3,563 research outputs found

    Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

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    Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic Ī²-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an āˆ¼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for Ī±-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. Ī²-Cell mass was reduced by āˆ¼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by Ī±-cell hyperplasia with the potential for evolution into neuroendocrine tumors

    Ī²-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.

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    ObjectiveThe islet in type 2 diabetes is characterized by Ī²-cell apoptosis, Ī²-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in Ī²-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in Ī²-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in Ī²-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in Ī²-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises Ī²-cell viability

    Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

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    Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass inĀ vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells

    Posterior cricoid region fluoroscopic findings: the posterior cricoid plication.

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    The region posterior to the cricoid cartilage is challenging to assess fluoroscopically. The purpose of this investigation is to critically evaluate the posterior cricoid (PC) region on fluoroscopy and describe patterns of common findings. This was a case control study. All fluoroscopic swallowing studies performed between June 16, 2009, and February 9, 2010, were reviewed for features seen in the PC region. These findings were categorized into distinct patterns and compared to fluoroscopic studies performed in a cohort of normal volunteers. Two hundred patient studies and 149 healthy volunteer studies were reviewed. The mean age of the referred patient cohort and the volunteer cohort was 57 years (Ā±19) and 61 years (Ā±16), respectively (p > 0.05). The patient cohort was 53% male and the control cohort was 56% female (p > 0.05). Four groups were identified. Pharyngoesophageal webs were seen in 7% (10/149) of controls and 14% (28/200) of patients (p = 0.03). A PC arch impression was seen in 16% of patients (32/200) and controls (24/149) (p = 1). A PC plication was demonstrated in 23% (34/149) of controls and 30% (60/200) of patients (p = 0.13). No distinctive PC region findings were seen in 54% (81/149) of controls and 42% (84/200) of referred patients (p = 0.02). Four patients (2%) had both a web and a PC plication. Four categories of PC region findings were identified (unremarkable PC region, web, PC arch impression, and PC plication). Both patients referred for swallowing studies and healthy volunteers demonstrated esophageal webs, PC arch impressions, and PC plications. Only webs were more common in patients than in control subjects (p = 0.03). The PC impression and PC plication are likely to represent normal variants that may be identified on fluoroscopic swallow studies

    Two Jovian-Mass Planets in Earthlike Orbits

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    We report the discovery of two new planets: a 1.94 M_Jup planet in a 1.8-year orbit of HD 5319, and a 2.51 M_Jup planet in a 1.1-year orbit of HD 75898. The measured eccentricities are 0.12 for HD 5319 b and 0.10 for HD 75898 b, and Markov Chain Monte Carlo simulations based on derived orbital parameters indicate that the radial velocities of both stars are consistent with circular planet orbits. With low eccentricity and 1 < a < 2 AU, our new planets have orbits similar to terrestrial planets in the solar system. The radial velocity residuals of both stars have significant trends, likely arising from substellar or low-mass stellar companions.Comment: 32 pages, including 11 figures and 5 tables. Accepted by Ap

    Biogeographical comparison of the emergent macrophyte, Sagittaria platyphylla in its native and introduced ranges

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    Understanding why some plant species become invasive is important to predict and prevent future weed threats and identify appropriate management strategies. Many hypotheses have been proposed to explain why plants become invasive, yet few studies have quantitatively compared plant and population parameters between native and introduced range populations to gain an objective perspective on the causes of plant invasion. The present study uses a biogeographical field survey to compare morphological and reproductive traits and abundance between the native range (USA) and two introduced ranges (Australia and South Africa) of Sagittaria platyphylla (Engelm.) J.G. Sm (Alismataceae), a highly invasive freshwater macrophyte. Introduced and native populations differed in sexual reproductive output with the number of achenes per fruiting head and individual achene weight found to be 40% and 50% greater in introduced populations respectively. However, no other morphological traits were found to be consistently different between the native and both introduced ranges, especially after taking into account differences in environmental conditions between the three ranges. Although populations in introduced regions were larger and occupied greater percentage cover, no differences in plant density were evident. Our results suggest that, apart from sexual reproduction, many of the trait patterns observed in S. platyphylla are influenced by environmental and habitat conditions within the native and invaded ranges. We conclude that the enemy release hypothesis best explains the results observed for sexual reproduction. In particular, we hypothesise that a release from natural enemies, specifically a pre-dispersal seed predator, may induce reproductive plasticity in S. platyphylla

    Updated respiration routines alter spatio-temporal patterns of carbon cycling in a global land surface model

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    We updated the routines used to estimate leaf maintenance respiration (MR) in the Energy Land Model (ELM) using a comprehensive global respiration data base. The updated algorithm includes a temperature acclimating base rate, an updated instantaneous temperature response, and new plant functional type specific parameters. The updated MR algorithm resulted in a very large increase in global MR of 16.1 Pg (38%), but the signal was not geographically uniform. The increase was concentrated in the tropics and humid warm-temperate forests. The increase in MR led to large but proportionally smaller decreases in global net primary production (19%) and in average global leaf area index (15%). The effect on global gross primary production (GPP) was a more modest 5.7 Pg (4%). A detailed site level analysis also demonstrated a wide range of effects the updated algorithm can have on the seasonal cycle of GPP. Output from the updated and old models did not differ markedly in how closely they matched a suite of benchmarks. Given the substantial impact on the land surface carbon cycle, a neutral influence on model benchmarks, and better alignment with empirical evidence, an MR algorithm similar to the one presented here should be adopted into ELM
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