Allele Summation of Diabetes Risk Genes Predicts Impaired Glucose Tolerance in Female and Obese Individuals

INTRODUCTION: Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists. METHODS: In our cohort of 1442 non-diabetic subjects of European origin (normal glucose tolerance [NGT] n = 1046, isolated IFG n = 142, isolated IGT n = 140, IFG+IGT n = 114), an impact on glucose homeostasis has been shown for 9 SNPs in previous studies in this specific cohort. We analyzed these SNPs (within or in the vicinity of the genes TCF7L2, KCNJ11, HHEX, SLC30A8, WFS1, KCNQ1, MTNR1B, FTO, PPARG) for association with prediabetes. RESULTS: The genetic risk load was significantly associated with the risk for IGT (p = 0.0006) in a model including gender, age, BMI and insulin sensitivity. To further evaluate potential confounding effects, we stratified the population on gender, BMI and insulin sensitivity. The association of the risk score with IGT was present in female participants (p = 0.008), but not in male participants. The risk score was significantly associated with IGT (p = 0.008) in subjects with a body mass index higher than 30 kg/m(2) but not in non-obese individuals. Furthermore, only in insulin resistant subjects a significant association between the genetic load and the risk for IGT (p = 0.01) was found. DISCUSSION: We found that T2D genetic risk alleles cause an increased risk for IGT. This effect was not present in male, lean and insulin sensitive subjects, suggesting a protective role of beneficial environmental factors on the genetic risk

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.ISSN:0092-8674ISSN:1097-417

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Synthesis of organobromines as a tool for their characterisation and environmental occurrence assessment

Polybrominated diphenyl ethers (PBDEs) have been intensively used as flame retardants (FRs) and have become ubiquitous environmental pollutants. PBDEs form hydroxylated PBDEs (OH-PBDEs) as metabolites. Further, some OH-PBDEs and methoxy-PBDEs (MeO-PBDEs) are natural products. These are all compounds of environmental and health concern and it is therefore important to confirm their identity and to assess their environmental levels and toxicities. Hence, it is vital to obtain authentic reference standards of individual PBDEs and OH/MeO-PBDEs. The thesis main aim was to develop synthesis methods of congener specific PBDEs, OH- and MeO-PBDEs. The second aim was to identify and quantify PBDEs, OH- and MeO-PBDEs in environmental samples. The third was to propose an abbreviation system for FRs. O-Arylation of brominated phenols, using either symmetrical or unsymmetrical brominated diphenyliodonium salts, was selected for synthesis of PBDEs and OH-/MeO-PBDEs. A total of 16 MeO-PBDEs, 11 OH-PBDEs, 1 diMeO-PBDE and 1 EtO-MeO-PBDE were synthesised. Three novel unsymmetrical diaryliodonium triflates were synthesised and used in synthesis. Optimisations were made to construct a reliable general method for congener specific PBDE synthesis, which was used in the synthesis of 8 representative PBDE congeners. The products were generally characterised by electron ionisation mass spectrometry (EIMS) and nuclear magnetic resonance (NMR) spectroscopy. Identification of PBDEs and OH-PBDEs in various matrixes was based on gas chromatographic and mass spectrometric analyses. Fourteen OH-PBDE congeners were identified in a pooled human blood sample. One previously uncharacterised natural PBDE analogue was identified as 6-OH-6’-MeO-BDE-194, and quantified in Swedish blue mussels. PBDE congeners and other BFRs were identified and quantified in workers and dust from a smelter in Sweden. A structured and practical abbreviation system was developed for halogen- and phosphorus containing FRs.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Submitted. Paper 4: Manuscript.</p

Synthesis of organobromines as a tool for their characterisation and environmental occurrence assessment

Polybrominated diphenyl ethers (PBDEs) have been intensively used as flame retardants (FRs) and have become ubiquitous environmental pollutants. PBDEs form hydroxylated PBDEs (OH-PBDEs) as metabolites. Further, some OH-PBDEs and methoxy-PBDEs (MeO-PBDEs) are natural products. These are all compounds of environmental and health concern and it is therefore important to confirm their identity and to assess their environmental levels and toxicities. Hence, it is vital to obtain authentic reference standards of individual PBDEs and OH/MeO-PBDEs. The thesis main aim was to develop synthesis methods of congener specific PBDEs, OH- and MeO-PBDEs. The second aim was to identify and quantify PBDEs, OH- and MeO-PBDEs in environmental samples. The third was to propose an abbreviation system for FRs. O-Arylation of brominated phenols, using either symmetrical or unsymmetrical brominated diphenyliodonium salts, was selected for synthesis of PBDEs and OH-/MeO-PBDEs. A total of 16 MeO-PBDEs, 11 OH-PBDEs, 1 diMeO-PBDE and 1 EtO-MeO-PBDE were synthesised. Three novel unsymmetrical diaryliodonium triflates were synthesised and used in synthesis. Optimisations were made to construct a reliable general method for congener specific PBDE synthesis, which was used in the synthesis of 8 representative PBDE congeners. The products were generally characterised by electron ionisation mass spectrometry (EIMS) and nuclear magnetic resonance (NMR) spectroscopy. Identification of PBDEs and OH-PBDEs in various matrixes was based on gas chromatographic and mass spectrometric analyses. Fourteen OH-PBDE congeners were identified in a pooled human blood sample. One previously uncharacterised natural PBDE analogue was identified as 6-OH-6’-MeO-BDE-194, and quantified in Swedish blue mussels. PBDE congeners and other BFRs were identified and quantified in workers and dust from a smelter in Sweden. A structured and practical abbreviation system was developed for halogen- and phosphorus containing FRs.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Submitted. Paper 4: Manuscript.</p

Characterization of progressive damage in concrete using impact non-linear reverberation spectroscopy

Nonlinear acoustic methods have shown potential for the identification of early damage in brittle materials such as concrete. Commonly, these methods evaluate relative nonlinearity parameters from multiple resonance tests at different amplitudes. We demonstrate a recently developed alternative method, Impact Nonlinear Reverberation Spectroscopy (INRS), where quantitative nonlinearity parameters are evaluated from a single impact resonance test. The recorded reverberation of the measured signal is matched to a synthetic nonlinear damped signal. The proposed model allows instantaneous true physical amplitude, frequency, and damping of each mode to be characterized as a function of time, allowing for quantitative information of the nonlinear parameters. The hysteretic material nonlinearity can be quantitatively characterized over a notably wider dynamic range compared to conventional methods. Two examples from the application to concrete and stabilized soil are presented

Damage Identification in Concrete using Impact Non-Linear Reverberation Spectroscopy

High amplitude non-linear acoustic methods have shown potential for the identification of micro damage in brittle materials such as concrete. Commonly, these methods evaluate a non-linearity parameter from the relative change in frequency and attenuation with strain amplitude. Here, a novel attenuation model is introduced to describe the free reverberation from a standard impact resonance frequency test, together with an algorithm for estimating the unknown model coefficients. The non-linear variation can hereby by analyzed over a wider dynamic range as compared to conventional methods. The experimental measurement is simple and fully compatible with the standardized free-free linear impact frequency test

Accuracy and precision of 3 intraoral scanners and accuracy of conventional impressions : A novel in vivo analysis method

Objective: To evaluate a novel methodology using industrial scanners as a reference, and assess in vivo accuracy of 3 intraoral scanners (IOS) and conventional impressions. Further, to evaluate IOS precision in vivo. Methods: Four reference-bodies were bonded to the buccal surfaces of upper premolars and incisors in five subjects. After three reference-scans, ATOS Core 80 (ATOS), subjects were scanned three times with three IOS systems: 3M True Definition (3M), CEREC Omnicam (OMNI) and Trios 3 (TRIOS). One conventional impression (IMPR) was taken, 3M Impregum Penta Soft, and poured models were digitized with laboratory scanner 3shape D1000 (D1000). Best-fit alignment of reference-bodies and 3D Compare Analysis was performed. Precision of ATOS and D1000 was assessed for quantitative evaluation and comparison. Accuracy of IOS and IMPR were analyzed using ATOS as reference. Precision of IOS was evaluated through intra-system comparison. Results: Precision of ATOS reference scanner (mean 0.6 mu m) and D1000 (mean 0.5 mu m) was high. Pairwise multiple comparisons of reference-bodies located in different tooth positions displayed a statistically significant difference of accuracy between two scanner-groups: 3M and TRIOS, over OMNI (p value range 0.0001 to 0.0006). IMPR did not show any statistically significant difference to IOS. However, deviations of IOS and IMPR were within a similar magnitude. No statistical difference was found for IOS precision. Conclusion: The methodology can be used for assessing accuracy of IOS and IMPR in vivo in up to five units bilaterally from midline. 3M and TRIOS had a higher accuracy than OMNI. IMPR overlapped both groups. Clinical significance: Intraoral scanners can be used as a replacement for conventional impressions when restoring up to ten units without extended edentulous spans