Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Weight change in the management of youth-onset type 2 diabetes: the TODAY clinical trial experience.

BACKGROUND: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial documented that metformin plus rosiglitazone, but not metformin plus lifestyle intervention, provided superior durability of glycemic control relative to metformin monotherapy. OBJECTIVES: We examined weight changes among TODAY participants that completed at least 6 months of treatment, evaluated predictors of lifestyle outcome, and examined whether weight changes were related to cardiometabolic outcomes across treatment arms. METHODS: The 595 youth with type 2 diabetes, (85.1% of randomized participants aged 11-17 years) completed assessments of weight-related and cardiometabolic measures at months 0, 6, 12 and 24. Repeated measures models were used to investigate associations over time. RESULTS: Lifestyle intervention did not enhance outcome relative to metformin alone and no predictors of response to lifestyle treatment were identified. However, changes in percent overweight across treatment arms were associated with changes in multiple cardiometabolic risk factors, and decreases of ≥ 7% in overweight were associated with significant benefits over 24 months. CONCLUSIONS: Although adjunctive intensive lifestyle intervention did not improve weight-related outcomes, weight changes in the full TODAY sample were associated with small, but significant improvements in cardiometabolic status, highlighting the importance of optimizing weight management in youth with T2DM.

Cardiovascular risk factors in multi-ethnic middle school students: the HEALTHY primary prevention trial.

OBJECTIVE: The objective of this study was to examine the effects of an integrated, multi-component, school-based intervention programme on cardiovascular disease (CVD) risk factors among a multi-ethnic cohort of middle school students. METHODS: HEALTHY was a cluster randomized, controlled, primary prevention trial. Middle school was the unit of randomization and intervention. Half of the schools were assigned to an intervention programme consisting of changes in the total school food environment and physical education classes, enhanced by educational outreach and behaviour change activities and promoted by a social marketing campaign consisting of reinforcing messages and images. Outcome data reported (anthropometrics, blood pressure and fasting lipid levels) were collected on a cohort of students enrolled at the start of 6th grade (∼11-12 years old) and followed to end of 8th grade (∼13-14 years old). RESULTS: Forty-two middle schools were enrolled at seven field centres; 4363 students provided both informed consent and CVD data at baseline and end of study. The sample was 52.7% female, 54.5% Hispanic, 17.6% non-Hispanic Black, 19.4% non-Hispanic White and 8.5% other racial/ethnic combinations, and 49.6% were categorized as overweight or obese (body mass index ≥ 85th percentile) at baseline. A significant intervention effect was detected in the prevalence of hypertension in non-Hispanic Black and White males. The intervention produced no significant changes in lipid levels. CONCLUSIONS: The prevalence of some CVD risk factors is high in minority middle school youth, particularly males. A multi-component, school-based programme achieved only modest reductions in these risk factors; however, promising findings occurred in non-Hispanic Black and White males with hypertension.

Binge eating, mood, and quality of life in youth with type 2 diabetes: baseline data from the today study.

OBJECTIVE: The current study examines the prevalence of binge eating and its association with adiposity and psychosocial functioning in a large, diverse sample of youth with type 2 diabetes. RESEARCH DESIGN AND METHODS: In the TODAY study, 678 (mean age 14.0 years; 64.9% girls) of the 704 youth randomized to the study completed a self-report measure of eating disorder symptoms and were categorized as nonovereaters, overeaters, subclinical binge eaters, or clinical binge eaters. RESULTS: Youth with clinical (6%) and subclinical (20%) levels of binge eating had significantly higher levels and rates of extreme obesity, global eating disorder and depressive symptoms, and impaired quality of life. CONCLUSIONS: These findings highlight the importance of evaluating youth with type 2 diabetes for the presence of binge eating. Future research is needed to determine the cumulative effects of disordered eating, obesity, and psychosocial distress on adherence to lifestyle change recommendations and longitudinal response to treatment.

Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes.

Despite the increased prevalence of type 2 diabetes mellitus (T2DM) in the pediatric population, there is limited information about the relative effectiveness of treatment approaches. This article describes the rationale and design of a National Institutes of Health-sponsored multi-site, randomized, parallel group clinical trial designed to test the hypothesis that aggressive reduction in insulin resistance early in the course of T2DM is beneficial for prolongation of glycemic control, as well as improvement in associated abnormalities and risk factors. Specifically, the trial compares treatment with metformin with two alternate approaches, one pharmacologic (combining metformin treatment with rosiglitazone) and one combining metformin with an intensive lifestyle intervention program. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study recruits 800 patients over a 4-yr period and follows them for a minimum of 2 yr and maximum of 6 yr. Patients are 10-17 yr of age, within 2 yr of diagnosis of diabetes at the time of randomization, lack evidence of autoimmunity, and have sustained C-peptide secretion. The primary outcome is time to loss of glycemic control, defined as a hemoglobin A1c >8% for 6 consecutive months. Secondary outcomes include the effect of the alternative treatments on insulin secretion and resistance, body composition, nutrition, physical activity and fitness, cardiovascular risk monitoring, microvascular complications, quality of life, depression, eating pathology, and resource utilization. TODAY is the first large-scale, systematic study of treatment effectiveness for T2DM in youth. When successfully completed, this study will provide critical new information regarding the natural history of T2DM in youth, the benefits of initiating early aggressive treatment in these patients, and the efficacy of delivering an intensive and sustained lifestyle intervention to children with T2DM.

Presence of diabetes risk factors in a large U.S. eighth-grade cohort.

OBJECTIVE: The study was conducted in 12 middle schools to determine the prevalence of diabetes, pre-diabetes, and diabetes risk factors in eighth-grade students who were predominantly minority and evaluate the feasibility of collecting physical and laboratory data in schools. RESEARCH DESIGN AND METHODS: Anthropometric measurements and fasting and 2-h post-glucose load blood draws were obtained from approximately 1,740 eighth-grade students. RESULTS: Mean recruitment rate was 50% per school, 49% had BMI > or = 85th percentile, 40.5% had fasting glucose > or = 100 mg/dl, 0.4% had fasting glucose > or = 126 mg/dl, and 2.0% had 2-h glucose > or = 140 mg/dl and 0.1% > or = 200 mg/dl. Mean fasting insulin value was 30.1 microU/ml, 36.2% had fasting insulin > or = 30 microU/ml, and 2-h mean insulin was 102.1 microU/ml. Fasting and 2-h glucose and insulin values increased across BMI percentiles, and fasting glucose was highest in Hispanic and Native American students. CONCLUSIONS: There was a high prevalence of risk factors for diabetes, including impaired fasting glucose (> or =100 mg/dl), hyperinsulinism suggestive of insulin resistance (fasting insulin > or = 30 microU/ml), and BMI > or = 85th percentile. These data suggest that middle schools are appropriate targets for population-based efforts to decrease overweight and diabetes risk.

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

VEGF gene transfer for diabetic neuropathy.

Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory defects involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the patient. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic patients. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic patients, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetics, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascularity and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive overexpression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two objectives: 1. Objective #1: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes and associated macrovascular disease involving the lower extremities. 2. Objective #2: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes without macrovascular disease involving the lower extremities. The protocol outlined in this Investigational New Drug Application has been designed as a Phase I/II, single-site, dose escalating, double-blind, placebo controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities. Diabetic males or females > 21 years old with sensory neuropathy with or without macrovascular disease will be eligible. A total of 192 patients will be recruited into two arms of the study (each arm consisting of 96 patients) over a period of 4 years (the fifth year will be limited to follow-up examinations). The 96 patients in each of the two arms of the study will comprise 3 cohorts, each consisting of 32 patients. Within each of these cohorts, patients will be randomized to receive phVEGF165 or placebo based upon a 3:1 randomization ratio. Thus, at the completion of the study, 24 patients will have each received a given dose (1, 2, or 4 mg phVEGF165) and 24 patients will have received placebo. Doses will be employed in a serial dose-escalating fashion. The entire volume of the study drug will be divided and delivered in 8 intramuscular injections administered into the foot, calf muscle, or distal thigh muscle of the affected extremity. Following the initial set of injections, repeat treatment with an identical dose will be provided 2 and 4 weeks after initial treatment.

The use of hepatitis C viral RNA levels in liver tissue to distinguish rejection from recurrent hepatitis C.

Persistence of hepatitis C virus (HCV) after orthotopic liver transplantation is almost universal in HCV-infected patients. Histological examination of liver biopsy specimens can be variable in distinguishing between recurrent hepatitis C and acute cellular rejection. The purpose of this study is to determine whether hepatic HCV RNA levels can be used to distinguish rejection from recurrent HCV by determining whether hepatic HCV RNA levels correlate with histological characteristics and clinical course. Seventy-two biopsy specimens were evaluated from 36 liver transplant recipients with HCV and elevated liver-related enzyme levels. Based on histological findings and clinical response to therapy, patients were defined as belonging to 1 of 5 groups: (1) definite rejection, (2) probable rejection, (3) indeterminate findings, (4) probable HCV, and (5) definite HCV. Hepatic HCV RNA was quantified using the Amplicor Monitor assay (Roche Diagnostic Systems Inc, Branchburg, NJ). There was a difference across groups in HCV RNA levels (P =.046). The median HCV RNA level was 10,695 copies/mg of tissue DNA in the definite-HCV group compared with 1,024 copies/mg of tissue DNA in the definite-rejection group. Using pairwise comparisons, significant differences were found between definite HCV and definite rejection, probable HCV and definite rejection, probable HCV and probable rejection, and probable HCV and indeterminate. Our findings support the following conclusions. (1) In liver transplant recipients, hepatic HCV RNA levels are statistically greater in patients with recurrent HCV than rejection, although there is considerable overlap between groups. (2) Patients with low HCV RNA levels were unlikely to have recurrent HCV. (3) Patients with minimal and indeterminate findings on biopsy (group 3) had low HCV RNA levels.

Refinement of the dentinogenesis imperfecta type II locus to an interval of less than 2 centiMorgans at chromosome 4q21 and the creation of a yeast artificial chromosome contig of the critical region.

Dentinogenesis imperfecta type II is an autosomal-dominant disorder of dentin formation which has been mapped to the 6.6 centiMorgan D4S2691-D4S2692 interval at human chromosome 4q21. In the current investigation, the use of four short tandem repeat polymorphisms has allowed the critical region to be refined to an interval of less than 2 centiMorgans defined by recombination events in unrelated, affected individuals from two families both of which show independent evidence for linkage to chromosome 4q21. The creation of a yeast artificial chromosome contig of this newly defined interval has allowed us to demonstrate that the critical region encompasses approximately 2 Mb of DNA and that the dentin-specific gene, dentin sialoprotein, maps to this interval within 300 kb of dentin matrix acidic phosphoprotein 1 and bone sialoprotein. Moreover, dentin sialoprotein shows no recombination with the dentinogenesis imperfecta type II phenotype. Dentin sialoprotein is therefore a candidate for the dentinogenesis imperfecta type II locus.

The Next Step Trial: impact of a worksite colorectal cancer screening promotion program.

BACKGROUND: The Next Step Trial was a randomized trial of worksite colorectal cancer screening promotion and nutrition interventions for automobile industry employees at increased risk of colorectal cancer. Interventions were tested at 28 worksites with 5,042 employees. This report describes results of the screening promotion intervention. METHODS: Worksites randomized to the control group received a standard program including rectal examination, fecal occult blood testing, and flexible sigmoidoscopy. Intervention worksites received an enhanced program (i.e., standard program plus an educational booklet/telephone call). Compliance (i.e., completion of all recommended screening examinations) and coverage (i.e., completion of at least one screening examination), the primary and secondary outcomes, were measured over 2 years. RESULTS: In the 2 years prior to baseline, 61% of employees had been screened. After random assignment, baseline differences in several employee characteristics and worksite screening procedures were detected, including more past history of screening in control worksites. After adjusting for differences, we found modest, but higher, compliance and coverage in intervention compared with control worksites (odds ratio [95% confidence limits] = 1.46 [1.1-2.0] and 1.33 [1.1, 1.6], respectively). CONCLUSIONS: Adding a personally tailored behavioral intervention to a standard colorectal cancer screening program can promote continued employee participation in screening as measured by compliance. Further research is needed to assess intervention effects in other populations.

Nutrition intervention for high-risk auto workers: results of the Next Step Trial.

BACKGROUND: The Next Step Trial tested interventions encouraging prevention and early detection practices in automotive-industry employees at increased colorectal cancer risk. This article describes results of the nutrition intervention promoting low-fat, high-fiber eating patterns. METHODS: Twenty-eight worksites (5,042 employees at baseline) were randomized to a 2-year nutrition intervention including classes, mailed self-help materials, and personalized dietary feedback. Control worksites received no intervention. Nutrition outcomes were assessed by mailed food frequency questionnaires (FFQs) Primary nutrition outcomes included percentage energy from fat and fiber density (g/1,000 kcal) at 1 year postrandomization. Secondary outcomes included servings of fruits/vegetables and dietary measures at 2 years postrandomization. Analyses were adjusted for within worksite correlations and baseline covariates. Fifty-eight percent of employees returned FFQs. RESULTS: At 1 year, there were modest but statistically significant intervention effects for fat (-0.9 %en), fiber (+0.5 g/1,000 kcal), and fruits/vegetables (+0.2 servings/day) (all P < 0.007). At 2 years, due to significant positive changes in control worksites, intervention effects were smaller, significant for fiber only. Intervention effects were larger in younger (<50 years), active employees and class attendees. CONCLUSION: The nutrition intervention produced significant but modest effects on dietary fat and fiber and fruits/vegetables in these high-risk employees. Age and dose effects suggest younger employees may be more responsive to this intervention.

Psychosocial correlates of healthful diets among male auto workers.

A better understanding of factors associated with healthful eating practices can improve the design and evaluation of dietary intervention programs. Up to now, little information has been available about these factors in high-risk but healthy populations. This article presents findings of a study of psychosocial factors, including stage of change, and their relationship to patterns of consumption of dietary fat, fiber, and fruits and vegetables in a population of males at increased risk of colorectal cancer. Data are from the baseline survey for the Next Step Trial, a randomized, controlled trial of worksite nutrition and colorectal cancer screening promotion interventions. The respondents (n = 2764) were actively employed or retired auto workers at increased colorectal cancer risk. The psychosocial constructs measured were predisposing factors (benefits, motivation, knowledge; eight items; Cronbach alpha = 0.50), enabling factors (barriers, norms, social support; six items; Cronbach alpha = 0.55), and stages of change for adopting diets lower in fat and higher in fiber/fruits and vegetables. The measures of diet, assessed with a food frequency questionnaire, were intakes of fat, fiber, and servings of fruits and vegetables. There were strong and statistically significant positive associations between both predisposing and enabling scale scores and stages of change for fat and fiber. The percentage of respondents in maintenance stage ranged from 4-80% for fat and 11-81% for fiber, across low to high predisposing scale scores; for enabling scale scores, ranges were 11-71% for fat and 22-81% for fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, with the greatest change observed between action and maintenance. Correlations with dietary outcomes were significantly greater for predisposing factors (r = -0.30 for fat and 0.36 for fiber) than for enabling factors (r = -0.23 for fat and 0.28 for fiber). Multiple regression models, which included the predisposing and enabling factor scales, stage of change, and covariates related to diet, explained a total of between 16 and 27% of the variance in diet. Predisposing and enabling factors are significantly associated with of stage of change and current diet in this high-risk sample of male auto workers. Stage of change is the strongest correlate examined and seems to serve as a mediating factor for dietary change. Results from the Next Step Trial will provide additional data on whether and how health promotion interventions influence these factors, and whether such changes are associated with dietary change.

Temporal profile of connexin 43 mRNA expression in a tetanus toxin-induced seizure disorder.

The messenger ribonucleic acid (mRNA) of gap junction protein connexin 43 was quantified in the tetanus toxin rat model of focal epilepsy following injection of toxin into the left amygdala. Animals were monitored electrographically at weekly intervals with bilateral amygdala electrodes. Cohorts of 3 rats were sacrificed at weeks 1, 2, 3, 4, 6, 8, and 10, and bilateral regions containing the amygdala and posterior cerebral cortex were sampled, frozen, and later pooled for northern blot analysis. Spike generation was manifest in all animals during the first 4 wk followed by variable attenuation and cessation by 10 wk. Electrode implantation alone was shown by regression analysis to cause significant (p < 0.05) elevation of connexin mRNA in weeks 1-4. Injection of toxin diminished connexin mRNA expression in the amygdala when compared to electrode implantation alone. No trend in connexin mRNA expression was established over time in either amygdala or cerebral cortex in the acute epileptic or chronic postepileptic phase. No association between connexin 43 mRNA expression and the development of epileptogenicity was found in the context of a self-limiting animal model of focal epilepsy.

Elucidation of the sequence and the genomic organization of the human dentin matrix acidic phosphoprotein 1 (DMP1) gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.

The dentin matrix acidic phosphoprotein 1 (DMP1) gene has been mapped to human chromosome 4q21 and shown to exhibit no recombination with the autosomal dominant disorder of dentin formation, dentinogenesis imperfecta type II. In the current study, sequencing of DMP1 cDNA and genomic clones has indicated that the human gene contains an open reading frame of 1539 bp, which predicts a highly acidic, serine-rich protein of 513 amino acids. Comparison of the human DMP1-coding sequence with that of the rat, mouse, and cow indicated that the predicted protein contains a conserved hydrophobic signal peptide sequence and an Arg-Gly-Asp cell attachment sequence. The gene is encoded by six exons, the splicing phase of which is type 0, the first exon containing solely 5' untranslated sequence. Sequencing of each of the coding exons in individuals affected by dentinogenesis imperfecta type II failed to reveal any disease-specific mutations, suggesting that mutations in DMP1 are not causative of this condition at least in the two families examined in this study.

Cloning and expression analysis of the bovine dentin matrix acidic phosphoprotein gene.

The dentin matrix acidic phosphoprotein gene has been mapped to human chromosome 4q21 and mouse chromosome 5q21. Expression studies have implicated a role for this gene in the mineralization of dentin. In the current investigation, a cDNA encoding bovine dentin matrix acidic phosphoprotein has been cloned and sequenced. A comparison of the bovine gene with its rat counterpart has indicated that the genes are conserved (67.4% identity; 79.5% similarity), particularly in the region of presumed functional elements such as the hydrophobic signal peptide sequence, the cell attachment Arg-Gly-Asp tripeptide, and numerous serine residues which are likely candidates for phosphorylation. Zoo blot analysis further indicated that a similar gene is found in all mammalian species tested, but not in chicks. However, Northern analysis has indicated that in the cow the message is detectable at high levels in fetal bovine brain and cultured long bone as well as in odontoblasts. These results support a potential role for dentin matrix acidic phosphoprotein in dentinogenesis.

Bone mineral density and biochemical markers of bone turnover in healthy elderly men and women.

BACKGROUND: Osteoporosis risk in middle-aged women is twofold greater than that in men, and the difference increases with age. Gender differences in bone mineral density, estimated rates of bone loss, and usefulness of markers of bone metabolism for predicting bone density have not been well described in healthy elders aged 65 and above. The purpose of this cross-sectional analysis was to describe associations of bone mineral density at the hip, spine, and whole body with age, serum osteocalcin, and urinary N-telopeptide crosslinks of Type I collagen in healthy elderly men and women. METHODS: A total of 1,087 healthy adults (273 men and 814 women) aged 65 to 87 years were enrolled in a collaborative study at 3 sites: Tufts University (Boston, MA), University of Connecticut Health Center (Farmington, CT), and Creighton University (Omaha, NE). Bone mineral density (BMD) at three regions of the hip, the lumbar spine, and whole body was determined by dual-energy x-ray absorptiometry. Serum osteocalcin was measured by immunoassay, and measurement of N-telopeptide crosslinks (Ntx) in urine was made using an enzyme-linked radioimmunoassay (ELISA). RESULTS: Among women, the age-related decline in BMD at all non-spine skeletal sites was significantly different from zero, with the largest decline seen at the femoral neck (-.0038 g/cm2/y, p < .001) and the smallest at the trochanter of the hip (-.0023 g/cm2/y, p = .03). Among men, the changes at all non-spine sites were not significant. In both sexes, spine BMD tended to increase with age (men, +.0045 g/cm2/y, women, +.0003 g/cm2/y). Serum osteocalcin and urinary Ntx were inversely related to BMD at all skeletal sites, but the weakest associations were observed at the spine. Individuals whose values of both osteocalcin and Ntx were in the lowest quartiles of the respective sex-specific distributions had mean femoral neck BMD that were 11% higher than individuals with marker values in the highest quartiles. CONCLUSIONS: These findings suggest that age-related decreases in BMD may vary by gender and skeletal site. Determinations of osteocalcin and N-telopeptide crosslinks at a single point in time may potentially be used as indicators of current bone status, particularly at non-spine skeletal sites.

Worksite cancer screening and nutrition intervention for high-risk auto workers: design and baseline findings of the Next Step Trial.

BACKGROUND: This article describes the design and baseline findings of The Next Step Trial, a health promotion intervention targeting automobile industry employees at increased colorectal cancer risk. The intervention encouraged colorectal cancer screening participation and adoption of low-fat, high-fiber diets. METHODS: Twenty-eight worksites (n = 5,042) were randomized to control (a company-sponsored screening program) or intervention (an enhanced screening program including a personalized educational booklet and motivational telephone call and diet-change program including nutrition classes, self-help materials, and computer-generated personalized feedback). Outcomes included screening compliance and fat and fiber intake. RESULTS: Pretrial data indicated targeted employees were predominantly older, well educated, married, Caucasian men. Sixty-one percent (SE = 2) participated in the screening program in the preceding 2 years, and 24% (SE = 1) reported a history of colorectal polyps or cancer. Fifty-eight percent of the cohort responded to the baseline questionnaire; respondents were older and more educated; more were married, retired, and Caucasian than nonrespondents. Mean dietary intakes were 36.9% energy from fat (SE = 0.21), 8.8 g fiber/1000 kcal (SE = 0.07), and 3.4 servings of fruits and vegetables per day (SE = 0.04). CONCLUSIONS: Baseline data show moderate screening participation and dietary intakes that did not meet guidelines; hence intervention efforts were warranted. Data from this trial will support a rigorous test of whether this high-risk employee population is responsive to targeted health promotion, early cancer detection, and prevention interventions.

A generalized Michaelis-Menten response surface.

We describe an application of recently developed generalized Michaelis-Menten response surface and non-linear mixed model methodologies to model glucose utilization in foetal sheep. More specifically, we model the response surface of glucose utilization rate in the foetal sheep as a function of glucose and insulin concentrations using a three-dimensional analogue of the Michaelis-Menten pharmacokinetic model. To account for multiple measurements per sheep, we apply the non-linear mixed effects model proposed by Lindstrom and Bates using the EM algorithm computational scheme presented by Hirst et al.