Neuropeptide Y in obese women during treatment with adrenergic modulation drugs.

BACKGROUND: The aim of the study is the assessment whether weight loss treatment with adrenergic modulation drugs modifies neuropeptide Y (NPY) plasma concentration in obese women. MATERIAL AND METHODS: 13 obese women (BMI 38.3 +/- 4.4) were tested before and subsequently 10 and 20 days after weight loss treatment. The treatment consisted of a very low caloric diet of 400 kcal (1670 kJ) daily combined with ephedrine with caffeine (E + C) or ephedrine with caffeine and yohimbine (E + C + Y) administered for 10 days using the cross-over method. The patients underwent physical examination, including heart rate and blood pressure measurements, spectral heart rate variability (HRV) at rest and after 3 minute handgrip and a 15 minute cycloergometer exercise at 75 W. All the above mentioned tests were carried out thrice in each patient. In 13 obese patients and in 6 control women plasma NPY concentrations were determined by a specific radioimmunoassay using rabbit anti-NPY antiserum and a standard synthetic porcine NPY (Peninsula Lab.). RESULTS: Plasma NPY concentrations were significantly lower in the obese persons compared with the control group. During weight loss treatment with adrenergic modulation drugs no changes in plasma NPY were found at rest and after physical exercise. Also no differences in HRV indices were observed. CONCLUSIONS: 1. Low plasma NPY concentration observed in obesity may be a contraregulatory factor that could prevent further weight increase. 2. Weight reduction treatment did not affect plasma NPY concentration and cardiovascular response to physical exercise. 3. The doses of adrenergic modulation drugs used in our study did not induce any serious side effects, and were so low that no change of plasma NPY concentration and cardiovascular responses were observed at rest.

Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.

PURPOSE. The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice. METHODS. Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment. RESULTS. As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib ( P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups. CONCLUSION. Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.

Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle.

The ubiquitin-proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia. The end-product of this pathway is oligopeptides and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while proteasome activity was determined as the 'chymotrypsin-like' enzyme activity. Both proteasome proteolytic activity and TPPII activity increased in parallel with increasing weight loss, reaching a maximum at 16% weight loss, after which there was a progressive decrease in activity for both proteases with increasing weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by eicosapentaenoic acid. These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors.

The effect of weight change on nursing care facility admission in the NHANES I Epidemiologic Followup Survey.

Data from the first National Health and Nutrition Examination Survey Epidemiologic Followup Survey were used to examine whether weight change was associated with an increased relative risk of nursing care facility admission. Hazard ratios were calculated with Cox proportional hazards models and stratified by overweight status at baseline. Moderate and large weight loss was associated with an increased risk of nursing care facility admission in overweight and non-overweight subjects. Large weight gain was associated with an increased relative risk in only overweight subjects. In the process of functional decline that results in nursing care facility admission, weight loss may be a sign of acute illness, starvation, or aging. Preventing weight loss may help delay this process of decline. In overweight subjects, preventing weight gain may also be important in delaying this process of decline.

Weight Loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study.

Although weight loss increases bone loss and hip fracture risk in older women, little is known about the relation between weight loss in middle-aged women and subsequent hip fracture risk. The objective of this study was to determine the association between weight loss from reported maximum body weight in middle-aged and older women and the risk of hip fracture. Data were from a nationally representative sample of 2180 community-dwelling white women aged 50-74 years from the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey (NHEFS). In this prospective cohort study, incident hip fracture was ascertained during 22 years of follow-up. The adjusted relative risks associated with weight loss of 10% or more from maximum body weight were elevated for both middle-aged (RR 2.54; 95% CI 1.10-5.86) and older women (RR 2.04; 95% CI 1.37-3.04). For both ages combined, women in the lowest tertile of body mass index at maximum who lost 10% or more of weight had the highest risk of hip fracture (RR 2.37; 95% CI 1.32-4.27). weight loss from maximum reported body weight in women aged 50-64 years and 65-74 years increased their risk of hip fracture, especially among those who were relatively thin. weight loss of 10% or more from maximum weight among both middle-aged and older women is an important indicator of hip fracture risk.

Training lay health educators to conduct a church-based weight-loss program for African American women.

PURPOSE: Community-based lay health educators have been utilized in a range of settings and with a variety of health issues. However, little has been published about the specifics of training lay health educators to effectively deliver community-based programs. This paper describes the training used to prepare volunteer, church-based lay health educators to conduct a community-based weight-loss program, and the evaluation of that training. METHODS: After recruitment through their respective churches, volunteer lay health educators were given structured training in how to conduct the PATHWAYS weight-loss program. Program sessions were observed to monitor program delivery, and participation rates and weight loss were evaluated. RESULTS: The lay health educators were highly consistent in their delivery of the program content. Participant attendance was high and virtually all of the participants completed the program. Participant weight loss averaged 8.3 pounds, which correlated with session attendance. CONCLUSIONS: Given training appropriate to the structure of the program and specific to the targeted health behavior, lay health educators can reliably and effectively administer even rather complex programs.

Effects of short-term modest weight loss on fasting and post-prandial lipoprotein sub-fractions in type 2 diabetes mellitus patients.

OBJECTIVE: We assessed the efficacy of a modest weight loss (1.5 +/- 0.3 kg) and simultaneous rapid improvement in glycemic control on fasting an post-prandial lipoprotein sub-fractions in nine overweight (BMI=28 +/- 1.7 kg/m(2)) well controlled Type 2 diabetic patients (HbA(1c)=7.3 +/- 0.1%). MATERIAL AND METHODS: They followed a non-drastical hypocaloric balanced diet (1 561 +/- 39 kcal/day) over ten days in hospital. The fat content of the diet was significantly lowered from 96 +/- 12 g/day to 62 +/- 4 g/day (p<0.03). Plasma lipid and lipoprotein levels were measured in fasting and four hours after standard breakfast and four hours after standard lunch twice before and after ten days of hospitalization. The sub-fractions of very low density and low density lipoprotein were obtained by cumulative flotation ultracentrifugation. RESULTS: This weight loss reduced two well known independent cardiovascular risk factors such as the post-prandial glycemic excursions (p<0.05) and the post-prandial lipemia (p<0.05). Multiple linear regression analyses identified weight loss as an independent variable accounting for the ability to predict post-prandial capillary triglyceride clearance (p<0.05). Improvements in post-prandial glycemic excursions which was also entered as a parameter did not appear as a variable being able to predict these changes (p=0.4). In addition to the 23% improvement in post-prandial capillary triglyceride clearance (p<0.02), a decrement in post-prandial VLDL-2 triglyceride enrichment was found (p<0.05). Finally, fasting and post-prandial LDL-3 cholesterol levels were diminished (p<0.05) and the LDL-2/LDL-3 mass ratio post-prandial kinetics were improved (p<0.05). CONCLUSIONS: Even a modest weight loss in overweight, average controlled type 2 diabetic patients can achieve a significant improvement in two cardiovascular risk factors, namely post-prandial triglyceride excursions and the LDL-2/LDL-3 mass ratio kinetics independently from glycemic control improvements.

Cortisol and its relation to insulin resistance before and after weight loss in obese children.

BACKGROUND: Insulin resistance occurs both in obesity and in Cushing's syndrome suggesting a pathogenetic role of cortisol in insulin-resistant obese subjects. METHODS: We examined serum cortisol in 81 insulin-resistant (homeostasis model assessment (HOMA) >4) obese children (age in median 12 years) and 151 obese children without insulin resistance (HOMA < or = 4) (age in median 10 years) and compared these to cortisol of 83 healthy children of normal weight (age in median 12 years). Multivariate linear regression analysis was conducted for the dependent variable insulin resistance (HOMA), including weight status (BMI), age, gender, pubertal stage and cortisol concentration as independent variables. Furthermore, we analyzed cortisol and insulin resistance in 45 obese children with significant weight loss (reduction in SDS-BMI > or = 0.5) and in 109 obese children without significant weight loss (reduction in SDS-BMI <0.5) over the time period of 1 year. RESULTS: Cortisol was significantly (p = 0.006) higher in obese insulin-resistant children (median 14.6 microg/dl) compared to those of normal weight (median 11.4 microg/dl) or obese without insulin resistance (median 11.7 microg/dl). Insulin resistance was significantly influenced by weight status (BMI), age and cortisol using multivariate linear regression analysis. A reduction in overweight showed a significant decrease in cortisol (p = 0.005) and insulin resistance (p = 0.002) in insulin-resistant children, whilst there were no significant changes in children not reducing their overweight and in non-insulin-resistant children. CONCLUSIONS: Cortisol was moderately increased in insulin-resistant, obese children and related to insulin resistance. Weight reduction led to a decrease in cortisol and insulin resistance. These facts point to an association between cortisol and insulin resistance in obesity. 2004 S. Karger AG, Basel