| 1. |
- Almgren, Malin, et al.
(författare)
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Adenovirus-36 Is Associated with Obesity in Children and Adults in Sweden as Determined by Rapid ELISA
- 2012
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Experimental and natural human adenovirus-36 (Adv36) infection of multiple animal species results in obesity through increasing adipogenesis and lipid accumulation in adipocytes. Presence of Adv36 antibodies detected by serum neutralization assay has previously been associated with obesity in children and adults living in the USA, South Korea and Italy, whereas no association with adult obesity was detected in Belgium/the Netherlands nor among USA military personnel. Adv36 infection has also been shown to reduce blood lipid levels, increase glucose uptake by adipose tissue and skeletal muscle biopsies, and to associate with improved glycemic control in non-diabetic individuals. Principal Findings: Using a novel ELISA, 1946 clinically well-characterized individuals including 424 children and 1522 nondiabetic adults, and 89 anonymous blood donors, residing in central Sweden representing the population in Stockholm area, were studied for the presence of antibodies against Adv36 in serum. The prevalence of Adv36 positivity in lean individuals increased from similar to 7% in 1992-1998 to 15-20% in 2002-2009, which paralleled the increase in obesity prevalence. We found that Adv36-positive serology was associated with pediatric obesity and with severe obesity in females compared to lean and overweight/mildly obese individuals, with a 1.5 to 2-fold Adv36 positivity increase in cases. Moreover, Adv36 positivity was less common among females and males on antilipid pharmacological treatment or with high blood triglyceride level. Insulin sensitivity, measured as lower HOMA-IR, showed a higher point estimate in Adv36-positive obese females and males, although it was not statistically significant (p = 0.08). Conclusion: Using a novel ELISA we show that Adv36 infection is associated with pediatric obesity, severe obesity in adult females and lower risk of high blood lipid levels in non-diabetic Swedish individuals.
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| 2. |
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| 3. |
- Almgren, Malin
(författare)
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Neural growth : with special emphasis on adult neurogenesis and the effect of antiepileptic drugs
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurons were for a long time thought to not renew themselves. In the 1960ies the phenomenon of neurogenesis was discovered, but it was not until 1998 that neurogenesis was demonstrated in humans. In this thesis neurogenesis was studied using a unique genetic mouse model (mceph/mceph), with postnatal epilepsy and excessive brain growth, due to a truncated Kv1.1 subunit. The model was used to learn more about how a channelopathy can disturb hippocampal neurogenesis, leading to hyperplasia, and how this can be treated. First, the expression and trafficking of the truncated potassium ion channel Kv1.1 was described to reveal its molecular nature. It was shown that the defective Kv1.1 does not form functional channels and moreover has the potential to render other potassium channel subunits non-functional. Even though lack of Kv1.1 is enough for excessive hippocampal growth, the defect Kv1.1 peptide worsens the epileptic condition by blocking additional Kv1 subunits. Cells have previously been shown to be enlarged in the hippocampus of this mouse. In this thesis a doubling in number of neurons and astrocytes was demonstrated by stereology. The increase in number of neurons was due to increased neurogenesis and altered apoptosis. To identify transcripts involved in the overgrowth of the mceph/mceph hippocampus a genome-wide screen for transcripts expressed at different levels in mceph/mceph versus wild type was performed. The following genes, involved in regulation of cell number, were verified as differentially regulated in mceph/mceph; NPY, Penk, Fjx1 and Vgf. Previously it was shown that oral treatment with the antiepileptic drug CBZ protect mceph/mceph mice from developing enlarged hippocampus. This thesis shows that all hippocampal regions studied were protected from overgrowth and that the number of both neurons and astrocytes were normalized despite ongoing severe seizures. Transcripts potentially involved in the protection against the hippocampal overgrowth and hyperplasia were identified based on different expression levels in a microarray analysis. Verified genes include Mlc1, Sstr4, ApoD, Ndn, Aatk and Rgs2. These transcripts have a proposed function in proliferation, differentiation and/or apoptosis. Finally, an analysis of the effect of AEDs in utero, with focus on the head size of the newborn, was conducted on a large population-based Swedish cohort. This study revealed that the use of CBZ and VPA is increasing despite reports of malformations and growth retardations of the baby. Furthermore, CBZ and VPA monotherapy significantly reduced the head circumference (HC) and AED polytherapy increase the rate of small HC (> 2 SD). The implications of a smaller head on the development of the child is uncertain but should be explored. CBZ mono ] and polytherapy significantly reduced gestational age (GA) and there was a tendency for clonazepam and gabapentin monotherapy to reduce GA. The relevance of the reduced pregnancy duration is not clear but indicates a need for further studies in order to optimize treatment regimes for epileptic pregnant women.
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| 4. |
- Almgren, Malin, et al.
(författare)
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Population-based study of antiepileptic drug exposure in utero-Influence on head circumference in newborns
- 2009
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Ingår i: Seizure. - : Elsevier BV. - 1532-2688 .- 1059-1311. ; 18:10, s. 672-675
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the effect of AED exposure on head circumference in the newborn. Methods: Data on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index. Results: A significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS) = 0.15, p < 0.001) and valproic acid (VPA) (SDS = 0.10, p = 0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR = 2.85, 95% CI: 1.74-4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ OF VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time. Conclusions: CBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored. (C) 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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| 5. |
- Bonander, Carl, et al.
(författare)
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A regression discontinuity analysis of the social distancing recommendations for older adults in Sweden during COVID-19.
- 2022
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 32:5, s. 799-806
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This paper investigates the impact of a non-mandatory and age-specific social distancing recommendation on isolation behaviors and disease outcomes in Sweden during the first wave of the COVID-19 pandemic (March to July, 2020). The policy stated that people aged 70 years or older should avoid crowded places and contact with people outside the household.METHODS: We used a regression discontinuity design-in combination with self-reported isolation data from COVID Symptom Study Sweden (n = 96,053; age range: 39-79 years) and national register data (age range: 39-100+ years) on severe COVID-19 disease (hospitalization or death, n = 21,804) and confirmed cases (n = 48,984)-to estimate the effects of the policy.RESULTS: Our primary analyses showed a sharp drop in the weekly number of visits to crowded places (-13%) and severe COVID-19 cases (-16%) at the 70-year-threshold. These results imply that the age-specific recommendations prevented approximately 1,800 to 2,700 severe COVID-19 cases, depending on model specification.CONCLUSION: It seems that the non-mandatory, age-specific recommendations helped control COVID-19 disease during the first wave of the pandemic in Sweden, as opposed to not implementing a social distancing policy aimed at older adults. Our study provides empirical data on how populations may react to non-mandatory, age-specific social distancing policies in the face of a novel virus.SUPPLEMENTARY MATERIAL: Online appendix with figures, tables, extra methods and results.
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| 6. |
- Hallengren, Erik, et al.
(författare)
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Genetic determinants of growth hormone and GH-related phenotypes
- 2017
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Higher fasting Growth Hormone (GH) has been associated with increased cardiovascular morbidity and mortality. Our objective was to find genetic determinants of fasting GH in order to facilitate future efforts of analyzing the association between fasting growth hormone and cardiovascular disease. A genome-wide association study (GWAS) was performed in a discovery cohort of 4134 persons (58% females; age 46-68 yrs), linking SNPs to fasting hs-GH. Fifteen SNPs were replicated in an independent cohort of 5262 persons (28.9% females; age 56-85 yrs). The best performing SNP was analyzed vs GH-related variables in a third independent cohort (n = 24,047; 61% females; age 44-73 yrs). A candidate gene approach searched for significant SNPs in the genes GH1 and GHR in the discovery cohort and was replicated as previously described.RESULTS: In the GWAS, the minor allele of rs7208736 was associated with lower GH in the discovery cohort (p = 5.15*10^-6) and the replication cohort (p = 0.005). The GH reducing allele was associated with lower BMI (P = 0.026) and waist (P = 0.021) in males only. In the candidate gene approach rs13153388 in the GHR-gene was associated with elevated GH-levels (P = 0.003) in the discovery cohort only and reduced height (P = 0.003).CONCLUSION: In the first GWAS ever for GH, we identify a novel locus on chromosome 17 associated with fasting GH levels, suggesting novel biological mechanisms behind GH secretion and GH-related traits. The candidate gene approach identified a genetic variant in the GHR, which was associated with an elevation of fasting hs-GH and lower height suggesting reduced GHR ligand sensitivity. Our findings need further replication.
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| 7. |
- Ma, Zuheng, et al.
(författare)
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Evidence for Presence and Functional Effects of Kv1.1 Channels in beta-Cells: General Survey and Results from mceph/mceph Mice
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Voltage-dependent K+ channels (Kv) mediate repolarisation of beta-cell action potentials, and thereby abrogate insulin secretion. The role of the Kv1.1 K+ channel in this process is however unclear. We tested for presence of Kv1.1 in different species and tested for a functional role of Kv1.1 by assessing pancreatic islet function in BALB/cByJ (wild-type) and megencephaly (mceph/mceph) mice, the latter having a deletion in the Kv1.1 gene. Methodology/Principal Findings: Kv1.1 expression was detected in islets from wild-type mice, SD rats and humans, and expression of truncated Kv1.1 was detected in mceph/mceph islets. Full-length Kv1.1 protein was present in islets from wildtype mice, but, as expected, not in those from mceph/mceph mice. Kv1.1 expression was localized to the beta-cell population and also to alpha-and delta-cells, with evidence of over-expression of truncated Kv1.1 in mceph/mceph islets. Blood glucose, insulin content, and islet morphology were normal in mceph/mceph mice, but glucose-induced insulin release from batch-incubated islets was (moderately) higher than that from wild-type islets. Reciprocal blocking of Kv1.1 by dendrotoxin-K increased insulin secretion from wild-type but not mceph/mceph islets. Glucose-induced action potential duration, as well as firing frequency, was increased in mceph/mceph mouse beta-cells. This duration effect on action potential in beta-cells from mceph/mceph mice was mimicked by dendrotoxin-K in beta-cells from wild-type mice. Observations concerning the effects of both the mceph mutation, and of dendrotoxin-K, on glucose-induced insulin release were confirmed in pancreatic islets from Kv1.1 null mice. Conclusion/Significance: Kv1.1 channels are expressed in the beta-cells of several species, and these channels can influence glucose-stimulated insulin release.
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| 8. |
- Nawaz, Imran, et al.
(författare)
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Integrin α9 gene promoter is hypermethylated and downregulated in nasopharyngeal carcinoma
- 2015
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Ingår i: Oncotarget. - Albany, NY, United States : Impact Journals LLC. - 1949-2553. ; 6:31, s. 31493-31507
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic silencing of tumor suppressor genes (TSGs) by promoter methylation can be an early event in the multi-step process of carcinogenesis. Human chromosome 3 contains clusters of TSGs involved in many cancer types including nasopharyngeal carcinoma (NPC), the most common cancer in Southern China. Among ten candidate TSGs identified in chromosome 3 using NotI microarray, ITGA9 and WNT7A could be validated. 5-aza-2 deoxycytidine treatment restored the expression of ITGA9 and WNT7A in two NPC cell lines. Immunostaining showed strong expression of these genes in the membrane and cytoplasm of adjacent control nasopharyngeal epithelium cells, while they were weakly expressed in NPC tumor cells. The ITGA9 promoter showed marked differentially methylation between tumor and control tissue, whereas no differentially methylation could be detected for the WNT7A promoter. The expression level of ITGA9 in NPC tumors was downregulated 4.9-fold, compared to the expression in control. ITGA9 methylation was detected by methylation specific PCR (MSP) in 56% of EBV positive NPC-cases with 100% specificity. Taken together, this suggests that ITGA9 might be a TSG in NPC that is involved in tumor cell biology. The possibility of using ITGA9 methylation as a marker for early detection of NPC should further be explored.
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| 9. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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| 10. |
- Tuomi, Tiinamaija, et al.
(författare)
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Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes
- 2016
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 23:6, s. 1067-1077
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.
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