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- Chase, A., et al.
(författare)
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Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29:10, s. 2069-2074
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Tidskriftsartikel (refereegranskat)abstract
- Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n = 7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P < 0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r = 0.76; P = 0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n = 11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.
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- McMurray, J. J. V., et al.
(författare)
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Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 381:21, s. 1995-2008
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.METHODS In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.RESULTS Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.CONCLUSIONS Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
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| 10. |
- Shen, L., et al.
(författare)
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Prior Pacemaker Implantation and Clinical Outcomes in Patients With Heart Failure and Preserved Ejection Fraction
- 2019
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Ingår i: Jacc-Heart Failure. - : Elsevier BV. - 2213-1779. ; 7:5, s. 418-427
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown. METHODS Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses. RESULTS Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro-B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses. CONCLUSIONS These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients. (C) 2019 by the American College of Cardiology Foundation.
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- Doody, A., et al.
(författare)
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Validating the association between plasma tumour necrosis factor receptor 1 levels and the presence of renal injury and functional decline in patients with Type 2 diabetes
- 2018
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Ingår i: Journal of Diabetes and Its Complications. - : Elsevier BV. - 1056-8727. ; 32:1, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Elevated plasma soluble tumour necrosis factor receptor 1 (TNFR1) predicts long-term progression of chronic kidney disease. We investigated the association between elevated TNFR1 and the presence of renal disease in patients with Type 2 diabetes mellitus registering a haemoglobin Mc (HbA1c) >48 mmol/mol despite medical therapy. Methods: Using sensitivity, specificity and regression analyses we interrogated the association between plasma TNFR1 and presence of chronic kidney disease as assessed by the presence of microalbuminuria and/or an estimated glomerular filtration rate of less than 60 ml/min/1.73 m(2) (stages 3-5 chronic kidney disease). The association of TNFR1 with C-reactive protein and leptin-adiponectin ratio as plasma markers of systemic inflammation and adipose stress respectively was also investigated. Results: Upper quartile TNFR1 is independently associated with elevated urinary albumin-creatinine ratios, reductions in eGFR and strongly predicts the presence of stages 3-5 chronic kidney disease in regression modelling. Elevated TNFR1 levels are associated with increased plasma C-reactive protein and augmented leptin-adiponectin ratio. Conclusions: Our study confirms plasma TNFR1 as a surrogate of renal structural and functional impairment in patients with type 2 diabetes mellitus. Association of TNFR1 with markers of systemic inflammation and adipose stress indicates that TNFR1 may be a biomarker of these processes as components of the pathogenesis of diabetic kidney disease. (C) 2017 Elsevier Inc. All rights reserved.
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- Elliott, J. A., et al.
(författare)
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Risk factors for loss of bone mineral density after curative esophagectomy
- 2019
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Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- .Summary Micronutrient and fat malabsorption and altered enteroendocrine signaling occur after esophagectomy for cancer; however, the impact of malnutrition on bone health in this cohort has not been previously investigated. In this study, the prevalence of osteoporosis increased after curative surgery, associated with disease-specific, treatment-related, and population risk factors.PurposeImproved oncologic outcomes in esophageal cancer (EC) have resulted in increased survivorship and a focus on long-term quality of life. Malnutrition and micronutrient malabsorption are common among patients with EC, but the effect on bone metabolism is not known. The aim of this study was to characterize changes in bone mineral density (BMD) following curative esophagectomy.MethodsConsecutive disease-free patients who underwent esophagectomy with gastric conduit for pathologically node-negative disease from 2000 to 2014 were included. BMD was assessed at vertebral levels T12-L5 by computed tomography using a simple trabecular region-of-interest attenuation technique, and serum markers of nutritional status and bone metabolism were examined. Independent risk factors for osteoporosis were identified by multivariable logistic regression.ResultsSeventy-five consecutive patients were studied. Osteoporosis was present in 25% at diagnosis. BMD declined at 1 and 2years postoperatively (144.345.8 versus 128.6 +/- 46.2 and 122.7 +/- 43.5 Hounsfield Units (HU), P<0.0001), with increased osteoporosis prevalence to 38% and 44% (P=0.049), respectively. No significant postoperative change in vitamin D, calcium, or phosphate was observed, but alkaline phosphatase increased significantly (P<0.001). While female sex (P=0.004) and ASA grade (P=0.043) were independently associated with osteoporosis at diagnosis, age (P=0.050), female sex (P=0.023), smoking (P=0.024), and pathologic T stage (P=0.023) were independently predictive of osteoporosis at 1year postoperatively.Conclusions p id=Par5 Osteoporosis is prevalent among disease-free patients post-esophagectomy for EC, associated with disease-specific, treatment-related, and population risk factors. Strategies which minimize BMD decline should be considered to avoid fragility fractures in this cohort.
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- Holland, J. A., et al.
(författare)
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Impact of intentional weight loss on diabetic kidney disease
- 2019
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 21:10, s. 2338-2341
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes mellitus (T2DM) and obesity constitute interwoven pandemics challenging healthcare systems in developed countries, where diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. Obesity accelerates renal functional decline in people with T2DM. Intentional weight loss (IWL) strategies in this population hold promise as a means of arresting DKD progression. In the present paper, we summarize the impact of IWL strategies (stratified by lifestyle intervention, medications, and metabolic surgery) on renal outcomes in obese people with DKD. We reviewed the Medline, EMBASE and Cochrane databases for relevant randomized control trials and observational studies published between August 1, 2018 and April 15, 2019. We found that IWL improves renal outcomes in the setting of DKD and obesity. Rate of progression of DKD slows with IWL, but varying outcome measures among studies makes direct comparison difficult. Furthermore, established means of estimating renal function are imperfect owing to loss of lean muscle mass with IWL strategies. The choice of optimal IWL strategy needs to be individualized; future work should establish the comparative efficacy of IWL strategies in obese people with DKD to better inform such decisions.
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- Maghsoodi, N., et al.
(författare)
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Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass
- 2017
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Ingår i: Annals of Clinical Biochemistry. - : SAGE Publications. - 0004-5632. ; 54:4, s. 495-500
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Tidskriftsartikel (refereegranskat)abstract
- Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.
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| 17. |
- Mangan, A. M., et al.
(författare)
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Effect of Macronutrient Type and Gastrointestinal Release Site on PYY Response in Normal Healthy Subjects
- 2019
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 104:9, s. 3661-3669
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Enteroendocrine L cells release satiety inducing hormones in response to stimulation by luminal macronutrients. We sought to profile the differential effect of macronutrient type and site of release on circulating concentrations of the L cell-derived enteroendocrine hormone peptide tyrosine tyrosine (amino acids 1 to 36) (PYY). Materials and Methods: Eight healthy volunteers were recruited to a randomized, double-blinded, six-way crossover study. At each visit, the participants consumed a 500-kcal drink containing carbohydrate, protein, or fat in either gastric or small intestinal release formulations. Plasma PYY concentrations and hunger ratings were assessed for 3 hours after consumption of the test drink. The food intake was recorded thereafter at an ad libitum lunch. Results: Microcapsular formulations targeting the distal small intestinal delivery of fat, but not carbohydrate or protein, markedly enhance PYY release relative to macronutrient delivery in gastric release formulations. Food intake at an ad libitum meal was lowest after consumption of the formulation releasing fat at the distal small intestine. Conclusion: Targeting of fat to the distal small intestine in delayed release microcapsules enhanced PYY release and was associated with reductions in food intake.
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- Sinclair, P., et al.
(författare)
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Metabolic Effects of Bariatric Surgery
- 2018
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 64:1, s. 72-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity can be defined as a chronic subcortical brain disease, as there is an important neurophysiological component to its etiology based on changes in the functioning of those areas of the brain controlling food intake and reward. Extensive metabolic changes accompany bariatric surgery-based treatment of obesity. Consequently, the term "metabolic" surgery is being increasingly adopted in relation to the beneficial effects these procedures have on chronic diseases like type 2 diabetes. CONTENT: In the present review, we focus on the key biochemical and physiological changes induced by metabolic surgery and highlight the beneficial effects accrued systemically with the use of an organ-based approach. Understanding the impact on and interactions between the gut, brain, adipose tissue, liver, muscle, pancreas, and kidney is key to understanding the sum of the metabolic effects of these operations. SUMMARY: Further mechanistic studies are essential to assess the true potential of metabolic surgery to treat metabolic comorbidities of obesity beyond type 2 diabetes. Approaches that may mitigate the metabolic side effects of surgery also require attention. Understanding the positive impact of metabolic surgery on metabolic health may result in a wider acceptance of this intervention as treatment for metabolic, comorbid conditions.
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| 20. |
- Zhang, Haofei, et al.
(författare)
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Monoterpenes are the largest source of summertime organic aerosol in the southeastern United States
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:9, s. 2038-2043
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Tidskriftsartikel (refereegranskat)abstract
- The chemical complexity of atmospheric organic aerosol (OA) has caused substantial uncertainties in understanding its origins and environmental impacts. Here, we provide constraints on OA origins through compositional characterization with molecular-level details. Our results suggest that secondary OA (SOA) from monoterpene oxidation accounts for approximately half of summertime fine OA in Centreville, AL, a forested area in the southeastern United States influenced by anthropogenic pollution. We find that different chemical processes involving nitrogen oxides, during days and nights, play a central role in determining the mass of monoterpene SOA produced. These findings elucidate the strong anthropogenic–biogenic interaction affecting ambient aerosol in the southeastern United States and point out the importance of reducing anthropogenic emissions, especially under a changing climate, where biogenic emissions will likely keep increasing.
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