| 1. |
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| 2. |
- Collingwood, T N, et al.
(författare)
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A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.
- 1997
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 94:1, s. 248-53
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Tidskriftsartikel (refereegranskat)abstract
- The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.
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| 3. |
- Delling, Lotta, et al.
(författare)
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Feasibility of bariatric surgery as a strategy for secondary prevention in cardiovascular disease: a report from the Swedish obese subjects trial.
- 2010
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Ingår i: Journal of obesity (Online). - : Hindawi Limited. - 2090-0716 .- 2090-0708. ; 2010
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Forskningsöversikt (refereegranskat)abstract
- Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD.
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| 4. |
- Einarsson, Snorri, 1973, et al.
(författare)
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Weight reduction intervention for obese infertile women prior to IVF: a randomized controlled trial.
- 2017
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Ingår i: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 32:8, s. 1621-1630
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Tidskriftsartikel (refereegranskat)abstract
- Does an intensive weight reduction programme prior to IVF increase live birth rates for infertile obese women?An intensive weight reduction programme resulted in a large weight loss but did not substantially affect live birth rates in obese women scheduled for IVF.Among obese women, fertility and obstetric outcomes are influenced negatively with increased risk of miscarriage and a higher risk of maternal and neonatal complications. A recent large randomized controlled trial found no effect of lifestyle intervention on live birth in infertile obese women.A prospective, multicentre, randomized controlled trial was performed between 2010 and 2016 in the Nordic countries. In total, 962 women were assessed for eligibility and 317 women were randomized. Computerized randomization with concealed allocation was performed in the proportions 1:1 to one of two groups: weight reduction intervention followed by IVF-treatment or IVF-treatment only. One cycle per patient was included.Nine infertility clinics in Sweden, Denmark and Iceland participated. Women under 38 years of age planning IVF, and having a BMI ≥30 and <35 kg/m2 were randomized to two groups: an intervention group (160 patients) with weight reduction before IVF, starting with 12 weeks of a low calorie liquid formula diet (LCD) of 880 kcal/day and thereafter weight stabilization for 2-5 weeks, or a control group (157 patients) with IVF only.In the full analysis set (FAS), the live birth rate was 29.6% (45/152) in the weight reduction and IVF group and 27.5% (42/153) in the IVF only group. The difference was not statistically significant (difference 2.2%, 95% CI: 12.9 to -8.6, P = 0.77). The mean weight change was -9.44 (6.57) kg in the weight reduction and IVF group as compared to +1.19 (1.95) kg in the IVF only group, being highly significant (P < 0.0001). Significantly more live births were achieved through spontaneous pregnancies in the weight reduction and IVF group, 10.5% (16) as compared to the IVF only group 2.6% (4) (P = 0.009). Miscarriage rates and gonadotropin dose used for IVF stimulation did not differ between groups. Two subgroup analyses were performed. The first compared women with PCOS in the two randomized groups, and the second compared women in the weight reduction group reaching BMI ≤ 25 kg/m2 or reaching a weight loss of at least five BMI units to the IVF only group. No statistical differences in live birth rates between the groups in either subgroup analysis were found.The study was not powered to detect a small increase in live births due to weight reduction and was not blinded for the patients or physician. Further, the intervention group had a longer time to achieve a spontaneous pregnancy, but were therefore slightly older than the control group at IVF. The study only included women with a BMI lower than 35 kg/m2.The study suggests that weight loss for obese women (BMI: 30-34.9 kg/m2) may not rectify the outcome in IVF cycles, although a significant higher number of spontaneous conceptions occurred in the weight loss group. Also, the study suggests that intensive weight reduction with LCD treatment does not negatively affects the results.The study was funded by Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB, Solna, Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation and Jane and Dan Olsson Foundation. Dr Thurin-Kjellberg reports grants from Merck, non-financial support from Impolin AB, during the conduct of the study, and personal fees from Merck outside the submitted work. Dr Friberg reports personal fees from Ferring, Merck, MSD, Finox and personal fees from Studentlitteratur, outside the submitted work. Dr Englund reports personal fees from Ferring, and non-financial support from Merck, outside the submitted work. Dr Bergh reports and has been reimbursed for: writing a newsletter twice a year (Ferring), lectures (Ferring, MSD, Merck), and Nordic working group meetings (Finox). Dr Karlström reports lectures (Ferring, Finox, Merck, MSD) and Nordic working group meetings (Ferring). Ms Kluge, Dr Einarsson, Dr Pinborg, Dr Klajnbard, Dr Stenlöf, Dr Larsson, Dr Loft and Dr Wistrand have nothing to disclose.ClinicalTrials.gov number, NCT01566929.23-03-2012.05-10-2010.
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| 5. |
- Elias, Erik, 1979, et al.
(författare)
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Central nervous system lipocalin-type prostaglandin D2-synthase is correlated with orexigenic neuropeptides, visceral adiposity and markers of the hypothalamic-pituitary-adrenal axis in obese humans.
- 2011
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Ingår i: Journal of neuroendocrinology. - : Wiley. - 1365-2826 .- 0953-8194. ; 23:6, s. 501-7
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Tidskriftsartikel (refereegranskat)abstract
- Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ=0.695, P<0.001, n=26) and galanin (ρ=0.651, P<0.001) as well as visceral adipose tissue (ρ=0.415, P=0.035). Furthermore, CSF L-PGDS was inversely correlated with CSF leptin (ρ=-0.529, P=0.005) and tended to correlate inversely with s.c. adipose tissue (ρ=-0.346, P=0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L-PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L-PGDS was significantly correlated with the change of CSF NPY levels (ρ=0.604, P=0.004, n=21). Because of the correlation between baseline CSF L-PGDS levels and visceral adipose tissue, we examined associations with hypothalamic-pituitary-adrenal (HPA) axis components. Baseline CSF L-PGDS was correlated with corticotrophin-releasing hormone (ρ=0.764, P<0.001) and β-endorphin (ρ=0.491, P<0.001). By contrast, serum L-PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L-PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail.
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| 6. |
- Eskandari, Davoud, et al.
(författare)
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Zonisamide reduces obstructive sleep apnoea: a randomised placebo-controlled study
- 2014
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 44:1, s. 140-149
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Tidskriftsartikel (refereegranskat)abstract
- Carbonic anhydrase inhibition reduces apnoeic events in sleep disordered breathing. Zonisamide inhibits carbonic anhydrase, and induces weight loss in obese patients. This study explored the relative influence of these two properties, which may both alleviate obstructive sleep apnoea (OSA). Continuous positive airway pressure (CPAP) was used as a standard care comparator. 47 patients with moderate-to-severe OSA and a body mass index of 27-35 kg.m(-2) were randomised to receive either zonisamide, placebo or CPAP for 4 weeks. The open extension phase (20 weeks) compared CPAP and zonisamide. Polysomnography, biochemistry and symptoms were evaluated. At 4 weeks, zonisamide reduced apnoea/hypopnoea index (AHI) by a mean +/- SD 33 +/- 39% and oxygen desaturation index by 28 +/- 31% (p=0.02 and 0.014, respectively; placebo adjusted). The mean compliance adjusted reduction of AHI after zonisamide and CPAP was 13 and 61%, respectively, (p=0.001) at 24 weeks. Body weight was marginally changed at 4 weeks, but reduced after zonisamide and increased after CPAP at 24 weeks (-2.7 +/- 3.0 kg versus 2.3 +/- 2.0 kg, p<0.001). Zonisamide decreased bicarbonate at 4 and 24 weeks. Side-effects were more common after zonisamide. Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. The effect was less pronounced than that obtained by CPAP.
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| 7. |
- Grunstein, R R, et al.
(författare)
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Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS) Study.
- 1995
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Ingår i: International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. - 0307-0565. ; 19:6, s. 410-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine if obstructive sleep apnea (OSA) is independently associated with cardiovascular risk factors and health status in subjects with severe obesity. DESIGN: Cross-sectional analysis of epidemiological data. SUBJECTS: 3034 participants in the Swedish Obese Subjects (SOS) Cohort. Two sub-groups with a high and low likelihood for OSA based on questionnaire data were analysed in detail. MEASUREMENTS: General health questionnaires, anthropometric data including CT calibrated values for body fat distribution and lean body mass, blood pressure, fasting insulin, triglycerides, cholesterol, uric acid, glucose. RESULTS: Self-reported loud snoring and observed breathing pauses (high likelihood of OSA) was associated with increased frequency of WHO Grade 4 dyspnea, admissions to hospital with chest pain, myocardial infarction, blood pressure, fasting insulin, fasting triglyceride (women only), uric acid (women only) after adjustment for body fat distribution and other potential confounders. CONCLUSION: OSA may be another medical disorder which contributes to morbidity in severe obesity and is associated with some of the components of the metabolic syndrome observed in the centrally obese.
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| 8. |
- Grunstein, R R, et al.
(författare)
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Impact of self-reported sleep-breathing disturbances on psychosocial performance in the Swedish Obese Subjects (SOS) Study.
- 1995
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Ingår i: Sleep. - 0161-8105. ; 18:8, s. 635-43
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Tidskriftsartikel (refereegranskat)abstract
- Patients with severe obesity commonly have obstructive sleep apnea (OSA). In order to determine the impact of OSA on psychosocial morbidity in severe obesity, subjects enrolled in the Swedish Obese Subjects (SOS) Study were classified into two subgroups based on questionnaire data: one group with a high likelihood and one with a low likelihood of OSA. These groups were contrasted and multivariable analysis was used to examine whether OSA had independent effects on divorce rate, sick leave, work performance, income and self-estimated general health after adjustment for obesity, fat distribution, alcohol, smoking, medications and coexisting medical conditions. A high likelihood of OSA was identified in 338 men and 155 women, compared with 216 men and 481 women who had a low likelihood of OSA. Men with OSA were identical in age to men without OSA and had slightly higher levels of visceral fat (p = 0.01), but were similar in most psychosocial variables except self-perceived general health. Women with OSA were identical in age and visceral fat mass to women without OSA, but were characterized by a higher rate of impaired work performance, sick leave and divorce. When frequent sleepiness was used as an additional discriminator between OSA and non-OSA groups, marked differences in psychosocial morbidity were observed. Multivariable analysis revealed either OSA or frequent sleepiness or both to be independent predictors of amount of sick leave, worse self-rated general health, impaired work performance and divorce rate. Therefore OSA, measured by self report, is an important independent predictor of psychosocial morbidity in subjects with severe obesity.
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| 9. |
- Grunstein, Ronald R, et al.
(författare)
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Two year reduction in sleep apnea symptoms and associated diabetes incidence after weight loss in severe obesity.
- 2007
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Ingår i: Sleep. - 0161-8105. ; 30:6, s. 703-10
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Tidskriftsartikel (refereegranskat)abstract
- STUDY OBJECTIVES: To evaluate the effect of bariatric surgery on sleep apnea symptoms and obesity-associated morbidity in patients with severe obesity. DESIGN: Prospective study. SETTING: University hospitals and community centers in Sweden. Intervention: We investigated the influence of weight loss surgery (n=1729) on sleep apnea symptoms and obesity-related morbidity using a conservatively treated group (n=1748) as a control. MEASUREMENTS AND RESULTS: Baseline BMI in surgical group (42.2+/-4.4 kg/m(2)) and control group (40.1+/-4.6 kg/m(2)) changed -9.7+/-5 kg/m(2) and 0+/-3 kg/m(2), respectively, at 2-year follow-up. In the surgery group, there was a marked improvement in all obstructive sleep apnea (OSA) symptoms compared with the control group (P <0.001). Persistence of snoring (21.6 vs 65.5%, adjusted OR 0.14, 95% CI 0.10-0.19) and apnea (27.9 vs 71.3%, adjusted OR 0.16, 95% I 0.10-0.23) were much less in the surgery group compared with controls. Compared with subjects with no observed apnea at follow-up (n=2453), subjects who continued to have or developed observed apnea (n=404) had a higher incidence of diabetes (adjusted OR 2.03, 95% CI 1.19-3.47) and hypertriglyceridemia (adjusted OR 1.86, 95% CI 1.07-3.25) but not hypertension (adjusted OR 1.09, 95% CI 0.65-1.83) or hypercholesterolemia (adjusted OR 0.91, 95% CI 0.53-1.58). CONCLUSION: Bariatric surgery results in a marked improvement in sleep apnea symptoms at 2 years. Despite adjustment for weight change and baseline central obesity, subjects reporting loss of OSA symptoms had a lower 2-year incidence of diabetes and hypertriglyceridemia. Improvement in OSA in patients losing weight may provide health benefits in addition to weight loss alone.
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| 10. |
- Gummesson, Anders, 1973, et al.
(författare)
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Intestinal Permeability Is Associated With Visceral Adiposity in Healthy Women.
- 2011
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Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-7381.
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Tidskriftsartikel (refereegranskat)abstract
- Increased visceral fat, as opposed to subcutaneous/gluteal, most strongly relates to key metabolic dysfunctions including insulin resistance, hepatic steatosis, and inflammation. Mesenteric fat hypertrophy in patients with Crohn's disease and in experimental rodent models of gut inflammation suggest that impaired gut barrier function with increased leakage of gut-derived antigens may drive visceral lipid deposition. The aim of this study was to determine whether increased intestinal permeability is associated with visceral adiposity in healthy humans. Normal to overweight female subjects were recruited from a population-based cohort. Intestinal permeability was assessed using the ratio of urinary excretion of orally ingested sucralose to mannitol (S/M). In study 1 (n = 67), we found a positive correlation between waist circumference and S/M excretion within a time frame of urine collection consistent with permeability of the lower gastrointestinal tract (6-9 hours post-ingestion; P = 0.022). These results were followed up in study 2 (n = 55) in which we used computed tomography and dual energy X-ray absorptiometry to measure visceral and subcutaneous fat areas of the abdomen, liver fat content, and total body fat of the same women. The S/M ratio from the 6-12 h urine sample correlated with visceral fat area (P = 0.0003) and liver fat content (P = 0.004), but not with subcutaneous or total body fat. This novel finding of an association between intestinal permeability and visceral adiposity and liver fat content in healthy humans suggests that impaired gut barrier function should be further explored as a possible mediator of excess visceral fat accumulation and metabolic dysfunction.
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