Validation of alternative behavioral observation methods in young broiler chickens.

Continuous sampling provides the most complete data set for behavioral research; however, it often requires a prohibitive investment of time and labor. The objectives of this study were to validate behavioral observation methods of young broiler chickens using 1) 7 scan sampling intervals (0.5, 1, 3, 5, 10, 15, and 30 min) and 2) an automated tracking software program (EthoVision XT 14) compared to continuous behavioral observation, considered the gold standard for behavior observation. Ten 19-day-old Ross 708 broiler cockerels were included in this study. All behavior was video recorded over an 8-h period, and data were collected using a continuous sampling methodology. The same video files were utilized for analysis for scan sampling and automated tracking software analysis. For both analyses, the following criteria were used to identify which method accurately reflected the true duration and frequency for each behavior, as determined by continuous observation: R2 ≥ 0.9, slope was not different from 1 (P > 0.05), and intercept was not different from 0 (P > 0.05). Active, eating, drinking, and maintenance behaviors were accurately estimated with 0.5-min scan sample intervals. Active, inactive, eating, and maintenance behaviors were accurately estimated with 1-min scan sample intervals. Inactive behavior was accurately estimated with 5-min scan sample intervals. The remainder of sampling intervals examined did not provide accurate estimates, and no scan sampling interval accurately estimated the number of behavior bouts. The automated tracking software was able to accurately detect true duration of inactive behavior but was unable to accurately detect activity. The results of this study suggest that high-frequency behaviors can be accurately observed with instantaneous scan sampling up to 1-min intervals. Automated tracking software can accurately identify inactivity in young broiler chickens, but further behavior identification will require refinement.

Comparative identification, nutritional, and physiological regulation of chicken liver-enriched genes.

The liver performs a number of vital functions in the chicken. In order to identify unique gene expression patterns and link them to potential functions in the chicken liver, genes enriched in the liver of chickens needed to be investigated in a comparative manner. In this study, 41 liver-enriched genes were identified through chicken microarray, and many of them were validated through comparative analysis of mice and humans. Thirteen of them were unique in chickens, and their liver enhancement was confirmed by reverse transcription PCR. Furthermore, the expression of those 13 chicken liver-enriched genes was investigated, in response to nutritional and physiological challenges. Real-time PCR revealed that expression of PIT54 (P < 0.01), phosphoribosyl pyrophosphate synthetase 2 (PRPS2) (P < 0.05), sulfotransferase (SULT) (P < 0.05), and cytochrome P450 family 2 subfamily C, polypeptide 18 (CYP2C18) (P < 0.05) were significantly decreased in the liver during fasting compared to ad libitum control. During the post-laying stage, expression of GAL8 was significantly increased (P < 0.01), but CYP2C18 expression was significantly reduced (P < 0.05). Liver-enriched genes that were identified in this study and their expression patterns under fasting and the post-laying stage will serve as future targets to gain a better understanding of liver physiology, function and development in poultry.

Lack of tacrolimus-induced cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) has been reported in pediatric transplant patients receiving tacrolimus. It is unclear whether tacrolimus is associated with HCM in adult transplant recipients. OBJECTIVE: To determine the prevalence of HCM in noncardlac adult transplant patients receiving tacrolimus. METHODS: A retrospective analysis of nonheart transplant recipients who received tacrolimus at our institution from January 1982 to April 1996 was conducted. Patients with left-ventricular hypertrophy (LVH) defined as a posterior or septal wall thickness > or = 1.3 cm by echocardiography (ECHO) were independently evaluated. RESULTS: There were 3609 patients who met entry criteria including 2257 liver, 1333 kidney, and 19 other organ transplants. Of the 502 patients who had undergone ECHOs after transplantation, 171 had LVH. The etiology of LVH was categorized as valvular disease (36%), hypertensive disease (29%), ischemic heart disease (17%), or multifactonal (15%). There were six patients in whom, after detailed chart review, no underlying cause of LVH was evident. Five of these patients had HCM, representing an overall prevalence of 0.1% in the entire group of tacrolimus-treated patients, and 1% in patients referred for ECHO. CONCLUSIONS: The prevalence of HCM in our tacrolimus-treated adult transplant population is similar to that reported in general population studies. These data suggest that tacrolimus is not a risk factor for HCM in adult transplant recipients.

Hemostatic effects of 1 mg daily warfarin on post CABG patients. Post CABG Studies Investigators.

Although coronary bypass graft surgery has increased the survival and quality of life of many individuals, patients remain at risk of restenosis and thrombotic occlusion of the coronary arteries and bypass grafts. In the screening period for participation in the multicenter Post Coronary Artery Bypass Graft (Post CABG) trial, the effects of 1 mg daily warfarin were evaluated using paired patient samples collected prior to and after at least 21 days of treatment. In stable patients (n = 40; 39 males 1 female; 51-74 years old) who previously had undergone coronary artery revascularization (1-10 years), no alterations in prothrombin time, international normalized ratio (INR), prothrombin fragment 1.2, or the hemostatic risk factors factor VII antigen and coagulant activity, von Willebrand's factor, fibrinogen, tPA, or PAI-1 were associated with the 1 mg daily warfarin treatment. The observations reported here supported the Post CABG Studies Steering Committee decision to treat patients with 1-4 mg warfarin daily adjusted to achieve INRs not to exceed 2. 0 consistent with low-intensity therapy.

Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.

Diabetic patients have greater risk for coronary heart disease (CHD) events after coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post CABG trial studied the effects of aggressive cholesterol lowering and low-dose anticoagulation in diabetic patients compared with nondiabetic patients. A double-blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the Post CABG trial consisted of two interventions (aggressive cholesterol-lowering versus moderate lowering and low-dose warfarin versus placebo) on angiographic end points. Angiographic changes in saphenous vein graft conduits 4.3 years after entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven clinical centers participated in the trial, as well as the National Institutes of Health project office (National Heart, Lung, and Blood Institute), the coordinating center (Maryland Medical Research Institute), and the Angiogram Reading Center (University of Minnesota). Baseline characteristics of the diabetic patients differed from the nondiabetic patients in the following ways: percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight, 87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and angiographic outcomes were not different. The benefits of aggressive cholesterol lowering were comparable in diabetic and nondiabetic patients for the angiographic end points. Warfarin use was not associated with clinical or angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk factors at study entry and higher clinical event rates during the study than nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic patients were comparable to those in nondiabetic patients for both angiographic and clinical end points. The small number of diabetic patients provided limited power to detect significant differences between diabetic and nondiabetic patients or between diabetic patients in the aggressive versus moderate cholesterol treatment strategies.

Lovastatin preserves renal function in experimental diabetes.

Although hyperlipidemia has been associated with the progression of glomerulosclerosis, little attention has been directed toward the use of lipid-lowering agents in altering diabetic nephropathy. We tested the hypothesis that lovastatin and the combination of lovastatin and enalapril would preserve renal function in streptozotocin-induced diabetic Wistar rats. Five groups of animals were studied: group 1, nondiabetic (n = 10); group 2, diabetic, insulin only (n = 12); group 3, lovastatin, (15 mg/kg/day, n = 13); group 4, enalapril, (50 mg/L drinking water, n = 10) and group 5, lovastatin plus enalapril, (n = 14). After 8 weeks of treatment, glomerular filtration rate (GFR, insulin clearance) was measured in anesthetized animals. The diabetic group was characterized by a GFR of 0.18 +/- 0.03 ml/min/g of kidney weight (gKW), a blood glucose level of 441 +/- 36 mg/dL, plasma cholesterol and triglyceride levels of 64 +/- 6.0 and 103 +/- 26.0 mg/dL. Lovastatin preserved GFR, 0.52 +/- 0.06 ml/min/gKW compared with the diabetic control subjects (P < 0.05). Enalapril also maintained GFR (0.42 +/- 0.06 ml/min/gKW, P < 0.05). In the lovastatin plus enalapril group, GFR (0.62 +/- 0.05 ml/min/gKW) was greater than in the enalapril group (P < 0.05), but was not different from the lovastatin group. Plasma lipid levels were not altered in any of the groups. Assessment of the kidneys by histology after treatment showed that the mesangial matrix injury score was better in the lovastatin, enalapril, and lovastatin plus enalapril groups compared with the diabetic group (P < 0.05). Lovastatin, enalapril, and lovastatin plus enalapril abrogated the decline in GFR and glomerular injury in diabetic rats. Lovastatin's direct renal protective effect seems to be independent of its lipid-lowering properties.

Teaching clinical pharmacology and therapeutics: selective for fourth-year medical students.

Teaching clinical pharmacology remains both a lifelong learning process and a lifelong challenge for clinical pharmacologists and other medical educators. In the current information age, with an explosion of drug-related data, the prime topic for discussion is how to teach clinical pharmacology. This article describes our response to the challenges in developing a selective course in clinical pharmacology, and our experience from the first 2 years of the course. Our emphasis is on how to provide in an efficient way knowledge, skills, and attitudes students will need as physicians in the coming decades. Faculty from the Center for Clinical Pharmacology at the University of Pittsburgh in conjunction with faculty from the University of Pittsburgh School of Medicine have developed a one-month intensive course in clinical pharmacology. The integrated course program consists of four overlapping components: 1) general clinical pharmacology (focused on individualization of drug therapy); 2) rational prescribing principles (general principles of drug selection, how to prepare a personal formulary); 3) disease-specific clinical topics (pharmacotherapy of diseases and medical conditions most commonly seen in routine medical practice); and 4) workshops for special attention topics (pharmacokinetics, pain treatment, toxicology, dialysis). In congruence with established educational goals, the course includes drug-, patient-, and disease-oriented concepts. A variety of learning formats (didactic and interactive lectures, one-day problem-based learning sessions, small group case discussions, self-directed and small group directed learning, quizzes, and computer-assisted learning) are used to teach students how to apply the general concepts of clinical pharmacology and rational pharmacotherapy to clinical medicine, and to prepare them to become independent lifelong learners in therapeutics. Student feedback from the first 2 years of this course indicates that this multi-modal teaching format is effective. The majority of students who took the course in clinical pharmacology in 1997 found it to be very beneficial.

Efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia.

PURPOSE: Patients with type I and type II diabetes mellitus have an increased risk of coronary heart disease. In many diabetics, hypercholesterolemia is present and further exacerbates this risk. We investigated the efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS: In this 24-week, multi-center, double-blind, placebo-controlled study, 94 patients (45 men, 49 women), 18 to 70 years of age, with type I or type II diabetes mellitus and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol [LDL-C] levels > 150 mg/dL and above the 75th percentile for the US population by age and gender) were randomized to receive pravastatin 20 mg hs or matching placebo. Two patients were randomized to treatment with drug for every 1 randomized to placebo. The dose could be doubled after 10 weeks, and cholestyramine or colestipol could be added after 18 weeks, as needed, to attempt to lower the LDL-C levels to below the 50th percentile for the US population. RESULTS: Significant reductions in LDL-C (-27.6%), total cholesterol (-22.1%), very-low-density lipoprotein cholesterol (-22.6%), and triglycerides (-12.8%) (P < or = 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P < or = 0.05 versus placebo) were noted in the pravastatin treatment group (average dose 29.5 mg) at 16 weeks. The beneficial lipid-lowering effects of pravastatin were maintained throughout the 24 weeks of the study. Pravastatin was well tolerated, and the frequency of side effects was similar in the pravastatin and placebo groups. No clinically significant changes in the control of diabetes, as assessed by fasting blood glucose levels and glycosylated hemoglobin measurements, were seen during this study. CONCLUSION: The results of this study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with type I or type II diabetes mellitus and hypercholesterolemia.

Effect of lovastatin on cholesterol content of cardiac and red blood cell membranes in normal and cardiomyopathic hamsters.

Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, is used therapeutically to lower plasma cholesterol levels. However, the effect of this therapy on cell membrane cholesterol in vivo is not known. The goal of this study was to investigate whether lovastatin treatment of hamsters decreases cholesterol in cardiac cell membranes and in red blood cell (RBC) membranes. Because abnormal cellular Ca++ regulation has been associated with altered membrane cholesterol in hearts of cardiomyopathic (CM) hamsters, we also measured the cholesterol content of cardiac and RBC membranes from lovastatin-treated and untreated Bio 14.6 CM hamsters to determine whether any differences existed with respect to normals. Sarcolemma-enriched cardiac membranes and RBC membranes were obtained from 42 to 45-day normal and CM hamsters after 13 days of lovastatin treatment (0.1% of food/day) and from untreated normal and CM hamsters. Plasma cholesterol, membrane cholesterol/phospholipid (C/PL) ratio and cholesterol per milligram of membrane protein (C/prot) were determined. In hearts from untreated CM hamsters, C/prot was significantly lower (P < .05) than in untreated normals. Lovastatin decreased plasma cholesterol by 76% and 81% in normal and CM hamsters, respectively (P < .001), but after lovastatin treatment, there was no significant change in C/PL or C/prot in cardiac membranes from either strain; there was also no significant decrease in C/prot or in C/PL of RBC membranes from normals or C/PL of CM hamster RBC membranes. However, lovastatin feeding resulted in a significant (P < .01) 24% decrease in C/prot of CM RBC membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of hemodiafiltration to enhance delivered dialysis.

Patients on hemodialysis for end-stage renal disease frequently have increased levels of lipoproteins and beta-2 microglobulin (B2M). In an effort to assess the effect of hemodiafiltration on TACUrea, delivered Kt/VUrea, normalized protein catabolic rate, and B2M level, 6 chronic hemodialysis patients (mean age 63.3 +/- 17 years; 3 men, 3 women) were randomly selected to undergo 4 weeks of hemodiafiltration. The therapy consisted of Qb: 400 ml/min, Qd: 800 ml/min, time: 3.5 hours and 10 L hemofiltrate exchanges with either Ringer's lactate or combination of Ringer's solution and saline using polysulfone membrane dialyzer. TACUrea, Kt/VUrea delivered, normalized protein catabolic rate, serum electrolytes, liver enzymes, lipoproteins, and B2M clearance were evaluated before and after hemodiafiltration. Kt/V increased significantly [pre: 1.3 +/- 0.2 vs post: 1.8 +/- 0.3; p < 0.05], and TACUrea decreased (pre: 44.3 +/- 15 vs post 32 +/- 6.7 mg/dl; p < 0.1). There was no change in normalized protein catabolic rate (pre: 0.88 +/- 0.21 vs post: 0.80 +/- 0.15). B2M clearance was greatly enhanced (pre: 22 +/- 11 vs post: 110 +/- 36 ml/min; p < 0.001) together with a reduction in serum B2M level (pre: 43.6 +/- 11.4 vs 31.2 +/- 6.4 mg/L; p < 0.05). There was no significant increase in total cholesterol, low density lipoprotein, high density lipoprotein, or triglyceride levels, nor was there a change in electrolyte, CO2, or liver enzyme levels. Blood pressure control was satisfactory throughout hemodiafiltration therapy. Hemodiafiltration using a polysulfone membrane dialyzer raised delivered Kt/VUrea and reduced TACUrea and B2M levels significantly.

The combination of lovastatin and enalapril in a model of progressive renal disease.

Puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril (EN) 50 mg/l dissolved in the drinking water; the second received lovastatin (L) 15 mg/kg given daily by gavage; the third received both agents; the fourth was left untreated, and the final group received no puromycin and served as the control group. Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Lp(a) and premature mortality during chronic hemodialysis treatment.

Lipoprotein(a) levels are approximately three to four times higher in patients with end-stage renal disease (ESRD) when compared to controls with normal renal function (H.J. Parra, H. Mezdour, C. Cachera et al., Clin. Chem. 33 (1987), 721). Hypertriglyceridemia occurs in approximately 50% of ESRD patients receiving chronic hemodialysis (HD) treatment and has been associated with an increased prevalence of cardiovascular disease (CVD) in cross-sectional studies of this subset of ESRD patients. We recently reported that HD patients with pre-existing ischemic or atherosclerotic CVD and patients with elevated Lp(a) levels had an increased risk of fatal and non-fatal clinical events attributable to CVD during a 48-month period of maintenance HD treatment. The current report describes a detailed analysis of study participants who did or did not have a history of ischemic CVD or angiographically documented severe atherosclerotic lesions prior to entry into our prospective study. Although baseline total cholesterol (TC), triglyceride (TG) and apoprotein B (apoB) levels were higher in the 36 participants with prevalent CVD than the remaining 93 study participants, total cholesterol levels were somewhat lower, while serum triglyceride levels were no different in patients who survived or experienced fatal CVD events during the period of observation on HD treatment. In contrast, Lp(a) levels were no different in participants with or without evidence of pre-existing CVD. Lp(a) was, however, an independent predictor of fatal events attributable to cardiovascular disease during the period of follow-up.

Lipid abnormalities and end-stage renal disease: implications for atherosclerotic cardiovascular disease?

Disorders of lipoprotein metabolism may have clinical implications as determinants of cardiovascular risk in patients with end-stage renal disease (ESRD). However, the role of hypertriglyceridemia or other parameters of lipoprotein metabolism as predictors of clinical measures of outcome during ESRD treatment is currently unknown. We determined the relationship between blood lipid, lipoprotein-cholesterol, apoprotein levels and the risk of cardiovascular death during 48 months of hemodialysis treatment in a prospective study of 129 patients with ESRD. Although serum triglyceride levels were increased in patients with preexisting cardiovascular disease, they were unrelated to clinical outcome during the period of follow-up. In contrast, lipoprotein(a) was an independent predictor of the risk of deaths attributable to cardiovascular disease during the prospective period of follow-up. Although these findings do not exclude the possibility that hypertriglyceridemic hemodialysis patients have atherogenic lipoproteins or associated metabolic conditions that predispose to cardiovascular death, our findings suggest that measurements of serum triglyceride concentration may not improve the cardiovascular risk assessment of hemodialysis patients.

Lipid and lipoprotein abnormalities in lower-extremity arteriosclerosis obliterans.

The prevalence of abnormal lipid and lipoprotein values was determined in 125 consecutive patients with lower-extremity arteriosclerosis obliterans, and the lipid and lipoprotein abnormalities in these patients were characterized. Only 13% of the patients had normal lipid/lipoprotein profiles. Forty-eight percent of patients had low levels of high-density lipoprotein cholesterol. High-density lipoprotein cholesterol values were lower in patients with concomitant coronary heart disease compared with those without heart disease. High-density lipoprotein cholesterol values were inversely related to weight, to triglyceride values, and to diabetes mellitus. Twenty-eight percent of patients had "desirable" total cholesterol levels (< 200 mg/dL), and 32% had low-density lipoprotein cholesterol values less than 130 mg/dL. Following National Cholesterol Education Program guidelines may be misleading in patients with documented lower-extremity atherosclerosis; therefore, complete lipid/lipoprotein profiles should be performed in these patients.

Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients.

BACKGROUND: Although serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis in the general population and Lp(a) levels are increased in hemodialysis patients, an association of Lp(a) with the risk of clinical events attributed to atherosclerosis has not been established in the chronic hemodialysis patient population. We therefore determined the association between Lp(a) levels and the risk of clinical events of presumed atherosclerotic etiology in a prospective study of an outpatient hemodialysis population. METHODS AND RESULTS: Lp(a) was measured by radioimmunoassay in a baseline cardiovascular disease risk assessment in a consecutive series of 129 hemodialysis patients. The relation between baseline Lp(a) and clinical events of presumed atherosclerotic etiology was determined during 48 months of follow-up. Hemodialysis patients had a median Lp(a) concentration that was approximately four times as high as the median Lp(a) concentration in normal controls and twice as high as the levels in controls with angiographic evidence of coronary artery disease [median Lp(a), 38.4 versus 16.9 mg/dl; p less than 0.001]. Baseline Lp(a) levels were no different in participants with or with no history of a previous clinical event at the time of the baseline examination. However, baseline Lp(a) concentration (p less than 0.001) and a history of atherosclerotic clinical events (p = 0.001) were associated with clinical events during the period of follow-up. In contrast, baseline serum total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, age, gender, race, or duration of hemodialysis were unrelated to this risk in the prospective study. Stepwise multiple logistic regression analysis demonstrated that serum Lp(a) concentration (p = 0.001) and the presence of a previous clinical event (p = 0.004) were the only independent contributors to the risk of a clinical event during the period of follow-up. CONCLUSIONS: Lp(a) is an independent risk factor for clinical events attributed to atherosclerotic cardiovascular disease in patients receiving chronic hemodialysis treatment of end-stage renal disease.

Differences in left ventricular structural and functional changes between pheochromocytoma and essential hypertension. Role of elevated circulating catecholamines.

Experimental findings suggest that catecholamines increase protein synthesis and play a role in cardiac hypertrophy. We hypothesize that elevated circulating plasma catecholamines in pheochromocytoma influence cardiac structural and functional remodeling. We compared 15 patients with surgically proven pheochromocytoma and 15 with untreated essential hypertension; we matched the patients for age, sex, body surface area, and blood pressure (BP) levels. Left ventricular hypertrophy (LVH) was identified by M-mode echocardiography in six patients with pheochromocytoma and in four with essential hypertension. Among both groups there were no differences in cardiac structure, no correlation between left ventricular mass and BP, no significant differences in mitral E-F slope, no correlation between either plasma norepinephrine or plasma epinephrine levels, and no differences in the left ventricular structural indices measured. In the pheochromocytoma group, left ventricular end systolic stress and end systolic diameter were significantly lower and left ventricular percent fractional shortening was higher. Plasma norepinephrine levels were higher in the pheochromocytoma group, but did not differ among patients of that group with and without LVH. We conclude that in both pheochromocytoma and essential hypertension, only a subset of patients develop evidence of LVH, and that in pheochromocytoma, the elevation of circulating plasma catecholamines is not necessarily associated with LVH. These results indicate that factors other than catecholamines and BP determine the development of LVH in pheochromocytoma.

Once-daily pravastatin in patients with primary hypercholesterolemia: a dose-response study.

This multicenter, double-blind, placebo-controlled study was conducted to evaluate dose-response effects and safety of once-daily administration of pravastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Pravastatin 5, 10, 20, 40 mg or placebo was administered at bedtime to 150 patients with primary hypercholesterolemia inadequately controlled on a low-fat, low-cholesterol (AHA Phase I) diet. After 8 weeks of treatment, pravastatin produced dose-dependent reductions in low-density lipoprotein (LDL) cholesterol of 19.2 to 34.1% (p less than or equal to .001 vs. baseline and placebo) and reductions in total cholesterol of 14.3 to 25.1% (p less than or equal to .01 to p less than or equal to .001 vs. placebo and p less than or equal to .001 vs. baseline). The relationship between the loge dose of pravastatin and decrease in LDL cholesterol was linear (p less than 0.002). High-density-lipoprotein cholesterol increased up to 11.7% and triglycerides decreased by as much as 23.9%. Pravastatin was well tolerated; no patient withdrew from the study as a consequence of treatment-related adverse events. Despite its relatively short serum half-life of approximately 2 h, once-daily administration of pravastatin provides a safe and effective means of reducing elevated LDL and total cholesterol.

Lipoprotein abnormalities in the progression of renal disease.

Chronic renal disease is a progressive process. Implicated factors include abnormalities of the clotting cascade, altered prostaglandin metabolism, increased dietary protein intake, and abnormalities of lipoprotein metabolism. Several animal models have associated increased serum concentrations of cholesterol and triglycerides with progressive decline in renal function. The mechanism(s) of lipid-associated renal injury are unknown but may relate to lipid uptake by glomerular mesangial cells, hyperviscosity secondary to the hyperlipidemia, and a direct effect of the lipids on the glomerular basement membrane. Patients with chronic renal disease have well recognized increases in serum lipid concentrations. Whether lowering these concentrations will delay or prevent progressive renal failure or renal histologic abnormalities is unknown, but studies are underway to evaluate the effect of lipid-lowering agents in patients at risk for chronic progressive renal disease.

A reevaluation of the hemodynamics of pheochromocytoma.

We examined the hemodynamic features of 24 untreated patients with surgically proven pheochromocytoma during steady-state periods and compared them with 24 untreated essential hypertensive patients individually matched for sex, age, body surface area, and arterial blood pressure. We found that, despite having 10-fold higher levels of circulating catecholamines, pheochromocytoma patients have hemodynamic characteristics similar to patients with essential hypertension and that, in individual patients, the ratio of circulating norepinephrine to epinephrine had no relation to the hemodynamic profile. In both groups, increased total peripheral resistance is primarily responsible for maintenance of hypertension. These results suggest that, unlike the acute administration of catecholamines, long-term exposure to high levels of circulating catecholamines does not produce hemodynamic responses characteristic of this group of compounds. This might be due in part to desensitization of the cardiovascular system to catecholamines and might explain the clinical observation that some patients can be completely asymptomatic despite harboring an actively catecholamine-secreting pheochromocytoma.