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| 2. |
- Locke, Adam E, et al.
(author)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- Shungin, Dmitry, et al.
(author)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 4. |
- Dormandy, J. A., et al.
(author)
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Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
- 2005
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In: Lancet. - 1474-547X. ; 366:9493, s. 1279-89
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Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
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| 5. |
- Martinello, K. A., et al.
(author)
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Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia
- 2022
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In: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 91:6, s. 1416-1427
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Journal article (peer-reviewed)abstract
- BACKGROUND: Perinatal inflammation combined with hypoxia-ischemia (HO exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. METHODS: Twelve newborn piglets received a 2 mu g/kg bolus and 1 mu g/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 degrees C 1-25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. RESULTS: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/ proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. CONCLUSIONS: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.
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| 7. |
- Ferrannini, E., et al.
(author)
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Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study
- 2011
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54:6, s. 1507-1516
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Journal article (peer-reviewed)abstract
- The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area. We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique (M/I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later. Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors. Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity.
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| 8. |
- Carrard, I, et al.
(author)
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Evaluation of a guided internet self-treatment programme for bulimia nervosa in several European countries.
- 2010
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In: European eating disorders review : the journal of the Eating Disorders Association. - : Wiley. - 1099-0968.
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The purposes of this study were to evaluate the use of an online guided self-treatment programme for bulimia nervosa (BN) and to determine predictors of outcome. Data were collected in four European countries where the programme was simultaneously used. METHOD: One hundred and twenty-seven BN or subthreshold BN female patients (mean age of 24.7 years) participated in a 4-month intervention using a CBT based online-guided self-help programme. Contact during the treatment period included weekly e-mails with a coach. ASSESSMENT: Measures included the Eating Disorders Inventory-2 (EDI-2) and the Symptom Check List-Revised (SCL-90R). RESULTS: Severity of eating disorders symptoms and general psychopathology improved significantly. Twenty-three per cent of patients were symptom free at the end of treatment. The dropout rate was 25.2%. A better score of general psychological health was a predictor of a better outcome. CONCLUSIONS: This study encourages further developments and research on innovative therapy approaches, particularly for those disorders such as BN, with difficult therapy and unclear prognosis. Copyright © 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
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| 9. |
- Martinello, K. A., et al.
(author)
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Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Co-existing infection/inflammation and birth asphyxia potentiate the risk of developing neonatal encephalopathy (NE) and adverse outcome. In a newborn piglet model we assessed the effect of E. coli lipopolysaccharide (LPS) infusion started 4 h prior to and continued for 48 h after hypoxia on brain cell death and systemic haematological changes compared to LPS and hypoxia alone. LPS sensitized hypoxia resulted in an increase in mortality and in brain cell death (TUNEL positive cells) throughout the whole brain, and in the internal capsule, periventricular white matter and sensorimotor cortex. LPS alone did not increase brain cell death at 48 h, despite evidence of neuroinflammation, including the greatest increases in microglial proliferation, reactive astrocytosis and cleavage of caspase-3. LPS exposure caused splenic hypertrophy and platelet count suppression. The combination of LPS and hypoxia resulted in the highest and most sustained systemic white cell count increase. These findings highlight the significant contribution of acute inflammation sensitization prior to an asphyxial insult on NE illness severity.
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| 10. |
- Pataky, Z., et al.
(author)
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Metabolic normality in overweight and obese subjects. Which parameters? Which risks?
- 2011
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 35:9, s. 1208-1215
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Journal article (peer-reviewed)abstract
- Objectives: The objective of this study was to define metabolic normality and to investigate the cardiometabolic profile of metabolically normal obese. Design: Cross-sectional study conducted at 21 research centers in Europe. Subjects: Normal body weight (nbw, n = 382) and overweight or obese (ow/ob, n = 185) subjects free from metabolic syndrome and with normal glucose tolerance, were selected among the Relationship between Insulin Sensitivity and Cardiovascular Disease study participants. Main outcome measures: Insulin sensitivity was assessed by the clamp technique. On the basis of quartiles in nbw subjects, the limits of normal insulin sensitivity and of normal fasting insulinemia were established. Subjects with normal insulin sensitivity and fasting insulin were defined as metabolically normal. Results: Among ow/ob subjects, 11% were metabolically normal vs 37% among nbw, P<0.0001. Ow/ob subjects showed increased fasting insulin (P = 0.0009), low-density lipoprotein cholesterol (LDL-cholesterol) (P = 0.004), systolic (P = 0.0007) and diastolic (P = 0.001) blood pressure, as compared with nbw. When evaluating the contribution of body mass index (BMI), hyperinsulinemia and insulin resistance, BMI showed an isolated effect on high-density lipoprotein (P = 0.007), high-sensitivity C-reactive protein (P<0.0001), systolic (P = 0.002) and diastolic (P = 0.008) blood pressures. BMI shared its influence with insulinemia on total cholesterol (P = 0.04 and 0.003, respectively), LDL-cholesterol (P = 0.003 and 0.006, respectively) and triglycerides (P = 0.02 and 0.001, respectively). Conclusion: In obese subjects, fasting insulin should be taken into account in the definition of metabolic normality. Even when metabolically normal, obese subjects could be at increased risk for cardiometabolic diseases. Increased BMI, alone or with fasting insulin, is the major responsible for the less favorable cardio-metabolic profile. International Journal of Obesity (2011) 35, 1208-1215; doi:10.1038/ijo.2010.264; published online 4 January 2011
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| 11. |
- Ruof, J, et al.
(author)
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Orlistat in responding obese type 2 diabetic patients : meta-analysis findings and cost-effectiveness as rationales for reimbursement in Sweden and Switzerland
- 2005
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 29:5, s. 517-523
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study is to review the clinical and economic rationale for the reimbursement of orlistat in responding obese patients with type 2 diabetes.METHODS: Data from seven randomized controlled clinical trials of orlistat in overweight and obese patients with type 2 diabetes were pooled. A subgroup analysis involving patients who achieved a response (defined as a weight loss of >/=5% after 12 weeks of treatment) was conducted. The outcomes of the pooled analysis were then used to construct a Markov health economic model covering an 11-y period. The incidences of diabetes-related micro- and macrovascular complications were derived from the United Kingdom Prospective Diabetes Study. The effects of changes in body mass index, and the impact of micro- and macrovascular complications on utilities were derived from published sources. Publicly available cost data were used and are presented here in 2001 Euros. Discounting of 3% was applied. A probabilistic sensitivity analysis was conducted to examine the robustness of results.RESULTS: A total of 1249 patients treated with orlistat and 1230 given placebo were eligible for the intent-to-treat analysis. At the end of the study period, 23% of orlistat patients achieved a weight reduction of >/=5%. These patients showed a mean decrease in HbA1C of 1.16%, a weight reduction of 8.6 kg, a reduction in total cholesterol of 5.3% and a reduction in systolic blood pressure of 5.2 mmHg. The base-case economic analysis revealed costs per quality-adjusted life year gained of euro14 000 in Sweden and euro13 600 in Switzerland.CONCLUSION: The data presented here support the utilization and reimbursement of orlistat in overweight and obese diabetic patients who respond to the treatment.
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| 18. |
- Fournier, Laure, et al.
(author)
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Incorporating radiomics into clinical trials : expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers
- 2021
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In: European Radiology. - : SPRINGER. - 0938-7994 .- 1432-1084. ; 31:8, s. 6001-6012
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Journal article (peer-reviewed)abstract
- Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials.
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| 20. |
- Lindner, Thomas, et al.
(author)
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Current state and guidance on arterial spin labeling perfusion MRI in clinical neuroimaging.
- 2023
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In: Magnetic Resonance in Medicine. - : John Wiley & Sons. - 0740-3194 .- 1522-2594. ; 89:5, s. 2024-2047
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Journal article (peer-reviewed)abstract
- This article focuses on clinical applications of arterial spin labeling (ASL) and is part of a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update and expand on the recommendations provided in the 2015 ASL consensus paper. Although the 2015 consensus paper provided general guidelines for clinical applications of ASL MRI, there was a lack of guidance on disease-specific parameters. Since that time, the clinical availability and clinical demand for ASL MRI has increased. This position paper provides guidance on using ASL in specific clinical scenarios, including acute ischemic stroke and steno-occlusive disease, arteriovenous malformations and fistulas, brain tumors, neurodegenerative disease, seizures/epilepsy, and pediatric neuroradiology applications, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications in which ASL provides unique information essential for making the diagnosis. This guidance is intended for anyone interested in using ASL in a routine clinical setting (i.e., on a single-subject basis rather than in cohort studies) building on the previous ASL consensus review.
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| 21. |
- Lingam, Ingran, et al.
(author)
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Serial blood cytokine and chemokine mRNA and microRNA over 48h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia.
- 2021
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In: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 89:3, s. 464-475
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Journal article (peer-reviewed)abstract
- Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS+Hypoxia) in an NE piglet model.Sixteen piglets were randomized: (i) LPS 2μg/kg bolus; 1μg/kg infusion (LPS; n=5), (ii) Saline with hypoxia (Hypoxia; n=6), (iii) LPS commencing 4h pre-hypoxia (LPS+Hypoxia; n=5). Total RNA was acquired at baseline, 4h after LPS and 1, 3, 6, 12, 24, 48h post-insult (animals euthanized at 48h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48h.Within 6h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS+Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS+Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R=0.69; p<0.01) at 1-3h and ENO2 (R=-0.69; p=0.01) at 48h.mRNA and miRNA differentiated hypoxia from inflammation-sensitized hypoxia within 6h in a piglet model. This information may inform human studies to enable triage for tailored neuroprotection in NE.Early stratification of infants with neonatal encephalopathy is key to provide tailored neuroprotection.IL1A, CXCL8, IL10, CCL2 and NSE mRNA are promising biomarkers of inflammation-sensitized hypoxia.IL10 mRNA levels differentiated all three pathological states; fold changes from baseline was the highest in LPS+Hypoxia animals, followed by LPS and Hypoxia at 6h.miR-23, -27, -31-5p and -193-5p were significantly upregulated within 6h of a hypoxia insult.Functional analysis highlighted the diverse roles of miRNA in the cellular processes.
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| 22. |
- Olson, Linus, et al.
(author)
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Comparison of Three Hypothermic Target Temperatures for the Treatment of Hypoxic Ischemia : MRNA Level Responses of Eight Genes in the Piglet Brain
- 2013
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In: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 248-257
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Journal article (peer-reviewed)abstract
- Hypothermia can reduce neurodevelopmental disabilities in asphyxiated newborn infants. However, the optimal cooling temperature for neuroprotection is not well defined. We studied the effects of transient piglet brain hypoxic ischemia (HI) on transcriptional activity of eight genes and if mRNA level alterations could be counteracted by whole body cooling to 35, 33. 5 or 30 °C. BDNF mRNA was globally upregulated by the insult, and none of the cooling temperatures counteracted this change. In contrast, MANF mRNA was downregulated, and these changes were modestly counteracted in different brain regions by hypothermic treatment at 33. 5 °C, while 30 °C aggravated the MANF mRNA loss. MAP2 mRNA was markedly downregulated in all brain regions except striatum, and cooling to 33. 5 °C modestly counteract this downregulation in the cortex cerebri. There was a tendency for GFAP mRNA levels in core, but not mantle regions to be downregulated and for these changes to be modestly counteracted by cooling to 33. 5 or 35 °C. Cooling to 30 °C caused global GFAP mRNA decrease. HSP70 mRNA tended to become upregulated by HI and to be more pronounced in cortex and CA1 of hippocampus during cooling to 33. 5 °C. We conclude that HI causes alterations of mRNA levels of many genes in superficial and deep piglet brain areas. Some of these changes may be beneficial, others detrimental, and lowering body temperature partly counteracts some, but not all changes. There may be general differences between core and mantle regions, as well as between the different cooling temperatures for protection. Comparing the three studied temperatures, cooling to 33. 5 °C, appears to provide the best cooling temperature compromise.
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