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Using a novel positron emission tomography (PET) method with oral administration of 14(R,S)-[¹⁸F]-fluoro-6-thia-heptadecanoic acid (¹⁸FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organ-specific postprandial dietary fatty acids partition using the oral ¹⁸FTHA method, and cardiac function and oxidative metabolic index using PET [¹¹C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects., (Copyright © 2014 the American Physiological Society.)

The aim of the study was to evaluate the influence of weight gain and changes in adiposity distribution on insulin resistance and circulating adiponectin variations over 4 years in free-living normal weight young adults. In this prospective observational cohort (n=42 women, 18 men), anthropometric measurements and blood samples were collected in the fasting state at baseline and at 4 years. Insulin resistance was estimated using the homeostatic model assessment (HOMA-IR). Circulating adiponectin levels were determined by radioimmunoassay. To investigate increase in adiposity more specifically, subsidiary analyses were performed in a subgroup of individuals (n=31) who gained adiposity over the course of the 4-year follow-up (defined as gain >1% in percent body fat). Regression analyses were performed to adjust for sex, age, parental education, lifestyle, and fitness levels. At baseline, the participants were young adults (age=20.0 years old) in the normal weight range [body mass index (BMI)=22.7 kg/m2 (IQR=21.1-24.4)]. Median change in body fat percentage was +1.4% (IQR=-0.3-3.4; p=0.01) and in waist circumference was +1.2 cm (IQR=-2.6-5.3; p=0.05). In the subgroup of individuals who gained more than 1% body fat, increase in HOMA-IR was associated with an increase in BMI (r=0.44; p=0.01; p<0.01 in fully adjusted model), while decrease in adiponectin levels was associated with an increase in waist circumference (r=-0.38; p=0.03) but this was no longer significant after adjustment for sex and other potential confounders (p=0.14). In a population of young adults, small variations in adiposity within the normal weight range were associated with increase in insulin resistance., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Obesity in Canada is a growing concern, but little is known about the available services for managing obesity in adults. Our objectives were to (a) survey and describe programs dedicated to weight management and (b) evaluate program adherence to established recommendations for care., Methods: We conducted an online environmental scan in 2011 to identify adult weight management services throughout Canada. We examined the degree to which programs adhered to the 2006 Canadian Clinical Practice Guidelines on the Management and Prevention of Obesity in Adults and Children (CCPGO) and the analysis criteria developed by the Association pour la Santé Publique du Québec (ASPQ)., Results: A total of 83 non-surgical (34 community-based, 42 primary care-based, 7 hospital-based) and 33 surgical programs were identified. All programs encouraged patient self-management. However, few non-surgical programs adhered to the CCPGO recommendations for assessment and intervention, and there was a general lack of screening for eating disorders, depression and other psychiatric diseases across all programs. Concordance with the ASPQ criteria was best among primary care-based programs, but less common in other settings with deficits most frequently revealed in multidisciplinary health assessment/management and physical activity counselling., Conclusions: With more than 60% of Canadians overweight or obese, our findings highlight that availability of weight management services is far outstripped by need. Our observation that evidence-based recommendations are applied inconsistently across the country validates the need for knowledge translation of effective health services for managing obesity in adults.

Aims: This study aimed to (1) describe the profile of adults with type 2 diabetes (T2D) in Canada and (2) assess the uptake of clinical care best practices, as defined by the Canadian Diabetes Association (CDA) Clinical Practice Guidelines (CPGs)., Methods: We used data from the 2011 Survey on Living with Chronic Diseases in Canada - Diabetes component. Participants were aged 20 years and older, living in the 10 Canadian provinces, with self-reported T2D. Descriptive analyses present the prevalence of complications and comorbidities, as well as the level of clinical monitoring and self-monitoring/lifestyle management recommendations participants received., Results: We included 2335 participants with T2D, a mean age of 62.9 years, and high prevalence of complications/comorbidities and prescription medication use. Most participants reported being monitored as recommended for eye disease (73.9%), weight (81.0%), blood pressure (89.0%) and blood cholesterol levels (94.3%), but only 65.5% reported having at least two HbA1c tests during the last year and 46.5% reported an annual foot examination by a health professional. About two-thirds of the participants reported having received recommendations on weight management (59.9%) and physical activity (64.7%) from a health professional in the previous year; only 47.8% of the participants reported having received diet counseling to improve diabetes control., Conclusion: Although the uptake of CDA CPGs for clinical and self-monitoring was high, with the majority of the participants reporting meeting most indicators, it was lower for HbA1c measurement and foot examination. Uptake of lifestyle management recommendations provided by health professionals was also significantly lower., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

In 2010, the American Heart Association established the concept of ideal cardiovascular health. Nationally representative data estimated that <1% of Americans meet the seven health metrics required for achieving ideal cardiovascular health, with the main challenge residing in meeting the criteria for an ideal Healthy Diet Score. In a cohort of young adults (N=196), we aimed to investigate the prevalence of ideal cardiovascular health and ideal Healthy Diet Score and its association to weight gain over a 4-year follow-up period. Anthropometric measures, blood pressure, and blood samples were taken according to standardized procedures. Dietary intake was measured by a 3-day food diary and verified by a registered dietitian. We observed that only 0.5% of our sample met the criteria for ideal cardiovascular health and only 4.1% met the criteria for an ideal Healthy Diet Score. The components of the Healthy Diet Score with the lowest observance were consumption of fruits and vegetables (9.7%) and whole grains (14.8%). Meeting zero or one out of five of the Healthy Diet Score components was associated with increased risk of weight gain over 4 years compared with meeting at least two components (P=0.03). With the exception of dietary criteria, prevalence was high for achieving ideal levels of the remaining six cardiovascular health metrics. In conclusion, in this sample of young adults, a very low prevalence of ideal overall cardiovascular health was observed, mainly driven by poor dietary habits, and a poor Healthy Diet Score was associated with increased weight gain., (Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Over 70% of people who undergo bariatric surgery (BS) develop excess skin (ES). The physical and psychosocial consequences of ES may become a barrier to the practice of physical activity (PA), which is highly recommended to optimize the results of BS. The purpose of this study was to evaluate the impact of ES on the practice of PA in women who have undergone BS., Methods: Questionnaires administered to 26 women having undergone BS 2 ± 0.2 years before (BMI = 29.1 ± 0.8 kg/m2) evaluated the impacts of ES, the practice of PA, physical self-perception, and physical exercise beliefs. We also used the 6-min walking test and muscular endurance tests to evaluate physical fitness and photographs with anatomical markers to quantify ES., Results: Of the women, 76.9% declared mobility limitations due to ES during the practice of PA and 45.2% stated avoiding PA because of ES which caused flapping and unwelcome stares from others. The women who stated that they avoided PA because of ES had significantly lower physical self-perception and physical fitness and reported experiencing more embarrassment during PA despite no significant difference in the magnitude of ES (p = 0.06), BMI, daily life inconveniences, and energy expenditure compared to those women who did not avoid PA., Conclusion: Although ES after BS is a barrier to the practice of PA for some women, it does not in itself prevent the regular practice of PA. The main reason women with ES avoid PA seems to have less to do with the magnitude of ES itself and more with psychosocial inconveniences.

It is presently unclear whether there is a significant association between thyroid function and cognitive decline in euthyroid elderly. This case-control study aimed to examine serum thyroid stimulating hormone (TSH), total thyroxine, free thyroxine, total triiodothyronine, and free triiodothyronine in relation to cognitive decline over a 3-year period in a subsample of 62 participants (31 pairs) aged 67 years and over at baseline from the NuAge study (Quebec longitudinal study). They were matched for age, sex and global cognition. In conditional regression logistic models, there was no significant association between any thyroid function indices and the 3-year risk of cognitive decline as measured with the Modified Mini-Mental State Examination (3MS). TSH and thyroid hormones do not appear to be associated with cognitive decline in euthyroid older persons. These findings need confirmation given the small number of pairs of subjects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Thyroid hormones play a critical role in the growth of many organs, especially the brain. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) interact with the thyroid pathway and may disturb neurodevelopment. This prospective study was designed to examine associations between maternal blood PBDEs and PCBs in early pregnancy and levels of thyroid hormones in maternal and umbilical-cord blood. Levels of low-brominated PBDEs, 3 PCB congeners, total and free thyroid hormones (triiodothyronine (T3) and thyroxine (T4)), thyroid-stimulating hormone, thyroid peroxidase antibodies, iodine, selenium, and mercury were measured in 380 pregnant women in the first trimester who were recruited at the University Hospital Center of Sherbrooke (Quebec, Canada) between September 2007 and December 2008. Thyroid hormone levels were also assessed at delivery and in cord blood (n = 260). Data were analyzed on both a volume basis and a lipid basis. At less than 20 weeks of pregnancy, no relationship was statistically significant in volume-based analysis. In lipid-based models, an inverse association between maternal PBDEs and total T3 and total T4 and a direct association with free T3 and free T4 were observed. At delivery, in both analyses, we observed negative associations between maternal total T4, free T3, cord-blood free T4, and PBDEs and between maternal free T3 and PCBs. Our results suggest that exposure to PBDEs and PCBs in pregnancy may interfere with thyroid hormone levels.

Background: To optimize bariatric surgery results, experts recommend regular practice of physical activity. However, no precise recommendations are available for the pre-surgical period. We aimed to evaluate, in this pilot study, the feasibility of a supervised Pre-Surgical Exercise Training (PreSET) and its short-term clinical impacts in subjects awaiting bariatric surgery., Methods: In addition to the usual interdisciplinary lifestyle management, eight women and four men [40.8 (37.6-47.5) years old, BMI = 51.4 (43.8-53.1) kg/m(2)] underwent the PreSET, which combined both endurance and strength training. They were instructed to perform three physical activity sessions per week during 12 weeks, with at least two sessions per week on site and the possibility to complete missed sessions at home. Before and after the PreSET, anthropometric measures, body composition, physical fitness, quality of life, and physical exercise beliefs were assessed., Results: The subjects participated in 57.3 % of the total supervised exercise sessions proposed and presented high satisfaction rates. Our program resulted in a significant improvement in weight (p = 0.007), physical fitness (p ≤ 0.05), and quality of life score (p = 0.012) as well as for the emotions, social interactions, and sexual life subscales (p < 0.03). Fear of injury (p = 0.028) and embarrassment during physical activity (p = 0.028) were significantly decreased, whereas no significant change in confidence in athletic ability and in beliefs in exercise benefits were noticed after the program., Conclusions: PreSET is feasible in subjects awaiting bariatric surgery and, combined with an interdisciplinary management, results in several short-term benefits.

Background: For insulin-treated patients with type 2 diabetes mellitus (T2DM), self-monitoring of blood glucose (SMBG) may be vital in adjusting insulin dosages. For patients who do not use insulin, evidence supporting the use of SMBG is inconclusive., Methods: The prevalence, frequency and correlates of SMBG are examined. Data pertain to 2,682 individuals aged 20 or older with T2DM who responded to the 2011 Survey on Living with Chronic Diseases in Canada. Multivariate prevalence rate ratios for associations between respondents' characteristics and their use of SMBG were derived using binomial regression models., Results: A large majority of the study population (87.8%) reported SMBG. No difference in the prevalence of SMBG was observed between oral medication users compared with insulin users; however, the frequency of SMBG was lower for those taking oral medication only. Significant determinants of SMBG were a health professional's recommendation, having insurance coverage, and receiving an A1C test from a health professional., Interpretation: The use of SMBG by adults with T2DM is common, and does not differ between those taking oral medication only and those treated with insulin.

Background: Lifestyle behavior modification is an essential component of self-management of type 2 diabetes. We evaluated the prevalence of engagement in lifestyle behaviors for management of the disease, as well as the impact of healthcare professional support on these behaviors., Methods: Self-reported data were available from 2682 adult respondents, age 20 years or older, to the 2011 Survey on Living with Chronic Diseases in Canada's diabetes component. Associations with never engaging in and not sustaining self-management behaviors (of dietary change, weight control, exercise, and smoking cessation) were evaluated using binomial regression models., Results: The prevalence of reported dietary change, weight control/loss, increased exercise and smoking cessation (among those who smoked since being diagnosed) were 89.7%, 72.1%, 69.5%, and 30.6%, respectively. Those who reported not receiving health professional advice in the previous 12 months were more likely to report never engaging in dietary change (RR = 2.7, 95% CI 1.8 - 4.2), exercise (RR = 1.7, 95% CI 1.3 - 2.1), or weight control/loss (RR = 2.2, 95% CI 1.3 - 3.6), but not smoking cessation (RR = 1.0; 95% CI: 0.7 - 1.5). Also, living with diabetes for more than six years was associated with not sustaining dietary change, weight loss and smoking cessation., Conclusion: Health professional advice for lifestyle behaviors for type 2 diabetes self-management may support individual actions. Patients living with the disease for more than 6 years may require additional support in sustaining recommended behaviors.

Aim: Mid-life obesity is associated with T2D risk. However, less is known about the cumulative effect of obesity during adulthood., Methods: Framingham Offspring Study participants who had an examination at 35±2 years and were initially free of T2D were included in this study (N=1026). A cumulative excess weight (CEW) score (year*kg/m²) was calculated until T2D diagnostic or the end of follow-up., Results: Eighty-four individuals (8.2%) developed T2D over 20±6 years. Mean CEW scores were 118.0±114.6 year*kg/m² in individuals who developed T2D and 30.2±91.4 year*kg/m² in those who did not develop T2D (P<0.01). T2D risk was doubled for each standard deviation increase in the CEW score (OR=1.99 [1.64-2.40]; P<0.001). However, CEW score was only significantly associated with T2D incidence for participants with a baseline BMI <25 kg/m² (OR =2.13 [1.36-3.36]; P<0.001)., Conclusions: Accumulating weight between the mid-thirties to the mid-fifties increases the risk of developing T2D. However, BMI in mid-thirties remains a stronger predictor of T2D risk., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Complete leptin deficiency is associated with weight gain and extreme obesity, according to studies of animals and of monogenic obesity in humans. It is still a matter of debate whether relative leptin deficiency plays a physiologic role in adiposity regulation in free-living humans. We hypothesized that leptin levels would be associated with subsequent weight changes in healthy normal-weight young adults. Our prospective cohort involved 150 healthy young adults (114 women and 36 men) followed over their years of study at the Université de Sherbrooke. Anthropometric measurements, fasting blood samples, 3-day food diaries, and a physical activity questionnaire were collected at baseline. Leptin levels were measured with radioimmunoassay. Associations between baseline leptin levels and subsequent anthropometric changes were assessed with multivariable linear regression models to account for adiposity at baseline, food intake, and energy expenditure. Over the 2-year follow-up, changes in body mass index (BMI) ranged from -0.8 to +2.6 kg·m(-2) in men (mean BMI change, +0.6 kg·m(-2)) and from -2.5 to +3.7 kg·m(-2) in women (mean BMI change, +0.1 kg·m(-2)). Lower leptin levels at baseline were associated with a higher risk of weight gain in women (r = -0.24; p = 0.01 for change in BMI) and in men (r = -0.27, p = 0.11), even after accounting for baseline BMI, total daily caloric intake, and energy expenditure (p = 0.02). In the subsample measured at 4 years (n = 63), baseline leptin levels were not associated with 4-year weight changes. Lower leptin levels are associated with a higher risk of weight gain over 2 years in healthy young adults.

This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPARγ expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPARγ remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.

Objective: The main objective of this study was to determine whether expectations and readiness to modify eating habits and physical activity (PA) level are different between young and older individuals with prediabetes who agreed to participate in a lifestyle modification program., Design: Cross-sectional analysis., Setting: Primary care or referral center., Participants: Adults between ages 27 and 78 years (N=74) were tested before starting a 12-month lifestyle intervention., Interventions: Not applicable., Main Outcome Measures: The visual analog scale questionnaire was used to assess expectations and readiness (ie, intentions, conviction, and self-confidence) to modify the PA level and eating habits. The PA level was assessed with a pedometer and eating habits with a questionnaire. Analyses were stratified by the age group: <60 years old versus ≥60 years old., Results: Body mass loss expectations in terms of goal (-22.9% vs -17.9% of the current body mass; P=.04), acceptable (-15.6% vs -9.4%; P=.01), and failure (-7.6% vs -3.8%; P=.05) in future body mass loss were all greater for the younger group. Despite no significant age group difference in the initial PA level and eating habits, the youngest group had a greater intention to increase the PA level (89% vs 81%; P=.004) and to eat healthier (90% vs 85%; P=.001). Finally, the PA level and the consumption of fruits and vegetables, but not body mass, were associated with intentions or self-confidence to make some lifestyle modifications within age groups., Conclusions: In individuals at high risk for diabetes, increasing age is associated with lower expectations and reduced readiness with regard to lifestyle modifications. Thus, age should be considered when planning a lifestyle modification program., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: To compare the effectiveness and cost of two lifestyle-modification programmes in individuals at high risk of developing type 2 diabetes., Methods: Forty-eight men and women with a body mass index ≥27 kg/m(2) and prediabetes were randomly assigned to either a 1-year interdisciplinary intervention including individual counseling every 6 weeks and 25 group seminars (group I; n=22) or a group intervention comprising seminars only (group G; n=26). These interventions were compared in terms of weight loss and improvement of anthropometric measures, metabolic variables and costs., Results: Participants in group I lost an average of 4.9 kg (95% CI: -7.3, -2.4; P<0.01) and 5 cm in waist circumference (95% CI: -7.0, -3.0; P<0.01), whereas no significant change was noted in those assigned to group G. Among the participants in group I, 50 and 27% lost at least 5 and 10% of their initial weight, respectively, compared with only 12 and 4%, respectively, in group G. Fasting glucose, 2-hour glucose and lipid profiles improved significantly in group I, and no participant (zero on 22) developed diabetes compared with 11.5% (3/26) in group G. Most participants (nine on 11) with impaired fasting glucose in group I returned to normal. The direct cost of the individual intervention was estimated to be $733.06/year per subject compared with $81.36/year per subject for the group intervention., Conclusion: This study demonstrates that a low-cost, moderate-intensity, individual interdisciplinary approach combined with group seminars leads to clinically significant weight loss and metabolic improvement in people with prediabetes. Group seminars alone were not effective in this population (www.ClinicalTrial.gov, Identifier: NCT00991549)., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Weight gain and appetite regulation are complex interplays between internal and external cues. Our aim was to investigate the association of eating behaviors with ghrelin taking into account lifestyle. We conducted a cross-sectional analysis in a sample of first-year university students at the Université de Sherbrooke. We collected medical history, anthropometric measurements, vital signs, fitness index, and fasting blood samples. Questionnaires included a lifestyle questionnaire and the Three-Factor Eating Questionnaire (TFEQ) estimating dietary restraint, disinhibition and hunger. We recruited 308 participants aged 20.7±3.2 years and a mean BMI of 23.3±3.4 kg/m(2). Hunger score was significantly associated with ghrelin levels (r=0.11, P<0.05). In women, this association was independent of age, BMI, dietary and lifestyle factors (P=0.02). The association between ghrelin level and hunger score was observable in leaner individuals (r=0.28, p<0.0001) but not in heavier individuals (r=-0.08, p=0.34; stratified by BMI < vs > 22.6 kg/m(2)). Restraint (R) and disinhibition (D) were not associated with ghrelin levels. The three eating behaviors demonstrated expected correlations with lifestyle supporting the validity of the TFEQ in this cohort. In conclusion, we demonstrated that ghrelin, a biological marker, is associated with self-reported perception of hunger, independently of anthropometric measures and lifestyle., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Obesity and the metabolic syndrome are significant determinants of functional capacity in women. In the past decade, the term "metabolically healthy obese" (MHO) emerged in the literature to identify a distinct category of obese individuals presenting less metabolic impairment than expected. However, MHO women might have similar risk than non-MHO women for nonmetabolic weight-related co-morbidities, including altered functional capacity., Methods: Eighty six obese women aged from 28 to 74 years old were studied. MHO was defined as a body mass index (BMI) ≥30.0 kg/m(2) with less than one metabolic syndrome criteria based on the Adult Treatment Panel III (ATP III) definition. Walking distance (m) and walking speed (m/sec), evaluated by the 6-min walk test, were used as indicators of functional capacity., Results: Twenty one percent of the sample was considered MHO. Age, BMI, physical activity level, and diastolic blood pressure were not significantly different between MHO and non-MHO women. MHO women performed better on the 6-min walk test (519.8 m±68.2 vs. 448.4 m±67.1; P≤0.01) compared to non-MHO women. Moreover, in multiple regression analyses, MHO status and BMI were significantly associated with walking speed after adjustment for age, physical activity level, the total number of chronic conditions, and arthritis/osteoarthritis., Conclusions: Our results show that MHO women have a better functional capacity than non-MHO women, and therefore could be at lower risk for future disability. However, weight management remains important because BMI was also an independent predictor of functional capacity regardless of metabolic profile.

Background: The degradation of many nuclear receptors is controlled by ligand-binding and mediated by the ubiquitin-proteasome pathway. However, the mechanisms implicated in thyroid hormone receptor (TR) degradation remain unclear. Our objective was to define the kinetics, mechanisms, and sub-cellular fractions involved in TRs degradation., Methods: We used pulse-chase analyses, time-course experiments carried out in presence of cycloheximide (to inhibit new protein synthesis), and biochemical fractionation with Western blot analyses to determine the kinetics of the degradation of the TRβ isoform, TRβ1, in transiently transfected QBI-HEK 293A cells., Results: We observed that TRβ1 degradation is mediated by the proteasome pathway. Also, the kinetics of TRβ1 degradation is atypical due to the co-existence of more than one TRβ1 population, located in different cellular compartments and having different stability profiles. Moreover, TRβ1 degradation was unaffected by a mutation in its putative PEST motif, which confers turnover of other proteins., Conclusion: Our findings introduce novel evidence suggesting that stable and unstable forms of TRβ1, which might have distinct functions, co-exist in cells.

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is a flame-retardant chemical appearing at increasing concentrations and frequency in the environment and human samples. A number of health effects of exposure to BDE-47 have been observed, thyroid disruption being the most sensitive. Our objective was to examine BDE-47 interaction with thyroid receptor beta (TRβ). We used a variety of approaches, including in vitro binding assays, luciferase reporter-gene transcriptional assays, and analysis of expression of thyroid responsive genes in rat offspring exposed perinatally to BDE-47. We found that BDE-47 alone or in mixture with 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), 2,2',4,4',6-pentabromodiphenyl ether (BDE-100), and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153) does not compete with [(125)I]T(3) for TRβ-binding even at 4000 fold higher concentrations. Also, BDE-47 does not affect thyroid responsive genes through TRβ in in vitro studies of transcription regulation. A subset of thyroid responsive genes were significantly differentially expressed in liver and frontal lobe brain samples of exposed pups, however, the action of BDE-47 was neither agonistic or antagonistic to that of thyroid hormone. We conclude that BDE-47 does not interact directly with TRβ1 nor does it influence its transcriptional activity. Developmental exposure of rats to BDE-47 leads to differential expression of thyroid responsive genes in liver and brain due to unknown mechanism., (Copyright © 2010 John Wiley & Sons, Ltd.)

This study aimed at identifying predictors of success (retention after one year of intervention with ≥5% weight loss) in subjects at high risk for type 2 diabetes enrolled in a lifestyle modification program. Fifty-one individuals with BMI ≥27kg/m(2) and pre-diabetes or metabolic syndrome were enrolled in an individualized multidisciplinary lifestyle intervention to induce weight loss. Subjects were assessed initially with a 16-item weight-loss readiness tool (WLRT) based on stages of change model; a 6-min walk test; and anthropometric measures. The most significant independent factor associated with no success was a lower result to the question "I am capable of doing more physical activity" (P=0.001). The second significant independent predictor was ≤0.5% weight loss 6 weeks after initiating intervention (P=0.01). Excluding subjects with both criteria would have reduced by 52% the number of subjects eligible for the program, decreased the dropout rate from 30% to 17%, and increased the proportion of subjects with ≥5% weight loss at one year from 51% to 80%. Importantly, only 4% of subjects would have been falsely identified as non-responders. These results indicate that a practical WLRT, in combination with early weight-loss response, is helpful to identify subjects with greater chances of success to lifestyle intervention., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Several techniques are currently used for measurement of body composition. Bioelectrical impedance assessment (BIA) is a simple, noninvasive method of assessing body composition. We aimed to compare multifrequency hand-to-foot (HF-BIA) and foot-to-foot (FF-BIA) bioelectrical impedance analysis techniques to assess fat-free mass (FFM) in a population with a wide range of body mass indices (BMI)., Methods: This was a cross-sectional study of 198 adult subjects. Anthropometric and BIA measures (HF-BIA with Hydra ICF/ECF, Xitron Technologies and FF-BIA with Tanita, model TBF-300A) were recorded after a 12-h fast., Results: Participants had a mean age of 42 years and BMI of 33.50.7 (range, 17.7-65.6) kg/m2. Mean FFM with HF-BIA (FFM BIA/HF) and FF-BIA (FFM BIA/FF) were 61.31.3 kg and 58.10.9 kg, respectively (P < 0.001). In subjects with BMI <25 kg/m2, FFM BIA/FF was not significantly different compared to FFMBIA/HF (-0.2 kg; P=0.8). However, FFM BIA/FF was significantly lower in subjects with BMI 25-30 kg/m2 (-2.0 kg; P=0.009), 30-34 kg/m2 (-1.8 kg; P¼0.04), 34-42 kg/m2 (-4.7 kg; P<0.001) and >42 kg/m2 (-8.0 kg; P=0.001). Pearson correlations between both methods were very high for FFM (r=0.92), fat mass (r=0.91), and % fat mass (r=0.85), all P<0.001. Correlation coefficients for FFM were high in each quintile of BMI. FFM BIA/FF was the only significant independent predictor of FFM BIA/HF (P<0.001) in linear regression analyses using clinical and FF-BIA variables, but introducing BMI in the model added precision., Conclusion: FFM BIA/FF correlates closely with FFM BIA/HF across all quintiles of BMI, but FF-BIA gives lower FFM in overweight and obese subjects.

The six-minute walk test (6MWT) is an inexpensive, quick and safe tool to evaluate the functional capacity of patients with heart failure and chronic obstructive pulmonary disease. The aim of this study was to determine the reproducibility of the 6MWT in overweight and obese individuals. We thus undertook a prospective repeated-measure validity study taking place in our academic weight management outpatient clinic. The 6MWT was conducted twice the same day in 21 overweight or obese adult subjects (15 females and 6 males). Repeatability of walking distance was the primary outcome. Anthropometric measures, blood pressure and heart rate were also recorded. Participant's mean BMI was 37.2+/-9.8 kg/m(2) (range: 27.0-62.3 kg/m(2)). Walking distance in the morning (mean=452+/-90 m) and in the afternoon (mean=458+/-97 m) were highly correlated (r=0.948; 95% Confidence Interval 0.877-0.978; p<0.001). Walking distance was negatively correlated with BMI (r=-0.47, p=0.03), waist circumference (r=-0.43, p=0.05) and pre-test heart rate (r=-0.54, p=0.01). Our findings indicate that the 6MWT is highly reproducible in obese subjects and could thus be used as a fitness indicator in clinical studies and clinical care in this population., (Georg Thieme Verlag KG Stuttgart New York.)

Background: Obesity is a worldwide health problem assuming epidemic proportions. Development of effective clinical interventions is needed to lower the impact of associated morbidity and mortality, without forgetting related costs. We have established an interdisciplinary clinic for obesity management, Unité d'Enseignement, de Traitement et de Recherche sur l'Obésité (UETRO), which consists of individual consultations combined with group sessions. We report here the effectiveness of this program for weight reduction over the first year of follow up., Methods: We performed retrospective analysis of standardized patient records of the first 115 consecutive subjects referred to UETRO with available follow up for 1 year., Results: Mean age, body mass index (BMI), and waist circumference (WC) of our cohort were 46 +/- 13 years, 44.7 +/- 0.9 kg/m(2), and 120.5 +/- 1.9 cm, respectively. Hypertension and diabetes were present in 46% and 23% of our patients. Weight and WC loss were gradual over 1 year and were significantly reduced by 6.6 +/- 0.8 kg and 6.7 +/- 0.7 cm, respectively (P < 0.001), without attainment of a plateau. Blood pressure and lipid profile significantly improved after 1 year of follow up. However, the proportion of patients taking metformin, lipid-lowering, antihypertensive, or antiobesity drugs increased significantly over follow up, reflecting intensification of treatment of co-morbidities and weight management. Significant weight and WC loss occurred independently of diabetes status and use of antiobesity medications., Conclusions: This program appears to be as effective for treating obesity as more intensive treatment programs. Future prospective studies are needed to evaluate the benefits and costs of this therapeutic approach.

The purpose of this study was to evaluate whether polybrominated diphenyl ethers (PBDE) at levels reported for human populations affect the thyroid state in pregnant sheep and lambs. Pregnant sheep were exposed to vehicle or BDE-47 (0.2, 2 and 20 microg/kg b.w.) from the 5th to 15th week of gestation by intravenous injections weekly. Thyroid hormone levels and BDE-47 content in the blood of sheep and lambs and adipose tissue were analyzed. We observed a significant decrease in total T(4) and T(3) in exposed lambs without any effect in pregnant sheep. Our finding indicates that prenatal low-dose PBDE exposure results in PBDE storage in fat of offspring and can affect thyroid metabolism in the developing fetus., (Copyright 2009 S. Karger AG, Basel.)

Objectives: This study aims to evaluate clinical practice of primary care physicians regarding common thyroid disorders., Materials and Methods: A sample of 210 primary care physicians was randomly selected in three Quebec's administrative regions. Four clinical vignettes (V1 to V4) were presented by mail: two cases of subclinical hypothyroidism (women of 25 years - V1 - and 70 - V2 - years of age) for which physicians had to choose to either treat or not with thyroid replacement and two cases of hyperthyroidism (women of 30 - V3 - and 66 - V4- years of age) for which they had to choose a course of action (observation, treatment or referral to a specialist). V1 and V2 where followed by four sub-questions presenting supportive elements that could influence the decision to treat (presence of antithyroid antibodies, accumulation of symptoms, LDL cholesterol and thyreostimulin levels)., Results: The overall response rate was 22%. Forty-two percent of respondents would have treated V1 outright and 49% would have treated V2. The therapeutic approach in the face of these two vignettes, independently of the presence or absence of supportive clinical or biochemical elements, did not vary according to geographic practice area. However, one region was significantly more conservative for V4. The number of years in practice or assistance to continuous medical education activities did not affect management of vignettes., Conclusion: This study outlines the importance of clinical practice guidelines and tools to facilitate their application in clinical management of thyroid disorders.

We summarize here the studies examining the association between thyroid function and cognitive performance from an aging perspective. The available data suggest that there may be a continuum in which cognitive dysfunction can result from increased or decreased concentrations of thyroid hormones. Clinical and subclinical hypothyroidism as well as hyperthyroidism in middle-aged and elderly adults are both associated with decreased cognitive functioning, especially memory, visuospatial organization, attention, and reaction time. Mild variations of thyroid function, even within normal limits, can have significant consequences for cognitive function in the elderly. Different cognitive deficits possibly related to thyroid failure do not necessarily follow a consistent pattern, and L-thyroxine treatment may not always completely restore normal functioning in patients with hypothyroidism. There is little or no consensus in the literature regarding how thyroid function is associated with cognitive performance in the elderly.

The aim of this review is to explore the dysregulation of adrenocortical secretions as a major contributor in the development of obesity and insulin resistance. Disturbance of adipose tissue physiology is one of the primary events in the development of pathologies associated with the metabolic syndrome, such as obesity and type 2 diabetes. Several studies indicate that alterations in metabolism of glucocorticoids (GC) and androgens, as well as aldosterone in excess, are involved in the emergence of metabolic syndrome. Cross talk among adipose tissue, the hypothalamo-pituitary complex, and adrenal gland activity plays a major role in the control of food intake, glucose metabolism, lipid storage, and energy balance. Perturbation of this cross talk induces alterations in the regulatory mechanisms of adrenocortical steroid synthesis, secretion, degradation, and/or recycling, at the level of the zonae glomerulosa (aldosterone), fasciculata (GC and GC metabolites), and reticularis (androgens and androgen precursors DHEA and DHEAS). As a whole, these adrenocortical perturbations contribute to the development of metabolic syndrome at both the paracrine and systemic level by favoring the physiological dysregulation of organs responsive to aldosterone, GC, and/or androgens, including adipose tissue.

Background: Patients with thyroid cancer often need whole-body scintigraphy (WBS) under TSH stimulation after 4-6 weeks withdrawal from levothyroxine (L-T(4)). Patients often become severely hypothyroid with impaired quality of life. Liothyronine (L-T(3)) substitution is used empirically to prepare patients; however, no data exist to prove its benefit. Objectives To compare the hypothyroid state in patients receiving either placebo or L-T(3) following L-T(4) withdrawal and to evaluate the time needed for adequate TSH elevation in preparation for WBS., Methods: At the time of L-T(4) withdrawal, patients were randomized to receive L-T(3 )(50 microg qd) or placebo for 3 weeks, after which treatment was stopped. A validated evaluation of hypothyroidism (Billewicz score) was administered in a double-blind fashion every 2 weeks until the WBS. TSH, fT(4) and fT(3) were measured weekly., Results: A total of 20 patients were randomized between September 2003 and May 2005. There was no difference in the Billewicz score at any time between the two groups. Before WBS, both groups were profoundly hypothyroid. TSH at time of WBS was similar in both groups. The time needed to reach a TSH level of more than 30 mUI/l was longer in L-T(3) group (mean +/- SD: 32 +/- 4 days vs. 17 +/- 9 days in placebo group, P = 0.006)., Conclusion: Preparation for WBS with L-T(3) does not prevent profound hypothyroidism and delays TSH elevation required for WBS. L-T(4) withdrawal alone for 2-3 weeks is simpler and sufficient to allow TSH to reach a level of more than 30 mUI/l in the majority of patients without increasing morbidity from hypothyroidism.

Although crucial for TH homeostasis, the molecular mechanisms responsible of thyroid hormone receptors (TRs)-mediated regulation of the hypothalamic-pituitary-thyroid axis (HPT) axis remain unclear. We examined the role played by TR-isoforms in combination with RanBPM, a novel coactivator of TRs. In transient transfections studies with the human TRH and TSH-alpha subunit promoters, we found that the overexpression of RanBPM increases the transcriptional activity of all TR-isoforms by a magnitude of 1.7- to 3-fold. The addition of RanBPM, in the absence of THs, increased the ligand-independent activation (LIA) of TRalpha1 and TRbeta1 on both promoters tested by 300% and 200%, respectively, whereas, the LIA of TRbeta2 was not significantly modified. This data reinforces the concept of isoform-specific regulation of genes of the HPT axis and demonstrates that RanBPM may be an important factor to achieve adequate regulation of nTREs in the presence of low TH levels.

Background: Nearly 50% of Canadians are overweight and their number is increasing rapidly. The majority of obese subjects are treated by primary care physicians (PCPs) who often feel uncomfortable with the management of obesity. The current research proposal is aimed at the development and implementation of an innovative, integrated, interdisciplinary obesity care management system involving both primary and secondary care professionals., Methods: We will use both action and evaluative research in order to achieve the following specific objectives. The first one is to develop and implement a preceptorship-based continuing medical education (CME) program complemented by a web site for physicians and nurses working in Family Medicine Groups (FMGs). This CME will be based on needs assessment and will be validated by one FMG using questionnaires and semi structured interviews. Also, references and teaching tools will be available for participants on the web site. Our second objective is to establish a collaborative intra and inter-regional interdisciplinary network to enable on-going expertise update and networking for FMG teams. This tool consists of a discussion forum and monthly virtual meetings of all participants. Our third objective is to evaluate the implementation of our program for its ability to train 8 FMGs per year, the access and utilization of electronic tools and the participants' satisfaction. This will be measured with questionnaires, web logging tools and group interviews. Our fourth objective is to determine the impact for the participants regarding knowledge and expertise, attitudes and perceptions, self-efficacy for the management of obesity, and changes in FMG organization for obesity management. Questionnaires and interviews will be used for this purpose. Our fifth objective is to deliver transferable knowledge for health professionals and decision-makers. Strategies and pitfalls of setting up this program will also be identified., Conclusion: This project is relevant to health system's decision-makers who are confronted with an important increase in the prevalence of obesity. It is therefore critical to develop strategies allowing the management of obesity in the 1st line setting. Results of this research project could therefore influence health care organization in the field of obesity but also eventually for other chronic diseases.

Objective: Prevention would be the ideal public health strategy to face the current obesity epidemic. Adoption of healthy lifestyles during the first years of college or university could prevent the onset of weight gain associated with this period of acquired independence and eventually decrease the incidence of obesity., Design: Randomized-controlled trial over a period of 2 years. The subjects received an educational/behavioral intervention (small group seminars) designed to help maintain a healthy lifestyle or no specific intervention (control group)., Subjects: One-hundred and fifteen non-obese freshmen in a Faculty of Medicine., Measurements: Anthropometric measurements, physical activity level, fitness level, food intake and lipid profile were recorded at predetermined intervals., Results: The control group gained weight, whereas the intervention group lost a slight amount of weight over 2 years. The difference between the two groups was 1.3 kg at the end of the follow-up, the trend of weight gain differing between the two groups during the 2-year intervention period (P=0.04). There was no detectable difference in fitness, physical activity level or total caloric intake between the two groups during follow-up. However, plasma triglyceride levels increased in the control group and decreased in the intervention group (P=0.04)., Conclusion: In this randomized-controlled trial, a small-group seminar educational/behavioral intervention successfully prevents weight gain in normal weight young healthy university students. Such small absolute changes in body composition and lipid profile, if maintained over a prolonged period, could result in significant long-term health benefits for the general population.

Obesity has now reached epidemic proportions. Epidemiological studies in the past decades have shown that adults gain weight and adiposity from the early twenties until their sixties. In the paediatric population, growing numbers of children and adolescents put on unhealthy weight. Many environmental, socio-economical and biological determinants that predispose to weight gain have been identified thus far. The aim of the present review is to summarize the current knowledge on the role of the circulating levels of adipokines and other entero-insular hormones and biological markers of obesity to predict weight gain in humans. The review focuses on relationship between hormonal and biochemical markers (insulin, insulin-like growth factors, gastrointestinal hormones, leptin, adiponectin, resistin, inflammatory proteins and cytokines) and weight gain in prospective studies. The complex relationships displayed by these hormonal factors with future weight gain in humans are critically reviewed and integrative models are proposed. Overall, most of the studies reported to date made adjustments for baseline body mass index but failed to consider dietary intake and physical activity as confounding factors. Outstanding questions are raised and new directions for future prospective studies are proposed in order to improve our understanding of the role of biological determinants of energy balance and development of obesity in humans.

Introduction: Metastases to the thyroid gland are considered a rare cause of thyroid tumor. Furthermore, a relationship between breast and thyroid carcinoma has been previously proposed., Case Description: We describe the case of a 59-year-old woman who presented with simultaneous papillary and breast carcinoma within the thyroid gland. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) done for the evaluation of her metastatic breast cancer revealed a thyroid incidentaloma with a high metabolic rate (standardized uptake value [SUV] of 13). She underwent thyroidectomy and the pathology revealed papillary thyroid carcinoma corresponding to the lesion visualized on FDG PET. However, small metastatic implants of breast carcinoma were seen within the opposite thyroid lobe., Conclusion: This is a rare description of a concomitant papillary thyroid carcinoma presenting as an FDG PET incidentaloma alongside breast cancer metastases to the thyroid gland. Thyroid and breast cancer sometimes occur in the same patient. However, no explanation has been found to link these 2 cancers. Although uncommon, FDG PET thyroid incidentalomas seem to harbor a higher rate of malignancy than incidentalomas found on conventional imaging. In the appropriate clinical setting, it is therefore suggested to investigate these lesions thoroughly.

Thyroid hormone receptors (TRs) are transcription factor members of the nuclear receptor superfamily. The transcriptional activity of TRs is controlled by thyroid hormones and cell-specific coregulators. Using the yeast two-hybrid system, we identified RanBPM as a new protein partner for TRs. RanBPM was initially discovered as an interacting partner for Ran, and was also shown to be a protein partner and coactivator of the androgen receptor. The novel interaction between RanBPM and TR isoforms was addressed by glutathione-S-transferase (GST) pull-down assays and co-immunoprecipitation in intact mammalian cells, where RanBPM was shown to bind TRs in a ligand-independent fashion. We also studied the regions implicated in the interaction with deletion mutants: the principal interacting region of RanBPM is comprised within its carboxyl-terminal end and the TR DNA-binding domain is sufficient to mediate the interaction. To investigate the potential role of RanBPM in thyroid hormone action, transient transfections with luciferase reporter genes were performed in CV-1 cells. We found that the over-expression of RanBPM increases the activation of TRETK- and DR+4-positive thyroid hormone response elements. Interestingly, over-expression of the truncated protein RanBPM55, which lacks the N-terminal polyglutaminated region but binds TRs, decreased the fold activation by almost 80%. Furthermore, we performed competition assays using transient transfection of RanBPM and increasing amounts of RanBPM55. This revealed that the stimulating effect on TR transactivation by the full-length protein is inhibited in a dose-dependent fashion by RanBPM55. This suggests that although the polyglutaminated region of RanBPM is not required for the binding to TRs, it is required for the stimulation of TR transactivation. Taken together, our results provide evidence that RanBPM is a potent novel coactivator for thyroid hormone receptors.

Context: Calcitonin is a well-established tumor marker for medullary thyroid carcinoma (MTC). Because surgery is the only effective treatment for patients with MTC, the postoperative level of serum calcitonin will dictate whether residual disease was left behind and whether reintervention is necessary., Results: We describe here the case of a 41-yr-old man with metastatic MTC. Despite extensive disease in the neck as well as metastatic lesions in the liver, his serum calcitonin, measured with a commercial one-step immunoradiometric assay, was only minimally elevated (244 ng/liter). After serial dilutions, a nonlinear relationship became evident, suggesting the presence of a "hook effect." Treatment of the serum with heterophilic blocking reagent revealed no change. Calcitonin was then measured with a different immunoradiometric assay and revealed a much higher level. Similar discrepancies were found in different samples from various patients when analyzed with different calcitonin immunoassays., Conclusion: To our knowledge, this is the first reported case of a phenomenon such as the hook effect in a calcitonin immunoradiometric assay in patients with MTC. Being aware of this phenomenon is important, because a low calcitonin result could give false reassurance to both the patient and the clinician and could dramatically change the prognosis of the patient.

This study estimates the incidence and prevalence of hypothyroidism in Quebec, based on a data bank produced by the Régie de l'assurance maladie du Québec (RAMQ) on the use of thyroid hormones by persons insured under RAMQ's public drug insurance plan between 1992 and 2001. In 2001, the prevalence of thyroid hormone use in women and men respectively was 10.8 and 2.9 percent. Prevalence increases with age, reaching, among those aged 65 and over, 21.9 percent in women and 8.0 percent in men in 2001. Incidence is highest in women between the ages of 45 and 64 and in men aged 65 and over. Age-related incidence is relatively stable in women but tends to increase in men. On a regional and local basis (by Centre local de services communautaires [CLSC]), incidence rates up to 2.4 times higher than anticipated on the basis of provincial incidence rates were observed.

Thyroid hormone receptors (TRs) bind to response elements (TREs) located in the promoter region of target genes and modulate their transcription. The effects of TRs require the presence of coregulators that act as adaptor molecules between TRs and complexes that are involved in chromatin remodeling or that directly contact the basal transcription machinery. Using the yeast two-hybrid system, we identified a new interacting partner for TRs: GRP1 (general receptor for phosphoinositides-1), a nucleotide exchange factor, which had never been shown to interact with nuclear receptors. We reconfirmed the interaction between TRs and GRP1 in yeast and glutathione-S-transferase pull-down assays, and determined the areas of TRs and GRP1 involved in the interaction. Coimmunoprecipitation studies demonstrated that the interaction between GRP1 and TRs takes place in the cytoplasm and the nucleus of mammalian cells. To assess functional consequences of the interaction, we used transient transfection of CV-1 cells with TR and GRP1 expression vectors and luciferase reporter genes. On positive TREs, GRP1 decreased activation by 45-60%. On the negative TREs it increased repression by blunting the activation in the absence of T3, except for TRbeta2, which was not affected. Using EMSA, we have determined that addition of GRP1 diminishes the formation of TR/TR homodimers and TR/retinoid X receptor heterodimers on TREs, which could explain the effect of GRP1 on transcription. Furthermore, protein interaction assays using increasing concentrations of double-stranded TREs show a dose-dependent decrease of the interaction between GRP1 and TRs. The homo/heterodimers formed by TRs and retinoic X receptor-alpha were not influenced by the presence of GRP1, also suggesting that GRP1 interferes directly with DNA binding. Taken together, these data provide evidence that GRP1 is a new corepressor for TRs, which modulates both positive and negative regulation by T3 by decreasing TR-complex formation on TREs.

Resistance to thyroid hormone (RTH) is a syndrome caused by a mutation in the carboxyl-terminal domain of the thyroid hormone receptor beta (TRbeta) gene. 3,5,3'-triiodothyroacetic acid (Triac) has been used on an empirical basis to treat RTH but its efficacy is still controversial. In previous studies, we demonstrated that Triac has TR isoform- and TRE-specific effects. In this report, we used five natural RTH mutations of the ligand-binding domain in both TRbeta1 and TRbeta2 isoforms for the evaluation of the effect of T3 and Triac on regulation of transcription and binding affinity. We show that Triac has superior activity on negatively and positively regulated promoters and higher binding affinity than T3 for a majority of TRbeta1 and TRbeta2 mutants. However, the difference of transcriptional activity and binding affinity between both ligands is less for RTH mutants than for wild type receptors. These results suggest that Triac could be a potential treatment for RTH patients.

3,5,3'-triiodothyroacetic acid (Triac) is a naturally occurring triiodothyronine (T(3)) analog, which has been used on an empirical basis to treat the syndrome of resistance to thyroid hormone (RTH). The aim of our studies was to compare the effects of Triac and T(3) on negative and positive thyroid hormone response elements (TREs). We used transient transfections with luciferase reporter genes to show that on palindromic, inverted palindrome and human TRH reporters, Triac is more potent than T(3) for transcriptional regulation by TRbeta1 and TRbeta2 isoforms, while regulation by TRalpha1 is equivalent for both ligands. Other TREs (direct repeat, hTSHalpha and hTSHbeta) are not regulated differently by Triac and T(3). Dose-response curves show that the difference between Triac and T(3) is maximal in the 1-10 nM range. Receptor-binding studies reveal a greater affinity of Triac than T(3) for TRbeta1 and TRbeta2 isoforms, which could explain its isoform-specific effects. These data suggest that the TRE- and TR isoform-specific effects of Triac favor its use in RTH.

Purpose: To report a case of severe coronary artery disease complicating pheochromocytoma, managed with combined coronary artery bypass grafting (CABG) and adrenalectomy., Clinical Features: A 55-yr-old woman presented with poorly controlled hypertension and investigation revealed an active pheochromocytoma of her left adrenal gland. During medical preparation for adrenalectomy, she developed an acute myocardial infarct complicated with unstable angina. This required urgent CABG, and combined surgery for the triple vessels coronary artery disease and the pheochromocytoma was planned. We explain the details of medical preparation before surgery and the anesthetic considerations during the surgical procedure. Postoperative recovery was normal and no complication occurred. Even if the pheochromocytoma was malignant, her urinary catecholamines two months after the surgery were normal and remain normal after more than two years of follow-up., Conclusion: We report a patient who underwent combined CABG and adrenalectomy for pheochromocytoma. The CABG was done first, followed by the adrenalectomy with invasive monitoring. The procedure was well tolerated with cure of the two underlying conditions. So we propose that combined procedure should be considered in this clinical setting.

Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-beta2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-beta2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein alpha-subunit genes than either TR-beta1 or TR-alpha1. A chimeric TR-beta isoform containing the TR-beta2 amino terminus linked to the TR-alpha1 DNA- and ligand-binding domains functioned like the TR-beta2 isoform on these promoters, confirming that the amino terminus of TR-beta2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-beta2 amino terminus, we demonstrate that amino acids 89-116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-beta2. We conclude that the central nervous system-restricted TR-beta2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-beta2.

Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). The mutant TR interferes with the action of normal TR to cause the clinical syndrome. Selective pituitary resistance to thyroid hormone (PRTH) results in inappropriate TSH secretion and peripheral sensitivity to elevated thyroid hormone levels. Association of the PRTH phenotype with in vitro behavior of the mutant TR has proved elusive. Alternative exon utilization results in two TR-beta isoforms, TR-beta 1 and TR-beta 2, which differ only in their amino termini. Although the TR-beta 1 isoform is ubiquitous, the TR-beta 2 isoform is found predominantly in the anterior pituitary and brain. To date, in vitro evaluation of RTH mutations has focused on the TR-beta 1 isoform. Site-directed mutagenesis was used to create several PRTH (R338L, R338W, V349M, R429Q, I431T) and generalized RTH (delta 337T, P453H) mutations in both TR-beta isoforms. The ability of mutant TRs to act as dominant negative inhibitors of wild type TR-beta function on positive and negative thyroid hormone response elements (pTREs and nTREs, respectively) was evaluated in transient transfection assays. PRTH mutants had no significant dominant negative activity as TR-beta 1 isoforms on pTREs found in peripheral tissues or on nTREs found on genes regulating TSH synthesis. PRTH mutants, in contrast, had strong dominant negative activity on these same nTREs as TR-beta 2 isoforms. Cotransfected retinoid X receptor-alpha was required for negative T3 regulation via the TR-beta 1 isoform but was not necessary for negative regulation via the TR-beta 2 isoform in CV-1 cells. The differing need for retinoid X receptor cotransfection demonstrates two distinct negative T3-regulatory pathways, one mediated by the TR-beta 1 and the other mediated by TR-beta 2. The selective effect of PRTH mutations on the TR-beta 2 isoform found in the hypothalamus and pituitary vs. the TR-beta 1 isoform found in peripheral tissues suggests a molecular mechanism for the PRTH disorder.

In obesity, it is well known that basal growth hormone (GH) levels can be suppressed and they may show an impaired response to various stimuli like hypoglycemia, stress, and GHRH. However, the inhibitory effect of hyperglycemia on GH in this condition has not been well studied. We analyzed the GH response to an oral glucose tolerance test (OGTT) in 25 unselected patients with morbid obesity who were not diabetic, glucose intolerant or affected by renal or hepatic disease. Ten (40%) of the 25 subjects had an abnormal response of GH to the OGTT, expressed by a lack of suppression of GH levels below 2 micrograms/L within 60 minutes of glucose administration. Three subjects even had a paradoxal increase of GH levels of more than 50% of the basal level. There was no significant difference between these subjects regarding their age, BMI and, serum levels of glucose, insulin, C peptide, or insulin/glucose ratio. After weight loss, three of four patients normalized their GH response. Thus, we conclude that patients with morbid obesity frequently have an abnormal response of GH to OGTT (40% vs 4-8% in normal subjects). This finding must be taken into consideration when interpreting GH levels in these patients. A normalization of this response can be expected after weight loss.

A 63-year-old female patient was referred to our hospital in February 1994 for a pituitary tumor. On a previous examination, in 1973, she had a goiter, nonspecific symptoms and only an elevated serum T3. In 1984 she had become hypothyroid, her goiter had increased, serum T4 was 69 nmol/L, TSH 34.4 mU/L, and TPO antibodies were positive. Hypothyroidism due to autoimmune thyroiditis was diagnosed and she received L-T4 100 micrograms/day. In 1985 and 1986, serum TSH had decreased but remained slightly elevated, while T4 was at the upper limits of normal. From 1987 to 1989 her serum TSH rose from 9 to 20 mU/L and remained at that level for the ensuing 4 years in spite of increasing L-T4 up to 150 micrograms/day. In October 1993, after discontinuing L-T4 for 6 weeks, TSH was 23.7 mU/L, T4 170 nmol/L, 131I thyroid uptake 52%, and the CT scan showed a large pituitary tumor with suprasellar extension. On preoperative investigation TSH was 40-51 mU/L with no response to TRH or GnRH. The alpha-subunit was increased at 6.33 micrograms/L with the alpha-TSH/TSH molar ratio of 1.23. Prolactin was elevated, but plasma cortisol, FSH, and LH were low. At surgery, we found a large chromophobe adenoma with few PAS-positive granules and with immunostaining positive for TSH and prolactin. From the clinical and biological data, we can conclude that the patient had probably a TSH-secreting adenoma since the goiter was first detected. The development, however, of autoimmune thyroiditis with hypothyroidism considerably modified the presentation of the disease and may have accelerated the growth of the tumor.

We report a case of rapid 99mTc-methoxyisobutylisonitrile (MIBI) clearance from a parathyroid adenoma. A double-phase 99mTc-MIBI parathyroid scintigraphy was performed on a 62-yr-old female evaluated for primary hyperparathyroidism. A large parathyroid adenoma was visualized caudal to the left lobe of the thyroid gland with an unusually rapid washout of the tracer from tumor tissue. Histologic tissue examination confirmed the presence of a parathyroid adenoma and the absence of oxyphil cells. Care should be taken in interpretation of 99mTc-MIBI parathyroid scintigrams because some adenomas can present a rapid release of the radiotracer in a double-phase study. Technetium-99m-MIBI retention could be related to the number of mitochondria-rich cells in parathyroid adenomas or to hyperplasia.