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SORL1 encodes a 250-kDa protein named sorLA, a functional sorting receptor for the amyloid precursor protein (APP). Several single nucleotide polymorphisms of the gene SORL1, encoding sorLA, are genetically associated with Alzheimer's disease (AD). In the existing literature, SORL1 is insufficiently described at the transcriptional level, and there is very limited amount of functional data defining different transcripts. We have characterized a SORL1 transcript containing a novel exon 30B. The transcript is expressed in most brain regions with highest expression in the temporal lobe and hippocampus. Exon 30B is spliced to exon 31, leading to a mature transcript that encodes an 829 amino acid sorLA receptor. This receptor variant lacks the binding site for APP and is unlikely to function in APP sorting. This transcript is expressed in equal amounts in the cerebellum from AD and non-AD individuals. Our data describe a transcript that encodes a truncated sorLA receptor, suggesting novel neuronal functions for sorLA and that alternative transcription provides a mechanism for SORL1 activity regulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The identification of peripheral biomarkers for bipolar disorder is of great importance and has the potential to improve diagnosis, treatment and prognosis. Recent studies have reported lower plasma progranulin levels in bipolar individuals compared with controls and association with single nucleotide polymorphisms (SNPs) within the progranulin gene (GRN). In the present study, we investigated the effect of GRN and sortilin (SORT1) gene variation on serum progranulin levels in bipolar individuals and controls., Materials and Methods: In a Danish cohort of individuals with bipolar disorder and controls, we analysed the serum progranulin level (nbipolar=80, ncontrols=76) and five SNPs located within GRN and two SNPs near the SORT1 gene encoding sortilin, a progranulin scavenger receptor known to affect circulating progranulin levels (nbipolar=166, ncontrols=186)., Results: We observed no significant difference in the serum progranulin level between cases and controls and none of the analysed SNPs located within GRN or close to SORT1 were associated with bipolar disorder. Crude and adjusted (adjusted for case-control status, sex and age) linear regression analyses showed no effect of any SNPs on the serum progranulin level. However, we observed that the mean serum progranulin level in cases and controls is affected differently depending on the genotypes of two SNPs within GRN (rs2879096 and rs4792938)., Limitation: The sample size is relatively small and detailed information on medication and polarity of the disorder is not available. No correction for multiple testing was performed., Conclusion: Our study suggests that the potential of progranulin as a biomarker for bipolar disorder is genotype dependent.

Pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma, is a serious, widespread medical condition usually caused by alcohol abuse or gallstone-mediated ductal obstruction. However, many cases of pancreatitis are of an unknown etiology. Pancreatitis has been linked to bacterial infection, but causality has yet to be established. Here, we found that persistent infection of mice with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) was sufficient to induce pancreatitis reminiscent of the human disease. Specifically, we found that pancreatitis induced by persistent S. Typhimurium infection was characterized by a loss of pancreatic acinar cells, acinar-to-ductal metaplasia, fibrosis and accumulation of inflammatory cells, including CD11b+ F4/80+, CD11b+ Ly6Cint Ly6G+ and CD11b+ Ly6Chi Ly6G- cells. Furthermore, we found that S. Typhimurium colonized and persisted in the pancreas, associated with pancreatic acinar cells in vivo, and could invade cultured pancreatic acinar cells in vitro. Thus, persistent infection of mice with S. Typhimurium may serve as a useful model for the study of pancreatitis as it relates to bacterial infection. Increased knowledge of how pathogenic bacteria can cause pancreatitis will provide a more integrated picture of the etiology of the disease and could lead to the development of new therapeutic approaches for treatment and prevention of pancreatitis and pancreatic ductal adenocarcinoma.

Background: Prior studies have shown a consistent relationship between coronary artery calcium (CAC) scores or the degree of coronary stenoses on coronary computed tomography angiography (CCTA) and all-cause mortality. Whether CCTA-targeted therapy, including intensive medical management, stress testing and/or invasive coronary angiography (ICA), can lead to a substantial reduction in adverse outcomes is not yet known., Methods: We retrospectively analyzed 691 patients (55±13 years, male=63%) from a single medical practice who underwent a CAC scan and CCTA and were followed for a mean of 2.9±1.0 years. Of these, 416 (60%) patients were asymptomatic. All changes in medications, coronary risk factors (including lipids profiles), downstream testing, revascularization procedures, and clinical events (myocardial infarction and death) were recorded., Results: Among our patients cohort 279 (40%) had no coronary artery disease. The most severe stenosis was <50% in 314 (46%) patients, 50-70% in 76 (11%) patients, and >70% in 22 (3%) patients. A high frequency of medical therapy was employed for those patients with any degree of stenosis, while stress testing was primarily applied for patients with >50% stenosis and ICA was primarily performed in those with >70% stenosis. Only two non-cardiovascular deaths and no cardiovascular deaths occurred during the follow-up period., Conclusions: Our findings support the hypotheses that among patients undergoing CCTA, comprehensive medical management, including targeted percutaneous coronary interventions and increasingly intensive medical therapy with progressively worse CCTA findings, can reduce event rates among patients with abnormal CCTA studies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In patients with normal results on stress single-photon emission computed tomographic (SPECT) studies, coronary artery disease risk factors (RFs) and the mode of testing can influence the trajectory of long-term outcomes. Nevertheless, the combined prognostic impact of these commonly assessed factors has heretofore not been considered. In this study, all-cause mortality rates were assessed in 5,762 patients with normal results on stress SPECT studies. Patients were divided according to mode of stress testing, exercise or pharmacologic, and by number of coronary artery disease RFs. Patients were followed for a mean of 8 ± 4.2 years for all-cause mortality. There were 1,051 deaths (18%), with an annualized mortality rate of 2.2% per year. The RF-adjusted event rate was significantly higher for pharmacologic versus exercise SPECT studies (3.6% per year vs 1.2% per year, p <0.0001) and for patients with increasing numbers of coronary artery disease RFs (p <0.0001). Kaplan-Meier survival analysis revealed wide heterogeneity in all-cause mortality rates when RF burden and performance of exercise versus pharmacologic testing were considered, ranging from only 0.8% per year in exercise patients with no RFs to 4.2% per year in pharmacologic patients with ≥2 RFs. Mortality rates in exercise patients with ≥2 RFs were comparable to those in pharmacologic patients with no RFs. In conclusion, long-term outcomes after cardiac stress testing are synergistically and strongly influenced by RF burden and inability to exercise. Given these findings, prospective study is indicated to determine whether enhanced risk categorization that combines the consideration of these 2 factors improves patient counseling and physician risk management among patients manifesting normal results on stress SPECT studies., (Copyright © 2013. Published by Elsevier Inc.)