| 1. |
- Walters, R G, et al.
(författare)
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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 463:7281, s. 671-5
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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| 2. |
- Sjöström, B, et al.
(författare)
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A method for the preparation of submicron particles of sparingly water-soluble drugs by precipitation in oil-in-water emulsions. II. Influence of the emulsifier, the solvent, and the drug substance
- 1993
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Ingår i: Journal of Pharmaceutical Sciences. - 0022-3549 .- 1520-6017. ; 82, s. 584-589
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Tidskriftsartikel (refereegranskat)abstract
- Small particles of two steroids; cholesteryl acetate and b-sitosterol, have been prepared by the following technique: The steroid was dissolved in an organic solvent, which was emulsified in water in the presence of sur--factant, thus giving a water continuous emulsion. As the organic solvent was evaporated the steroid precipitated. One particle was found to form in each emulsion droplet. Particle sizes down to 25 nm were obtained by this method. Particles were prepared from emulsions containing different organic solvents and surfactants and the effect on the size and the colloi--dal stability of the particles were examined. It was found that the final particle suspension is relatively stable provided the initial emulsion is stable. Furthermore, there is a close correlation between the initial emul--sion droplet size and the final particle size. The particle size, therefore, can be varied in the same manner as the size of emulsion droplets, e.g. by changing the emulsification process parameters, the amount and choice of surfactant and the oil/water ratio. Finally, the particle size depends on the choice of solvent and only slightly on the concentration of drug in the oil phase of the emulsion.
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| 3. |
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| 4. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Serum leptin concentration and insulin sensitivity in men with abdominal obesity.
- 1998
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Ingår i: Obesity research. - 1071-7323. ; 6:6, s. 416-21
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Tidskriftsartikel (refereegranskat)abstract
- We have examined the association between generalized adiposity, abdominal adiposity, insulin sensitivity, and serum levels of leptin in a cross-sectional study of abdominally obese men.Thirty men, 48 to 66 years of age with a body mass index (BMI) of between 25 kg/m2 and 35 kg/m2 and a waist hip ratio of >0.95, were included in the study. Serum leptin concentration was measured using radioimmunoassay. Total body fat percentage was determined from total body potassium, abdominal adiposity was measured by computed tomography, and the glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp.Significant correlations were found between serum leptin concentration and BMI, percentage body fat, abdominal subcutaneous adipose tissue, serum insulin, GDR, and 24-hour urinary-free cortisol. In a multiple regression analysis, it was shown that abdominal subcutaneous adipose tissue, GDR, and BMI explained 72% of the variability of serum leptin concentration. GDR demonstrated an independent inverse correlation with serum leptin concentration.In abdominally obese men with insulin resistance, it was demonstrated that most of the individual variability in serum leptin concentration was explained by the amount of subcutaneous abdominal adipose tissue, insulin sensitivity, and BMI.
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| 5. |
- Kilinçalp, G., et al.
(författare)
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Predictive Value of Ambulatory Objective Movement Measurement for Outcomes of Levodopa/Carbidopa Intestinal Gel Infusion
- 2022
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Ingår i: Journal of Personalized Medicine. - : MDPI AG. - 2075-4426. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Parkinson’s disease that may benefit from device-assisted therapy can be identified with guidelines like Navigate PD. The decision to offer advanced treatment and the choice of treatment modality are, however, not straightforward, and some patients respond less favorably to a chosen therapy. Measurements with the Parkinson Kinetigraph (PKG) can detect motor fluctuations and could therefore predict patients that respond better or worse to intestinal levodopa/carbidopa gel infusion (LCIG). In a retrospective analysis of 45 patients that had been selected to start LCIG between 2014 and 2020, the effects of baseline PKG and clinical characteristic on the outcome were determined with ordinal regression. Although all patients had been found to have handicapping medication-related symptom fluctuations, patients without clear objective off fluctuations in the baseline PKG had low odds ratio for success. Lower odds for success were also found with increasing age, whereas gender, medication intensity and baseline PKG summary scores (median bradykinesia and dyskinesia scores, fluctuation dyskinesia score and percent time with tremor) had no significant effect. Absence of easily identified off-periods in the PKG has a negative prognostic value for the effect of LCIG and could prompt noninvasive infusion evaluation before surgery. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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| 6. |
- Labbé, David P., et al.
(författare)
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TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:22, s. 7072-7083
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches.
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| 7. |
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| 8. |
- Mårin, P, et al.
(författare)
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The morphology and metabolism of intraabdominal adipose tissue in men.
- 1992
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Ingår i: Metabolism: clinical and experimental. - 0026-0495. ; 41:11, s. 1242-8
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Tidskriftsartikel (refereegranskat)abstract
- Mass, morphology, and metabolism of total adipose tissue and its subcutaneous, visceral, and retroperitoneal subcompartments were examined in 16 men with a wide variation of total body fat. Computerized tomography (CT) scans showed that the intraabdominal fat mass comprised approximately 20% of total fat mass. Visceral and retroperitoneal fat masses were approximately 80% and 20% of total intraabdominal fat mass, respectively. Enlargement of intraabdominal fat depots was due to a parallel adipocyte enlargement only. Direct significant correlations were found between these adipose tissue masses and blood glucose and plasma insulin levels, blood pressure, and liver function tests, while glucose disposal rate during euglycemic glucose clamp measurements at submaximal insulin concentrations (GDR), plasma testosterone, and sex hormone-binding globulin concentrations correlated negatively. The correlations for glucose, insulin, and GDR were strongest with visceral fat mass. Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues. Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines. Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin. Both lipid uptake and lipolytic sensitivity and responsiveness showed strong correlations (r = 0.8 to 0.9) to blood glucose and plasma insulin concentrations and also to the GDR (negative), while no such correlations were found with lipid uptake in subcutaneous or retroperitoneal abdominal adipose tissues. Taken together, these results suggest a higher turnover of lipids in visceral than in the other fat depots, which is closely correlated to systemic insulin resistance and glucose metabolism in men.
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| 9. |
- Sjöström, B, et al.
(författare)
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A method for the preparation of submicron particles of sparingly water-soluble drugs by precipitation in oil-in-water emulsions. I. Influence of emulsification and surfactant concentration
- 1993
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Ingår i: Journal of Pharmaceutical Sciences. - 0022-3549 .- 1520-6017. ; 82, s. 579-583
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we present a method for the synthesis of small particles of poorly water soluble drug substances using emulsions. In the first place, the drug is dissolved in an organic solvent and a water soluble surfactant is dissolved in water. Secondly, these two solutions are mixed to form an emulsion, where the organic solution is emulsified into small droplets in the aqueous phase. The action of the surfactant is partly to decrease the interfacial tension between the water and the organic solution, thus increasing the ease of emulsification, and partly to stabilize the droplets formed against aggregation, or coalescence. The final step in the process is to remove the organic solvent by evaporation in doing which the drug precipitates and one particle is formed in each droplet. If the surfactant is sufficiently effective in stabilizing the particles formed against coagula--tion, we have a suspension of small spherical drug particles. In this paper we use a model system consisting of cholesteryl acetate and toluene. Particles down to 50 nm were obtained by this method. The sizes of the particles were found to be dependent on the surfactant concentration and the emulsification energy.
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| 10. |
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