EDITORIAL

 

MILESTONES.

Snatches from a familiar song keep coming to my mind every December:

"Something old; something new; something borrowed something blue"

Ernest Henry Starling  has been immortalised in the way the ventricles contract in response to stretch. So shall we remember the Starling forces  which filter 24 litres of interstitial fluid and 180 litres of glomerular filtrate every day. The golden age of endocrinology dawned with Bayliss and Starling discovering that extracts of the intestine caused the gall bladder to contract and the pancreas to secrete pancreatic juice; they named the substance "secretin" and classified it as a hormone ( L = I excite to action). The discovery of insulin by Banting and Best has made life easier for the millions of diabetics in the world today. Our understanding of the nervous system (classification of nerves, action potentials, propagation) was greatly enhanced by the work of Eccles,  Hodgkin and Huxley. " Reflex" was our legacy from Sir Charles Sherrington  and conditioned reflexes were made clear by Ivan Petrovich Pavlov. Pavlov's work on the gastrointestinal system also clarified control of gastric secretion; of great impact in a world full of stress . The word "stress" is, of course, synonymous with Hans Selye, the acknowledged authority on stress.   The Golden age of Immunology dawned in the 1960s although Edward Jenner had demonstrated the value of vaccination in the 1940s. The ubiquitous prostaglandins described by von Euler in the 1930s resurfaced in the early 1970s, opening the way for a spate of discoveries. We can explain most phenomena today based on the prostaglandins.  Henry Dale's work clarified the way neurotransmitters work in the autonomic nerve endings, paving the way for classification  of the adrenergic receptors.  Discovery of the membrane receptors and channels has explained a lot of phenomena : "Why do substances act differently in different tissues?" "Why do ions go in and out and why at selective times?". Management of heart conditions has changed because of our understanding of these fluxes.The advance of reproductive physiology led the way to fertility control as well as understanding pathophysiological processes. It was a great triumph for the world when smallpox was finally eradicated in the 1970s. The year 2000 is targeted for eradication of poliomyelitis. The war against malaria still goes on, as the war against infectious diseases of childhood. Pharmacologists still have a daunting task as the little "beasties" develop drug resistance. And, of course, the scourge of the 1980s and 90s: HIV  which causes immunodeficiency; inviting infection. Tuberculosis is once again rearing its ugly head even in developed countries, aided by AIDS, overcrowding, non- compliance of patients, drug resistance. Finding a cure for AIDS is not impossible, although we may be quite far off. [Nostradamus wrote :"A very great plague will come in the great shell, relief near, but the remedies far away.."] Let us hope he is wrong ( he has been proved wrong in a lot of his predictions) and that a miracle will happen. I hear Mariah  Carey's voice now, singing "There can be miracles if you believe...."

 

 

MSPP HPLC Workshop

The proposed MSPP Workshop Postponed

 

Proposed visit to Prince of Songkhla University

The Medical School and Science Faculty's Physiology and Pharmacology Departments has agreed to a visit by members of the MSPP.  We are looking for a good date and to see how many members are interested in dropping by Hadyai.  It should very interesting both scientifically and otherwise.  Can we have some feedback?  Send comments to the secretary Dr. Rosnah (e-mail: rosnah@medicine.med.um.edu.my).

 

Article in Berita Harian

The following article appeared in the centre pages of Berita Harian on 26 May, 1999.  It was sent on behalf of the MSPP.  The main text was written by Dr. Cheah Swee Hung with feedback by various members and translation was done by Dr. Zaiton Zakaria, Dr. Ibrahim Noor and Dr. Rosnah Ismail.  The text has been edited by the newspaper.  The newspaper paid RM150 for the article most of which will go to MSPP (there was a fee for the extraction of the article from the NST archives).  A copy of the article has been posted on the MSPP website.

From Thailand

Subject: FAOPS Newsletter web site

 Dear Members of FAOPS,

 Sincerely yours,

Chumpol Pholpramool

sccpp@mahidol.ac.th

The Editor, FAOPS Newsletter

[It is too late for 1999. Aim for future issues-Ed]

From the International Medical University

The School of Medical Sciences of the IMU will be moving to Bukit Jalil this month. The new address will be:

The IMU

Sesama Centre

Plaza Komanwel

57000 Seri Petaling,KL

Tel: 03 8656 7228

Introducing the physiologists at IMU

 (Clinical) staff. The challenges of an integrated curriculum for Physiology !- Prof. Greg.Tan, IMU

[ More information on the Section and its activities may be obtained from Prof Greg Tan at GregT@imu.edu.my

The Section looks forward to participating actively in the MSPP and welcome any help required by the organisation for the coming FAOPS in 2002.  A helping hand to fellow Physiologists/ pharmacologists. ] 

 

From USM, Penang

REPORT OF THE 14^TH SCIENTIFIC MEETING OF THE MALAYSIAN SOCIETY OF PHARMACOLOGY AND PHYSIOLOGY  7-9 May 1999, UNIVERSITI SAINS MALAYSIA, PENANG.

            USM, Penang               31

            USM, Kubang Kerian  5

            UM                              19

            UKM                           3

            UPM                            2

            FRIM                           2

Japan                           1(plenary

                                      speaker)

The Annual General Meeting was held on the 8^th May (Saturday) and it was decided that the coming 15^th Scientific Meeting of the MSPP will be held in Kubang Kerian, Kelantan.

[Report submitted by :Dr Abas Hj Hussin - Secretariat, 14^th Scientific Meeting of MSPP.]

 

 

AND VIEWS

 

Advances in Basic Science Hold Promise for New Therapies in Gastrointestinal Dysmotility

Eamonn M.M. Quigley, MD

Introduction

Symptoms and clinical syndromes associated with disturbances in gastrointestinal motor function continue to pose a major challenge for the clinician. These functional disorders remain poorly defined, are difficult to evaluate, and have proven particularly resistant to successful therapy. Indeed, therapy remains, for the most part, largely empiric and symptomatic. In contrast, there have been tremendous advances in the physiology, neuroanatomy, molecular biology, and pharmacology of gastrointestinal motor function. In a state-of-the-art lecture presented at the 7th United European Gastroenterology Week in Rome, Italy, Dr. Lionel Bueno from the Department of Pharmacology at the INRA Institute in Toulouse, France, described how these advances in basic science may translate into new therapeutic options for patients.^[1]

A Neurophysiologic Basis for Motility Therapeutics

Professor Bueno introduced us to the broad concept of brain/gut communications as the template for any understanding of gut-motor dysfunction in disease. This relatively new concept, which has led some to propose that this entire field of effort should be referred to as "neuro-gastroenterology" rather than "motility," emphasizes the inclusion of all elements that may lead to gastrointestinal symptoms. These elements include the smooth muscle of the gut wall, the enteric and autonomic nervous systems, sensory receptors in the gut wall, afferent neurons, and those centers in the spinal cord and brain involved in the reception of stimuli from the gut and in the initiation or modulation of gut motor activity. In this manner, nerve-gut interactions may take place at any one of three levels -- in the central nervous system, at the prevertebral ganglia, and within the enteric nervous system.

Professor Bueno subsequently discussed some experimental models of disease that have provided considerable insight into the pathophysiology and pharmacology of functional bowel disorders, namely altered intestinal reflexes, visceral hypersensitivity and hyperalgesia, immune-mediated gut/brain dysfunction, and abnormal central modulation. The models are not mutually exclusive; indeed, there is considerable evidence for extensive interaction between them.

Abnormal Gut Reflexes in Functional Gastrointestinal Disease: A Basis for New Pharmacological Approaches?

Evidence, primarily from animal models, but supported by some recent data in humans, suggests that dysfunction of gut reflexes may play a role in the pathogenesis of a variety of functional gastrointestinal disorders. The gastroesophageal reflex, initiated by gastric distention, mediated by a vagovagal pathway and leading to transient lower esophageal sphincter relaxation (TLESR), is now regarded as central to physiologic gastroesophageal reflux and gastroesophageal reflux disease (GERD). Nitric oxide (NO), cholecystokinin (CCK)_A, and serotonin (5-HT)₃ receptors have all been identified as being involved in either the afferent or efferent arms of this reflex. Indeed, the CCK_A antagonist, devazepide, has been shown to inhibit TLESR. Given the prevalence of GERD, it is likely that the regulation of TLESR is going to be the subject of major interest in the coming years.

Gastric emptying, tone, and motility are influenced by intestino- and duodeno-gastric reflexes, whose dysfunction has been proposed to play a role in the pathogenesis of symptoms in functional or nonulcer dyspepsia (FD and NUD, respectively). Receptors involved in this reflex include those for CCK_A, dopamine (D)₂, 5-HT_1A, and gastrin-releasing peptide (GRP). A cologastric reflex can also modulate gastric motor function and has been proposed to play a role in both FD and irritable bowel syndrome (IBS). Opioid, substance P (SP), neurokinin (NK₁), and peptide YY (PYY) receptors have been implicated in this reflex, and the kappa opioid agonist, fedotozine, has been shown to inhibit the cologastric reflex. Indeed, this drug has been investigated in clinical trials for a number of functional bowel disorders. The rectocolonic reflex has also been implicated in IBS, and has attracted considerable interest recently. Vasoactive intestinal peptide (VIP), SP₁, NK₁, NK₃, and bradykinin (BK)₂ receptors have been associated with this reflex, and NK₁, NK₃, CCK_A, BK₂ antagonists, calcium channel blockers, trimebutine, and alverine have all been shown to inhibit the rectocolonic reflex.  While the role of the peritoneo-gastrointestinal reflex in functional disease is almost unknown, this reflex, whereby in experimental animals peritoneal stimulation leads to motor inhibition, has provided considerable insight into the pathophysiology of colonic ileus and the pharmacology of gut reflex activity. Receptor types involved in this reflex include NK₁, BK₂, calcitonin gene-related peptide (CGRP), and corticotropin-releasing factor (CRF)-R₁. Experimentally, this reflex can be inhibited by CRF-R₁ antagonists, kappa opioid agonists, cyclooxygenase (COX)-2 inhibitors, ICAM (intracellular adhesion molecules) antibodies, and mast cell stabilizers.

Visceral Hypersensitivity and Hyperalgesia in Functional Gastrointestinal Disease

The description of visceral hypersensitivity and hyperalgesia (the phenomenon whereby a previously nonpainful stimulus is now perceived as painful) in several functional gastrointestinal diseases, including noncardiac chest pain, FD, and IBS, has led to a flurry of activity in the areas of gut sensation and perception. While a whole host of receptors, neuropeptides, and neuromodulators is known to be involved at a variety of levels in the mediation of both normal sensation and hyperalgesia, a few have attracted particular interest in view of either their ubiquity and/or apparent key roles. For most visceral sensations, the first-order neuron (primary sensory afferent) synapses with the second-order neuron in the dorsal horn of the spinal cord, which in turn project, thereafter, to the various centers in the brain. Serotonin appears to play a key role. Both 5HT₃ and 5HT_1A receptor subtypes are involved at different sites in the mediation of gut nociception and several antagonists are currently undergoing study -- some may soon reach the clinical arena.

Opioids acting as mu, gamma, and kappa receptors appear to be involved at the peripheral receptor in primary afferents and in dorsal root ganglia, as well as in the spinal cord and the central nervous system. Substance P and NK_A also appear to be involved at a number of levels, whereas CGRP has been localized to primary sensory afferents.

Professor Bueno placed considerable emphasis on gut hyperalgesia and, in particular, on the role of inflammatory mediators in sensitizing primary afferent neurons. A variety of experimental models have demonstrated that inflammatory mediators will lead to the development of pain in response to a level of gut distention that previously did not elicit this sensation. Several peptides, including BK, CGRP, tachykinins, VIP, 5HT, adenosine, noradrenaline, eicosanoids (including prostaglandin (PG)E₂, cytokines [interleukin {IL}-1, IL-8], tumor necrosis factor-alpha [TNF-alpha], and growth factors [nerve growth factor or NGF]), have all been shown to be involved in the sensitization process.

A fascinating development has been the realization that such peripheral events can lead to both short- and long-term changes in neural activity in the spinal cord and central nervous system. For example, peripheral sensitization of sensory neurons may alter the membrane properties of the second-order neurons originating in the dorsal horn of the spinal cord through N-methyl-d-aspartate (NMDA) receptors, leading to long-lasting adaptation. SP, dynorphins, and glutamate may also be involved. Thyrotropin-releasing factor (TRF), vasopressin, CCK₈, SP, IL-1, TNF-alpha, norepinephrine, dopamine, 5HT_1A, and PGE₂ have all been shown to modulate the central mediation of events initiated at peripheral sensitization.

Motility-Immune Reactions

The potential role of gut-immune interactions in the pathogenesis of functional gastrointestinal disorders is, perhaps, best illustrated by the phenomenon of the postinfective IBS. It is now evident that prior exposure to bacterial gastroenteritis may lead to the development of full-blown IBS in a proportion of exposed subjects. Such dysfunction may persist for months or even years after the infectious agent has completely cleared. This observation has stimulated intense interest in the potential interactions between inflammation, intestinal muscle, and the enteric, autonomic, and central nervous systems.

Professor Bueno reviewed three animal-based models of disease that have provided considerable insight into these interactions: hypermastocytosis (related to experimental helminthic infestation), lipopolysaccharide-induced allodynia (a model of systemic sepsis), and peripheral inflammation. NK₂ receptor antagonists appear to be active in each model, and the NK₂ antagonists, SR 48968 and MEN 11420, have been shown to reduce the pain induced by visceral distention in hypermastocytosis models, such as the rat infected with Nippostrongylus brasiliensis, or in experimentally induced inflammation. BK₁ and BK₂ antagonists, as well as 5HT_1A antagonists, such as WAY 100425, also have efficacy in the lipopolysaccharide-induced allodynia model. Serotonin, NK, and BK antagonists appear to hold particular promise for efficacy in the latter setting.

Central Input

It has been stressed repeatedly that many proposed mechanisms of abnormal nerve-gut responses may include alterations in neurotransmission at the level of the spinal cord and brain. There are other circumstances where gut-motor dysfunction appears to originate centrally. The clinician will immediately recognize the profound effects of stress, be it short- or long-term, on such motor functions as gastric emptying and small bowel transit. Indeed, animal studies and experiments in humans have demonstrated the ability of stimuli of central origin to modulate and disrupt a host of motor and sensory activities in the gastrointestinal tract.

Similarly, central nervous system activity may modulate incoming signals from the periphery initiated by physiologic or pathologic events, including inflammation. Many of the receptors identified as active in the peripheral regulation of gut motor activity appear to be at least as important in central regulation. These receptors include 5HT, CRF, NK, CCK, and SP. Cytokines, such as IL-1 and TNF-alpha, also appear to be centrally active. It should come as no surprise, therefore, that the efficacy of some of the newer motility agents that are currently undergoing clinical evaluation may be exerted, at least in part, through effects on the central nervous system. For example, the 5HT₄ agonist, HTF 919 (or tegaserod), has been shown to reverse stress-induced delay in gastric emptying.

Summary: Implications for Clinical Practice

Experimental animal models have provided tremendous insights into the regulation of a variety of gut motor functions, and have led to the identification of many of the receptors involved.

Gut reflexes, visceral hypersensitivity, and hyperalgesia, as well as stimuli of central origin, may all have a role in generating symptoms in functional bowel disease and are likely to interact.

Sensitization of visceral afferents by local inflammation, leading to hyperalgesia, may explain some functional bowel disorders.

Interventions targeted at serotonin, NK, CCK, and opioid receptors appear to provide the most immediate promise for clinical application in functional bowel disorders.

Reference

1.      Bueno L. New and future drugs in nerve-gut dysfunctions. State-of-the-Art Lecture. Program and abstracts of the 7th United European Gastroenterology Week; November 13-17, 1999; Rome, Italy.

 

INFLUENZA A VIRUS A, 1918 STRAIN DETECTED AGAIN - NORWAY

A  pro MED- mail post

Date: Thu, 16 Dec 1999

From: Marjorie P.Pollack

< pollackmp@mindspring.com>

 Source: M2 Communications, 16 Dec 1999

[ edited]

Frozen bodies on Spitsbergen, Norway found to contain 1920s virus.

 

British scientists have managed to isolate the virus behind the 1918 influenza. The virus was isolated from the bodies of victims that had been buried in the eternal frost on Spitsbergen, Norway. Traces of the virus were  also found in the brains of the dead, which may eventually give a link between the influenza and "sleepy sickness", encephalitis lethargica, a disease that put the sufferers into long - lasting comas in the 1920s, researchers hope. The victims were coal miners and researchers had been hoping that the frozen state of the bodies would have also preserved the virus.

 

 

In order to get PCR positives from old and possibly degraded tissues the labs may sequence short genome segments. By sequencing multiple different short sequences they can try tro reconstruct what the whole genome, or just the HA ( hemagglutinin) gene, looks like.

 

The reason all of  this is important is that it holds the secret to whatever it was about the 1918 virus that made it so deadly. So far no one has reported anything that would suggest a virulence mutation, but it is hoped that the key to what happened in 1918 lies somewhere in the sequence of the HA, and/or in any of the other 7 influenza virus genome segments.

 

[David Moren, M.D., Influenza Rapporteur NIAID. National Institutes of Health, USA e-mail: DMORENS@niaid.nih.gov]

 

FOOD FOR THOUGHT:

Living

A person asked God, "What surprises you most about mankind? "God answered, "They lose their health to make money and then lose their money to restore their health. By thinking anxiously about the future, they forget the present, such that they live neither for the present nor the future. They live as though they will never die, and they die as if they had never lived." 

Footprints

            A person died and went to Heaven. When he met God, he was shown his whole life in retrospect. There were two sets of footprints on some stretches and only one in some. He asked God if the second set of footprints were his. God replied that they were. Puzzled, he said, "Those stretches with only one set were the most difficult in my life. Why did you desert me then?". God replied, "Those were my footprints, Son. In your times of trouble, I was carrying you".

           

  SMILE AND THE WORLD SMILES WITH YOU

A short history of Medicine

"Doctor, I have an ear ache."

2000 B.C. - "Here, eat this root."

1000 B.C. - "That root is heathen, say this prayer."

1850 A.D. - "That prayer is superstition, drink this potion."

1940 A.D. - "That potion is snake oil, swallow this pill."

1985 A.D. - "That pill is ineffective, take this antibiotic."

2000 A.D. - "That antibiotic is artificial. Here, eat this root! 

Models

A doctor said to his car mechanic, "Your debit is several times more per hour then we get paid for medical care."

"Yeah, but you see, doc, you have always had  the same model. It hasn't changed since Adam; but we have to keep up- to - date with

new models coming every year."

 

Communication Breakdown

A fellow walked into a doctor's office and the receptionist asked him what he had.

He said, "Shingles." So she took down his name, address, medical insurance number and told him to have a seat.

 

A few minutes later a nurse's aide came out and asked him what he had. He said, "Shingles." So she took down his height, weight, a complete medical history and told him to wait in the examining room.

 

Ten minutes later a nurse came in and asked him what he had. He said, "Shingles."

So she gave him a blood test, a blood pressure test, an electrocardiogram, told him to take off all his clothes and wait for the doctor.

 

Fifteen minutes later the doctor came in and asked him what he had. He said, "Shingles."

The doctor said, "Where?" He said, "Outside in the truck. Where do you want them?"