Issue 25

APRIL 2014 | ISSUE 25

WWW.MEDUCATOR.ORG

introduction

E X P LO R I N G T H E S O C I A L C A U S E S O F A D E VA S TAT I N G E P I D E M I C

DR. ERIC SEIDLITZ AIRING OUT THE SMOKE OF DOUBT

A P R I L 2014

MEDICAL MARIJUANA

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LEARNING FROM THE DIVERSE AND UNCONVENTIONAL

M E D U CATO R

CKDu AND THE ISLAND OF WIDOWS

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table of

CONTENTS APRIL 20 14 | I S S U E 2 5

table of contents

02 INTRODUCTION 03 MEDBULLETINS 06 PATHOPROFILE 07 OPINIONS 17 FORUMSPACE 19 CRITICAL REVIEWS 31 INTERVIEW SPOTLIGHT 35 GLOBAL PERSPECTIVE 38 CONTRIBUTORS

OPINIONS 07 C H I L D N O N - V O L U N TA RY E U T H A N A S I A 09 I N C E N T I V I Z E D O R G A N D O N AT I O N 11 M E D I C A L M A R I J U A N A 13 O P P O S I N G G E N D E R C I D E 15 H I E R A R C H Y O F E V I D E N C E

CRITICAL REVIEWS 19 O B E S I TY A N D A LZ H E I M E R’ S D I S E A S E An uncanny bridge between two worlds

23 T H E R A P I E S F O R CY S T I C F I B R O S I S A look at cystic fibrosis transmembrane conductance regulator correctors and potentiators

27 L - C A R N I T I N E S U P P L E M E N TAT I O N A potential treatment for cancer cachexia

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A P R I L 2014

COVER ART BY DAVID HU

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It is often said that complex theories and principles often stem from simple sparks of creativity. However, it is the development and growth of these ideas which bear the fruit of science, as illustrated by the branching of the neuronal trees on the cover of this issue. This process of generating, refining, and applying ideas is paramount to scientific progress. As such, Issue 25 of The Meducator showcases many contemporary ideas in the field of health sciences, which can eventually be applied to research and practice.

One of the most unique aspects of this issue is its abundance of thought-provoking Opinion columns which use evidence, logic, and critical thinking to widen our perspectives about current topics in the health sciences. Featured topics include child non-voluntary euthanasia, ideas to improve Canada’s organ donation system, the legalization of medical marijuana, and connections between gendercide and abortion. These pieces highlight how it can be helpful to step back and re-evaluate the fundamental principles behind surfacing issues in our society before hastily addressing them.

Complementing the development of opinions, the other pieces featured in this issue show how previous knowledge can be leveraged to build research questions and drive applications. For instance, through exploring common pathways explored in previous literature, Ishan Aditya and Jason Fan introduce the potential relationship between obesity and Alzheimer’s Disease. Furthermore, Spencer Jones’ Critical Review on cystic fibrosis looks at the various pharmacological approaches to modifying the mutated proteins responsible for this incurable condition. Next, Aaron Kwong et al.’s Critical Review on L-Carnitine supplementation explores the use of a common dietary supplements in treating metabolic disorders such as cancer cachexia. On a larger scale, the ForumSpace describes how to improve current methods of disease prevention through effective disease screening of large populations. Finally, Arun Partridge and Louise Chong share their first-hand Global Perspective in order to bring attention to the underaddressed epidemic of chronic kidney disease of unknown etiology in Nicaragua.

Our Interview Spotlight features Dr. Eric Seidlitz, who is a researcher in the Singh Lab at the Hamilton Cancer Center and a professor of the first year B.H.Sc. Cellular and Molecular Biology course at McMaster University. Through sharing a multitude of other notable lessons and experiences, Dr. Seidlitz highlights the importance of diversifying one’s experiences in order to foster creativity, which is a valuable yet often overlooked asset in the field of research.

Sincerely,

M E D U CATO R

The Meducator has seen exceptional growth this past year, as we have watched our journal substantially increase its impact on the McMaster community. The enthusiasm, energy, and dedication of our staff has been essential to our success, and we are confident that this energy will extend into future years. We would like to offer a special thank you to Ilia Ostrovski, Ellen Liang, and Sebastian Swic, for all of their dedication and commitment as team managers. As well, it has been an immensely valuable experience for us to facilitate such a talented team of students, whether through our creative brainstorm sessions with the Graphics and Design team, arduous but fruitful on-copy edits with the Editorial Board, or energetic discussions with the Video team. We are proud to say that every member of this year’s Meducator team has truly embodied the collaborative and inquisitive nature of the health sciences that our journal continually strives to represent.

introduction

INTRODUCTION ISSUE 25

dear reader,

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JOHNNY-WEI BAI

A P R I L 2014

YASMEEN MANSOOR Bachelor of Health Sciences (Hons.)

Class of 2015

Bachelor of Health Sciences (Hons.)

Class of 2015

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MEDBULLETIN METABOLISM

CANCER

RONA LD LE UNG

MAYLYNN D IN G

While cold weather can be unpleasant, a new study published in Cell Metabolism suggests that the human reaction of shivering can trigger a cascade of biochemical reactions that mimic the benefits of exercise by examining the mechanisms of thermogenesis. 1 Shivering thermogenesis occurs as a consequence of muscle contractions, while non-shivering thermogenesis occurs through the mobilization of energy from brown adipose tissue (BAT) in humans. 2

Cancer stem cells (CSCs), also known as cancer-initiating cells, have become an area of increasing interest due to their implications for tumourigenesis. 1 CSCs differ from other cancer cell populations in their display of stem cell properties. These properties include the ability to self-renew and to differentiate into multiple, non-selfrenewable cell types, which form the bulk of the tumour masses. They are also largely resistant to existing cytotoxic chemotherapies and radiation developed to target differentiated or differentiating cells. As a result, CSCs can persist in tumours causing tumour relapse and metastasis, which can ultimately lead to death.

medbulletin

EXERCISE HAS EVOLUTIONARY TARGETING SELF-RENEWAL IN ROOTS DERIVED FROM SHIVERING CANCER CELLS

Researchers Lee et al. compared adipose tissue samples of individuals who underwent intense exercise to those of individuals exposed to cold temperatures. In particular, they compared levels of circulating irisin, an exerciseinduced cytokine that activates BAT-like thermogenesis in white adipose tissue. 3 The research team found that cold exposure increases irisin secretion in a magnitude proportional to shivering intensity, similar to the dependency of exercise-induced irisin secretion on exercise intensity. This suggests that exercise-stimulated irisin secretion may have evolved from secretion mediated by shivering-related muscle contractions. 3

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In vitro experiments showed that up-regulated thermogenesis in BAT could result in substantial wholebody energy expenditure. 3 While further research is required to understand the mechanisms of irisin secretion, the irisin-mediated interaction between muscle and adipose tissue represents a cold-induced, thermogenic system that can be targeted in therapeutic treatments for obesity.

3

1.

The New York Times. Shivering as a form of exercise. [Online] Available from: http://well.blogs. nytimes.com/2014/02/05/shivering-as-a-form-of-exercise/?ref=health [Accessed 11 Feb 2014].

2. Saito M. Brown adipose tissue as a regulator of energy expenditure and body fat in humans. Diabetes Metab J. 2013;37(1):22-9.

3. Lee P, Linderman J, Smith S, Brychta R, Wang J, Idelson C, Perron R, Werner C, Phan G, Kammula U, Kebebew E, Pacak K, Chen K, Celi F. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metabolism. 2014;19(2): 302-9. [Accessed 10th Feb 2014] Available from: http:// www.sciencedirect.com/science/article/pii/S1550413114000060 4. Cold Weather Runner [Image from the internet]. [Accessed 28 Feb 2014] Available from http:// rockmyrun.files.wordpress.com/2013/10/cold-weather-runner.jpg

In a new study published in Nature Medicine, a team of researchers led by Dr. John Dick at the University of Toronto successfully eliminated human colon cancer stem cells from xenograft mice models by inhibiting the self-renewal regulator, BMI-1. 2 The over-expression of BMI-1 has previously been linked to malignant stem cell renewal in the breast and hematopoietic system, as well as to chemotherapy and radiation resistance. First, the researchers demonstrated that reducing the expression of BMI-1 transcripts significantly debilitates human colorectal CSCs’ self-renewal abilities, thus decreasing their production. Selective inhibitors of BMI-1 were then identified using a BMI-1 reporter system. One identified inhibitor is PTC-209, a small molecule capable of inhibiting BMI-1 at sub-micromolar concentrations. The in vitro inhibition of BMI-1 and consequently of CSC self-renewal

by PTC-209 effectively blocked the growth of colorectal cancer in mouse xenografts. The tumours did not relapse following discontinuation of treatment with PTC-209, suggesting that the molecule produces irreversible effects.

Therapies targeting the self-renewal mechanism of CSCs are potentially more effective than chemotherapy or radiation at halting the growth of certain cancers. 3 The development of these therapies can dramatically improve the survival rates and quality of life of cancer patients, particularly those suffering from metastatic diseases.

1. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006 Sep 21; 355:1253-1261.

2. Kreso A, Galen P, Pedley N, Lima-Fernandes E, Frelin C, Davis T, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014 Jan; 20(1):29-36.

3. Wicha MS. Targeting self-renewal, an Achilles’ heel of cancer stem cells. Nat Med. 2014 Jan 7; 20(1):145.

4. Anti-tumor [Image from the internet]. [Accessed 28 Feb 2014] Available from http://www.research. chop.edu/blog/wp-content/uploads/2013/08/anti_tumor.jpg

DEVELOPMENT

CLINICAL

THE IMPORTANCE OF COMMUNICATION IN MEDICINE

SANA GILL

ISH AN AD ITYA

Mother-infant contact is often the first social experience of a child. It is an empowering connection which demonstrates the human capacity to love irrespective of culture. 1,2 Premature babies often lack this experience as their incubator-dependent care results in maternal separation at birth. There is compelling scientific evidence that suggests a combination of brain immaturity and maternal separation produces negative effects on development, such as an atypical stress response. 3 Disruption of mother-infant bonding may also induce depression in mothers. 4 Although short-term gains from touch-based interventions are welldocumented, it is unclear if the strategies show lasting effects on child development beyond infancy.

A study from the University of Western Ontario draws our attention to the fact that pre-procedure briefings are not routinely done in operating rooms. 1 However, these briefings are a part of the standard practice in other highrisk industries such as aviation, the military and space exploration.

A recent study conducted at the Gonda Multi-Disciplinary Brain Research Centre explored the issue by evaluating Kangaroo Care (KC) intervention, which involves skin-toskin contact between a naked baby and its mother’s chest. 5 KC was administered to premature infants and its influence on child development and maternal mental health was documented and studied over the first decade of each child’s life. When compared to a control group of premature infants receiving no touch-based intervention, infants and mothers in the KC treatment group showed greater improvements in physiological development and mood, respectively. Further investigation suggests that KC treatment enhances oxytocin release via mother-infant contact, which strengthens the mother-child bond. This fortified connection improves maternal mood and enhances receptiveness to the infant’s needs. Consequently, the child’s positive experience during this sensitive period, when external influences greatly shape development, has stable and long-term benefits for development.

Surgical teams at Toronto’s Hospital for Sick Children participated in a pilot study to determine the value of pre-operative briefings. Various members of the surgical team discussed their role in the context of a surgical procedure, and concerns specific to the patient prior to entering the operating room. Briefings were limited to eight minutes in length. Participants of the briefings included general surgeons, surgical residents and fellows, anesthesiologists, and operating room nurses. These briefings focused on communication in the event of nonpredictable errors, emotional concerns of the patient, and challenges which may arise during the procedure. Overall, this intervention increased dialogue between members of the surgical team and thereby improved the efficiency of preparing for surgical procedures. However, it was not possible to integrate pre-operative briefings for every procedure due to shift and staff changes during long and complex surgeries and overlapping schedules that made it difficult to assemble the team. In conclusion, the authors of the article make a strong case for the integration of pre-operative briefings in the overall preparation for a surgical procedure and suggest extending the pilot to other medical divisions.

medbulletin

THE LASTING TOUCH OF MATERNAL CONTACT

M E D U CATO R |

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Lingard L, Regehr G, Cartmill C, Orser B, Espin S, Bohnen J, Reznick R, Baker R, Rotstein L, Doran D. Evaluation of a preoperative team briefing: a new communication routine results in improved clinical practice. BMJ Qual Saf. 2011 Jun 1;20(6):475–82. [Accessed Feb 28th 2014]. Available from: http:// qualitysafety.bmj.com/content/20/6/475.long#ref-list-1 2. Surgery Team [Image from the internet]. [Accessed 28 Feb 2014] Available from http://blog.plazamedicalcenter.com/wp-content/uploads/2013/01/surgery-team.jpg

A P R I L 2014

1. Feldman R. Oxytocin and social affiliation in humans. Horm Behav. 2012 Mar; 61 (3): 380--391.

2. Sue Carter C. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology. 1998 Nov; 23 (8): 779--818.

3. Greene J, Fox N, Lewis M. The relationship between neonatal characteristics and three-month mother-infant interaction in high-risk infants. Child Dev. 1983 Oct; 1286--1296.

4. Brooten D, Gennaro S, Brown L, Butts P, Gibbons A, Bakewell-Sachs S, Kumar S. Anxiety, depression, and hostility in mothers of preterm infants. Nurs Res. 1988 Jul-Aug; 37 (4): 213--216.

5. Feldman R, Rosenthal Z, Eidelman A. Maternal-preterm skin-to-skin contact enhances child physiologic organization and cognitive control across the first 10 years of life. Biol Psychiatry. 2014 Jan 1; 75 (1): 56--64.

6. 6. Mom and baby [Image from the internet]. [Accessed 28 Feb 2014] Available from http://2. bp.blogspot.com/-G0bb1pnP41U/T2-7JqPSCkI/AAAAAAAAF7A/RN8UC2Bdfpo/s1600/ Mom+and+Baby.jpg

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STEM CELLS

BACTERIA

AVR ILYNN D ING

NICO LE FALZO NE

The most common treatment for bone marrow cancers is bone marrow transplantation, which replaces damaged bone marrow with healthy hematopoietic stem cells (HSCs).

HSCs efficiently retain stem cell properties in their natural microenvironment: stem cell niches in the bone marrow region where blood cell production occurs. However, the practice of bone marrow transplantation is limited due to the shortage of matching donors and stem cells. 1 While scientists have developed procedures to culture HSCs in vitro , these methods do not allow HSCs to sustain their self-renewability and multipotency to an extent sufficient for clinical application. 2

Methicillin-resistant Staphylococcus aureus (MRSA) is an infection-causing bacteria that is resistant to many antibiotics. It is largely acquired in hospital settings, and can cause life-threatening systemic infection as well as pneumonia. Approximately 20% of individuals have persistent nasal colonies of the S. aureus bacteria, which can infect the body if immunological defenses are breached. 1 Hospital procedures, such as surgery, facilitate S. aureus infections by weakening the immune system, which presents a major problem in clinical medicine. From 1995 to 2007, Canadian hospitals have experienced a 17-fold increase in incidences of MRSA colonization and infection. 2

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GROWING ARTIFICIAL BONE MARROW

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Recently, a team of German researchers headed by Dr. Cornelia Lee-Thedieck created artificial bone marrow from a synthetic polymer that can effectively support the self-renewal of HSCs. 3 Using macroporous polyethylene glycol diacrylate (PEGDA) hydrogels, the research team engineered scaffolds that mimic the spongy threedimensional (3D) structure of this bone marrow region. 2 To allow HSCs to attach to the synthetic matrix, they prepared PEGDA hydrogels with Arg-Gly-Asp, a peptide that mediates cell adhesion. 3,4 The 3D architecture provides HSCs with stability and anchor positions, better preserving their multipotency. The 3D structure can also accommodate feeder cells, which are derived from mesenchymal cells, and can support HSC self-renewal and proliferation.

The feeder cells’ positive effects on HSC multiplication and stem cell property preservation are amplified when they are co-cultured with HSCs in the synthetic bone marrow compared to standard two-dimensional cultures. 2 Although many studies have sought to develop optimum methods for culturing HSCs, few considered the significance of the physical scaffolding provided by stem cell niches in natural bone marrow. The researchers estimate it will take another 15 years before artificial bone marrow can be applied for clinical use, but the invention opens a new avenue by which stem cells can be grown and used for transplantation. 3

SILVER NANOPARTICLES FOR PREVENTING MRSA INFECTION

Once a person is infected, S. aureus can form small-colony variants (SCVs) inside of host cells, which may cause recurring infections. 2 MRSA is difficult to treat because it is resistant to the first-line antibiotics normally used against Staphylococcus infections, such as amoxicillin. 2,3 Therefore, it is important to prevent the spread of this infection in hospital settings. Research featured in the journal Nanomedicine: Nanotechnology, Biology and Medicine has shown silver bionanoparticles (AgNPs) to be a potential treatment in combatting bacterial infections. Silver ions (Ag+) were electrochemically reduced with the culture supernatants of S. aureus and shown to have antimicrobial effects against MRSA. 4 Although silver particles have been known to possess antibacterial properties, this research demonstrates a novel application to alleviate the present public health crisis. 5 According to the Public Health Agency of Canada, the rate of detected MRSA cases per patient admissions has been steadily increasing since 1995. 6 As this particular S. aureus strain is resistant to many antibiotics, silver nanoparticles can serve as a potential alternative treatment for infection. 5

1.

2.

1.

National Cancer Institute. Bone marrow transplantation and peripheral blood stem cell transplantation [Internet]. Bethesda: National Cancer Institute; 2013 Aug 12 [2014 Feb 8]. Available from: http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant 2. Raic A, Rodling L, Kalbacher H, Lee-Thedieck C. Biomimetic macroporous PEG hydrogels as 3D scaffolds for the multiplication of human hematopoietic stem and progenitor cells. Biomaterials.

2014;35(3):928-40.

3. Palmer R. Artificial bone marrow created by German scientists, could be used to treat leukemia someday. International Business Times. 2014 Jan 10.

4. Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol.

1996;12:697-715.

5. Mesenchymal Stem Cell [Image from the internet]. [Accessed on 28 Feb 2014] Available from http://stemcelldoc.files.wordpress.com/2011/12/mesenchymal-stem-cell1.jpg

3.

4.

5.

6.

7.

Gordon RJ, Lowy FD. Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2008 Jun 01;46(Suppl 5):S350-9.

Simor AE, Gilbert NL, Gravel D, Mulvey MR, Bryce E, Loeb M, et al. Methicillin‐resistant Staphylococcus aureus colonization or infection in Canada: National surveillance and changing epidemiology, 1995–2007.

Infect Control Hosp Epidemiol 2010 Apr;31(4):348-56.

Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998 Aug 20 [cited 2014 Feb 12];339(8):52032.

Nanda A, Saravanan M. Biosynthesis of silver nanoparticles from Staphylococcus aureus and its antimicrobial activity against MRSA and MRSE. Nanomedicine 2009 Dec;5(4):452-6.

Monteiro DR, Gorup LF, Takamiya AS, Ruvollo-Filho AC, Camargo ERd, Barbosa DB. The growing importance of materials that prevent microbial adhesion: antimicrobial effect of medical devices containing silver. Int J Antimicrob Agents 2009 Aug;34(2):103-10.

Canada. The Canada Nosociomal Infection Surveillance Program. Results of the surveillance of methicillin resistant Staphylococcus aureus, from 1995 to 2009. Ottawa: Public Health Agency of Canada; 2011.

MRSA [Image from the internet]. [Accessed 28 Feb 2014] Available from http://www.microbeworld.org/ index.php?option=com_jlibrary&view=article&task=download&id=11559

PATHOPROFILE

Type 2 Diabetes

What Went Wrong with Insulin?

AUTHOR KIM I A SOR OU R I ARTI ST ELLEN LI ANG

Type 2 diabetes mellitus, or non-insulin dependent diabetes mellitus (NIDDM), is a pathological condition characterized by an inadequate response to insulin, a hormone responsible for regulating blood glucose levels. NIDDM comprises of 90-95% of all cases of diabetes.1 Normally, insulin is released by pancreatic beta cells into the bloodstream, acting on receptors found in tissues such as skeletal muscle and the liver.2 The binding of insulin to insulin receptors stimulates glucose uptake into cells and the storage of glucose as glycogen (glycogenesis).3 Evidence suggests that genetic mutations may increase susceptibility to NIDDM. Specifically, a reduction of insulin receptor gene expression may be partly responsible for insulin resistance in NIDDM.4 While molecular pathways are not very well understood, evidence suggests high blood fatty acid levels may inhibit insulin receptor substrates (IRS) in the insulin-signalling cascade.4 The isoforms of the glucose transporters (GLUTs) primarily involved in diabetes are GLUT2 and GLUT4.5 There is currently limited data linking specific genes to diabetic pathology, warranting for genome-wide analyses.6 Despite an increasing prevalence of diabetes, there is encouraging evidence supporting the ability of exercise to reduce insulin resistance.7

The following two diagrams depict aspects of the normal insulin signalling pathway in myocytes and hepatocytes, respectively.

Potential disruptions to any components of this pathway can increase the risk of NIDDM, and are highlighted in red.3

insulin

MYOCYTES

glucose

Activated Akt, a protein kinase, inhibits the protein TBC1D1, which usually prevents GLUT4 vesicles from translocating to the membrane. Therefore, the vesicle can move towards the membrane on tracks and microtubules and fuse with the membrane. This also increases glucose transporter expression, while directly facilitating glucose uptake by the cell.

Akt (initially activated through insulin pathway) helps activate the enzyme glycogen synthase

GLUT2

GLUT2

insulin receptor

glycolysis

glycogenin/ branching enzyme

glycogen synthase

glycogen

A P R I L 2014

5. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabetic Medicine. 2005 Jun;22(6):674–82.

6. McCarthy MI, Zeggini E. Genome-wide association studies in type 2 diabetes. Curr Diab Rep. 2009;9:164–171.

7. Steinberg GR, O’Neill HM, Dzamko NL, Galic S, Naim T, Koopman R, et al.

Whole body deletion of AMP-activated protein kinase {beta}2 reduces muscle AMPK activity and exercise capacity. J Biol Chem. 2010 Nov 26;285(48):37198–209.

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American Diabetes Association. Diagnosis and classification of Diabetes Mellitus. Diabetes Care. 2012 Dec 20;36(Supplement_1):S67–S74.

2. Seino S, Shibasaki T, Minami K. Pancreatic -β cell signaling: toward better understanding of diabetes and its treatment. Proceedings of the Japan Academy, Series B. 2010;86(6):563–77.

3. Gropper SS. Advanced nutrition and human metabolism. 6th Ed. Belmont, OH: Cengage Learning; 2012.

4. Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J Diabetes. 2010 Jul 15;1(3):68–75.

3.

UDP-glucose is added to the protein glycogenin with the help of gylcogen synthase and a branching enzyme to form glycogen

M E D U CATO R

Akt

2.

Glucose undergoes a series of modifications to become uracildiphosphate (UDP) glucose

UDP glucose

signalling cascade

1.

1.

glucose altered gene expression

GLUT4

GLUT4

3.

2.

A signalling cascade is triggered by auto-phosphorylation of the beta subunit.

insulin

circulating fatty acids

GLUT4 GLUT4

1.

HEPATOCYTES

TBC1D1

circulating fatty acids

Insulin binds to the alpha subunit of the insulin receptor, a dimeric tyrosine kinase, causing autophosphorylation of the beta subunit.

LIVER

Akt

PDK

pathoprofile

insulin receptor

p85 IRS-1

GLUT4

altered gene expression

GLUT4

MUSCLE

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Child Non-Voluntary Euthanasia

WHEN QUALITY TRUMPS QUANTITY JULIA GOYAL 1 AND SALVATORE GIULIANO VIVONA 2 Bachelor of Science, Biology (Honours), Class of 2016.

Bachelor of Science, Biophysics (Honours), Class of 2016 McMaster University Correspondence: goyalj3@mcmaster.ca and saller101@msn.com 1

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opinion

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You sit down on the chair Wolfe investigated parental accounts of symptoms suffered by the hospital bed of by children in the terminal stages of cancer. The results a young girl. The little revealed that 89% of children endured substantial suffering angel is no longer the girl from at least one symptom, with mostly ineffective you knew with her curious treatments, as shown in Figure 1.2 The ineffectiveness eyes, contagious laughter, of symptom treatments leads to a patient’s poor quality and sweet smile. She lies of life until death. Euthanasia, however, is a promising there, as if she is dead. She has alternative as it provides an opportunity for physicians to no recollection of who you are, relieve their patients from intractable suffering rather than where she is, or how she got here. prolong a painful dying process.

You try to believe that the doctors are “doing everything they can” and Euthanasia should be given special consideration in it is only a matter of time. But pain, paediatrics, where infants and children who are terminally ill are unable to or are inept at giving legal consent to both hers and your own, consumes you. medical procedures. Legal protocols can provide a safe For decades, the medical community procedure for non-voluntary euthanasia. For example, has debated how best to alleviate the the Groningen Protocol establishes criteria under which pain and suffering of patients while physicians in the Netherlands can euthanize infants respecting moral values and judgement. without fear of prosecution.3 The protocol outlines four Throughout these years, the field of requirements: “The presence of hopeless and unbearable medicine has birthed new methods suffering and a very poor quality of life, parental consent, and technology to enhance palliative consultation with an independent physician and his or her care. However, at times, the patients’ agreement with the treating physicians, and the carrying conditions only worsen and the use of out of the procedure in accordance with the accepted treatments and medications are to no medical standards.”3 With regards to the first criterion, avail. In these circumstances, euthanasia it is important to recognize that verbally incapacitated provides an alternative solution to the children are unable to explicitly indicate their symptoms suffering of patients and their families. and communicate their suffering to physicians. Instead, Euthanasia is defined as “knowingly and physicians must try to determine the child’s level of intentionally performing an act that is suffering by observing vital signs and behaviour.3 The explicitly intended to end another person’s protocol enforces standards for non-voluntary euthanasia life.”1 It is currently legal in only eight that prioritize morality and the comfort of the patient jurisdictions around the globe. However, in late while providing legal protection for physicians. Its success 2013, Bill 52 by the Québec legislature proposed in the Netherlands indicates that child euthanasia can be to decriminalize euthanasia as a medical aid for authorized and well-accommodated without significant death. Not only has this initiated further debate legal and moral tension in a developed country that on the topic in Canada, but it may encourage other embodies Western cultural values. governments to consider implementing euthanasia.

MORALITY AND DIGNITY This opinion piece discusses how legalizing euthanasia would serve the interests of the patient and healthcare Establishing a legal protocol for non-voluntary child system, with a particular focus on child euthanasia. euthanasia not only prioritizes morality and the comfort of the patient, but also protects a patient’s dignity.

RELIEF FROM SUFFERING Terminally ill patients may experience an unimaginable Within the clinical setting, there are numerous cases degree of suffering.3 Without the option of euthanasia, where patients experience extreme discomfort caused by they are forced to spend their final moments in a state virtually untreatable illnesses. A 2000 study led by Joanne of severe deterioration. Their worsening state will

also occupy their friends’ and relatives’ last memories of them. This argument hence raises the question of whether a newborn or child has personal dignity. Personal dignity should be defined such that it indiscriminately emphasizes the value of human life, thus entitling children or infants to the same level of dignity as adults. For many, relying on life support for sustenance is neither a dignified nor desirable way to live the last days of one’s life. The loss of independence can cause adult patients to suffer depression and other mental illnesses; a child should not have to be forced to endure this experience at such a young age. Circumvention of the suffering through euthanasia may be a proper way of preserving morality and dignity.

HEALTH ECONOMICS

Treatment Attempted Treatment Successful

50

0

Fatigue

Pain

Dyspnea

Poor Appetite

Nausea/ Constipation Diarrhea Vomiting

A hospitalized child requires a high degree of care, but statistical analysis has shown that there are also great financial and social burdens placed on the child’s family.8 Loved ones struggle emotionally when they witness the child suffering; this distress is heightened by their inability to meet the patient’s needs.

Child euthanasia can play a role in optimizing the utility and performance of the Canadian medical system in the paediatric field as well as in relieving loved ones from the socioeconomic, psychological, and emotional burdens associated with sustaining the child.

FIGURE 1: In children who showed sufferable symptoms, according to parental accounts., the percentages of successful symptom treatments: Treatments to relieve symptoms were seldom successful, as the most effective treatments for pain and dyspnea were respectively only 27% and 16% effective. Consequently, a majority of patients were reported to have little fun and immense fear, while 63% of the patients appeared distressed to their parents.2

CONCLUSION

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Dr. Elisabeth Gedge is the Chair of the Department of Philosophy at McMaster University with research interests in feminist bioethics, the philosophy of law, the philosophy of religion, and environmental philosophy. Her research focus in feminist bioethics and law has centered on the regulation of reproductive technologies, in which she published several articles regarding legal equality and practices of sex selection and contract pregnancy.

2.

Canadian Medical Association. Euthanasia and assisted suicide [Internet].

Ottawa: Canadian Medical Association; 2007. [cited 2014 Jan 16]. Available from: http://policybase.cma.ca/dbtwwpd/Policypdf/PD07-01.pdf.

Wolfe J, Grier HE, Klar N, Levin SB, Ellenbogen JM, Salem-Schatz S, et al.

Symptoms and suffering at the end of life in children with cancer. N Engl J Med. 2000; 342(5): 326-33.

Verhagen E, Sauer PJ. The Groningen protocol: euthanasia in severely ill newborns. N Engl J Med. 2005; 352 (10): 959-62. Available from: http:// www.nejm.org/doi/full/10.1056/ NEJMp058026#t=article.

The Nemours Foundation [Internet].

When your child’s in the pediatric intensive care unit. 2012 [cited 2014 Jan 15]. Available from: http://kidshealth. org/parent/system/ill/picu.html#.

Dasta JF, McLaughlin TP, Mody SH, Piech CT. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005; 33(6):1266-71.

Beck AT, Steer RA, Beck JS, Newman CF. Hopelessness, depression, suicidal ideation, and clinical diagnosis of depression., Suicide Life Threat Behav.; 23(2); 139-45.

Pruchno RA, Potashnik SL. Caregiving spouses: physical and mental health in perspective. J Am Geriartr Soc.1989; 37(8):697-705.

Emanuel EJ, Fairclough, DL, Slutsman J, Emanuel LL. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann Intern Med. 2000; 6(132): 451-459.

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REVIEWED BY DR. ELISABETH GEDGE

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In considering the suffering of the patient of the patient, preservation of dignity, and economic pressures, the benefits of implementing child euthanasia should not be overlooked. Death is a private matter, and it can be argued that the government should not interfere with such a personal decision. The Groningen Protocol from the Netherlands presents an effective routine and structure, setting an example that can be adopted by other countries around the world to practice euthanasia on reasonable grounds in paediatrics. Authorizing An efficiency standpoint may appear euthanasia under regulations will also allow insensitive and uncompassionate, as one can for more optimal resource allocation in the argue that an infinitesimal chance of recovery Canadian healthcare system. Though illegal is still hope. However, the child in his or now, euthanasia should one day be adopted her physical state is not only an economic by consensus and no longer regarded as a burden to the health care system, but is also moral equivalent to killing. It is important to a source of emotional and physical strain understand that there is a difference between on overlooking physicians and nursing staff. keeping an individual alive and allowing him Studies show that primary caregivers of or her to truly live; medical technology and terminally ill patients experience increased palliative care are not enough to bridge the health problems, depression symptoms, and gap between the two. After all, quality trumps psychosocial stress.7 This is particularly true quantity, and life is no exception. ■ for the close family and friends of the child.

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Health economics is the study of optimal resource allocation to maximize efficiency and effectiveness in the healthcare system, on both an individual and aggregate level. With this understanding, another argument that supports child euthanasia is the allowance for a better distribution of limited resources amongst patients. Children suffering from terminal illnesses or medical conditions are placed in paediatric intensive care units, which provide the highest level of medical care in a hospital.4 The average daily cost for an intensive care unit bed in Canada is $3,184, amounting to over $1 million a year. There are around 3,500 of these beds across the country.5 Based on a cost-benefit analysis, it would be more economical to allocate the hospital bed, nurse, medication, and financial resources to a child with a reasonable chance of recovery.6

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Compulsory Incentivized Organ Donation A CASE FOR FAIRER ORGAN DONOR POLICY IN ONTARIO JASMINE GITE AND NIRON SUKUMAR

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Bachelor of Life Sciences (Honours), Class of 2015 McMaster University Correspondence: gitej@mcmaster.ca and nironsuku@hotmail.com

FLAWS OF THE CURRENT SYSTEM

DECREASED STANDARD OF LIFE The extensive wait-time for organ transplantations in Ontario is Ontario, like many other countries around the world, follows a a severe flaw in our current organ donation policy. The average voluntary organ donor system. Citizens are given the option of waitlisted patient has to wait four to six years before receiving a becoming donors at the age of 16 and are scarcely reminded of kidney transplant in Ontario.2 This prolonged delay can cause the option ever after. As such, less than a quarter of Ontarians further deterioration in the patient’s condition. The resulting are registered organ donors. Not only is this an unnecessary consequence is two-fold. First, deterioration may occur to the waste of precious organs, it is also an extremely unfair system, point where an organ transplant may not be viable for the as both donors and non-donors are considered of equal priority patient. Second, for those patients that do undergo successful to receive organ transplants. We thus call for a compulsory transplantation, their deteriorated condition during the waitincentivized organ donation system in Ontario, as a fairer and time may lead to a shorter lifespan than otherwise expected if more efficient organ donor policy. This policy automatically an earlier transplantation had occurred. In essence, our current considers all citizens as organ donors after a certain age, where organ donation policy creates wait-times that not only decrease unwilling citizens can opt out if they wish to do so. However, viability for organ transplantations, but also decrease the individuals that choose to opt out are given less priority for effectiveness of the transplanted organs. organ transplants as compared to those who remain as organ donors. By automating organ donor registration and providing USE OF LIVING DONORS disincentive to opt out of organ donation, such a policy ensures In many cases, patients waiting for transplants often turn to a greater availability of organs for all Ontarians. living donors for organs. It is truly unfortunate that the standard of living for healthy individuals must be sacrificed to save the INTRODUCTION lives of the living,A while so many perfectly viable organs are lost everyday due to the wishes of the deceased (or their unexpressed There are approximately 1,500 individuals on the waitlist for wishes to donate). Respecting these wishes is important; organ transplantation in Ontario.1 Many of these people will harvesting organs without permission would be an infringement not receive the organs they so desperately need simply because of an individual’s freedom of choice and right to a personal there is a lack of available organs. In 2012, 68 waitlisted Ontarians belief system. However, requiring potential donors to opt in died for this very reason. Apart from unnecessary loss of life, organ to become registered donors does not maximize the number shortages cause significant harm to society in numerous ways. of organs that can be harvested with donor consent. This is Despite this, less than 25% of Ontarians are registered donors.1 evidenced by the fact that many Ontarians who have expressed Evidently, our discretionary organ donor system is a sub-optimal an interest in becoming organ donors have not registered to allocation of human resources. A potential improvement to our do so.1 These individuals are listed as non-donors. Even if such healthcare system would be to adopt a compulsory incentivized potential donors would have otherwise chosen to donate, their organ donation policy. loved ones may disallow organ harvest out of the mistaken belief In some studies, it has been noted that the quality of life of living donors has improved after kidney donation, as measured by the SF-36 standardized quality of life health questionnaire. The long-term follow up study by Johnson et al. shows positive results of overall wellbeing and encourage the continuation of living donor kidney transplants.(7) A

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that it was the deceased individual’s decision not to the notion that choosing to be a non-donor is the donate. This is an unavoidable negative externality “safe” option. Furthermore, it serves as a means for of our current opt-in policy, and one that seriously society to facilitate altruism as much as possible. questions the fairness of our use of organs from Requiring social benefactors to fill out paperwork living donors when viable organs from deceased to contribute to society seems both inconsiderate but otherwise willing owners are simply wasted. and counterproductive.

CREATION OF ORGAN BLACK MARKET The creation of an organ black market is also an undesirable outcome of organ shortage. In lowincome countries, citizens living in poverty can often be tempted to sell their organs for money.

Although transaction of organs is illegal in Ontario and many other parts of the world, there is such a vast shortage of organs that certain organs can be sold for up to $200,000 in some countries.3 Apart from the ethical concerns of organ transaction, the existence of a black market can be a powerful motivation to steal organs from helpless individuals.

Traffickers and surgeons who sustain these markets earn huge profits from selling organs at a much higher price than what the donors themselves are paid, if they are at all compensated. The World Health Organization recently revealed that the illegal kidney trade has reached a rate of more than one purchase per hour.3

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It is evident that Ontario’s organ donation policy is in need of revision. Our current system creates organ shortages that lead to decreased collective welfare and social efficiency. Not only would a compulsory incentivized system reduce these shortages, it would also increase efficacy and equity in Canadian healthcare. It is high time that Ontario, and Canada as a whole, begins to progress towards a fairer and more optimal policy for organ allocation. ■

Ontario Trillium Gift of Life Network.

Registration stats [Internet]. 2014 [cited 2014 Jan]. Available from: https:// beadonor.ca/scoreboard Sher, J. Ontario, B.C. residents wait longer for kidney transplants than any other Canadians. The Toronto Star [Internet]. 2012 Jan 23 [cited 2014 Jan]; Available from: http://www.thestar. com/news/canada/2012/01/23/ontario_bc_residents_wait_longer_for_ kidney_transplants_than_any_other_ canadians.html Campbell, D., & Davison, N. Illegal kidney trade booms as new organ is ‘sold every hour’. The Guardian [Internet].

2012 May 27 [cited 2014 Jan]; Available from: http://www.theguardian. com/world/2012/may/27/kidneytrade-illegal-operations-who Farrel, A., Price, P., Quigley, M. Organ Shortage: Ethics, Law and Pragmatism.

Cambridge University Press; 2011.

Singapore Ministry of Health. Human Organ Transplant Act (HOTA). Singapore: Singapore Government; 2007 Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A. A systematic review of presumed consent systems for deceased organ donation.

Health Technology Assessment 2009; 13(26):23.

Johnson EM, Anderson JK, Jacobs C, Suh G, Humar A, Suhr BD, Kerr SR, Matas AJ et al.. Long-Term Follow-Up of Living Kidney Donors: Quality of Life After Donation. Transplantation 1999; 67(5): 717-721.

M E D U CATO R

COMPULSORY DONATION Compulsory organ donation systems have already been implemented in many European countries. In these countries, each citizen automatically becomes a donor at a certain age, but can opt out at his or her discretion. As a result, organ donation rates are much higher in comparison to countries that have not adopted a similar policy.4 The most obvious benefit of such a system is a decreased shortage of organs, which consequently decreases the need for funding to increase awareness about organ donation. One of the biggest reasons why more people have not signed up as organ donors is a lack of awareness about the issue and a lack of social pressure to register as a donor. The most exposure that many people receive concerning the option of becoming a donor is a simple question when they renew their health card or driver’s license. With no context or additional information, the “safe” option then becomes to not opt-in for the time being, until more information is received. However, due to the lack of awareness about organ shortages, many of these individuals will never receive the additional information needed to make a fully informed decision. In comparison, an opt-out system ensures that individuals who are against organ donation will take the time to opt out. Also, by changing the status quo, adopting an opt-out policy can decrease

Singapore has already established a policy that closely resembles the compulsory incentivized system proposed in this paper. The Human Organ Transplant Act in Singapore presumes consent for the recovery of certain organs for transplantation after death. The act includes all mentally healthy Singapore citizens and permanent residents of 21 years and above, unless they have chosen to opt out.

Moreover, individuals who opt out are designated a lower priority to receive organs should they require transplantation in the future.5 A systematic review comparing countries with opt-in policies versus presumed consent found that kidney donation rates increased over six-fold in the three years following legislation.6 The policy’s successful outcome in Singapore makes it worthy of consideration for implementation in Canada.

opinion

COMPULSORY INCENTIVIZED ORGAN DONATION

INCENTIVIZED DONATION Although a compulsory organ donation policy would address many problems in our current system, there is still a question of fairness that is not addressed by this policy. Regardless of what reason or belief system an individual would have for opting out of organ donation, for an organ donor and non-donor patient to be considered equally viable to receive an organ transplant is unfair. It is thus necessary to further adopt an incentivized policy whereby organ donors would have priority to receive transplants over non-donors. Of course, the degree of organ necessity and consideration for special circumstances (i.e. if someone were to opt-out due to a medical condition), must also be factored into the equation. However, blindly allocating scarce altruistically-derived resources to non-participating individuals is ill-conceived.

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Medical Marijuana

AIRING OUT THE SMOKE OF DOUBT ANEESH KARIR

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Bachelor of Health Sciences (Honours), Class of 2017 McMaster University Correspondence: aneesh.karir@learnlink.mcmaster.ca

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Marihuana for Medical Purposes Regulations, effective April 1, 2014.5 All current authorizations and licenses will expire: the only legal access to medical marijuana will be through newly licensed producers.6 Instead of requiring a Health Canada permit, healthcare practitioners will be responsible for signing a medical document that enables a patient to purchase a specified amount of marijuana directly from a licensed producer.5 Rather than criminalizing illicit medical marijuana users, the regulations attempt to remove the negative stigma associated with users, allowing the industry to become more corporate.

On April 1, 2014, Canada will implement a drastically new set of regulations that will redefine the laws on the production and acquisition of medical marijuana, affecting over 35,000 patients nationwide. Patients will have to exclusively seek commercial vendors for medical marijuana and pay a much higher price compared to the costs of growing marijuana in their residences. This provides several benefits to the Canadian economy and protects against drug abuse, yet worries citizens and users who are trying to minimize costs.

The Canadian government will require patients to obtain a IMPLICATIONS prescription from a general physician, rather than a specialist, to gain access to medical marijuana. This new legislation THE NATION therefore introduces a new source of pressure for general According to Brian Hutchinson of National Post Canada, practitioners and makes them reluctant to support the bill. encouraging the commercial sale of medical marijuana Still, with a plethora of viable solutions, such as increased provides several advantages to the general welfare of users, safety and quality assurance for citizens who are wary about along with an inevitable boost to the nation’s economy. the new system, the commercialization of medical marijuana Preventing consumers from growing marijuana in their own could prove to be a reasonable decision for the nation’s future. homes will prevent home invasions, fire hazards, and reduce the risk of its diversion to the black market.7 Furthermore, BACKGROUND the quality and consistency of the product will be assured, due to specific guidelines imposed on licensed producers.

In 2001, Canada was the first country to pioneer a federal legislation regarding medical marijuana — a topic considered The new regulations for medical marijuana also provide a taboo by many at the time.1 The Marihuana Medical an avenue for economic expansion. Health Canada’s Access Regulations policy outlined the requirements implementation of this program could recover the large a patient would have to meet in order to produce and sums of money spent on enforcing laws against illict drugs consume medical marijuana as a treatment for a variety of over the past decade, which had a negligible impact on the ailments.2 While this may have alleviated tension between nation’s drug abuse problem. With the implementation of the government and citizens regarding the use of marijuana, new medical marijuana policies over the next decade, Health strict law enforcement pertaining to illicit drug use persisted. Canada estimates that the number of medical marijuana Between 2004 and 2005, 73% of the $368 million spent on consumers will increase tenfold to 309,000 due to its addressing issues caused by illicit drug use was used for law- increased ease of accessibility. This surge in demand will enforcement, with the remaining 27% spent on treatment, fuel the growth of the legal marijuana industry, estimated research, prevention, and harm-reduction programs.3 There to generate $1.3 billion in annual revenue. Municipalities has been growing evidence that many of the dangers of illicit will also benefit from these operations, with licensed drugs may have been exacerbated by the increased law- producers using local facilities, purchasing local power, enforcement, and Canada’s Drug Strategy has been indolent paying business taxes, and expanding the job market.7 in addressing these claims.4 Dr. Thomas Kerr, co-director at Patients the British Columbia Centre for Excellence in HIV/AIDS, While the commercialization of medical marijuana could mentioned that “If Canada wants to fulfill its mission of prove to be beneficial from an economic standpoint, reducing the most severe harms associated with illicit drug patients may be reluctant to accept the new change, as use, steps must now be taken to implement a truly evidence- lawsuits have already been filed in an effort to prevent the based national drug strategy rather than shoveling millions complete implementation of the regulations.7 The fact of dollars towards these failed programs.”3 that there are currently four licensed producers in Canada is indicative of the monopoly of medical marijuana that The original Marihuana Medical Access Program will could be potentially created in the future.8 According to give way to a completely new set of rules under the title Health Canada, the price of medical marijuana is expected

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to rise drastically in the short run, which may dissuade a large portion of consumers from purchasing marijuana initially. Sophie Galarneau, an executive director of Health Canada’s CONCLUSION medical marijuana department, addressed these concerns: “We expect that over time, prices will be driven down by the free market.” She believes Health Canada’s resolute decision that competition between licensed producers to completely restructure its policies will aid in keeping prices at an affordable rate as on medical marijuana was not aimless; it was a strategic approach to push the nation time progresses after the initial spike.11 forward in terms of controlled drug use and Now that general practitioners can prescribe production, while redirecting revenue to the marijuana, patients no longer need to obtain government. No matter the policy, when a the approval of a specialist. While this may large number of people are affected, there cause doctors to feel additional pressure in will be shortcomings. Yet the marijuana prescribing medical marijuana, the increase in medical access legislation was not meant as an patient accessibility seems to be a commensurate inconvenience to patients and doctors. With benefit. Although Dr. Arnold Schoichet, a sufficient awareness and debate, new policies member of the Medical Cannabis Resource can be created to remedy any inconveniences Centre, believes that medical marijuana is that may arise in the future. As mentioned efficacious, he acknowledges why his colleagues by Mark Gobuty, the co-founder of Peace may have apprehensions about the drug:“There Naturals (a licensed marijuana producer), are no guidelines for dosage or administration. “It’s really about the purpose and intent of No clear outlines of side effects and risks. the medicine we can provide. If we can do There are no standards for preparation… It’s one thing, we want to provide people with a very awkward position for doctors to be in.”12 peace.”10 ■ REVIEWED BY DR. MICHAEL WONG Dr. Michael Wong (B.Sc., Ph.D.) is a professor at McMaster University in the Faculty of Health Sciences. His research involves applying a combination of physics, neurophysiology, and probability calculus to investigate tactile spatial acuity. The themes of his research include exploring the concept of enhanced tactile perception in the blind, and changes in tactile acuity during development and aging.

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mps/marihuana/info/faq-eng.php 10. Medical marijuana users worry about prices as market expands. The Canadian Press [Internet]. 2013 Dec 21 [cited 2014 Jan 18].

Available from: http://www.cbc.ca/news/ canada/medical-marijuana-users-worryabout-prices-as-market-expands-1.2472969 11. Health Canada presides over birth of billiondollar free market in marijuana. The Canadian Press [Internet]. 2013 Sep 29 [cited 2014 Jan 18]. Available from: http://www.cp24.com/ world/health-canada-presides-over-birthof-billion-dollar-free-market-in-marijuana1.1475706#ixzz2gJEOCJ3H 12. Curt Petrovich. Medical marijuana rules change means expansion for B.C. business.

CBC News [Internet]. 2014 Jan 16 [cited 2014 Jan 18]. Available from: http://www. cbc.ca/news/canada/british-columbia/medical-marijuana-rule-change-means-expansionfor-b-c-business-1.2500016

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18]. Available from: http://www.hc-sc.gc.ca/ ahc-asc/media/nr-cp/_2013/2013-79-eng. php 6. Medical Use of Marihuana [Internet]. Health Canada; 2013 Nov 27 [cited 2014 Jan 18].

Available from: http://www.hc-sc.gc.ca/dhpmps/marihuana/index-eng.php 7. Brian Hutchinson. Medical marijuana production in Canada set for dramatic change.

National Post Canada [Internet]. 2014 Jan 17 [cited 2014 Jan 18]; Available from: http:// news.nationalpost.com/2014/01/17/medical-marijuana-production-in-canada-set-fordramatic-change/ 8. List of Authorised Licensed Producers under the Marihuana for Medical Purposes Regulations [Internet]. Health Canada; 2014 Jan 10 [cited 2014 Jan 18]. Available from: http:// www.hc-sc.gc.ca/dhp-mps/marihuana/info/ list-eng.php 9. Frequently Asked Questions [Internet]. Health Canada; 2013 Jun 19 [cited 2014 Jan 18].

Available from: http://www.hc-sc.gc.ca/dhp-

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A history of marijuana use in Canada. Toronto Star [Internet]. [cited 2014 Jan 17]. Available from: http://www.thestar.com/news/ canada/marijuanaincanada.html# 2. Marihuana Medical Access Regulations.

Canada: Minister of Justice; 2013 Oct 1. 41p.

Report No.: SOR/2001-227 3. Canada’s renewed drug strategy lacks accountability: review. British Columbia Centre for Excellence in HIV/AIDS [Internet]. 2007 Jan 15 [cited 2014 Jan 17]. Available from: http://www.cfenet.ubc.ca/news/releases/ canada%E2%80%99s-renewed-drug-strategy-lacks-accountability-review 4. Friedman SR, Cooper HL, Tempalski B, Keem M, Friedman R, Flom PL, Des Jarlais DC. Relationships of deterrence and law enforcement to drug-related harms among drug injectors in US metropolitan areas. NDRI 2006 Jan 2;20(1):93-9.

5. Harper Government Announces New Medical Marihuana Regulations [Internet]. Ottawa: Health Canada; 2013 Jun 10 [cited 2014 Jan

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Conceived in Liberty

ACKNOWLEDGING THE HUMAN RIGHTS OF THE UNBORN THROUGH OPPOSING GENDERCIDE NATHAN GAMBLE1 AND JOEL GAMBLE 2

opinion

Bachelor of Health Sciences (Honours), Class of 20151, Class of 20172 McMaster University Correspondence: nathan.gamble@learnlink.mcmaster.ca and joel.gamble@learnlink.mcmaster.ca

Sex-selective abortion, also colloquially referred to as “gendercide,” has become an increasingly prevalent issue.

Technological advancements have allowed parents to know the sex of their child in utero. In some ethnic groups, parents frequently abort their unborn child (almost always female) if the sex does not align with cultural desires and pressure.1 In India and China, the problem has become so endemic that physicians are barred from notifying parents of the sex of their baby in utero. This, however, has done little to curb the problem.2 By the early 1990s, it was reported that 100 million girls had gone “missing.”1 In 2010, the Journal of Obstetrics and Gynaecology Canada published an article describing the creeping prevalence of sex-selective abortions into Canada – a trend linked to immigration patterns – despite 92% of Canadians being against the practice.3 An article in the Canadian Medical Association Journal claims that gendercide “is about discrimination against women in its most extreme form.” 4

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To discriminate is to “make an unjust or prejudicial

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distinction in the treatment of different categories of people” [emphasis added] (Oxford English Dictionary). Article 7 of the United Nation’s Universal Declaration of Human states, “All are entitled to equal protection against any discrimination in violation of this Declaration and against any incitement to such discrimination.”5 In gendercide, the prejudicial distinction is made through abortion, and the object of discrimination is unborn females. Since sexselective abortion discriminates against the unborn and is considered to be unjust discrimination, the following premise is formed: a sex-selective abortion is the violation of an unborn female’s human rights.

Another premise can be formed by assuming that human rights violations ought to be stopped. Thus, the following syllogistic argument can be made: (1) A sex-selective abortion is a violation of an unborn female’s human rights. (2) Human rights violations ought to be stopped. (3) Therefore, sexselective abortion ought to be stopped.

gendercide violates human rights – namely, that unborn females are human persons – as has been demonstrated.

To feel moral aversion to sex-selective abortions is to acknowledge that unborn females belong to the same category of things as born females: female human persons. The aversion cannot simply be because abortion is a traumatic procedure. Most surgeries involve blood and many feel sick when they think about the details, but such nausea cannot be described as moral aversion. The strong emotive reaction to sex-selective abortion is rather a response to the fact that it kills a female for being a female.

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Dr. David Hitchcock received a Bachelor’s degree in Honours Philosophy from McMaster University and then obtained a Ph.D. in Philosophy from Claremont Graduate School. He is currently a tenured professor at McMaster University and conducts research on argumentation theory and ancient Greek philosophy. He has taught courses on informal logic, ancient Greek and Roman philosophy, argumentation theory, the history of logic, and symbolic logic.

Fikree FF, Pasha O. Role of gender in health disparity: the South Asian context. BMJ. 2004 Apr 3;328(7443):8236. PubMed PMID: 15070642. Pubmed Central PMCID: 383384.

2. Hesketh T, Lu L, Xing ZW. The consequences of son preference and sex-selective abortion in China and other Asian countries. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2011 Sep 6;183(12):1374-7. PubMed PMID: 21402684. Pubmed Central PMCID: 3168620.

3. Thiele AT, Leier B. Towards an ethical policy for the prevention of fetal sex selection in Canada. Journal of obstetrics and gynaecology Canada : JOGC = Journal d’obstetrique et gynecologie du Canada : JOGC. 2010 Jan;32(1):54-7.

PubMed PMID: 20370982.

4. Kale R. “It’s a girl!”--could be a death sentence. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne.

2012 Mar 6;184(4):387-8. PubMed PMID: 22249985. Pubmed Central PMCID: 3291664.

5. United Nations. General Assembly. The Universal declaration of human rights.

New York,: King Typographic Service Corp.; 1949. 14 p. p.

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Yet, the insult to female persons does not merely arise because something female is killed. Male persons would not be insulted if only bucks were culled to protect the environment from an overpopulation of deer.

Female persons would not be offended if an arborist decided to chop down only female The strength of an argument depends on holly bushes. It is not the killing of a female the acceptability of its premises. The present thing, but the killing of a female person that argument relies on the premise that “a sex- is an affront to other female persons. In other selective abortion is a violation of an unborn words, females are insulted by sex-selective female’s human rights.” This statement abortion in the same way that they would reflects common word choice in the debate be denigrated if women in another country against sex-selective abortions. However, it were executed en masse because the women is possible that opponents of gendercide are were considered an economic nuisance. Sexusing the language of rights for its rhetorical selective abortions are an abuse of females weight, not because they actually admit sex- inasmuch as unborn females are, like them, selective abortions to be violations of human female persons. rights. Females may intuitively deem sexselective abortions as insults against them, If the unborn female is considered a human since unborn females are being killed solely person with the preeminent right to life, then for a trait they too possess – being female. sex-selective abortion is a violation of this Their opposition could be articulated, “Sex- right. Furthermore, if the unborn are persons, selective abortion is reprehensible because they possess human rights regardless of their it insults born females.” This rationale has sex. Therefore, abortion is a violation of the same assumption as the proposition that human rights that ought to be stopped. ■

opinion

However, if the rights of an unborn female are violated through a sex-selective abortion, an unborn female must possess human rights to be violated. One cannot violate something that does not exist. If an unborn female has human rights, she must be a human being and not merely tissue. Skin cells in a Petri dish do not receive human rights, for instance. All signatories of the United Nation’s Universal Declaration of Human Rights agree that human rights include the right to life; the right to security of person; the right not to be subject to torture or to cruel, inhuman, or degrading treatment; and the right to recognition everywhere as a person before the law.5 Abortion inherently violates all four, but most specifically, it violates the preeminent right to life. All other rights are predicated upon an individual’s existence. Therefore, if a sex-selective abortion of an unborn female is a violation of human rights, both unborn males and females are human beings and possessors of human rights.

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Re-evaluating the Hierarchy of Evidence WHAT IS THE GOLD STANDARD? BRANDON TANG1 AND STEPHANIE WAN 2 Bachelor of Science, Biology & Psychology (Honours), Class of 2014 Bachelor of Arts & Science (Honours), Class of 2015 McMaster University Correspondence: tangb8@mcmaster.ca and faline.wan@gmail.com 1

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On October 16, 1846, William Morton took part in an operation to remove a tumour from a patient’s neck. However, this surgery was unlike any other that had been completed before.1 Morton’s stage was the local surgical amphitheater in the Massachusetts General Hospital, and his main prop was the ether, a novel substance that promised to alleviate pain in an unprecedented manner. Within the amphitheater, scientists, dentists, and doctors eagerly awaited the awakening of Morton’s patient after the surgery.

To everyone’s delight, after awakening, the patient announced that he did not feel any pain during the operation. Barely a month later, this local stage turned global when Henry Jacob Bigelow published this case study in the Boston

Medical & Surgical Journal.2,3 To this date, the birth of anesthesia is considered a landmark medical discovery.

This story is remarkable for three main reasons. First, Morton wagered his time and reputation in order to investigate the use of ether as an anesthetic. Though the analgesic effects of ether had been previously known, it was used predominantly for entertainment purposes at the time, producing effects similar to alcohol, but with a faster onset.4 Morton was the first to demonstrate that ether could be used within a medical setting.5 Second, this public demonstration occurred on October 16th, 1846 and was published in the high-impact Boston Medical and Surgical Journal (the present-day New England Journal of Medicine) on November 18, a mere 33 days later.2 The third and final reason is that Morton’s bold investigation effectively launched the widespread use of anesthetics, which are now incorporated into virtually every area of modern medicine. Today, a story like this would seem more based on fiction rather than fact. In the contemporary and regulated research environment of the 21st century, would this remarkable story have been possible?

Since Morton’s time, the conception of evidencebased medicine has significantly altered the landscape of medical research. Central to evidence-based medical research is the hierarchy of evidence, which ranks different study designs based on the strength of their methods.6 The studies best protected against bias are ranked highest in the hierarchy. At the top of the hierarchy of evidence rest randomized control trials, which test enormous numbers of patients; at the bottom of the hierarchy rest case studies, as they typically focus on a physician’s experience with a single patient. By acknowledging that medical research is prone to error, the hierarchy of evidence is crucial to the practice of evidence-based medicine. It enables fast and efficient identification of the

strongest evidence amongst a vast body of existing literature. Adoption of the hierarchy of evidence lends confidence to physicians and policy makers who use scientific evidence to direct decision-making.

It is clear that the modern research environment is tremendously different than that of Morton’s time. Morton’s case study would have been ranked lowest in the hierarchy of evidence; it would be a near miracle if it reached the pages of a high-impact journal within 33 days using today’s standards. Often in medical research, controlled studies are deemed more “fit” for journals and academic discourse, while more audacious investigations, like Morton’s case study, may be considered so anecdotal that they ought to be reserved for the diaries of deranged scientists.

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Robinson DH, Toledo AH. Historical development of modern anesthesia. J Invest Surg. 2012; 25(3):141-149.

Stephanie JS. Blessed days of anaesthesia: How anaesthetics changed the world. New York: Oxford University Press; 2008.

Bigelow HJ. Insensibility during surgical operations produced by inhalation. Boston Med Surg J. 1846; 35(16):309-317.

Miller, RL. Ether. In: The Encyclopedia of Addictive Drugs. Westport: Greenwood Press, 2002. pp. 153–154 Desai SP, Desai MS, Pandav CS. The discovery of modern anaesthesia-contributions of Davy, Clarke, Long, Wells and Morton. Indian J Anaesth. 2007; 51(6), 472-478.

Elamin MB, Montori VM. The hierarchy of evidence: From unsystematic clinical observations to systematic reviews. In: Neurology. New York: Springer; 2012. p. 11-24.

Parente R, Oliveira M, Celeste R. Case reports and case series in the era of evidence-based medicine. Bras J VideoSur. 2010; 3(2), 63-66.

Massachussets General Hospital. (2013).

The Roots of Critical Care [Image from the internet]. Available from http:// giving.massgeneral.org/the-roots-ofcritical-care [accessed 6 Mar 2014] Alexandre Y, Le Blay G, Boisrame-Gastrin S, Le Gall F, Hery-Arnaud G, Gouriou S, et al. Probiotics: A new way to fight bacterial pulmonary infections? Med Mal Infect. 2014; 44(1): 91-7.

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Dr. Michael Wong (B.Sc., Ph.D.) is a professor at McMaster University in the Faculty of Health Sciences. His research involves applying a combination of physics, neurophysiology, and probability calculus to investigate tactile spatial acuity. The themes of his research include exploring the concept of enhanced tactile perception in the blind, and changes in tactile acuity during development and aging.

1.

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REVIEWED BY DR. MICHAEL WONG

FIGURE 1: The public demonstration of medical ether: On October 16, 1846, Wiliam T. G. Morton publicly demonstrated for the first time the use of ether as an anesthetic.8

opinion

How does this practice impact the scientific community? As stated earlier, each level of the hierarchy of evidence has its own merits; yet certain forms of evidence are preferentially published in high-impact journals. Such published research can be easily circulated to the scientific community and receive more exposure than unpublished evidence. We A hierarchical system of evidence is valuable argue that this is a misuse of the hierarchy. The as it establishes a firm set of guidelines to hierarchy of evidence was originally intended follow when sifting through large quantities to make us aware of the biases in studies, not of information. However, there are some to make us uncritically cast aside research problems with this approach. Case studies are based on its classification. Unfortunately, the considered inherently biased in the hierarchy, pervasiveness of publication biases in the as they are observational by nature. However, modern research environment dictates the their merits lie in their lack of a controlled types of studies we conduct, thus limiting the design, which offers an unfiltered and unique scope of the knowledge we choose to pursue. insight. They can spark new ideas and hypotheses or even launch a movement, as Discoveries are often catalyzed by the work seen in Morton’s case. By offering a different of observant scientists who pursue ideas that perspective from randomized control trials, deviate from previous lines of work. The studies with a higher risk of bias are still development of penicillin, like anesthesia, worthwhile endeavours for the unique insight was largely based on a scientist’s subtle they can provide. observations.9 Underscoring these discoveries are scientists with open minds who had opted Although science claims to be an objective for a less restrictive scientific process. However, endeavour, those who practice it are not free this freedom in the scientific process is now from biases. The “publish or perish” mentality somewhat lost by favouring certain research describes the pressure on academic researchers methodologies over others. This preference to publish frequently in high-impact journals. is not a direct result of the hierarchy of Perhaps because case studies are considered evidence’s establishment or its goals, but a lower level of evidence, they are often less rather a result of the manner with which the frequently cited in journals than other forms hierarchy is used by research journals when of evidence.7 Consequently, journal editors selecting studies for publication. The solution may opt to avoid publishing these studies is not to dismantle the hierarchy altogether, in favour of larger investigations that will but to ensure that we remain open to the garner citations and maximize their journal’s different ways we can approach scientific purported influence. research; otherwise, we run the risk of leaving fruitful avenues of knowledge unexplored. ■

EDITED BY MAYLYNN DING | ART BY YASMEEN MANSOOR

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FORUMSPACE

Optimal Screening Approaches COORDINATING OPTIMAL SCREENING PROGRAMS IN CANADA: A MULTIFACETED APPROACH ERIC CHEN1 AND HAMZA QAMAR 2 Bachelor of Health Science (Honours), Class of 2015 Bachelor of Science, Biology (Honours), Class of 2017 McMaster University Correspondence: eric.chen3742@icloud.com and qamarh@mcmaster.ca 1

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forumspace table of contents

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INTRODUCTION

The McMaster Health Forum strives to be a leading hub for improving health outcomes at the regional and provincial level in Canada. Through problem-solving and discussion, they harness information, convene stakeholders, and prepare action-oriented leaders to meet pressing health issues creatively.

three times as many screening tests for newborns compared to the maritime provinces of Prince Disease screening is the process of testing Edward Island and New Brunswick.6,7 Screening asymptomatic individuals for the risk or presence of guidelines for ailments such as hypertension disease.1 However, the advent of advanced screening and diabetes are also yet to be made regionally technologies in recent decades poses a challenge consistent.8-9 Furthermore, competing interests in to the Canadian healthcare system. The lack of healthcare impede the implementation of optimal a consistent screening policy among Canadian screening practices, such as the financial gains to provinces and poor adherence to screening physicians who offer more tests, and the political guidelines have compounded the challenge.2-4 The gains to candidates who promise to implement largeMcMaster Health Forum convened a stakeholder scale screening efforts that are unsupported by current dialogue on October 17, 2013 with regards to evidence.10 Together, these inconsistencies lead to supporting optimal screening practices in Canada. a great variation in screening approaches within In consultation with stakeholders, the Forum Canada, and must be addressed when implementing created an issue brief describing the problem, optimal screening practices to benefit all Canadians. three elements of a comprehensive approach to The Canadian healthcare system also faces significant address this problem, and key implementation challenges in the implementation of coordinated considerations for this approach.5 screening approaches. Screening uptake appears to be significantly lower in rural and northern areas, as WHAT IS THE PROBLEM? well as among immigrants, refugees, and members of ethno-cultural communities.11-13 Currently, there are Three key issues have contributed to sub-optimal no existing national requirements for adherence to screening practices in Canada: 1) screening policies screening protocols, nor cross-jurisdictional reviews and practices vary between provinces and territories; of current efforts in screening.

2) the structure of the healthcare system in Canada limits efforts to coordinate the implementation Finally, healthcare consumers often do not of optimal screening approaches; and 3) there consistently adhere to evidence-based screening is inconsistent adherence to existing screening guidelines, even when the optimal screening options guidelines and principles. Together, these three are available. Adherence to recommendations is problems pose significant challenges to optimal severely limited by the ease of obtaining screening screening practices for Canadians across provinces tests at the patients’ request, and by the widespread and territories. The level of screening provided availability of screening tests outside formal screening greatly differs between Canadian provinces and programs.14 territories. For example, Manitoba offers more than

APPROACHES TO ADDRESS THE PROBLEM

IMPLEMENTATION CONSIDERATIONS Potential barriers exist at each level of individuals and institutions involved in the provision of optimal screening in Canada. For instance, consumers may not adopt recommended guidelines due to over-enthusiasm for one approach. Alternatively, physicians may be unwilling to change their current practice, and may view the proposal as an encroachment on their professional autonomy. Governments also may not be willing or have sufficient resources to create, develop, and sustain a central hub for evidence synthesis decision-making to support optimal screening practices.

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More details on the problem and the suggested approaches to optimizing screening in Canada as identified by the McMaster Health Forum are available in the Forum issue brief, which can be found at http://www.mcmasterhealthforum.org/

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Second, a “hub” to coordinate evidence synthesis and recommendation development to support optimal screening practices While each element of this approach has could be established. A centralized hub can unique or shared barriers that may prevent serve the needs of all Canadians through 1) their full or effective implementation, there panel discussions with appropriate experts; also exist ‘windows of opportunity’ through 2) providing specific locales with access to which an effective implementation can research evidence; and 3) facilitating local be achieved. The Canadian Task Force on adaptations to research evidence. These Preventive Health Care, established in 2010, combined interventions will minimize cross- provides a model and infrastructure through jurisdictional variations in screening. which the elements of optimal screening can be supported.23 Additionally, the success of the Third, support for optimal implementation National Immunization Strategy implemented of screening approaches could be offered to in 2003 can serve as an example of how to all stakeholders. For healthcare providers, operationalize all the elements of the plan practices such as the distribution of educational proposed for optimizing screening practices. ■

1. Raffle A, Gray M. Screening Evidence and Practice. Oxford, United Kingdom: Oxford University Press; 2007.

2. Andermann A, Blancquaert I, Déry V. Genetic screening: a conceptual framework for programmes and policy-making. Journal of Health Services Research & Policy 2010;15(2):90-7.

3. Leddin DJ, Enns R, Hilsden R, Plourde V, Rabeneck L, Sadowski D et al. Canadian Association of Gastroenterology position statement on screening individuals at average risk for developing colorectal cancer. Canadian Journal of Gastroenterology 2010;24(12):705-14.

4. Mema SC, McIntryre L, Musto R. Childhood vision screening in Canada: Public health evidence and practice. Canadian Journal of Public Health 2012;103(1):40-5.

5. Wilson MG, Lavis JN. Evidence Brief: Supporting Optimal Screening Approaches in Canada. Hamilton, Canada: McMaster Health Forum, 17 October 2013.

6. Canadian Organization for Rare Disorders. Newborn Screening in Canada Status Report. Toronto, Canada: Canadian Organization for Rare Disorders; 2013.

7. Canadian Partnership Against Cancer. Breast Cancer Control in Canada: A System Performance Special Focus Report. Toronto, Canada: Canadian Partnership Against Cancer; 2012.

8. Canadian Task Force on Preventive Health Care.

Recommendations on Screening for High Blood Pressure in Canadian Adults. Edmonton, Canada: Canadian Task Force on Preventive Health Care; 2012.

9. Canadian Task Force on Preventive Health Care.

Recommendations on screening for Type 2 diabetes in adults. Canadian Medical Association Journal 2012;184(15):1687-96.

10. Moynihan RN, Cooke GPE, Doust JA, Bero L, Hill S, Glasziou PP. Expanding Disease Definitions in Guidelines and Expert Panel Ties to Industry: A Cross-sectional Study of Common Conditions in the United States. PLoS Med 2013;10(8):e1001500.

11. Maddison AR, Asada Y, Urquhart R. Inequity in access to cancer care: A review of the Canadian literature. Cancer Causes Control 2011;22(3):359-66.

12. Grewal S, Bottorff JL, Balneaves LG. A Pap test screening clinic in a South Asian community of Vancouver, British Columbia: challenges to maintaining utilization. Public Health Nurs 2004 September;21(5):412-8.

13. Redwood-Campbell L, Fowler N, Laryea S, Howard M, Kaczorowski J. ‘Before you teach me, I cannot know’: immigrant women’s barriers and enablers with regard to cervical cancer screening among different ethnolinguistic groups in Canada.

Can J Public Health 2011 May;102(3):230-4.

14. Canadian Breast Cancer Foundation. Where Should I go for a Mammogram. Canadian Breast Cancer Foundation 2013 September 16;Available from: URL: http://www.cbcf.org/central/AboutBreastHealth/EarlyDetection/Mammography/ Pages/Where- to-Get-a-Mammogram.aspx 15. Martin-Misener R, Valaitis R, Wong ST, MacDonald M, Meagher-Stewart D, Kaczorowski J et al.

A scoping literature review of collaboration between primary care and public health. Primary Health Care Research & Development 2012; 13(4):327-46.

16. Noorani HZ, Husereau DR, Boudreau R, Skidmore B. Priority setting for health technology assessments: A systematic review of current practical approaches. International Journal of Technology Assessment in Health Care 2007;23(3):310-5.

17. Guindo AL, Wagner M, Baltussen R, Rindress D, van TJ, Kind P et al. From efficacy to equity: Literature review of decision criteria for resource allocation and healthcare decision making. Cost Effectiveness and Resource Allocation 2012;10(1):9.

18. Vuorenkoski L, Toiviainen H, Hemminki E. Decision-making in priority setting for medicines - A review of empirical studies. Health Policy 2008;86(1):1-9.

19. Menon D, Stafinski T, Martin D, Windwick B, Singer P, Caulfield T.State of the science review: Incorporating public values and technical information into health care resource allocation decision- making.

Edmonton, Canada: Alberta Innovates - Health Solutions; 2003.

20. Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L et al. Effectiveness and efficiency of guideline dissemination and implementation strategies. Health Technology Assessment 2004;8(6).

21. Stacey D, Bennett CL, Barry MJ, Col NF, Eden KB, Holmes-Rovner M et al. Decision aids for people facing health treatment or screening decisions.

Cochrane Database of Systematic Reviews 2011;(10):1-215.

22. Camilloni L, Ferroni E, Cendales B, Pezzarossi A, Furnari G, Borgia P et al. Methods to increase participation in organised screening programs: a systematic review. BMC Public Health 2013;13(1):464.23. Canadian Task Force on Preventive Health Care.

23. Canadian Task Force on Preventive Health Care 2013 July 30; Available from: URL: http://canadiantaskforce.ca/

introduction forumspace

The McMaster Health Forum, in consultation with expert informants, identified three elements of a comprehensive approach to improve screening practices in Canada. The Forum then appraised systematic reviews relevant to each of the three elements. First, a model could be created to coordinate decisionmaking about screening across multiple sectors and jurisdictions. This approach includes the establishment of a process to identify potential coordination models and set priorities for evidence synthesis as part of a pan-Canadian coordinating hub on optimal screening practices.15-16 Additionally, it could include the development of criteria to guide healthcare decision-making with respect to resource allocation in terms of the costs and benefits provided by screening tests.17-18 Efforts to consult and engage consumers and other relevant stakeholders could also be made to inform the decision-making process.19 These strategies would ensure the establishment of models that are optimal for screening practices.

materials as well as audit and feedback have been shown to improve adherence to practice guidelines.20 With regards to patients, the development of decision aids and personalized risk communications improved patient risk assessment. Frequent postal and telephone reminders also significantly improved participation in organized screening programs.21-22 These efforts may collectively serve to improve adherence to established screening guidelines.

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table of contents ARTIST ANNIE ZHU

CRITICAL REVIEW

Obesity and Alzheimer’s Disease A BRIDGE BETWEEN TWO WORLDS 19

ISHAN ADITYA AND JASON FAN Bachelor of Health Sciences (Honours), Class of 2017 McMaster University Correspondence: ishan.aditya@learnlink.mcmaster.ca and jason.fan@learnlink.mcmaster.ca

ABSTRACT Obesity and Alzheimer’s disease (AD) are two chronic illnesses with far reaching effects. Although both diseases are manifested in physiologically different ways, they share many molecular similarities and affect millions of individuals. Three mechanistic links for these two diseases include: brain derived neurotrophic factor (BDNF), insulin, and chronic inflammation. BDNF has long been associated with neuronal growth and synaptic plasticity but has also been linked to hunger control. Studies independently investigating obesity and AD have shown down-regulation of BDNF in both pathologies. While insulin functions as a critical regulator of blood glucose, insulin resistance and feedback inhibition of insulin production have both been described in the initiation and maintenance of obesity and AD. Lastly, chronic inflammation may lead to and result from AD and obesity. For example, brain inflammation in AD may lead to neurodegeneration, while obesity may also place the body in a state of chronic inflammation. This review seeks to elucidate and bridge the gap between obesity and AD, thus identifying new therapeutic targets common to both diseases.

INTRODUCTION

The negative impact of obesity on cognitive function is attributable to vascular defects, impaired insulin metabolism and signalling, or a defect in glucose transport mechanisms in the brain. Interestingly, recent studies in humans have also detected impaired insulin signalling in the brain of patients afflicted by Alzheimer’s disease (AD).2 AD is the most common form of dementia affecting 5-10 percent of North Americans over the age of 65.3 Recent studies have noted the marked increase of AD susceptibility with older age, diabetes, and obesity.4-6

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a BDNF gene deletion.21,22 Moreover, human disorders that have been associated with defects at the BDNF gene locus are also characterized with elevated levels of adiposity.20

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BDNF is also an important mediator of energy balance, and its loss has been implicated in obesity. Acting downstream to the melanocortin-4 receptor, BDNF expressed in the hypothalamus is able to suppress hunger.15 Chronic injections of BDNF into rat ventricles have resulted in suppressed hunger and a decrease in body weight.16 Conversely, studies on food deprivation have shown decreased IN 1997 THE WORLD HEALTH levels of BDNF in the dorsal vagal ORGANIZATION STATED THAT complex of the brainstem.17 In “…OBESITY SHOULD NOW BE addition, this region has already REGARDED AS ONE OF THE been shown to possess the highest GREATEST NEGLECTED PUBLIC density of melanocortin-4 receptors.

HEALTH PROBLEMS OF OUR However, BDNF expression in TIME…”1 response to food deprivation has yet to be demonstrated in other parts of the brain.18,19 Kernie et al. conducted in vivo studies on heterozygous BDNF knockout mice and observed phenotypes consistent with obesity.20 For example, transgenic BDNF heterozygous mutant mice showed increased weight (4-fold increase in lipid to water percentage and adipose cell hypertrophy) compared to wild types.20 Supportive data has been described with an obese phenotype in postnatal mice containing

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This review seeks to elucidate the relationship between the two seemingly different pathologies, discuss possible treatments, and promote further research in this field. Both intercellular and intracellular mechanisms of disease onset and progression will be examined for both AD and obesity, but particular emphasis will be placed on the pathophysiological similarities between the two diseases.

BDNF, a member of the neurotrophin family, plays a key role in enhancing survival, differentiation and growth of certain neural populations.7 It is particularly important for synaptic plasticity and long-term potentiation, which underlie learning and memory.8,9 In the cerebral cortex and hippocampus, regions of the brain important for memory and cognitive function, a high level of BDNF expression functions to promote neuronal survival and growth.10-12 Notably, BDNF mRNA and protein expression are dramatically reduced in patients afflicted with AD. 10,13,14

critical introduction review

In 1997 the World Health Organization stated that “…obesity should now be regarded as one of the greatest neglected public health problems of our time…” In fact, the onset of a ‘globesity epidemic’ was predicted, with more than 1 billion adults being overweight and at least 300 million of these being clinically obese (defined by a body mass index greater than 30).1

BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF)

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BDNF signaling may serve as a potential link between AD and obesity. Further research should investigate the effects of BDNF on the adipocytes and neural cells of AD and obese patients to establish a clear link.23

critical review table of contents

INSULIN

Insulin, a peptide hormone synthesized by the pancreas, is responsible for various roles such as fat metabolism and control of gene expression in cells. Generally, many obese individuals become resistant to the effects of insulin on glucose uptake, metabolism, or storage.24 With regards to AD, insulin functions as INFLAMMATION a key molecule in the phosphoinositidekinase (PI3-K) pathway – a pathway heavily implicated in neurodegeneration and the Recent research initiatives have explored aging process, as well as diabetes and obesity.25 the link between obesity and high sugar/ fat diets with immune cells functioning as Several studies have implicated the key mediators of this link. Obesity is BRAIN-DERIVED insulin deficiency and insulin regarded by some as an inflammatory disease concentrations NEUROTROPHIC FACTOR resistance with the clinically- due to the secretion of high 38,39 Research (BDNF) SIGNALING MAY defining histological findings of inflammatory regulators. efforts are in progress to develop drugs to 26 SERVE AS A POTENTIAL of AD. In particular, protein block specific inflammatory proteins in order fragments termed amyloid-beta LINK BETWEEN AD AND to prevent and possibly treat obesity, which (Aβ) are thought to be one of OBESITY. FURTHER is the precursor to several cardiovascular and the key hallmarks of AD. Aβ RESEARCH SHOULD 39 cognitive degenerative diseases. is cleaved from the amyloid

INVESTIGATE THE EFFECTS OF BDNF ON THE ADIPOCYTES AND NEURAL CELLS OF AD AND OBESE PATIENTS TO ESTABLISH A CLEAR LINK.23

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FIGURE 1: A schematic diagram outlining the mechanisms by which sustained activation of the PI3-K/Akt/ mTOR pathway due to

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Increased production of Aβ overactivates the PI3-K pathway by competitively binding to insulin receptors (IR), inducing IR internalization.33,34 This effect of IR internalization is further compounded by Aβ-induced activation of the Jun N-terminal Kinase ( JNK) pathway.25 Activation of this pathway thereby leads to decreased levels of insulin,35,36 as JNK is involved in a feedback inhibition loop of insulin production.25,37 Consequently, the complex signaling network established by insulin may promote obesity and AD through a number of mechanisms.

amyloid-beta (Aβββ) leads to decreased Forkhead box-O class transcription factors (FOXO), increased phosphorylation of protein tau – leading to neurofibrillary tangles (NFTs), as well as insulin receptor (IR)/insulin growth factor (IGF) receptor desensitization.19

precursor protein (APP).25 Pathology occurs when A-β42 (the 42- amino acid length product) aggregates to form cytotoxic soluble oligomers and extracellular senile plaques.27-30 The resulting Aβ aggregation is thought to be one of the triggers for the characteristic decline observed in AD.31,32

Insulin plays an important role in memory and brain function, and individuals who suffer from insulin resistance may be at risk for AD. Obesity may also be a consequence of elevated insulin levels as a compensatory mechanism to insulin resistance, as seen in many diabetic patients. The association of age-related obesity with increased inflammation in blood vessels initiating as a result of insulin signaling has been further cognitive described in disrupting the blood-brain Aβ also plays an important role in modulating barrier in the elderly population. The resulting the PI3-K/Akt/mTOR signalling pathway, neuroinflammation and oxidative stress as which is involved in both obesity and AD. observed in the mouse hippocampus may be disease progression/cognitive decline

EARLY

Defective proteostatis Decreased stress resistance Diminished DNA Repair

FOXO

Aβ

LATE

PI3K / Akt / mTOR PTEN

Neurofibrillary tangles

tau P

IR/IGF-1R desensitization

one mechanism for the phenotypic cognitive decline seen in aged obese animals.40, 41

FUTURE INQUIRY In modern Western society, sedentary lifestyles and the access to caloric-rich foods are becoming increasingly prevalant. These two factors have led to an obesity epidemic and possibly an increased vulnerability to neurodegenerative diseases such as AD. However, recent studies have identified exercise, an antioxidant diet, and intermittent energy restrictions to not only combat obesity but reverse dementia through the up-regulation of BDNF and IGF-1.42-44 In adolescent studies, cognitive functions were significantly better in those who played sports and kept active lifestyles than those who did not.45 Thus, maintaining an active lifestyle with a low-calorie, antioxidantrich diet is one approach to combat the negative effects of obesity and AD.

CONCLUSION Obesity has transformed from being simply a state of disruption in metabolism into a global epidemic that is affecting over one-seventh of the world’s population. In addition to contributing to cardiovascular disease, obesity negatively impacts the brain. AD is a neurodegenerative disease resulting from a multitude of different pathogenic mechanisms, including decreased neurotrophic support, energy metabolism, oxidative stress, and inflammation. Obesity and AD surprisingly share numerous similarities in terms of both intercellular and intracellular communication. Researchers have already identified several factors that connect obesity and AD, such as the down-regulation of BDNF in both insulin resistance and chronic inflammation.

The PI3K/Akt/mTOR pathway downstream of both BDNF and insulin receptors provides an additional point of convergence. Great progress has been made to elucidate the mechanisms behind these common factors, promising future treatments and preventative therapies. By integrating the seemingly unrelated fields of immunometabolism and neuroscience, a viable solution may be attainable. ■

REVIEWED BY DR. MARGARET FAHNESTOCK Dr. Margaret Fahnestock is a professor in the department of Psychiatry & Behavioural Neurosciences and is also an associate member of both Biology and the McMaster Institute for Molecular Biology and Biotechnology (MOBIX). Her primary research interests lie in determining the mechanisms of regulation of neurotrophic factors and their role in human diseases.

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41. Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al. Obesity in Aging Exacerbates Blood-Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci. 2013 Nov 22; 42. Lau Y-S, Patki G, Das-Panja K, Le W-D, Ahmad SO. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur J Neurosci. 2011 Apr;33(7):1264–74.

43. Cheng A, Wang S, Cai J, Rao MS, Mattson MP. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain.

Dev Biol. 2003 Jun 15;258(2):319–33.

44. Joseph D’Ercole A, Ye P. Expanding the mind: insulin-like growth factor I and brain development. Endocrinology.

2008 Dec;149(12):5958–62.

45. Ruiz JR, Ortega FB, Castillo R, MartínMatillas M, Kwak L, Vicente-Rodríguez G, et al. Physical activity, fitness, weight status, and cognitive performance in adolescents. J Pediatr. 2010 Dec;157(6):917–922.e1–5.

critical introduction review

Although the previously mentioned therapy is accessible and practical, it is by no means a silver bullet that can cure obesity or AD. Both pathologies are a result of highly complex mechanisms of which researchers have only skimmed the surface. Manipulations at very specific sites have yielded both negative and positive results; thus researchers must first elucidate the mechanisms behind each signalling

network. This review skims the surface of a highly complex relationship between obesity and AD with hopes that it may inspire individuals to delve further into this field.

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critical review 3 ARTIST ELLEN LIANG

CRITICAL REVIEW

Potential Therapies for Cystic Fibrosis A LOOK AT CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CORRECTORS AND POTENTIATORS 23

SPENCER G. JONES Bachelor of Health Sciences (Honours), Class of 2015 McMaster University Correspondence: spencer.jones@learnlink.mcmaster.ca

ABSTRACT Cystic fibrosis (CF) is an autosomal recessive genetic disorder that is caused by a mutation of the anion channel termed the cystic fibrosis transmembrane conductance regulator (CFTR). Treatment for CF has improved over time; however, many therapies focus only on alleviating symptoms as they occur. There have been recent advances in therapies that repair mutant CFTR, including the administration of small molecules called CFTR modulators. CFTR modulators fall under two categories: correctors that prevent early degradation of CFTR and potentiators that increase conductance of existing CFTR. This review discusses the advantages of repairing mutant CFTR, some recent advances in treatment development, and the future of CFTR modulator therapy.

INTRODUCTION

States from ~28 in 1991 to 36.8 in 2011, and the hope is that it will be common for children born with CF in the 21st century to live beyond 50 years of age.7 However, the purpose of many current CF treatments is only to alleviate symptoms. To improve survival of CF patients, future treatments must address the root cause of the disease: mutant CFTR. This review will explore CFTR modulators, specifically correctors and potentiators, which are molecules that can “repair” mutant CFTR.

GENETICS OF CFTR

CF PHENOTYPE

I

Defective protein synthesis

Severe phenotype from reduced functional CFTR

II

Abnormal trafficking from improper conformation

Severe phenotype from reduced functional CFTR

III

Defective regulation; prevention of ATP binding

Severe phenotype from a normal amount of non-functional CFTR

IV

Decreased conductance

Mild phenotype from a normal amount of reduced functioning CFTR

V

Reduced synthesis and trafficking

Mild phenotype from a reduced amount of normal functioning CFTR

VI

Decreased stability

Severe phenotype from minimal functional CFTR

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In the past 50 years, there have been important developments in the treatments that improve the survival and quality of life of CF patients.

These treatments have increased the median survival age in the United

TABLE 1: Classification system for CFTR mutations

M E D U CATO R

CF is reduced airway mucociliary clearance, resulting in chronic sinopulmonary infection by pathogens including Pseudomonas aeruginosa and Burkholderia cepacia. These infections cause chronic coughing and sputum production resulting in airway obstruction.6 CF mutations also affect most exocrine glands, leading to impaired function of the pancreas, intestine, liver and bile duct.4

critical review

Cystic fibrosis (CF) is an autosomal recessive The CFTR gene, which spans approximately genetic disorder that was first documented in the 230 kb, was first identified in 1989. Since 1930s by Dorothy Hansine Andersen.1 CF is most then, approximately 2000 variants have been prominent in Caucasians, with other ethnic groups identified.2,8 CFTR mutations can have differing being affected at lower incidence rates. In Europe, effects on the CFTR protein and create varying the incidence of CF is one in every 2000-3000 phenotypes; however, these mutations usually fall neonates, and in Canada nearly 4000 individuals in one of six classes (Table 1).9 The most common are affected by the disorder.2,3 CF is caused by variant of CFTR is ΔF508, a Class II mutation mutation to the cystic fibrosis transmembrane which accounts for 66-70% of mutations.4 ΔF508 conductance regulator (CFTR) gene which is is a deletion of the amino acid phenylalanine located on chromosome 7 and encodes the anion at position 508. This deletion causes CFTR to channel, CFTR.2 This channel is found in secretory become mislocalized in the endoplasmic reticulum, epithelial cells of various organs including the lung, preventing the protein from attaining a mature pancreas, and reproductive tract.4 CFTR utilizes conformation. Without this conformation, the the energy of adenosine triphosphate (ATP) to ΔF508 CFTR protein rapidly degrades through allow for anions such as chloride and bicarbonate an ubiquitin-proteasome pathway.10 to flow down their electrochemical gradient.5 Clinical symptoms of cystic fibrosis occur when a The product of the CFTR gene is a 1480-aminomutation alters the function of CFTR, preventing proper anion movement.

CLASS OF EFFECT ON PROTEIN MUTATION The classic clinical manifestation of

24

initial lung damage. Additionally, these treatments do little to prevent symptoms from recurring and, in the case of infection, further reduction in lung function. Thus, it is important that future therapies directly target mutant CFTR to prevent CF symptoms from initially occurring.

carbohydrate

transmembrane domains

THE IDEAL CFTR-REPAIRING DRUG

Site of ∆FS08 mutation ATP

ATP

nucleotide binding domain

nucleotide binding domain

chloride phosphate

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phosphorylation site FIGURE 1: A diagram displaying the current understanding of the structure of CFTR protein.4

CYTOPLASM

acid-long polypeptide chain.11 The CFTR structure consists of two transmembrane domains (TMD1/2), two nucleotide binding domains (NBD1/2), and a regulatory domain with multiple phosphorylation sites (Figure 1). Channel opening is thought to occur when the regulatory domain of CFTR is phosphorylated by protein kinase A. After phosphorylation, ATP is recruited to NBD1 and NBD2. These domains dimerise (NBD1:NBD2) to open the channel pore. Upon subsequent ATP hydrolysis the NBDs dissociate, thereby forcing CFTR into a closed conformation.

This entire process is called “gating.”2, 11 Knowledge regarding the structure of CFTR is important as it allows researchers to develop molecules that can be targeted to fix specific mutations.

M E D U CATO R

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THE IMPORTANCE OF REPAIRING MUTANT CFTR

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Treatments that can directly correct mutant CFTR and restore anion channel function are important as they directly prevent manifestations of CF. For example, a treatment that repairs CFTR would theoretically restore airway ciliary functioning, thereby effectively reducing or eliminating the probability of developing a pathogenic infection, a primary cause of respiratory failure in CF patients.11 When pathogenic infections occur, the immune system releases neutrophils in an attempt to remove the infection. However, these neutrophils also indiscriminately destroy lung tissue such as the muscular and elastic portions of the bronchi, which creates potential for further infection and loss of lung function.12 Treatments that deal solely with the symptoms of pathogenic infection, like antibiotics, may not be able to prevent some of the

When repairing mutant CFTR, two important questions must be asked: How much CFTR needs to be repaired in order to see therapeutic benefits and how will such a treatment be administered?

To address the former question, Zhang et al. looked to restore CFTR function in ΔF508 cells by delivering a normal copy of CFTR through use of a human parainfluenza virus vector. They demonstrated that to restore near-normal mucus transport, non-mutant CFTR must be delivered to approximately 25% of surface epithelial cells.13 This figure is debated as some early trials of CFTRrepairing drugs have shown that in vitro potency does not necessarily correlate with therapeutic benefits.14 Thus, results from the Zhang et al. study should, at most, be regarded as a benchmark.

To answer the latter question about treatment administration, one must look at the ideal profile of a pharmacological agent. The ideal drug can be orally administered, has high potency, and displays minimal side effects.4 CFTR-repairing drugs or CFTR modulators have been shown to display this profile and, therefore, could have strong therapeutic potential.

CFTR MODULATORS CFTR modulators can be broadly defined as small molecules that target and repair specific defects caused by mutations to the CFTR gene.

CFTR modulator drugs can either have corrector or potentiator capabilities.2,11 CFTR correctors allow for mutated CFTR proteins, which would normally be degraded prior to embedding in the cell membrane, to be trafficked to the cell surface. The mechanism of CFTR correctors is unique to the specific mutant. For example, CFTR correctors that are designed to target ΔF508 are thought to inhibit deglycosylation, thus reducing CFTR interaction with calnexin, a protein that induces early degradation.15 By definition, correctors could be used for therapy on CF patients with mutations in Class I, II, V and VI.2, 11 Conversely, CFTR potentiators interact with mutated CFTR channels that are able to embed in the cell membrane, but display reduced conductance or altered gating. These potentiators

than 10%. Additionally, these subjects had 55% fewer pulmonary exacerbations.19 Due to the positive clinical effects of VX-770, it is thought that this potentiator could have synergistic effects with VX-809 in patients with the ΔF508 mutation. Combining these two therapies in a dual therapy is sensible, as a corrector drug like VX-809 may save CFTR from degradation, but once embedded in the apical membrane it still may display minimal function. By utilizing both a corrector and a potentiator drug, CFTR could be fully “repaired” by the combination of correctorinduced degradation prevention and potentiatorinduced conductance increase.

As ΔF508 is the most prevalent mutation of CFTR, it will be the focus of the discussion of treatments. Currently, the most advanced chemical corrector of ΔF508 is an efficacious and selective ΔF508 corrector, VX-809, as demonstrated in vitro by Van Goor et al. This was confirmed by measuring the fractional conversion of endoplasmic reticulum-associated, immature CFTR to the mature glycosylated form. Van Goor et al. also showed that VX-809 was able to restore chloride transport in cultured human bronchial epithelial (HBE) cells to approximately 14% of that measured in non-CF HBE cells.17 As these early results of VX-809 have shown the potential for clinical benefits, Phase II trials have begun. One early trial by Clancy et al. has shown that VX-809 has a good safety and adverse events profile. Additionally, VX-809 was shown to reduce sweat chloride levels in a dose-dependent manner.

However, when using forced expiratory volume in one second (FEV1) as a measure of clinical efficacy, no significant differences were seen in patients taking VX-809 in comparison to placebo.18 Thus, it is currently thought that a CFTR corrector alone is not sufficient to be clinically significant and needs to be administered adjunctively with a CFTR potentiator.

The combination of VX-809 and VX-770 has been tested in two Phase I trials.20,21 The purpose of these trials was to test for drug-drug interactions and safety. Although the results of these trials were not published, it can be assumed that there were no serious safety issues, as a Phase II study is currently in progress.22 The primary outcome measures of this trial are to look at safety and tolerability assessments, change in sweat chloride, and the relative change in percent predicted FEV1. Results of this trial could be important in determining if a combination of CFTR potentiators and correctors could be useful in a clinical setting. Although trials are still occurring for VX-809 and VX-707, they have been designated as “breakthrough therapies” by the US Food and Drug Administration. This designation gives patients access to these drugs, which aid in reducing mutant CFTR.23

CONCLUSION

EDITED BY ANNIE CHEUNG

Dr. Viola Freeman is an Associate Professor in the Department of Pathology and Molecular Medicine at McMaster University. She also teaches part-time in the BHSc and MD programs.

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5.

6.

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Dr. John Waye is a professor in the Department of Pathology and Molecular Medicine at McMaster University. His current research interests lie in the area of human molecular genetics. Specifically, he studies the genetic determinants of hemoglobinopathy syndromes and has an interest in the application of DNA technology in forensic science.

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REVIEWED BY DR. JOHN WAYE & DR. VIOLA FREEMAN

2.

Andersen, DH. Cystic fibrosis of the pancreas and its relation to celiac disease.

Am J Dis Child. 1938; 56: 344-399 Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013; 22(127):58–65.

Cystic Fibrosis Canada. 2012 Annual Report. 2012.

Hanrahan JW, Sampson HM, Thomas DY. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol. Sci. 2013; 34(2):119–25.

Cai Z, Liu J, Li H, Sheppard DN. Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis. Acta Pharmacol Sin. 2011; 32(6):693–701.

Lyczak J, Cannon C, Pier, G. Lung infections associated with cystic fibrosis. Clin Microbiol Rev. 2002; 15(2): 194-222.

Simmonds N. Ageing in Cystic Fibrosis and Long-term Survival. Paediatr Respir Rev. 2013;145:6-9.

Kerem B, Rommens J, Buchanan J, Markiewicz D, Cox T, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245(4922):1073-1080.

Zielenski K. Genotype and Phenotype in Cystic Fibrosis. Respiration. 2000; 67(2):117-133 Maattanen P, Gehring, K, Bergeron J, Thomas D. Protein quality control in the ER: The recognition of misfolded proteins.

Semin Cell Dev Biol. 2010; 21: 500-511.

Merk D, Schubert-Zsilavecz M. Repairing mutated proteins--development of small molecules targeting defects in the cystic fibrosis transmembrane conductance regulator. Expert Opin. Drug Discov. 2013; 8(6):691–708.

Mall M, Grubb, B, Harkema, J, O’Neal W, Boucher R. Increased airway epithelial Na+ absorption produces cystic fibrosislike lung disease in mice. Nat Med. 2004; 10(5):487-493.

Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, Skiadopoulos MH, et al. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 2009; 7(7): e1000155.

Flume P, Liou, T, Borowitz D, Li H, Yen K, Ordonez C, Geller D. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest.

2012; 142(3):718-724.

Okiyoneda T, Veit G, Dekkers J, Bagdany M, Soya N, Xu H, Roldan A, Verkman A, Kurth M, Simon A, Hegedus T, Beekman J, Lukacs G. Mechanism-based corrector combination restores FΔ 508-CFTR folding and function. Nat Chem Biol. 2013; 9(7): 444-454.

Ai T, Bombpadre S, Wang X, Hu S, Li M, Hwang T. Caspsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents. Mol Pharmacol. 2004; 65: 1415-26.

Van Goor F, Hadida S, Grootenhuis P, Burton B, Stack J, Straley K, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA. 2011; 108(46):18843-18848.

Clancy J, Rowe S, Accurso F, Aitken M, Amin R, Ashlock M, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax.

2012; 67(1):12-18.

Ramsey B, Davies J, McElvaney N, Tullis E, Bell S, Dřevínek P, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551DMutation. New Engl J Med 2011; 365:1663-16672.

U.S. National Institutes of Health. DrugDrug Interaction Study of Vx-770 and VX809 in Healthy Subjects (NCT01216046).

2012; Available at: http://clinicaltrials. gov/show/NCT01216046.

U.S. National Institutes of Health.

Drug-Drug Interaction Study of VX809 and VX-770 in Health Subjects (NCT00966602).

2010; Available at: http://clinicaltrials.gov/show/ NCT00966602.

U.S. National Institutes of Health. Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation (NCT01225211).

2014; Available at: http://clinicaltrials. gov/show/NCT01225211.

M E D U CATO R

In summary, CF is a disorder that has benefited greatly from advancements in treatment, as evidenced by the increased survival age of CF patients. However, it is clear that to see further improvement, treatments need to be developed to directly target the root cause of CF: mutant One important CFTR potentiator that has been CFTR. CFTR modulators, small molecules developed is VX-770.5 It has been tested on that repair CFTR, have shown great potential patients carrying the CFTR mutation G551D, to improve CFTR function in vitro, though which causes altered CFTR gating (Class III results in the clinical setting are varying. Due to mutation). Like VX-809, VX-770 has shown these varied results, the potency of some CFTR to be well-tolerated without notable side-effects. modulators has been questioned. Currently, the Additionally, in one randomized, double-blind, use of multiple CFTR modulators is being tested placebo-controlled trial of VX-770, positive for synergy in the clinical setting. If these CFTR clinical effects have been shown. In comparison modulators prove to be clinically beneficial, it is to the placebo, patients with the G551D mutation likely that we will see further improvement in the taking VX-770 showed an FEV1 change of more quality of life and survival age of CF patients. ■

1.

critical review

act to either enhance anion movement or repair the gating mechanism of the mutant CFTR. It is thought that potentiators work by altering NBD dimerization. Specifically, these potentiators might be binding at the interface of the NBD dimer, lowering the free energy of the transition state and accelerating channel opening. Also, it is thought that potentiators may slow down the rate of channel closure by stabilizing the dimer conformation.11, 16 Potentiators could be used as therapy for CF patients with mutations in Class III and IV. It should also be noted that some small molecule CFTR modulators have been shown to have both corrector and potentiator properties.

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critical review 3

ARTIST YASMEEN MANSOOR

CRITICAL REVIEW

L-Carnitine Supplementation A POTENTIAL TREATMENT FOR CANCER CACHEXIA 27

AARON KWONG, OBAIDULLAH KHAN, KATRINA FLEMING, SINA MOSHIRI, AND MUHAMMAD HASHMI Bachelor of Life Sciences (Honours) in Biochemistry, Class of 2014 McMaster University Correspondence: aaronkwong777@gmail.com

ABSTRACT Cachexia is a paraneoplastic syndrome that exhibits rampant muscle wasting, unintentional weight loss, fatigue, weakness, and overall loss of appetite, none of which can be abated by an increase in caloric intake. Metabolic derailment by cachexia is so severe in cancer patients that it can shorten lifetime expectancy and lead to death before the course of treatment is finished. Etiology may involve proinflammatory cytokines, but the abnormal loss of muscle, protein, and fat suggests an underlying metabolic dysfunction that contributes to cachexia.

Previous research has shown reduction of L-carnitine in cachectic patients and chemotherapy-induced damage to the L-carnitine transport system that may further exacerbate symptoms. As such, a possible avenue of treatment for cachexia-induced fat loss may involve L-carnitine supplementation to restore metabolic homeostasis through various mechanisms such as lowering levels of proinflammatory cytokines and restoring L-carnitine palmitoyltransferase activity. While the precise mechanism of L-carnitinemediated amelioration has not been determined, research findings support the notion of L-carnitine as an alleviator of several cachectic symptoms that have previously been unmanageable in a clinical setting.

patients with malignant tumours.

Levo-carnitine (L-carnitine), an amino acid derivative involved in fat and muscle metabolism, is a commonly-used supplement currently being considered as a potential therapeutic agent for treating CC. Studies on this molecule have shown it to have promising benefits for cancer patients.

L-CARNITINE IN FATTY ACID METABOLISM

critical review M E D U CATO R | A P R I L 2014

L-carnitine is a popular workout supplement which prevents exhaustion by assisting with the conversion of fat into useful energy during exercise.4 It is a naturally synthesized metabolite found in the human body, and is necessary for fatty acid metabolism. In eukaryotic cells, the mitochondria plays the If you were to walk down your local role of energy production by metabolising supermarket’s health and fitness aisle, you dietary carbohydrates, fats, and proteins into would quickly find yourself lost in the vast useful energy for the body. In general, energyarray of commercially available workout rich nutrients must be transported past the supplements. Stacked bottles of pills and mitochondrial double membrane into the powders with eye-catching claims such as inner matrix core, which is composed of a “enhance your workout” or “burn more fat” can complex “soup” of protein machinery which be quite overwhelming to a novice in the field serves to break down nutrients. The outer of fitness supplements. Today, supplements and inner mitochondrial membranes act as have become a popular option for augmenting a gated checkpoint to regulate molecules one’s workout regime, as they can offer an entering or leaving the mitochondria. Since increasingly wider range of functions and the mitochondrial membranes have a relatively applications for consumers with varying low permeability to fatty acids, these molecules lifestyles and needs. Looking for a supplement are unable to passively enter the mitochondrial to enhance muscle mass? Try whey protein matrix core.5 Instead, L-carnitine is shakes to stimulate muscle protein synthesis.1 required as a molecular “chauffeur” Want to increase the number of repetitions to allow passage of fatty acids CANCER CACHEXIA (CC) during high intensity training? Consider through the inner mitochondrial A PARANEOPLASTIC SYNDROME using creatine supplements.2 Need an membrane to initiate fat catabolism.

THAT IS CHARACTERIZED AS SKELETAL MUSCLE AND affordable supplement for endurance training?

ADIPOSE TISSUE ATROPHY, Simple chocolate milk has been shown to Fat catabolism begins with the WEIGHT LOSS, FATIGUE, provide benefits as a post-workout recovery physical linkage of the long-chain NEGATIVE ENERGY AND aid.3 Indeed, advancements in research have acyl groups of fatty acids and PROTEIN BALANCE, AND REDUCED TOLERANCE TO provided greater insight into the benefits and L-carnitine in the cytosol through ANTICANCER THERAPY.7,8,9 optimal uses of various supplements. transesterification, carried out by the integral mitochondrial In addition to their benefits in fitness training, membrane protein L-carnitine workout supplements are now being considered palmitoyltransferase I (CPT I). as treatments for various metabolic disorders. The fatty acids linked to L-carnitine can One such condition is cancer cachexia (CC), then be transported through the outer and a syndrome of progressive muscle atrophy inner mitochondrial membranes (Figure 1). and weight loss that is often observed in Once inside the mitochondria, the complex

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is cleaved by CPT II to produce L-carnitine, which L-carnitine L-carnitine will be recycled for + + additional fatty acid ENERGY Acyl-CoA Acyl-CoA transport, and AcylCPT I CPT II CoA, which will be further catabolized Acylcarnitine to produce useful Acylcarnitine CACT energy.6 By regulating the entry of fatty OUTER acids into the INNER MITOCHONDRIAL MITOCHONDRIAL mitochondrial MEMBRANE MEMBRANE matrix, L-carnitine serves as the rateFIGURE 1: The carnitine determining factor which dictates how much transport system: L-carnitine is linked to long-chain acyl groups fat can be catabolized at a given time. By of fatty acids by CPT I, forming increasing the amount of L-carnitine in the acylcarnitine.

Acylcarnitine is body, fat can be metabolised at a higher rate, transported passively through the thus providing more energy for the body during outer mitochondrial membrane and through carnitine–acylcarnitine periods of exercise. This also has the benefit translocase (CACT) on the inner of enhancing weight loss during exercise by mitochondrial membrane. CPT II metabolising more fat. then cleaves acylcarnitine into acyl-

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CYTOSOL

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coA and L-carnitine. L-carnitine is recycled back into the cytosol (not shown), while Acyl-CoA undergoes ββ-oxidation in the mitochondrial matrix in order to produce useful energy.6

FIGURE 2: Effects of L-carnitine supplementation on hepatocyte morphology in experimental cancer cachexia. Ultrastructural aspect of hepatocytes from control (a) control, (b) control supplemented with L-carnitine, (c) tumour-bearing supplemented, (d) tumour-bearing supplemented with L-carnitine rats.

Note the presence of lipid droplets in the cytoplasm of tumour-bearing rats. LD lipid droplets, N nucleus.

Bars 1 μm. Adapted from: Silvério, R., Laviano, A., Fanelli, F. R., and Seelaender, M. (2012) Amino acids, 42, 1783-1792

MITOCHONDRIAL MATRIX

APPLICATION TO CANCER CACHEXIA

clinical practice, CC is often not recognized or managed appropriately,12,13 in part due to a lack of sophistication in characterizing and diagnosing this syndrome.8 It is only recently that diagnostic criterion for different stages of CC were more clearly defined.9 As the aetiology of CC is multifactorial, its underlying mechanism has yet to be completely elucidated. However, L-carnitine supplementation has recently been shown to buffer the symptoms of CC, making it a promising treatment for combating this deadly syndrome. Current research exploring the molecular-level modulation of CC through L-carnitine supplementation has demonstrated two unique modes of action: manipulation of proinflammatory cytokine levels and restoration of L-carnitine palmitoyl-transferase (CPT) activity.14,15,16

EFFECTS ON PROINFLAMMATORY CYTOKINES

Both host-derived and tumour-secreted proinflammatory cytokines interleukin 1 The uses of L-carnitine are not solely limited (IL-1) and interleukin 6 (IL-6) are known to weight loss and perturbing the onset of contributors of inflammation. Excess levels exhaustion during exercise. The concept of of these signalling molecules are associated upregulating the L-carnitine-CPT transport with muscle wasting and impaired lipid system can also be used therapeutically in the metabolism, which are characteristics of severe newly classified disease of cancer cachexia CC. Thus, by reducing inflammation through (CC). CC is a paraneoplastic syndrome decreasing proinflammatory cytokine levels, that is characterized by skeletal muscle and it may be possible to mitigate the severity of adipose tissue atrophy, weight loss, fatigue, cachexia and impede muscle wasting. A study negative energy and protein balance, and conducted by Winter et. al (1995) examined reduced tolerance to anticancer therapy. This the effects of L-carnitine supplementation on condition is often what leads to an unhealthy, cytokine levels, and the possible amelioration gaunt complexion in cancer patients.7,8,9 of cachexia symptoms in sarcoma-induced Approximately two-thirds of late-stage cancer rats. Daily administration of L-carnitine patients prematurely die due to CC, making it was associated with significant reductions in an imposing health risk for cancer patients.8,10,11 tumour necrosis factor α (TNF-α) (54.6%) CC is thought to result from a combination and IL-1 (37.4%) levels, compared to salineof altered intermediary injected tumourous rats.17 These depressed metabolic processes and cytokine responses are a promising sign for inflammatory responses treating inflammation-based weight loss in in patients with cancer. CC patients.

These changes result in a significant degree of RESTORATION OF L-CARNITINE catabolism in affected PALMITOYL-TRANSFERASE individuals, to the extent ACTIVITY that increases in caloric intake do not abate weight The fundamental role of L-carnitine in loss.7,8 Simple nutrition the CPT transport system is to shuttle supplementation plans fatty acids into mitochondria, thereby are not sufficient to rendering L-carnitine as a key regulator of counteract the severe fatty catabolism.18 The decrease in CPT I weight loss and tissue and CPT II activity, coupled with other degeneration observed CC symptoms such as hypertriglyceremia in these patients. In and low lipoprotein lipase activity, would

therefore increase the risk of fatty liver disease tremendously.18,19 When this was investigated

by Silvério et al. (2011), they found large lipid droplets in the liver hepatocyte cells of carcinosarcoma rats (Fig. 2C).20 Indeed, decreased activity of CPT I was observed in tumour-bearing rats, while no significant difference was observed in CPT II activity or mRNA levels of CPT I and II. When these rats were given injections of L-carnitine, their CPT I activity was partially restored and elicited 1.4 times the activity in untreated rats. However, increase in activity could not be attributed to mere increase of L-carnitine availability, since tumour-bearing rats in fact had greater liver incorporation of L-carnitine, suggesting that L-carnitine may have a role in mediating anti-inflammatory properties as well.20 Although several studies on the effects of L-carnitine have indicated improvement in lipid metabolism and decrease in cytokine levels,17,21 more clinical trials are needed to improve other symptoms observed in CC, such as fatigue and the oxidative profile in cachectic patients.9

and the largely successful trials observed in animal models have not been conducted in humans to the same extent.25 Interestingly, the combination of EPA treatment with physical exercise have been shown to effectively ameliorate the symptoms of CC.26 It seems the future of CC treatments may be a cocktail of different chemical and physical therapeutic agents to simultaneously tackle this deadly disease.

CONCLUSION

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Cond Res.2014 Feb;28(2):514-9.

5. Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr.

2000 Aug 1;72(2):618s–623s.

6. Rufer, A.C., Thoma, R., Hennig, M. (2009) Structural insight into function and regulation of carnitine palmitoyltransferase. - Cell Mol Life Sci.2009 Aug;66(15):2489-501.

7. Tisdale, M. J. (1997) Biology of cachexia. J. Natl. Cancer. I. 89, 1763-1773 8. Fearon, K., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L., and Baracos, V. E. (2011) Definition and classification of cancer cachexia: an international consensus. Lancet. Oncol. 12, 489-495 9. Silvério, R., Laviano, A., Fanelli, F. R., and Seelaender, M. (2011) Lcarnitine and cancer cachexia: Clinical and experimental aspects.

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Kanda, A. Nakayama, K., Fukasawa, T., Koga, J., Kanegae, M., Kawanaka, K., Higuichi, M. (2013) Postexercise whey protein hydrolysate supplementation induces a greater increase in muscle protein synthesis than its constituent amino acid content. - Br J Nutr.2013 Sep 28;110(6):981-7.

2. Cooper, R,. Naclerio, F., Allgrove, J., Jimenez, A. (2012) Creatine supplementation with specific view to exercise/sports performance: an update. - J Int Soc Sports Nutr.2012 Jul 20;9(1):33.

3. Pritchett, K., Pritchett, R. (2012) Chocolate milk: a post-exercise recovery beverage for endurance sports. - Med Sport Sci.2012;59:12734.Doi: 10.1159/000341954.Epub 2012 Oct 15.

4. Orer G.E., Guzel, N.A. (2014 The Effects of Acute L-carnitine Supplementation on Endurance Performance of Athletes. - J Strength

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Sujeivan Mahendram is currently a Research Technologist at the McMaster Stem Cell & Cancer Research Institute. He completed his Honours Bachelor of Science in Molecular Biology at McMaster in 2011 and proceeded to complete a Master’s in Science in embryonic stem cell signaling research in the lab of Dr. Bradley Doble. His current research interests surround the use of novel gene manipulation strategies to selectively knockout genes implicated in the functions of cancer stem cells.

1.

critical review

In summary, muscle and fat atrophy caused

by CC can be drastic and may impede the effectiveness of cancer treatment.

In experimental models of CC in rats, L-carnitine supplementation has been found to lower levels of TNF-α and IL-1, which would otherwise increase inflammationbased muscle wasting and fat loss. L-carnitine supplementation has also been shown to partially rescue the CPT transport system for shuttling fatty acids into the mitochondria in liver hepatocytes, thus lowering the risk of hypertriglyceridemia-related diseases such as EICOSAPENTANOIC ACID fatty liver disease. Elevated proinflammatory SUPPLEMENTS cytokine levels exist in cachectic cancer patients and are caused directly by the tumour, Alternate treatments for CC have focused on indirectly by an innate bodily response to the mechanisms separate from targeting the CPT tumour, or an entirely separate cause elicited transport system and cytokine signalling. from chemotherapy. Current research supports A promising treatment that targets the the ability of L-carnitine supplementation to rampant proteolysis observed in cachexia is decrease these levels. Maintaining normal eicosapentanoic acid (EPA), an omega-3 fatty cytokine levels helps to resume a balance acid that is the only supplement currently between catabolic and anabolic processes. It is known to interfere with proteolysis in likely that future therapeutic applications of cachexia.21,22 There have been reports of small- L-carnitine for treating CC symptoms will be scale human trials in which decreased levels incorporated into cocktail treatments. Indeed, of cytokines, improvement of weight and L-carnitine supplementation is a promising functional status, and increased appetite were therapeutic tool with applications that can observed in cachectic patients treated with extend beyond the gym and be delivered as a EPA.23,24 However, trials investigating anti- lifesaving product in a hospital setting. ■ cachectic effects of EPA are contradictory

J. Cachexia, sarcopenia and muscle.

2, 37-44 10. Bachmann, J., Heiligensetzer, M., Krakowski-Roosen, H., Büchler, M. W., Friess, H., and Martignoni, M. E. (2008) Cachexia worsens prognosis in patients with resectable pancreatic cancer. J. Gastrointest. Surg. 12, 1193-1201.

11. Bing, C., Russell, S., Becket, E., Pope, M., Tisdale, M. J., Trayhurn, P., and Jenkins, J. R. (2006) Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Brit.

J. Cancer. 95, 1028-1037.

12. Churm, D., Andrew, I. M., Holden, K., Hildreth, A. J., and Hawkins, C. (2009) A questionnaire study of the approach to the anorexia–cachexia syndrome in patients with cancer by staff in a district general hospital.

Support. Care. Cancer. 17, 503-507.

13. Spiro, A., Baldwin, C., Patterson, A., Thomas, J., and Andreyev, H. J. N. (2006) The views and practice of oncologists towards nutritional support in patients receiving chemotherapy. Brit. J. Cancer. 95, 431434.

14. Barber, M. D., Powell, J. J., Lynch, S. F., Fearon, K. C. H., and Ross, J. A. (2000) A polymorphism of the interleukin-1 β gene influences survival in pancreatic cancer. Brit. J. Cancer.

83, 1443.

15. Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscella, K., and Morrow, G. R. (2007). Mechanisms of cancer-related fatigue. Oncologist.

12, 22-34.

16. Tijerina, A. J. (2004) The biochemical basis of metabolism in cancer cachexia. C. C. Nurs. 23, 237-243.

17. Winter, B. K., Fiskum, G., and Gallo, L. L. (1995) Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock. Brit. J. Cancer.

72, 1173.

18. Peluso, G., Nicolai, R., Reda, E., Benatti, P. Barbarisi, A. and Calvani, M. (2000) Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine cystem. J. Cell. Phys. 182, 339-550 19. Manzato, E., and Romanato, G. (2006) Lipid Metabolism in Cachexia. In Cachexia and Wasting: A Modern Approach (pp. 191-194).

Springer Milan.

20. Silvério, R., Laviano, A., Fanelli, F. R., and Seelaender, M. (2012) LCarnitine induces recovery of liver lipid metabolism in cancer cachexia.

Amino acids, 42, 1783-1792.

21. Laviano, A., Molfino, A., Seelaender, M., Frascaria, T., Bertini, G., Ramaccini, C., Bollea, M.R., Citro, G., and Rossi, F.F. (2011) Carnitine administration reduces cytokine levels, improves food intake, and ameliorates body composition in tumour-bearing rats. Cancer Invest. 29, 696-700 22. Vaughan, V.C., Martin, P., and Lewandowski, P.A. (2012) Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle 23. Wigmore, S.J., Fearon, K.C., Maingay, J.P., and Ross, J.A. (1997) Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6. Clin.Sci. 92, 215-221 24. Wigmore, S.J., Barber, M.D., Ross, J.A., Tisdale, M.J., and Fearon, K.C.H. (2000) Effect of Oral Eicosapentaenoic Acid on Weight Loss in Patients With Pancreatic Cancer. Nutr.Cancer.

36, 177-184 25. Jatoi, A., Rowland, K., Loprinzi, C.L., Sloan, J.A., Dakhil, S.R., MacDonald, N., Gagnon, B., Novotny, P.J., Mailliard, J.A., Bushey, T.I.L., Nair, S., and Christensen, B. (2004) An Eicosapentaenoic Acid Supplement Versus Megestrol Acetate Versus Both for Patients With Cancer-Associated Wasting: A North Central Cancer Treatment Group and National Cancer Institute of Canada Collaborative Effort. Journal of Clinical Oncology.

22,2469-2476 26. Penna, F., Busquets, S., Pin, F., Toledo, M., Baccino, F., López-Soriano, F., Costelli, P., and Argilés, J. (2011) Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise. J Cachexia Sarcopenia Muscle.

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INTERVIEW SPOTLIGHT

dr.eric seidlitz VALUABLE LESSONS FROM THE UNCONVENTIONAL

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HELLO DR. SEIDLITZ. FIRST OF ALL, THANK YOU FOR HAVING US ON BEHALF OF THE MEDUCATOR. IT IS A REAL HONOUR TO INTERVIEW YOU AND ASK YOU QUESTIONS ABOUT YOUR RESEARCH AND YOUR FIELD OF INTEREST. CAN YOU PLEASE TELLS US ABOUT THE BACKGROUND OF YOUR EDUCATIONAL JOURNEY, AND HOW YOU ENDED UP AT THE SINGH LAB?

I actually started in Manitoba—that’s where I went to high school. I decided at the end of high school I wanted to go to medical school, like almost everybody else that I was going to school with. I went to  DR. ERIC SEIDLITZ is a researcher in the department of Pathology the University of Manitoba for what they & Molecular Medicine at McMaster University. He has a diverse called a “pre-med” program, which was background, with a B.Sc. in Zoology/Botany, a B.A. (first class Honours) just basic sciences. I really did not get the degree in Physiological Psychology, a M.Sc. degree in Psychology/ feel for it at the time, so I decided to finish Electrophysiology, and a Ph.D. in Physiology and Pharmacology. After with a 3-year undergraduate degree; I did working for 8 years at the Sick Children Hospital in Toronto, he joined the my Biology, Botany, and Zoology and then Singh Lab at the Cancer Centre in Hamilton in 1998, where he started his decided at that point that the thing that research in bone metastasis. Aside from his research, he currently teaches I liked the most from my undergraduate the first year Cellular & Molecular Biology course in the Bachelor of studies was first year psychology, which Health Sciences (Honours) program, alongside Dr. P. K. Rangachari. was a bit of a unusual thing for me. So,

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might be interested in offering a position. I started working at the Singh lab as an animal technician, and kept working there for a good fifteen years or so. This length of time generally marks the end of your academic career, and at this point my position was not going to actually go any further. I was at the top of the pay scale and there was not much I could do.

We came up with the option, kind of out of the blue, that I would go back to school to complete a Ph.D. I was qualified, and I would get all that work plus all the work I would do as a grad student. So I did that for quite a long time—it was almost six years of being a grad student yet again. The year of turning forty, instead of buying a Ferrari, I went to school—but that happens. When I finally graduated, I stuck with the Singh lab for a post-doctoral position, and here I am.

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I decided to go back for another undergraduate degree, which most people usually didn’t do. I completed a fouryear honours degree in psychology, but was able to cut a whole year out of that because most of my electives were in the first degree. Within six years, I ended up with two undergraduate degrees.

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After my master’s degree, I worked as a technician for about nine years at Sick Kids Hospital in downtown Toronto. Eventually came along kids, a house, and all of that stuff. I grew tired of going to Toronto every single day and wasting three to five hours on a bus or train, so I decided that I would get a job in Hamilton. That’s how I actually connected with the Singh lab. One of our neighbours was their colleague and said that they

From there, we moved into the stuff that I did for my Ph.D., which was glutamate secretion from cancer cells.

This focus was mostly by accident. From my psychology days working with electrophysiology, I was very interested in glutamate receptors, how they store information, and how the communication of this information occurs. I was thinking, “Okay maybe the cancer cells have these receptors and somehow there’s going to be a connection that I can grab a hold of and shut them down and stop them from growing.” In all the series of experiments that I did, I was trying to get rid of as much glutamate as possible, so that I could then stimulate the glutamate receptors. However, I found that I couldn’t get rid of it— it kept coming.

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After undergrad, I wanted to do research and I wanted to go into something biology and psychology-related, so I applied to graduate school. Both McMaster and the University of Victoria had accepted me, but the latter offered no money, and money made a big difference at that time. So, I came to Mac; this was during the late 80’s, which is a long time ago. I decided to directly start with research. However, I did not have a good interaction with my supervisor, and ended up leaving with a master’s degree, which, in that program, wasn’t a good thing.

Well, when I first started at the lab back in the 90’s, we were just working on bone metastasis. It was largely based on how cells interact with bone and how drugs modify that interaction. We did a lot of work on tetracycline derivatives, which were drugs that could actually adhere to the calcium in bone. Calcium would normally get chewed up by cancer cells, resulting in damage to the bone. We did a huge number of experiments on that and found that doxycycline, one of the derivatives of tetracycline, worked very well for knocking down the tumour cells responsible for degrading bone. We actually were able to get that into a clinical trial. It was kind of neat to be able to see us going from the dish, to an animal, and then to a clinical trial. Normally you don’t see that kind of thing since the time-scale is so long.

interview spotlight

SO DR. SEIDLITZ, COULD YOU TELL US A LITTLE BIT ABOUT YOUR RESEARCH ON BONE METASTASIS AND CANCER-INDUCED BONE PAIN?

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“THAT’S PROBABLY THE MOST IMPORTANT THING IF YOU’RE GOING INTO RESEARCH. THE MORE WIDE-BASED YOU ARE IN YOUR BACKGROUND, THE MORE LIKELY THAT YOU’RE GOING TO SEE THE CONNECTIONS THAT ARE THERE WHEN OTHERS MAY NOT.”

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There was so much glutamate in there that there was nothing I could do but start measuring levels of it. That’s what you do if you have an experiment fail: you end up measuring something. I ended up figuring out that cancer cells dumped out all this glutamate.

Now, glutamate coming out of the cancer cells is just normal biology.

These cells are protecting themselves from the oxidative stress induced by chemotherapy drugs. The glutamate is just a waste product of that whole antioxidant process. Now, if you have cancer cells in your lung producing glutamate, there probably will not be a problem. However, if this same glutamate is produced in your bone, it’s a huge problem. In the bone, your bone cells all listen to glutamate. As a result, excess glutamate production completely messes up their communication; it’s like two cells in the bone are talking to teach other, whispering in English, and someone comes yelling in Japanese. When they can’t understand each other, everything goes crazy.

We developed this idea for a while, which was the focus of my Ph.D. We then realized that the most relevant thing for patients with bone cancer was pain, because that’s what brings them in to say, “Hey I’ve got a problem.” We realized that the most important signalling molecule in the pain system is glutamate, and we have it in the bone—it’s messing up the bone, and so why not mess up the pain system—that’s really what we saw as our main focus. This is how it went, all the way from playing around, trying to slow down cancer cells, to getting this focus on glutamate, and then figuring out that glutamate was relevant for certain areas of the body. If you put a tumour in the brain, the glutamate gets into the brain and completely changes how the brain cells function. It’s just the same thing, but in the bone. So that’s kind of where we went with that whole project.

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YOU TEACH THE FIRST YEAR CELLULAR BIOLOGY HEALTH SCIENCES COURSE. CAN YOU TELL US A LITTLE BIT ABOUT WHAT THIS EXPERIENCE HAS BEEN LIKE FOR YOU? Well, this is my third year teaching it. After I had finished graduate school and was puttering around the lab, I realized that I had some extra time and I wanted to get into teaching. The offer came up that they needed somebody and it seemed to fit with what my interests were. I, not reluctantly, jumped in and said, “OK I’m going to do this.” At first, it’s a little nerve wracking to see over 200 people looking at you, and it took me a long time the first year to get over that. Now I find it’s more energizing than I thought, especially because of the youthful energy that comes exuding from the class. Everybody’s interested, everybody’s asking questions, and that’s very challenging and very rewarding. I really enjoy that. It’s not specifically the area that I focused my research on, but it has certainly helped me as well. For some reason after teaching cellular communication, most of my work in the lab has become related to cellular communication. So there’s a connection there that’s probably more rewarding for me than most of the students in that way.

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THANK YOU FOR THAT DR. SEIDLITZ. WHAT ADVICE WOULD YOU GIVE TO ASPIRING UNDERGRADUATE STUDENTS, THINKING OF ENTERING THE FIELD OF RESEARCH? Well, actually, if you’re going to be entering research, the first thing you should do is the stuff that you really enjoy. When I started undergrad, I was doing things for reasons I didn’t quite know. For example, I figured out after

completing my first degree that the stuff that I actually wanted to learn were the things that were not offered in the degree. I was in science, but most of the things I wanted were in the faculty of arts, like psychology.

I eventually started taking courses in different areas like Latin and Astronomy. I had Organic Chemistry in the morning, and art courses in the afternoon where I would be drawing nude models and whatever. You wouldn’t believe how important that is because you normally don’t get the chance to do that in a fairly structured undergraduate program which has very specific courses you have to take.

For me, I was able to take the stuff that I wanted to take and I was interested in and thought would be fun.

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ASIDE FROM YOUR WORK IN ACADEMIA, WHAT OTHER INTERESTS OR PASSIONS DO YOU HAVE? I used to be a pilot. Unfortunately, I can’t do that anymore because of my health; I can’t pass the medical. When you’re over forty, you automatically get put on a list that says you have to do your medical check-up every two years. The first time I did my medical, it took over a year to get the paperwork done. And then I couldn’t renew it because of a change in medications and stuff. Regardless, that is still always going to be an interest of mine. I tell my wife that if there’s a plane going over, I’m going to go to look at it, and I’m going to go to air shows. I even grew up in an air force family and airplanes are kind of the “thing”.

Well, Iceland is a bucket-list kind of place. It’s somewhere everyone should go to, and how I ended up going was a bit odd. At the time, I had things I liked to do—I was flying air planes, you know, that was a joy for me. My kids had their own things too; one of them is a scuba diver and one of them is a hockey player. My wife still needed a goal, and so she came up to me one day and said, “This is what I’m going to do—I’m going to raise money for the Arthritis Society,” because it was a good cause for our family. She said, “I’m going to Iceland.” And I said, “Oh good, when are we going?” She didn’t think I would go, because who would go on a 80 km trek across a frozen wasteland with arthritis that was actually getting to a point where I was using a cane? Well, we ended up going together and raising $5 less than our goal of $18,000 just between the two of us. We even had national trainers that trained us with an entire year of hiking, exercise, and all sorts of other things. We went to the trip with 30 other people from all across Canada, and we had a wonderful time. And we got to go to Iceland, which is just an impressive country with very interesting people.

That kind of experience was something we probably would never have done otherwise. ■

interviewers

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AMEIR MAKAR

WASIMUDDIN SYED

Bachelor of Health Sciences Bachelor of Health Sciences (Honours), Class of 2015 (Honours), Class of 2015

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PHOTOS COURTESY OF DR. SEIDTLIZ

WE FOUND OUT THAT IN 2012, YOU WENT TREKKING IN ICELAND FOR THE ARTHRITIS SOCIETY. WHAT WAS THAT EXPERIENCE LIKE FOR YOU?

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I also have a lot of other hobbies. Photography is one.

I do a lot of stain glass. I do all the cooking at home. I would say to do as many things as you can and get good at your hobbies, so that when you’re 75, you’re going to be very good at it, and you don’t have to learn to paint when you’re 90.

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interview spotlight contributors

When I got into graduate school, all of that stuff became useful. Looking at a microscope and drawing what you see—oh, that’s easy (however, nowadays you take pictures). Oh, everything’s Latin, well I took Latin.

There are a lot of things you can gain by doing things that are not in the “mainstream”, and that’s probably the most important thing if you’re going into research.

Enrol in a flexible program with many different course options available, because if you narrow in, you’re too narrow. Then, when you get into research you have no imagination whatsoever—and I’ve seen that many times.

The more wide-based you are in your background, the more likely that you’re going to see the connections that are there when others may not.

ARTICLE EDITED BY YASMEEN MANSOOR

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CDKu and the Island of Widows ARUN PARTRIDGE AND LOUISE CHONG Bachelor of Health Sciences (Honours), Class of 2015 Correspondence: arun.partridge@learnlink.mcmaster.ca and louise,chong@learnlink.mcmaster.ca

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global perspective table of contents

GLOBAL PERSPECTIVE

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ABSTRACT We recently had the opportunity to spend 3 months working with La Isla Foundation (LIF), a non-governmental organization that aims to raise awareness and combat the Chronic Kidney Disease of Unknown Etiology Epidemic (CKDu) ravaging regions of Nicaragua. This epidemic has not received the international coverage and awareness that it deserves, but recent research studies and news articles have been published which have drawn global attention. There have been multiple anecdotal reports of a high chronic kidney disease prevalence in rural parts of Nicaragua and El Salvador. We assisted La Isla Foundation in their work, contributing to a variety of community development, public health, and human rights projects which gave us exposure to the important cause for which they fight.

OUR PERSPECTIVE

As third year Bachelor of Health Sciences students specializing in global health, we had the opportunity to complete an embedded learning experience and spend three months in Nicaragua working with La Isla Foundation (LIF). LIF is a non-governmental organization (NGO) that aims to raise awareness and combat the chronic kidney disease of unknown etiology (CKDu) epidemic. This epidemic is afflicting rural regions of Nicaragua as well as other areas throughout Central America. This epidemic has not previously received the international coverage and awareness that it deserves, but in recent months, research studies have been published that have drawn great global media attention. Reports of related epidemics have led many to believe that CKDu may be present amongst rice paddy workers for India and Sri Lanka.1 Since this disease is not as isolated as previously thought, international attention to the impacts of CKDu are rising and leading to increased awareness, funding, and treatment, ultimately working towards eventual abolition of the epidemic.

UNDERSTANDING CKDU

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The community of La Isla is one of five communities that constitute the larger Guanacastal-Sur in the rural sector of Chichigalpa, Nicaragua. It has become known as “La Isla de las Viudas”, or “The Island of the Widows”, due to the devastating effects of the CKDu epidemic on the community. The majority of working-age men are employed by local sugar production companies to perform various jobs in the fields or factories. In Chichigalpa, a small city near where La Isla is located, 75% of all male deaths in those aged 33-55 from 2002-2012 were due to CKDu.2 In the small community of La Isla itself, 40% of males 15 and older have stage 3 “THE MEN OF THE or higher CKDu.2 This COMMUNITY DIE YOUNG, leaves workers searching LEAVING BEHIND WIDOWS, desperately for treatment.

FATHERLESS CHILDREN, AND LIVES UNLIVED. THE While the Nicaraguan DISEASE HAS LEFT A social security system SENSE OF HOPELESSNESS covers certain medical AMONGST THE PEOPLE.” services, kidney transplant is not included.

Furthermore, there is a lack of capacity for a large-scale transplantation network. As a result, afflicted individuals must resort to dialysis as the only treatment option. In theory, two types of dialysis are feasible: hemodialysis and peritoneal dialysis. Hemodialysis involves blood being filtered outside the body in order to reintroduce clean blood into the system, while peritoneal dialysis involves fluid filtration across the peritoneal membrane in the abdomen through a catheter.2 In order to qualify for hemodialysis coverage, one must meet the strict requirement of having worked for 750 full weeks; it is almost impossible for the young workers to fulfill this before the disease itself prevents them from working.

This leaves peritoneal dialysis (PD) as the only feasible option for the impoverished people of this community.

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CKDu seen in Nicaragua differs greatly from the traditional chronic kidney disease (CKD), despite the fact that both conditions present with a progressive degeneration of renal tissue. While traditional CKD is associated with hypertension, diabetes, and obesity, CKDu has been associated with grueling manual labour in hot

THE COMMUNITY

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Contributing to a variety of community development, public health, and human rights projects provided us with a unique perspective on the important cause that LIF fights for. The LIF team’s passion, dedication, and unyielding pursuit of social justice was truly inspiring.

During our time in Nicaragua, we witnessed the profound impact that this disease has on the local people.

Exposure to environmental toxins is also being investigated as a potential compounding cause of CKDu, but much of the research suggests chronic dehydration is a primary cause.5 Unfortunately, misconceptions regarding toxins in the water have resulted in some workers avoiding the hydration that their bodies so desperately need.6 In fact, it has been shown that patients with CKDu show damaged renal tubules and interstitial tissues consistent with chronic dehydration. Hydration with fructoserich hydration packs provided by the sugar mills which employ the workers may exacerbate the problem.5

global introduction perspective

“The Island of the Widows” is a small community in Northwestern Nicaragua devastated by a unique and rapidly progressing kidney disease epidemic. The men of the community die young, leaving behind widows, fatherless children, and lives unlived. The disease has left a sense of hopelessness amongst the people.

However, we have learned first-hand of their great strength and perseverance in the face of uncertainty.

temperatures.2 Recent research has demonstrated that fructokinase, a liver and kidney enzyme, plays a key role in regulating the disease. Using mouse models, Roncal Jiminez et al. showed that extreme heat, strenuous work, dehydration, and hydration using fructose-rich drinks causes the metabolism of fructose through the aldose reductase pathway with fructokinase. The activation of this particular metabolic pathway produces oxidants and other inflammatory mediators, resulting in renal damage.4

The CKD mortality rate in Chichigalpa is approximately

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global perspective table of contents

10 times higher than the national and international Aside from the significant lack of resources, a major average, mainly due to the mortality caused by CKDu.3 impediment to the home dialysis program is the high rate La Isla is just one of many small communities across of infection among patients. Although infection is a major Nicaragua and Central America that are believed to be complication of PD in any part of the world, the unsterile suffering quietly from this epidemic. As volunteers within environments in rural areas further increase PD infection this community, we spent our rates. The living conditions in the time managing an arts and sports rural communities contribute club at the local school. We found to a lack of functional, sterile THE CHRONIC KIDNEY that the majority of children we clean rooms, which the patients DISEASE MORTALITY RATE IN worked with had a father, uncle, must pay for out-of-pocket at CHICHIGALPA IS APPROXIMATELY or brother taken from their a cost of $2,000 USD. Once 10 TIMES HIGHER THAN THE family much too early by CKDu. infected, the PD catheter should NATIONAL AND INTERNATIONAL Tragically, the people of La Isla be removed, the patient treated AVERAGE...3 have come to expect this and with antibiotics, and the catheter have little ability to find other replaced. However, the difficulties work to escape this cycle of death. of travel and seeing a doctor mean that many choose to continue to use the old catheter, thus worsening the infection.8 Infections also cannot BARRIERS TO CARE be controlled in most cases because of the nonspecific prescription of antibiotics and the inability to continue Near the end of our time in Nicaragua, we had the dialysis while the catheter is removed. As a result, the opportunity to visit and talk with some of the staff at catheter remains and the patient is left in an extremely the local public hospital about the patients they receive. vulnerable condition, unable to fight off the infection.

Hospital España is the nearest Ministry of Health hospital to the community and is the only one that offers REFLECTIONS PD in the department of Chinandega.7 There are 8 beds in 4 rooms of the Hospital España dialysis unit, with Measures must be taken in order to end the injustice that only 4 functional PD machines. Baxter, a pharmaceutical is occurring in Nicaragua and other areas affected by this company, donates PD equipment to the Nicaraguan epidemic. LIF’s multi-faceted approach to tackling the Ministry of Health, which in turn buys fluids and epidemic through a variety of initiatives including public other supplies. This system theoretically allows for the health, law and human rights, community development, provision of treatment to all without cost.2 However, the and scientific research will allow for a lucid appraisal of lack of medical personnel and resources combined with the problem and a holistic response. An example of a the large demand makes this more difficult in practice. recent effort by LIF is their PD project, which attempts to evaluate, improve, and expand the current PD program At the hospital, there is an outpatient program and at Hospital España. LIF attempts to take an integrated a home dialysis program, overseen by a nephrologist approach through lobbying, awareness campaigns, and who is at the hospital for only 4 hours per week. The grassroots partnerships with community organizations capacity of the outpatient program is limited because as well as academic research institutions and multilateral of the high demand, compounded with the lack of beds organizations. Corporate responsibility must also be and requirement for each patient to have two sessions encouraged through the sugar mills to create a safe working of 12-24 hours each per week. This outpatient program environment that respects basic human rights. Furthermore, makes use of the PD machines through Automatic PD, since treatment is not feasible in many cases, focus must be which exchanges the renal fluids across the peritoneal placed on prevention through humane working conditions, membrane. In the hospital, there is also one training information dissemination amongst community members, room devoted to the home dialysis program, which and improved access to medical care. To this day, we are consists of 28 patients. A nurse or doctor teaches the moved by the magnitude of this situation and can only patients the practices of home PD, which requires manual hope for change in sugarcane production. If these measures exchange of fluids every 6 hours throughout the day.2 are implemented and the problem is addressed thoroughly and responsibly, we can build lasting partnerships and repair the damage done in this fractured community. ■ NARMEEN HAIDER graduated from the B.H.Sc. program at McMaster University and earned her M.Sc. in International Health Policy from the London School of Economics and Political Science. She is currently a manager for the Health Impact Fund and an instructor for the Department of Health Sciences at McMaster University. ILANA WEISS is the director of policy and public health at La Isla Foundation.

EDITED BY NICOLE FALZONE | PHOTO COURTESY OF LOUISE CHONG & ARUN PARTRIDGE

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1.

Countries target pesticides as suspected link to rare kidney disease [Internet]. International Consortium of Investigative Journalists. [cited 2014 Feb 1].

2. Weiss I, Glaser J. Improving Home PD for cane workers affected by CKDu. La Isla Foundation. 2013.

3. Wesseling C. Mesoamerican Nephropathy, Rapport from the first international research workshop on MeN. Page 40 table 1.

4. Brooks D. Final Scoping Study Report: Epidemiology of Chronic Kidney Disease in Nicaragua. Boston

University; 2009. P 42 Table 5. Availble at http:// www.cao-ombudsman.org/cases/documentlinks/ documents/03H_BU_FINAL_report_scopestudyCRI_18.Dec.2009.pdf last visited August 12, 2013.

5. Johnson RJ, Sánchez-Lozada LG. Chronic kidney disease: Mesoamerican nephropathy—new clues to the cause. Nat Rev Nephrol. 2013 Oct;9(10):560–1.

6. O’Donnell JK, Tobey M, Weiner DE, Stevens LA, Johnson S, Stringham P, et al. Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.

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