school of biosciences

Click here to load reader

Post on 30-Dec-2015

21 views

Category:

Documents

0 download

Embed Size (px)

DESCRIPTION

School of Biosciences. Ole H Petersen [email protected] Using clinical case stories to motivate students to study the relevant basic science - PowerPoint PPT Presentation

TRANSCRIPT

  • School of BiosciencesOle H [email protected]

    Using clinical case stories to motivate students to study the relevant basic science Providing links to relevant and exciting research to enable students to understand how progress is made and how this will change future clinical practices

  • A great Medical School has great TeachersJrn Hess ThaysenProfessor of Internal MedicineUniversity of CopenhagenProfessor Niels Anker ThornProfessor of PhysiologyUniversity of CopenhagenMeeting at the Royal Danish Academy, Copenhagen, June 19871742Royal Danish Academy of Sciences & LettersTwo teachers who had a great influence on me as an undergraduate medical student(here seen ~20 years later)Jrn Hess Thaysen, the top clinician at The Kingdom in Copenhagen, was a tireless defender and supporter of physiology as the essential basis of medicine

  • Sir Richard Doll FRSRegius Professor of Medicine, University of Oxford, 1969-1979

    As External Examiner in the Oxford Prelims in the late 1970s, I was impressed by the fact that Sir Richard spent a great deal of time participating in the basic science examinations, including the vivas, always insisting on the highest standards.

  • Credo:Physiology and pathophysiology are the basis of Medicine All diseases are due to malfunction of one or more cell typesTextbooks are importantIt is a duty (for both educators and students) to be competent, but unfortunately nobody is sufficiently competent. Dedication makes up the deficit

  • These are, in my view, by far the most serious challenges

  • C21:The core Values are: Teaching Excellence, Patient Safety, Scholarship, Science andServiceTo me the most important point about teaching excellence is COMPETENCE in the relevant subject matter

    Interdisciplinarity IS important, but the quality of interdisciplinary teaching (and indeed research) is totally dependent on competence in the eductors own (primary) discipline

  • Learning initiated and inspired by specific case studiesAn example: Acute pancreatitis (AP)Why chose a relatively minor (infrequent) disease?

    One of the major factors responsible for AP is alcohol abuse; the second-leading cause of preventable death in the UK

    AP is due to malfunction of pancreatic acinar cells. This cell type has been, and continues to be, used as one of the most important cell biological models. Studies of pancreatic acinar cells have been fundamental in establishing:[1] The basis for our understanding of intracellular protein synthesis, processing and secretion (Palade, Nobel Prize 1974)[2] The basis for our understanding of intracellular signalling, by the discovery of the ubiquitous intracellular messenger function of the Ca2+-releasing agent inositol trisphosphate (Sir Michael Berridge FRS, Lasker Award 1989)

  • Acute pancreatitis (AP) a case studyhttp://www.nhs.uk/Conditions/Pancreatitis/Pages/Introduction.aspx

    Stephanie Atts was diagnosed with pancreatitis when she was 24. She hasgiven up drinking but the condition still causes her pain.I kept going into hospital back in 2002 because I was suffering from severe stomach pain. But the doctors couldnt find anything wrong with me. They took some blood tests. They said they had my results and it was something quite serious. When they told me it was pancreatitis, I was really shocked and upset. Pancreatitis is incredibly painful. The stomach pain just comes on all of a sudden. Theres no run-up to it, it just hits you. It starts in my guts and moves round to my back, then I throw up. Its hard to describe how bad the pain is. It'sworse than being in labour, which is saying something. And theres no position where you can get comfortable. Its so bad you can barely move.They did some more tests to find out the extent of the damage and found that a quarter of my pancreas was terminally damaged. I was told to stop drinking immediately, which I did. I had been drinking heavily for about eight months, which is what caused the pancreatitis.

  • Themes to explore (selection): How does the body deal with alcohol (ethanol) (basics: absorption, metabolism, elimination quantitative approach) Biochemistry/Physiology Mechanisms of cellular action of ethanol (and metabolites) (basics: ion channels in plasma membrane and organelle membranes; research link: molecular mechanisms of alcohol actions) Physiology/Pathophysiology/Neurophysiology How could actions on ion channel opening and closure in nerve cell membranes affect behaviour? (research link: molecular neurobiology and behavioural studies) Neurophysiology/Psychology/Psychiatry AP is initiated by activation of digestive pro-enzymes (particularly proteases such as trypsinogen) inside the pancreatic acinar cells (basics: intracellular processing of proteins and secretion). How can ethanol or ethanol products induce such inappropriate activation (research link: live cell imaging of protease activation, gene deletion studies)? Physiology/Pathophysiology/Cell Biology Disease progression: How does AP become chronic pancreatitis and why does chronic pancreatitis predispose to pancreatic cancer (basics: stellate cells and fibrosis; research link: the cancer-promoting intercellular matrix)? Cell Biology/Cancer Biology Other causes of AP (gallstones, high lipid concentration in blood) (basics: anatomy/phsyiology of biliary and pancreatic systems) (fat-alcohol interactions) (research link: cellular mechanisms of action of bile acids). Anatomy/Physiology/Biochemistry Prevention and treatment of AP (dealing with excessive use of alcohol, dietary advice, exploration of ways to diminish intracellular protease activation) (basics and many research links). General Practice/Psychiatry/Sociology/Pathophysiology/Pharmacology/Pharmacy

  • Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)]BALminBlood Alcohol Level (BAL) as a function of time after intake of single alcohol doseAbsorption from G-I TractElimination by oxidation in liverExample of one set of Learning Outcomes, arising from critical considerations of a simple quantitative experiment:

  • Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)]BALmin[1] Alcohol is absorbed relatively quickly from the G-I tract. [2] After appearance in blood it is rapidly distributed in a fluid volume corresponding to ~50 - 70 % of the body weight. [3] At BAL > 0.10/00, alcohol is metabolized at a constant rate (mostly by oxidation) of ~7 g per hour for a person weighing 70 kg. Alcohol dehydrogenase is a key (liver) enzyme and low levels of this enzyme will decrease alcohol tolerance [4] Alcohol is excreted via lung ventilation (concentration in alveolar air ~1/2000 of BAL) and in the urine (~same concentration as in plasma). [5] The rate of elimination of alcohol via the lungs and urine is small compared to elimination by oxidation, which occurs principally in the liver (a substantial part of oxidation in the liver is only partial to acetate, which can then be further broken down in extra-hepatic tissues). [6] The rate of alcohol oxidation in the liver is rate limiting for disposal of alcohol from the whole body. Increased energy consumption by skeletal muscles (physical work), for example, will therefore NOT affect the rate of elimination.Blood Alcohol Level (BAL) as a function of time after intake of single alcohol doseAbsorption from G-I TractElimination by oxidation in liverExample of Required Core Knowledge

  • How to assess the Blood Alcohol Level (BAL) at the time of an accident on the basis of later repeated measurements of BAL and extrapolationTime course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)]BALminMeasurement periodAccidentA basis for a quantitiative test question

  • Research Project: Clinically relevant pathophysiology

  • Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, Gerasimenko Calmodulin (CaM) protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through inositol trisphosphate receptors. Proc. Natl. Acad. Sci. USA (PNAS) 108, 5873-5878, 2011(MRC press release: http://www.mrc.ac.uk/Newspublications/News/MRC007775)

    The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitisTrypsin activity(ethanol)Research Project: Clinically relevant pathophysiologyIsolated live pancreatic acinar cell

  • Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, Gerasimenko Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through inositol trisphosphate receptors. Proc. Natl. Acad. Sci. USA (PNAS) 108, 5873-5878, 2011(MRC press release: http://www.mrc.ac.uk/Newspublications/News/MRC007775)

    The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitisCALP-3 is a cell-permeable CaM agonist(Val-Lys-Phe-Gly-Val-Gly-Phe-Lys)Trypsin activity(ethanol)Research Project: Clinically relevant pathophysiologyIsolated live pancreat