Clinical results with gemfibrozil and background to the Helsinki Heart Study

The efficacy and safety of gemfibrozil in the treatment of dyslipidemia were investigated in a 6-year follow-up study of 254 patients with primary dyslipidemia. Most were middle-aged men with type IIA or IIB hyperlipoproteinemia. A significant correction in plasma lipid levels was seen in nearly 90% of all cases irrespective of the type of lipid abnormality. Overall, gemfibrozil therapy decreased levels of plasma total cholesterol 16%, triglycerides 45 % and low-density lipoprotein (LDL) cholesterol 21 %. The high-density lipoprotein (HDL) cholesterol concentration was increased 23%. The ratio of HDL cholesterol to total cholesterol increased from 0.13 to 0.20, approaching the value of matched controls in the population (0.23). Results in small pilot studies of patients with renal failure and uremia, the nephrotic syndrome or chemical diabetes were also encouraging. Plasma prekallikrein and kininogen values increased with gemfibrozil, possibly indicating correction of defective blood coagulation and fibrinolysis. Side effects were few; abdominal discomfort was noted in some patients and a skin rash in 2. In the intervention group, the number of myocardial infarctions was lower than expected (5 rather than 16). Results to date indicate that gemfibrozil effectively corrects most types of dyslipidemia, with minor side effects. The small number of observed myocardial infarctions supports the suggestion that an increase in HDL and a decrease in LDL levels during gemfibrozil therapy may be of clinical benefit in the prevention and management of coronary artery disease in subjects with dyslipidemia. The Helsinki Heart Study was designed as a definitive test of this hypothesis. This large, double-blind, placebo-controlled, primary (4,050 patients) and secondary (650 patients) prevention study is currently in progress.     

Quantification of liver perfusion with [(15)O]H(2)O-PET and its relationship with glucose metabolism and substrate levels

BACKGROUND/AIMS: Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. METHODS: Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. RESULTS: Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). CONCLUSIONS: Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.     

Comparative study using oral solutions of bambuterol once daily or terbutaline three times daily in 2-5-year-old children with asthma. Bambuterol Multicentre Study Group

The aim of this study was to compare safety and efficacy of bambuterol hydrochloride (10 mg) oral solution administered once daily in the evening with terbutaline sulphate (0.075 mg/kg body weight) oral solution administered three times daily in 2-5-year-old children with asthma. There were two treatment groups: (2/3) of the patients received bambuterol and (1/3) received terbutaline. The study was double-blind, randomized, and of a parallel group design, and it lasted for 3 months after a 2-week run-in period. The primary objective was to evaluate safety (adverse events, and changes in blood pressure, pulse rate, hematology, and clinical chemistry parameters). Plasma concentrations of terbutaline and/or bambuterol were also measured. Evaluation of efficacy (diary card data) was a secondary objective. A total of 155 patients (range, 2-6 years; 3 patients were 6 years old at randomization) were treated with the study drugs; 104 patients received bambuterol and 51 patients received terbutaline. Both treatments showed a good safety profile with respect to clinical and laboratory tests, and they were generally well tolerated. Reported adverse events were mild to moderate. There were no statistically significant differences between treatment groups in any of the efficacy variables (diary variables: peak expiratory flow (PEF), asthma symptoms, restlessness, other reported symptoms, use of inhaled bronchodilators, and nighttime awakenings). For morning PEF, the mean increase from run-in to treatment was 16.9 L/min in the terbutaline group and 23.3 L/min in the bambuterol group. For evening PEF, the mean increase was 20.2 L/min in the terbutaline group and 20.6 L/min in the bambuterol group. In conclusion, once-daily bambuterol is as safe and effective as terbutaline given three times daily. The study also confirmed that bambuterol has a 24-hr duration of action, and therefore its once daily administration, makes it a preferred bronchodilator agent. Pediatr Pulmonol. 2000:29:194-201.     

Temporal changes and prognostic significance of measures of heart rate dynamics after acute myocardial infarction in the beta-blocking era

Previous studies have shown that indexes describing heart rate (HR) dynamics may predict subsequent deaths of patients after an acute myocardial infarction (AMI). Because beta-blocking (BB) drugs affect both mortality and HR dynamics, the prognostic power of measurements of HR dynamics may have changed in the current era of BB therapy. This study assessed the temporal changes and prognostic significance of time-domain, spectral, and fractal indexes of HR variability along with HR turbulence after an AMI among patients with optimized BB medication. SD of NN intervals, spectral indexes, the short-term fractal scaling exponent (alpha(1)), power-law slope (beta), and turbulence onset and slope were measured in 600 patients at 5 to 7 days after AMI and in 416 patients at 12 months after AMI. In the multivariate analysis, after adjusting for clinical variables, only reduced fractal HR indexes, alpha1 and beta (p <0.01 for both), turbulence onset, and slope (p <0.05 for both), measured at the convalescent phase after AMI, predicted subsequent cardiac death. All time-domain and spectral HR variability indexes and turbulence onset increased significantly during the 12-month period after AMI (p <0.001 for all), whereas the fractal indexes and turbulence slope remained unchanged. Late after AMI, reduced beta (p <0.05) and turbulence slope (p <0.01) were the only independent predictors of cardiac mortality. Traditional time-domain and spectral measurements of HR variability and turbulence onset improved significantly after AMI, whereas the fractal HR dynamics and turbulence slope remained stable. Fractal HR variability and HR turbulence retain their prognostic power in the BB era, when measured either at the convalescent or late phase after AMI.     

Insulin-mediated hepatic glucose uptake is impaired in type 2 diabetes: evidence for a relationship with glycemic control

Impaired hepatic glucose uptake (HGU) has been implicated in the development of hyperglycemia in type 2 diabetes; the relative impact of plasma glucose and insulin levels on this process remains controversial. We compared the effects of euglycemic hyperinsulinemia on HGU, skeletal muscle glucose uptake, and hepatic influx rate-constant (H-Ki) in 38 diet-treated diabetic patients and 22 nondiabetic controls, using positron emission tomography with (18)F-fluorodeoxyglucose and the insulin clamp technique. Control subjects were divided into two subgroups: one including older, heavier, insulin-resistant controls (whole-body glucose uptake, M = 21.4 +/- 5.4 micromol x min(-1) x kg(-1)) to match characteristics of diabetic patients (M = 20.4 +/- 9.9); the other including younger, leaner, insulin-sensitive controls (M = 48.2 +/- 9.9, P < 0.01). Skeletal muscle glucose uptake showed a similar group distribution as the M value. Insulin clearance rates were lower, whereas glycosylated hemoglobin and clamp plasma insulin levels were higher in diabetic patients than in controls. HGU and H-Ki were similar in the two nondiabetic subgroups and lower in diabetic patients than in controls (1.9 +/- 0.5 vs. 2.3 +/- 0.7 micromol x min(-1) x 100 ml(-1), and 0.37 +/- 0.09 vs. 0.44 +/- 0.14 ml x min(-1) x 100 ml(-1), P < or = 0.01). In the whole dataset, H-Ki was inversely related to fasting plasma glucose (correlation coefficient = -0.40, P = 0.0018). In diabetic subjects, H-Ki was reciprocally related to glycosylated hemoglobin (correlation coefficient = -0.36, P = 0.029). We conclude that insulin-mediated HGU is impaired, in type 2 diabetes, in some proportion to the degree of glycemic control.     

Cognitive flexibility modulates maturation and music‐training‐related changes in neural sound discrimination

Previous research has demonstrated that musicians show superior neural sound discrimination when compared to non‐musicians, and that these changes emerge with accumulation of training. Our aim was to investigate whether individual differences in executive functions predict training‐related changes in neural sound discrimination. We measured event‐related potentials induced by sound changes coupled with tests for executive functions in musically trained and non‐trained children aged 9–11 years and 13–15 years. High performance in a set‐shifting task, indexing cognitive flexibility, was linked to enhanced maturation of neural sound discrimination in both musically trained and non‐trained children. Specifically, well‐performing musically trained children already showed large mismatch negativity (MMN) responses at a young age as well as at an older age, indicating accurate sound discrimination. In contrast, the musically trained low‐performing children still showed an increase in MMN amplitude with age, suggesting that they were behind their high‐performing peers in the development of sound discrimination. In the non‐trained group, in turn, only the high‐performing children showed evidence of an age‐related increase in MMN amplitude, and the low‐performing children showed a small MMN with no age‐related change. These latter results suggest an advantage in MMN development also for high‐performing non‐trained individuals. For the P3a amplitude, there was an age‐related increase only in the children who performed well in the set‐shifting task, irrespective of music training, indicating enhanced attention‐related processes in these children. Thus, the current study provides the first evidence that, in children, cognitive flexibility may influence age‐related and training‐related plasticity of neural sound discrimination.     

Demonstration of fibronectin in human cerebrospinal fluid.

Fibronectin is a glycoprotein found in plasma (cold-insoluble globulin), connective tissues, and cultures of fibroblasts and astroglial cells. This paper describes the identification of fibronectin in human CSF. Fibronectin in CSF was immunologically indistinguishable from the plasma form, as shown by double-diffusion analysis and by radioimmunoassay specific for fibronectin. Fibronectin was isolated from human CSF by affinity chromatography on Sepharose-coupled gelatin and was further analyzed by SDS-polyacrylamide gel electrophoresis. It showed a polypeptide band similar to that of plasma fibronectin. The fibronectin concentration in CSF of 17 neurological outpatients without demonstrable organic lesion in the CNS was 3.0 +/- 1.6 microgram/ml (mean +/- S.D.) which is about 0.6% of total CSF protein. In CSF of 11 MS patients, the concentration was significantly (p less than 0.005) lower (1.6 +/- 0.2 microgram/ml). Of patients with brain tumors, seven had very low levels, three were normal, and two had very high levels. The cause for the low levels in MS and tumor patients is not known.     

XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study

Introduction

It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking.

Methods

The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses.

Results

No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1-399 Gln allele (OR 2.33, 95% CI 1.30–4.19, p _int 0.025) or XPD-751 Gln/Gln genotype (OR 2.52, 95% CI 1.27–5.03, p _int 0.011) compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66–10.3) and 4.41 (95% CI 1.62–12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00–2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes.

Conclusion

Our results do not indicate a major role for XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women.