| 1. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 2. |
- Dahlin, Lars B., et al.
(författare)
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Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.
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| 3. |
- Jackson, Victoria E, et al.
(författare)
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Meta-analysis of exome array data identifies six novel genetic loci for lung function.
- 2018
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Ingår i: Wellcome open research. - : F1000 Research Ltd. - 2398-502X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
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| 4. |
- Dahlin, Erik, et al.
(författare)
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Outcome of simple decompression of the compressed ulnar nerve at the elbow – influence of smoking, gender, and electrophysiological findings
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - 2000-656X. ; 51:2, s. 149-155
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Tidskriftsartikel (refereegranskat)abstract
- Background: Compression of the ulnar nerve at elbow is frequently treated with simple decompression. Knowledge about factors influencing results of surgery of the nerve is limited and contradictory. The primary aim was to evaluate outcome of simple decompression of the nerve using a QuickDASH questionnaire, and to investigate any influence of smoking, gender, and preoperative electrophysiological findings. A second aim was to estimate the relation between QuickDASH score and a clinical assessment of outcome by the surgeon. Methods: Patients who were operated on with simple decompression of the ulnar nerve, excluding reoperations, from September 2009 to February 2011 were evaluated before and at 1 year after surgery using QuickDASH. Data were collected from medical records and from a self-reported health declaration. Results: There were no differences in QuickDASH scores or change in total score between smokers and non-smokers or between women and men. Nerve pathology, assessed by preoperative electrophysiology, did not affect outcome. The surgeon’s assessment of outcome mirrored QuickDASH score. Among all patients, 12/33 (36%) did not have a decrease in QuickDASH score >8, which is considered as a minimal clinically important difference. Conclusion: Smoking, gender, and preoperative electrophysiological findings do not affect outcome of surgery. There are a high number of patients who do not benefit from simple decompression of the ulnar nerve at the elbow. Patients who are planned for surgery should be informed that there is a risk for persistent problems. A simple outcome assessment by the surgeon mirrors QuickDASH score at 1 year.
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| 5. |
- Dahlin, Lars, et al.
(författare)
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Impact of smoking and preoperative electrophysiology on outcome after open carpal tunnel release
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - 2000-656X. ; 51:5, s. 329-335
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to evaluate the influence of smoking and preoperative electrophysiology on the outcome of open carpal tunnel release. Methods: This retrospective observational study evaluated the outcome in 493 patients (531 hands) primary operated for carpal tunnel syndrome. Data were collected from medical records, health evaluations, and QuickDASH questionnaires before surgery and 1 year after. Results: Smokers had a higher QuickDASH score preoperatively as well as postoperatively, but the change in total score did not differ. The odds of having a postoperative QuickDASH score >10 were 2.5 times higher in smoking patients than in non-smoking patients. In 124/493 patients (25%), no clinically significant improvement was seen. Normal and extreme preoperative electrophysiology values were associated with higher postoperative scores. No correlation was found between preoperative QuickDASH scores and preoperative electrophysiology values. Conclusions: Smokers with carpal tunnel syndrome experience more symptoms preoperatively. Smokers have remaining symptoms after surgery. There is no correlation between preoperative QuickDASH scores and preoperative electrophysiology values. Patients with normal or near to normal preoperative electrophysiology results have limited improvement after surgery.
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| 6. |
- Ising, Erik, et al.
(författare)
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Quantification of heat shock proteins in the posterior interosseous nerve among subjects with type 1 and type 2 diabetes compared to healthy controls
- 2023
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Ingår i: Frontiers in Neuroscience. - : FRONTIERS MEDIA SA. - 1662-4548 .- 1662-453X. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 (T1D) and type 2 diabetes (T2D). No cure for DPN is available, but several potential targets have been proposed for treatment. Heat shock proteins (HSPs) are known to respond to both hyper- and hypoglycemia. DPN can be diagnosed using electrophysiology and studied using peripheral nerve biopsies.Aim: This study aimed to analyze the presence and patterns of HSPs in peripheral nerve biopsies from subjects with T1D, T2D, and healthy controls.Methods: Posterior interosseous nerves (PIN) from a total of 56 subjects with T1D (n = 9), with T2D (n = 24), and without diabetes (i.e., healthy controls, n = 23) were harvested under local anesthesia and prepared for quantitative mass spectrometry analysis. Protein intensities were associated with electrophysiology data of the ulnar nerve and morphometry of the same PIN, and differences in protein intensities between groups were analyzed.Results: In total, 32 different HSPs were identified and quantified in the nerve specimens. No statistically significant differences were observed regarding protein intensities between groups. Furthermore, protein intensities did not correlate with amplitude or conduction velocity in the ulnar nerve or with the myelinated nerve fiber density of PIN.Conclusion: Quantitative proteomics can be used to study HSPs in nerve biopsies, but no clear differences in protein quantities were observed between groups in this cohort.
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| 7. |
- Ising, Erik, et al.
(författare)
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Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes
- 2021
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 38:11
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes (T2D). The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN.METHODS: A quantitative mass spectrometry-based proteomics analysis was made of peripheral nerves from age- and gender-matched living human male tissue donors; nine T2D subjects, with decreased sural nerve action potentials indicating DPN, and six controls without T2D, with normal electrophysiology results.RESULTS: A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between T2D and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins were made in order to find clusters of similar proteins in T2D subjects and healthy controls.CONCLUSIONS: This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without T2D, which may aid in finding biomarkers of importance to DPN development.
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| 8. |
- Mohseni, Simin, et al.
(författare)
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Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve : Implications for diabetic neuropathy
- 2017
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Ingår i: Brain and Behavior. - : Wiley Online Library. - 2162-3279 .- 2162-3279. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy-related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy. Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM. Subjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g-ratio versus subjects who remained NGT. At follow-up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline. We conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy.
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| 9. |
- Thomsen, Niels O.B., et al.
(författare)
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Neurophysiological recovery 5 years after carpal tunnel release in patients with diabetes
- 2017
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Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X. ; 56:6, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The long-term results of neurophysiological recovery after carpal tunnel release in patients with diabetes have not been studied. Methods: Thirty-five patients with diabetes and carpal tunnel syndrome (CTS) were matched with 31 patients without diabetes who had idiopathic CTS, and 27 and 30 patients, respectively, participated in this follow-up study. Nerve conduction results at 5 years were compared with previously published results at baseline and 1 year. Results: Significant neurophysiological improvement continued from 1 to 5 years after carpal tunnel release for patients with and without diabetes. However, wrist-palm sensory conduction velocity was still abnormal for 85% and 43% of patients with and without diabetes, respectively. Although diabetes had an impact on 4 of 10 measured neurophysiological parameters, the influence of peripheral neuropathy seemed insignificant. Discussion: After carpal tunnel release, significant long-term neurophysiological improvement is possible for patients with diabetes, and it is not influenced by the presence of peripheral neuropathy.
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| 10. |
- Thomsen, Niels O.B., et al.
(författare)
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Vibrotactile sense 5 years after carpal tunnel release in people with diabetes : A prospective study with matched controls
- 2021
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 38:7
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To compare vibrotactile sense, 5 years after carpal tunnel release in people with and without diabetes. Methods: Out of 35 people with diabetes and carpal tunnel syndrome, age- and gender-matched with 31 people without diabetes but with idiopathic carpal tunnel syndrome, 27 and 30 people, respectively, participated in this prolonged follow-up. Vibration perception threshold of the index and little finger (median and ulnar nerve, respectively), 5 years after surgery, was measured at seven different frequencies (8, 16, 32, 64, 125, 250 and 500 Hz). Results: Significant improvement of vibration perception threshold from 1 to 5 years after carpal tunnel release was found at 64 Hz for people with diabetes, while improvement for people without diabetes was demonstrated at several frequencies (64–250 Hz). However, both groups demonstrated a significant decrease in vibration perception threshold for the low frequencies (8–16 Hz). At 5 years, people with diabetes had significantly impaired vibration perception threshold at the index finger for high frequencies (125–500 Hz), and for nearly all frequencies (16 Hz, 64–500 Hz) at the little finger, compared to people without diabetes. Conclusion: After carpal tunnel release, significant mid-term improvement of vibrotactile sense appears limited for people with diabetes, compared to a continuous improvement for people without diabetes. In addition, a decline in low-frequency vibrotactile sense occurs for the median as well as the ulnar nerve innervated fingers. Clinical Trial Registration NCT01201109.
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