Issue 19 by The Meducator

March 2011 | Issue 19 | www.meducator.org

Gut Bacteria: Friend or Foe? Probiotics as an Emerging Treatment for Gastrointestinal Diseases

To Mix and Match: Searching for Drug Combinations against p. aeruginosa Highlighting the High Throughout Screening Lab in McMasterâ&#x20AC;&#x2122;s Centre for Microbial Chemical Biology

interview: Dr. Salim Yusuf Taking Cardiovascular Research to a Global Level

The McMaster Health Forum: Evidence >> Insight >> Action

Towards a Canadian Response to Emerging Global Health Issues

issue 19 | March 2011 LETTER FROM THE EDITOR

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MEDBULLETINS

FEATURE McMASTER HEALTH FORUM:

Towards a Canadian Response to Emerging Global Health Issues by Ahmad AlKhatib & Theresa Tang

A Probiotic Modulator of Gastrointestinal Motility

by Richard You Wu

Combinations of Previously-Approved Drugs Targeting Pseudomonas aeruginosa Development

by Alexander Leung

INTERVIEW with Dr. Salim Yusuf

President Ahmad AlKhatib Vice-President Hiten Naik Editorial Board Khaled Ramadan

Mohsin Ali Matthew Macdonald Matthew Chong Mustafa Ahmadzai Daniel Elbirt Charles Yin Shelly Chopra Vaibhav Mokashi

Graphics & Design Brian Chin

articles LACTOBACILLUS:

MEDUCATOR STAFF

Daniel Lee Lebei Pi Xena Li Ellen Liang

Web Directors Ijlal Syed Aashish Kalani Public Relations Sangeeta Sutradhar Louis Winston Paul Cheon Alyssa Cantarutti

ADDRESS

A Critical Look at Cardiovascular Disease by Jordan Campbell, Sheiry Dhillon, Caylea Foster & Hiten Naik

B.H.Sc. (Honours) Program The Meducator Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1200 Main Street West Hamilton, Ontario L8N 3Z5

the.meducator @learnlink.mcmaster.ca

ABOUT Us: Established in April 2002 with the support of the Bachelor of Health Sciences (Honours) Program (B.H.Sc.), The Meducator is McMaster Universityâ&#x20AC;&#x2122;s undergraduate health sciences publication. Through biyearly publications, a web page, and Facebook, we aim to provide an opportunity for undergraduate students to publish their work and share information with their peers. Our protocol strives to maintain the highest standard of academic integrity by having each article edited by a postgraduate in the relevant field. We invite you to offer us your feedback by writing to our email: the.meducator@learnlink.mcmaster.ca

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LETTER FROM THE EDITOR EVIDENCE >> INSIGHT >> ACTION This issue’s cover is a view of the McMaster Health Forum’s DialogueSpace, a state-of-the-art, multipurpose venue that supports collective problem solving (for a full view of the DialogueSpace, see page 11). The DialogueSpace hosts stakeholder dialogues, an innovative process developed by the Forum that marshals the best research evidence and convenes stakeholders for an off-the-record discussion on pressing health challenges. This approach aims to facilitate the integration of research evidence and the tacit knowledge, views and experiences of stakeholders towards generating unique insights that can inform future policies and actions. In this issue’s feature article, Theresa Tang and I discuss the Forum’s stakeholder dialogue on “health and emerging global issues”. It is expected that this dialogue will generate unique insights that can inform the development of Canadian global health policies. Photos of past and present leaders in Canadian healthcare are found on the wall of the DialogueSpace in the McMaster Health Forum. They serve to inspire stakeholders to make the difficult decisions demanded by current healthcare challenges. Our cover captures some of these photos, starting from left to right, Emily Stowe, first women to practice medicine in Canada; Oronhyatekha, first aboriginal Oxford scholar and second aboriginal physician in Canada; Boron Chisholm, first deputy minister of health in Canada and first director general of the World Health Organization; and John Evans, proponent of problem-based learning, which the Forum has extended into collective problem-solving. We chose to represent the McMaster Health Forum through these photos because they captured the spirit of the Forum’s mission: galvanizing our current healthcare leaders towards informed action. Our feature article is followed by an interview with McMaster’s renowned Dr. Salim Yusuf. Jordan Campbell, Sheiry Dhillon, Caylea Foster, and Hiten Naik sat down with Dr. Yusuf to discuss determinants of cardiovascular

disease in developing nations. The interview is followed by Alexander Leung’s Research Insight article on searching for novel therapies against the ubiquitous opportunistic pathogen, Pseudomonas aeruginosa. Leung describes the use of high throughput screening in identifying compounds that synergize with known antibiotics. Finally, Richard Wu’s Research Insight article discusses the physiological effects that Lactobacillus reuteri evoke on murine gastrointestinal motility. The central focus of his research is to characterize these effects to better understand the communication between beneficial gut microorganisms and the host nervous system. In closing this letter, I would like to extend my thanks towards The Meducator Team for their tireless work in implementing many of the changes that the publication has undergone over this last year. In particular, I would like to thank Brian Chin, Creative Director, for leading our Graphics & Design Team towards a complete redesign of the publication’s layout. I would also like to thank Ijlal Syed, Web Director, for launching a new website that contains a professional archive, which will serve to preserve The Meducator’s work in the coming years. I also extend thanks to Khaled Ramadan, Lead Senior Editor, for managing the Editorial Board towards a review of our content during this semester. Thanks are also extended to Sangeeta Sutradhar, Lead, Public Relations, for overseeing the successful marketing of the publication. Finally, I thank Hiten Naik, Vice-President, for his support and leadership during the year. I wish him good luck as he takes on the presidency for the 2011-12 term.

AHMAD ALKHATIB

President & Editor-in-Chief Bachelor of Health Sciences (Honours) Program, Class of 2012

The Meducator | March 2011

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MEDWIRES MEDWIRESare arebrief briefsummaries summariesofof are brief in summaries recent recent breakthroughs breakthroughs in health health science research and researchatatinMcMaster McMaster and ofscience recent breakthroughs health science around the world. aroundat the world. research McMaser and around the world.

medwires

New New DNA DNA sequencers sequencers track track DNA DNA polymerase polymerase asasit itadds addsfluorescent fluorescent bases toto synthesize DNA. bases synthesize DNA. Each Eachbase basecorresponds corresponds totoa adifferent differentcolour colourthat that flashes flasheswhen whenit itis isadded added into a DNA strand. into a DNA strand.

A Anovel novelimaging imagingagent, agent, florbetapir, florbetapir, may may allow allow scientists scientiststotodetermine determine whether whether dementia dementia is is caused caused byby Alzheimer’s Alzheimer’s disease diseaseand andmay mayhelp help diagnose diagnose Alzheimer’s Alzheimer’s before beforeonset onsetofofobvious obvious symptoms symptomssuch suchasasmemmemory loss. ory loss.

The recent suicide ofof footThe recent suicide footballer ballerDave DaveDuerson Duersonhas has brought broughtrenewed renewedattenattention tionononchronic chronictraumatic traumatic encephalopathy encephalopathy(CTE) (CTE)inin atheletes. atheletes.Duerson Duersonwilled willed that hishis brain bebe left toto the that brain left the NFL NFLBrain BrainBank Bankforforstudy. study. Scientists Scientists atat the the Brain Brain Bank Bankhope hopetotouse useDuerDuerson’s brain forfor research onon son’s brain research how toto identify CTE before how identify CTE before symptoms begin toto manisymptoms begin manifest. fest.

A Acure curetotodiabetes diabetesmay may lielieininharvesting harvestingsperspermatogonial matogonial stem stem cells. cells. These Thesecan canbebeconverted converted into into pluripotent pluripotent stem stem cells difcellsthat thatare areable abletotodif differentiate ferentiateinto intoany anycell cell type, and then implanted type, and then implanted inside insidepancreatic pancreaticislets islets where wherethey theydifferentiate differentiate into intothe theinsulin-producinsulin-producing islet cells ing islet cells

Researchers Researchershave havevisuvisualized alizedthe theB-adrenergic B-adrenergic receptor, receptor,a akey keytransport transport protein protein activated activated byby many many pharmaceuticals. pharmaceuticals. AnAnunderstanding understandingofofthe the structure structureofofthese theseproproteins teinswill willaid aidininthe thedisdiscovery coveryofofnew newdrugs drugsforfor heart and lung disease. heart and lung disease.

A Arecent recentstudy studyreveals reveals that thatfast fastfood foodconsumers consumers arearenot noteasily easilypersuaded persuaded toto change their high calochange their high calorieriechoices. choices.Researchers Researchers found foundnonodifferences differencesinin consumer preferences beconsumer preferences before foreand andafter afterthe thedisplay display ofofnutritional nutritionalinformation, information, thereby therebyhighlighting highlightingthe the addictive addictive properties properties ofof popular fast food items. popular fast food items.

A Avaccine vaccineforforthe thepneupneumococcal mococcalvirus viruswill willbebe released releasedsimultaneously simultaneously ininrich richand andpoor poorcouncountries trieswithout withoutthe the1515year year lag lagperiod periodthat thatdevelopdeveloping ingcountries countriesnormally normally experience. It It is is expected experience. expected totoprevent preventover over7 7million million deaths byby 2030 deaths 2030

Dr.Dr.Shannon ShannonDahl Dahland and her herteam teamhave havediscovdiscovered a novel technique ofof ered a novel technique synthesizing synthesizingblood bloodvesvessels selsforforbypass bypasssurgeries surgeries using donor cells instead using donor cells instead ofof the patient’s own cells. the patient’s own cells. This Thisenables enablesa awhole wholeli-library braryofofblood bloodvessels vesselstoto bebecreated createdand andused usedinin medicine onon demand. medicine demand.

AA single Daphnia, dubbed single Daphnia, dubbed “The “The Chosen Chosen One” One”byby the theresearchers researchersinvolved, involved, became becamethe thefirst firstcrustacrustacean ceantotohave haveitsitsgenome genome sequenced. sequenced. Shockingly, Shockingly, Daphnia Daphniahas hasa agenome genome 8,000 8,000genes geneslarger largerthan than our ourown. own.36% 36%ofofthese these genes areare uncharacterized genes uncharacterized and may bebe important forfor and may important the field ofof environmental the field environmental genetics. genetics.

Soft Softdrinks drinksacross acrossCanaCanadadawill willsoon soonbebesporting sporting a anew newlook. look.Under Underthe the newly newlydevised devisedClear Clearonon Calories Caloriesinitiative, initiative,major major beverage beveragemanufacturers manufacturers nationwide nationwidewill willbebepostposting ing calorie calorie counts counts onon their packaging. their packaging.

With Withananalready alreadymassive massive and ever-growing store ofof and ever-growing store knowledge knowledgeononstem stemcells, cells, scientists scientists have have begun begun exploring exploringtheir theirpotential potential usage usageininscreening screeningnew new drugs. ByBy harvesting stem drugs. harvesting stem cells from individuals who cells from individuals who suffer sufferfrom fromgenetic geneticdisdisease, researchers can now ease, researchers can now grow growselectively selectivelydefective defective tissues tissuesininvitro vitroforfortesting testing purposes. purposes.

AnAnenzyme, enzyme,protein proteinki-kinase MM (PKM), is is implicatnase (PKM), implicatededininlong-term long-termmemory memory formation formationand andmay maybebe used usedtototreat treatdiseases diseases where wherelong-term long-termmemmemory oryis islost. lost.Conversely, Conversely, blocking blockingPKM PKMmay mayallow allow sufferers sufferersofofPost PostTrauTraumatic matic Stress Stress Disorder Disorder totoovercome overcometraumatic traumatic memories. memories.

Oncology Oncologyhas hastaken takenananother othersmall smallstep stepforward forward today todaywith withthe thecharaccharacterization terizationofofthe theactivity activity ofofa anovel novelregulator regulatorofof cancer cancer development. development. SCF(FBW7) was shown toto SCF(FBW7) was shown induce the destruction ofof induce the destruction a akey keyprotein proteinassociated associated with the development ofof with the development several cancers. several cancers.

When When wewe see see people people move moveininways wayswewecannot, cannot, mirror mirrorneurons neuronsallow allowthe the brain toto imagine ourselves brain imagine ourselves performing performingthat thataction. action. Thereafter, Thereafter,the thebrain’s brain’sex-extrastriate body area allows trastriate body area allows usustotopredict predictthat thatthe theac-action is is indeed unrealistic. tion indeed unrealistic.

Genetically Genetically modified modified chickens chickens have have been been developed developedthat thatdodonot not transmit transmitthe theH5N1 H5N1strain strain ofof influenza influenza toto other other birds. birds. These These chickens chickens could could help help countries countries such suchasasEgypt Egyptand andIndoIndonesia where this strain ofof nesia where this strain influenza is is widespread influenza widespread

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Microbubbles are emerging as a promising way to treat neurodegenerative disease. This technique involves creating perforations in the blood-brain barrier using bubbles of gas. The result is a significant increase in the effectiveness of CNStargeted drugs

In 2007, Harvard researchers constructed a microchip that trapped cancer cells from blood samples. Johnson & Johnson has now teamed up with the researchers to further develop the chip for use as a cancer detector. If standardized as a blood test, this technique could increase the efficacy of cancer treatment and rate of recovery.

Scientists at Johns Hopkins University have discovered that pancreatic cancer appears almost 10 years after the first oncogenic mutations arise. This discovery challenges the belief that pancreatic cancers grow too quickly for screening to be effective.

Although often described as â&#x20AC;&#x153;putting a patient to sleep,â&#x20AC;? anaesthesia is, in reality, more similar to inducing a coma. The ethics behind anaesthetic procedures and the explanation offered to patients is currently under debate. Neuroscientists believe further research is required to model the nuances of the unconsciousness that develops.

During pregnancy, 10% of DNA found in the mother`s blood is from the fetus. Scientists have recently sequenced the first fetal genome, raising the possibility of noninvasive genome-wide screening for fetal genetic disorders.

A new study shows that groups of friends tend to be more genetically similar than average. However, the study only used 2 genes (DRD2 and CYP2A6) to test for similarity and hence, its validity is still questioned.

Researchers at Cornell University have developed a robot that uses a trial-and-error method to understand how its body was put together. This feature allows the robot to think for itself and adapt appropriately to novel situations. The ultimate aim is to elucidate how humans develop their sense of self-awareness.

Research at the US National Institute on Drug Abuse has implicated a group of neurons, the ventral medial prefrontal cortex (mPFC) neurons, in relapse to heroin addiction. Scientists found that reactivation of mPFC neurons after detox provoked drug-seeking behaviour in a rat model.

Scientists at the University of Tuebingen, Germany recently became the first to partially restore eyesight in humans using an artificial eye implanted subretinally. Although external cameras have been used to achieve similar results, the subretinal approach requires less processing of received images.

Many observational studies demonstrate a link between high vitamin D intake and reduced risk of chronic disease. However, upon review of randomized controlled trials, the Institute of Medicine has advised physicians that vitamin D supplements are unnecessary and potentially detrimental to oneâ&#x20AC;&#x2122;s health.

The perceived value of empathy in patient-doctor communication has led to the development of courses that attempt to teach empathy to medical residents. However, a recent ethics research paper suggests that the importance of empathy is simply assumed and that it is not a necessary component of good medical practice.

Research into adult stem cells has recently suffered a setback. Adult stem cells have been found to differ in DNA methylation patterns compared to their embryonic counterparts, indicating that they may not be suitable for modelling or treating disease.

In a recent study on voting behaviours, researchers found that students who conversed with volunteers that mimicked their body language were more likely to vote for a leftist party if an election was held at that moment. These findings suggest imitation may initiate feelings of empathy and compassion, resulting in a prosocial viewpoint.

The protein hormone, insulin-like growth factor II (IGF-II), has been shown to enhance memories and memory retention when injected into the hippocampus of rats, highlighting the key role of IGF-II in memory processes.

The season in which a baby is born may have a bearing on their lifelong health. Mouse pups raised in winter sunlight conditions developed defective biological clocks. In humans this could translate into disorders such as schizophrenia or depression

The Meducator | March 2011

MedBulletin

A PAPER CUT THAT COULD CAUSE CANCER

THE ROLE OF RHO-KINASE SIGNALLING IN OBESITY Shelly Chopra

Vaibhav Mokashi

t is widely known that chronic wounding or burn sites on the skin have been associated with tumours such as the Marjolin’s ulcer or “kangri cancer”. However, the possibility of mutated cells migrating to the skin’s surface and causing cancer was not considered.1

Wong and Reiter studied a mouse model for basal cell carcinoma, a common type of skin cancer that is associated with mutations in an oncogene called Smoothened one batch of mice, the mutated oncogene was activated but this alone did not increase the rate of cancer. However, in the second group, the mutated oncogene was activated and then a wound the size of a paper cut was made by removing a small piece of skin from the mice’s back. Wong and Reiter found that in the second batch of mice, stem cells with the mutated genes remained near the follicles in the lower layer of skin until the mice were wounded. Once injured, the mutated stem cells migrated to the upper layers in an attempt to fix the damage. Due to the mutation, the stem cells actually activated a biochemical pathway associated with carcinoma rather than healing the tiny wound.2 In conclusion, the study provides evidence in favour of an important principle movement of cells with oncogenic mutations to sites that are susceptible to cancer can lead to tumour formation.1

besity is characterized by a dependence on excessive consumption to fulfill one’s daily needs. This dependence has been attributed to a variety of factors that range from low testosterone levels to a reduced neural sensitivity to the taste of food. In a recent study, Hara et al. investigated another propagating factor in obesity: activation of the Rho to Rho-kinase signalling pathway.1 Excess energy is stored in lipid form in adipocytes, fat cells, in the body. A distinct property of adipocytes is their ability to stretch to contain greater quantities of fat. This expansion, known as hypertrophy, causes structural changes and activates inflammatory signalling pathways— both of which contribute to weight gain.

Rho-kinase signalling regulates vascular smooth muscle contraction and has been shown to activate during mechanical stress in the cardiovascular system.2 As adipocytes also undergo physical stress, Hara et al. hypothesized that Rho-kinase signalling is activated during hypertrophy and thus participates in the progression of obesity. In the study, mice on a high-fat diet developed significantly larger adipocytes in comparison to mice on a low-fat diet. This hypertrophy led to greater lipid storage, inflammation, and stress fibre formation. Treatment with fasudil, a Rho-kinase inhibitor, resulted in decreased weight gain, demonstrating the role of Rho-kinase signalling in fat accumulation. This finding was confirmed in subsequent in vitro cultures where manual stretching of adipocytes upregulated Rho-kinase activity. The study suggests that activation of the Rho-Rho-kinase pathway stimulates increased lipid storage and thus contributes to the development of obesity. Further research on Rho-kinase inhibitors, such as fasduil, may elucidate their potential as therapeutic agents in overcoming obesity.

Hara Y, Wakino S, Tanabe Y, Saito M, Tokuyama H, Washida N, et al. Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch. Sci Signal 2011 January 25; 4(157):3. 2 Numaguchi K, Eguchi S, Yamakawa T, Motley ED, Inagami T. Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments. Circ Res 1999; 85(1):5-11. 1

Hayden E. Mutant stem cells can cause skin cancer at cuts. Nature News [Internet]. 14 February 2011. Available from: http://www.nature.com/news/2011/110214/full/news.2011.91.html. 2 Wong SY, Reiter JF. Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl Acad. Sci. USA 2011; doi: 10.1078/pnas.1013098108. 1

Charles Yin

recent study conducted by researchers at the University of Michigan and University of California, Irvine reported the discovery of an alternate functional form of DNA.1 Hoogsteen base pairing was found to occur in actively transcribing DNA 1% of the time, inducing a change in its structure.1

Hoogsteen base pairing was discovered by German chemist Karst Hoogsteen in 1963.2 Hoogsteen observed that in a solution of heated adenine and thymine, a different nitrogen atom is utilized by adenine as its hydrogen bond acceptor.2 An implication of this discovery is the possibility of triplex or even quadruplex DNA helixes, since each base could form hydrogen bonds to two other complementary bases. Previously, this phenomenon has only been observed in RNA and damaged DNA.1 The formation of a triple helix has interesting implications for the treatment of genetic disease. Several studies have investigated the potential of using a triplexforming oligonucleotide (TFO) in anti-gene silencing.3 The binding of TFO’s interferes with transcription factor binding and the formation of initiation complexes, down-regulating gene expression. There is also interest in transcription-TFO duplexes that can potentially be used to up-regulate expression of genes normally depressed in disease.3 The discovery of Hoogsteen base pairing in functional DNA is an indicator that anti-gene therapy holds considerable promise in the treatment of genetic disease.

Nikolova EN, Euane K, Wise AA, O’Brien PJ, Andricioaei I, Al-Hashimi HM. Transient Hoogsteen base pairs in canonical duplex DNA. Nature 2011; doi:10.1038/nature09775. Nelson DL and Cox MM. Lehninger Principles of Biochemistry. 4th ed. New York: W.H. Freeman; 2004. 3 Hélène C. The anti-gene strategy: control of gene expression by triplex-forming-oligonucleotides. Anticancer Drug Design 1991; 6(6): 569-584.

Vaibhav Mokashi

MedBulletin

HOOGSTEEN BASE PAIRING BIOTECHNOLOGY: IN GENE THERAPY BLOOD VESSEL SYNTHESIS

atients with arterial diseases are usually treated with bypass surgeries in which blood vessels which have narrowed are closed off and an alternative route for blood flow is provided by implanting another vessel. However, harvesting another compatible blood vessel can be difficult. The best alternative so far involves using the patient’s own cells to develop vessels but these take up to 9 months to grow and cost over $15000.1 Shannon Dahl, cofounder of the biotechnology firm, Humacyte, has developed a novel technique for bioengineering veins from donor cells. Donor cells are placed into scaffolds of polyglycolic acid and grown in a bioreactor. Once grown, cellular material attached to the blood vessels is removed using special detergents resulting in collagen tubes that are unlikely to be rejected by the patient’s immune system. This technique allows 37 large or 74 smaller artificial blood vessels to be developed per donor in a shorter period of time. Also, because the technology does not depend on the patient’s own cells, a large bank of vessels ca n be developed and used on demand.2 Furthermore, the durability of these blood vessels has been tested and proven on animal models. When the vessels were transplanted into baboons, they continued to function 6 months after implantation. The vessels were also successfully implanted in dogs, however, the dogs’ own endothelial cells were required when it came to developing very small blood vessels.2 In conclusion, Dahl’s artificial blood vessels may become extremely useful in bypass surgeries that require larger blood vessels once their long term stability is confirmed.2

O’Callaghan T. Options for off-the-shelf blood vessels expand. Nature News [Internet]. 2 February 2011. Available from: http://www.nature.com/news/2011/110202/full/news.2011.66.html. Dahl S. et al. Readily Available Tissue-Engineered Vascular Grafts. Science Translational Medicine 2011; 3(68):68ra9.

The Meducator | March 2011

MedBulletin

HERBAL MEDICINE INDUCTION OF DEPRESSION REDUCES CHEMO TOXICITY THROUGH INFLAMMATION Charles Yin

Shelly Chopra

Unlike many other drugs that target chemotherapy toxicity, PHY906 has been found highly effective in relieving gastrointestinal malfunction. Lam et al. tested PHY906 on tumor-bearing mice that were also administered irinotecan. Researchers found that PHY906’s positive effects were not limited to the regeneration of cells harmed by irinotecan. The herbal mixture also improved irinotecan’s inhibitory action in reducing tumor growth and prevented rapid decreases in body weight, another side effect of the cancer treatment.1

In 2009, O’Connor et al.2 described the absence of depressive behavior in response to severe bacterial infection in mice deficient in a critical cytokine (signaling molecules used by the immune system to mediate immune response). This cytokine was also found to be expressed at greater levels in mice that do suffer from depression. It was a connection that nobody expected. It is difficult to envision that the immune system could play such a critical role in the maintenance of the nervous system, but connections like this one may be more common than researchers previously expected. In fact, a recent discovery found that patients with chronic depression who are unresponsive to traditional anti-depressants exhibit higher levels of inflammation. The inhibition of cytokines associated with inflammation was observed to help alleviate depressive symptoms in these patients.1

hile chemotherapy has undoubtedly helped millions of cancer patients overcome their condition, the side effects of anticancer drugs often pose a hindrance to a patient’s quality of life during the treatment period. In a recent study, Lam et al. tested the effects of PHY906, a herbal medicine extract, on the reduction of gastrointestinal irritation produced by DNA topoisomerase inhibitor, irinotecan.1 This inhibitor, involved in the treatment of colon cancer, is responsible for minor side effects such as diarrhea and nausea, as well as more severe effects such as intestinal bleeding.

Lam et al. also investigated the mechanism by which PHY906 attenuated the inflammation caused by irinotecan. Decreased infiltration of neutrophils and macrophages—key cells involved in inflammatory responses —was found in the intestines of PHY906 treated rats.1 Furthermore, PHY906 inhibited the effects of secondary messengers necessary for the onset of inflammation. In a period of incessant biomedical advancement where pharmacological research has taken precedence over traditional remedies, this study evidences the potential of natural substances in counteracting chemotherapeutic drug toxicity.

n recent years, researchers in the fields of immunology and psychiatry have begun to notice a startling trend: patients with chronic inflammatory disorders reported being afflicted with depression, bipolar disorder, and other psychiatric conditions in abnormally high numbers.1

The discovery of such links has generated renewed public interest in an interdisciplinary field of study, aptly if unimaginatively, named ‘psychoneuroimmunology’. Dr. Andrew Miller, professor of psychiatry and behavioural sciences at Emory University School of Medicine, is optimistic about the future of this field. According to Miller, there are still a lot of unknowns in the nervous system and psychoneuroimmunology may hold the key in shedding some light into those dark corners of the human brain.1

Harmon K. (2010). Some depression might have roots in immune-generated inflammation. Scientific American. Available at:http://www.scientificamerican.com/blog/post.cfm?id=some-depression-mighthave-roots-in-2010-10-28 [Accessed October 31, 2010]. 2 O’Connor JC et. al. (2009). Interferon-y and tumor necrosis factor-a mediate the upregulations of indoleamine 2,3-dioxygenase and the induction of depressive-like behaviour in mice in response to Bacillus Calmette-Guerin. J of Neurosci, 29(13), 4200-9. Available at: http://www.jneurosci.org/cgi/reprint/29/13/4200 [Accessed October 31, 2010]. 1

Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, et al. (2010). The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Science translational medicine, 2(45), Available from: http://stm.sciencemag.org/content/2/45/45ra59.abstract. [Accessed 29 October 2010]. 1

A NOVEL NANO-THERAPY FOR TUBERCULOSIS

Hiten Naik

he field of rehabilitation therapy has been transformed with the advent of new technologies such as radiation-based treatments. But are these therapies actually superior to tried-and-true methods?

A team of researchers at Leeds University conducted a study which looked at the use of low dose ultrasound to treat leg ulcers. The ultrasound approach has become a popular rehabilitation strategy in many hospitals and the authors sought to determine if it was as effective as traditional protocols. A total of 337 patients with leg ulcers were studied for 12 weeks each. Patients that received ultrasound in addition to dressings and compression therapy were compared to those that only received standard care.1 After five years of research, the results of the study were somewhat surprising. It was found that the ultrasound technology did not the speed of healing, prevent the ulcers from returning or even improve quality of life of rehabilitating patients.1 Instead, the most effective means to aid healing was through promotion of a good diet and exercise.1 The authors commented that what ultimately aids in ulcer healing is the increased flow of blood up the legs and to the heart. Thus, according to lead researcher Dr. Andrea Nelson, a “really healthy chuckle” can help aid the process, as laughing causes increased diaphragm activity which in turn potentiates the flow of blood throughout the body.2 Indeed, laughter sometimes is the best medicine.

Watson, JM, Kang’omb, AR, Soares, MO, Chuang, LH, Worthy, G., Bland, JM., Iglesias, C., Cullum, N., Torgerson, D., Nelson, EA. Use of weekly, low dose, high frequency ultrasound for hard to heal venous leg ulcers: the VenUS III randomized controlled trial. BMJ. 2011. 2 BBC News. Laughing ‘better than latest technology for leg ulcers’ [online] Available at: http://www.bbc. co.uk/news/health-12699016.

Vaibhav Mokashi

MedBulletin

TRADITIONAL REHAB GETS THE LAST LAUGH

uberculosis (TB) is caused by inhalation of airborne particles containing Mycobacterium tuberculosis, which subsequently infiltrate the immune system to give rise to a productive cough, fever and lethargy. Antibiotics against TB have become ineffective due to the emergence of multiple strains of drug resistant M. tuberculosis. Consequently, a novel therapy is being developed that involves oral or aerosol administration of antibiotics encapsulated in nanobeads.1

Nanobeads consist of a polymer membrane that protects commonly used anti-TB drugs such as isoniazid and rifampin. Once nanobeads enter the body, they are actively transported across the epithelial layer of the lungs and are taken up by macrophages, the cells principally infected with and harboring M. tuberculosis. Macrophages engulf nanobeads through phagocytosis. The nanobeads then enter a phagolysosome, a digestive organelle within macrophages. The acidic environment of the phagolysosome catalyzes the breakdown of the polymer coating the nanobeads, thus releasing active drug to combat invading bacteria.1 Interestingly, animal trials found that three oral doses of nanotherapy were as effective as 45 doses of traditionally administered antibiotic treatments.1 Based on these results, this new technology may greatly reduce the dosing frequency for patients, as well as the possibility of reoccurrence due to drug resistance. Furthermore, since the nanotherapy mainly targets infected cells, it enables administration of more toxic drugs without significant damage to healthy cells. Moreover, nanobead encapsulation does not decrease the shelf life or efficacy of antibiotics.1 Overall, this newfound nanotherapy has the potential to revolutionize treatment for TB, a disease that claims 1.8 million lives a year.

Griffiths G, Nyström B, Sable SB, & Khuller GK. (2010). Nanobead-based interventions for the treatment and prevention of tuberculosis. Nature Reviews Microbiology, 8, 827-834. Available from: doi:10.1038/nrmicro2437 [Accessed 23rd October 2010].

The Meducator | March 2011

McMaster Health Forum: Towards a Canadian Response to Emerging Global Health Issues Ahmad AlKhatib Bachelor of Health Sciences (Honours) Program, Class of 2012 Theresa Tang Bachelor of Health Sciences (Honours) Program, Class of 2011 Health is now truly global. Health crises in one part of the world can affect the health of people everywhere. Governments around the world are increasingly recognizing the importance of acting upon global health issues as a means of protecting national health security. They have begun to invest in the necessary governmental infrastructure and domestic partnerships needed to coordinate a national response to address global health issues. Norway, Switzerland and the United Kingdom, among others, have now developed national global health strategies that articulate national global health objectives and the means by which government agencies and departments can cooperate towards achieving them. Canada has not yet developed anything similar; its efforts to address global health issues remain largely uncoordinated and reactive. Ahmad AlKhatib and Theresa Tang, McMaster Health Forum Fellows (2010-11), discuss the Forum’s planned stakeholder dialogue on“health and emerging global issues”– a key first step in the development of an evidence-informed Canadian response to emerging global health issues.

uring the writing of the World Health Organization’s ated with unhealthy diets, tobacco products and sedentary work (WHO) constitution in 1947, Canadian delegate Brock Ch- – has led to a rise in chronic diseases in many poor countries (For isholm argued for broad and inclusive membership in the organi- more on the global rise in cardiovascular diseases, read The Meducator’s interview with Dr. Salim Yusuf, p. X-X).[2,4] The global zation, stating: rise in both infectious and chronic illnesses has had a disruptive We cannot afford to have gaps in the fence against disease; impact on state capacity in underdeveloped countries.[2] This has and any country, no matter what its political attitudes or affiliaweakened healthcare services, disrupting these nations’ already tions are, can be a serious detriment to the effectiveness of the weak capacity to respond to internal health threats, as well as World Health Organization if it is left outside. It is important those that are transnational in nature.[4] A decline in state capacity that health should be regarded as a world-wide question, quite can also progress to state failure, which can spark national and independent of political attitudes in any country in the world.[1] regional conflicts, which in turn pose an obvious threat to global health.[4] Chisholm’s view of health as a “world-wide” issue underpins global health, the field of study and practise that works toward As Table 1 shows, global health is also affected by determinants the establishment of health equity among all nations.[2] As Ch- outside of the traditional health realm.[2] The increasing level of isholm suggests, such an objective requires global cooperation. international travel has the capacity to perpetuate the spread of Cooperation is needed because, as Chisholm exemplifies through infectious disease and elements of the “western lifestyle” associthe example of infectious diseases, numerous determinants of ated with chronic illnesses.[4] Drastic changes in the environment health are transnational – by virtue of their nature, they do not due to climate change may have consequences for the living conrespect national borders.[2] Within this context, health becomes a ditions of people everywhere.[4] The migration of health workers global problem. Its absence in one part of the world – “gaps in from developing to developed countries weakens health systems the fence” – affects the health of people everywhere.[3] As such, in origin countries. Bioterrorism has the capacity to inflict harm the status of public health in any one nation becomes intertwined on a large number of people around the world.[4] The internawith the status of “global health”.[3] tional trade of foodstuffs and other goods carries safety risks.[4] Finally, the international laws and policies pursued by national governments, international governing bodies, civil society groups, TRANSNATIONAL DETERMINANTS professional associations, global action networks, and public-priOF HEALTH vate partnerships – actors in the realm of global governance – will have an impact on global health.[4] Many determinants of public health (see “health issues” in Table 1) have transnational features that influence their capacity to im- The process of globalization has increased the interdependence pact global health. Infectious diseases, as illustrated by the recent between nations and thus has augmented the impact of transnacases of SARS and H1N1 influenza pandemic, are clearly global tional determinants of health.[6] As a result of rapid increases in by virtue of their communicable nature.[4,5] However, chronic ill- the speed of travel and communication, economic interdepennesses, such as cancer, diabetes and heart disease, also have trans- dence through trade, and international institutions, nations are national features.[2,4] The export of a “western lifestyle” – associ- far more connected and interdependent than ever before.[2,7] This

Issues traditionally addressed by health decision-makers (“health issues”)

Issues not traditionally addressed by health decision-makers (“non-health issues”)

Anti-microbial and anti-viral resistance: Theriskofbeinginfectedwithdrug-resistantstrainsofbacterioaorviruseshas increased with the global rise in anti-microbial and anti-viral resistance.

International travel and health: Canadiansmade7.4millionovernighttripsoverseasin2007.Thishighlevel of international travel carries the risk of increasing the spread of infectious diseases.

Cross-border transmission of infectious disease: The risk of a global pandemic is a direct threat to the health of Canadians, aswellasanindirectthreatthroughthepotentialforlarge-scaleeconomic impacts.

Climate change: Theimpactofclimatechangeonhumanhealthwillvarybasedonthenature of a region’s geography.

Obesity, diets, and chronic diseases: TheexportoftheWesternlifestyle,associatedwithunhealthydiets,tobacco productsandsedentarywork,hasledtoariseinobesityandchronicdiseases amid many developing countries.

Migration: ThemigrationofhealthworkersfromdevelopingcountriestoCanadacanhave negativeimpactsonthehealthsystemsofthedevelopingcountries,leadingto aweakeninginglobalhealth.However,ifhealthworkersreturntotheirorigin countriestocontributetheirlearnedskillsandknowledge,migrationcanalso have positive impacts.

HIV/AIDS, health systems in develping countries & national security: The spread of HIV/AIDS through a country will weaken states, leading to instabilityinregions,whichcanhaveconsequencesforCanadiannational security, through impacts on the global economy or global health.

Chemical, biological, nuclear and terrorist threats: Bioterrorism has the capacity to inflict harm on a large number of people around the world. Trade: Trade can have an impact on public health through various routes: -safetyrisksassociatedwiththecross-bordermovementoffood&othergoods - impact of greater economic integration on social determinants of health - impact of trade agreement on health systems, and - impact of trade agreements on intellectual property rights and access to medicines Global Governance: Therehasbeenarecentproliferationofinternationalactorsoperatinginthe global health sphere, both state and non-state (civil society organizations, professionalassociations,globalactionnetworksandpublic-privatepartnerships. Theinternationallawsandpoliciesthattheseactorsinfluence/adopttoaddress challenges will have both direct and indirect impacts on global health.

TABLE1: Emerging global health issues (adapted from Blouin (2009))[4]

has facilitated the world-wide spread of infectious and chronic diseases and increased the rate of health-worker migration.[5,7] Globalization has effectively deepened the extent of health interdependence between nations.[5,7] As such, globalization has arisen as a leading determinant of health.[5]

In recognition of this challenge faced by countries around the world, various governments – including Norway, Switzerland and the United Kingdom – have started to respond by developing national global health strategies.[8] These plans outline the government’s overarching objectives in global health, as well as specifying each department and agency’s role in achieving these goals.[5,8] NATIONAL GLOBAL HEALTH STRATEGIES The strategies also articulate the inter-departmental infrastructure needed to facilitate coordination, cooperation and collaboration In a globalized and interdependent world, where threats are trans- between the numerous government units involved in addressing national in nature, the state of global health has a direct influence global health challenges.[5] For example, the United Kingdom has on the state of public health in any one nation.[6] Within this con- developed an extensive global health strategy, in which it articutext, national governments are obliged to address global health lates five priority areas for government action: 1) better global challenges in order to protect their public health security.[6] This health security; 2) stronger, fairer and safer systems to deliver can be difficult – as outlined in the above discussion, global health health; 3) more effective international health organizations; 4) issues touch upon a wide breadth of issues.[5] As such, the policies stronger, freer and fairer trade for better health; and 5) the use of of numerous government departments and agencies can have a evidence to improve policy and practice.[5] bearing on global health, including departments of health, departments of food safety and consumer protection, development Canada currently lacks a coordinated response to global health agencies, research institutes, and the foreign service.[5,8] The list of issues. The Canadian response to global health challenges is fragstakeholders in Table 2 shows the wide breadth of actors within mented and uncoordinated; each governmental department and the Canadian government whose actions affect global health and agency (see “policymakers” in Table 2) addresses global health the health of Canadians. This multiplicity of stakeholders poses issues without an overarching cross-government objective.[5] Rea challenge for establishing a coordinated national strategy for sponding to this challenge, the McMaster Health Forum is planning responding to global health concerns.[8] a stakeholder dialogue on “health and emerging global issues.”

Research Insight

The Meducator | March 2011

Category of Stakeholder

“Health-related” stakeholder groups

“Non-health related” stakeholder groups

Policymakers

- Canadian Institutes for Health Research - Health Canada Health Products and Food Branch - Health Council of Canada - International Development Research Centre - Public Health Agency of Canada Disease Prevention Branch

- Agriculture and Agri-Food Canada - Canadian Food Inspection Agency - Department of National Defence - Environment Canada - Industry Canada - Public Safety Canada - Prime Minister’s Office

Leader/member of civil society

- Canadian Cancer Society -CanadianCoalitionforGlobalHealthResearch - Canadian Public Health Association - Canadian Society for International Health

-ActionCanadaforPopulation&Development - Canadian Bureau for International Education - Canadian International Council - CUSO-VSO

Staff/member of a health provider association or group

-CanadianAssociationforInternationalNursing - Canadian Medical Association - Canadian Nurse’s Association

Staff of a biotechnology or other private sector company

- Apotex Inc. - BIOTECanada - Pfizer Canada

- Campbell Company of Canada - Danone Canada - Desjardins Group

Researchers in a university in the jurisdiction

- Universite Laval Centre de Recherche en Infectiologie - University of Toronto Centre for Global eHealth Innovation - WHO Collaborating Centre for Emerging & Zoonotic Diseases Detection, Diagnostics, Reference and Research

- Canadian Agri-Food Policy Institute - Carelton University Norman Paterson School of International Affairs - McGill University Desautels Faculty of Management - University of Toronto Munk School of Global Affairs

N.A.

TABLE 2: Examples of actors operating in the Canadian global health sphere

and circulate a concise, plain-language issue brief that draws on the best available research evidence to define the challenges facing Canada and its domestic partners, as well as to identify and A stakeholder dialogue is an innovative process developed by the characterize possible policy and program options for meeting this McMaster Health Forum that marshals research evidence and challenge. The Forum will then convene a day-long meeting that brings together relevant stakeholders for an off-the-record dis- provides 18-22 government officials, civil society leaders and recussion that will inform future actions and policies.[9] A typical searchers (representatives from some of the organizations listed dialogue involves representatives from government (policymak- in Table 2) with the opportunity to bring their tacit knowledge, ers), but also citizens, researchers, and leaders from civil society.[9] views and experiences to bear on the challenge. It is expected that Stakeholders outside of government are invited for the purpose the dialogue will facilitate the integration of evidence and stakeof bringing together multiple viewpoints on a problem, with the holder experience towards elucidating insights that can inform hope that these diverse perspectives can spark unique insights to- the development of Canadian global health policies. wards uncovering viable solutions to the health challenge.[9] Before the dialogue, the invited stakeholders are provided with an issue brief, which summarizes what is known about a problem and options for addressing it, using the best research evidence available.[9] Each dialogue is expected to generate insights derived from the creative interplay of the best available research evidence and the tacit knowledge, views and experiences of stakeholders involved in or affected by the health issue.[9] Stakeholder dialogues are conducted in the DialogueSpace, the Forum’s state-of-the-art dialogue facility (Figure 1).

STAKEHOLDER DIALOGUE ON HEALTH & EMERGING GLOBAL ISSUES

The purpose of the Forum’s dialogue on “health and emerging global issues” is to assist government officials and stakeholders who lead Canada’s global health efforts to develop their own policies that are rooted, from the very start, in the best available evidence and greatest possible range of insights from key stakeholders. In preparation for the dialogue, the Forum will prepare

FIGURE 1: DialogueSpace. The McMaster Health Forum’s dialogue facility

Reviewed by Steven J. Hoffman, M.A., J.D. Steven J. Hoffman works full-time for Gilbert’s LLP, an elite law firm specializing in intellectual property litigation and government relations for health-related industries. He is an adjunct faculty with the McMaster Health Forum, an Instructor with the Faculty of Health Sciences, McMaster University, and a Research Fellow with the Munk School of Global Affairs, University of Toronto. He teaches two undergraduate courses at McMaster University on global health advocacy (HTH SCI 4ZZ3) and global health governance (HTH SCI 4LD3). Steven previously worked for the World Health Organization in Geneva, Switzerland, where he managed the UN agency’s Global Programme on Interprofessional Education and Collaborative Practice. He also previously worked for the Ontario Ministry of Health and Long-Term Care and the WHO-based Alliance for Health Policy and Systems Research. He sits on the board of directors of the International Association for Interprofessional Education and Collaborative Practice, chairs that association’s Global Affairs Committee, and serves as an advisor to the Pan-American Health Organization’s Office of Caribbean Programme Coordination. He is currently guest editor on a series of papers for the Journal of Interprofessional Care on global health and development. Steven holds a Bachelor of Health Sciences from McMaster University, and both a Masters of Arts in political science and a Juris Doctor from the University of Toronto.

REFERENCES Sharp WR. The new World Health Organization. Journal of International Law. 1947; 41(3): pp. 509-530. 2 Koplan JP, Bond TC, Merson MH, Reddy KS, Rodriguez MH, Sewankambo NK, & Wasserheit JN. Towards a common definition of global health. Lancet. 2009; 373: pp. 1993-95. 3 Kirton J, Orbinski J, & Guebert J. The case for a global health strategy for Canada. Ottawa (ON): Strategic Policy Branch in the International Affairs Directorate of Health Canada; 2010 Mar. 49. 4 Blouin C. Review of emerging issues and trends affecting global health. Ottawa (ON): Health Canada; 2009 Feb. 41. 5 Percival V, & Blouin C. Canada, global health, and foreign policy: Muddling through is not good enough. Canadian Foreign Policy. 2009; 15(3): pp. 1-9. 6 Ministers of Foreign Affairs of Brazil, France, Indonesia, 1

Research Insight

Norway, Senegal, South Africa & Thailand. Oslo Ministerial Declaration – global health: a pressing foreign policy issue of our time. Lancet. 2007; 369: pp. 1373-78. 7 Blouin C, Foster J, & Labonte R. Canada’s foreign policy and health: Toward policy coherence. Ottawa (ON): Commission on the future of health care in Canada; 2002 Jun. 95. 8 Sridhar D. Foreign policy and global health: Country strategies. 9 McMaster Health Forum. Stakeholder Dialogue [internet]. [cited 2011 Feb 11]. Available from: http://www. mcmasterhealthforum.org/st_dialogues.php.

The Meducator | March 2011

Lactobacillus: A Probiotic Modulator of Gastrointestinal Motility Richard You Yu Bachelor of Health Sciences (Honours) Program, Class of 2012 Laboratory of Dr. Wolfgang Kunze, McMaster University Richard is a third year student in the Bachelor of Health Sciences (Honours) Program and a recipient of the Bachelor of Health Sciences Summer Research Scholarship. He spent his past summer researching the physiological effects that Lactobacillus reuteri evoke on murine gastrointestinal motility.The central focus of his research is to characterize these effectstobetterunderstandthecommunicationbetweenbeneficialgutmicroorganismsandthehostnervoussystem.

ithin the gastrointestinal (GI) tract lives a highly complex community of bacteria from over 1800 genera.[1,2] Many of these bacteria interact with each other and many are also classified as commensals, which can produce positive effects on the host organism.[1,2] Some common examples include strains of lactic acid bacteria that aid in the absorption of lactose for humans.[1,2] These beneficial species are often referred collectively to as “probiotics.” A vast majority of these probiotics are vital to human health. For instance, Escherichia coli found in the lower intestine produces Vitamin K2 that is essential for blood coagulation in humans. But more importantly, ongoing research has demonstrated that an imbalance of these commensal species in the GI tract, known medically as “dysbiosis”, is associated with various GI diseases, gut inflammation and many disorders that elicit visceral pain.[3] Therefore, further research on probiotics and the characterization of their physiological effects are a clinically relevant endeavor.

these experiments pave the way for the development of probiotics as a cheap, effective strategy to help treat various GI diseases.

METHODS

The experimental setup comprises of an ex vivo organ bath stimulation in conjunction with real-time pressure and video recordings of an intestinal segment isolated from mice. The concept of “ex vivo” refers to the conducting of experiments on tissues in heavily controlled artificial conditions outside of the organism’s body to better maintain the environmental variables.[10] This is important because it reduces the possibility for confounding and facilitates the elucidation of true cause-and-effect relationships. To this end, an organ bath setup achieves this because the tissue is submersed in a buffer solution, which maintains constant pH, osmolarity and electrolyte content. These conditions enable the tissue to carry out its natural activities as the researchers adDue to the potential to extend the clinical benefits of probiot- minister different chemicals to stimulate the tissue. In this case, ics, recent research has focused on the brain-gut axis (framework the ‘chemical’ is actually the probiotic L. reuteri, which will be of how the interaction of intestinal organs and brain modulates applied intraluminally (to the inner surfaces of the intestine) at organ behaviors) to explore how intestinal probiotic species com- various concentrations. Intraluminal pressure recording and video municate to the central nervous system.[4,5,6] Little is known about imaging will then be performed to analyse the tissue’s state of the method by which bacteria communicate with the host nervous intestinal motility. system, but preliminary evidence shows that probiotics may modulate the sensory neuron excitability(by reducing hyperpolarization) in the myenteric plexus, a network of nerves that innervates the intestines. This strongly suggests the possibility that these bacteria may signal to the central nervous system via a potent neuromodulator.[7] To further understand signaling between probiotics and the GI tract, our laboratory utilizes the common gut bacteria L. reuteri. Many lactobacillus strains, including L. reuteri, release gamma-aminobutyric acid (GABA)—a neurotransmitter normally produced by the human body known to be able to influence intestinal motility, anxiety and depression.[8,9] In addition to releasing GABA, L. reuteri also releases additional molecules that could potentially act as neuromodulators like carbohydrates, peptides or other neurotransmitters.[8,9] Thus, with L. reuteri as the focus of this research, this project seeks to characterize the probiotic’s effects on intestinal motility. We believe that this approach may help to elucidate some of the unknowns underlying the communication process between the enteric nervous system and probiotics. Any discoveries from

FIGURE 1: Spatiotemporal representation of jejunum contractility at different time points in the experiment. Figure 1A depicts the Motor Complexes(intestinalcontraction)at5-6minutesintotheexperiment,whereas Figure1BdepictstheMotorComplexesat90-91minutes.ThefrequencyandpatternofMotorComplexes(intestinalcontraction)remainssimilarfortheduration of the experiment.

FIGURE 2: Spatiotemporal representation of jejunum contractility with Krebs (left) and with L. reuteri administration (right). Administration of L. reuteri disrupts the pattern of MCs by reduces MC frequency and contractility (maximum height of the waves).

RESULTS

In addition to providing information about MC frequency, the imaging technique provides another useful measure to characterize the patterns of motility: rate of change in diameter. This measure looks at how fast the intestinal diameter at a specific location on the intestine reaches its minimum as it undergoes a propagating MC. Interestingly, remarkable decreases were observed in rate of the change of diameter following L. reuteri application, suggesting an altered mode of distension/contraction in the intestinal peristalsis.

L. reuteri reduces intraluminal pressure: During peristalsis, the intestine carries out alternating events of distension and contraction in order to facilitate the digestion and passage of food through the intestine. These regular contractions are known as motor complexes (MCs).[10,13] Experimentally, MCs can be identified through two approaches. The first being the rise in intraluminal pressure when a contraction is initiated (think of squeezing a tube that contains water), and the second being the decrease in diameter when a contraction occurs. Therefore, since MCs are The two pieces of information yielded by the imaging techneural-dependent events,[10,13] investigating their changes in re- nique—the MC frequency and rate of change of diameter—are sponse to L. reuteri helps us to understand how probiotics influ- represented graphically in Figure 3. Dose-response relationships were observed for both measures, and this further strengthens ence GI motility. the evidence for L. reuteri as the causative agent. Therefore, the Following the intraluminal application of L. reuteri, the average imaging results reinforce those from the pressure analysis by demintraluminal pressure of the intestinal MCs demonstrated robust onstrating that L. reuteri weakens the contractility of the intestine decreases in amplitudes in a concentration-dependent manner.[10] through weakened, infrequent, and slower MCs. This modulating effect on the pressure amplitudes was also accompanied by a decrease in MC frequency. These two findings reflect an overall diminished contractility of the intestine evoked by intraluminal L. reuteri administration, resulting in weakened and infrequent MCs.[10] Intestinal imaging shows that L. reuteri reduces the frequency and contractility of MCs: Despite these findings, one drawback to this technique is that the pressure is only recorded at one location along the intestine; thus, the pressure probe may easily pick up noises or sporadic contractile events that are not truly MCs. To account for this possibility, imaging was also conducted because it captures the changes in diameter of all positions along the intestine. This gives a better indication of which contractions are true MCs (which are represented by the light bands in Figure 1). Initial control recordings without L. reuteri were performed to determine the natural pattern of intestinal contraction (Figure 1), and it was observed that this natural pattern was consistent over the duration of the experiment. In agreement with the intraluminal pressure measurements, the imaging results reflect a similar relaxing effect of L. reuteri on intestinal motility as evidenced by the reduced frequency and contractility of MCs upon administration of the probiotic (Figure 2).

Research Insight

CONCLUSION Based on the present findings, L. reuteri can serve as a potent modulator of GI motility. The observed decreases in MC frequency, contractility and rate of change in diameter indicate that L. reuteri administration induces a moderation of peristalsis, which needs to be further characterized. These decreased effects were also dose-dependent in nature. Dose-dependent relationships are characteristic of ligand-receptor interactions, and as such, this suggests that probiotic to nervous system interactions occur at a molecular receptor level.[10] Consequently, this further extends our laboratory focus into L. reuteri conditioned media (the culture medium containing the microorganism’s secretion of proteins, cytokines, neurotransmitters and other chemicals), as it is plausible that the ligand responsible for these events may be secreted by the bacterium. These findings contribute to the scientific state of the art on multiple levels. They provide pioneering evidence of the possible therapeutic benefits of utilizing L. reuteri as drug substitutes or supplements to therapeutically affect patient intestinal motility. This is especially important given the present findings pertaining to L. reuteri’s relaxant effects on the gut, which may point to L. reuteri as a potential treatment to diseases involving

The Meducator | March 2011

100

% Response in MC Frequency

Percent Response in Rate of Change in Diameter

120

80 60 40 20 0

0 Control

MC Frequency

100

FIGURE 3: L. reuteri-induced changes in frequency and rate of change in diameter. Concentration-dependenteffects were seen in the reduction of the intestinal contractility as both frequency and the rate of diameter changes diminished.

80 60 40 20 0 Control

log [lactobacillus reuteri], M

log [lactobacillus reuteri]

hypermotility of the gut, such as ulcerative colitis, irritable bowel syndrome and inflammatory bowel disease.[11] These results further mount to the existing benefits of providing “living drugs” (probiotics) as therapy. This is a compelling approach since probiotic delivery removes the potential side-effects that drug-users would incur; they are easier and cheaper to culture than drug pharmaceuticals, and from a patient’s standpoint, they can be readily supplemented into patients’ diet (i.e. probiotic yogurts).[12] Hence, the rigorous investigation of probiotic effects and their mechanisms of action are paramount to the eventual advancements in treating human digestive diseases. However, before we progress

onto human applications, more detailed research on the nature of the neuromodulator and its human applicability is required before this work can lead to practical clinical trials for public usage. Regardless, the findings presented herein contribute to an emerging body of literature concerning the influence of L. reuteri on intestinal motility and sets an important stage for the development of probiotics as feasible alternatives to treat GI diseases. I would also like to thank Michael Pasyk for his assistance with performing the experiments discussed herein.

Reviewed by Dr. Wolfgang Kunze, Ph.D. Dr Wolfgang Kunze is an Associate Professor of Psychiatry at McMaster University. He obtained his PhD in Melbourne University, Melbourne, Australia. He is a biophysicist with a strong interest in electrophysiology, neuronal sensory processing and enteric nervous system function. Dr Kunze has supervised Richard in his laboratory for the past 2 years and wholeheartedly supports his projects.

REFERENCES Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol 2008; 24: pp. 4-10. 2 Kinross JM, von Roon AC, Holmes E, Darzi A, Nicholson JK. The human gut microbiome: implications for future health care. Curr Gastroenterol 2008; 10: pp. 396-40. 3 Tamboli CP, Neut C, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut 2004; 53: pp. 1-4. 4 Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009; 136: pp. 2003-2014. 5 Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J. Mood and gut feelings. Brain Behav Immun 2010: 24: pp. 9-16. 6 Forsythe P, Bienenstock J. Probiotics in Neurology and Psychiatry. In: Versalovic J, Wilson M. (eds.) Therapeutic Microbiology: Probiotics and Related Strategies. Herndon, VA: ASM Press; 2008. pp. 285-298. 7 Powley TL, Wang XY, Fox EA, Phillips RJ, Liu LW, Huizinga JD. Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus. Neurogastroenterol Motil 2008; 20: pp. 69-79. 1

Siragusa S, De Angelis M, Di Cagno R, Rizzello CG, Coda R, Gobbetti M. Synthesis of Gamma-aminobutyric acid (GABA) by lactic acid bacteria isolated from Italian cheese varieties. Appl Environ Microbiol 2007; 73: pp. 7283–7290. 9 Hayakawa K, Kimura M, Kasaha K, Matsumoto K, Sansawa H, Yamori Y. Effect of a Gamma-aminobutyric acid-enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats. Br J Nutr 2004; 92: pp. 411-417. 10 Wang BX, Mao YK, Diorio C, Pasyk M, Wu RY, Bienenstock J, Kunze WA. Luminal administration ex vivo of a live Lactobacillus species moderates mouse jejunal motility within minutes. FASEB J 2010; 24: pp. 4078-4088. 11 Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neutrogastroenterol 2011. Motil; 23(3): pp. 187-192. 12 Wilhelm SM, Brubaker CM, Varcak B, Kale-Pradhan PB. Effectiveness of probiotics in the treatment of irritable bowel syndrome. Pharmacotherapy 2008; 28(4): pp. 496-505. 13 Huizinga JD, Ambrous K, Der-Silaphet T. Co-operation between neural and myogenic mechanisms in the control of distension-induced peristalsis in the mouse intestine. J. Physiol 1998; 506: pp. 843-856. 8

Combinations of Previously-Approved Drugs Targeting Pseudomonas aeruginosa Development Alexander Leung Bachelor of Health Sciences (Honours) Program, Class of 2012 Laboratory of Dr. Eric Brown, McMaster University Alexander Leung is a third year student in the Biomedical Sciences Specialization of the Bachelor of Health Sciences (Honours) Program. Under the supervision of Dr. Eric Brown, Alexander has been searching for novel therapies against the ubiquitous opportunistic pathogen, Pseudomonas aeruginosa. Herein, he introduces the bacterium and provides a primer on antibiotics with a particular focus on those used to combat P. aeruginosa infections. The focus of his research, conducted at the High Throughput Screening Laboratory in McMaster’s Centre for Microbial ChemicalBiology,istoutilizehighthroughputscreeningtoidentifycompoundsthatsynergizewithknownantibiotics.

ultidrug resistant bacteria remain an under-recognized epi- floxacin with inhaled tobramycin or colistin.[9] The rationale for demic.[1] Indeed, the top three infectious diseases (septice- the use of antibiotic combinations is based largely on empirical mia, influenza and pneumonia) together account for over 100,000 success in therapy, particularly in preventing the emergence of deaths per year in the United States.[2] In light of increasing an- antibiotic resistance. With that, fresh approaches towards identibiotic resistance in bacteria[3] and the emergence of multidrug tifying antibacterial combinations beyond traditional antibiotic resistant pathogens like Pseudomonas aeruginosa,[1,4] the need combinations are worth investigating. For example, it is possible for new antibiotics is obvious. However, with reduced interest that combining non-antibiotic drugs with traditional antibiotics from pharmaceutical companies and the decade-long process of may produce a synergistic effect that is greater than the antibiotic securing drug regulatory approval, the antibiotic pipeline has run alone. Previously approved drugs are also have the benefit well dry.[1,3] characterized pharmacology and toxicology profiles, which greatly accelerates drug development timelines. Therefore, the stratAntibiotics are toxic compounds which kill or perturb the growth egy of discovering approved non-antibiotics which can augment of bacteria but not humans. This is achieved by targeting essen- the activity of conventional antibiotics against P. aeruginosa is a tial physiological and biochemical processes that are unique to practical approach in addressing the shortage of new treatments bacteria. In general, the different classes of antibiotics affect five for multi-drug resistant infections. major targets: the bacterial cell wall, the cell membrane, protein synthesis, DNA and RNA synthesis, and folic acid metabolism. For example, penicillins, cephalosporins and carbapenems are HIGH THROUGHPUT SCREENING AND THE SEARCH FOR NOVEL THERAPIES classified as β-lactam antibiotics, which kill by disrupting syntheAGAINST P. AERUGINOSA sis of the bacterial cell wall.[5] Resistance to antibiotics is a natural bacterial phenomenon that results from the evolutionary selective pressure that comes hand in hand with continued exposure to To rapidly generate the desired antibiotic/non-antibiotic comsuch compounds. Bacteria achieve antibiotic resistance through binations, a process known as screening was employed. First, a four general mechanisms: target modification, efflux, immunity diverse library of 2080 FDA-approved drugs (FAD) was assemand bypass, and enzyme-catalyzed destruction.[5] Hence, the use bled and 9 antibiotics (See Table 1), some of which are currently of antibiotics paradoxically accelerates its disuse.[1,3] For instance, prescribed to treat P. aeruginosa infections in cystic fibrosis paP. aeruginosa possess numerous families of efflux pumps with tients, were selected.[10] Using robots and liquid handling devices, overlapping substrate ranges that effectively pump out antibiot- aliquots of FAD compounds and antibiotic were dispensed into ics. In total, with insensitivity to almost all commercially available assay plates. This process was controlled by using custom protoantibiotics, P. aeruginosa is a particularly worrisome opportunistic cols at the High Throughput Screening Laboratory in McMaspathogen.[1,6,7] Indeed, P. aeruginosa lung infection is a common ter’s Centre for Microbial Chemical Biology. A fixed amount of nosocomial infection and a major cause of morbidity and mortal- P. aeruginosa (strain PA01) was then added into the assay plates ity in cystic fibrosis patients.[8] Pan-resistant strains of P. aerugi- and allowed to incubate overnight. A FAD compound would be nosa are becoming increasingly common in both the clinic and identified as a positive result or “hit” if in combination with an community, and the health hazard it presents is exacerbated by antibiotic there was significant planktonic growth inhibition of P. the lack of new antibiotics that would otherwise have the poten- aeruginosa after overnight incubation. tial to treat such infections for the next decade.[1,6] Screening the FAD library with 9 different antibiotics resulted in Treatment of P. aeruginosa infection in cystic fibrosis patients 607 unique hits for P. aeruginosa out of a possible 18720 (2080 often consists of combinations of antibiotics, such as oral cipro- FADs x 9 antibiotics) combinations. The list of hits was ranked

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The Meducator | March 2011

Antibiotic Ceftazidime

# of hits (out of 2080 per screen) 47

# of uninteresting compounds 47

# of Hits - # of uninteresting molecules 0

Cefuroxime

Ciprofloxacin

Clarithryomycin

Erythromycin

Meropenem

105

Piperacillin

Tetracycline

Tobramycin

607

548

59 (48 unique compounds)

Total

TABLE1:Summarystatisticsofthe9antibioticscreensperformed. Compoundsthatwereuninteresting(i.e.knownantimicrobialcompounds)wereexcludedfrom

according to their magnitude of effect on the viability of P. aeruginosa, and filtered for known antibacterial agents and other uninteresting compounds. In total, 48 unique and unexpected FADs that potentiated growth inhibition of P. aeruginosa were identified, of which 7 were selected based on immediate availability and function for further experimentation (See Table 2). The study then focused on 2 non-antibiotic FADs, 2-aminoheptane (2AH) and ticlopidine. Both compounds were observed to increase the antibacterial activities of certain known antibiotics, an effect known as synergy. This synergy was validated by growth recovery and other experiments which demonstrated growth inhibition of PA01 in combination with sub-lethal concentrations of antibiotics (See Figure 1). However, the synergy was limited to P. aeruginosa. Ticlopidine, an ADP receptor agonist used to decrease platelet aggregation and thrombotic events,[11] possessed anti-Pseudomonal activity in combination with cefuroxime, a 2nd generation cephalosporin which P. aeruginosa is clinically resistant.[12] Interestingly, 2AH, a nasal decongestant and vasoconstrictor[13] synergized with both ciprofloxacin and tetracycline, antibiotics which affect bacterial viability by inhibiting DNA and protein synthesis respectively.[5] Furthermore, P. aeruginosa is resistant to tetracycline.[14] The current results provide ample room for future exploration of the in vitro efficacy of the listed combinations. These include identifying the mechanism of action of the combination with a genome-scale collection of Escherichia coli deletion strains,[15] and further investigating the synergy of the 46 other FADs which were filtered out during analysis. From there, in vivo activity of drug combinations should also be tested in mouse models. The screening could also be expanded to include additional antibiotics and FADs which are not presently included. Altogether, the systematic combination of FADs and antibiotics may prove to be useful in the search for new drug regimens against P. aeruginosa. By combining FADs and antibiotics in their screening process, researchers achieve a level of diversity that far exceeds the range of compounds explored by even the biggest

2-Aminoheptane

further analysis.

Ciprofloxacin FIGURE 1: Representative checkerboard from a synergy experiment.

Themapshowsthecombinedeffectof2-aminoheptaneandciprofloxacininan 8x8matrix.Eachsquarerepresentsadifferentconcentrationof2-aminoheptane andciprofloxacin(includingazeroconcentrationpoint,bottom-leftdarkblue square)each.Theabsenceofcolorinasquareindicatesahigherlevelofgrowth inhibition.

pharmceutical companies in their search for single agents.[1] Since the pharmacology and toxicology profiles of FADs have been well characterized, the unfavourable economics associated with antibiotic development can be ameliorated.[1,3,5] The surprising combinations of drugs that were identified can potentially give rise to novel multi-component therapies in the treatment of diseases like cystic fibrosis.

Compound

Antibiotic

Function of Compound

2-Aminoheptane

Ciprofloxacin

Nasal decongestant

2-Aminoheptane

Tetracycline

Nasal decongestant

Biperiden

Clarithromycin

Antiparkinson

Fipexide

Clarithromycin

Psychoactive drug

Lidoflazine

Clarithromycin

Calcium channel blocker

Simvastatin

Cefuroxime

Statin

Ticlopidine

Piperacillin

Antiplatelet drug, ADP receptor inhibitor

Ticlopidine

Cefuroxime

Antiplatelet drug, ADP receptor inhibitor

Ursolic Acid

Cefuroxime

STAT3 inactivation, anti-cancer

TABLE 2: Summary of compounds identified as hits after screening and selected for further investigation to identify potential antimicrobial activity.

ACKNOWLEDGEMENTS IthankPh.D.candidateMayaFarhaandthemembersoftheBrownLaboratoryfortheirexcellenttraining andguidance.Ialsowant to express my great appreciation for Dr. Eric Brown’s support and mentorship throughoutthisworkandasIcontinueasathesisstudentunderhissupervision.Thisworkwassupported byaSummerStudentshipfromCysticFibrosisCanada(formerlyknownastheCanadianCysticFibrosis Foundation).Iwouldliketoexpressmydeepgratitudeforthehardworkoftheorganization’svolunteersand staff, as well as the as the generosity of their donors, for making this experience possible.

Reviewed by Maya Farha Maya Farha is a Ph.D. candidate under the supervision of Dr. Eric Brown at McMaster University in the Department of Biochemistry and Biomedical Sciences. She is currently studying chemical-chemical combinations as tools to gain biological insight and as routes to drug discovery.

REFERENCES Spellberg, B. Rising Plague. Amherst, New York: Prometheus Books, 2009. 2 Xu J, Kockanek KD, Murphy SL, Tejada-Vera BS. National Vital Statistics Reports: Deaths –Final Data for 2007, National Center for Health Statistics 2010. http://www.cdc. gov/NCHS/data/nvsr/nvsr58/nvsr58_19.pdf (accessed December 31, 2010) 3 Wright GD. Q&A: Antibiotic resistance: where does it come from and what can we do about it? BMC Biol. 2010 Sep 20;8:123. 4 Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st century--a clinical super-challenge. N Engl J Med 2009 Jan 29;360(5):439-43. 5 Walsh C. Antibiotics. Washington, D.C.: American Society for Microbiology Press: 2003. 6 Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis. 2006 Sep 1;43 Suppl 2:S43-8. 7 Spellberg B. Antibiotic resistance and antibiotic development. Lancet Infect Dis. 2008 Apr;8(4):211-2;2-4. 8 Salyers AA, Whitt DD. Bacterial pathogenesis: a molecular approach. Washington, D.C.: American Society for Microbiology Press: 1994. 1

Research Insight

Bilton D, Henig N, Morrissey B, Gotfried M. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest. 2006 Nov;130(5):1503-10. 10 Doring G, Conway SP, Heijerman HG, Hodson ME, Hoiby N, Smyth A, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000 Oct;16(4):749-67. 11 Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev. 2000(2):CD001246. 12 Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009 Aug 28;325(5944):1089-93. 13 Proetz AW. Certain aliphatic compounds as nasal vasoconstrictors. Arch. Otolaryngol. 1943 Jan;37(1):15-22. 14 Tseng JT, Bryan LE. Mechanisms of R factor R931 and chromosomal tetracycline resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1973 May;3(5):638-41. 15 Liu A, Tran L, Becket E, Lee K, Chinn L, Park E, et al. Antibiotic sensitivity profiles determined with an Escherichia coli gene knockout collection: generating an antibiotic bar code. Antimicrob Agents Chemother. 2010 Apr;54(4):1393403. 9

The Meducator | March 2011

INTERVIEW: Dr. Salim Yusuf A Critical Look at Cardiovascular Disease Interview with Dr. Salim Yusuf MD, PhD, MRCP Conducted by Jordan Campbell, Sheiry Dhillon, Caylea Foster and Hiten Naik Bachelor of Health Sciences (Honours) Program Class of 2012 Dr. Salim Yusuf, MD DPhil (Oxford), is a Professor of Medicine (Cardiology) and Clinical Epidemiology & Biostatistics at McMaster University. He is the director of the Population Health Research Institute and the Vice-President of Research and Chief Scientific Officer, Hamilton Health Sciences. He was elected fellow of the Royal Society of Canada, and also holds a Research Chair in Cardiology from the Heart and Stroke Foundation of Ontario. His recent research interestsincludesocietal,biologicandgeneticdeterminantsofpopulationhealthindevelopingpopulations,specifically in the realm of cardiovascular disease. Dr.Yusuf is regarded as a pioneer in cardiovascular disease research and epidemiology in general. By conducting ambitious, multinational studies, he has been able to take fundamental questions and ask them on a global scale. His studies have involved over 83 countries in all inhabited continents of the world.

Q: Dr. Yusuf, could you give our readers a brief work with the INTERHEART study, could you tell us background of where your experience with Cardio- more about that? vascular Disease in developing nations started? Of course—after that single study that I just menWell, I trained in India and did my medical schooling tioned, we decided to design a study in multiple centers there. I was then fortunate enough to receive a Rhodes in India using the same case-control approach and the scholarship to go to Oxford to further my studies. Here, same protocol as the first study. We were able to get I was involved with research to improve outcomes in funding. people with heart attacks—all this work was mainly in western countries like the UK. I eventually found As we began the study we asked ourselves “why can’t myself in the US working for the NIH [National Insti- we use the same approach for multiple countries?” tutes for Health] where I learned from colleagues that And this is how the idea of the INTERHEART study South Asian populations were highly prone to heart was born. With only $25,000, we began exploring opdisease. As a person from a developing country I al- tions for study locations. Because I was also involved ways had this feeling that I wanted to do something for in clinical trials in many different countries I was able the developing countries and particularly with India. to collaborate with those locations; soon the project gained momentum and like a snowball effect more An opportunity came about in 1990 when a colleague countries joined—it ultimately became a movement of mine, Dr. Pipes, now a good friend, said he wanted rather than just a study. Through the INTERHEART to learn more about the increased prevalence of heart study, we found that nine simple risk factors cause disease in South Asia. We decided to do a simple case- heart disease and they were unanimous globally. This control study on the risk factors for heart attacks in made the thought of global prevention very possible. South Asians in India because most of the data on heart disease was from South Asians outside of India at the time. At St. Johns Medical College in Bangalore, Q: Are there other projects that you are still currentwe studied 300 people with their first heart attack and ly involved with? compared them to 300 age and gender matched controls. That paper demonstrated that smoking is bad, Yes, following the INTERHEART study, we then set hypertension is bad, diabetes, abdominal obesity, are up three different studies. First, we set up the INTERall bad—things that you worry about in western popu- STROKE study, which is still running. Phase one was lations was the same for South Asians. That paper was published this year. Because of the complexity of published in the Lancet and that study got us thinking. stroke, in order to get enough information, we needed Q: This study you mention sounds familiar to your thousands of people from many different countries. It

will be interesting to see what we find. A second study we started in Hamilton is called the Family Study. We began with the questions: “when do these risk factors occur? Do they happen at birth, early, or later in life?” In this study, we are following 950 children over ten years and we are beginning to expand the study to rural and urban India as well as Brampton, Ontario specifically South Asian population, to see if there are ethnic variations. We hope to identify a few more countries to help us understand these questions more. Come back and talk to me in 10 years and I will tell you what we have found. We also asked the question, “why do risk factors develop?” and “are the risk factors at different levels in different parts of the world?” This is what we call “finding the causes of the causes”. What has changed in our environment? So we want to ask, “What aspect of the environment has changed and how has this affected us?” So we set up a study called PUrE [Prospective Urban Epidemiology study]. This study includes 17 low, middle, and high income countries. One thing that we are finding in countries, like Canada or Sweden, we only spend 10 to 11 percent of our income on food. If you go to rural areas in poor countries 80% of their income is on food. They often buy the least expensive food, which gives them calories and fats. People from rural areas in developing nations may be growing fruits and vegetables, but resort to selling the food and not eating it. This is an important aspect of their environment. We are trying to relate the environment to the behaviors then we are taking the behaviors and seeing how they interact with genes to see what happens to the risk factors and then look at the risk factors and see what happens with the disease. That is a massive thing, so this study is huge. My hope is to follow these people for 10 more years.

Q: You mentioned nine risk factors that are common risk factors for heart disease globally. Specifically, we were wondering what is the role of urbanization in this process? I think what urbanization has done is it has decreased the amount of energy we expend in day to day activities by shifting occupations from more manually oriented to more intellectually oriented occupation and sedentary occupation. It has changed people’s habits for expending energy, especially in developing countries. The second thing is, urbanization is associated with access to foods that are less common, particularly processed foods that are less common. This is typical in developing countries. Now in developed countries, the rural areas have access to all the nasties and those people in the rural areas have access to cars and now that farming is all automated, they are exposed to the same risk factors. Rural health and CVD [cardiovascular disease] in developed countries is going to be worse in rural areas than urban areas. Now in developing countries it is the reverse. The other idea that has come to me is by bringing people closer to each other you are at risk of a contagion, like contagious habits (ie adopting smoking). That is an aspect of social networking we have not studied and we are thinking about studying. Another thing to think about is the fact that cities have always been with us, the nature of cities have changed. If you read Gandhi’s autobiography when he lived in London, his room was 6-7 miles from the law school. He would walk each day. Now people take buses. Today you could not walk across a city in a day. Suburbanization is more of a problem than urbanization. Cities are built around the car and not waking and cycling.

Q: At the policy level, what do you think the government of India is doing? Do you think they are Q: It seems like you had a clinical interest in cardio- doing enough? vascular disease, which shifted to an interest in the social origins of the disease—when did this hap- I don’t know what they are doing, so anything I say in that direction would be substantially incomplete. It is pen? hard to know whether or not they are doing enough, so You mean like a “road to Damascus” thing. It is hard to I won’t comment on that. But I will comment on the say. There was no single shift it was more of a gradual fact that there is now a great deal of awareness on the shift. It became a gradual appreciation for the fact that national level of what we call lifestyle diseases. They if you really want to improve health, focusing on treat- are trying to fund programs. I think one step further ing people after they have fallen ill will only get you so is the fact that the WHO [World Health Organization] far. You have to couple that with preventative medi- is recognizing non-communicable diseases is going to cine. It is a gradual evolution. And it’s fun to do dif- be the biggest burden worldwide including developing ficult things. It is gradual. There is no eureka moment. countries. There is a meeting of the UN [United Na-

Interview

The Meducator | March 2011

tions] generally assembly next year and there is a significant task force of the WHO that is putting the control of non-communicable disease as a priority, and I am involved in writing a report of recommendations. So there is an effort. Once that happens, hopefully more countries will take this seriously, but these things take time, policy changes take time. And once you change policy it takes a long time to implement the changes. So all the effort we are doing now will only have an impact 20 years from now.

be in public health. We donâ&#x20AC;&#x2122;t need doctors for public health; prevention can be done without doctors. Public health requires regular people. You can have a big impact there. Public health requires the public and medical care requires the doctors. The two must meet with each other. Q: Does decreasing the exposure to infectious diseases increase the risk of chronic disease?

Not quite. When you prevent people from dying at the age of 5 or 10 and they live to the age of fifty they will get the disease of the people at the age of 50. It is not that you are increasing the prevalence of these diseases, I think you need both. I think it is a mistake to try it is that there are more people in these age categories. to make a choice between both. When people fall ill It is not an inevitable consequence that the prevention there is an imperative to look after them, plus it is a of communicable diseases causes heart disease to rise. point of care you cannot avoid and we are quite good at. So if you take the reduction of CVD in the US by 50% half is due to better treatments and half is due Q: Thanks for taking the time to talk to us, and good to better prevention. Prevention and PH is important luck with your work. and more remote. You never see the heart attack you prevent. Obviously if you can reduce smoking and in- It was a pleasure. crease activity, there is value in this. There needs to be a balance, I think the imbalance of this is that most of our dollars is spent on healthcare. Part of it needs to Q: Should governments emphasize efforts more in clinical medicine or public health?

LEFT: Dr. Salim Yusuf, Professor of Medicine (Cardiology) and Clinical Epidemiology & Biostatistics, McMaster University RIGHT: The David Braley Cardiac Vascular and Stroke Research Institute is located at the Hamilton General Hospital. The institute is currently home to Dr. Yusuf â&#x20AC;&#x2122;s world renowned Population Health Research Institute, as well as

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