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- Hugosson, Jonas, 1955, et al.
(author)
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Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only.
- 2022
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In: The New England journal of medicine. - 1533-4406. ; 387:23, s. 2126-2137
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Journal article (peer-reviewed)abstract
- Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown.We invited 37,887 men who were 50 to 60 years of age to undergo regular prostate-specific antigen (PSA) screening. Participants with a PSA level of 3 ng per milliliter or higher underwent magnetic resonance imaging (MRI) of the prostate; one third of the participants were randomly assigned to a reference group that underwent systematic biopsy as well as targeted biopsy of suspicious lesions shown on MRI. The remaining participants were assigned to the experimental group and underwent MRI-targeted biopsy only. The primary outcome was clinically insignificant prostate cancer, defined as a Gleason score of 3+3. The secondary outcome was clinically significant prostate cancer, defined as a Gleason score of at least 3+4. Safety was also assessed.Of the men who were invited to undergo screening, 17,980 (47%) participated in the trial. A total of 66 of the 11,986 participants in the experimental group (0.6%) received a diagnosis of clinically insignificant prostate cancer, as compared with 72 of 5994 participants (1.2%) in the reference group, a difference of -0.7 percentage points (95% confidence interval [CI], -1.0 to -0.4; relative risk, 0.46; 95% CI, 0.33 to 0.64; P<0.001). The relative risk of clinically significant prostate cancer in the experimental group as compared with the reference group was 0.81 (95% CI, 0.60 to 1.1). Clinically significant cancer that was detected only by systematic biopsy was diagnosed in 10 participants in the reference group; all cases were of intermediate risk and involved mainly low-volume disease that was managed with active surveillance. Serious adverse events were rare (<0.1%) in the two groups.The avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduced the risk of overdiagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients. (Funded by Karin and Christer Johansson's Foundation and others; GÖTEBORG-2 ISRCTN Registry number, ISRCTN94604465.).
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| 2. |
- Karlsson, Sven, et al.
(author)
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Beta cell adaptation to dexamethasone-induced insulin resistance in rats involves increased glucose responsiveness but not glucose effectiveness
- 2001
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In: Pancreas. - 0885-3177. ; 22:2, s. 148-156
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Journal article (peer-reviewed)abstract
- Islet beta cell adaptation to dexamethasone-induced insulin resistance was characterized with respect to glucose-stimulated insulin secretion and islet innervation. Male Sprague-Dawley rats were injected daily with dexamethasone (2 mg/kg for 12 days), which resulted in hyperinsulinemia and hyperglycemia compared with controls (which were injected with sodium chloride). Insulin secretion was characterized in collagenase-isolated islets. Islet innervation was examined by immunocytochemical analysis of tyrosine hydroxylase, neuropeptide Y (sympathetic nerves), and vasoactive intestinal polypeptide (cholinergic nerves). In islets isolated from the insulin-resistant animals, the insulin response to 3.3 or 8.3 mM glucose was three times greater during perifusion compared with controls (p < 0.001). Incubation of islets at 0 to 20 mM glucose revealed a marked leftward shift of the glucose dose-response relation after dexamethasone treatment (potency ratio, 1.78; p < 0.01), with no difference at 0 or 20 mM glucose. Thus, the potency but not the efficacy of glucose was increased. The number of islet nerves did not differ between dexamethasone-treated rats and controls. Dexamethasone-induced insulin resistance leads to adaptively increased glucose responsiveness of the islet beta cells, with increased potency, but not increased efficacy, of glucose to stimulate insulin secretion without any evidence of altered islet innervation.
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| 3. |
- Myrsén Axcrona, Ulrika
(author)
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Expression and Regulation of Neuropeptide Y (NPY) in the Islets of Langerhans
- 1997
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Doctoral thesis (other academic/artistic)abstract
- This thesis deals with the expression, localization and regulation of neuropeptide Y (NPY) in the pancreatic islets of Langerhans under normal and experimental conditions. NPY is widely distributed in the mammalian nervous system and belongs to a family of closely related petides also comprising peptide YY (PYY) and pancreatic polypeptide (PP). NPY exerts a variety of biological effects, such as stimulation of food intake, vasoconstriction, regulation of endocrine functions, and in the pancreas inhibition of insulin secretion. All three peptides occur in the mammalian pancreas; NPY in neuronal elements adrenergic as well as nonadrenergic, and PP and PYY in endocrine cells. Reinnervation of xenografts consisting of purified rat ß-cells and nonß-cells, respectively, transplanted beneath the kidney capsule of nude mouse revealed ingrowth of numerous sympathetic NPY-containing nerves into the ß-cell grafts while reinnervation of nonß-cell grafts was scarce, suggesting a neurotrophic action of the ß-cells. The islet expression and localization of NPY differed between species and was related to the developmental stage in rat. In islets of the hamster, NPY was detected in numerous nerve fibers as well as in somatostatin producing cells, while NPY was confined to nerve fibers within islets of the adult rat. During rat embryogenesis expression of NPY was detected in islet cells and co-localized with insulin. The expression of NPY in fetal rat ß-cells coincides with the known prepartal glucocorticoid surge, which rapidly declines after birth. At the same time the expression of NPY in the ß-cells disappears. Following treatment with the potent glucocorticoid dexamethasone of adult rats, a model for type 2 diabetes, NPY expression was re-induced in the ß-cells. The NPY expression in rat ß-cells rapidly declined after cessation of dexamethasone treatment, indicating that expression of NPY in rat ß-cells is dependent on continuous excessive levels of glucocorticoids. The glucocorticoid-induced expression of NPY in rat ß-cells was found to be markedly reduced by concomitant treatment with insulin or by sympathectomy. Culture of the insulin-producing cell line RINm5F with dexamethasone also induced expression of NPY. Stimulation of RINm5F cells with D-glyceraldehyde and depolarization with KCl increased the release of insulin Ca2+-dependently. However, the release of NPY was not affected by stimulation or removal of extracellular Ca2+, reflecting a constitutive release of NPY in contrast to the regulated release of insulin. Glucocorticoids induce peripheral insulin resistance with increased demands on the functional capacity of the ß-cells to produce and secrete insulin, as in type 2 diabetes. Our findings suggest that the expression of NPY in ß-cells could be part of the ß-cell activation upon the increased secretory demands induced by dexamethasone. Possibly, NPY, being a potent inhibitor of insulin secretion, could act by paracrine or autocrine mechanisms to prevent overwork of the ß-cells.
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