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Biomedical subjects

D P Schuster

Publications and source records attributed to D P Schuster.

At least 19 recordsLinked to original sources
PubMed2005

Long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance: double blind, prospective, randomised study.

OBJECTIVE: To study the long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance. PATIENTS: 181 African American subjects with insulin resistance and normal glucose tolerance test were randomised to receive glipizide 5 mg/day (n = 25), metformin 500 mg/day (n = 59), or placebo (n = 97) for 24 months. Insulin sensitivity, glucose tolerance, lipid profile, left ventricular mass (echocardiography), aortic distensibility (echocardiography, blood pressure), aortic pulse wave velocity (PWV, carotid to femoral artery, Doppler) were measured at baseline and at 12 and 24 months after randomisation. RESULTS: A significant increase in PWV was observed in both glipizide (mean (SEM) change at 24 months 2.8 (2.7) m/s, p = 0.012) and metformin (2.2 (0.7) m/s, p = 0.01) groups during the follow up period. In contrast, PWV remained unchanged in the placebo group. The increase in PWV in the treatment groups was significant compared with placebo (analysis of variance p < 0.05). Other cardiovascular or metabolic variables did not change significantly compared with placebo during follow up. CONCLUSIONS: The observed increase in PWV is consistent with a decrease in the elastic properties of the aorta. The use of oral antidiabetic agents for the prevention of cardiovascular complications in non-diabetic African Americans with insulin resistance needs to be critically evaluated.

Administration, Oral↗
PubMed2003

Insulin sensitivity and cardiovascular risk factors in hypertensive and normotensive native Ghanaians.

AIMS/HYPOTHESIS: The objective of this study was to examine the relationships among insulin and insulin sensitivity and risk factors for cardiovascular diseases in native Ghanaians with and without hypertension. METHODS: We measured the anthropometric parameters, systolic and diastolic blood pressure, fasting serum triglycerides, cholesterol and high-density lipoprotein cholesterol and fasting and stimulated glucose, insulin and C-peptide of 200 Ghanaian subjects, who were between 25 to 74 years of age, and residing in the Accra Metropolitan area. Serum glucose, C-peptide and insulin concentrations were measured at baseline (fasting) and also 2 h after 75 gm oral glucose drink. Homeostasis model assessment was used to measure insulin resistance. Hypertension was defined as a blood pressure higher than 140/90 mmHg. RESULTS: There were 53 subjects with hypertension (HBP) and 147 subjects with normal blood pressure (NBP). The mean BMI, waist circumference and waist-to-hip circumference ratio for HBP and NBP subjects were 27.4+/-0.8, 24.8+/-0.4 kg/m(2); 89.8+/-11.7, 81.1+/-0.9 cm; and 0.87+/-0.08, 0.82+/-0.08 respectively, (p<0.05). The fasting and 2-h plasma glucose concentrations in HBP and NBP subjects were 5.5+/-0.2, 7.2+/-0.3 mmol/l and 5.2+/-01, 6.8+/-0.2 mmol/l respectively (p>0.05). The corresponding fasting and 2-h insulin concentrations were 10.0+/-0.7, 8.0+/-0.4 uU/ml and 47.3+/-3.7, 37.3+/-2.5 uU/ml respectively (p<0.05). The insulin resistance index (HOMA-IR) in the HBP and the NBP groups were 2.49+/-0.2 and 1.95+/-0.13 (p<0.05). The two groups had similar fasting and stimulated C-peptide, lipids and HDL concentrations. Correlations were found between blood pressure and the concentrations of lipids, HDL, fasting and stimulated insulin and C-peptide, and between fasting insulin and HOMA-IR with lipids and HDL concentrations. On multiple regression analysis, fasting insulin and HOMA-IR did not influence blood pressure variations significantly. CONCLUSIONS/INTERPRETATION: We found clustering of hyperinsulinaemia, insulin resistance and truncal obesity in hypertensive Ghanaian subjects but dissociation between insulin resistance, hypertension and atherogenic lipid and lipoprotein profile.

Adult↗
PubMed2003

Imaging the spatial distribution of transgene expression in the lungs with positron emission tomography.

This study was designed to evaluate the utility of positron emission tomography (PET) to quantify the magnitude and spatial distribution of transgene expression after different methods of adenoviral vector delivery (with surfactant- and saline-based vehicles) within rat lungs. In all, 17 animals (eight in the surfactant group, nine in the saline group) were studied 3 days after intratracheal administration of a replication-incompetent adenovirus encoding a mutant Herpes simplex virus-1 thymidine kinase (mHSV1-TK)-enhanced green fluorescent protein fusion gene driven by a Cytomegalovirus promoter (Ad-CMV-mNLS-HSV1sr39tk-egfp). PET images were obtained 1 h after i.v. administration of 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]-FHBG), an imaging substrate for mHSV1-TK. Overall, the average lung concentration of [(18)F]-FHBG was significantly greater in the surfactant group than in the saline group (0.24+/-0.06 versus 0.17+/-0.03% injected dose/ml lung, P< or =0.05). Lung [(18)F]-FHBG distribution was more peripheral and more homogeneous in the surfactant group than in the saline group (mean coefficient of variation=31+/-4 versus 36+/-3%, respectively, P< or =0.05). Regions of increased tracer concentration in the surfactant group compared to the saline group were evenly distributed throughout the lungs. We conclude that PET imaging provides useful and meaningful information about the effectiveness of different gene transfer delivery strategies within the lungs, and that surfactant-based vehicles may be a superior strategy for pulmonary gene transfer.

Adenoviruses, Human↗
PubMed2001

Cardiovascular effects of aging. Interrelationships of aortic, left ventricular, and left atrial function.

BACKGROUND: Previous studies have shown that elastic properties of the aorta decrease, while left atrial dimensions, the contribution of left atrial systole to left ventricular filling, and left ventricular mass increase with age. In most studies, however, aortic function, and ventricular and atrial parameters were performed in different populations, and thus, the earliest manifestation of aging in the cardiovascular system is not known. The present study was undertaken to define the earliest cardiovascular abnormality(ies) occurring in the cardiovascular system with age. PATIENTS AND METHOD: In 181 normotensive subjects (147 females and 34 males) age 22-64 years, left ventricular mass, volumes, function and work (echocardiography and blood pressure), left atrial volumes and stroke volume (biplane area-length method by echo), pulse wave velocity (PWV) (carotid to femoral artery, Doppler), and left atrial kinetic energy were measured simultaneously: left atrial kinetic energy = 1/2 mv2, where m = left atrial stroke volume x 1.06 (blood specific gravity), v = transmitral A wave velocity. Regression analyses were performed to correlate all measured cardiovascular parameters with age. RESULTS: Pulse wave velocity (r = 0.51), left atrial kinetic energy (r = 0.42), and A wave velocity (r = 0.38) were correlated to age, while left ventricular mass, function and work were not. Multiple regression analysis among ten clinical and echocardiographic parameters demonstrated that only age contributed independently to pulse wave velocity; only age and pulse wave velocity were contributed independently to left atrial kinetic energy; and only age contributed independently to A wave velocity. CONCLUSIONS: The data demonstrate that age-related alterations in aortic function and left atrial work (left atrial kinetic energy) can be defined prior to changes in left ventricular structure and systolic function. Simultaneous studies of left atrial, left ventricular, and aortic function are required to better understand the effect of aging on the cardiovascular system.

Adult↗
PubMed2001

Effect of endotoxin on oleic acid lung injury does not depend on priming.

Recent studies have demonstrated significant synergistic physiological and biochemical effects between low-dose endotoxin (Etx) administration and oleic acid (OA)-induced canine lung injury. To evaluate whether this interaction depends on Etx priming of some key cell population, we compared the effects of giving low-dose Etx both after as well as before inducing lung injury with OA. In addition to hemodynamic and blood-gas measurements, positron emission tomographic imaging was used to measure edema accumulation and intrapulmonary blood flow distribution. Biochemical measurements of the stable metabolites of prostacyclin and thromboxane were obtained as well as measurements of isoprostanes and reactive sulfhydryls as evidence for possible concomitant oxidant production. We found that the physiological and biochemical effects of low-dose Etx developed 30-45 min after its administration, regardless of whether Etx was administered before or after OA. No increase in either isoprostane or reactive sulfhydryl production after Etx and/or OA was detected. These data suggest that the synergistic effect of low-dose Etx and OA-induced lung injury is not due to a priming effect of Etx.

Animals↗
PubMed2001

Clinical correlation with changing radiographic appearance during partial liquid ventilation.

STUDY OBJECTIVES: To evaluate the chest radiographic filling pattern associated with partial liquid ventilation (PLV) with the perfluorochemical perflubron (LiquiVent; Alliance Pharmaceutical Corp; San Diego CA) as a function of dose and timing. DESIGN: Post hoc review of chest radiographs by three independent observers with correlation to clinical variables. SETTING: Phase II randomized, uncontrolled, prospective, multicenter clinical trial. PATIENTS: Sixteen adult patients with diffuse bilateral infiltrates consistent with acute lung injury and a PaO(2)/fraction of inspired oxygen (FIO(2)) ratio < 300 with positive end-expiratory pressure of 13 cm H(2)O and FIO(2) > or = 0.5. INTERVENTIONS: All patients were treated with either a 10-mL/kg or 20-mL/kg loading dose of perflubron followed by maintenance dosing at 3-h intervals to protocol-determined levels. RESULTS: There was a significant relationship between inhomogeneous radiographic filling during the first 48 h of treatment and the use of the lower loading dose of perflubron. Inhomogeneous radiographic filling (in 5 patients) was associated with a lower high-dose/FIO(2) ratio at 24 h compared with the remaining patients. These differences resolved by 48 h. There were no other statistically significant correlations identified. CONCLUSIONS: The radiographic appearance of PLV with perflubron appears to depend on the dose administered. Lower doses can be associated with both inhomogeneous radiographic filling and a transient deterioration in oxygenation during the first 24 to 48 h of treatment.

Adolescent↗
PubMed2000

Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study.

Angiotensin-converting enzyme (ACE) inhibition attenuates pulmonary hypertension and delays the development of pulmonary vascular remodeling in animal models. Thus, ACE inhibition might be a useful treatment for primary pulmonary hypertension (PPH). To determine the dose of ACE inhibitor required to specifically block pulmonary ACE in humans, we measured the combined forward rate constant (CFRC) for [(18)F]-fluorocaptopril, which is proportional to the mass of ACE in the lung, using positron emission tomography (PET). In five normal subjects, CFRC was measured twice, 1 wk apart, to assess measurement reproducibility. The CFRC was 0.151 +/- 0.067 for the first measurement and 0.140 +/- 0.060 for the second measurement (p = not significant [NS]). In five normals, CFRC decreased on average 84%, from 0.177 +/- 0.053/s to 0.028 +/- 0.017/s (p < 0.05), after 1 wk ingestion of 5 mg enalapril orally once a day (the scans were performed 24 h after the last medication). Similarly, in five patients with PPH, CFRC decreased on average 76%, from 0.052 +/- 0. 020/s to 0.012 +/- 0.003 (p < 0.01), after 1 wk enalapril, despite much lower baseline values. We conclude that the total mass of pulmonary ACE appears to be significantly reduced in PPH and that only low doses of ACE inhibitors may be needed to block the effects of ACE on vascular remodeling in PPH.

Adult↗
PubMed2000

Effect of partial liquid ventilation on pulmonary vascular permeability and edema after experimental acute lung injury.

We evaluated the effects of partial liquid ventilation (PLV) with two different dosages of the perfluorocarbon LiquiVent (perflubron) on pulmonary vascular permeability and edema formation after oleic acid (OA)-induced acute lung injury in dogs. We used imaging with positron emission tomography to measure fractional pulmonary blood flow, lung water concentration (LWC), and the pulmonary transcapillary escape rate (PTCER) of (68)Ga-labeled transferrin at 5 and 21 h after lung injury in five dogs undergoing conventional mechanical ventilation (CMV), five dogs undergoing low-dose PLV (perflubron at 10 ml/kg), and four dogs undergoing high dose PLV (perflubron at 30 ml/kg). A positive end-expiratory pressure of 7.5 cm H(2)O was used in all dogs. After OA (0.08 ml/kg)- induced lung injury, there were no significant differences or trends for PTCER or LWC at any time when the PLV groups were compared with the CMV group. However, lung tissue myeloperoxidase activity was significantly lower in the combined PLV group than in the CMV group (p = 0.016). We conclude that after OA-induced lung injury, the addition of PLV to CMV does not directly attenuate pulmonary vascular leak or lung water accumulation. Rather, the benefits of such treatment may be due to modifications of the inflammatory response.

Animals↗
PubMed1999

Response to inhaled nitric oxide in acute lung injury depends on distribution of pulmonary blood flow prior to its administration.

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Role of cyclooxygenase-2 in oleic acid-induced acute lung injury.

Eicosanoid production appears to be important to both edemagenesis and the pattern of pulmonary perfusion in experimental acute lung injury (ALI). We hypothesized that these effects could be mediated by the inducible form of cyclooxygenase (COX-2). We used positron emission tomography to evaluate the pulmonary perfusion pattern in dogs given oleic acid (OA) only (n = 6), the novel COX-2 inhibitor SC-236 50 min before OA (n = 3), and SC-236 given 20 min before endotoxin (Etx), followed by OA given 30 min after Etx (n = 5). Thromboxane B(2) (TXB(2)) and prostacyclin (6-keto prostaglandin F(1alpha); 6-keto PGF(1alpha)) metabolite concentrations in plasma and lung tissue were measured in these groups and in another group given Etx + OA (n = 4). Inhibition of COX-2 before administration of OA alone or before administration of Etx and OA did not have any significant effect on plasma or lung tissue concentrations of TXB(2). However, inhibition of COX-2 prior to Etx and OA significantly reduced the plasma and lung tissue concentrations of 6-keto PGF(1alpha) as compared with those in the group given only Etx + OA. Moreover, SC-236 prevented the expected loss of perfusion redistribution associated with Etx + OA only. The effect of endotoxin on pulmonary perfusion in ALI is therefore the result of a COX-2-mediated increase in prostacyclin production in lung tissue.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

The evaluation of lung function with PET.

In many ways, the lung is an ideal organ for study with positron emission tomography (PET). First, structure-function relations are homogeneous over larger areas than in other organs (reducing problems associated with otherwise relatively poor spatial resolution and partial-volume averaging). Second, many physiologic and metabolic processes can be studied, including pulmonary blood flow, ventilation, vascular permeability, endothelial receptor and enzyme function, among others. A variety of radiotracers have been used to evaluate pulmonary blood flow with PET, including 68Ga- or 11C-albumin microspheres administered intravenously, H2 15O administered by i.v. infusion, and 13N-N2 administered by inhalation. Pulmonary ventilation has been evaluated with both 13N-N2 and 19Ne gas, also administered by inhalation. In general, the relative advantage of one approach over another depends on site-specific cyclotron capacity and experience, and on the nature and timing of concomitant studies with other positron-emitting radiopharmaceuticals. The various blood flow methods have been used primarily in studies of pulmonary gas exchange, in both experimental animals and in humans. Acute lung injury is usually defined by both an increase in extravascular water (pulmonary edema) and an increase in the permeability of the pulmonary endothelium to protein. Both processes can easily be evaluated with PET. Extravascular water is measured by a combination of scans with i.v. H2 15O and C15O. The latter is administered by inhalation to label the blood pool (to calculate intravascular water concentrations). Pulmonary vascular permeability has been evaluated with dynamic sequential imaging after either 68Ga-transferrin or 11C-methylalbumin infusions. The rate of uptake of either tracer into the pulmonary extravascular space is an index of "leakiness" of the pulmonary endothelium, and is quantified as the pulmonary transcapillary escape rate, or PTCER. PTCER appears to be a highly sensitive index of acute lung injury. Two receptor/ enzyme systems that have been evaluated include the beta-adrenergic receptor system (using 11CGP-12177 as the ligand) and angiotensin converting enzyme (using 18F-fluorocaptopril). In each case, the object is to measure Bmax, or the maximum binding-capacity for the ligand in question. Changes in Bmax can be used to infer changes in protein expression of the receptor or enzyme, or can be used to quantify adequacy of therapy with inhibitor drugs. Given the highly active nature of the pulmonary endothelium, it is likely that many other pulmonary receptor or enzyme systems can be studied in a similar fashion.

Animals↗
PubMed1998

Differential impact of obesity on glucose metabolism in black and white American adolescents.

BACKGROUND: The authors have previously demonstrated abnormalities in glucose and insulin metabolism in nondiabetic black American (BA) adults versus white American (WA) adults. Whether similar glucoregulatory alterations extend to BA adolescents remain unknown. In addition, obesity, a known risk factor for insulin resistance and hyperinsulinemia, occurs in a greater proportion of BA adults and children when compared to WA. The objective of the present study was to examine the differential effects of obesity on glucose homeostasis in BA and WA adolescents. METHODS: We examined glucose homeostasis in BA and WA adolescents using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), and [6,6-2H2]-glucose infusion. The study consisted of four age-, sex-, and pubertal stage-matched groups: 15 lean BA, 29 lean WA, 7 obese BA, and 9 obese WA. RESULTS: Both obese groups had significantly increased insulin and C-peptide area under the curve (AUC) during OGTT and IVGTT when compared to their same-race lean counterparts. During OGTT, obese BA demonstrated greater insulin and C-peptide when compared to obese WA. During IVGTT, first- and second-phase insulin were significantly greater in obese BA versus obese WA. CONCLUSION: In summary, BA adolescents demonstrated insulin resistance which is markedly exaggerated in the face of obesity when compared to WA adolescents, implying a differential impact for obesity on glucose homeostasis that is unique to the obese BA adolescent group. In conclusion, there is a need for early aggressive weight management in obese BA adolescents.

Adolescent↗
PubMed1998

Positron emission tomography measurements of pulmonary vascular permeability with Ga-68 transferrin or C-11 methylalbumin.

OBJECTIVE: To compare estimates of pulmonary endothelial barrier integrity obtained using two different tracer proteins. DESIGN: Measure the pulmonary transcapillary escape rate with gallium (Ga)-68 labeled transferrin (PTCER(tf)) and positron emission tomography (PET) imaging and compare the results to similar measurements obtained with C-11 labeled methylalbumin (PTCER(alb)). SETTING: Laboratory investigation. SUBJECTS: Mongrel dogs. INTERVENTIONS: No intervention in one group of dogs (n = 3); oleic-acid induced lung injury in another set (n = 4). MEASUREMENTS AND MAIN RESULTS: Although PTCER(tf) was consistently higher than PTCER(alb) (mean difference: 50 x 10(-4)/min), the overall correlation between the two methods, after normalizing for differences in regression slope and intercept among the individual dogs, was excellent (r2 = .67). CONCLUSION: The data support the continued use of PET and Ga-68 transferrin as an appropriate means of evaluating and quantifying lung injury.

Albumins↗
PubMed1998

Synergistic hemodynamic effects of low-dose endotoxin and acute lung injury.

We evaluated the effects of low-dose endotoxin (15 microg/kg) on the pulmonary and systemic responses to oleic acid (OA)-induced acute lung injury in dogs. Animals given endotoxin alone (n = 5) showed a modest decrease in arterial blood pressure, but no effects on pulmonary hemodynamics, blood gases, cardiac output, or lung water accumulation. Animals (n = 6) given only OA (0.08 ml/kg) showed the expected development of mild-moderate pulmonary hypertension, a comparable reduction in arterial blood pressure, hypoxemia, increased lung water concentration, and an altered intrapulmonary perfusion pattern, as assessed by positron emission tomography. Animals (n = 7) given the same dose of endotoxin, followed 30 min later by the same dose of OA, developed a similar increase in lung water concentration as the group given OA alone, but failed to develop pulmonary hypertension or to redistribute pulmonary blood flow away from the edematous lung regions. In addition, arterial blood pressure fell significantly more than in the other groups. These responses were associated with a 30-fold increase in circulating prostacyclin (assayed as 6-keto prostaglandin F1 alpha [PGF1alpha]). The effects on systemic blood pressure, intrapulmonary blood flow redistribution, and eicosanoid production were eliminated by pretreating (n = 5) animals with meclofenamate (2 mg/kg). The results are consistent with a "priming" effect of low-dose endotoxin on the pulmonary endothelium, with exaggerated prostacyclin production in response to a subsequent lung injury. This interaction leads to altered intrapulmonary hemodynamics that exacerbate the development of hypoxemia, and to significant decreases in systemic blood pressure. To the extent that the lung is the most likely source of the increased prostacyclin production, the synergistic effects of low-dose endotoxin and lung injury may produce a kind of "lung shock."

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation.

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.

Angiotensin Receptor Antagonists↗