The relationship between circulating fibrinogen and lipoprotein (a) levels in patients with primary dyslipidemia.

The correlation between 2 predictors of vascular events, plasma fibrinogen and serum lipoprotein (a), was evaluated in patients referred to a specialist clinic because of primary hyperlipidemia. A significant correlation existed between fibrinogen and lipoprotein (a) in nonsmokers but not in smokers. Plasma fibrinogen concentration correlated positively and significantly with serum lipoprotein (a) levels in men nonsmokers without cardiovascular disease and in women nonsmokers with cardiovascular disease. Nonsmoker women without cardiovascular disease had significantly higher plasma fibrinogen (3.63 g/L versus 3.07 g/L, P < .0001) than the corresponding men. Nonsmoker women with and without cardiovascular disease had significantly higher lipoprotein (a) levels than the corresponding groups of men (0.36 versus 0.18 g/L; P = .0015 and 0.40 versus 0.26 g/L; P = .008), respectively. The relationship between fibrinogen and lipoprotein (a) levels alters markedly depending on the population selected. This relationship is influenced by gender, the presence of cardiovascular disease and smoking status.     

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.     

Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle

A progressive decline in muscle performance in the rapidly expanding aging population is causing a dramatic increase in disability and health care costs. A decrease in muscle endurance capacity due to mitochondrial decay likely contributes to this decline in muscle performance. We developed a novel stable isotope technique to measure in vivo rates of mitochondrial protein synthesis in human skeletal muscle using needle biopsy samples and applied this technique to elucidate a potential mechanism for the age-related decline in the mitochondrial content and function of skeletal muscle. The fractional rate of muscle mitochondrial protein synthesis in young humans (24 ± 1 year) was 0.081 ± 0.004%·h⁻¹, and this rate declined to 0.047 ± 0.005%·h⁻¹ by middle age (54 ± 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 ± 0.004%·h⁻¹) occurred with advancing age (73 ± 2 years). The mitochondrial synthesis rate was about 95% higher than that of mixed protein in the young, whereas it was approximately 35% higher in the middle-aged and elderly subjects. In addition, decreasing activities of mitochondrial enzymes were observed in muscle homogenates (cytochrome c oxidase and citrate synthase) and in isolated mitochondria (citrate synthase) with increasing age, indicating declines in muscle oxidative capacity and mitochondrial function, respectively. The decrease in the rates of mitochondrial protein synthesis is likely to be responsible for this decline in muscle oxidative capacity and mitochondrial function. These changes in muscle mitochondrial protein metabolism may contribute to the age-related decline in aerobic capacity and muscle performance.     

Dietary fat and hormonal influences on lipoprotein fluidity and composition in premenopausal women

LDL and HDL became more fluid when health, free-living, premenopausal women were fed reduced fat diets with higher proportions of polyunsaturated fatty acids. Lipoproteins were isolated from plasma of 31 female subjects fed one of two sets of diets from typical U.S.A. foods with P/S ratios of 0.3 or 1.0. All subjects were fed high-fat diets (40% of energy) for the duration of four menstrual cycles followed by low-fat diets (20% of energy) for the next four cycles. Blood samples were collected during mid-follicular and mid-luteal phases of the fourth menstrual cycle of each diet period to assess interactive dietary and hormonal control of lipoprotein fluidity. LDL was significantly more fluid, as determined by DPH fluorescence, upon reducing fat consumption from 40 to 20% of energy for subjects eating foods with P/S = 1.0 or 0.3. Generally LDL was more fluid during the follicular phase than the luteal phase of the cycles, thus indicating hormonal influences on LDL fluidity. HDL results were similar but not as pronounced as with LDL. Lipoprotein phospholipid (PL) and cholesteryl ester (CE) fatty acyl compositions were also subject to dietary and hormonal influences. Effects were noted in several fatty acids depending upon diet and hormonal state; however, generally diet fat reduction resulted in reduced linoleate and increased oleate contents. Regression analyses showed that fluidity was more dependent upon the lipoprotein cholesterol content than upon fatty acyl composition.     

Reproducibility and Simplification of 13C-Octanoic Acid Breath Test for Gastric Emptying of Solids

Objective: The accuracy of the ¹³C-octanoic acid breath test is enhanced by breath sampling over 6 h rather than 4 h, but this increases the cost of the test. Our aim was to validate a less costly but accurate sequence of breath sampling for measuring gastric emptying of solids.
Methods: We performed the ¹³C-octanoic acid breath test and tested its reproducibility relative to simultaneous scintigraphy in 30 healthy volunteers.
Results: There was a significant but weak correlation between t _1/2 measured by the two tests (   r _s= 0.54  ,   p < 0.005  ), but not between the duration of the lag phase. The differences in the t _1/2 measurements between the tests were different between subjects but were highly reproducible within subjects. Within- and between-subject variations of measurements of gastric emptying with the ¹³C-octanoic acid breath test were not significantly different from the variations observed with scintigraphy. A subset of 11 breath samples collected over 6 h (24 samples) predicted (   r ² > 0.95  ) the variables characterizing the cumulative appearance of ¹³CO₂ in breath; these samples were at 35, 50, 95, 110, 140, 155, 215, 245, 260, 290, and 335 min. The accuracy of this subset of sampling times was confirmed in a separate set of breath test samples over 6 h from the same 30 subjects.
Conclusions: The ¹³C-octanoic acid breath test for gastric emptying of solids is as reproducible as scintigraphy. A subset of 11 sampling times provides sufficient information to characterize the whole breath-test curve, but the sampling period should be extended to 6 h after dosing.     

Mortality from hepatocellular and biliary cancers: changing epidemiological trends

OBJECTIVES: The incidence of hepatocellular carcinoma may be rising in the United States. The aim of this study was to determine the epidemiological trends in mortality from hepatocellular carcinoma (HCC) and biliary cancers (BCs) in Maryland during the last 3 decades. METHODS: The number of deaths due to HCC and BCs from 1970 to 1997 were obtained from the Maryland State Department of Health & Hygiene vital statistics database. Malignant neoplasms of the gallbladder and intrahepatic and extrahepatic bile ducts were grouped together as biliary cancers. To determine the trend in mortality, the total time period was divided into seven 4-yr periods. RESULTS: Mortality from HCC increased from 0.94 to 1.84 per 100,000 population (rate ratio = 1.94, CI = 1.87-2.03) and that from BCs increased from 1.28 to 1.7 per 100,000 population (rate ratio = 1.31, CI = 1.26-1.36) over the study period. Although mortality due to HCC doubled in men (1.34 to 2.7 per 100,000) during this period, only a modest increase was observed among women (0.59 to 1.06 per 100,000). Because of a marked increase in the number of deaths among white Americans, the difference in HCC-related mortality between white Americans and African Americans decreased considerably during this period. Mean age at death increased steadily for BCs from 67 to 73 yr, whereas there was no real trend for HCC. Among African Americans, the death from HCC remained stable, but there was a 2-fold increase in BC-related death. CONCLUSIONS: There was a marked increase in deaths from HCC over the past 3 decades in Maryland. This increase was more evident among men and white Americans. Deaths due to BCs increased modestly during the same period of observation. The marked rise in BC-related deaths among African Americans remains unexplained.     

Diagnostic and prognostic significance of exercise-induced premature ventricular complexes in men and women: a four year follow-up

Two hundred eighty patients (197 men and 83 women) with normal rest electrocardiograms and no history of prior myocardial infarction were referred for evaluation of chest pain. It was found that exercise-induced premature ventricular complexes had a lower sensitivity, specificity, positive predictive value and negative predictive value in predicting significant coronary artery disease than exercise-induced ST segment depression greater than or equal to 1 mm. The incidence of exercise-induced premature ventricular complexes was not significantly different in patients with no significant coronary artery disease, single vessel disease or multivessel disease. The site of origin of exercise-induced premature ventricular complexes was not helpful in predicting the presence or severity of coronary artery disease. At a mean follow-up period of 47.1 months, exercise-induced premature ventricular complexes did not predict coronary events (cardiac death or nonfatal myocardial infarction) in men or women.     

Glanzmann's thrombasthenia: updated

Glanzmann's thrombasthenia is an autosomal recessive disorder, rare in a global context, but a relatively more common platelet function defect in communities where consanguineous marriages are more frequent. On clinical grounds alone, it cannot be distinguished from other congenital platelet function defects. Epistaxis, gum bleeding, menorrhagia are the common clinical manifestations, whereas large muscle hematoma or hemarthrosis seldom occur in these patients. Essential diagnostic features are a normal platelet count and morphology, a greatly prolonged bleeding time, absence of platelet aggregation in response to ADP, collagen, epinephrine, thrombin and to all aggregating agents which ultimately depend on fibrinogen binding to platelets for this effect, flow cytometry, studies of GPIIb-IIIa receptors on the platelet membrane surface using monoclonal antibodies. The present review describes some of the uncommon features of the disorders and the currently available options which the treating physicians should be aware of during the management of these patients. Although by definition all patients with Glanzmann's thrombasthenia have a virtually complete failure of platelet aggregation, a number of variant forms of GT have been described in which the glycoproteins are present in normal or near normal amounts but are functionally defective. Understanding the pathophysiology of the disorder by the treating physicians is of utmost importance. Presence of high affinity platelet receptors resulting in thrombasthennia-like phenotype may require an antagonistic treatment atypical of classical GT management. It has now been established that different genetic mutations of either GPIIb or IIIa genes results in such a heterogeneity of thrombasthenia phenotype. Glanzmann's thrombasthenia is a paradigm for treating coronary artery disease patients with GPIIb-IIIa antibody and inhibitors. By using these medicines we create a temporary GT-like situation. Hence, understanding this disease is of utmost importance to the practicing cardiologist. As mutations for different variant forms of GT become known, our understanding of how GPIIb-IIIa molecules can be activated to act as a receptor for fibrinogen molecules will be increased. Such understanding undoubtedly will help us to devise better drugs with GPIIb-IIIa inhibitors. Molecular biology techniques have enabled us to equivocally detect heterozygote carriers who are clinically asymptomatic. However, there may be several laboratories in the developing world, which have no access to molecular biology techniques. Development of more robust techniques of quantitation of platelet receptors has enabled an accurate diagnosis of heterozygote carriers or an unborn fetus in the second trimester. The importance of the GPIIb-IIIa polymorphisms in carrier and prenatal diagnosis has not been properly studied. Nowadays the less direct method of PLA1 typing (determination of the levels of platelet antigen) of the foetal platelets as early as 16 weeks of intrauterine life can be used for prenatal diagnosis of GT.