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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 109 records · Page 6Linked to original sources

Caco-2 cell iron uptake from meat and casein digests parallels in vivo studies: use of a novel in vitro method for rapid estimation of iron bioavailability.

We developed a model for assessing iron bioavailability from foods which combines simulated peptic and intestinal digestion with measurement of iron uptake by Caco-2 cell monolayers. Our objective was to further validate this model by determining if meat enhances Caco-2 cell iron uptake relative to casein. Caco-2 cell monolayers were covered with Hank's balanced salt solution (HBSS) buffered with HEPES, pH 7.4. An upper chamber was created over the cells by fitting the bottom of a Costar Transwell insert with a 12,000-14,000 molecular weight cut-off dialysis membrane. This membrane allowed low molecular weight iron complexes to diffuse into the media bathing the cells and prevented damage to the cells from the digestive enzymes. Prior to digestion, each sample (homogenate of beef, chicken, fish or casein) was mixed with 59FeCl3 to achieve an iron concentration of 10 mumol/L. Following pepsin digestion (pH2), pH was adjusted to 7.4, pancreatic enzymes and bile extract were added to each digest, and an aliquot was then introduced into the upper chamber of the culture dish. During this intestinal digestion period, 59Fe uptake occurred from iron that dialyzed into the lower chamber. The 59Fe uptake from beef, chicken and fish digests was 300-400% of the 59Fe uptake from a casein digest. Our results parallel human absorption studies indicating that meat enhances iron absorption. The results suggest that digestion products of the meat proteins were at least partially responsible for the enhancement of iron uptake. Overall, this study supports the usefulness of our model as a means of assessing iron bioavailability.

Analysis of Variance↗

Ferrous iron uptake but not transfer is down-regulated in Caco-2 cells grown in high iron serum-free medium.

Caco-2 cells in culture provide an attractive model for the study of human iron absorption. Because iron status has a marked effect on human iron absorption, we devised serum-free growth conditions that allow manipulation of Caco-2 cell iron stores while maintaining growth. Caco-2 cells were cultured in serum-free media containing 0-20 micromol/L added iron. Intracellular ferritin, measured by radioimmunoassay, increased 100-fold with the addition of 20 micromol/L iron to the serum-free growth medium. Iron uptake and transfer across Caco-2 cell monolayers were measured from balanced salt solutions of ferrous and ferric forms of iron. Uptake from ferrous, but not ferric, iron was inversely related to cell ferritin concentration and culture medium iron concentration. Kinetic analysis of uptake data from solutions of ferrous and ferric iron revealed saturable and nonsaturable components for ferrous iron, but only a nonsaturable component for ferric iron. Uptake by the nonsaturable pathway was not affected by cell ferritin concentration for either form of iron. Maximal uptake from a ferrous iron solution via the saturable pathway was nearly 100% greater in cells cultured under low compared with high iron conditions. Iron transfer across Caco-2 monolayers was not proportional to iron uptake, but was related to monolayer permeability. Iron uptake by Caco-2 cells was a reliable indicator of relative iron availability. We observed no difference in iron transfer that was related to the iron status of the cell monolayer. The lack of this effect suggests that this model may be inadequate for studies of iron transfer.

Caco-2 Cells↗

Evaluation of coronary artery disease in women.

Diagnostic techniques have been refined to improve the accuracy of coronary artery disease detection in women compared to that achieved by clinical assessment and stress electrocardiography alone. Noninvasive cardiac imaging with 99mTc myocardial perfusion agents improves the specificity of coronary artery disease diagnosis over that achieved with 201Tl imaging, particularly when this technique is combined with ECG-gated image analysis. Improvements in diagnostic accuracy should enhance physician confidence in the use of noninvasive diagnostic testing in women. Combined clinical and noninvase imaging assessment can define those women at very high and very low risk for future cardiac events, permitting physicians to direct appropriate patients to aggressive treatment (ie, coronary revascularization) to improve outcomes. The reduction in unneccessary coronary cardiac catheterization accomplished by improved specificity, and the accurate determination of cardiac risk, provides for the most cost-efficient use of medical resources in the female population with known or suspected coronary artery disease.

Aged↗

Myocardial cell damage by fatty acid ethyl esters.

Fatty acid ethyl ester (FAEE), a myocardial metabolite of ethanol, causes mitochondrial dysfunction in vitro in rabbits. We investigated the effect of these esters on rat heart mitochondria in vitro and in vivo. In vitro studies were conducted to investigate the binding of ethyl oleate (FAEE) to mitochondria and their capacity to hydrolyze these FAEE. In vivo effects of ethyl esters were studied by the direct transfer of [3H]oleate into the myocardium. Mitochondria were prepared from the myocardium of injected rats, and the amount of [3H]oleate bound to them was determined. In another in vivo study, 50 microliters of 50 microM cold oleic acid ethyl ester was injected into the rat myocardium and the histopathological changes induced by oleic acid ethyl ester were examined by light microscopy. Our results show that fatty acid ethyl ester can bind to myocardial mitochondria in vitro as well as in vivo and the mitochondria can hydrolyze FAEE to fatty acid, which is a known uncoupler of oxidative phosphorylation. Of the total ethyl [3H] oleate injected, 8 microM [3H]oleate and 1 microM ethyl [3H]oleate was bound to the mitochondria. Significant myocardial cell damage was first observed on day 4 and markedly increased on day 30 after ethyl ester injection, with cells showing gross deformation and enlargement. However, no significant histopathological changes were observed in the myocardial tissue on day 2 after injection. Our results suggest that the FAEE may damage the myocardial cells as well as the mitochondria and may provide a metabolic link between ethanol abuse and myocardial dysfunction.

Animals↗

Prognostic value of noninvasive risk stratification in younger and older patients referred for evaluation of suspected coronary artery disease.

OBJECTIVES: The purpose of this investigation is to explore the relationship of patient gender and age on coronary artery disease diagnostic evaluation and to assess the impact of noninvasive testing results on coronary revascularization rates and cardiac event-free survival. STUDY DESIGN: Retrospective observational cohort. PARTICIPANTS: From a series of 5322 consecutively tested patients from a Midwestern university tertiary medical center, a hospital cohort of 1345 patients with clinically suspected coronary artery disease was enrolled from 1988 through 1989. MEASUREMENTS AND RESULTS: Cardiac risk factor and symptom profiles were worse in women, whereas rates of positive test results were similar in both sexes. Multivariable-adjusted risk for follow-up diagnostic testing was 1.8 and 1.9 times greater, respectively, for men < or = and > 65 years of age than for women (P < .01). Younger women were 4.9 times (P = .001) more likely to experience a cardiac event than younger men, with no differences between younger and older women (relative risk = 1.1; P > .20). Overall cardiac event rates were 2.3, 7.4, 16.7, and 20.2% for young men, young women, older women, and older men, respectively. Initial screening was delayed 2 to 7 times longer for older and younger women compared with men (P < .001); the greatest delays were observed for younger women. Diagnostic follow-up and subsequent cost of total care from initial evaluation through 2 years of follow-up were higher for men than for women (P < .0001), with older women having the lowest rate of subsequent diagnostic and interventional follow-up. In the highest risk patients, subsequent utilization rates were 40 and 20% higher for younger and older men than for similarly aged women. In particular, diabetics were less likely to undergo follow-up diagnostic testing and revascularization (67% younger women). CONCLUSIONS: Age appears to significantly and differently influence decisions regarding noninvasive and invasive medical service utilization in men and women and may partially account for variable outcomes in this and previous gender-based comparisons.

Adult↗

Enantioselective binding of Casodex to the androgen receptor.

1. The biologic activity of androgens is mediated through the formation of a non-covalent androgen receptor (AR)-steroid complex. Casodex and other antiandrogens inhibit formation of this complex and thus negate the role of endogenous steroids in androgen-dependent growth of prostate. 2. Casodex is currently available as a racemic mixture. The goal of this investigation was to determine the in vitro AR binding affinities of the individual isomers of Casodex. 3. The (R) or (S) isomers of Casodex were synthesized according to the general synthetic scheme proposed by Tucker et al. for (S)-Casodex, using (R) or (S)-proline as the chiral matrix respectively. 4. ARs were isolated from rat ventral prostate tissue by homogenization and differential centrifugation, and used as the receptor source. 5. AR binding studies were conducted by incubation of the cytosol with 1 nM 3H-mibolerone (a synthetic androgen) and increasing concentrations of each isomer (10(-12) - 10(-5) M). Bound radioligand was quantitated by liquid scintillation counting. 6. Ki for (R)-Casodex (11.0 +/- 1.5 nM) was about 30 times lower than that of (S)-Casodex (364 +/- 10 nM). Ki for the racemate was 20.2 +/- 2.0 nM. 7. This study demonstrated that (R)-Casodex has a higher binding affinity than its stereoisomer and suggests that the antiandrogenic activity of racemic Casodex is almost completely due to the (R)-isomer.

Androgen Antagonists↗

The clinical use of clozapine plasma concentrations in the management of treatment-refractory schizophrenia.

The introduction of clozapine into clinical practice represented a major breakthrough in antipsychotic pharmacotherapy. However, in spite of 5 years of use and a extensive research, there has previously been no clinically useful means to predict response to clozapine. Six recent studies have examined the utility of clozapine plasma concentrations in predicting response in treatment-refractory patients with schizophrenia. Five of these studies found that clozapine plasma concentrations above 350 to 420 ng/ml significantly increase the likelihood of clinical response in this patient population. Thus, there is now compelling evidence that clozapine plasma concentrations may play an important role in maximizing the probability of clinical response to clozapine in treatment-refractory schizophrenia. This article provides an overview of studies investigating the relationship between clozapine plasma concentrations and clinical response. The discussion includes guidelines regarding the clinical use of clozapine plasma concentrations in the pharmacological management of persons with treatment-refractory schizophrenia.

Antipsychotic Agents↗

Withdrawal-emergent dyskinesia in patients with schizophrenia during antipsychotic discontinuation.

We examined whether patients exhibiting withdrawal-emergent dyskinesia (WE-D) represent a group vulnerable to subsequent development of tardive dyskinesia (TD). WE-D was defined as moderate abnormal movements during antipsychotic withdrawal in persons without persistent TD. We assessed patients with schizophrenia-spectrum illness participating in withdrawal from antipsychotic medication. Patients with WE-D were compared to those without dyskinesia and to those with persistent TD. Clinical measures included duration of illness and antipsychotic exposure, negative symptoms, and neurologic soft signs. We hypothesized that WE-D patients would not differ from persistent-TD patients across the above variables, but would differ from non-TD patients. Patients without TD significantly differed from persistent TD in duration of illness, medication exposure and neurologic soft signs. WE-D did not differ from TD across these measures. No-TD patients also showed less duration of medication exposure and neurologic soft signs than those with WE-D.

Adolescent↗

Exercise technetium-99m myocardial tomography for the risk stratification of men with medically treated unstable angina pectoris.

The prognostic value of predischarge maximal exercise stress testing with technetium-99m sestamibi (MIBI) myocardial tomography was assessed in 126 consecutive men hospitalized with a diagnosis of unstable angina pectoris who were medically stabilized. None had coronary revascularization for < or = 6 months after testing. Over a mean follow-up of 12 +/- 7 months (range 1 to 29), 35 patients (28%) had a cardiac event--nonfatal acute myocardial infarction (n = 6), cardiac death (n = 5), or rehospitalization for unstable angina (n = 24). Any type of cardiac event occurred in 12% of patients with normal MIBI scans, compared with 39% of those with an abnormal MIBI scan (p < 0.001) and 60% of those with a reversible perfusion defect (p < 0.0001). Only 2% of patients with normal scans had either a nonfatal myocardial infarction or cardiac death, compared with 14% of those with abnormal MIBI scans (p < 0.05) and 25% with a reversible defect (p < 0.001). A fixed perfusion defect was not associated with increased cardiac risk. With use of multivariable Cox proportional-hazards modeling, the only scintigraphic variable with independent predictive value was the presence of a reversible MIBI defect, with a relative risk of 3.8 (95% confidence interval 1.6 to 8.6, p < 0.05) for any cardiac event, and 19.2 (95% confidence interval 2.2 to 167.0, p < 0.05) for a nonfatal myocardial infarction or cardiac death. Cardiac event-free survival was also significantly decreased in patients with a reversible perfusion defect (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Histomorphometric and biochemical correlates of arterial procollagen gene expression during vascular repair after experimental angioplasty.

BACKGROUND: To determine the transcriptional, biochemical, and histomorphometric correlates of neointimal procollagen accumulation during arterial repair after balloon angioplasty of atherogenic vessels, rabbit iliac artery collagen content and the induction of alpha 1(I) and alpha 1(III) procollagen mRNA were assessed in normal vessels and at 2, 7, and 30 days after angioplasty. METHODS AND RESULTS: Quantitative iliac artery histomorphometric neointimal collagen analysis was performed using a specific picrosirius red stain under polarized light. Arterial cross-sectional area reduction, total cellularity, and vascular smooth muscle cell density (per 10(4) mu2 of neointima) were quantified in routine and immunohistochemically stained sections (alpha-actin and RAM-11), from which biochemical concentrations of tissue protein, RNA, and DNA were also measured. Collagen comprised 0.23 +/- 0.1 mg/mg of total protein in the normal vessel wall and did not increase in vessels studied 2 and 7 days after angioplasty (0.26 +/- 0.06, 0.28 +/- 0.05 mg/mg of protein, P = NS). By 30 days after angioplasty, > 50% of the protein concentration was collagen (0.55 +/- 0.11 mg/mg of protein, P = .02). Collagen-positive histological staining also increased significantly from 17 +/- 2% of the neointima at day 2 to 32 +/- 5% by day 30 (P = .01). The transcript regulatory signal for alpha 1(I) procollagen mRNA was induced 2 days after angioplasty, peaking at 7 days for both alpha 1(I) and alpha 1(III), and returning to control levels 30 days after angioplasty. A significant luminal cross-sectional area reduction of the arterial wall was confirmed both by angiography and histomorphometry (P = .01). This was not associated with a significant change in alpha-actin (+) vascular smooth muscle cell density (38 +/- 7 nuclei per 10(4) mu2 at day 2 and at day 30) or tissue DNA concentration (P = NS). CONCLUSIONS: We conclude that procollagen genes are transcriptionally activated early (2 to 7 days) after angioplasty vessel injury and that collagen subsequently constitutes a major biochemical and histological component of the proliferative neointima by 30 days after angioplasty. Alterations in pathways regulating procollagen metabolism may also contribute to the accumulation of extracellular matrix and growth of the neointima in the late repair phase after vessel wall injury.

Angioplasty, Balloon↗

Preoperative strategies to assess cardiac risk before noncardiac surgery.

The strategies recommended in the preoperative cardiac risk assessment prior to major vascular and nonvascular surgery are reviewed. The role of clinical evaluation, noninvasive stress testing (exercise test, stress myocardial perfusion imaging, stress echocardiography), and Holter monitoring during the preoperative evaluation are outlined and the value of intervention based on the use of each test is discussed. Recommended strategies to evaluate patients based on their clinical risk markers in addition to the results of the noninvasive risk assessment are presented.

Heart Diseases↗

Clinical comparison of sevoflurane and isoflurane when administered with nitrous oxide for surgical procedures of intermediate duration.

The purpose of this study was to compare the haemodynamic effects and emergence times of anaesthesia with sevoflurane with those of isoflurane when the agents were administered with nitrous oxide to adult patients (ASA I and II) undergoing surgery of at least an hour in duration. Fifty patients were randomly assigned to receive either 0.65 minimum alveolar concentration (MAC) (1.3%) sevoflurane or 0.65 MAC (0.8%) isoflurane together with 60% nitrous oxide following induction with thiopentone, fentanyl, and succinylcholine. Systemic blood pressure and heart rate trends were similar for both groups for the duration of anaesthesia. However, differences in systolic blood pressure measurements were noted at one minute after incision (99 +/- 3 mmHg, mean +/- SE, in the sevoflurane group compared with 109 +/- 4 mmHg for isoflurane), and at emergence (125 +/- 3 mmHg for sevoflurane, 134 +/- 3 mmHg for isoflurane), and in diastolic blood pressure measurements at five minutes after intubation (64 +/- 2 mmHg for sevoflurane, 73 +/- 3 mmHg for isoflurane). Recovery of response to command was more rapid after discontinuation of sevoflurane-nitrous oxide (9.9 +/- 1.1 min) than after isoflurane-nitrous oxide (13.9 +/- 1.3 min). Despite earlier emergence, patients who had received sevoflurane did not request postoperative analgesia sooner. We conclude that the purported advantages of sevoflurane, namely haemodynamic stability and rapid emergence, can be expected even when the agent is administered at 0.65 MAC (1.3%) in nitrous oxide to a typical adult surgical population undergoing procedures of intermediate duration (2.3 +/- 0.2 hr).

Age Factors↗

Comparison of pressure-derived fractional flow reserve with poststenotic coronary flow velocity reserve for prediction of stress myocardial perfusion imaging results.

The physiologic importance of coronary stenoses can be assessed indirectly by stress myocardial perfusion imaging or directly by translesional pressure and flow measurements. The aims of this study were to compare myocardial fractional flow reserve (FFRmyo), a recently proposed index of lesion significance derived from hyperemic translesional pressure gradients, with directly measured poststenotic flow velocity reserve for the prediction of myocardial perfusion stress imaging results in corresponding vascular beds. Poststenotic coronary flow velocity (0.018-inch guide wire) and translesional pressure gradients (2.7F fluid-filled catheter) were measured at baseline and after intracoronary adenosine (12 to 18 micrograms) in 70 arteries (diameter stenosis: mean 56% +/- 15%, range 14% to 94% by quantitative angiography). Coronary flow reserve was calculated as the ratio of hyperemic to basal mean flow velocity. FFRmyo was calculated during maximal hyperemia as equal to 1-(hyperemic gradient [mean aortic pressure-5]), where 5 is the assumed central venous pressure. Positive and negative predictive values and predictive accuracy for reversible stress myocardial perfusion abnormalities were computed. There was a significant correlation between pressure-derived FFRmyo and distal coronary flow reserve (r = 0.46; p < 0.0001). The strongest predictor of stress myocardial perfusion imaging results was the poststenotic coronary flow reserve (chi square = 33.2; p < 0.0001). The correlation between stress myocardial perfusion imaging and FFRmyo was also significant (chi square = 8.3; p < 0.005). There was no correlation between stress myocardial perfusion imaging and percentage diameter stenosis (chi square = 2.9; p = 0.10) or minimal lumen diameter (chi square = 0.47; p = 0.73). A poststenotic coronary flow reserve of < or = 2 had a positive predictive value of 89% for regionally abnormal myocardial perfusion imaging abnormalities, whereas the positive predictive values of FFRmyo and angiographic percentage diameter stenosis were only 71% and 67% respectively. In conclusion, the predictive value of poststenotic coronary flow velocity reserve for stress-induced myocardial perfusion abnormalities exceeds that of the translesional FFRmyo. These findings should be considered when applying these techniques for clinical decision making in the assessment of coronary stenosis severity.

Adult↗

Prognostic value of predischarge dipyridamole technetium 99m sestamibi myocardial tomography in medically treated patients with unstable angina.

Recently developed unstable angina clinical practice guidelines have recommended risk stratification with dipyridamole thallium-201 myocardial imaging in patients at "intermediate" pretest clinical risk who cannot exercise maximally. The prognostic value of predischarge dipyridamole technetium 99m sestamibi (MIBI) tomography has not been assessed in this clinical setting. To this end, 128 medically treated patients with unstable angina at intermediate pretest clinical risk underwent follow-up for 16 +/- 11 (mean +/- SD) months after predischarge intravenous dipyridamole MIBI tomography. An abnormal MIBI scan result was present in 99 patients (77%), of whom 47 had one or more reversible and 76 had one or more fixed perfusion defects. Cardiac events occurred in 68 (53%) patients after dipyridamole testing: recurrent unstable angina (n = 36), nonfatal acute myocardial infarction (n = 6), or death (n = 26). A cardiac event occurred in 10% of patients with normal MIBI tomography results compared with 69% of those with abnormal results (p < 0.01). Event rates associated with specific perfusion defects were similar (reversible = 68%; fixed = 71%) and were greater than rates in patients without defects (both p < 0.05). Clinical variables associated with increased risk of cardiac events by univariate analysis included a history of congestive heart failure, prior myocardial infarction, and diabetes mellitus (all p < 0.05). Independent multivariable predictors (Cox proportional hazards model) of any cardiac event were an abnormal result of MIBI scan (relative risk [RR] = 4.3, 95% confidence interval [CI] 1.5 to 12.0) and a reversible (RR = 1.8, 95% CI 1.1 to 2.9) or a fixed perfusion defect (RR = 2.9, 95% CI 1.6 to 5.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Angina, Unstable↗

Identification of an aldose reductase inhibitor site by affinity labeling.

Animal studies indicate that aldose reductase inhibitors represent a pharmacological method for inhibiting the onset of diabetic complications that is independent of blood sugar control. This has spurred the development of aldose reductase inhibitors (ARIs). To facilitate the rational development of more potent and direct ARIs, more specific knowledge of the structural and pharmacophoric requirements of the site at which ARIs interact are required. Co-crystallization of human placental aldose reductase with the inhibitor zopolrestat has been reported to result in a complex where the inhibitor is almost completely sequestered in the hydrophobic pocket which forms the substrate site. Zopolrestat's observed location, which makes the active site pocket inaccessible to solvent or further productive binding of substrate, is not supported by published inhibitor structure-activity relationships (SAR) studies or kinetic results which indicate that aldose reductase inhibitors such as zopolrestat are either non-competitive or uncompetitive inhibitors. Using a 5-iodoacetamido analog of alrestatin as an affinity labeled aldose reductase inhibitor, an inhibitor binding site on aldose reductase has been located. This inhibitor binding site contains a number of pharmacophoric elements previously proposed for the inhibitor site. Its location and composition is consistent with reported kinetic data, SAR observations, stereochemical requirements, and quantum chemical calculations.

Affinity Labels↗

Nuclear spreads: I. Visualization of bipartite ribosomal RNA domains.

Visualization of nuclear architecture is key to the understanding of the association between RNA synthesis and processing. This architecture is obscured by the high density of components in most nuclei. We have developed a method of spreading nuclei and nucleoli that reduces overlap of weakly associated components. Strong interactions among nuclear components are not disrupted by this method. Spread nucleoli remained structurally distinct and functionally competent in ribosomal RNA synthesis. Nascent ribosomal RNA colocalized with RNA polymerase I and fibrillarin, a protein required for processing of ribosomal RNA. Colocalization of nascent transcripts and fibrillarin was seen in nucleoli spread over several microns, suggesting a strong interaction. These data suggest that nucleoli are superassemblies of bipartite domains, each composed of a ribosomal RNA synthesis center tightly associated with areas likely to be involved in ribosomal RNA processing.

Animals↗

Bathophenanthrolene disulfonic acid and sodium dithionite effectively remove surface-bound iron from Caco-2 cell monolayers.

Iron uptake by Caco-2 cell monolayers is commonly assessed by incubating the cells under radiolabeled iron solutions, removing the radiolabeled solution, rinsing to stop uptake and measuring the radioactivity retained by the cells. It is therefore essential to differentiate between iron that is nonspecifically bound to the cell surface from that which has been taken up by the cell. We report here on a method for removal of surface-bound iron from Caco-2 cell monolayers. We used a 140 mmol/L NaCl, 10 mmol/L PIPES, pH 6.7 solution containing 5.0 mmol/L sodium dithionite (Na2S2O4) and 5.0 mmol/L bathophenanthroline disulfonic acid to reduce, remove and chelate iron bound to the cell surface. We validated our method by demonstrating the removal of 97% of an insoluble iron complex from the apical surface of Caco-2 cell monolayers. Our data indicate that the removal solution does not damage the apical membrane and thereby does not have access to intracellular iron; thus only surface bound iron is removed. The remaining cell-associated iron represents that which has been transported into the cell. We present data on the uptake and nonspecific binding of iron from iron complexes of both ferrous and ferric forms, and show that iron removal treatment resulted in uptake measurements that agree more closely with accepted principles of iron uptake by intestinal epithelium. The iron removal method used in this study should provide investigators with a valuable tool for accurately determining iron uptake by epithelial cells in culture.

Biological Transport↗