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Biomedical subjects

R S Lees

Publications and source records attributed to R S Lees.

At least 37 records · Page 2Linked to original sources
PubMed1994

Homozygous Tangier disease and cardiovascular disease.

Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (+/- S.D.) lipid values of all cases were as follows: total cholesterol 68 +/- 30 mg/dl (32% of normal), triglycerides 201 +/- 118 mg/dl (162% of normal), HDL cholesterol 3 +/- 3 mg/dl (6% of normal) and LDL cholesterol 50 +/- 38 mg/dl (37% of normal). The most common clinical finding in these subjects (n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects (n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls (P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group (P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Low-density lipoprotein modification and arterial wall accumulation in a rabbit model of atherosclerosis.

Chemically or enzymatically modified low-density lipoproteins (LDL), with and without changes in surface charge, were studied in vivo in the healing, balloon catheter-deendothelialized rabbit aorta to determine the effect of LDL modification on its accumulation in arterial lesions. In this model, in which healing (reendothelialization) proceeds radially outward from individual aortic branch arteries, it was previously shown by autoradiography that two kinetically distinct compartments accumulated 125I-labeled LDL. In aortic regions which were still deendothelialized, accumulation was diffuse and labile. In contrast, at the edges of the islands of regenerating endothelium, LDL accumulation was intensely focal, as it is in human atherosclerotic lesions, and persisted for at least 40 h after injection in spite of falling levels of radiolabeled LDL in plasma [Chang, M. Y., et al. (1992) Arterioscler. Thromb. 12, 1088-1098]. In the present study, modified LDLs with gradations in charge change were prepared to clarify the role of changes in surface charge on focal aortic LDL accumulation. Oxidized LDL (weakly anionized), desialated LDL (weakly cationized), and reductively methylated LDL (no change in net charge) all accumulated focally. Focal accumulation of native LDL also occurred in ballooned rabbits fed probucol to inhibit LDL oxidation. Strongly anionized succinylated and diazobenzenearsonylated LDL and strongly cationized dimethylpropanediamine LDL did not accumulate focally. The results support the concept that focal sequestration of LDL in arterial lesions is mediated by specific, oxidation-independent patterns of charge and polarity on LDL which are disrupted by major changes in LDL surface charge.

Aniline Compounds↗
PubMed1993

Enzymatic modification of plasma low density lipoproteins in rabbits: a potential treatment for hypercholesterolemia.

Phospholipase A2 (EC 3.1.1.4) hydrolyzes certain phospholipids of low density lipoprotein (LDL). Plasma clearance of phospholipase A2-modified human LDL is up to 17 times faster than that of native human LDL in hypercholesterolemic rabbits. Modification of blood lipoproteins of hypercholesterolemic rabbits was performed by using an extracorporeal circuit containing immobilized phospholipase A2. After 90-min treatments, nearly 30% decreases in plasma cholesterol concentrations were observed. Erythrocyte, leukocyte, and platelet counts showed no net change after treatment. This technique does not require any fluid replacement or sorbent regeneration and offers a potential approach for lowering serum cholesterol and LDL levels.

Animals↗
PubMed1993

External imaging of atherosclerosis in rabbits using an 123I-labeled synthetic peptide fragment.

The oligopeptide fragment of apolipoprotein B, SP-4, has demonstrated pronounced uptake in the healing edges of balloon-injured rabbit aortic endothelium. To assess 123I-labeled SP-4 for identification of atherosclerotic plaques by gamma camera imaging, 14 Watanabe heritable hyperlipidemic (WHHL) and 5 normal rabbits were imaged 5 minutes and 12 and 24 hours after intravenous injection of 123I-SP-4. In addition, two WHHL and two normal rabbits were injected with 125I-SP-4 for autoradiography. Twelve of the 14 WHHL, but none of the normal, rabbits had visually apparent focal radioiodine accumulation in the region of the aorta. Focus-to-lung and focus-to-heart count ratios were 2.4 +/- 1.3 and 1.0 +/- 0.4, respectively. Five of the visually positive WHHL rabbits were reimaged 4 and 8 weeks later with 123I-NaI and 123I-SP-2 (an apo E peptide), respectively, as negative controls. Perceptible, but faint, aortic localization of 123I-NaI and of 123I-SP-2 was seen in only one animal each. The distributions of atherosclerotic lesions on photographs of the opened WHHL aortas and of film blackening on 125I-SP-4 autoradiograms were identical. In contrast, the two normal rabbit aortas did not exhibit plaques on photographs or film blackening on autoradiograms. Thus, in an animal model closely simulating human atherosclerotic disease, SP-4 localizes specifically in aortic atherosclerotic lesions.

Amino Acid Sequence↗
PubMed1993

The QUinapril Ischemic Event Trial (QUIET) design and methods: evaluation of chronic ACE inhibitor therapy after coronary artery intervention.

The rationale, trial design, and statistical aspects of QUIET, the QUinapril Ischemic Event Trial, are described. QUIET is a prospective, double-blind placebo-controlled study that will assess the ability of the angiotensin-converting enzyme (ACE) inhibitor quinapril to reduce the rate of cardiac ischemic events and to slow or prevent the development of coronary artery atherosclerosis as assessed by serial angiography in a normolipidemic population without left ventricular dysfunction. The study began in September 1991 and has completed recruitment with 1740 patients across 38 centers (28 U.S., 4 Canada, 6 Europe) by the end of 1992. Patients are randomized to 20 mg of quinapril or placebo once daily and continue in the study for 3 years. Study completion is projected for 1995.

Adult↗
PubMed1993

Surface-induced conformational switching in amphiphilic peptide segments of apolipoproteins B and E and model peptides.

The conformational and surface-binding properties of a synthetic peptide corresponding to Tyr-apolipoprotein B-100(1000-1016) amide, SP-4, which was previously shown to mimic the focal accumulation pattern of LDL on the healing de-endothelialized rabbit aorta [Shih et al. (1990) Proc. Natl. Acad. Sci. USA 87, 1436-1440], have been investigated. SP-4 behaves as an amphiphilic alpha-helical peptide at the air-water interface and bound to siliconized quartz slides. However, its N alpha-acetylated analogue formed beta-sheet structures at the air-water interface. Nonhomologous peptide models of SP-4 also exhibited mixed alpha-helical and beta-sheet surface-binding behavior. Peptides corresponding to the cationic apolipoprotein (apo) B/E receptor binding regions of apoE (SP-2) and apoB (SP-11) were also studied. SP-2 behaved as an amphiphilic alpha helix, but, surprisingly, SP-11 formed surface-induced beta-sheets. These results demonstrate that all of the peptides studied have surface-binding properties, and suggest further that either alpha-helical or beta-sheet peptide structures may determine the binding of LDL to the arterial wall or the apoB/E receptor.

Amino Acid Sequence↗
PubMed1992

Time course of 125I-labeled LDL accumulation in the healing, balloon-deendothelialized rabbit aorta.

We previously showed by qualitative en face autoradiography that after 24 hours of circulation, 125I-labeled low density lipoprotein (LDL) injected in tracer amounts accumulated focally at the edges of regenerating endothelial islands in the balloon catheter-deendothelialized aorta of the normocholesterolemic rabbit. In the present study with the same animal model, we have used quantitative autoradiography to examine 125I-LDL accumulation in the healing aorta as a function of LDL circulation time from 2.5 to 40 hours. The results demonstrated that 125I-LDL accumulation in the healing aorta occurred in two kinetically and biochemically distinct compartments, one of which was in equilibrium with plasma and one of which sequestered LDL. LDL accumulation in the still-deendothelialized aorta (DEA) was diffuse and only moderately intense on autoradiography. It peaked 4 hours after injection; over the following 36 hours the disappearance of 125I-LDL from DEA paralleled the disappearance of 125I-LDL from plasma. In contrast, accumulation of 125I-LDL at the edges of regenerating endothelial islands was focal and intense. LDL accumulation in this compartment also peaked 4 hours after injection but remained elevated even at 40 hours, despite falling plasma levels of LDL. At 24 hours, edge LDL accumulation per unit area was more than five times greater than DEA accumulation. The data indicate that LDL accumulation in specific compartments of the functionally modified arterial wall occurs independently of either acute or chronic hypercholesterolemia. The contrast between labile LDL accumulation in DEA and persistent accumulation at the edges of healing aortic islands indicates that LDL accumulation in the two areas must involve different processes within the arterial wall itself.

Animals↗
PubMed1991

99mTechnetium-labeled low density lipoprotein: receptor recognition and intracellular sequestration of radiolabel.

99MTechnetium-labeled low density lipoprotein (99MTc-labeled LDL) was developed to detect atherosclerosis by external imaging with the gamma scintillation camera (Lees, et al. J. Nucl. Med. 1985. 26: 1056-1062; Lees, et al. Arteriosclerosis. 1988. 8: 461-470). The present study examined high affinity LDL receptor recognition and intracellular sequestration of 99MTc-labeled LDL by fibroblasts. There were no significant differences between 99MTc-labeled LDL and 125I-labeled LDL in binding parameters or percent inhibition of accumulation, which indicated that 99MTc labeling did not alter receptor recognition of LDL. At 4 degrees C the Kd (+SE) for 99MTc-labeled LDL and 125I-labeled LDL, respectively, was 1.52 +/- 0.24 and 1.45 +/- 0.14 micrograms/ml; Bmax (+/- SE) was 5.45 +/- 0.48 and 4.89 +/- 0.25 ng/well, respectively. Binding was saturated at about 2 micrograms/ml. The complete linearity of 99MTc-labeled LDL accumulation from 0-6 h and the positive slope from 6-24 h indicated that radiolabel that entered cells as 99MTc-labeled LDL was sequestered; pulse-chase experiments, which measured residual cell-associated radioactivity out to 24 h, also showed that radiolabel was trapped. Because radiolabel sequestration was essentially complete, and because 99MTc-labeled LDL was recognized by the LDL receptor equally as well as 125I-labeled LDL, it should be useful not only for imaging atherosclerosis, but also for quantitatively determining sites of utilization and degradation of LDL.

Affinity Labels↗
PubMed1990

Focal accumulation of an apolipoprotein B-based synthetic oligopeptide in the healing rabbit arterial wall.

The functions of surface-accessible domains of apolipoprotein (apo) B, the protein moiety of low density lipoprotein (LDL), are unknown, aside from the LDL receptor-binding domain, which lies toward the carboxyl-terminal end of apoB. Since LDL accumulation in arterial lesions does not depend on recognition of LDLs by a cell-surface receptor, we synthesized an oligopeptide with the sequence of the trypsin-accessible domain of apoB that lies closest to the amino-terminal end of the protein and compared its biological activity to that of another synthetic oligopeptide with the sequence of the heparin- and apoB/apoE receptor-binding domains of apoE. (Tyrosine was added at the amino-terminal end of each peptide to facilitate radiolabeling.) The 18-amino acid apoB-based peptide included residues 1000-1016 of apoB, for which no function has been previously described. In radioautographs, the 125I-labeled peptide accumulated focally at the healing edges of regenerating endothelial islands in the balloon-catheter deendothelialized rabbit aorta. In contrast, the 21-residue apoE-based peptide, which included residues 129-148 of apoE, accumulated diffusely and uniformly throughout the deendothelialized areas of the aorta. The data show that focal binding of the apoB-based peptide can delineate arterial lesions and suggest that this arterial wall-binding domain of apoB mediates accumulation of LDLs in arterial lesions.

Amino Acid Sequence↗
PubMed1989

Routine intraoperative angioscopy in lower extremity revascularization.

The inability to see through blood remains the main obstacle to the widespread and routine use of angioscopy. Local irrigation with a balanced salt solution is presently the most widely used method to clear the blood. By applying basic principles of irrigation and using a unique, dedicated, irrigation pump, we found that routine angioscopy during lower extremity revascularization that yields consistent high-quality studies is feasible, clinically useful, and safe. Between May 1, 1987, and July 31, 1988, 136 intraoperative angioscopies were performed during 112 peripheral bypass procedures, 15 thrombectomies, 2 embolectomies, and 7 miscellaneous revascularization procedures. Mean total irrigation fluid used in the peripheral bypasses was 398 mL (range, 0 to 1400 mL). Good visual quality was obtained in more than 80% of angioscopies and the failure rate was only 1.8%. On the basis of the findings in 71 of the 136 angioscopies, 78 clinical or surgical decisions were made. No complications were directly attributable to the insertion of the angioscope or use of the pump.

Angiography↗
PubMed1989

Intraoperative angioscopy: principles of irrigation and description of a new dedicated irrigation pump.

The value of intraoperative angioscopy in the detection and immediate correction of technical errors and deficiencies during vascular surgery has been previously documented. The inability to see through blood remains the most significant limitation to the general application of angioscopy. Local irrigation with a balanced salt solution is the most commonly used method to clear the blood from a restricted field in a particular vessel. We have developed a new catheter irrigation pump system (maximum flow rate 340 ml/min) to establish and maintain visibility of the field during intraoperative angioscopy. Furthermore, we have demonstrated the safety of irrigating with high volume flows in the peripheral arteries and defined the basic principles of irrigation for angioscopy. The prototype pump tested in this study provides a wide range of flow rates and permits precise measurements of the fluid delivered. The instrument's display and its control with a single foot pedal makes its use relatively simple, obviating the need for additional support personnel while increasing the efficacy and safety of the angioscopic examination and increasing the number of situations where angioscopy may be very useful.

Animals↗
PubMed1987

Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolemia. A multicenter study.

STUDY OBJECTIVE: To evaluate the efficacy and tolerability of lovastatin under controlled conditions in heterozygous familial hypercholesterolemia. DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Five lipid clinics with a central laboratory and coordinating center. PATIENTS: 101 adult patients with heterozygous familial hypercholesterolemia. INTERVENTIONS: Patients were on a lipid-lowering diet throughout the study. After a 4-week placebo baseline period, patients were randomized to five equal treatment groups. Each group received a different sequence of placebo or lovastatin 5 to 40 mg twice daily or 20 to 40 mg once daily in the evening, during three consecutive 6-week periods. MEASUREMENTS AND MAIN RESULTS: The mean reductions in total plasma cholesterol and low-density lipoprotein cholesterol across the dosage ranges were 14% to 34% and 17% to 39%, respectively (p compared with zero and placebo less than 0.01). High-density lipoprotein cholesterol and apolipoproteins AI and AII rose slightly. Apolipoprotein B fell substantially at the higher dosage levels (-23% at 40 mg twice daily, p less than 0.01), indicating a reduction in the concentration of circulating low-density lipoprotein particles. Maximum response was achieved in 4 to 6 weeks. Twice-daily dosing was slightly more efficient than once-daily dosing. Of those patients receiving 40 mg twice a day, 89% had a fall in low-density lipoprotein cholesterol of at least 20%, and 61% had a fall of at least 40%. Adverse effects attributable to lovastatin were minimal, and no patient was withdrawn from the study. CONCLUSION: Lovastatin was well tolerated and effective in the treatment of familial hypercholesterolemia.

Adult↗
PubMed1986

Adrenal imaging with technetium-99m-labelled low density lipoproteins.

Evaluation of adrenal cortical function by external imaging is currently accomplished by injection of radiolabelled analogs of cholesterol. Although the adrenals do utilized exogenous cholesterol for steroid hormone synthesis, the cholesterol is delivered to the glands not as free cholesterol but through the uptake of low density lipoproteins (LDL), which are subsequently degraded within the adrenal cortical cells to provide cholesterol. Thus, we sought to assess the use of 99mTc-labelled LDL injected into rabbits to obtain external images of the adrenal glands. Adrenal images of all nine rabbits tested were obtained within 18 to 21 hours after injection of 99mTc-LDL. Seven of the rabbits were subjected to adrenal cortical suppression with dexamethasone and then all nine rabbits were imaged a second time. In the untreated animals, visualization of the adrenal glands was accompanied by normal serum cortisol concentrations and accumulation of radiolabel in the adrenals, whereas in the dexamethasone-treated animals, lack of visualization of the adrenal glands was correlated with low serum cortisols, and greatly decreased accumulation of the radionuclide in the adrenals. These findings demonstrate for the first time that LDL, when labelled with 99mTc, can be used to evaluate adrenal cortical function by external imaging.

Adrenal Cortex Function Tests↗
PubMed1985

Evaluation of aortic stenosis by spectral analysis of the murmur.

A relation between the peak transaortic pressure gradient and the frequency content of the murmur (r = 0.79) was demonstrated in a prospective "test" set of 50 patients with the clinical diagnosis of aortic stenosis. After heart sounds were recorded and digitized, three segments of the systolic murmur were isolated and analyzed by fast Fourier transform technique. An average frequency spectrum was quantitated by a previously described empiric spectral estimator. Clinical data and spectral ratio were correlated with the transaortic pressure gradient and aortic valve area was calculated from cardiac catheterization data. The best prediction of the transaortic pressure gradient was obtained when a 170 ms murmur segment was analyzed and when the predictive algorithm also included the aortic dimension (r = 0.87). The aortic valve area was poorly predicted (r = -0.48) unless estimates of blood flow and valvular calcification were included in the algorithm (r = 0.84). Further refinement of this technique may provide a non-invasive and clinically useful method for the estimation of aortic valve stenosis.

Adult↗
PubMed1985

Vascular calcification in types II and IV hyperlipoproteinemia: radiographic appearance and clinical significance.

Nearly 90% of patients with clear-cut hyperlipidemia seen in clinical practice have type II or IV hyperlipoproteinemia. Previous studies have shown that these syndromes have different distributions of coronary artery atherosclerosis and different outcomes after coronary bypass grafting. A characteristic pattern of vascular calcification on chest films might have some prognostic value. Therefore, to determine the location and extent of aortic root and coronary artery calcification seen on chest films, 33 consecutive patients with type II and 17 with type IV hyperlipoproteinemia were studied who were admitted for coronary arteriography between 1970 and 1982. Among the 33 patients with type II disease, 21 women and 12 men, 22 had radiographically visible calcification that was different in distribution from that usually found in atherosclerotic disease. The ascending aorta was involved in 21 and the arch in 12. In eight patients, the calcium outlined a distinctive narrowing of the ascending aorta. Six patients had significant left ventricular obstruction; in five it was from aortic valve stenosis. Of the 17 type IV patients, 16 men and one woman, none had aortic calcification or left ventricular outflow obstruction, and only one had coronary artery calcification. These data demonstrate that patients with type II hyperlipoproteinemia have severe calcific atherosclerosis of the aortic root that often is visible on chest films. Such calcification may alert physicians to the presence of type II hyperlipoproteinemia and the high probability of severe coronary artery disease.

Adolescent↗
PubMed1985

Technetium-99m low density lipoproteins: preparation and biodistribution.

The focal uptake by human atherosclerotic lesions of 125I bound to low density lipoproteins (LDL) can be demonstrated by external imaging. However, 125I has poor imaging characteristics. Therefore, we have developed a technique for labeling LDL with technetium. To facilitate analysis, LDL was first labeled with 99mTc, by reduction of TcO4- with dithionite in the presence of the protein. The labeled LDL was stable to electrophoresis, ultracentrifugation, and passage in vivo. This technique was repeated with minor modification with 99mTc to prepare [99mTc] LDL for use as an imaging agent. Its biodistribution in 16 rabbits was similar to that of [125I] LDL and it allowed high resolution external imaging of LDL uptake by tissues, including the injured, healing, arterial wall, and the adrenal cortex.

Animals↗
PubMed1984

Phonoangiography: qualitative and quantitative.

Bruit analysis (phonoangiography) has been performed for many years as a method of characterizing arterial disease. Time displays of arterial bruits, particularly at the carotid bifurcation, have been used in an attempt to quantitate arterial narrowing. Despite the generalization that longer bruits and bruits which look and sound higher in frequency are often associated with severe disease, prospective studies have shown no useful predictive value for qualitative phonoangiography. In marked contrast, spectral bruit analysis or quantitative phonoangiography has been quite accurate in predicting the location and extent of carotid stenosis, and in distinguishing intrinsic from transmitted bruits. With this method, the peak systolic portion of the bruit is subjected to fast Fourier transform analysis. The peak frequency, beyond which amplitude drops as frequency increases further, is directly related to the residual lumen diameter of the stenotic common or internal carotid artery. Several blinded trials of this method have given results accurate to within 1 mm of angiographic values in 83-93% of cases studied. When used in conjunction with duplex doppler ultrasound scanning, 95% accuracy in diagnosis of patients with and without bruits may be achieved. This completely noninvasive method deserves more widespread use and may also be applicable to other cardiovascular sounds.

Animals↗