total body mineral estimated from bone mineral (measured via dual-energy x-ray absorptiometry). Skinfold (SKF), bioelectrical impedance analysis (BIA), and near-infrared interactance (NIR) are 3 body composition methods used in clinical settings. Unfortunately, the overwhelming majority of field method prediction equations have been developed and cross-validated for White populations and are based on 2-component model reference measures. Because ethnicity may affect the composition of the FFB and regional fat distribution, race-specific prediction equations may need to be developed for some ethnic groups. To date, race-specific SKF (American Indian women, Black men, and Asian adults), BIA (American Indian women and Asian adults), and NIR (American Indian women and White women) equations have been developed. However, these equations need to be cross-validated on additional samples from these ethnic groups. In summary, research strongly suggests that multicomponent models need to be used in order to quantify differences in FFB composition due to ethnicity so that accurate SKF, BIA, and NIR prediction equations can be developed. Assessment of body composition in vivo may be enhanced by using advanced technologies such as dual-energy x-ray absorptiometry and hydrometry to refine hydrodensitometry. Practitioners should carefully select and use only those prediction equations that have been developed and cross-validated for specific ethnic groups. Additional research is needed to test the accuracy and applicability of previously published prediction equations for the American Indian, Asian, Black, and Hispanic populations.

Catecholamines and self-stimulation: Evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine

Investigation of the role of noradrenaline (NA) and dopamine (DA) in self-stimulation showed that d-amphetamine (which releases more DA than does l-amphetamine, but not more NA) was much more effective than l-amphetamine in enhancing self-stimulation of NA sites in the locus coerulus and near-lateral hypothalamus. In DA sites in the substantia nigra and far-lateral hypothalamus the effects of the 2 isomers were confirmed to be more nearly equal. Thymoxamine HCl (10 mg/kg IP), a specific α-adrenergic receptor blocker, depressed self-stimulation at all sites, but significantly more severely at DA sites. Thus the drugs most effective in influencing self-stimulation at a particular site were those acting predominantly on the unstimulated system. These findings were interpreted in terms of a hypothesis that DA and NA play complementary roles in self-stimulation and that both are essential; or, more specifically, that DA pathways, implicated in other motivational activities, contribute to a state of drive or arousal necessary for self-stimulation; while response-contingent noradrenergic activity (elicited by the electrodes directly, or indirectly via a transsynaptic route) mediates reinforcement. Further predictions from this hypothesis were tested as follows: (1) Direct pharmacological stimulants of adrenergic α-receptors should disrupt self-stimulation by acting randomly on the reinforcement system and disrupting response-reward contingencies; this was confirmed by the finding that the α-receptor stimulant clonidine HCl (0.05 mg/kg) depressed self-stimulation at all sites tested. (2) Direct stimulants of DA receptors should enhance self-stimulation of NA sites by augmenting dopaminergic motivational activity; but in rats with DA electrodes, noncontingent stimulation of DA receptors would also impose similar noncontingent activity on the transsynaptic noradrenergic reinforcement pathways and thus depress self-stimulation; this was confirmed by the finding that apomorphine (0.3–1.0 mg/kg) was strongly stimulant for NA electrodes but strongly depressant for DA electrodes, and that the degree and direction of these effects was highly correlated with the differential effects of d- and l-amphetamine (rho = .65, p<0.01). Neither effect of apomorphine depended on the occurrence of motor stereotypy. These results can be interpreted in terms of 2-component models for self-stimulation, with the predominant transmitter of the drive component being identified as DA and that g the reinforcing component as NA.