A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin.

Human serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein (LDL). PON1 has a Glu to Arg polymorphism at codon 192 (CGA-->CAA) which is designated R/Q192. The R/Q192 polymorphism has been associated with coronary artery disease (CAD) in several, but not all, case-control studies. We prospectively studied the association of the Q/R192 genotypes with the severity, progression and regression of CAD, plasma lipid levels, clinical events and response to treatment with fluvastatin in a well-characterized cohort. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. A total of 177 (50%), 142 (40%) and 37 (10%) subjects had Q/Q, Q/R and R/R genotypes, respectively. Baseline and final plasma levels of HDL, LDL, triglyceride and other lipoproteins, lesion-specific minimum lumen diameters (MLD), mean MLD, number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes. There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD. The Q/R192 variants of PON1 are not associated with severity, progression or regression of coronary atherosclerosis, plasma lipid levels, clinical events, or response to treatment with fluvastatin. Thus, the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population.

Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy.

OBJECTIVES: We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). BACKGROUND: Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown. METHODS: Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment. RESULTS: Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events. CONCLUSIONS: Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.

Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.

OBJECTIVES: Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND: Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS: Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS: Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS: Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy.

Inflammation plays a key role in susceptibility to coronary atherosclerosis and response to therapy. A diverse array of factors modulates inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and CD14 receptors on the surface of macrophages. Genes encoding for inflammatory markers have variants that regulate their expression and are potential risk factors for atherosclerosis. We prospectively analyzed the possible association of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C variants, located in the promoter regions, with the severity, progression, and response to therapy of coronary atherosclerosis in a well-characterized cohort. We studied 375 subjects enrolled in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping. Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Distributions of genotypes were--for CD14: 100 CC, 184 CT, and 86 TT; IL-6: 152 GG, 153 GC, and 62 CC; and TNF-alpha: 244 GG, 110 GA, and 17 AA. The CD14 CC genotype was associated with incidence of new coronary occlusion (P=0.026); TNF-alpha AA genotype with history of myocardial infarction (MI, P=0.04), and A allele with total occlusions at baseline (P=0.027), and systolic blood pressure (P=0.046); and IL-6-174 CC genotype with baseline minimum lumen diameter (P=0.043) and reduction in lipoprotein(a) with fluvastatin (P=0.03). Otherwise, no association between the genotypes and the biochemical, angiographic, and clinical phenotypes was detected, and neither were genotype-treatment interactions. Functional variants of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C, implicated in the susceptibility to infection, are unlikely to confer major risk for susceptibility to coronary atherosclerosis and its progression or response to therapy in the LCAS population.

Shocks as predictors of survival in patients with implantable cardioverter-defibrillators.

OBJECTIVES: The objective of the study was to determine whether the occurrence of shocks for ventricular tachyarrhythmias during therapy with implantable cardioverter-defibrillators (ICD) is predictive of shortened survival. BACKGROUND: Ventricular tachyarrhythmias eliciting shocks are often associated with depressed ventricular function, making assessment of shocks as an independent risk factor difficult. METHODS: Consecutive patients (n = 421) with a mean follow-up of 756+/-523 days were classified into those who had received no shock (n = 262) or either one of two shock types, defined as single (n = 111) or multiple shocks (n = 48) per arrhythmia episode. Endpoints were all-cause and cardiac deaths. A survival analysis using a stepwise proportional hazards model evaluated the influence of two primary variables, shock type and left ventricular ejection fraction (LVEF <35% or >35%). Covariates analyzed were age, gender, NYHA Class, coronary artery disease, myocardial infarction, coronary revascularization, defibrillation threshold and tachyarrhythmia inducibility. RESULTS: The most complete model retained LVEF (p = 0.005) and age (p = 0.023) for the comparison of any shock versus no shock (p = 0.031). The occurrence of any versus no shock, or of multiple versus single shocks significantly decreased survival at four years, and these differences persisted after adjustment for LVEF. In the LVEF subgroups <35% and <25%, occurrence of multiple versus no shock more than doubled the risk of death. Compared with the most favorable group LVEF > or =35% and no shock, risk in the group multiple shocks and LVEF <35% was increased 16-fold. CONCLUSIONS: In defibrillator recipients, shocks act as potent predictors of survival independent of several other risk factors, particularly ejection fraction.

Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study.

Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.

Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy.

BACKGROUND--Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C. METHODS AND RESULTS--Patients in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) had mildly to moderately elevated LDL-C; many also had low HDL-C, providing an opportunity to compare angiographic progression and the benefits of the HMG-CoA reductase inhibitor fluvastatin in patients with low versus patients with higher HDL-C. Of the 339 patients with biochemical and angiographic data, 68 had baseline HDL-C <0.91 mmol/L (35 mg/dL), mean 0.82+/-0.06 mmol/L (31. 7+/-2.2 mg/dL), versus 1.23+/-0.29 mmol/L (47.4+/-11.2 mg/dL) in patients with baseline HDL-C >/=0.91 mmol/L. Among patients on placebo, those with low HDL-C had significantly more angiographic progression than those with higher HDL-C. Fluvastatin significantly reduced progression among low-HDL-C patients: 0.065+/-0.036 mm versus 0.274+/-0.045 mm in placebo patients (P=0.0004); respective minimum lumen diameter decreases among higher-HDL-C patients were 0. 036+/-0.021 mm and 0.083+/-0.019 mm (P=0.09). The treatment effect of fluvastatin on minimum lumen diameter change was significantly greater among low-HDL-C patients than among higher-HDL-C patients (P=0.01); among low-HDL-C patients, fluvastatin patients had improved event-free survival compared with placebo patients. CONCLUSIONS--Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.

Skin-to-skin holding in the neonatal intensive care unit influences maternal milk volume.

OBJECTIVES: To evaluate the effect of early initiation of skin-to-skin (STS) holding on lactation, we compared 24-hour milk volumes of mothers of ventilated low birth weight infants in an STS group to mothers in a non-STS control group. STUDY DESIGN: Mean 24-hour milk volumes at 2, 3, and 4 weeks after delivery of mothers participating in STS holding were compared with those of a retrospective control group from the 12-month period immediately preceding the introduction of STS holding in the neonatal intensive care unit. A repeated-measures analysis of variance adjusting for baseline volumes (1 week after delivery) was used to evaluate the difference in milk volumes between STS and control groups. RESULTS: Sixteen mothers initiated STS holding during the 2-month study period. Eight mothers met study criteria by initiating STS holding during the first 4 weeks after delivery. During a 2-week period the study group had a strong linear increase in milk volume in contrast to no indicative change of the control group's milk volume. CONCLUSION: STS holding of low birth weight infants initiated in the early intensive care phase can result in a significant increase in maternal milk volume, thereby overcoming the frequently seen insufficient lactation experienced by these mothers.

Body weight gain is correlated with serum cholesterol at 8 weeks of age in pigs selected for four generations for low or high serum cholesterol.

We determined the relationship of BW at birth, weaning (4 wk of age), and 8 wk of age to serum total cholesterol (C), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (TG) at 8 wk of age in pigs, from the fourth generation that had been selected for low (10 litters, 75 pigs, LC) or high (10 litters, 63 pigs, HC) C at 8 wk of age. Mean C concentration at 8 wk of age was 81 +/- 30 mg/dL for LC groups and 136 +/- 19 mg/dL for HC groups. Serum C, HDL-C, and TG concentrations were not correlated with birth weight, suggesting that the physiological factors that may cause reduced weight gain in older animals are not operative in newborn pigs. All three constituents were correlated (P < .05) with BW at weaning and at 8 wk. However, only 4% of the variation in weight at weaning and 7% at 8 wk could be explained by a relationship with serum TG. There was a positive correlation between C and BW at 8 wk (r = .46, P < .05), which was apparent within the subgroups of LC and HC females and LC males (r = .46, .48, .68, respectively); the correlation was low (r = .26) in HC males.

Improved mammography with a reduced radiation dose.

A 2-cm-high focused air-interspaced grid with a 7:1 ratio and eight lamellae per inch was devised. The grid is arc-shaped and pivots on its focal point, the anode-cathode axis. Milliamperage was 35% less for breast phantom radiographs obtained with the new grid versus those obtained with a conventional 5:1 mammographic grid. In a comparison study of five mammograms, each evaluated for five parameters, the images obtained with the new grid were judged to be of equal or better quality than those obtained with a conventional grid in 17 of 20 comparisons.

Growth failure in children with inflammatory bowel disease: a prospective study.

BACKGROUND: Growth failure frequently complicates the clinical course of inflammatory bowel disease (IBD) in children. This study was designed to investigate the role of disease activity versus steroid therapy on growth faltering in this disorder. METHODS: We studied growth failure and its relationship to disease activity and steroid therapy in 69 children who have IBD by prospectively monitoring height for a maximum of 3 years. Disease activity and steroid use were recorded at entry into the study. RESULTS: The prevalence of growth failure was 24%, 23%, and 39% by height velocity, Z score, and height-for-age criteria, respectively; deficits were equally prevalent regardless of the stage of pubertal development. A delay in linear growth persisted throughout puberty and was not reversed after surgery. Patients who had Crohn's disease were twice as likely to have growth abnormalities than patients who had ulcerative colitis. We detected significant negative associations between linear growth and disease activity but not steroid therapy. CONCLUSIONS: In a unique group of children, growth failure is an early, "prepatterned" manifestation of IBD. The inflammatory process, rather than steroid use, has a predominant influence on the development of growth faltering.

The use of cotton balls to collect infant urine samples for 2H/1H and 18O/16O isotope ratio measurements.

To test the validity of cotton balls as a urine collection medium for hydrogen and oxygen isotope ratio measurements, we moistened cotton balls with 1-, 5-, and 10-mL aliquots of urine that contained either natural abundances or one of two enriched levels of 2H and 18O. The liquids were then expressed from the cotton balls, either at once, or after 30 or 60 min of atmospheric exposure, and analyzed for their 2H/1H and 18O/16O isotope ratios. The 2H abundances of the fluids expressed from the cotton balls were significantly lower than the original values. This dilution of 2H, however, diminished in the samples that had a greater volume of urine. We observed no effects of volume or time on 18O. Our results indicate that at low urine volumes, ambient moisture dilutes 2H in the cotton balls, but isotope exchanges and evaporation have little or no effect on the hydrogen and oxygen isotopic abundances of the urine samples. Total body water and energy expenditure values calculated from the 2H and 18O enrichments of 5- and 10-mL urine samples were within 1% of the theoretical values. Therefore, cotton balls are suitable for collection of infant urine samples for hydrogen and oxygen isotope ratio measurements, if the volume of urine that can be expressed from a cotton ball is > or = 5 mL.

Energy expenditure and deposition of breast-fed and formula-fed infants during early infancy.

The energy intake, expenditure, and deposition of 40 breast-fed and formula-fed infants were investigated at 1 and 4 mo of age to explore possible differences in energy utilization between feeding groups. Energy intake was calculated from 5-d test-weighing records or pre- and postweighing of formula bottles, in combination with bomb calorimetry of the milks. Total daily energy expenditure (TDEE) was determined by the doubly labeled water method. Sleeping metabolic rate (SMR) and minimal observable energy expenditure were measured by indirect calorimetry. Activity was estimated as the difference between TDEE and SMR. Energy deposition was estimated from dietary intake and TDEE. Energy intakes were significantly higher for the formula-fed than breast-fed infants at 1 mo (118 +/- 17 versus 101 +/- 16 kcal/kg/d) and 4 mo (87 +/- 11 versus 72 +/- 9 kcal/kg/d) (p less than 0.001). TDEE averaged 67 +/- 8 and 64 +/- 7 kcal/kg/d at 1 mo and 73 +/- 9 and 64 +/- 8 kcal/kg/d at 4 mo for the formula-fed and breast-fed infants, respectively, and differed between feeding groups (p less than 0.04). SMR and minimal observable energy expenditure (kcal/min) were higher among the formula-fed infants at 1 and 4 mo (p less than 0.005). The energy available for activity and the thermic effect of feeding did not differ between feeding groups. Rates of weight gain (g/d) and energy deposition (kcal/kg/d) tended to be greater among the formula-fed infants at 1 and 4 mo (p less than 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)