Predicting glycated hemoglobin levels in the non-diabetic general population:Development and validation of the DIRECT-DETECT prediction model - a DIRECT study

AIMS/HYPOTHESIS: To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors. METHODS: Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM. RESULTS: At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model's intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort. CONCLUSIONS/INTERPRETATION: In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent

Tomografía computerizada: Un buen uso, no un abuso, de la radiación ionizante.

Computed Tomography: a good use, not an abuse, of ionizing radation - Computer Tomography (CT) using X-rays has become an essential tool in current medical diagnosis. However, its increasing use has already caused worldwide concern regarding the radiation expposure related to these examinations. In this contribution, the basics of CT data acquisition technology and its current drawbacks are presented. At the end, a current research proyect intended to solve or reduce those problems is briefly introduced

A patient-centric approach to quality control and dosimetry in CT including CBCT.

One measurement and an algebraic formula are used to calculate the incident air kerma (Ka,i) at the skin after any CT examination, including cone-beam CT (CBCT) and multi-slice CT (MSCT). Empty scans were performed with X-ray CBCT systems (dental, C-arm and linac guidance scanners) as well as two MSCT scanners. The accumulated Ka,i at the flat panel (in CBCT) or the maximum incident air kerma at the isocentre (in MSCT) were measured using a solid-state probe. The average Ka,i(skin), at the skin of a hypothetical patient, was calculated using the proposed formula. Additional measurements of dose at the isocentre (DFOV) and kerma-area product (KAP), as well as Ka,i(skin) from thermoluminiscence dosimeters (TLDs) and size-specific dose estimates are presented for comparison. The Ka,i(skin) for the standard head size in the dental scanner, the C-arm (high dose head protocol) and the linac (head protocol) were respectively 3.33 ± 0.19 mGy, 15.15 ± 0.76 mGy and 3.23 ± 0.16 mGy. For the first MSCT, the calculated Ka,i(skin) was 13.1 ± 0.7 mGy and the TLDs provided a Ka,i(skin) between 10.3 ± 1.1 mGy and 13.8 ± 1.4 mGy. Estimation of patient air kerma in tomography with an uncertainty below 7% is thus feasible using an empty scan and conventional measurement tools. The provided equations and website can be applied to a standard size for the sake of quality control or to several sizes for the definition of diagnostic reference levels (DRLs). The obtained incident air kerma can be directly compared to the Ka,i from other X-ray modalities as recommended by ICRU and IAEA

Entwicklung und Überprüfung einer Nicht-Standard-CT-Scannergeometrie mit potentiellen Dosisminderungseigenschaften.

Die Idee einer neuen Scannergeometrie für CT-Untersuchungen wurde auf der Konferenz SPIE Medical Imaging 2006 präsentiert. Die neue Geometrie bekommt die Radon-Daten nach Einblendung des Strahlenfächers durch eine besondere Maske und die Verwendung von zwei unterschiedlichen Detektorebenen. Diese Maske wird mit einer effizienten Art und Weise der Datensammlung kombiniert und könnte deshalb die Dosis um einen Faktor zwei reduzieren. Dieser Beitrag behandelt die Sammlung der experimentellen Daten aus der Detektionsmaske jener neuen Scangeometrie. Mehrere Eigenschaften wurden betrachtet, um die optimalen Parameter des Geräts zu finden: Detektorelemente, Abschirmungsform, Fan-Beam-Winkel, Drehgeschwindigkeit und Materialien. Die Detektorkalibrierung brauchte eine besondere Aufmerksamkeit auf Grund der Abhängigkeit der Detektorempfindlichkeit von der Strahlenqualität. Die besten Parameter wurden benutzt, um den Prototyp wie vorgeschlagen aufzubauen. Daten aus Phantommessungen wurden mit dem Prototyp gesammelt und daraus eine Bildrekonstruktion angefertigt. Die Ergebnisse sind viel versprechend, obwohl der entwickelte Prototyp eine vereinfachte Annäherung an das theoretische Konzept ist

Prospective association of vitamin D with frailty status and all-cause mortality in older adults: Results from the KORA-Age study.

OBJECTIVE: To assess the prospective association of serum 25-hydroxyvitamin D [25(OH)D] levels with frailty status and all-cause mortality in a cohort of community-dwelling participants of the population-based KORA [Cooperative Health Research in the Region of Augsburg]-Age Study. METHODS: 727 non-frail participants, aged ≥65years, with 25(OH)D measurement at baseline in 2009, were followed for 2.9±0.1years. Participants were classified as pre-frail or frail if they met 1-2 or ≥3, respectively, of the following five criteria: weight loss, exhaustion, physical inactivity, low walking speed, weakness. The association between 25(OH)D and mortality was assessed in 954 participants. Multivariable adjusted logistic regression models were calculated for each outcome. RESULTS: The incidence of pre-frailty and frailty was 21.2% and 3.9% respectively. After multivariable adjustment, participants with very low 25(OH)D levels (<15ng/ml vs. ≥30ng/ml) had a significantly higher odds of pre-frailty (OR=2.43 [95% CI: 1.17-5.03]) and pre-frailty/frailty combined (OR=2.53 [95% CI: 1.23-5.22]), but not for frailty alone (OR=2.63 [95% CI: 0.39-17.67]). The association between 25(OH)D and mortality (OR=3.39 [95% CI: 1.08-10.65]) was partly mediated by frailty. CONCLUSION: Very low 25(OH)D levels were independently associated with incident pre-frailty, pre-frailty/frailty combined and all-cause mortality

A high fat diet during mouse pregnancy and lactation targets GIP-regulated metabolic pathways in adult male offspring.

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the Gastric Inhibitory Polypeptide Receptor (GIPR) prevents high fat diet induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or high fat diet (HFD) during pregnancy (IU) and lactation (L). Male wild type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant, obese, exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being re-introduced to HFD similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared to Gipr(-/-) mice on control diet during IU/L. DNA-methylation analysis revealed increased methylation of CpG-dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in muscle of Gipr(-/-) offspring on HFD during IU/L which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming

The cardiovascularmarkers copeptin and highsensitive C-reactive protein decrease following specific therapy for primary aldosteronism.

Context: Copeptin and high-sensitive C-reactive protein (hsCRP) are biomarkers associated with increased mortality in patients with cardiovascular and cerebrovascular disease as well as in the general population. No data exist regarding these markers in patients with primary aldosteronism. Objective: To evaluate copeptin and hsCRP levels as cardiovascular risk markers in primary aldosteronism patients. Methods: A total of 113 primary aldosteronism patients (64% male) from two centers of the prospective German Conn's Registry were identified, for whom a full data set and blood samples at baseline and follow-up (143.4 months) after initiation of specific primary aldosteronism treatment were available. These cases were matched 1 : 3 (n 339) for sex, renal function, BMI, age and SBP with participants from the Cooperative Health Research in the Region of Augsburg F4 survey. Copeptin and hsCRP were determined by sandwich fluoroimmunoassay. Results: HsCRP was significantly higher in primary aldosteronism patients at baseline compared with matched controls. Following specific therapy, hsCRP and copeptin decreased significantly in primary aldosteronism patients [median (25th and 75th percentile): 1.6 (0.8, 3.4) to 1.2 (0.6, 2.1) mg/l, P<0.001; 7.8 (4.6, 13.5) to 5.0 (3.1, 8.9) pmol/l, P<0.001, respectively]. Men had higher hsCRP and copeptin levels at baseline and follow-up compared with women. The combination of sex, hypokalemia, lateralization index and blood pressure were the best predictors of outcome. However, copeptin and hsCRP had no predictive value despite the association of lower copeptin levels with better outcome regarding cure of primary aldosteronism. Conclusion: Copeptin and hsCRP levels decrease following specific primary aldosteronism therapy reflecting successful cardiovascular risk reduction. However, they are no independent predictors regarding cure of primary aldosteronism

Modulation of insulin degrading enzyme activity and liver cell proliferation.

Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n=22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis