Biomedical subjects

Elizabeth A Tolley

Publications and source records attributed to Elizabeth A Tolley.

12 recordsLinked to original sources

PubMed2006

Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans.

Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults with apo-A IV 1/1 or apo-E 3/3 genotypes. Study 1 included 11 subjects 24 to 37 years of age, taking 15 mg/kg/day chenodeoxycholic acid (CDCA) or no bile acid for 20 days while being fed a controlled diet. Study 2 included 9 adults 25 to 38 years of age, taking 15 mg/kg/day deoxycholic acid (DCA) or no bile acid, following the same experimental design and procedures as study 1. CDCA had no effect on plasma lipid concentrations, whereas DCA decreased (P < 0.05) plasma high-density lipoprotein (HDL)-cholesterol and tended to decrease (P = 0.15) low-density lipoprotein (LDL)-cholesterol. CDCA treatment enriched (P < 0.0001) bile with CDCA and increased cholesterol concentration in micelles, whereas meal-stimulated bile acid concentrations were decreased. DCA treatment enriched (P < 0.0001) bile with DCA and tended to increase intralumenal cholesterol solubilized in micelles (P = 0.06). No changes were found in cholesterol absorption, free cholesterol fractional synthetic rate (FSR), or 3-hydroxy-3 methylglutaryl (HMG) CoA reductase and LDL receptor messenger ribonucleic acid (mRNA) levels after CDCA treatment. DCA supplementation tended to decrease cholesterol absorption and reciprocally increase FSR and HMG CoA reductase and LDL receptor mRNA levels. Results of these 2 studies suggest that the solubilization of cholesterol in the intestinal micelles is not a rate-limiting step for its absorption.

Absorption↗

PubMed2005

Rapamycin-coated expanded polytetrafluoroethylene bypass grafts exhibit decreased anastomotic neointimal hyperplasia in a porcine model.

OBJECTIVE: We tested the hypothesis that rapamycin coated onto, and eluted from, expanded polytetrafluoroethylene (ePTFE) grafts would diminish neointimal hyperplasia in a porcine model. METHODS: Rapamycin (also called sirolimus) was coated onto the luminal surface of 6-mm-internal-diameter thin-walled ePTFE grafts by using an adhesive polymer that allows timed release of the drug. An adhesive polymer that allows timed release of rapamycin from ePTFE was developed with commercially available chemicals and applied on 6-mm ePTFE grafts. Graft integrity was characterized by scanning electron microscopy, and rapamycin levels were quantified by using high-performance liquid chromatography. Twenty-two mongrel pigs were randomized into three groups: untreated ePTFE (n = 6), adhesive-only coated ePTFE (n = 6), or adhesive- and rapamycin-coated ePTFE (n = 10). End-to-side unilateral aortoiliac bypasses were performed by using 6-mm-internal-diameter ePTFE grafts and standardized anastomotic lengths. Unilateral end-to-side aortoiliac ePTFE grafts (6-mm internal diameter) were inserted by using polypropylene sutures, 6-0 proximally and 7-0 distally; all anastomoses were 12 mm long. All animals received aspirin (325 mg orally) daily. All animals were given oral aspirin (325 mg) daily beginning on the day before surgery. At 28 days, the animals were killed, and the grafts were explanted in continuity with the adjacent aortic cuff and the outflow iliac artery. Variables compared between groups included graft patency, distal anastomotic length and cross-sectional narrowing, and intimal thickness at the arterial-graft junction indexed to the adjacent graft thickness. Microscopic analysis was performed with hematoxylin and eosin and Masson trichrome stains on paraffin sections. A pathologist blinded to experimental groups graded sections for collagen deposition, neointima formation, inflammatory cellular infiltrates, medial necrosis, and aneurysmal degeneration. RESULTS: All animals survived until they were killed without clinical evidence of limb ischemia or graft infection. Preplanned t tests in the context of one-way analysis of variance showed no difference in outcome measures between the untreated ePTFE and adhesive-only coated ePTFE groups; therefore, they were combined in further comparisons with the adhesive- and rapamycin-coated ePTFE group. The Rapamycine eluting expanded polytetrafluoroethylene group had longer anastomoses (85.6% vs 60.6% of the initial anastomotic length maintained; P < .0001) and less cross-sectional narrowing in the outflow graft (16.2% vs 28.5%; P = .0007) when compared with the other two groups by using two-tailed Student t tests. There was no evidence of medial necrosis or aneurysmal degeneration. All patent grafts had complete endothelialization on hematoxylin and eosin sections. Rapamycin was detectable and quantifiable in the arterial wall at 28 days after implantation. CONCLUSIONS: Rapamycin can be coated onto and eluted from ePTFE by using a nonionic polymer and a simple coating technique. At 4 weeks after implantation, the rapamycin-eluting ePTFE grafts demonstrate gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with non-drug-eluting ePTFE. Four weeks after implantation in a porcine model, rapamycin-eluting ePTFE grafts demonstrated gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with untreated and adhesive-only coated ePTFE grafts. CLINICAL RELEVANCE: Rapamycin-eluting ePTFE grafts decrease neointimal hyperplasia in a porcine model. Further studies are needed to evaluate whether patency will be improved. Rapamycin-eluting ePTFE grafts may allow the use of prosthetic grafts in situations in which autologous vein is unavailable and in which neointimal hyperplasia is pronounced, such as in small-diameter (<6-mm) vessels typical of infrapopliteal interventions.

Anastomosis, Surgical↗

PubMed2005

Meta-analyses: what they can and cannot tell us about clinical research.

PURPOSE OF REVIEW: The number of published clinical trials has increased exponentially over the past few decades. The majority of clinical research questions has been addressed by several small or moderately sized trials. Statisticians have developed guidelines for meta-analyses, which provide objective quantitative reviews to lighten the burden of clinicians who seek to keep themselves current in one or more areas of clinical investigation. The purpose of this review is to illustrate how to read critically a meta-analysis of nutrition support in critically ill patients. RECENT FINDINGS: Summary evidence based on a meta-analysis is observational, even though the individual elements of the meta-analysis are clinical trials. The level of evidence from a meta-analysis is thus similar to that derived from a case series or a cohort, with the stipulation that the 'subjects' are clinical trials instead of individuals. The effects of the combination of parenteral and enteral nutrition on mortality and infection rates in critically ill patients have been compared with enteral nutrition alone. Meta-analysis results show non-significant reductions in mortality and infectious complications favoring enteral nutrition. In patients with acute pancreatitis, the summary effects of parenteral versus enteral nutrition on the infection rate indicate a significant reduction in risk favoring enteral nutrition. SUMMARY: An interpretation of meta-analysis summary results is put in perspective with underlying medical assumptions. This critical review indicates what issues a meta-analysis can and cannot address.

Data Interpretation, Statistical↗

PubMed2005

Transfusions result in pulmonary morbidity and death after a moderate degree of injury.

BACKGROUND: Prior studies have suggested that blood transfusion (Tx) is associated with infectious and respiratory complications in trauma patients. However, these studies are difficult to interpret because of small sample size, inclusion of severely injured patients in traumatic shock, and combination of a variety of unrelated low-morbidity/mortality infections, such as wound, catheter-related, and urinary tract infection as outcomes. To eliminate these confounding variables, this study evaluates the association between delayed Tx and serious, well-defined respiratory complications (ventilator-associated pneumonia [VAP] and acute respiratory distress syndrome [ARDS]) and death in a cohort of intensive care unit (ICU) admissions with less severe (Injury Severity Score [ISS] < 25) blunt trauma who received no Tx within the initial 48 hours after admission. METHODS: Patients with blunt injury and ISS < 25 admitted to the ICU over a 7-year period were identified from the registry and excluded if within 48 hours from admission they received any Tx or if they died. VAP required quantitative bronchoalveolar lavage culture (> or =10(5) colonies/mL), and ARDS required Pao2/Fio2 ratio < 200 mm Hg, *** no congestive heart failure, diffuse bilateral infiltrates, and peak airway pressure > 50 cm H2O for diagnosis. Outcomes were VAP, ARDS, and death. RESULTS: Nine thousand one hundred twenty-six with blunt injury were ICU admissions, and 5,260 (58%) met study criteria (72% male). Means for age, ISS, and Glasgow Coma Scale score were 39, 12, and 14, respectively. There were 778 (15%) who received delayed Tx. Incidences of VAP, ARDS, and death were 5%, 1%, and 1%, respectively. Logistic regression analysis identified age, base excess, chest Abbreviated Injury Scale score, ISS, and any transfusion as significant predictors for VAP; chest Abbreviated Injury Scale score and transfusion as significant predictors for ARDS; and age and transfusion as significant predictors for death. CONCLUSION: Delayed transfusion is independently associated with VAP, ARDS, and death in trauma patients regardless of injury severity. These data mandate a judicious transfusion policy after resuscitation and emphasize the need for safe and effective blood substitutes and transfusion alternatives.

Adult↗

PubMed2005

Gender differences in the use of peak flow meters and their effect on peak expiratory flow.

STUDY OBJECTIVE: To determine if gender differences in the skill of using peak flow meters affect peak expiratory flow (PEF). DESIGN: Prospective observational study. SETTING: University classroom. SUBJECTS: One hundred sixteen first-year pharmacy students (76 women, 40 men). INTERVENTION: Students were taught correct use of a peak flow meter by means of classroom discussion and demonstrations. MEASUREMENTS AND MAIN RESULTS: The students' technique in use of the peak flow meter was scored 3 times, and their PEF was recorded. Men scored higher than women (p=0.03) for the steps of "inhale fully" and "exhale as hard and as fast as you can" in the first attempt. Percentage increases in PEF did not significantly differ between the groups. Percentage change in PEF improved from the second attempt to the third attempt in women (p=0.036) but not men. On the third attempt, 13.2% of women versus 2.6% of men had an increase in PEF of more than 50% (p=0.1). CONCLUSION: This study found that men learned the correct technique for using a peak flow meter and attained their best PEF more quickly than women.

Adult↗

PubMed2004

Cholic acid supplementation enhances cholesterol absorption in humans.

BACKGROUND & AIMS: Qualitative and quantitative changes in intralumenal bile acid composition may alter cholesterol absorption and synthesis and low-density lipoprotein (LDL) receptor expression. The role of cholic acid (CA) in cholesterol absorption in humans remains unclear and, thus, was examined in the current study. METHODS: In a crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day (CA) or no bile acid supplement (control) while being fed a controlled diet (AHA heart-healthy diet). A liquid meal of defined composition was given on day 14 of the diet, and lumenal samples were collected. Thereafter, cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods from days 16 to 20. RESULTS: With CA treatment, bile was enriched significantly with CA (P < 0.0004) to 60.2% +/- 2.4% (mean +/- SEM) compared with 43.3% +/- 2.4% for controls. CA plus diet treatment significantly increased (P = 0.013) cholesterol absorption (72.6% +/- 2.9%) compared with diet treatment alone (60.4% +/- 2.9%). Percentage micellar cholesterol was increased by CA plus diet treatment vs. diet alone after meal ingestion (P = 0.004). Plasma total and high-density lipoprotein (HDL) and LDL cholesterol was unchanged with CA treatment. CONCLUSIONS: Thus, enrichment in lumenal bile with CA results in an increase in cholesterol absorption, an effect potentially mediated by enhanced cholesterol solubilization in micelles.

Absorption↗

PubMed2004

Clinical relevance of angiotensin-converting enzyme gene polymorphisms to predict risk of mechanical ventilation after coronary artery bypass graft surgery.

OBJECTIVE: Prolonged mechanical ventilation is a significant complication after coronary artery bypass graft surgery. Angiotensin-converting enzyme mediates ischemia-reperfusion injury, which is an important mechanism of postcoronary artery bypass graft complications. An insertion/deletion polymorphism within the angiotensin-converting enzyme gene is associated with variable concentrations of angiotensin-converting enzyme. Whether this polymorphism is associated with prolonged mechanical ventilation is not known. The primary objective was to determine whether the insertion/deletion angiotensin-converting enzyme gene polymorphism is associated with prolonged mechanical ventilation. The release of inflammatory mediators and risk of prolonged mechanical ventilation are higher after conventional coronary artery bypass graft compared with off-pump coronary artery bypass graft. Therefore, we examined the risk of prolonged mechanical ventilation for angiotensin-converting enzyme genotypes in patients undergoing conventional coronary artery bypass graft and off-pump coronary artery bypass graft separately. Tumor necrosis factor down-regulates angiotensin-converting enzyme concentrations, and functional polymorphisms within the tumor necrosis factor gene have been associated previously with prolonged mechanical ventilation. Therefore, we examined interactions between these polymorphisms. DESIGN: Prospective observational cohort study. SETTING: Tertiary care center. SUBJECTS: Patients who underwent coronary artery bypass graft (with or without valve replacement surgery). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured angiotensin-converting enzyme genotype and time to extubate. Patients with the DD and DI genotypes were at higher risk of prolonged mechanical ventilation compared with those with the II genotypes (hazard ratio = 2.2 and 1.6, respectively, p =.0005). Interactions were seen between the angiotensin-converting enzyme genotypes with surgical technique and with tumor necrosis factor-308/lymphotoxin + 250 GG haplotype for prolonged mechanical ventilation (p =.078 and.0003, respectively). The association was stronger for those undergoing conventional coronary artery bypass graft, whereas neither angiotensin-converting enzyme genotype conferred higher risk to those undergoing off-pump coronary artery bypass graft. CONCLUSIONS: Angiotensin-converting enzyme gene polymorphisms are associated with respiratory complications postcardiopulmonary bypass. The increased risk associated with genotype may be amenable to alternative surgical technique or pharmacologic manipulation.

Aged↗

PubMed2003

Effect of ursodeoxycholic acid on cholesterol absorption and metabolism in humans.

Qualitative and quantitative changes in intraluminal bile acid composition may alter cholesterol absorption and synthesis and LDL receptor expression. In a randomized crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20 days while being fed a controlled diet (AHA Step II). A liquid meal of defined composition was then given and luminal samples collected. Cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods. With UDCA treatment, bile was enriched significantly (P < 0.0001) to 40.6 +/- 2.6% (mean +/- SEM) compared with 2.2 +/- 2.6% for controls. Regardless, plasma total, HDL, and LDL cholesterol were unchanged with UDCA treatment. Intraluminal cholesterol solubilized in the aqueous phase during the entire collection was decreased (P = 0.012) in UDCA-treated subjects (101.0 +/- 7.2 mg/ml/120 min) compared with controls (132.5 +/- 7.2 mg/ml/120 min.). Percent micellar cholesterol was increased in UDCA-treated versus controls after meal ingestion. No changes were found in cholesterol absorption, FSR, or LDL receptor mRNA with UDCA treatment compared with controls. Thus, despite marked enrichment in luminal bile with UDCA and decreased cholesterol solubilization, no differences in cholesterol absorption or metabolism are found when diet and genetic differences in absorption are carefully controlled.

Adult↗

PubMed2003

A formula for prediction of posttraumatic pneumonia based on early anatomic and physiologic parameters.

BACKGROUND: Identification of risks for development of ventilator-associated pneumonia (VAP), which might be identified early after injury, would allow for prognostic estimates and targeting of high-risk cohorts for clinical trials of preventive strategies. This study was performed to develop an equation that can be applied to estimate the probability of pneumonia based on parameters collected in the early postinjury interval. METHODS: Over a 28-month period, patient admissions were reviewed for mechanism and severity of injury, patterns of injury, shock, and need for emergent intubation. Early deaths (<48 hours) were excluded. VAP diagnosis required > or = 10(5) colony-forming units/mL organisms in the bronchoalveolar lavage effluent. Multiple logistic regression analysis was used to develop the prediction equation and estimate odds ratios. The equation was then tested on consecutive patients admitted over a 2-month period. RESULTS: We reviewed 9,721 admissions (77% blunt, 23% penetrating). VAP incidence was 5.6%. Overall mortality was 2% (21% for patients with VAP vs. 1% for no VAP; p < 0.0001). Multiple logistic regression analysis for all patients produced the following equation: f(x) = -3.08 - 1.56 (MOI) - 0.12 (GCS) + 1.37 (SCI) + 0.30 (chest AIS) + 1.87 (lap) + 0.67 (tx) + 0.05 (ISS) + 0.66 (int), where MOI is mechanism of injury (penetrating = 1, blunt = 0), GCS is Glasgow Coma Scale score, SCI is spinal cord injury (yes = 1, no = 0), lap is emergent laparotomy (yes = 1, no = 0), ISS is Injury Severity Score, tx is units of blood transfused in the resuscitation room, and int is intubation in either the field or the resuscitation room (yes = 1, no = 0). The probability of VAP was calculated as follows: P(VAP) = e(f)(x)/1 + e(f)(x). This formula was concordant in 95% and discordant in 5%. CONCLUSION: It is possible to accurately predict risk for VAP in trauma patients based on data available early after injury. This calculation could be useful for counseling families relative to prognosis and research protocols, and addressing hospitalization issues with third-party payors.

Adult↗

PubMed2002

Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids.

Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation- induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta. These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS. Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Preoperative albumin and surgical site identify surgical risk for major postoperative complications.

BACKGROUND: Although malnutrition contributes to morbidity, studies of pre- and postoperative nutrition often include well-nourished patients unlikely to benefit from therapy and usually do not stratify by the site of surgical pathology. This study evaluates whether perceived preoperative markers of nutritional status recorded in charts correlates with postoperative complications and resource use in patients who receive no preoperative nutrition support and reinterprets the results of several conflicting randomized, prospective studies in this context. METHODS: This is a retrospective cohort study of 526 surgical patients who had preoperative serum albumin levels measured and were undergoing elective esophageal, gastric, pancreaticoduodenal, or colon surgery between 1992 and 1996 who could have received preoperative nutrition but did not. RESULTS: Most medical records contained inadequate analysis of preoperative nutritional status, but preoperative albumin correlated inversely with complications, length of stay, postoperative stay, intensive care unit (ICU) stay, mortality, and resumption of oral intake. Patients undergoing esophageal or pancreatic procedures sustained a significantly higher complication rate at most albumin levels, whereas colonic surgery resulted in lower complication rates at the same albumin levels. Resource use (eg, length of stay and ICU stay) related to these complication rates; esophageal and pancreatic procedures used the most resources and colon procedures used the fewest at most albumin levels. This lack of appreciation for nutritional risk and operative site can explain discrepancies in outcome noted in several randomized, prospective nutritional studies and must be applied to the design and implementation of new studies. CONCLUSIONS: Elective, non-emergent esophageal and pancreatic procedures performed in patients who could have had surgery delayed for preoperative nutrition, but did not, result in higher risk than colon surgery at any given level of serum albumin below 3.25 g/dL. Patient populations in trials should be stratified by operative site and by markers of nutritional status. Degree of hypoalbuminemia and other potential markers of nutritional status may explain many of the discrepancies between trials of nutrition support. Preexisting hypoalbuminemia in patients undergoing elective surgery remains underappreciated, unrecognized, and untreated in many hospitalized patients.

Cohort Studies↗

PubMedDate not supplied

Lipoprotein compositional changes with combination hormone therapy (conjugated estrogen and medroxyprogesterone) in African American women.

OBJECTIVE: To determine whether combination hormone therapy (HT) significantly alters lipoprotein composition in healthy African American women. METHODS: Postmenopausal African American women, 45 to 65 years old, were randomly assigned to receive daily HT (conjugated equine estrogen, 0.625 mg, and medroxyprogesterone, 2.5 mg) or placebo (treated, 44; placebo, 16) for 12 weeks. Lipoproteins were separated by gradient ultracentrifugation into very-low-density, intermediate-density, and low-density lipoproteins (VLDL, IDL, and LDL) and 3 high-density lipoprotein (HDL) subfractions (light, medium, and dense--L, M, and D). Apolipoprotein (apo) A-I, A-II, C-III, C-II, and C-I were measured by high-performance liquid chromatography. Apo B, phospholipids, triglycerides, cholesterol, and free cholesterol were measured by standard assays. RESULTS: Total plasma cholesterol, triglycerides, LDL apo B, and total apo B did not change during HT. A small, transient reduction occurred in LDL cholesterol, and a persistent reduction was noted in VLDL apo B, apo C-II, and apo C-III. Total HDL phospholipids, cholesterol, apo A-I, and apo A-II increased, whereas the LDL/HDL ratio and the apo B/apo A-I ratio decreased. Cholesterol ester increased in both HDL-L and HDL-M, but only a transient increase occurred in HDL-L phospholipids. Apo A-I increased in HDL-L, HDL-M, and HDL-D; however, a similar increase occurred in HDL-D apo A-I in the control subjects. Moreover, an increase occurred in apo A-II in HDL-M. A reduction in the apo A-II:A-I ratio in HDL-L but not in HDL-M indicated an increase in HDL-L LpA-I particles. The increase in HDL particles in HDL-M was entirely due to an increase in LpA-I:A-II particles. Apo C-III increased in both HDL-L and HDL-M. The absence of changes in the HDL lipid ratios indicated an unaltered lipid composition of these particles. No changes were found in IDL compositional measurements. In 12 treated patients and 4 control subjects, Lp(a) was detected by ultracentrifugation; no changes were noted in Lp(a) composition or quantity with HT. Total Lp(a) measured by enzyme immunosorbent assay showed a trend toward an increase in treated patients after 12 weeks of HT. CONCLUSION: African American women had a beneficial response to HT by increasing the number of LpA-I particles in HDL-L and LpA-I:A-II particles in HDL-M as well as cholesterol esters in both. There was a small reduction in VLDL apo B (and thus particle number) but only a transient reduction in LDL cholesterol. A shift of apo C-III from VLDL to HDL was noted. No detrimental changes occurred in any lipoprotein subfraction (specifically, no increase in triglycerides).

Black or African American↗