Activation of PyMT in β Cells Induces Irreversible Hyperplasia, but Oncogene-Dependent Acinar Cell Carcinomas When Activated in Pancreatic Progenitors

It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in β cells causes β-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, β cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded β cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and β-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the β cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival

Markers of cerebral damage during delirium in elderly patients with hip fracture

BACKGROUND: S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium. METHODS: The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay. RESULTS: Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p<0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 ug/L, p=<0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p=0.97). Delirious state (before, during, after) (p<0.001), day of blood withdrawal (p<0.001), pre- or postoperative status (p=0.001) and type of fracture (p=0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p=0.43) or NSE levels (p=0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium. CONCLUSIONS: Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for deliriu

The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis

Aspekter på ordspråk : föredrag vid ett symposium i Uppsala 27–28 april, 2011

Kungl. Gustav Adolfs Akademien för svensk folkkultur är en riksakademi med säte i Uppsala. Sin uppgift att främja forskning rörande svensk folklig kultur, begreppet taget i vid mening, skall Akademien enligt sina stadgar bland annat fullgöra genom att i sina skriftserier offentliggöra forskningsrön inom ämnesområden som den har till uppgift att vårda sig om. Huvudserien är Acta Academiae Regiae Gustavi Adolphi, vars första nummerutkom 1933. Bland övriga serier kan nämnas Folklivsskildringar och bygdestudier, Kungl. Gustav Adolfs Akademiens småskrifter och Svenska sagor och sägner.På senare år har intresset för ordspråksforskning eller - med en internationell term - paremiologi varit på uppgång i flera av de nordiska länderna. Ett tecken på detta är symposiet Aspekter på ordspråk som i april 2011 anordnades i Uppsala av Kungl. Gustav Adolfs Akademien för svensk folkkultur. Syftet var att skapa kontakter mellan nordiska ordspråksforskare inom skilda discipliner. Studiet av ordspråk är nämligen ett tvärvetenskapligt forskningsfält i skärningspunkten mellan folkloristik, språkvetenskap och pedagogik.I föreliggande volym ingår elva bidrag som presenterades vid symposiet. Både geografiskt och tidsmässigt uppvisar artiklarna stor spännvidd: från Island i väster till Ryssland i öster, från medeltida samlingar till dagens ordspråkstravestier. En del av författarna anlägger språkliga perspektiv, andra betraktar ordspråken utifrån en genreteoretisk eller kulturhistorisk synvinkel, och ytterligare några fokuserar på insamlingen av ordspråk eller enskilda betydelsefulla samlingar. Tillsammans ger artiklarna en bild av mångfalden av angreppspunkter i dagens ordspråksforskning.There has been a growing interest in several of the Nordic countries in recent years in the study of proverbs, or paremiology to use an international term. One manifestation of this was the symposium Aspekter på ordspråk (Angles on Proverbs), arranged in Uppsala in April 2011 by the Royal Gustavus Adolphus Academy for Swedish Folk Culture. Its aim was to build bridges between Nordic proverb scholars from different disciplines, paremiology being an interdisciplinary field of research at the intersection of folklore studies, linguistics and education.The present volume contains eleven contributions that were presented at the symposium. Four of the authors are from Sweden (Daniel Andersson, Bengt af Klintberg, Janken Myrdal, Emma Sköldberg), four from Finland (Carola Ekrem, Liisa Granbom-Herranen, Pekka Hakamies, Outi Lauhakangas) and one each from Iceland (Helgi Haraldsson), Norway (Arne Bugge Amundsen) and Russia (Konstantin Zhukov).Chronologically, the papers span a wide range: from medieval collections to modern-day 'anti- proverbs' – parodies or distortions of traditional proverbs. Some of the authors apply a linguistic perspective, others view proverbs from the vantage point of genre theory or cultural history, and yet others focus on proverb collecting or significant individual collections, such as those of Peder Låle, Christopher Grubb, Erik Pontoppidan and Väinö Solstrand. Between them, the articles give a sense of the diversity of approaches used in paremiology today.</p

Association of Care Practices with Suicide Attempts in US Veterans Prescribed Opioid Medications for Chronic Pain Management

IMPORTANCE: Patients receiving opioid therapy are at elevated risk of attempting suicide. Guidelines recommend practices to mitigate risk, but it is not known whether these are effective. OBJECTIVE: Our aim was to examine associations between the receipt of guideline-recommended care for opioid therapy and risk of suicide attempt. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of administrative data for all Veteran patients prescribed any short-acting opioids on a chronic basis or any long-acting opioids from the Veterans Health Administration during fiscal year 2010. MAIN OUTCOMES AND MEASURES: Multivariate, mixed-effects logistic regression analyses were conducted to define the associations between the risk of suicide attempt and receipt of guideline-recommended care at the individual level and rates of use of recommended care at the facility level, while accounting for patient risk factors. RESULTS: At the individual level, having a mood disorder was highly associated with suicide attempts (odds ratios [ORs] = 3.5, 3.9; 95 % confidence intervals [CIs] = 3.3–3.9, 3.3–4.6 for chronic short-acting and long-acting groups, respectively). At the facility level, patients on opioid therapy within the facilities ordering more drug screens were associated with decreased risk of suicide attempt (ORs = 0.2, 0.3; CIs = 0.1–0.3, 0.2–0.6 for chronic short-acting and long-acting groups, respectively). In addition, patients on long-acting opioid therapy within the facilities providing more follow-up after new prescriptions were associated with decreased risk of suicide attempt (OR = 0.2, CI = 0.0–0.7), and patients on long-acting opioid therapy within the facilities having higher sedative co-prescription rates were associated with increased risk of suicide attempt (OR = 20.3, CI = 1.1–382.2). CONCLUSIONS AND RELEVANCE: Encouraging facilities to make more consistent use of drug screening, provide follow-up within 4 weeks for patients initiating new opioid prescriptions, and avoid sedative co-prescription in combination with long-acting opioids may help prevent suicide attempts. Some clinicians may selectively employ guideline-recommended practices with at-risk patients

Genetic and clinical characteristics of maturity-onset diabetes of the young

Genetic factors play an important role in various forms of diabetes mellitus (DM), but inheritance is complex and interacts with environmental factors. Although in most cases type 2 DM (T2DM) and T1DM are polygenic disorders, several monogenic forms have been identified. Among them, maturity-onset diabetes of the young (MODY) has been the most intensively investigated. MODY is a group of six different forms of monogenic diabetes, characterized by insulin secretion defects in pancreatic P-cells, supposed to be responsible for 2-5% of all cases of diabetes. the most common are MODY2 and MODY3, caused by mutations in the genes encoding glucokinase and hepatocyte nuclear factor 1-alpha respectively. MODY2 is characterized by glucose sensing defects, leading to an increase in insulin secretion threshold. This causes lifelong sustained and mild hyperglycaemia from birth, most often in non-diabetic levels. Diagnosis is incidental in most cases. These patients are asymptomatic, seldom need treatment and rarely present chronic complications. MODY3 is characterized by a severe insulin secretion defect in response to glucose. Diagnosis is made usually in adolescence and early adulthood, often by osmotic symptoms. Hyperglycaemia is progressive, and patients frequently need treatment with oral drugs or insulin some time in their follow up. This group seems to have a marked sensitivity to sulphonylureas compared to other types of diabetes. the recognition of MODY as a monogenic disorder and a thorough understanding of its pathophysiology are important for correct diagnosis and treatment, with great impact on prognosis. Besides, the study of these forms of diabetes brings important contributions the understanding of glucose homeostasis as a whole.Universidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilFleury Lab, São Paulo, BrazilUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilWeb of Scienc