Control-relevant modeling in drug delivery.

The development of control-relevant models for a variety of biomedical engineering drug delivery problems is reviewed in this paper. A summary of each control problem is followed by a review of relevant patient models from literature, an examination of the control approaches taken to solve the problem, and a discussion of the control-relevance of the models used in each case. The areas examined are regulating the depth of anesthesia, blood pressure control, optimal cancer chemotherapy, regulation of cardiac assist devices, and insulin delivery to diabetic patients.

Carotenoid and tocopherol composition of human adipose tissue.

Concentrations of individual carotenoids and tocopherols were determined in abdominal adipose tissue from 19 adults undergoing corrective surgery. Samples were extracted and saponified before separation and quantitation of carotenoids and tocopherols by reverse-phase high-performance liquid chromatography. Total carotenoid concentration varied 40-fold between individuals, from 0.34 to 13.51 micrograms/g adipose tissue. Beta-carotene and lycopene were the predominant carotenoids, averaging 20.2 and 18.5% of total carotenoids, respectively. In 10 of 19 subjects, the lycopene concentration exceeded that of beta-carotene. Total tocopherol concentrations varied 11-fold, with alpha-tocopherol representing 80.6 +/- 8.1% of the total. Absolute concentrations of both carotenoids and tocopherols were more variable than their relative concentrations. Both beta-carotene and lycopene concentrations were highly correlated with total carotenoid content but there was no correlation between beta-carotene and lycopene or between beta-carotene and alpha-tocopherol concentrations.

Effect of beta-carotene supplementation on photosuppression of delayed-type hypersensitivity in normal young men.

The aim of this study was to examine whether beta-carotene protects against the immunosuppression seen with long-wave ultraviolet-light (UV-A) exposure. Free-living, healthy men, aged 19-39 y received 30 mg beta-carotene/d or a placebo while on a single-menu, low-carotenoid diet. After 28 d all subjects received 12 exposures to a UV-A/B light source over a 16-d period. The total UV-A dose received ranged from 15.9 to 19.3 J/cm2. The total shorter-wave ultraviolet-light (UV-B) dose varied from 1.59 to 1.96 J/cm2. Follow-up continued for 21 d. Carotenoid assays and delayed-type hypersensitivity (DTH) tests were performed at baseline, pre-UV, post-UV, and after follow-up. The DTH-test responses were significantly suppressed in the placebo group after UV treatments. The suppression was inversely related to plasma beta-carotene concentrations in this group. There was no significant suppression of DTH test responses in the beta-carotene group. It is concluded that beta-carotene protects against photosuppression of immune function.

Evidence of cis-trans isomerization of 9-cis-beta-carotene during absorption in humans.

Absorption and metabolism of [13C]9-cis-beta-carotene ([13C]9c beta C) was studied in three subjects after a single oral dose. Subjects given 1.0 mg [13C]beta-carotene (mean: 99.4% 9-cis-beta-carotene, 0.6% all-trans-beta-carotene; dose A) had substantial concentrations of [13C]all-trans-beta-carotene ([13C]tr beta C) and [13C]all-trans retinol ([13C]retinol) but very low concentrations of [13C]cis-beta-carotene ([13C]cis beta C) in saponified plasma 5 h after dosing, as determined by HPLC and isotope-ratio mass spectrometry. There was no evidence of appreciable absorption of [13C]9-cis retinol. To determine the proportion of [13C]tr beta C and [13C]retinol derived from [13C]9c beta C, a second set of studies in the same subjects was performed with the same isomeric composition except with 13C labeling only in all-trans-beta-carotene (dose B). The results indicated that > 95% of plasma [13C]tr beta C and [13C]retinol observed after dose A was derived from [13C]9c beta C. The concentrations of [13C]tr beta C observed, in excess of that derived from the trace amounts of [13C]tr beta C in the dose, indicated that a significant proportion of the [13C]9c beta C dose was isomerized to [13C]tr beta C before entering the bloodstream. Although precise quantitative estimates of the extent of isomerization of 9-cis-beta-carotene could not be made, it is apparent that cis-trans isomerization of 9-cis-beta-carotene to all-trans-beta-carotene contributed to the near absence of postprandial plasma 9-cis-beta-carotene after its oral administration in humans. The observation of different ratios of beta-carotene to retinol between the two dosing protocols suggests that isomerization did not occur exclusively before uptake by the intestinal mucosa. These results indicate that isomerization of ingested 9-cis-beta-carotene before its secretion into the bloodstream limits the potential supply of 9-cis retinoids to tissues, and increases the vitamin A value of 9-cis-beta-carotene.

A novel extrinsic reference method for assessing the vitamin A value of plant foods.

BACKGROUND: The amounts of vitamin A that are metabolically derived from specific carotene-containing foods are largely unknown. OBJECTIVE: We sought to develop an improved method for estimating the metabolic vitamin A potential of provitamin A carotenoids by using [2H4]retinyl acetate (d4-RA) as an extrinsic reference standard. DESIGN: Healthy subjects consumed a standardized test meal containing 6 mg beta-carotene as either raw carrot or spinach, either 20 or 1 g added fat, and 6.0 micromol d4-RA. Concentrations of unlabeled (d0) retinyl esters (RE), labeled (d4) RE, and carotenoids in the plasma triacylglycerol-rich lipoprotein fraction (d < 1.006 kg/L) were determined in serial blood samples with HPLC and gas chromatography-mass spectrometry. Baseline-corrected areas under the curve for d0-RE, d4-RE, and carotenoids were calculated, and the masses of absorbed d0-retinol and carotenes were estimated assuming 80% absorption of the d4-RA reference dose. RESULTS: In trials with ample (20 g) fat (n = 6), 7 +/- 4% of the 6 mg beta-carotene ingested was taken up as beta-carotene plus RE with 0.3 +/- 0.1 mg as retinol. Test meals without carotenes yielded no beta-carotene or d0-RE response and there was no effect of treatment (either fat amount or vegetable, n = 6) on the mean d4-RE area under the curve. The lower-than-expected vitamin A yields were attributed to poor intestinal uptake rather than to low conversion of beta-carotene to RE. CONCLUSION: The triacylglycerol-rich lipoprotein and d4-RA method, which controls for variation in chylomicron kinetics in vivo and RE recovery during analysis, is useful for obtaining quantitative estimates of the vitamin A potential of single meals.

Analysis of carotenoids in human plasma and tissues.

Procedures are described for the extraction and analysis of carotenoid pigments from human tissues and plasma. The method allows resolution of many polar pigments, including several such compounds more polar than zeaxanthin. While the method requires two separate HPLC runs when applied to tissues containing significant quantities of triglyceride, the additional information made available on the polar carotenoid composition of such samples is substantial.

Metabolism of N-nitrosodi-n-propylamine and N-nitrosodiallylamine by isolated rat hepatocytes.

Isolated rat hepatocytes were incubated with approximately equimolar amounts of N-nitrosodi-n-propylamine (NDPA) and N-nitrosodiallylamine (NDAA) in order to compare their metabolism. The principal metabolite of NDPA was N-nitroso-(2-hydroxypropyl)propylamine, which was present as a glucuronide. N-Nitroso-(3-hydroxypropyl)propylamine and N-nitrosopropyl-(carboxyethyl)amine were minor metabolites; no N-nitrosomethylpropyl-amine (NMPA) was detected. A single N-nitroso metabolite of NDAA was found and identified as N-nitroso-(2,3-dihydroxypropyl)allylamine. These data indicate that the allyl group of N-nitrosodiallylamine is readily oxidized by hepatocytes in vitro. It appears unlikely that N-nitrosomethylpropylamine is an intermediate in N-nitrosodi-n-propylamine metabolism.

Iron status of middle-aged women in five counties of rural China.

OBJECTIVE: To determine the relationships of dietary iron sources, other dietary factors, and lifestyle to iron status among premenopausal and recently postmenopausal Chinese women with widely varying regional dietary patterns. DESIGN: Cross-sectional. Subjects were interviewed, blood samples were drawn, and dietary intakes were measured by a 3-day dietary survey for subjects in the five survey counties. SETTING: Rural China. SUBJECTS: About 80 randomly selected subjects per county among women aged 32 66 y. MAIN OUTCOME MEASURES: Blood hemoglobin, plasma ferritin, and plasma iron. RESULTS: Total iron intake was relatively high (15-29 mg/d) compared to developed counties. Heme iron intake was negligible in two of the study counties. Overall levels of iron deficiency anemia were relatively low in these generally iron-stressed women. There was no clear statistical relationship between iron intake and physiological iron status. Although several measures of dietary intake (heme iron, dietary calcium, animal protein) were correlated with several measures of iron status before adjusting for survey county, only dietary animal protein was significantly positively correlated with plasma ferritin after adjusting for the possibly confounding factor of the survey county (r= 0.15, P = 0.009). Intakes of potential inhibitors of iron absorption, such as tea, even in very high amounts, were not correlated to iron status. Plasma ferritin was positively correlated with plasma retinol (P = 0.024) and cholesterol (P = 0.007). Systemic inflammatory response, as indicated by high plasma C-reactive protein levels, was shown to be raised in a group of subjects with apparently contradictory high levels of ferritin and low levels of hemoglobin (P = 0.03). CONCLUSIONS: Iron nutriture in these areas of rural China seemed more related to physiological factors such as inflammatory response, menses, plasma vitamin A and cholesterol, than to dietary factors.

Determinants of plasma retinol concentrations of middle-aged women in rural China.

The purpose of this study was to assess the correlates and possible determinants of plasma vitamin A among middle-aged women in rural China. The vitamin A adequacy of the different diets at the five widely varying survey sites was also assessed. Patterns of correlations among dietary and biochemical measurements were strikingly different from previous studies in Western subjects. Plasma beta-carotene was uncorrelated with beta-carotene intake even after adjusting for potential confounders. In counties with low preformed vitamin A intake, plasma retinol correlated with plasma copper (P = 0.007), which in turn was correlated with dietary intake of copper (P = 0.007). In these counties plasma retinol was correlated with plasma beta-carotene (P = 0.001) and was increased 10% in women in the first 2 y of menopause (P = 0.028). Plasma retinol and C-reactive protein levels are inversely correlated (r = -0.15, P < 0.001), indicating that vitamin A status and inflammatory response may be related but the causal direction is unknown. Despite low intake of vitamin A (county averages of 13-78% of recommended daily allowance [RDA]), and particularly of preformed vitamin A, only 3% of these women had plasma retinol levels below 0.7 mumol/L, considered to indicate possible marginal deficiency. Plasma levels of retinol and beta-carotene were more influenced by intrinsic factors such as menopause, lipid status, retinol requirements, and possibly copper status and inflammation than by extrinsic factors such as diet and lifestyle.

A model-based algorithm for blood glucose control in type I diabetic patients.

A model-based predictive control algorithm is developed to maintain normoglycemia in the Type I diabetic patient using a closed-loop insulin infusion pump. Utilizing compartmental modeling techniques, a fundamental model of the diabetic patient is constructed. The resulting nineteenth-order nonlinear pharmacokinetic-pharmacodynamic representation is used in controller synthesis. Linear identification of an input-output model from noisy patient data is performed by filtering the impulse-response coefficients via projection onto the Laguerre basis. A linear model predictive controller is developed using the identified step response model. Controller performance for unmeasured disturbance rejection (50 g oral glucose tolerance test) is examined. Glucose setpoint tracking performance is improved by designing a second controller which substitutes a more detailed internal model including state-estimation and a Kalman filter for the input-output representation. The state-estimating controller maintains glucose within 15 mg/dl of the setpoint in the presence of measurement noise. Under noise-free conditions, the model-based predictive controller using state estimation outperforms an internal model controller from literature (49.4% reduction in undershoot and 45.7% reduction in settling time). These results demonstrate the potential use of predictive algorithms for blood glucose control in an insulin infusion pump.

Effects of dietary fat level and aflatoxin B1 treatment on rat hepatic lipid composition.

Sprague-Dawley rats were given either ten daily doses of aflatoxin B1 (AFB1) or the solvent tricaprylin intragastrically over a 2-wk period and were fed diets containing either 1.6 or 20% corn oil throughout the study. Hepatic lipid composition was analysed in groups of five rats both 3 and 13 wk after the start of treatment, in order to determine short-term and longer-term alterations. Total lipid and cholesterols (total, free and esterified) increased on the high-fat diet at wk 3. At wk 13 only total and esterified cholesterol were increased by 20% corn oil. AFB1 treatment resulted in large intra-group variations in total lipid and cholesterol at wk 3, but these were no longer apparent by wk 13. AFB1 produced various alterations in the fatty acid composition of hepatic phosphatidylcholine (PC) and phosphatidylethanolamine (PE), apparent at wk 3 but not at wk 13. The unsaturation index decreased but no changes were seen in the saturated fatty acids. Only in animals fed 20% corn oil did AFB1 result in significant changes in 18:2, 20:3 and 22:6 fatty acids, while 20:4 and 22:5 tended to decrease and 18:1 to increase in response to AFB1 treatment with both diets in both phospholipids. The high-corn oil diet was found to increase 18:2, 22:6, and total unsaturation in PC and PE, while the ratio of 20:4 to 18:2 tended to decrease in these phospholipids. gamma-Glutamyltranspeptidase, an indicator of liver damage, was significantly increased in AFB1-treated animals, with the greatest increase over controls in those fed the high-fat diet.

Anhydrolutein in the zebra finch: a new, metabolically derived carotenoid in birds.

Many birds acquire carotenoid pigments from the diet that they deposit into feathers and bare parts to develop extravagant sexual coloration. Although biologists have shown interest in both the mechanisms and function of these colorful displays, the carotenoids ingested and processed by these birds are poorly described. Here we document the carotenoid-pigment profile in the diet, blood and tissue of captive male and female zebra finches (Taeniopygia guttata). Dietary carotenoids including: lutein; zeaxanthin; and beta-cryptoxanthin were also present in the plasma, liver, adipose tissue and egg-yolk. These were accompanied in the blood and tissues by a fourth pigment, 2',3'-anhydrolutein, that was absent from the diet. To our knowledge, this is the first reported documentation of anhydrolutein in any avian species; among animals, it has been previously described only in human skin and serum and in fish liver. We also identified anhydrolutein in the plasma of two closely related estrildid finch species (Estrilda astrild and Sporaeginthus subflavus). Anhydrolutein was the major carotenoid found in zebra finch serum and liver, but did not exceed the concentration of lutein and zeaxanthin in adipose tissue or egg yolk. Whereas the percent composition of zeaxanthin and beta-cryptoxanthin were similar between diet and plasma, lutein was comparatively less abundant in plasma than in the diet. Lutein also was proportionally deficient in plasma from birds that circulated a higher percentage of anhydrolutein. These results suggest that zebra finches metabolically derive anhydrolutein from dietary sources of lutein. The production site and physiological function of anhydrolutein have yet to be determined.

The effect of dietary carotenoid access on sexual dichromatism and plumage pigment composition in the American goldfinch.

We investigated potential dietary and biochemical bases for carotenoid-based sexual dichromatism in American goldfinches (Carduelis tristis). Captive male and female finches were given access to the same type and amount of carotenoid pigments in the diet during their nuptial molt to assess differences in the degree to which the two sexes incorporated ingested pigments into their plumage. When birds were fed a uniform, plain-seed diet, or one that was supplemented with the red carotenoid canthaxanthin, we found that males grew more colorful plumage than females. HPLC analyses of feather pigments revealed that male finches incorporated a higher concentration of carotenoids into their pigmented feathers than females. Compared to females, males also deposited significantly more canary xanthophyll B into feathers when fed a plain-seed diet and a greater concentration and proportion of canthaxanthin when fed a carotenoid-supplemented diet. These results indicate that sex-specific expression of carotenoid pigmentation in American goldfinches may be affected by the means by which males and females physiologically utilize (e.g. absorb, transport, metabolize, deposit) carotenoid pigments available to them in the diet.

Lutein-based plumage coloration in songbirds is a consequence of selective pigment incorporation into feathers.

Many birds obtain colorful carotenoid pigments from the diet and deposit them into growing tissues to develop extravagant red, orange or yellow sexual ornaments. In these instances, it is often unclear whether all dietary pigments are used as integumentary colorants or whether certain carotenoids are preferentially excluded or incorporated into tissues. We examined the carotenoid profiles of three New World passerines that display yellow plumage coloration-the yellow warbler (Dendroica petechia), common yellowthroat (Geothlypis trichas) and evening grosbeak (Coccothraustes vespertinus). Using high-performance liquid chromatography, we found that all species used only one carotenoid-lutein-to color their plumage yellow. Analyses of blood carotenoids (which document those pigments taken up from the diet) in two of the species, however, revealed the presence of two dietary xanthophylls-lutein and zeaxanthin-that commonly co-occur in plants and animals. These findings demonstrate post-absorptive selectivity of carotenoid deposition in bird feathers. To learn more about the site of pigment discrimination, we also analyzed the carotenoid composition of lipid fractions from the follicles of immature yellow-pigmented feathers in G. trichas and D. petechia and again detected both lutein and zeaxanthin. This suggests that selective lutein incorporation in feathers is under local control at the maturing feather follicle.

Subcellular distribution of dietary beta-carotene in chick liver.

Studies were conducted examining the subcellular distribution of beta-carotene (BC), alpha-tocopherol (E) and retinol (A) in livers of control and BC-fed male White Leghorn chicks. Chicks were fed Cornell B chick starter diet with or without the addition of 0.5 g BC/kg diet. A first study involved liver fractionation by differential centrifugation in 0.25 M sucrose followed by high performance liquid chromatographic (HPLC) analyses of all fractions for quantitation of BC, E and A. A second study employed both intravenous injection of Triton WR-1339 four days prior to sacrifice and centrifugation in 1.0 M sucrose to separate mitochondria from lysosomes more efficiently. Fraction purity was assessed by marker enzyme analyses. Results showed that chick liver accumulated BC; BC-fed chicks had higher concentrations of BC in all fractions relative to controls, and the mitochondrial fraction contained the highest concentration of BC, followed by lysosomes, microsomes and nuclei, respectively. Plasma BC increased more than fivefold in BC-fed chicks. Dietary BC increased A and E levels in liver and in the mitochondrial and lysosomal fractions while the plasma E level was decreased. Plasma A changed little with BC feeding. While dietary BC had no effect on fatty acid composition of subcellular fractions, the increase in E resulted in a large increase in the molar ratio of E to polyunsaturated fatty acids. The incorporation of BC and increased amounts of E into cellular membranes presumably would result in increased resistance to peroxidative damage.

Turnover of label from [1-14C]linolenic acid in phospholipids of coho salmon, Oncorhynchus kisutch.

Juvenile coho salmon were injected intraperitoneally with [1-14C] linolenic acid and sampled at 24, 120, and 240 hr. Liver, heart and gill lipids were extracted analyzed, and halflives of individual liver glycerophospholipids and n-3 fatty acids determined from rates of loss of radioactivity. Incorporation of label into gill was much less than into either heart or liver. Total acyl halflife was shorter for the choline phospholipids than for the ethanolamine phospholipids, as were the halflives of all individual n-3 fatty acids. Eicosapentaenoic acid (20:5n-3) had the shortest halflife in both phospholipids (50-60 hr), while docosapentaenoic acid (22:5n-3) and docosahexaenoic acid (22:6n-3) had much longer halflives. Specific activities of the shorter chain n-3 fatty acids were much greater than the longer, more unsaturated homologs at all times, suggesting possible differences in their mechanisms of incorporation into phospholipids. Diacylglycerol analysis indicated that de novo synthesis could be responsible for the incorporation of only a small portion of the labeled long chain fatty acids found in phospholipids. The fatty acid halflives reported here for salmon are in general agreement with those found previously in mammals.

The influence of carotenoid acquisition and utilization on the maintenance of species-typical plumage pigmentation in male American goldfinches (Carduelis tristis) and northern cardinals (Cardinalis cardinalis).

Birds display a tremendous variety of carotenoid-based colors in their plumage, but the mechanisms underlying interspecific variability in carotenoid pigmentation remain poorly understood. Because vertebrates cannot synthesize carotenoids de novo, access to pigments in the diet is one proximate factor that may shape species differences in carotenoid-based plumage coloration. However, some birds metabolize ingested carotenoids and deposit pigments that differ in color from their dietary precursors, indicating that metabolic capabilities may also contribute to the diversity of plumage colors we see in nature. In this study, we investigated how the acquisition and utilization of carotenoids influence the maintenance of species-typical plumage pigmentation in male American goldfinches (Carduelis tristis) and northern cardinals (Cardinalis cardinalis). We supplemented the diet of captive goldfinches with red carotenoids to determine whether males, which are typically yellow in color, were capable of growing red plumage. We also deprived cardinals of red dietary pigments to determine whether they could manufacture red carotenoids from yellow precursors to grow species-typical red plumage. We found that American goldfinches were able to deposit novel pigments in their plumage and develop a striking orange appearance. Thus, dietary access to pigments plays a role in determining the degree to which goldfinches express carotenoid-based plumage coloration. We also found that northern cardinals grew pale red feathers in the absence of red dietary pigments, indicating that their ability to metabolize yellow carotenoids in the diet contributes to the bright red plumage that they display.

Carotenoids and antioxidant vitamins in patients after burn injury.

Oxidative stress may contribute to secondary tissue damage and impaired immune function in patients after burn injury. The purpose of our study was to describe plasma antioxidant micronutrient concentrations in 26 adult patients admitted with extensive burn injuries (> 20 % total burn surface area) to a level-1 trauma burn center during a 21-day period after admission. The effect of administering beta-carotene was also examined with use of a prospective randomized subjects design: patients received either placebo or 30 mg/day in an enteral feeding. Plasma concentrations of alpha- and gamma-tocopherol, carotenoids (alpha and beta-carotene, lycopene, beta-cryptoxanthin, lutein), and retinol were measured with high- performance liquid chromatography, and vitamin C was quantified with spectrophotometry, at baseline and twice per week. Vitamin C, tocopherol, and retinol concentrations were low at baseline, but levels increased significantly over the study period in both groups (p < 0.05). Plasma beta-carotene concentration increased when this carotenoid was provided in the oral feeding. Otherwise, plasma carotenoid concentrations were low at baseline and remained low throughout the study period despite normalization of associated lipids.

Nurses' stories: the search for a relational ethic of care.

The author begins by telling "Mike's story," a personal narrative account of an interaction with a patient. "Mike's story" provides a lens through which the author explores an alternative paradigm for nursing ethics--a paradigm grounded in a relational ethic of care. Mike's case is used to demonstrate how the moral experience of the nurse is distorted by the standard of moral rationality in traditional biomedical ethics. An interpretive analysis of "Mike's story" attempts to capture some of the fundamental assumptions of a relational ethic of care. The author identifies the benefits of grounding a theory of nursing ethics in nurses' conflicting stories of caregiving and encourages nurses to claim those stories that reflect the moral foundation of nursing.

Pharmacokinetic∕pharmacodynamic modelling of intracellular gemcitabine triphosphate accumulation: translating in vitro to in vivo.

A detailed intracellular (IC) model describing the pharmacokinetics (PK) of gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) was developed and linked to a systemic plasma dFdC PK model. Based on in vivo PK, pharmacodynamic (PD) effect predictions were made using a simplified cell-cycle model (CCM). A reduced-order compartmental model describing the IC metabolism of dFdC was fit to in vitro data taken from the literature to estimate the kinetic parameters of gemcitabine triphosphate (dFdCTP) generation and elimination in leukaemia cells. For comparison with in vivo patient data, the proposed detailed IC model, coupled with the systemic PK model and the CCM PD model, was simulated; Monte Carlo randomisation of the parameter vector was used to simulate interpatient variability. This comparison of model-generated IC dFdCTP concentrations with literature values in peripheral blood mononuclear cells (PBMCs) revealed qualitative and quantitative agreement. A tumour interstitial compartment connecting the plasma and IC models allowed prediction of solid tumour dFdCTP concentration.