Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. METHODS: To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4+/-0.8 months [mean+/-SD], 58 children aged 7.9+/-3.8 years, 42 adults aged 42.5+/-5.1 years, and 40 elderly subjects aged 71.8+/-3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. RESULTS: Atherosclerosis was 6- to 19-fold greater (P<0.01) in extracranial arteries than in intracranial arteries, and it increased linearly with age. Intracranial arteries showed significantly greater antioxidant enzyme activities than did extracranial arteries. However, the antioxidant protection of intracranial arteries decreased significantly in older age, coinciding with a marked acceleration of atherogenesis. An increase in matrix metalloproteinase-9 protein expression and in gelatinolytic activity consistent with the degree of intracranial atherosclerosis was also observed. CONCLUSIONS: These results suggest that a greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherogenesis and that with increasing age intracranial arteries respond with accelerated atherogenesis when their antioxidant protection decreases relatively more than that of extracranial arteries.

Scintigraphic features of autoimmune thyroiditis.

The term autoimmune thyroiditis encompasses multiple inflammatory conditions of the thyroid gland, each with variable clinical manifestations. The more acute forms, silent (painless) thyroiditis and postpartum thyroiditis, are associated with transient hyperthyroidism and are sometimes mistaken for Graves disease. The chronic form, Hashimoto thyroiditis (chronic autoimmune thyroiditis), results in goiter and eventual hypothyroidism unless it is recognized and treated promptly. Thyroid uptake measurements and scintigraphic findings (usually obtained with technetium-99m or iodine-123) play a complementary role along with thyroid function testing in differentiating autoimmune thyroiditis from other thyroid diseases, thereby influencing treatment. In some cases, histologic evaluation of biopsy specimens is required to yield the definitive diagnosis. Knowledge of the entire spectrum of these disorders is essential for appropriate case management.

Lipid disorders in type 1 and type 2 diabetes.

Atherosclerotic cardiovascular disease is the most important cause of morbidity and mortality in diabetic subjects. Abnormalities in circulating lipids and lipoproteins are considered to be important risk factors for cardiovascular disease because they occur with increased frequency in diabetic individuals. Because reversal of these abnormalities carries the potential for preventing or ameliorating cardiovascular disease, their identification and management with other cardiovascular disease risk factors deserve equal importance to the management of hyperglycemia and frequently are complementary to it.

Niacin dosing: relationship to benefits and adverse effects.

Because of the original observation by Altschul et al., that nicotinic acid (niacin), not nicotinamide, in pharmacologic doses lowered human serum cholesterol levels, an avalanche of reports have been published over the past 45 years on the plasma lipid-regulating properties of this drug and its beneficial cardiovascular effects. A myriad of studies that have examined efficacy, safety, adverse effects, and pharmacologic properties of niacin rendered convincing evidence that niacin, used alone or combined with other agents, has favorable effects on serum lipoprotein regulation and on containment of atherothrombotic cardiovascular diseases. However, because of the unusual side effect profile of niacin and the availability of various formulations of this drug, niacin must be used prudently and with careful instruction and monitoring of patients. This review summarizes the pertinent and recent literature on niacin that impacts its therapeutic use. We also discuss some controversial issues and personal clinical experience and opinions on this topic.

Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.

This study compares the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low-density lipoprotein (LDL) cholesterol. This was a randomized, double-blind, placebo-controlled clinical trial, with 67 women and 100 men with LDL cholesterol >/=130 mg/dl and triglycerides

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.

This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.

Fhit expression in gastric adenocarcinoma: correlation with disease stage and survival.

BACKGROUND: The FHIT gene is inactivated by deletion in a large fraction of human tumors, including gastric carcinomas, and the Fhit protein has been proposed to act as a tumor suppressor in multiple tumor types. A large fraction of gastric adenocarcinomas have lost expression of the candidate tumor suppressor protein, Fhit, whereas normal gastric epithelial cells are strongly positive and Fhit loss has been found to correlate with alterations of the FHIT locus. Because the majority of gastric tumors in the current study were found to be entirely negative for Fhit protein, it is possible that alteration of the carcinogen-susceptible fragile region within the FHIT gene is an early event in gastric carcinoma, as it is in lung carcinoma. METHODS: To determine whether the absence of Fhit protein correlates with expression of tumor markers or with clinical parameters, such as grade, stage, and survival time, the authors assessed Fhit expression using immunohistochemistry in a well characterized set of 55 gastric adenocarcinomas resected over several years, with longitudinal follow-up of patients for outcome. RESULTS: In this set of 55 gastric cancers, the absence of Fhit protein correlated with higher tumor stage (P = 0.003) and higher histologic grade (P = 0.007). In addition, patients whose tumors had lost expression of Fhit died of disease significantly earlier than those with Fhit positive tumors (P = 0.017). The absence of Fhit expression did not correlate with the expression of any tumor markers. CONCLUSIONS: Larger studies will be required to elucidate further the relation between tumor stage, grade, and Fhit loss and to determine whether inclusion of Fhit antiserum in immunophenotyping of gastric adenocarcinomas will be a useful indicator of post-diagnosis prognosis.

Endometrial polyps: MR imaging features and distinction from endometrial carcinoma.

PURPOSE: To determine the magnetic resonance (MR) imaging characteristics of endometrial polyps and the accuracy of MR imaging in distinguishing endometrial polyps from endometrial carcinomas in a case-control study. MATERIALS AND METHODS: Cross-referencing pathology records with MR studies from two institutions disclosed 35 patients with surgically proved endometrial polyp or carcinoma after controlling for tumor size. All MR examinations were performed at 1.5 T with T2-weighted fast spin-echo sequences in multiple planes. Three independent readers blinded to histologic diagnoses and clinical data scored each image for the presence of several defined findings. RESULTS: A central fibrous core (low signal intensity on T2-weighted images) and intratumoral cysts (high signal intensity on T2-weighted images) were seen more frequently in endometrial polyps than in carcinomas; myometrial invasion and necrosis showed high predictive value for carcinomas. The readers' responses showed a mean sensitivity of 79%, specificity of 89%, accuracy of 86%, positive predictive value of 82%, and negative predictive value of 88% for diagnosis of carcinoma. The mean area under the receiver operating characteristic curve for the three readers was 0.87 for the diagnosis of carcinoma. CONCLUSION: MR images can help to distinguish most polyps from endometrial carcinomas on the basis of morphologic features. Accuracy does not appear to be sufficient to obviate biopsy, partly because carcinomas and polyps frequently coexist.

1,4-Dihydropyridine calcium channel blockers inhibit plasma and LDL oxidation and formation of oxidation-specific epitopes in the arterial wall and prolong survival in stroke-prone spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Calcium-channel blockers (CCBs) reduce systolic blood pressure and stroke-related mortality in stroke-prone spontaneously hypertensive rats (SPSHR). Brain ischemia is associated with loss of intracellular antioxidants. Increased formation of oxygen radicals and oxidation of LDL may enhance arterial vasoconstriction by various mechanisms. CCBs that also exert antioxidative properties in vitro may therefore be particularly useful. To investigate such antioxidant effects in vivo, we determined several parameters of LDL oxidation in SPSHR treated with two 1,4-dihydropyridine-type (1,4-DHP) CCBs of different lipophilic properties and compared them with antioxidant-treated and untreated controls. We also tested whether these drugs decrease the formation of oxidation-specific epitopes in arteries. METHODS: Five groups of 9 to 14 SPSHR each (aged 8 weeks) were treated with 80 mg/kg body wt per day nifedipine, 1 mg or 0.3 mg/kg body wt per day lacidipine, vitamin E (100 IU/d), or carrier for 5 weeks. A group of Wistar-Kyoto rats was used as normotensive control. Plasma samples were taken, and LDL was isolated by ultracentrifugation. Then LDL was exposed to oxygen radicals generated by xanthine/xanthine oxidase reaction (2 mmol/L xanthine+100 mU/mL xanthine oxidase), and several parameters of oxidation were determined. The presence of native apolipoprotein B and oxidation-specific epitopes in the carotid and middle cerebral arteries was determined immunocytochemically. RESULTS: 1,4-DHP CCBs completely prevented mortality. Normotensive Wistar-Kyoto rats showed less oxidation than control SPSHR. Plasma lipoperoxide levels were 0.87+/-0.27 micromol/L in control SPSHR, 0.69+/-0.19 and 0.63+/-0.20 micromol/L in the groups treated with 0.3 and 1 mg lacidipine, respectively, and 0.68+/-0.23 micromol/L in nifedipine-treated animals (P<0.05 versus control SPSHR for all values). Both CCBs significantly decreased formation of conjugated dienes and prolonged the lag time in LDL exposed to oxygen radicals. Similarly, lipoperoxides and malondialdehyde were significantly reduced (P<0.05). Reduced relative electrophoretic mobility and increased trinitrobenzenesulfonic acid reactivity of LDL from treated rats (P<0.01) also indicated that fewer lysine residues of apolipoprotein B were oxidatively modified in the presence of 1,4-DHP CCBs. Finally, these drugs reduced the intimal presence of apolipoprotein B and oxidized LDL (oxidation-specific epitopes) in carotid and middle cerebral arteries. CONCLUSIONS: In the SPSHR model, 1,4-DHP CCBs reduce plasma and LDL oxidation and formation of oxidation-specific epitopes and prolong survival independently of blood pressure modifications. Our results support the concept that the in vivo protective effect of these drugs on cerebral ischemia and stroke may in part result from inhibition of oxidative processes.

Color Doppler sonographic detection of tumor flow in superficial melanoma metastases: histologic correlation.

Color Doppler sonographic detection of tumor flow within superficial melanoma metastases was investigated to determine if tumor size, vessel size, or vessel number influences signal detection. Color Doppler imaging of 32 pathologically proved melanoma metastases was performed at 6 MHz with color Doppler imaging parameters optimized for each lesion scanned. All lesions were measured in three dimensions and the presence or absence of internal flow was documented. Seven surgically excised metastases underwent immunohistochemical staining for endothelial markers. Internal flow was detected in 21 of 32 masses and was completely absent in 11. In comparison to all masses without flow, the masses with flow had significantly greater anteroposterior dimensions (P < 0.00036) and volumes (P < 0.01). Histologically, mean vessel diameter in masses with flow was significantly greater (P < 0.05) than in those without flow, but mean vessel number was not significantly different. In conclusion, detectability of tumor blood flow in superficial melanoma metastasis may be related more to tumor size and vessel size than vessel number. Failure to detect color signal within a superficial melanoma mass does not indicate a lack of internal vascularity.

Superficial melanoma metastases: appearances on gray-scale and color Doppler sonography.

OBJECTIVE: The purpose of this study was to describe the sonographic appearances of melanoma metastases of the skin, subcutaneous tissues, and superficial lymph nodes. MATERIALS AND METHODS: Gray-scale sonography was performed on 31 superficial melanoma metastases in 18 patients. Discreteness of borders, contours, echogenicity, echotexture, and degree of acoustic through-transmission were evaluated for each lesion. Color Doppler sonography was also performed on 25 of the 31 lesions, by which the amount of internal color flow was qualitatively assessed. RESULTS: Twenty-eight (90%) of the 31 metastases had well-defined borders. Contours were smooth in 17 (55%), lobulated in 12 (39%), and spiculated in two (6%). Nineteen metastases (61%) were hypoechoic to muscle, 10 (32%) were isoechoic, and two (6%) were hyperechoic. Echotexture was homogeneous in six lesions (19%), mildly heterogeneous in 13 (42%), moderately heterogeneous in 11 (35%), and markedly heterogeneous in one (3%). Twenty-two lesions (71%) showed enhanced acoustic through-transmission. Of the 25 melanoma metastases for which we performed color Doppler sonography, 18 (72%) had internal arterial color flow and seven (28%) did not. The flow was characterized as mild in 13 (72%) of 18, moderate in four (22%), and marked in one (6%). CONCLUSION: On sonography, superficial melanoma metastases typically are well-defined hypoechoic lesions with smooth or lobulated contours, mild to moderate heterogeneity, and enhanced acoustic through-transmission. Internal flow revealed by color Doppler sonography is present in many, but not all, superficial melanoma metastases.

A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients.

Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides <9 mmol/L [800 mg/dL]) into 3 treatment groups: (1) Niaspan 1,000 mg/day; (2) Niaspan 2,000 mg/day; and (3) placebo. The primary treatment endpoint was LDL-cholesterol level. This endpoint was not significantly affected by placebo (0.2% increase), but Niaspan decreased LDL cholesterol by 5.8% (1,000 mg/day) and 14.6% (2,000 mg/day) (p <0.001). Likewise, with placebo there were significant changes in total cholesterol, triglycerides, lipoprotein(a), and apoprotein B, whereas both Niaspan 1,000 and 2,000 mg/day significantly (p <0.001) decreased these parameters. In addition, both Niaspan groups showed significant (p <0.001) increases in HDL cholesterol (17% and 23%, respectively), including HDL subfractions. With respect to flushing, 20% of the placebo group reported at least 1 episode, whereas 88% and 83% of the Niaspon 1,000- and 2,000-mg/day groups, respectively, reported episodes. There was no hepatotoxicity as liver enzyme levels remained within clinically accepted limits in all treatment groups. However, Niaspan 2,000 mg/day showed a significant increase in aspartate aminotransferase compared with baseline and placebo. This trial demonstrated a cholesterol-modifying effect of Niaspan consistent with those reported for niacin, but demonstrated a better tolerance for flushing. Moreover, in contrast to sustained-release formulations, Niaspan showed relatively mild hepatic effects.

Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.

Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p <0.001). Niaspan was generally well tolerated, although flushing was common (75%); however, there was a progressive decrease in flushing with time from 3.3 episodes in the first month to < or = 1 episode by week 48. Aspirin was used by one third of patients before Niaspan dosing to minimize flushing episodes. Although serious adverse events occurred in about 10% of patients, none were considered probably or definitely related to Niaspan. Adverse events in general varied widely, but their true relation to the study drug is difficult to ascertain without a placebo (control) group. No deaths occurred. There were statistically significant changes in hepatic transaminases, alkaline phosphatase, direct bilirubin, phosphorus, glucose, amylase, and uric acid. However, these changes were mostly small and are not likely to be biologically or clinically significant (the decrease in phosphorus is a new finding in niacin therapy). No myopathy was observed. Thus, this long-term study confirms the earlier short-term findings that Niaspan is safe and effective as monotherapy in plasma lipoprotein regulation.

Treatment of hyperlipidemia with combined niacin-statin regimens.

Combined use of niacin with a statin is an attractive option, since these types of medication have the best records in clinical trials for reduction in cardiovascular events and improvement in progression/regression of coronary lesions. In early use, the niacin-statin combination generated a few case reports documenting severe myopathy and rhabdomyolysis. Subsequent prospective trials in >400 patients, however, have not encountered myopathy. This experience includes 165 patients who took a statin in combination with Niaspan, a new, extended-release niacin administered once nightly. Hepatic toxicity with immediate-release niacin and with Niaspan used in combination with statins has been minimal. However, substantial transaminase elevations occurred with the use of a sustained-release niacin (Nicobid) given twice daily. The niacin-statin treatment regimens gave augmented low-density lipoprotein (LDL)-cholesterol reduction along with favorable changes in high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and triglycerides. This combination therapy can be used safely as long as (1) careful attention is given to niacin formulation and dosing; (2) liver functions are monitored; and (3) patients are educated to recognize symptoms of myopathy. However, special caution should apply to use of niacin in combination with high doses of statins, or with statins introduced into clinical practice in 1997 or later, since little experience has accumulated in these circumstances.

Papillary projections in ovarian neoplasms: appearance on MRI.

Papillary projections are distinctive pathologic features of epithelial ovarian neoplasms. We sought to determine whether these structures have recognizable features on MRI. A search of a database of 125 patients on whom MRI was performed with pelvic phased-array coil and abdominal surgical exploration was performed for suspected gynecologic disease identified 15 patients who had either MRI reports or pathology reports mentioning papillary projections in an adnexal mass. The MR images were reviewed to characterize the size, structure, and signal intensity of papillary projections. Pathologic correlation was performed on these and on four surgical specimens imaged with high resolution technique. Pathologic correlation showed that larger papillary projections had a distinctive structure of a fibrous stalk supporting clumps of edematous papillae with signal intensity similar to that of fluid on T2-weighted images. Smaller papillae showed nondescript intracystic projections of intermediate signal intensity on T2-weighted images. All papillary projections in vivo enhanced after injection of gadopentetate dimeglumine. Papillary projections have an appearance on MRI that reflects their histologic structure.

In situ endothelin in coronary artery disease.

Despite the significant advances made in the understanding and treatment of coronary artery disease much remains unclear about the pathogenesis of this complex atherothrombotic process. Atherogenesis may reflect a combination of multiple factors interacting with one another leading to coronary artery occlusion. One potential participant may be endothelin-1 (ET-1), a potent mitogenic vasoconstrictor. The presence of endothelin within saphenous veins before insertion and after removal during coronary artery bypass grafting (CABG) because of bypass closure, within internal mammary arteries before and after surgical intervention, and within native coronary artery segments resected during CABG was demonstrated immunocytochemically with an antiendothelin antibody and aminoethyl carbazole as the indicator chromogen. Increased amounts of ET-1 were observed in failed venous grafts, in damaged internal mammary artery grafts, and in vessels of the myocardium. These results suggest that ET-1 may play a significant pathophysiologic role in the evolution of coronary heart disease.

Pharmacodynamics of a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) on glucose and insulin levels in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) was evaluated in 7 healthy males to determine the pharmacodynamics on glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/h over 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (p > 0.05) from their pre-dose levels. Compared to the saline (control) infusion, glucose levels were statistically lower (p < 0.05) 2 hours into the rhIGF-I infusion, and were suppressed until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. Therefore, suppression of insulin levels may be due to hypoglycemia rather than a direct action of rhIGF-I. This trial demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic or insulin resistant states.

Binding of thrombospondin to human plasma lipoproteins.

Immunohistochemical studies have localized thrombospondin (TSP), a platelet adhesive protein, to the atherosclerotic plaque. To investigate how TSP may become incorporated in the plaque, we evaluated the interaction of TSP with human plasma lipoproteins and apolipoproteins. Chylomicrons, VLDL, LDL, HDL, and apolipoproteins AI, AII, C were immobilized on microtiter plates. Binding to TSP was measured directly with [125I]TSP. Labeled TSP bound saturably to all the plasma lipoproteins tested, showing the highest capacity for binding to VLDL. This binding to VLDL was maximal in the presence of 1 mM CaCl2 and MgCl2 and only partially inhibited with EDTA. The binding was inhibited totally by incubation with fluid-phase lipoproteins, apolipoproteins or anti-TSP monoclonal antibodies. The dissociation constants (Kd) for VLDL and apo C were 153 nM and 150 nM, respectively. Thus, TSP exhibits specific and saturable binding with high affinity to VLDL, perhaps mediated by its surface apo C. This binding may facilitate TSP incorporation into nascent atherosclerotic plaques and delivery of VLDL cholesterol into these lesions.