Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia.

We have investigated the effect of standard doses of two fibrates, gemfibrozil and fenofibrate, on fasting and postprandial remnant-like particles (RLP) in subjects with combined hyperlipidemia. Forty-eight subjects participated; of these, 14 underwent a Vitamin A-fat loading test before and after 6 months of treatment with gemfibrozil (n = 8) and fenofibrate (n = 6). Blood was drawn every 2h for 12h after the test meal. The postprandial response was calculated as the area under the curve (AUC). There was no difference in fasting levels and pre-treatment AUC for triglycerides (TG), RLP cholesterol (RLP-C), RLP triglycerides (RLP-TG) and retinyl palmitate (RetP) between the two treatment groups. There was also no difference in the treatment effect on all parameters between the two treatment groups. Combining the two treatment groups, treatment resulted in a significant reduction in fasting levels and AUC of all four parameters. Assigning the difference observed between pre-treatment AUC of the combined study group and AUC of a normolipidemic (NL) control group as 100%, fibrate treatment resulted in decreases in AUC for TG, RLP-C, RLP-TG and RetP of 68, 69, 69 and 94%, respectively. These results indicate that fibrates are effective agents in reducing the postprandial increase in remnant lipoprotein particles.

Systematic assessment of the quality of osteoporosis guidelines.

BACKGROUND: Numerous agencies have developed clinical practice guidelines for the management of postmenopausal osteoporosis. The study objective was to conduct a systematic assessment of the quality of osteoporosis guidelines produced since 1998. METHODS: Guidelines were identified by searching MEDLINE (1998+), the world wide web, known guideline developer websites, bibliographies of retrieved guidelines, and through consultation with content experts. Each guideline was then assessed by three independent appraisers using the 'Appraisal Instrument for Clinical Guidelines' (version 1) by Cluzeau. RESULTS: We identified 26 unique guidelines from 1998-2001 and 21 met our inclusion criteria. Of the 21 guidelines reviewed, 8 were developed by medical societies, 6 by national groups, 6 by government agencies, and 1 by an international group. Twelve of the guidelines were published, 7 were organizational reports, and 2 were accessible only from the web. Half or more of the 20 items assessing the rigor of guideline development were met by 15% (median quality score 23%, range 5-80%, (95% CI 16.5, 34.7)), 81% met at least half of the 12 items assessing guideline content and context (median score 58%, range 17-83%, (95% CI 50.8, 65.5)), and none met half or more of the items assessing guideline application (median score 0%, range 0-47%, (95% CI -0.5 to 12.6)). Eight guidelines described the method used to assess the strength of evidence, and in 6 there was an explicit link between recommendations and the supporting evidence. Ten guidelines were judged not suitable for use in practice, 10 were acceptable with modification, and one was acceptable for use without modification. CONCLUSION: The methodological quality of current osteoporosis guidelines is low, although their scores for clinical content were higher. Virtually no guidelines covered dissemination issues. Few guidelines were judged as acceptable for use in their current format.

The effect of low dose methotrexate on bone density.

OBJECTIVE: High dose methotrexate (MTX) has been linked with bone loss in oncology patients. However, it is unclear whether longterm low dose MTX used in the treatment of inflammatory arthritis is associated with bone loss. We compared the effect of low dose MTX on bone density in prospectively recruited patients with rheumatoid arthritis (RA) and psoriasis/psoriatic arthritis (Ps/PsA). METHODS: Thirty RA patients and 30 Ps/PsA patients taking MTX were compared to controls not taking MTX (30 with RA, 27 Ps/PsA). Bone mineral density (BMD) of the radius, lumbar spine, trochanter, and femoral neck was measured using Lunar dual energy x-ray absorptiometry. Student t tests were used to detect differences in bone density (using Z scores) of the MTX group versus controls for both the RA and Ps/PsA groups. Analysis of covariance was used to examine for confounders including disease duration, disease activity, age, and sex. RESULTS: BMD of the radius/femoral neck/trochanter did not differ significantly between the MTX treated groups and controls when analyzed by Z scores. The mean difference between the MTX group and controls of the femoral neck was 0.040 (95% CI -0.40, 0.12) and 0.060 (95% CI -0.30, 0.15) for the RA and Ps/PsA groups, respectively. The absolute BMD of the lumbar spine (L2-L4) was higher in the RA MTX group than in controls. Analysis of covariance did not reveal an effect of study group on bone density. CONCLUSION: This study suggests that low dose MTX does not have a negative effect on bone density, at either cortical or trabecular sites.

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100. The study aim was to look for information from postprandial RLP data that could not be known from other markers of triglyceride-rich lipoproteins and fasting TG and RLP data alone. A total of 41 subjects were studied. Eight subjects had hypertriglyceridemia (HTG) and low high-density lipoprotein (HDL), 14 had combined hyperlipidemia (CH), 5 had the apo E2/2 genotype receiving gemfibrozil, 10 were normolipidemic (NL) controls, and 4 had hypercholesterolemia. As a whole group, there was correlation among 1) fasting TG, RLP cholesterol (RLP-C), and RLP-TG but not VLDL apo B100, VLDL apo B48 and their respective postprandial responses measured as incremental area under the curve (IAUC), 2) fasting TG and postprandial IAUC of RLP-C and RLP-TG, 3) RLP-C IAUC, RLP-TG IAUC, and TG IAUC, retinyl palmitate (RP) IAUC, and VLDL apo B48 IAUC but not VLDL apo B100 IAUC. The HTG/low HDL-C and CH groups had higher IAUC for RLP-C, RLP-TG, TG, and RP than the NL group. Fasting and postprandial RLP were triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group. The HTG/low HDL-C and CH groups had a delay in their RLP-C but not RLP-TG peaks suggesting a delay in hepatic clearance of RLP and/or a protracted period of lipolysis and/or processing of RLP. The fasting and postprandial RLP-C/RLP-TG and RLP-C/TG ratios were elevated in the apo E2/2 group in spite of gemfibrozil therapy. The increment in postprandial RLP was, however, not exaggerated. Our data indicate that 1) postprandial RLP lipemia is enhanced in HTG subjects when compared with NL subjects, 2) postprandial RLP lipemia is proportional to fasting RLP and TG levels and mirrors, to a large extent, increases in postprandial TG, RP, and VLDL apo B48 but not VLDL apo B100, 3) there are compositional differences in fasting and postprandial RLP in the three forms of HTG studied, RLP being triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group, and cholesterol-enriched in the apo E2/2 group, and 4) apo E2/2 subjects had high fasting and postprandial RLP-C concentrations in spite of being on treatment with gemfibrozil and having normal fasting and postprandial TG concentrations.

Cardiac troponin T predicts long-term outcomes in hemodialysis patients.

BACKGROUND: Increased plasma troponin T (cTnT), but not troponin I (cTnI), is frequently observed in end-stage renal failure patients. Although generally considered spurious, we previously reported an associated increased mortality at 12 months. METHODS: We studied long-term outcomes in 244 patients on chronic hemodialysis for up to 34 months, correlating the outcomes to plasma cTnT in routine predialysis samples. In addition, subsequent plasma samples at least 1 year later and within 6 months of data analysis were available in 97 patients and were used to identify patients with increasing plasma cTnT. The endpoints used were death and new or worsening coronary, cerebro-, and peripheral vascular disease and neuropathy. RESULTS: Transplantation occurred more frequently in patients with low initial cTnT: 31%, 13%, and 3% in the groups with cTnT < 0.010, 0.010-0.099, and > or = 0.100 microg/L, respectively. In the same groups, total deaths occurred in 6%, 43%, and 59% and cardiac deaths in 0%, 14%, and 24% of patients. In patients with follow-up samples, the group with increasing cTnT had a significantly increased death (relative risk, 2.0; P = 0.028). The increase was mainly in cardiac and sudden deaths. CONCLUSIONS: Higher plasma cTnT predicts long-term all-cause mortality in hemodialysis patients, even at concentrations < 0.100 microg/L, as does an increasing cTnT concentration over time.

Gastric lipoma causing gastroduodenal intussusception.

A case of gastroduodenal intussusception caused by a submucosal gastric lipoma in a 48-year-old man is presented. He had intermittent symptoms of regurgitation and heartburn for a period of three years. Barium meal and CT scan showed a mass in the first part of duodenum. At laparotomy there was intussusception of gastric antrum into the duodenum with a submucosal lipoma in the antrum which formed the apex of the intussusception.

Correlation of antemortem serum creatine kinase, creatine kinase-MB, troponin I, and troponin T with cardiac pathology.

BACKGROUND: Spurious increases in serum troponins, especially troponin T, have been reported in patients with and without acute myocardial syndromes. METHODS: We studied 78 autopsied patients without clinical myocardial infarction (MI) and correlated histologic cardiac findings with antemortem serum creatine kinase (CK), its MB isoenzyme (CK-MB), cardiac troponin I (cTnI), and cardiac troponin T (cTnT). RESULTS: There was no significant myocardial pathology in 15 patients. Cardiac pathologies were in five groups: scarring from previous MI or patchy ventricular fibrosis (n = 9), recent MI (n = 27), healing MI (n = 7), degenerative myocyte changes consistent with congestive heart failure (CHF; n = 12), and other cardiac pathologies (n = 8). The median concentrations in the five groups were not significantly different for either CK or CK-MB. Compared with the no-pathology group, only the MI group was significantly different for cTnI, and the MI and other pathology groups were significantly different for cTnT. For patients with MI, 22%, 19%, 48%, and 65% had increased CK, CK-MB, cTnI, and cTnT, respectively; for CHF and other cardiac pathologies combined, the percentages were 28%, 17%, 22%, and 50%. For patients with increased cTnI, 72% and 28% had MI and other myocardial pathologies, respectively; patients with increased cTnT had 64% and 36%, respectively. Patients without myocardial pathology had no increases in CK-MB, cTnI, or cTnT. CONCLUSIONS: All patients with increased serum CK-MB, cTnI, and cTnT had significant cardiac histologic changes. The second-generation cTnT assay appears to be a more sensitive indicator of MI and other myocardial pathologies than the cTnI assay used in this study.

Increased mortality in hemodialyzed patients with elevated serum troponin T: a one-year outcome study.

OBJECTIVES: To determine the significance of elevated serum troponin T (cTnT) occurring in hemodialysis patients in the absence of clinical evidence of acute coronary ischemia. DESIGN AND METHODS: Twelve-month follow-up of cohort of 172 hemodialyzed patients with known serum cTnT concentration. The cohort consisted of patients undergoing hemodialysis in a hospital unit over a 5-month period, with one to four measurements of cTnT. The main outcome measure was death. Cause of death was determined by autopsy in six patients. RESULTS: Of the 31 deaths, 12 were due to acute coronary disease, 14 were noncoronary, and 5 were undefined. Death rates of patients with cTnT <0.1, 0.1-0.2, and >0.2 microg/L were 9.9% (11/111), 32.4% (12/37), and 33.3% (8/24), respectively. The increase in death rate with cTnT > or =0.1 microg/L was significant (p<0.001) for noncoronary deaths, but not for acute coronary deaths. The risk ratios for noncoronary deaths in the subgroups were: nondiabetics 6.6 (95% CI 1.9-23.6), patients with no coronary artery disease 7.3 (1.6-32.4), patients with no peripheral vascular disease 8.9 (2.0-39.7), and hypertensives 9.0 (1.1-76.5). Significant increase in coronary deaths was seen only in patients without hypertension and those aged > or =50 years. The risk ratios for these groups were 9.3 (1.2-74.3) and 3.3 (1.0-10.6), respectively. CONCLUSIONS: Serum cTnT is a potential prognostic marker of mortality in hemodialyzed patient, with increase in death from coronary and noncoronary causes.

Cardiac troponin T in hemodialyzed patients.

We studied the extent and pattern of increased cardiac troponin T (cTnT) concentrations in 174 hemodialyzed patients. cTnT concentrations were above 0.10 and 0.20 microg/L in 29% and 10% of patients, respectively. In patients without acute coronary disease, the highest value observed was 3.2 microg/L. cTnT increased after dialysis in 10 of 12 patients, with a mean increase of 0.14 microg/L. In 125 patients with samples taken at 1-month intervals, 34% of patients showed differences <20%, but 16% of patients had differences greater than twofold. Serum creatinine and urea, adequacy of dialysis, and duration on dialysis did not explain increased concentrations. Sixty percent of 57 diabetic patients had increased concentrations; the patients with multiple diabetic complications had the highest positivity. cTnT was increased in all eight patients with complications of neuropathy, retinopathy, coronary, and peripheral vascular disease; in 80% of patients with neuropathy; in 77% with peripheral vascular disease; in 73% with retinopathy; and in 70% with coronary artery disease.

Establishing reference intervals for DPC's free testosterone radioimmunoassay.

OBJECTIVE: To establish reference intervals for serum free testosterone for DPC's Free Testosterone assay. METHODS: We used data from healthy subjects and patients to determine reference intervals by parametric and non-parametric methods after partitioning by sex and age. RESULTS: In males, there was a significant decrease in free testosterone concentrations with age. Reference intervals derived from a combination of 2075 "healthy" and patients' results gave similar values by parametric and nonparametric methods. However, the subgroups failed the test for Gaussian distribution. For each decade from 20 years on and > or = 60 years, the intervals based on 2.5th and 97.5th percentiles were: 24.1-94.8, 25.0-89.3, 23.4-81.7, 22.5-80.4, and 21.5-74.3 pmol/L respectively, in females, there was little change with age. The frequency distribution of 1915 patients was positively skewed, and showed a wider range than "healthy." Using square roots of values gave a Gaussian distribution. The central 95% intervals based on 187 "healthy" subjects were: 0.5-8.1 and 0.0-6.4 pmol/L for 20-59 and > or = 60 years, respectively. CONCLUSION: Developing reference intervals for free testosterone was complicated by the need to partition data by gender and age, difficulty in establishing disease in subjects and presence of physiological and other factors which can affect concentration in health and disease.

The atherogenic significance of an elevated plasma triglyceride level.

The importance of hypertriglyceridemia as an independent predictor of coronary artery disease (CAD) remains unsettled. Hypertriglyceridemia, with or without associated hypercholesterolemia, occurs more frequently in premature CAD subjects than does hypercholesterolemia alone. With univariate analysis, most studies show a positive correlation between plasma triglyceride (TG) level and risk for CAD, but with multivariate analysis plasma TG level is no longer an independent risk factor except in women and diabetics. Prospective studies have shown that subjects with a high LDL/HDL cholesterol ratio and a high plasma TG level have the highest risk for CAD. Hypertriglyceridemia signifies the presence of excess triglyceride-rich lipoproteins (TRL), including chylomicrons, VLDL, and their remnants. The question then becomes one of whether TRL are directly or indirectly involved in atherogenesis. TRL were thought to be too big to infiltrate the arterial wall, and histopathological studies have shown cholesterol but not triglyceride accumulation in the atherosclerotic plaque. However, there was a recent demonstration of undegraded VLDL and IDL in atherosclerotic plaques. Larger TRL may undergo hydrolysis on the arterial surface to become smaller particles before entry into the intima. Possible cellular pathways for the uptake of TRL by macrophages have been described. The smaller TRL (Sf 20-60), including postprandial chylomicron remnants, are believed to be the most atherogenic of all TRL particles. Because large amounts of TRL are produced in the postprandial period, atherogenesis involving TRL may be primarily a postprandial phenomenon. Once in the intima, TG may undergo hydrolysis, releasing free fatty acids and mono- and diacyl glycerol, accounting for the dearth of TG in atherosclerotic lesions. Particle for particle, VLDL delivers five times as much cholesterol as LDL does to the macrophage.

Chronic increased serum lipase without evidence of pancreatitis: tumor-derived lipase?

A 51-year-old man developed a large retroperitoneal tumor with liver and lymph node metastases; there was no radiological evidence of pancreatic involvement. Despite the progression of disease, results of laboratory tests, notably serum amylase, were normal except for minor increases in aspartate aminotransferase and gamma-glutamyltransferase and a marked increase in lipase. The increased lipase was not attributable to formation of macroenzyme. To determine the source of the lipase, we fractionated serum and a tumor biopsy homogenate, using electrophoresis. The lipase pattern obtained from the patient's serum differed from that seen in serum from a patient with acute pancreatitis. Additionally, the lipase pattern obtained from a homogenate of biopsy sample from the retroperitoneal tumor did not match the pattern observed for normal pancreas. Apparently, the source of this increased serum lipase activity was the nonpancreatic tumor.