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Biomedical subjects

R S Lees

Publications and source records attributed to R S Lees.

At least 19 recordsLinked to original sources
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↗
PubMed1983

Adrenal cortical function in homozygous familial hypercholesterolemia.

The biosynthesis of adrenal corticosteroids requires a supply of cholesterol that can be derived from both local synthesis and uptake of plasma lipoproteins. Recent studies have provided evidence that receptor-mediated uptake of low density lipoproteins provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells that are grown in tissue culture. In the present study we have examined parameters of adrenocortical function in three patients with homozygous familial hypercholesterolemia (two receptor negative, one receptor defective) to assess whether a decreased number of LDL receptors, measured in vitro, influences in vivo corticosteroid production under basal conditions and in response to prolonged stimulation with ACTH. Basal adrenocortical function (assessed by the serum concentrations of cortisol and ACTH plus urinary excretion of 17 OHCS, 17 KS, and urine-free cortisol) was normal in all three patients. Stimulation with intravenous ACTH resulted in rapid increases in the serum concentrations of cortisol in all patients. Plateau concentrations of cortisol during prolonged ACTH stimulation were lower in the two receptor-negative patients (36 to 41 micrograms/dl) but all subjects had at least a threefold increase over basal values. Excretion of urine-free cortisol was reduced in both receptor-negative patients (33% to 36% of controls); this was paralleled by decreased excretion of 17 KS in both patients and of 17 OHCS in one patient. Urine-free cortisol excretion was reduced in the receptor-defective patient (57% of controls), but excretion of 17 OHCS and 17 KS was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1979

Low density lipoprotein metabolism in type IV and type V hyperlipoproteinemia.

Low density lipoproteins (LDL) are thought to arise largely from degradation of triglyceride-rich very-low-density lipoproteins (VLDL). LDL kinetics in patients with Type IV and Type V hyperlipoproteinmia were studied and compared with normal subjects. LDL labeled in the protein moiety with 125I was used as a tracer. There was no significant difference in LDL turnover between the three groups, suggesting that a catabolic defect in VLDL degradation to LDL may exist in both Type IV and Type V hyperlipoproteinemia.

Adult↗
PubMed1979

The natural history and surgical significance of hyperlipemic abdominal crisis.

Although it is widely known that patients with severe hyperlipemia may have pancreatitis, it is not generally appreciated that such patients may have recurrent abdominal pain of variable character and intensity not due to pancreatitis. Review of 35 patients followed in our clinic for 1--11 years showed that 54% had recurrent abdominal pain, while only 29% had pancreatitis. Although mild pain occurred frequently with plasma triglycerides in the 2000--5000 mg/dl range, triglycerides over 6000 mg/dl were often associated with severe pain and physical findings which necessitated hospitalization, often led to the misdiagnosis of pancreatitis and other intra-abdominal catastrophes and resulted in multiple unnecessary diagnostic studies and operations. When recognized, the pain subsided within 48 hours upon cessation of oral intake and treatment with intravenous electrolyte solutions. Furthermore, effective treatment of the hyperlipemia prevented both the attacks of severe pain and the pancreatitis which otherwise occurred (or recurred) in a significant fraction of the patients. These data confirm the existence of hyperlipemic abdominal crisis as a distinct entity and testify to the importance of recognizing this syndrome in order to avoid the occurrence of acute pancreatitis and the performance of unnecessary and potentially harmful surgery.

Abdomen↗
PubMed1979

Immunofluorescence studies of apolipoprotein B in intestinal mucosa. Absence in abetalipoproteinemia.

During fat absorption, active synthesis of cholesterol, phospholipids, and specific apolipoproteins are required for chylomicron formation and secretion. In the inherited disease abetalipoproteinema, chylomicrons cannot be made in response to fat feeding, and they as well as low and very low density lipoproteins are completely absent from plasma. The genetic defect in the disease is presumed to be an inability to synthesize apolipoprotein B, the apoprotein common to all the above lipoprotein classes, but such a defect has not been directly demonstrated. With peroral intestinal biopsies and immunofluorescence and intracellular localization of apolipoprotein B within jejunal epithelial cells of five normal subjects and have shown that its content increases markedly after fat feeding. In two patients with abetalipoproteinemia no apolipoprotein B was seen by immunofluorescence techniques in the jejunal mucosa in the fasting state or after a fatty meal. Intestinal synthesis of apolipoprotein B appears not to occur in abetalipoproteinemia.

Abetalipoproteinemia↗
PubMed1978

Apoprotein A-I synthesis in normal intestinal mucosa and in Tangier disease.

To determine whether human small intestine synthesizes apoA-I, the major apoprotein of plasma high-density lipoproteins, we used immunofluorescence technics and monospecific antiserums to visualize apoA-I within intestinal epithelial cells from four normal subjects and one patient with Tangier disease. Biopsies from all subjects during fasting showed limited fluorescence. After lipid feeding intracellular apoA-I markedly increased in both normal subjects and the patient. During alimentary lipemia, mean plasma apoA-I levels (milligrams per deciliter) increased in four normal subjects from 161 +/- 12 (+/- S.E.M.) to 180 +/- 15 (P less than 0.05) and in the patient from 1.9 to 6.8. Normal plasma chylomicrons contained apoB, apoE and the C peptides but not apoA-I. The patient's chylomicrons contained ap0A-I. Normal and Tangier-disease intestinal-mucosa cells increase their content of apoA-I during chylomicron formation and subsequently contribute to plasma apoA-I levels. The low levels of apoA-I in Tangier disease are not due to a failure of intestinal synthesis but might be due to abnormal metabolism of chylomicron apoproteins.

Apolipoproteins↗