Frank A. Franklin

The Relation of Apolipoproteins A-I and B in Children to Parental Myocardial Infarction

Clinical studies suggest that serum levels of apolipoproteins A-I and B may be more strongly related to coronary artery disease than are their respective lipoprotein-cholesterol fractions. Therefore, we assessed the association between levels of apolipoprotein B, apolipoprotein A-I, lipids, and lipoprotein cholesterols in children and the reported histories of myocardial infarction in their parents in a survey of 2416 black and white school-age children. As compared with children whose fathers did not report a myocardial infarction, those whose fathers reported having had an infarction (n = 139) had a lower mean level of apolipoprotein A-I (137 vs. 141 mg per deciliter; P = 0.04) and a lower ratio of low-density lipoprotein cholesterol to apolipoprotein B (1.08 vs. 1.11; P = 0.007), along with a higher ratio of apolipoprotein B to apolipoprotein A-I (0.64 vs. 0.61; P = 0.04). These associations existed independently of the childrens race, sex, age, and history of obesity, smoking, alcohol intake, and use of oral contraceptives. Children whose mothers reported having had a myocardial infarction (n = 56) had no decrease in the ratio of low-density lipoprotein cholesterol to apolipoprotein B, but they tended to have an elevated ratio of apolipoprotein B to apolipoprotein A-I. In contrast, serum lipoprotein-cholesterol fractions in children were not related to myocardial infarctions in either parent. These results provide further evidence that apolipoproteins are more strongly related to the risk of cardiovascular disease than are lipoprotein-cholesterol fractions.

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin

This randomized, double-blind, multicenter, diet-and-placebo-controlled study was designed to clarify the dose-response relationship of lovastatin therapy to lipid-modifying efficacy and drug-related adverse events. Exclusion criteria were minimized so that study patients were representative of the majority of patients with moderate hypercholesterolemia seen in medical practice. After 6 weeks on the American Heart Association Step 1 Diet, a total of 8,245 patients were randomly assigned to 48 weeks of treatment with diet and placebo or lovastatin at dosages of 20 or 40 mg once a day or 20 or 40 mg twice a day. All adverse events were monitored, with particular attention to evaluation of liver and muscle. Liver transaminase elevations suggestive of possible hepatotoxicity, defined as successive elevations in either aspartate transaminase or alanine aminotransferase greater than 3 times the upper limit of normal, occurred in equal numbers of placebo and lovastatin 20 mg/day treated patients (0.1%). The frequencies were higher in lovastatin 40 mg/day and 80 mg/day patient groups (0.9 and 1.5%, respectively). No patient was diagnosed as having clinically symptomatic hepatic dysfunction. Creatinine kinase (CK) elevations above the upper limit of normal occurred frequently in placebo- (29%), as well as lovastatin-treated patients (29-35%), and muscle symptoms were reported with similar frequency in all groups (7-9%). The combination of muscle symptoms with marked CK elevations (greater than 10 times the upper limit of normal) was seen in only five patients: one in a 40 mg/day dose group and four in the 80 mg/day dose group. No patient developed rhabdomyolysis. The incidence of clinical and laboratory adverse events requiring discontinuation was 6% for the placebo group and from 7% (20 mg/day) to 9% (80 mg/day) for lovastatin treatment groups. No new types of adverse experiences related to lovastatin treatment were reported. Lovastatin, as an adjunct to diet for the reduction of elevated LDL cholesterol, was generally very well tolerated.

Threshold for Effects of Vitamin D Deficiency on Glucose Metabolism in Obese Female African-American Adolescents

CONTEXT Vitamin D status can influence insulin resistance. OBJECTIVE The aim of the study was to determine the prevalence of vitamin D deficiency in obese African-American (AA) adolescent females in a southeastern latitude and to determine the relationship of 25-hydroxyvitamin D [25(OH)D] with insulin and glucose dynamics. DESIGN We conducted a cross-sectional study in a University Childrens Hospital. METHODS Serum 25(OH)D, fasting glucose, PTH, serum calcium, serum lipids, serum transaminases, and C-reactive protein were assessed. Indices of insulin sensitivity and resistance were determined from an oral glucose tolerance test. Subjects were classified as vitamin D deficient or sufficient, based on the traditional vitamin D deficiency definition [serum 25(OH)D <20 ng/ml] and also by a lower 25(OH)D cut-point of 15 ng/ml or less. RESULTS A total of 51 AA adolescent females (body mass index, 43.3 +/- 9.9 kg/m(2); age, 14 +/- 2 yr) were studied. Serum 25(OH)D concentrations were 20 ng/ml or less in 78.4% and 15 ng/ml or less in 60.8% of subjects. There were no significant group differences in the metabolic outcomes when subjects were classified using the traditional vitamin D deficiency definition. The Matsuda index of insulin sensitivity was significantly lower (P = 0.02), and insulin area under the curve was significantly higher (P = 0.04) in subjects with 25(OH)D concentrations of 15 ng/ml or less vs. those with higher concentrations. CONCLUSIONS Vitamin D deficiency is highly prevalent in obese, AA female adolescents and may promote insulin resistance. Our data suggest that a 25(OH)D concentration of 15 ng/ml or less may be the threshold by which vitamin D deficiency confers negative effects on insulin sensitivity.

Testing mediating variables in a school-based nutrition intervention program.

This study identified mediators of a school-based nutrition intervention for 4th graders and their parents. Nine variables were tested for satisfying 4 conclusions necessary to establish mediation of intervention effects on changes in fruit and vegetable consumption (FVC) in 4th graders (N = 1,676). FVC was measured in children by the use of 24-hr dietary recalls. Mediators were assessed by the use of questionnaires completed by children and parents. All 4 conclusions were met for positive outcome expectancies. Knowledge, self-efficacy, and parent consumption satisfied the first 3 conclusions for mediation but the mediating effects were not statistically significant (Conclusion 4). Future mediational analyses and the creation of a national database of mediators are crucial for increasing strength and efficiency of school-based nutrition programs.

Methods, Results, and Lessons Learned from Process Evaluation of the High 5 School-Based Nutrition Intervention:

This article describes the process evaluation of High 5, a school-based intervention targeting fruit and vegetable consumption among fourth graders and their families. The outcome evaluation involved 28 schools randomized to intervention or control conditions. The intervention included classroom, family, and cafeteria components. Process evaluation was completed on each of these components by using observations, self-report checklists, surveys, and other measures. Results indicated high implementation rates on the classroom activities. Moderate family involvement was attained, perhaps diminishing intervention effects on parent consumption. Cafeterias provided environmental cues, and fruit and vegetable offerings as directed by the program. A lower dose of the intervention was delivered to schools with larger African American enrollments and lower-income families. This article provides insights into the effective elements of a school-based dietary intervention and provides suggestions for process evaluation in similar studies.

Effect of weight loss on urinary incontinence in overweight and obese women: results at 12 and 18 months.

PURPOSE Initial weight loss improves urinary incontinence in overweight and obese women. In this study we examined the longer term effects of a weight loss intervention on urinary incontinence. MATERIALS AND METHODS Overweight and obese women (mean +/- SD age 53 +/- 10 years) with 10 or more urinary incontinence episodes weekly were randomized to an 18-month behavioral weight loss intervention (226) or control group (112). Outcome measures were collected at 12 and 18 months. RESULTS At baseline women had a mean body mass index of 36 +/- 6 kg/m(2) and reported a mean of 24 +/- 18 incontinence episodes weekly. Of the patients 86% completed 18-month measurements. The percent weight loss in the intervention group averaged 8.0%, 7.5% and 5.5% at 6, 12 and 18 months, respectively, vs approximately 1.5% in the control group (all values p <0.001). Compared with controls at 12 months the intervention group reported a greater percent reduction in weekly stress urinary incontinence episodes (65% vs 47%, p <0.001), and a greater proportion achieved at least a 70% decrease in weekly total and stress urinary incontinence episodes. At 18 months a greater proportion of women in the weight loss intervention group had more than 70% improvement in urge incontinence episodes but there were no significant differences between the groups for stress or total urinary incontinence. The intervention group also reported greater satisfaction with changes in urinary incontinence than the control group at 6, 12 and 18 months. CONCLUSIONS Weight loss intervention reduced the frequency of stress incontinence episodes through 12 months and improved patient satisfaction with changes in incontinence through 18 months. Improving weight loss maintenance may provide longer term benefits for urinary incontinence.

Improving urinary incontinence in overweight and obese women through modest weight loss.

OBJECTIVE: To examine the relationship between magnitude of weight loss and changes in urinary incontinence frequency. METHODS: Overweight and obese women (N=338) with 10 or more urinary incontinence episodes per week were assigned randomly to an intensive 6-month behavioral weight loss program followed immediately by a 12-month weight maintenance program (intervention; n=226) or to a structured education program (control; n=112). The intervention and control groups were combined to examine the effects of the magnitude of weight loss on changes in urinary incontinence assessed by 7-day voiding diary, pad test, and self-reported satisfaction with change in urinary incontinence. RESULTS: Compared with participants who gained weight (reference), those who lost 5% to less than 10% or 10% or more of their body weight had significantly greater percent reductions in urinary incontinence episodes and were more likely to achieve at least a 70% reduction in the frequency of total and urge urinary incontinence episodes at 6, 12, and 18 months. Satisfaction was also related to magnitude of weight loss; approximately 75% of women who lost 5% to less than 10% of their body weight reported being moderately or very satisfied with their changes in urine leakage. CONCLUSION: Weight losses between 5% and 10% of body weight were sufficient for significant urinary incontinence benefits. Thus, weight loss should be considered as initial treatment for incontinence in overweight and obese women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00091988. LEVEL OF EVIDENCE: II

Impact of intestinal lengthening on the nutritional outcome for children with short bowel syndrome

Survival among children with short bowel syndrome has increased with the use of supportive nutritional techniques including parenteral and enteral nutrition. Further improvement in outcome has been sought by using intestinal lengthening procedures to lengthen the bowel, improve intestinal motility, initiate a progressive increase in intestinal mucosal mass, and thereby improve tolerance to enteral nutrition. The authors examine the growth parameters and the tolerance to enteral nutrition in children with refractory short bowel syndrome before and after intestinal lengthening procedures. For seven children, the percentage of calories from enteral nutrition, the medical and surgical complications, and the number of days in the hospital (1 year before and 2 years after the lengthening procedure) were evaluated. The mean birth weight was 1,991 g (range, 1,198 to 3,096 g). The initial diagnoses requiring bowel resection included necrotizing enterocolitis, multiple small bowel atresias, gastroschisis with midgut volvulus, cloacal exstrophy, and long-segment Hirschsprungs disease. The mean length of the residual small bowel was 49 cm (range, 6 to 92 cm). All but one child had surgical resection of the ileocecal valve. The percentage of enteral nutrition calories significantly increased by 9 months after the procedure (P < .008, analysis of variance). Only one child has been completely weaned from parenteral nutrition. All childrens growth parameters have been maintained or improved (weight/age, height/age, and weight/height). Few major medical and surgical complications have been observed. Central venous catheter infection has been the most common medical complication. The mean number of hospitalization days decreased during the second year after the lengthening procedure. The authors conclude that the intestinal lengthening procedure enhances the tolerance for enteral nutrition, improves the nutritional status, and decreases the need for hospitalization. The procedure should be considered for children with refractory short bowel syndrome who require prolonged parenteral nutrition.

Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia

In the multicenter, double-blind EXCEL (Expanded Clinical Evaluation of Lovastatin) study the efficacy of lovastatin in modifying plasma lipids and lipoproteins in 8,245 participants with moderate primary hypercholesterolemia was evaluated. Patients were randomly assigned to 48 weeks of treatment with diet and placebo or diet and lovastatin 20 or 40 mg once a day, or 20 or 40 mg twice a day. At all of these dosages, lovastatin produced substantial dose-dependent reductions in low-density-lipoprotein (LDL)-cholesterol levels, averaging 24% (20 mg/day) to 40% (80 mg/day). The magnitude of the effect of this lipoprotein was further reflected by the percentage of patients who achieved National Cholesterol Education Program (NCEP) goals. In the absence of coronary artery disease (CAD) or two other CAD risk factors, the LDL-cholesterol goal of 4.14 mmol/L (160 mg/dL) was attained by 22% of patients in the placebo group and between 81% (20 mg/day) and 96% (80 mg/day) of those treated with lovastatin. For those with CAD or at least two other CAD risk factors, the LDL-cholesterol goal of 3.36 mmol/L (130 mg/dL) was attained by 4% of placebo patients and between 38% (20 mg/day) and 83% (80 mg/day) of those treated with lovastatin. Lovastatin also increased high-density-lipoprotein cholesterol (7-10%) and decreased triglycerides (10-19%) in a dose-dependent manner. Thus, when used as an adjunct to a prudent diet, lovastatin produces favorable changes in the entire lipoprotein profile and is a highly effective agent for managing patients with primary hypercholesterolemia.