Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Online adaption approaches for intensity modulated proton therapy for head and neck patients based on cone beam CTs and Monte Carlo simulations.

To develop an online plan adaptation algorithm for intensity modulated proton therapy (IMPT) based on fast Monte Carlo dose calculation and cone beam CT (CBCT) imaging. A cohort of ten head and neck cancer patients with an average of six CBCT scans were studied. To adapt the treatment plan to the new patient geometry, contours were propagated to the CBCTs with a vector field (VF) calculated with deformable image registration between the CT and the CBCTs. Within the adaptive planning algorithm, beamlets were shifted following the VF at their distal falloff and raytraced in the CBCT to adjust their energies, creating a geometrically adapted plan. Four geometric adaptation modes were studied: unconstrained geometric shifts (Free), isocenter shift (Iso), a range shifter (RS), or isocenter shift and range shifter (Iso-RS). After evaluation of the geometrical adaptation, the weights of a selected subset of beamlets were automatically tuned using MC-generated influence matrices to fulfill the original plan requirements. All beamlet calculations were done with a fast Monte Carlo running on a GPU (graphics processing unit). Geometrical adaptation alone only worked with small anatomy changes. The weight-tuned adaptation worked for every fraction, with the Free and Iso modes performing similarly and being superior than the two range shifters modes. The mean V95 and V107 were 99.4 ± 0.9 and 6.4% ± 4.7% in the Free mode with weight tuning. The calculation time per fraction was ~5 min, but further task parallelization could reduce it to ~1-2 min for delivery adaptation right after patient setup. An online adaptation algorithm was developed that significantly improved the treatment quality for inter-fractional geometry changes. Clinical implementation of the algorithm would allow delivery adaptation right before treatment and thus allow planning margin reductions for IMPT.

HbA(1c) in the prediction of type 2 diabetes compared with fasting and 2-h post-challenge plasma glucose: The Asturias study (1998-2005).

AIM: Fasting plasma glucose (FPG) and the 2-h post-challenge plasma glucose (2hPG) are commonly used to identify those at risk of type 2 diabetes. However, the role of HbA(1c) in this prediction has still not been ascertained. METHODS: The Asturias study is a prospective population-based survey of diabetes and cardiovascular risk factors. Baseline examination, carried out during 1998-1999, involved 1034 individuals, aged 30-75 years, randomly selected to determine the prevalence of type 2 diabetes and prediabetes in the principality of Asturias (northern Spain). In 2004-2005, these same subjects were invited to a follow-up examination, and 700 participated. The present study includes only those who did not have diabetes at baseline. All participants with no known diabetes underwent an OGTT. Baseline HbA(1c) levels were measured by HPLC. RESULTS: Diabetes had developed in 44 participants at the time of follow-up. Quartiles of baseline HbA(1c) values were 3.4-4.8 (Q1), 4.9-5.1 (Q2), 5.2-5.4 (Q3) and 5.5-6.9 (Q4), and the incidence rates of diabetes by quartiles were 1.0 (0.1-7.1), 4.0 (1.5-10.7), 7.9 (4.0-15.9) and 32.6 (22.9-46.4) cases/1000 person-years, respectively. ROC curve analysis comparing HbA(1c), FPG and 2hPG in the prediction of diabetes showed areas under the curve (ROC-AUC) of 0.80 (0.74-0.86), 0.83 (0.77-0.90) and 0.79 (0.72-0.87), respectively. The combination of FPG and HbA(1c) had the best predictive performance with an ROC-AUC of 0.88 (0.82-0.93). CONCLUSION: Our study indicates that HbA(1c) is strongly predictive of new-onset diabetes in this northern Spanish population, and was similar to FPG and 2hPG in predictive capability. Also, the combined measurement of FPG and HbA(1c) improved their individual predictive performance.

Vitamin D deficiency in Spain: a population-based cohort study.

BACKGROUND: Vitamin D deficiency is common worldwide. No homogenous reference values have yet been established and no studies of values have been conducted in Spain involving a large number of participants. OBJECTIVE: To study the population concentrations of vitamin D in a representative sample of the Spanish population. SUBJECTS/METHODS: The study involved two cohorts from Spain, the Asturias study and the Pizarra study, which are two prospective, population-based studies involving 2260 participants. In 1262 subjects (age: 20-83 years) we studied 25-hydroxyvitamin D, intact parathyroid hormone (iPTH), calcium, phosphorus and creatinine. RESULTS: The median population values of 25-hydroxyvitamin D and iPTH were 22.46 ng/ml and 42.29 pg/ml, respectively. The values of 25-hydroxyvitamin D were significantly higher in summer and correlated with age (ß = -0.05 ± 0.01, P < 0.0001), creatinine (ß = 6.42 ± 1.17, P < 0.0001) and iPTH (-0.07 ± 0.01, P < 0.0001), but not with calcium, phosphorus or sex. The increase in iPTH with age was seen whatever the values of 25-hydroxyvitamin D, and was greater in the older persons. The concentration of iPTH rose continuously with effect from 25-hydroxyvitamin D values below ≈30 ng/ml. Values above ≈35 ng/ml were associated with a significantly lower concentration of iPTH. CONCLUSIONS: One-third (33.9%) of the Spanish population may be at risk for Vitamin D deficiency. The 25-hydroxyvitamin D values above 30 ng/ml can safely discard 'hyper PTH'. The increase in iPTH concentration is greater in older persons for similar values of 25-hydroxyvitamin D.

Comparison of the diagnostic criteria for diabetes mellitus, WHO-1985, ADA-1997 and WHO-1999 in the adult population of Asturias (Spain).

AIMS: To estimate the prevalence of diabetes mellitus with three diagnostic criteria (WHO-1985 and 1999 and ADA-1997), evaluate their concordance and analyse the sensitivity and specificity of the different screening strategies for diabetes. METHODS: A cross-sectional population study with two-step sampling. One thousand and 34 people were selected randomly. A 75-g oral glucose tolerance test (OGTT) was performed and venous blood samples were obtained fasting and at 2 h. RESULTS: The prevalence of known Type 2 diabetes mellitus (DM-2) is 4%[95% confidence interval (CI) 2.8, 5.1]. By WHO-1985 criteria the prevalence of unknown DM-2 is 5.9% (4.5, 7.4); by ADA-1997 criteria 3.5% (2.5, 4.6) and by WHO-1999 criteria 7.3% (5.8, 8.8). Diagnostic overlap and statistical concordance (coefficient K) are WHO-1985/ADA-1997 29.3%, K=0.42; WHO-1985/WHO-1999 80%, K=0.88; ADA-1997/WHO-1999 48%, K=0.63. If only fasting glucose was used (following ADA-1997), 36.3% of those with diabetes (2-h glucose > or =11.1 mmol/l) would be diagnosed. If OGTT was performed (i) in those with a fasting glucose between 6.1 mmol/l and 6.9 mmol/l (9.8% of the population) we would diagnose 66.6%, and (ii) in all those between 5.7 mmol/l and 6.9 mmol/l (18.9% of the population) 81.8% would be diagnosed. CONCLUSIONS: The ADA criteria decrease the prevalence of DM in the adult population of Asturias by 2.4% and concordance with the classical criteria (WHO-1985) was only 29.3%. Using fasting glucose only (ADA-1997) diagnoses 36.3% of those with diabetes. The recent recommendations of the WHO-1999 increases this to 66.6%. To improve the diagnostic strategy for diabetes and detect up to 81.8% of patients, we propose the use of OGTT for all those with a fasting glucose between 5.7 mmol/l and 6.9 mmol/l.