Issue 2

Table of Contents

T H E TNSTDF SCOOP Manjur Asdhir

(a). M A C

MFD

14

Atrial Myxoma

Presidential Address

15

Telesurgery Jennifer Clara

Med @ Mac Kianosh Keyvani

Tang

Feeling the Blues

17

Kapilan Kugathasan Jennifer Clara

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I

Professional in Focus Tang

After the Stb|-m '§ " AbhishetiKhut Shedding Some Light on Glaucoma 20

RESEARCH ARTICLE!

Jonathan M. Ng

Adenoviral Vectors Deborah Leung

HIV: Terror of our Time r

10 Patient Privacy and Unsing Medical Records in Research i Ajit

Thakur

22

erry N g

REFERENCES

Andrea Dumbrell

Anthrax and the Three Amigos

18

0*%,, References ÂŤm

The Meducator Perspective W e at the Meducator adopt an educational approach to our publication. Despite our efforts to ensure correctness, w e recognize that the publication is subject to errors and omissions. In light of these inevitable errors and n e w developments in the medical field, the Meducator invites you to partake in feedback, discussion and constructive criticism of the content herein with the purpose of furthering the understanding of the topic - in the n a m e of meducation and discovery. A n online discussion forum for each article will be available on our website: www.meducator.org . Students and professors alike are welcome. Please enjoy the Meducator online experience!

Additional Meducator Contact Information: The Meducator may also be contacted via our e-mail address: meducator@learnlink.mcmaster.ca or our snail mail address: B.H.Sc. (Honours) Programme Attention: The Meducator HSC-1J11 1200 Main St. West Hamilton, Ontario L8N 3Z5

www.meducator.org t~~** 'j

25

THE INSIDE SCOOP

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Issue 2 I March 2003

President/Chief Editor JONATHAN

Dear Reader,

NG

Vice President/Deputy Chief Editor TERRY NG

.his year marks the exciting release of our second publication with a fresh, n e w set of articles spanning from deadly anthrax spores to an in-depth discussion of the ethics of patient privacy. Highlights of the publication include an interview with the Director of the Centre for Minimal Access Surgery in Hamilton and a n in-depth focus on the findings of a McMaster glaucoma researcher in the Department of Pathology and Molecular Medicine. With generous editing conducted by P h D s , M D s and post-graduates, as well as an interactive online discussion forum (www.meducator.org) for you to discuss your findings with peers, professors and researchers, w e are proud to present to you the culmination of our intellectual pursuits - the McMaster Meducator.

I've always believed that a quality product is the result of quality people. .

O u r publication is n o exception. T o our dedicated writers and generous contributors, w e extend our heartfelt gratitude - you have helped m a k e the McMaster Meducator what it is today. To the executive, your intensity and perseverance has been the vehicle to our success. I extend a special thanks to you: Terry Ng, Vice-President, as m y voice of reason and source of support; Kianosh Keyvani, in layout and design, w h o s e creative skills m a k e the publication d a n c e with life; Karen Ho, leader of the website division, w h o s e beautiful online creation brings us into cyberspace; K a m y a R a m a s w a m y , our managing editor, for maintaining high literary quality; Co-VP's Medical Research and Health Ethics Kapilan Kugathasan, Abhishek Raut, Zain K a s s a m and Ajit Thakur, the catalysts of the writing process a n d gatekeepers of content quality; Katayun Treasurywala and Nisha Sivagurunathan, Co-VP's Internal/ External* affairs, w h o s e lucrative efforts maintain the high quality of publication and keep it free for everyone. Finally, as m y model of educational excellence since our inception, a s o u r c e of inspiration a n d patronage, an earnest thank you goes to Del Harnish.

After all the effort that has been invested, your readings herein and participation in the discussions online will expand your horizon of k n o w l e d g e a n d inspire y o u to explore different areas of health. W e l c o m e to the McMaster Meducator experience. yours Sincerely,

Managing Editor KAMYA

RAMASWAMY

j VP of Newspaper Production & Design KIANOSH

KEYVANI

V P of Website Production &Design KAREN HO

C O - V P s of Internal & External Affairs KATAYUN NISHA

TREASURYWALA SIVAGURUNATHAN

Co-VPs/Co-editors of Medical Research KAPILAN KUGATHASAN ABHISHEK RAUT

Co-VPs/Co-editors of Health Ethics ZAIN KASSAM AJIT THAKUR

j Special Thanks to: Meducator Header Design JAY

HIGGERTY

Meducator Logo Design SHAWN

MCGRATH

Post-Graduate Editing ALISON ROBERTS MICULAN, MA

| Professor of Health Ethics and Critical thinking McMaster.

KENNETH L. ROSENTHAL, PHD

'Professor Department of Pathology and Molecular Medicine STASH NASTOS. ,.^^**

Research Assistant; Bffflser

j A L E X A N D E R K. BALL, B S C , P H D

Professor, Department of Pathology and Molecular Medicine FRANK L. GRAHAM, PH.D.

Professor, Biology & Pathology ROBERT D. HOLLENBERG, MD

Associate Professor, Surgery F.R.C.P.(C), FA. A. P. Paediatrician

DR. KUNWAR R. SINGH, M D .

DR. ANNE T. HENDRY, P H D

Associate Professor, Pathology & Molecular Medicine. H.G.H. Volunteer Writers Jonathan N g

MANJUR ASDHIR DEBORAH LEUNG

ANDREA DUMBRELL JENNIFER CLARA TANG

Issue 2 | March 2003

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HEALTH UTIIJTIES GROUP / HEALTH LtamiES INDEX T h e Health Utilities Index (HUI R ) is a generic, preferencescored system used to measure health status, health-related quality of life, and producing utility scores. It relies on these methods of measuring the quality of life to help describe treatment outcomes and processes in clinical studies, for population health studies, and economic evaluations of health care services (http://www.fhs.mcmaster.ca/hug/)

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CanChild is a childhood disability research centre that tries to increase the quality of life for disable children, youth and their families.

Their mission includes: taking a leadership role in identifying emerging issues for research, practice, policy and education, as well as conducting high-quality research. / Furthermore, CanChild strives to provide education for consumers, service providers, policy makers and students.

T h e focus of the program is on ' interpersonal relationships between the disabled individual, his/her family and the community in which they live in.

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SMOOTH MUSCLE RESEARCH PROGRAMME

"The Smooth Muscle Research Programme (SMRP) is a multi-disciplinary, inter-professional, inter-departmental, and inter-institutional programme whose mission, is to provide a common forum for the researchers in this Faculty for the sharing of ideas and expertise, and for the promotion of collaborative and multidisciplinary research on smooth muscle structure and function in health and disease." (http://www. fhs. mem aster, ca/smrp/)

Information obtained from the health sciences' research website: http://www.fhs.mcmaster.ca/res.htm

Issue 2 I March 2003

C.O.M.P.E.T.E. - THE COMPUTERIZATION OF MEDICAE PRACTICES FOR THE ENHANCEMENT OF THERAPEUTIC EFFECTIVENESS C O M P E T E will be thefirstproject of the Patient Diagnosis and Therapy Review Network, a volunteer network of 50 family practices involving approximately 125 family doctors in the Hamilton-Wentworth area. C O M P E T E is a three year project with several objectives. Thefirstis to to set up the computer-based network and electronic medical record software to support all clinical activities and practice-based research. Each practice will be randomized to early versus late computerization. Next, they aim to study the quality of prescribing/drug utilization data obtained by paper chart reviews versus review of the electronic chart. This will be done using a before after design such that physicians serve as their o w n control. Furthermore, the project will study the influence of computerization on the appropriateness of prescribing for musculoskeletal conditions in each practice using a before-after design. Lastly, in the third year C O M P E T E will analyze the the randomized controlled trial design, the efficacy of academic detailing versus patient-specific, computerbased audit and feedback on prescribing for musculoskelatal and cardiovascular conditions.

It is anticipated that C O M P E T E will be thefirstof m a n y such projects that involve this network, which will continue to expand in participants and research on areas of disease management, (http:// www.fhs.mcmaster.ca/compete/)

THE NURSING EFFECTIVENESS, UTILIZATION AND OUTCOMES RESEARCH UNIT

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The Nursing Effectiveness, Utilization and Outcomes Research Unit (NRU) is a collaborative project of the University of Toronto, Faculty of Nursing and McMaster University, School of Nursing.

"Our [NRU] mission is to develop, conduct and disseminate research that focuses on design, management, utilization, outcomes and provision of nursing."

The programs overall purpose is first to investigate the appropriate supply, distribution and deployment of nurses and h o w h o w to help enable the nurses to complete their tasks fully in light of restructuring of the health care system. Secondly, the program will try to determine ways in which quality can be maintained while still increasing funding efficiencies in the health care system. Lastly, they provice the M O H L T C with the basic information needed to m a k e necessary changes to H H R practices in Ontario. (http://www.fhs.mcmaster.ca/nru/)

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JENNIFER CLARA TANG

T H E C A N A D I A N TELESURGERY INITIATIVE Dr. Mehran Anyari

M.B.B.S., Ph.S, F.R.C.S.(c), F.A.C.S.

Dr. Mehran Anvari, Associate Professor in McMaster's Department of Surgery is leading Canada's initiative to research and develop telesurgery. He is the director of the CMAS (Centre for Minimal Access Surgery) in Hamilton and also holds a clinical position at Hamilton's St. Joseph's Hospital. Anvari's long-term goal is to develop a national telesurgery network within the next 7 years (Brehl, 2002). On April 8, 2003, Dr. Anvari will be giving a lecture at the Hamilton Spectator Auditorium entitled "Dr. Robot: Telementoring and Telerobotic Surgery.

H o w did the concept for developing a centre for teleroboticsurgery in C a n a d a c o m e about?

The CMAS (Centre for Minimal Access Surgery) was developed four years ago to help surgeons train in these techniques, which allows us to perform complex operation without a need for opening patients up without making large incisions, basically keyhole surgery. This is an area which really has major advantages for a patient. W e started research into the outcomes of these procedures to show its potential benefit. The result of our training at the C M A S was a large number of surgeons around the country (450). Many needed more than just a short training course, they needed to be mentored into performing these procedures safely. That required some of our faculty and experts to travel to sites to mentor.

W e then started the process of telementoring where w e could observe the surgery live and give instructions live without having to travel long distance. The big thing at that time was that there are times where you need more than just advice, [you need to] perform part of the surgery, the difficult parts.

That's when the concept of telerobotic surgery came about. Two and a half years ago w e put in a proposal to see if w e could use robots which w e can't use in the OR, telerobotically as a way of providing true telepresence of an expert to a rural site.

And that's how the concept grew. Initially people did not think the technology was advanced enough to do this. The first telerobotic surgery in Strasbourg to N Y was a simple operation to make sure the technology was ready and available. We're now taking the next step, trying to develop telerobotic program to assist rural surgeons during some of the more complex procedures.

The September 23, 2002 edition of Canadian TIME m a g a z i n e stated your plans for a Hamilton to Yellowknife telesurgery in N o v e m b e r 2002. W h a t is the current status of this operation?

Well we were planning to do Hamilton to Yellowknife but w e realized the telecommunication lines between Hamilton and

Yellowknife were not yet advanced enough, so what w e were planning to do in the first stage was [attempt a] Hamilton to North Bay [telesurgery]. Then to go to Hamilton to Chicoutimi and then Hamilton to Yellowknife as soon as w e can get secure enough lines to make that possible. We're going to go ahead and do it, but not with Yellowknife as our first site.

And when were you planning to do the Hamilton to North B a y telesurgery?

We were just discussing it. Everything is set, even the patient is set. However, w e need to have a very secure broadband telecommunication. Right now, we're looking potentially January.

Again, until w e can have safe and appropriate connection, w e do not want to jeopardize the safety of the patient. That's the key.

And as I said w e were hoping to get it sooner, but at the latest, January.

W h a t has to be d o n e to ensure y o u h a v e a completely safe line?

You need to have a line which is has a broad enough band capable of transmitting data up to 10 mbps per second which is significant size. You also need a band which has redundancy; that is if one line goes down, there is a second line that can step in immediately.

You need a band which has quality of service, meaning that the signals traveling for the telerobotic surgery is given highest priority so that if there are other users on the line, they will not compromise the quality of the transmission.

So there's no possibility that something like a virus of a p o w e r outage will affect the surgery?

No, we have looked at those possibilities to make sure that w e have this [secure] band. So that's what's taking a little bit longer, the fact that w e have to make sure that this is the highest quality communication possible for this telesurgery.

Issue 2 | March 2003 Please briefly walk m e through the surgical procedure. H o w long d o e s it take to prepare:

7 ongoing support from centers like McMaster and remove that sense of professional isolation. And so w e not only improve the range and quality of care, w e also hope to improve the chances or recruitment and retainment of young surgeons to rural areas W e hope this has an impact as well.

For telerobotic surgery we need at least 2 weeks, something like this, at least 6 to 8 weeks. W e have started preparing for it now. The surgery itself, once it becomes routine, all w e will hopefully need is a couple weeks notice to ensure that With the integration of robots how difficult will it be the surgeons are available and everything is set. But at the to c h a n g e s o m e o n e w h o has been to trained moment, for the first surgery, there is a fair bit of preparation, which is to be expected. traditionally to robotics?

Is the actual procedure enhanced by using a computer/robot versus h u m a n contact?

The robot actually is designed to enhance certain types of maneuvers, particularly high fidelity maneuvers where you're actually working in a fine space doing fine movements like suturing or very fine dissection. In the cases that w e are using, there may be added benefit but it is now being used not just purely for enhanced accuracy, but to act as an assistant to the rural surgeon, basically providing telepresence for the expert surgeon so that w e can take part in the operation from a distance The telerobot has a different concept than the current robots which are really there to enhance the surgery. So yes, they may enhance the surgery but the primary reason w e are looking at them is for [telepresence].

What about something like limited tactile feedback with regards to the use of robot?

Some people believe that robots make the transition between open and laparoscopy easier for the surgeon. There is no doubt, there is a transition. The robotics improves the transition from open surgery to laparoscopic surgery.

How much training would a surgeon have to undergo in your p r o g r a m m e s ?

Well depending on the type and how many procedures.

Each procedure w e run a training course that runs between two to five days and then followed by mentorship for 6 to 12 cases and then telementoring and potentially telementoring another telerobotic surgeon What are some of the other areas of surgery that robotics is used in?

Robotic surgery is used in general surgery, cardiac surgery, urology... a wide range of surgical procedures have used robots. Neurosurgery, robotics is very useful, w e can do a more accurate spine movement.

That's one of the limitations with the current robots, the fact that you don't have a sense of tension. And what w e are trying to do with the next generation of robots is include this whole issue of haptics, the ability for the surgeon to feel tension as he Is there any type of surgery that would not be pulls. Right now that sense of tension only comes from visual suitable for telerobotic surgery? clues. So you see the tissues change colour, there are visual clues but really isn't enough to allow the surgeon to have a very You can adapt a robot to do anything. A robot is not to good feel of how hard he can pull on something. That's an issue take over, it is to enhance and help the surgeon. People can that's being addressed. The current robots are equivalent to the enhance and adapt the robots Robots can simply be your original PCs, bulky, limited functionality but that's the best. Over assistant. the next years, w e will come up with the "slick laptop". So there needs to be many improvements to this current robot in order for What do you think the biggest impact of the it to be user friendly. That's the road w e will travel if w e can show telehealth p r o g r a m and robotic surgery will h a v e o n that they are useful.

C a n a d a in the next 20 years?

How long do you think it will take until telerobotic surgery, telehealth b e c o m e s a c o m m o n part of healthcare in C a n a d a ?

I would say hopefully in 5 to 10 years. As I said the importance here is to develop the robot which are cheap enough and user friendly enough to be able to be bought by various rural hospitals. S O w e do have a bit of work to do before w e get there but I'm sure that it is something w e will develop. I'm convinced that it's the only way w e can address the major shortage in our surgical care in remote parts of Canada. What w e have is a vicious cycle: Surgeons that are unable to perform a large number of procedures. As a result, w e cannot recruit young surgeons w h o have been trained to do these procedures; they don't want to go there and be stuck. After a while if you don't do a procedure you lose the touch. [Telepresence] allows surgeons to have

I think it will change the paradigm of healthcare. Right now, the way telehealth is being used by many is as a means of providing people consultation, simple diagnosis. I think now, this will allow us to see telhealth as a means of performing a wide range of interventional procedures which would change the whole paradigm. People would then be looking at things like teleendoscopy, teleradiotherapy, a wide range of interventional teleradiology, teleangiography so you can see it opens up that whole spectrum.!

8

Issue 2 | March 2003

ADENOVIRAL VECTORS: NOVEl TREATMENTS AND POTENTlAl CURES

BY DEBORAH LEUNG Figure 1: Structure of the Adenovirus

Overview Vectors are an integral component of gene therapeutics. Serving as molecular vehicles designed to introduce specific genes into the g e n o m e of an organism, they attract the scientific research community with promises of treatments and cures for genetic diseases.

A n infectious agent causing acute respiratory and other diseases (Ryan, 1994), the adenovirus (Ad) has become a highly promising viral vector in current medical technology. N a m e d after the adenoid tissue in which they were first discovered, adenoviruses consist of linear, double-stranded D N A and associated proteins, all within an icosahedral capsid - a twentysided polyhedron. This capsid is m a d e up of 252 mostly identical protein molecules, arranged to form 20 triangular faces with a glycoprotein spike, also known as a penton fibre, at each of the 12 vertices (Campbell et at, 1999) (Fig. 1 & Fig. 2). Of the almost 100 different serotypes of adenoviruses, 4 7 are known to infect humans (Ryan, 1994) and are identified as Ad1 through Ad47 Used to deliver genes to mammalian cells, Ads are among the most c o m m o n vectors used in gene therapy, second only to retroviruses (Vorburger & Hunt, 2002). Aside from applications in g e n e therapy, A d vectors are used in the development of recombinant viral vaccines and in situations where high-level expression of transgene products is desired (Graham, 2000). The popularity of Ads for use as vectors can be partially attributed to its large and easily manipulated 36 kilobases (kb) double-stranded D N A genome, the stability of the viral particle itself, its efficiency in replication, and its ability to transduce a variety of different cell types (Hitter a/., 1994).

Various methods exist for inserting foreign genes into the Ad genome, most of which involve either the Ad5 or A d 2 genome and are distinguished, in part, by which genome regions are deleted and by where the foreign D N A is inserted. The replication cycle of the normal, or 'wild-type' adenovirus is typically divided into three stages - immediate early, early, and late. Immediate early replication pertains to the genetic region of the viral g e n o m e referred to as E1A. This region plays an essential role in regulating the genes of the early replication stage: genes E1B, E2A, E2B, E3, and E4. G e n e products encoded by the E 3 region are involved in host immune response during infection (Tollefson et a/., 1991; Wold & Gooding, 1991). Different construction procedures result in an assortment of A d vectors, each with its o w n advantages, limitations, and ideal uses. Basic descriptions of two such types of Ad vectors are given here.

First-Generation and Helper Dependent vectors: an introduction The two divisions of Ad vectors that merit the most attention first-generation (FG) vectors and helper-dependent (HD) vectors.

Most commonly used are the F G vectors. Typically, these vectors have substantial E1 region deletions and may contain other deletions in the E 3 region. Foreign D N A can be inserted into both

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the E1 and E 3 regions, to a m a x i m u m of 8.3 kb (Bett et a/., 1994).

Because the characteristic E1 deletion removes essential segments of the wild-type A d g e n o m e , the virus is rendered replication-defective and propagation of the vectors can occur only in cells that express the lacking E1 proteins in trans (Latin, 'in transit'). O n e example of an E1-complementing cell type is the 293 cell line, derived from h u m a n embryonic kidney cells and developed in the 1970s by McMaster University's o w n Dr. F. L. Graham and colleagues (Graham et a/., 1977).

In contrast, H D vectors are able to contain significantly greater amounts of foreign D N A inserts than F G vectors, as H D vectors possess large g e n o m e deletions - typically almost the entire viral genome. It is known that Ad-based vectors can accept inserts of up to 1 0 5 % of the wild-type g e n o m e (Parks et a/., 1996), and H D vectors take full advantage of this ability. Recalling that the wild-type Ad g e n o me is 36 kb, H D vectors could allow for inserts of up to 37 kb (Hitt & Graham, 2000). A s their n a m e suggests, H D ('helper-dependent') vectors can only replicate in cells coinfected with a helper virus to provide the essential proteins that the H D vector can no longer create itself. Because virtually all their viral genes have been deleted, H D vectors elicit less of an immune response than their F G vector counterparts (Morsy et a/., 1998; Maoine et at, 2001).

Advantages and limitations of First-Generation and Helper D e p e n d e n t vectors

Recalling that FG vectors retain most of their original viral genes, they are a poor choice for long-term treatment as they are capable of eliciting a host immune response, leading to cellular immunity with repeated treatment (Kafri et a/., 1998). However, animal models have shown that short-term applications of Ad-based vaccines are sufficient to protect against various types of pathogen areinfection (Imler, 1995). Short-term gene therapy using F G vectors is also being studied in the field of cancer research, one example of which will be addressed later in this article.

More suitable for treatments of chronic conditions, such as Cystic Fibrosis, H D vectors are being examined for their potential in long-term gene therapy. Unfortunately, the H D vector system is

Issue 2 | March 2003

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figure 3: Targeting of an Adenoviral Vector

*" The knob domain (round structure) of the penton fibre is the normal binding molecule of the adenovirus, and interacts with the C A R expressed on the majority of healthy epithelial cells (light spheres). Replacement of the C A R domain with an antibody (yi> shaped structure) will allow for targeting of the viral vector against specific cells, such as cancer cells (dark sphere).

Image courtesy of The American Association for the Advancement

s o m e cases, accessibility of target tissue m a y be limited in many other cases. O n e possible solution is to modify the interactions between cellular Ad receptors and the Ad vector proteins involved in receptor binding (Fig. 3). Modification of Ad and Ad receptor interactions, aside from increasing the specificity of A d vectors, m a y also have applications in broadening the range of tissues responsive to Ad vector treatment (Reynolds & Curiel, 1999).

Adenoviruses in cancer therapy

O n e very exciting possibility for Ad vectors is their use in cancer therapy. The Ad vectors previously discussed in this article have been replication-incompetent, as a result of major deletions in the E1 region. Recently, interest has turned to replication-competent still plagued by several problems. Not only is the HD vector itself Ad vectors for use in cancer therapy, as these vectors have the sometimes relatively unstable, but the helper virus used during potentialtoselectively kill tumour cells and to amplify their oncolytic propagation of the vectors can also contaminate the final potential within the tumour mass (Ries & Korn, 2002). O n e of the preparation (Hitt & Graham, 2000). However, interest in these first such vectors is the ONYX-015 vector. This adenovirus mutant promising vectors is great and studies are underway to create more lacks the E1b 55k gene, which normally functions to attenuate the appropriate structural designs and production methods for H D virus-combating actions of a healthy cell's p53 gene. (McCormick, vectors.

2000). The p53 gene, which is defective in cancerous cells, is responsible for blocking cell division or causing the cell to selfdestruct in response to D N A damage or viral D N A infection (Evans P r o b l e m s facing adenovirus vectors & Lahoti, 2000). Thus, O N Y X - 0 1 5 will be destroyed in healthy Since their development, there have been certain issues that are cells because it cannot defend itself against the products of the c o m m o n to all A d vectors, and which continue to prove challenging p53 gene and, conversely, O N Y X - 0 1 5 will proliferate within p53in varying degrees in the implementation of the different vector deficient cancerous cells, resulting in host cell lysis (Fig. 4). types.

Another application of Ad vectors in cancer therapy is O n e such challenge is that of the immune system. H D their use to deliver and express immune modulating genes, such vectors were developed in part to minimize host immune response, as those encoding cytokines, in hopes of stimulating a host immune but immunogenicity still remains a hindrance to both F G and H D response against tumour cells (Addison et al., 1995; Stewart et vectors. The immune response can be stimulated by proteins for al., 1999). which the virus encodes and/or transgene immunogenicity (Morsy et al., 1998), and presents the problems of transient duration of Concluding remarks transgene expression and reduced efficacy in both initial and repeated administration (Hitt & Graham, 2000). Progress is being Past and present A d research encompasses a m u c h greater m a d e in this area, however, and it should be noted that s o m e expanse of information than could be addressed in the scope of studies have shown long-term expression with H D vectors (Morsy this article, and it is hoped that the curious reader will continue to ef al., 1998; Morral ef al., 1999; Maione et al., 2001). pursue his or her interest beyond the material discussed here.

Being a partial result of repeated administration of A d These are only a few of several A d vector cancer treatment vector treatment, the immune response can also be attenuated by methods currently under investigation. In addition to applications reducing the frequency of patient exposure to the treatment. in the field of cancer research, Ad vectors have also shown much Prolonged in vivo transgene expression cannot occur with potential in the treatment of genetic disorders such as cystic fibrosis conventional A d vectors, as they do not integrate with high (Goldman ef al., 1995), haemophilia (Kay ef al., 1994), and frequency into the host g e n o m e (Hitt & Graham, 2000). So, even muscular dystrophy (Acsadi ef al., 1996). Although more research as a diseased cell is successfully treated by genetic therapy, the is required, the promise of novel treatments and cures remain, s a m e treatment in other cells will be lost when those modified cells and it is hoped that this promise will be fulfilled in the near futurei die and do not pass on their altered genomes to their daughter cells. In response to this challenge, the possibility of hybrid vectors figure A: Life Cycle of the Adenovirus c is currently under investigation. These hybrid vectors combine the high transduction capabilities of A d with an integrationWhereas replication-incompetent competent virus, typically an adeno-associated virus or a retrovirus A d vectors express the proteins Qr" (Fisher ef al., 1996; Bilbao ef al., 1997). coded for in their D N A but do not Another challenge of utmost importance is that of cell enter the lytic cycle, replicationcompetent A d vectors cause host targeting. A d vectors are capable of transducing a wide range of cell lysis as n e w viruses are cell types - an attribute that, although advantageous under certain released. It is hoped that selective conditions, can prove to be highly unfavourable. This lack of target internalization of mutated, Adtion cell specificity is due in part to the presence of Ad receptors on replication-competent A d vectors m a n y cell types, the primary receptor being the coxsackiewill result in destruction of adenovirus receptor (CAR) (Hunt & Vorburger, 2002). Intravenous cancerous cells without negatively administration of A d vector treatment results in the majority of the affecting the healthy cells of the virions being taken up and expressed in the liver (Reynolds & organism. /mage courtesy of The Curiel, 1999) and this m a y not be appropriate for most applications.

Oncologist (2002).

Although direct administration to target tissue is a viable option in of Science (2003).

Issue 2 | March 2003

10

PATIENT PRIVACY AND USING MEDICAI, RECORDS IN RESEARCH BALANCING CONFIDENTIALITY AND THE NEED FOR PUBLIC HEALTH DATA RvANTMEA DMMERELL Informed consent dictates that an individual has the right to choose whether or not to join an epidemiological study based on a full disclosure of its methods, treatments, possible side effects and so on (English 1994, Beaucham p 1999). A s c o m m o n sense would suggest, informed consent is an essential ethical aspect of the patient's right to autonomy and self-determination w h e n participating Since the time of the ancient Greek physician Hippocrates, respecting in a clinical study. However, it has been noted "that informed consent to research is generally viewed as something very different from patients' privacy has been considered imperative to the ethical practice informed consent to medical practice" (Levine 1986). Consequently, of medicine. The reasons for such a stipulation are many but, most this difference between what constitutes informed consent in either generally, it has been reasoned that ensuring patient privacy has setting provides a ripe opportunity for the concept of patient privacy favourable consequences for the patient-doctor relationship (Lo 2000). to falter. In m a n y cases in the research field, medical records are For example, the assurance of privacy encourages patients to seek medical help for all kinds of illnesses and to openly discuss their condition considered to have "legitimate extended uses" beyond the private with a physician. A s a result, both the patient's and public's health benefit documentation of a patient's medical history (Knox 1992). Indeed, hospitals often disclose identifiable health information to qualified w h e n conditions like sexually transmitted diseases, psychological disorders or other stigmatized illnesses are reported (Dodek 1997, Lo researchers in order to perform retrospective analyses, following approval by an IRB or similar committee (Dodek 1997).

2000).

Subsequently, there are two main visions of how patient Patient privacy is related to the ethical concept of autonomy, privacy can be secured while allowing epidemiological research to that is, one's capacity for "self-rule" (Beauchamp 1994). Furthermore, progress. The first and most extreme position is that any access to one of the major notions inherent in the concept of autonomy is informed consent: the idea that a patient has the right to m a k e self-ruling decisions medical records for the purposes of research must follow the explicit informed consent of the patient to do so (Black 1994). The other based on relevant information provided about such a decision (English view is that medical records used for research purposes must be 1994, Beauchamp 1999). However, these central concepts are precisely provided in a way that reveals no identifiable features of a patient, those at stake in s o m e m o d e m medical research settings. Of course, including name, age, address, postal code, sexual orientation and occasionally there are reasonable (and indeed, compelling) grounds for overriding a patient's privacy: the mandatory reporting of gunshot wounds, so on. Complete preservation of autonomy, as endorsed in the first position, initially appears to be ideal but is impossible to reconcile domestic violence and impaired drivers are just a few examples (Lo with the needs of biomedical research (Dodek 1997, Beauchamp 2000). But the need for epidemiological (public health) research has 1994, Black 1994). For example, retrospective studies that examine the potential to challenge the conception of patient privacy in a way that temporal trends in diseases like cancer often need health data on greatly concerns m a n y ethicists, physicians and researchers. tens of thousands of individuals in ordertohave sufficient statistical Doubtless, the value and justification for public health research power behind their conclusions (English 1994, B e a u c h a mp 1991); is "self evident" (Black 1994). By studying epidemiological trends, the gathering informed consent for the use of each patient's confidential public benefits from improved health care and carefully targeted health medical data would be a hopelessly time-consuming task. In interventions (Beauchamp 1991, Black 1994). Hospitals are permitted addition to the hundreds of work hours needed to do so, a researcher to disclose identifiable health care information to researchers, provided put in charge of obtaining explicit consent would likely be unable to that an institutional review board (IRB) has given approval for the study. trace patients w h o had moved or died in the time between the study A s a result, much epidemiological research could not be conducted if and the date of their medical records. obtaining consent from each patient w a s a mandatory requirement.

Unfortunately, the apparent compromise evident in the Moreover, such a loss of research would effectively contravene the second view of balancing patient privacy and the need for health assumptions of the Geneva Convention, which state that medicine and data also has detrimental implications for biomedical research. research bear responsibility not only to the individual but also to humanity M a n y studies rely on personal information like addresses or postal at large (Knox 1992). Accordingly, Beauchamp (1991) explains that the codes to investigate the association between residential areas and "use of records without consent is not necessarily an ethical violation.

[Epidemiological research]...may be the first stage of an investigation certain diseases (for example, the U K Childhood Cancer Study that determines whether there is a need to trace and contact particular Investigators' study of exposure to power frequency magnetic fields individuals and obtain their permission for further participation in a study." and the risk of childhood cancer). Consequently, eliminating access Indeed, if patients' medical records were not available for public health to this type of data would prevent studies that relate the occurrence research, the ability to identify and remedy illnesses in a population would of disease to personal details such as place of residence. Likewise, be severely limited. Clearly, strong cases exist for the necessity of both much valuable epidemiological research is based on information patient privacy and the need for reliable, accessible health data. provided by death certificates (such as the Ontario Cancer Registry's However, these two concepts can be - and often are - put into conflict studies of correlative factors in cancer development). Clearly, in the biomedical setting. By examining the issues at stake in balancing banning researchers' access to the identifying details of personal patient privacy and the use of medical records in research, possible information would most certainly c o m e at a great cost to these types changes or solutions to this tenuous relationship can be considered. of epidemiological studies. Furthermore, other types of data, particularly genomic information, m a y b e impossible to keep O n e of the issues at the core of the debate between patient privacy and the need for research is the notion of informed consent.

"Whatever, in connection with my professional practice or not in connection with it, I see or hear, in the life of men, which ought not to be spoken of abroad, i will not divulge, as reckoning that all such should be kept secret."

-Excerpt from The Hippocratic Oath

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Issue 2 | March 2003 "anonymous" in that it is intrinsically associated with, and identifiable to, only one individual (Gostin 1995).

The solution to the problem of balancing the needs for patient privacy and accessible health data is hardly straightforward. Various suggestions have been made, including the possibility of separating the contents of medical records into confidential and non-confidential portions in order to allow researchers and other third parties (such as insurance companies) access to the valuable information within (Dodek 1997, Black 1994, Seigler 1982). Other ideas include promoting a renewed prudence and awareness of the many methods by which patient confidentiality can be breached, with particular attention directed towards the hazards posed by modern technology. T h e growing computerization of medical records, while a convenient feature for clinicians and researchers alike, has produced yet another domain in which the confidentiality of medical records can be compromised (English 1994, Beauchamp 1991).

Although Siegler (1982) famously asserts that confidentiality in medicine has become "a decrepit concept," such a pessimistic opinion need not be the last word on this subject. Without question, physicians, researchers and patients alike must address the changing reality of patient privacy. A s a result, due to the ever-increasing demand for updated, accurate health research, patients should be aware of the fact that their personal information may be shared with others for the good intentions of research. What this requires of physicians, however, is the responsibility to discuss frankly this reality with their patients, in order to ensure that they are aware of the limits of patient confidentiality. Although the reality of accessibility to medical records m a y be unsettling for some, ultimately patients must understand what the operating concept of patient privacy does and does not entail in the clinical and research realms of medicine. •

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ANTHRAX AND THE THREE AMIGOS RY A.JJT THAKUR Bioterrorism involves the deliberate use of microorganisms destruction and to cause infection and long-term destabilization of the human population.

The notion of Bioterrororism was conceived during World War I and II by the Germans, Japanese, Americans, Russians and the English. Only recently has Iraq developed the powder form of this microorganism. Even C a n a d a had once actively participated in the development of weapons grade Anthrax spores for Britain. At the end of W W I I , hundreds of pounds of Anthrax spores were barrelled and cast away into the depths of the St. Lawrence River in Canada.

There are thirty different pathogenic microbes used in Biological warfare. They include viruses, bacteria, toxins, and animal v e n o m eg: Anthrax, Clostridium botulinum, Plague, Smallpox virus, and Tularaemia.

T h e anthrax bacillus, Bacillus anthracis, w a s the first bacterium shown to be the cause of a disease. In 1877, Robert Koch incubated pure cultures of the organism and demonstrated

its ability to form endospores. H e w a s the first to experimentally induce anthrax by injecting it into animals. It w a s later found that Bacillus anthracis is a gram-positive bacterium. It is non-motile and multiplies as vegetative rods capable of spore formation that enable it to resist extreme environmental conditions.

The Anthrax bacteria and the spores are present in the soil in all developing and developed countries. It is endemic, most commonly present in the soil of Asia, Middle East, Africa and even s o m e places in the United States, like Texas, O k l a h o m a , Minnesota, Dakota and Nevada.

Grazing animals commonly acquire this disease. W h e n the animal ingests the bacterium, the poison of the anthrax kills the animal cells. O n c e the animal is dead, the spores and the vegetative rods multiply and spread from the carcass into the soil and then are spread by the wind and soil into the environment This is the only way through which the bacterium propagates itself.

It might be surprising to note that Anthrax bacteria are actually harmless themselves, if not for a few mutations that sets them apart from the others. A n individual bacterium can be

Issue 2 | March 2003

12 compared to a terrorist state, which harbours three infamous proteins whose teamwork is unlike any seen before. Together, these three amigos are capable of manipulating cellular machinery into reprogrammed self-destructing units.

These three amigos are aptly named: 1. Protective Antigen ( P A ) 2. E d e m a Factor ( E F ) 3. Lethal Factor ( LF ) *JI:±-I;< •.•>.• .ju uvi gyfcara uiczl liuxm'u: .V; y!. J: -y.\ >;.: ~ •. •.

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Inhalation Anthrax is the most common bioterrorist weapon.

Symptoms usually develop in seven days as flu like feelings including lethargy, runny nose, headache, fever, cough and sweating. T w o days after the symptoms, the patient develops respiratory failure and the mediastinal chest lymph glands swell, which leads to bleeding inside the lungs, soon followed by patient death.

Japan used anthrax spores against Chinese in Manchuria during World War II in the 1940s. Germans used it against Jews and their enemies in World W a r I and II. Aerosol dispersed anthrax spores were once the preferred biowarfare agent used in controlling enemy soldier populations. Recently, the World Health Organization reported that a powdered aerosol anthrax spore attack even today would unquestionably be deadly to the masses.

Current Research When B.anthracis spores are inhaled, they become ingrained into the lungs, where the body's immune system sends security guards called macrophages to ingest them. However, these unsuspecting cellular security guards (macrophages) are being used as a sporetransport vehicle to attain access to the secure distribution centre (lymphatic system) of the body. Unlike other ingested organisms, these spores are not destroyed, and are free to germinate and multiply within m e m b r a n o u s compartments called phagolysosomes in macrophages. The spores then form vegetative cells that alter cellular processes leading to cell death. However, this process of vegetative propagation has been carefully orchestrated and ensures that sufficient time has elapsed for the macrophagetomigrate to the lymph nodes, where the mature bacteria are released. At this point the

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bacteria have a direct route into the bloodstream, where they are equippedtoproliferate unhindered and begin to secrete their infamous anthrax toxin.

It turns out that B. anthracis is itself no different from other harmless, soil-dwelling bacteria were it not for the two extra D N A molecules known as p X 0 1 and p X 0 2 . p X 0 2 codes for the proteins that form a protective capsule around B. anthracis. O n the other hand, p X 0 1 encodes for several proteins including the deadly trinary arsenal of toxin it formulates. The toxin turns out to consist of three proteins: Protective antigen, e d e m a factor and lethal factor. These proteins are the three amigos that act cooperatively to slip past cellular defences. For example, the e d e m a factor present in the bloodstream immediately disables a key protein involved in calcium-triggered signalling pathways, and uses ittostimulate its o w n catalytic activity. The resulting activity inhibits the body's i m m u n e response against the bacterium, thereby permitting their proliferation. Despite the bacterium's progress, researchers have implied that the bacterium is essentially harmless until this stage of the infection, where they have not yet begun to attach and penetrate cells. It is n o w that these amigos can begin to sabotage cellular machinery into submission.

First, the protective antigen binds to the surface of a cell, where it is activated by an enzyme (protease) that cleaves its tip. Seven of these cleaved molecules aggregate to form a ring shaped structure known as a heptamer, that subsequently binds to varying numbers of e d e m a and lethal factors. T h e receptor for the protective antigen then aids this complex, consisting of the heptamer bound to the two factors, in their transport into an internal membrane-bound compartment called an endosome. Mild acidity causes the heptamer to embed itself into the compartment's m e m b r a n e w h e r e subsequent conformational changes leads to the transport of the e d e m a factor and lethal factor across the endosomal m e m b r a n e into the internal matrix of cells. After a successful entry, the two factors proceed to hijack the cell. In essence, the heptamer is like a door, between the e n d o s o m e and the cellular matrix, which opens to provide a passage for e d e m a factor and lethal factor in response to the slight acidity of the endosomal environment.

O n c e inside the cell, e d e m a factor and lethal factor catalyze different molecular reactions. E d e m a factor upsets the controls on ion and water flow across cell m e m b r a n e s and thereby promotes the swelling of tissues. In phagocytes it also saps energy that would otherwise be used to engulf bacteria

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Above from: www.che.utexas.edu/.../Research/ researchpic/anthrpic.htm Figure 1:

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Issue 2 I March 2003

from moving across the endosome's membrane In contrast to the previously stated method, this approach will effectively catch these amigos in the act of sabotage, thus preventing any further terrorism on other cellular nations. Such attempts to foil the toxins' ability to function effectively are the key to developing an anthrax vaccine and are currently being researched at the leading research institutions Figure 3: Robert Koch's original micrographs of the anthrax bacillus of North America.

Anthrax is primarily a disease of domesticated and wild animals, particularly The latest research has aimed at producing a large-scale effective herbivorous animals, such as cattle, sheep, horses, mules, and goafs. Humans vaccine and an antidote for the anthrax toxin. S o m e of the most become infected incidentally when brought into contact with diseased animals, successful methods have focused on producing mutant toxins as which includes their flesh, bones, hides, hair and excrement. cellular competition for the real toxins. However, the mutants lack the operational ability of the real toxin. Thus, these mutant toxins Above from: www.bact.wisc.edu/Boct330/ lectureanthrax plug the heptamers, making them unavailable for the realtoxin.Other aim to neutralize the anthrax toxin using antidotes. methods The focus of current research is to find a cure and In any case, bioterrorism has opened a n e w chapter in effective control for this potent disease. There are three viable science and medicine. To combat the threat of bioterrorism is to be means of preventing an epidemic of anthrax. O n e approach uses aware of the multiple agents that can be used to counter-react and antibiotics to kill the bacteria, the source of the problem, which control against such acts. It would be best for a society to be prepared produces thetoxin.S o m e c o m m o n antibiotics are: Penicillin and to combat and manage the overall impact of such serious destruction.

Ciproflaxin. However this approach fails to take into consideration There is no doubt that the current research on the biology of Bacillus any toxin that has already been produced, leaving the toxin to anthracis and on possible therapies and vaccines will one day provide wreak havoc in the body. This approach will only be effective if a range of effective therapies for anthrax treatments. It is fervently implemented early. In conjunction with anti-toxins, this form of hoped that every human life will be spared from infection and death treatment constitutes the second approach to battling an anthrax due to biological terrorism, which in fact is the very essence of medical epidemic. Another pre-emptive approach involves use of a research. • vaccine to neutralize the effect of the anthrax toxin For example, Anthrax Vaccine Adsorbed (A.V.A.) is currently being administered to American soldiers as a preventative shield to combat anthrax. This anthrax vaccine works by stimulating the h u m a n immune system to produce antibodies that bind to the toxin and cause protective immunity. Livestocks in parts of U S are routinely given anthrax vaccine. However, due to limited supplies, this approach cannot be applied on a large scale, when it becomes necessary if the entire population is to be protected against the toxin.

Waging War at the Cellular level There are three primary treatment ideas. One innovative approach involves the use of decoy receptors that prevents the protective antigen from linking to its receptor on the cell. These decoys can be introduced as soluble copies of the toxin receptors' protective antigen-binding site called sATR. The next approach involves distancing edema factor and lethal factor and preventing their attachment to the binding sites on protective antigen heptamers. This can be achieved by plugging heptamer sites, the entrance doorstothe cellular interior, with linked copies of a molecule that also has affinity for that site. This idea is effective, however, these cellular terrorists are free to find any of the innumerable number of other unprotected and unplugged _ heptamers to bear the brunt Figure A: of the attack. T h e last approach also hinges on the This picture shows idea that involves blocking the the effects of the transport of e d e m a and lethal three main types of Anthrax: factor from the endosome into the cytosol. This can be Cutaneous, Gastrointestinal achieved by incorporating a and Inholotion. version of protective antigen k n o w n as a dominant Above From: negative inhibitor, DNI, into http://www.a nthrax.osd. mill newly formed heptamers thus disease /infec inhibiting them from moving tion.asp e d e m a factor and lethal factor

Figure 5: The multiple layers of protection shield the anthrax bacterium from extreme environmental conditions and maintain its dehydrated dormant state. .

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Issue 2 I March 2003

14

ATRIAL MYXOMA CANCER OF THE HEART RY MANTTJR ASDHIR Cancer is one word that many humans fear. Millions of people are currently living with cancer or have had cancer previously in their lives, and millions more know people w h o have acquired cancer or unfortunately, have died from it. Regardless of the type of cancer one acquires, the result is the same: uncontrollable cell growth.

Cancerous cells continuously grow and divide; instead of dying, they outlive normal cells to form abnormal cells (www.cancer.org).

In s o m e cases, cancerous cells m a y form tumors unlike other cancerous cells that circulate through the tissues where bloodforming organs are located.

O n e misconception about cancer is that any form of it is dangerous. Different cancers behave in different manners. Overall, there may be cases in which a tumor is non-cancerous and does not metastasize: this is known as a benign tumor. Benign tumors, with very few rare exceptions are also not life-threatening (Reynen, 1995). A n example of a benign tumor may be cardiac myxomas, which are also referred to as primary tumors of the heart. Although this condition is rare, it can nonetheless be present in human beings and thereby cause a great deal of stress.

Cardiac myxomas are rare, usually noncancerous, primary tumors (new growth of tissue) of the heart. Of primary cardiac tumors that are benign, myxomas are c o m m o n in adults. In children the most c o m m o n type of cardiac tumors are k n o w n as rhabdomyomas. M y x o m a is an intercardiac tumor; 75 percent of people w h o have myxomas have them develop in the left atrium of the heart, the latter twenty-five percent developing in the right atrium (Lohr, 1999). The condition of the m y x o ma does not usually take place in either of the ventricles; the chances of this occurring are merely three to four percent.

The macroscopic appearance of the m y x o m a takes on two basic shapes: one is a round, hard mass and the other, an irregular shaped, soft mass. They are attached to the inner lining of the heart, the endocardium. The actual movement of the tumor varies with the amount of collagen and the extent of the attachment of the tumorto the endocardium (Reynen, 1995). Myxomas appear white, gray-white, yellow or brownish and they may also contain calcium.

The tumors range from one to fifteen centimeters in length with most being five to six centimeters. The weight of the tumor ranges from twenty to one-hundred and twelve grams. Cells that make up the tumor are spindle-shaped and e m b e d d e d in a matrix of carbohydrates. The tumor gets its blood supply through capillaries that bring in blood to the heart. Thrombi, "a clot formed in the blood vessel or chamber of the heart" (Dictionary.com) m a y be attached to the outside of the myxoma.

The major syndromes of m y x o m a m a y be one of the following: embolic events, obstruction of blood flow, and constitutional syndromes. Embolic events often occur w h e n fragments of the tumor are released and enter the blood stream.

Irregular shaped tumors that are soft in mass are more likely to embolize than the firm form of the tumor.

More so, the obstruction of blood flow in the heart occurs in the heart valves where the mitral valve is one that is mainly affected. Blood flow restrictions commonly lead to pulmonary congestion and heart valve disease. Embolization leads to different

consequences such as entrance in the brain, kidneys and other extremities, which can then cause pulmonary congestion or heart valve disease. T h e third syndrome caused by a m y x o m a is comprised of constitutional syndromes and has nonspecified symptoms. has no Myxoma Norma) causative agent and the main symptoms in its detection are very generic; many include fever, weight loss, anemia, high white blood cell count, and a decrease in platelet count (Reynen, 1995). Most patients w h o acquire m y x o m a are between the ages of thirty and sixty. M y x o m a s usually occur sporadically, but familial m y x o m a s have been noted, where patients are considerably younger than those with non-familial myxomas. The differential diagnosis of m y x o m a encompasses benign and malignant tumors. Metastatic tumors to the heart are twenty to forty times more c o m m o n than primary tumors (Reynen, 1995). If there is suspicion of having a myxoma, this can be confirmed through an endocardiogram.

In order to treat a person from myxoma, the best thing to do is to surgically remove the tumor. The tumor is unlikely to grow back; it will only do so if a piece of it has been left behind in the surgery. In most cases the surgery is promptly performed, so the possibility of embolic complications does not usually lead to death. However, m y x o m a s can be removed easily because they are pedunculated (Lohr, 1999). The short- and long-term prognosis is excellent in that the rate of mortality from the operation is as little as zero to three per cent. There are only few cases in which the patient m a y require cardiac pacing due to disturbances of the atrioventrical conduction.

There are few cases in which m y x o m a reoccurs; tumors have been detected mainly four years after the surgery has been performed. The chances for reoccurrence of the tumor are only one to three per cent. The explanations for this p h e n o m e n o n have been incomplete tumor removal and embolization, but endocardiographic examinations allow the person to detect if she/he has regained the tumor.

So although cardiac tumors are mainly benign, they can be lethal due to their positioning. The positioning of the tumor mimics cardiac disease and moreover immunologic, malignant and infective processes. Symptoms depend on size, mobility and location of the tumor.

Although the occurrence of m y x o m a is rare, it still should be taken seriously, and if symptoms are detected, an endocardiograph test should be administered. In today's day and age, there are many factors that m a y leadtothe occurrence of cancer, but none of these factors can be labeled as distinct cancerous agents. Therefore, since researchers have no c o m m o n cause for cancer, no cure can be formed either. If a h u m a n being does have cancer, the faster it is found and treated, the greater the chances are of him/her living a happy and healthy life. â&#x20AC;˘

Issue 2 | March 2003

15

TELESURGERY THE WAY OF THE FUTURE ?

R Y JENNIFER CI.A RA TA NG Introduction You're sitting in a doctor's office on a cold blustery day in the Yukon territory, waiting for the prognosis. Surgery? When?

Will I have to travel back and forth to the city for the procedure?

You breathe a sigh of relief when you discover that thanks to modern robotic technology, surgery has become more accessible and convenient for rural areas like the one you live in...

Telesurgery: a term evocative of Star Trek futuristic technology combines the advances from the world of telecommunications with robotics. The marriage of these two technologies has m a d e it possible to perform "remote surgery", advanced telementoring and other procedures that will advance the "telehealth" movement. It is important to understand the various terminologies used in telehealth. The term "telerobotic surgery" is used to describe "remote manipulation wherein the slave manipulator has an 'intelligence' and actions of its own and the master acts in a supervisory role" (Sheridan, 1992).

"Telesurgery" is a term used to describe an operation in which the surgeon is separated by great distance from the patient and uses remote manipulation to perform the surgery "Telementoring" or "telepresence" describes a situation where a senior surgeon can remotely observe, mentor or even physically assist a fellow surgeon in an operation.

Telehealth, which is the application of "information technology to offer treatments and procedures over long distances" (Behran, 47) promises to revolutionize the face of international healthcare. Telehealth is of specific interest to Canada, as there are many remote rural areas which suffer due to the shortage of specialists. Dr. Mehran Anvari of McMaster University is spearheading research into use of telerobotic surgery to service remote rural areas. Dr. Anvari, is the director of the C M A S (Centre for Minimal Access Surgery) which w a s formed in 1999.

The concept of using robots to assist surgeons in the operating room is not new. In 1988, minimally invasive surgery w a s performed using small cameras inserted through small incisions. O n July 11, 2000, the F D A approved use of the first robotic system used in American operating rooms: the da Vinci surgical system. Since then, other robotic systems like the Zeus ™ a n d A E S O P have been developed. These will be discussed in further detail. Telesurgery is an exciting n e w medical technology which m a y prove useful as h u m a n s expand their exploration of space. In the case of emergency, a surgeon on Earth could treat an astronaut using telesurgery. With further research and development, telesurgery m a y one day be incorporated into the space program.

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Transatlantic Telesurgery: Strasbourg, France - N e w York, U S A On September 7, 2001 a milestone in surgery was reached. Stationed in N e w York, Dr. Marescaux and Dr. Gagner performed the first transatlantic telesurgery using the Z e u s ™ robotic system. To ensure a smooth operation, connections had to be flawless with delays of no more than 2 0 0 milliseconds. Five elements had to be simultaneously coordinated (Figure 1): surgeon's actions (via robot and data transmission, voice commands (AESOP), images from the endoscope, videoconference link, and continuous control data exchanged between the computers on each continent. The patient, a 68 year old w o m a n , w a s stationed 7 000 k m away from the surgeons in Strasbourg, France. T h e 4 5 minute surgery, a laparoscopic cholecystectomy (removal of the gall bladder) w a s performed successfully without any complications. This landmark surgery has set an important precedent for international healthcare.

Under the direction of Dr. Anvari, Canada is planning a long distance surgery between a remote rural area and Hamilton, O N . The success of the transatlantic surgery demonstrates the potential of this new technology.

Zeus™ daVinci and AESOP Z e u s ™ (Figure 2), the robotic system responsible for the success of the transatlantic telesurgery, w a s recently approved for use in Canada. Developed by Computer Motion, Z e u s ™ is a master-slave system consisting of three robotic arms; two arms manipulate the surgical instruments, the other arm is a voice or foot-pedal controlled endoscope. Newer models of Z e u ™ are very flexible as they have five degrees of freedom (DOF). D O F m a y be defined as "the number of coordinates that it takes to uniquely specify the position of a system" (Stone). For example, in Figure 4, the block has only one D O F since it can only move along the y axis. In Figure 3, the block can rotate and m o v e along the y-axis, thus it has two DOF. The endoscope

Issue 2 | March 2003

16

technology is called A E S O P (Automated Endoscope System for Optimal Positioning). Not only does A E S O P helptomaintain a steady image of the surgical area, it also eliminates the need for surgical assistants. A E S O P is flexible, with six D O F (degrees of freedom).

The surgeon manipulates the Zeus™using joysticks (called the Microwrist ™ grasped in each hand while observing the surgery on a television screen. The joysticks are form-fittedtoensure that the surgeon's hand movements are correctly interpreted by Z e u s ™ The surgeon also has the option of viewing the surgery in 2 D or 3D. Although the surgeon and patient in the transatlantic surgery discussed were separated by great distance, the Zeus™is also used in conventional operating rooms where the doctor and patient are separated by a few metres.

The da Vinci surgical system (figure 2) is quite similar to the Z e u s ™ m o d e l ; however, it lacks the A E S O P voice recognition function. Unlike the Z e u s ™ da Vinci instruments have a limited Figure 2 The da Vinci robot lifespan. With six DOF, the da Vinci is more flexible than the Zeus ™ http://robosapiens.mit.edu/05/imgs/davinci_ Iyr_r2_cl.jpg The da Vinci system provides a 3 D view of the area (fig 5). Both telesurgery does not exceed the traditional expenses involved systems operate in a similar fashion. For example, in a given with transporting patients and surgeons. operation, the system would begin by making 3 incisions, roughly Many questions exist about the future applications of the diameter of a pencil. The three arms of the robot would then telesurgery. Will robotic surgery units b e c o m e a standard in insert themselves into the incisions and begin the minimally invasive space stations, battlefields and Arctic bases? A s telesurgery is surgery (MIS). a relatively young medical technology, further long-term study Conclusion with regards to patient advantages, cost effectiveness, safety Telerobotic surgery promises to revolutionize healthcare and speed post-operation recovery. Yet, the technology requires a great and clinical applicability (Getman, 2002) is required before the technology can be integrated into the healthcare system.* deal of further development. O n e of the main drawbacks of existing surgical robots is the lack of tactile feedback. Surgeons using the joysticks do not actually "feel" the patient; they must rely on visual cues to judge tension. Haptics, defined -T—™™nmmnmttr<Tr-rimrmmftmrrtimriTm'~r-~1 TrrirrrninirirnniT-rtiir-nnntwMH ••mil •Jin as the ability to sense touch, will likely be a quality achieved by the next generation of surgical robots. Another challenge that telesurgery faces is maintaining a secure, continuous connection with little or no delay in transmission. Major advances in technology are required before these connections can b e implemented. T h e coming of telesurgery does not m e a n that surgeons can abandon traditional methods. In the words of Dr. Hollenberg, (Assoc.

Professor Dept. Surgery, McMaster University), "If I were to be performing a robotic procedure on a patient at a distance, there would need to be an individual at the scene w h o w a s |i competent to convert to an open procedure should things go wrong.". A s well, the economics of telesurgery must be further analyzed. Institutions must ensure that the cost of

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Issue 2 | March 2003

17

EEEUNG THE BlJJES

BY KAPILAN KUGATHASAN Depression is a widespread illness that affects people regardless of age, nationality, race, and gender. Nearly everyone has feelings of blue moods at s o m e point in their lives. It is when these feelings persist, recur, or become severe that one m a y be experiencing depression and should seek medical help. People with a depressive illness cannot merely "pull themselves together" and get better.

Without treatment, symptoms can last for weeks, months, or years and it can be debilitating. Fortunately, today, there is a wide range of medications and therapies available to treat depression.

A complex interplay of factors involving genetics, stress, and changes in body and brain function are thought to play a role in the development of depression (Kaufman, 2001). O n e of the reasons that depression is so c o m m o n is because the illness m a y develop for a variety of reasons. A recent study suggests that abnormalities of the hippocampus m a y play a role in the pathophysiology of depression (Posener et al, 2003). The exact causes of depression are still in question, but scientists have identified certain risk factors that could increase the likelihood of one becoming depressed Family history of depression, stressful situations such as a death in the family or relationship troubles, dependence on alcohol or drugs, medical conditions such as diabetes or cancer, and other mental illnesses are all risk factors that could lead to depression.

Depression can take m a n y forms. What differentiates these forms are the severity and duration of the symptoms. However, there often is not a clear distinction between these different types of depression, since they frequently share m a n y of the s a m e characteristics. The different types of depression can be classified as minor depression or dysthymia, major depression, and manic depression (bipolar disorder), and within each of these main categories there are several subtypes.

Major depression, sometimes called clinical depression, is the most c o m m o n form of depression. It is characterized by a mood change that lasts more than two weeks and includes one or both primary signs of depression: overwhelming feelings of sadness or grief, and loss of interest or pleasure in usually enjoyable activities (Kaufman, 2001). People with major depression m a y also experience recurrent thoughts of death or suicide, feelings of worthlessness, impaired thinking or concentration, insomnia, feeling tired all the time, significant weight loss or gain. These symptoms m a y differ from person to person as well as from one depressive episode to the next. For example, s o m e people m a y have insomnia and lose weight while depressed, whereas others m a y oversleep, overeat and gain weight (Madison Institute of Medicine). In addition, major depression can range from mild to severe, with varying intensity of symptoms. In extreme cases, people with severe depression m a y be unable to work or care for themselves. Although major depression is the most c o m m o n form of depression, approximately 26 per cent of individuals with major depression also suffer from chronic minor depression or dsythymia (Harkness et al, 2002).

Dysthymia is a long-lasting form of mild depression characterized by a persistently gloomy outlook. Dysthymia generally lasts for at least two years and sometimes more than five years (Mayclinic.com). It usually isn't as disabling as major depression and periods of dysthymia m a y alternate with intervals of feeling normal. Signs and symptoms of dysthymia are like those of major depression but not as intense (Rapaport et al, 2002).

People with bipolar disorder, on the other hand, experience recurring cycles of depression and euphoria (mania). This illness isn't as c o m m o n as major depression or dysthymia, but it has a strong genetic component. About 80 to 90 per cent of people w h o have bipolar disorder also have a relative with s o m e form of depression. Bipolar disorder typically emerges in adolescence or young adulthood and continues to occur intermittently throughout life (National Institute of Mental Health).

As with other forms of depression, it is critical to seek treatment for manic depression to prevent worsening illness and decrease theriskof suicide.

The effects of depression are far reaching. There is emerging evidence that depressed patients have a significant loss of cells in the prefrontal cortex, a brain area important in shifting m o o d from one state to the other (Gold and Charney, 2002) Depressed patients also have increased levels of Cortisol and norepinephrine, which represents a highly adverse biochemical environment that could contribute to m a n y different adverse outcomes, including increased body fat, insulin resistance, increased inflammation, enhanced blood coagulation, and decreased bone formation (Gold and Charney, 2002). In addition, depression heightens the risk of increased morbidity of other diseases such as coronary artery disease and osteoporosis. Indeed, emerging data have shown that treating depression in people w h o have experienced myocardial infarction increases their chances of a good medical outcome and survival. Thus, detection and treatment of depression in all ill persons is critical.

There are a number of approaches to treating depression. Just as the cause of depression m a y be related to complex interplay of many factors, finding the most effective treatment for depression m a y b e a complex process that takes time and experimenting. Presumed cause of the depression, the availability of various treatments, and the patient and clinician's preferences are all factors that determine the choice of treatment.

At present, antidepressant medications are the cornerstones of treating depression, especially depressions that are at least moderately severe (Manji, 2003). The brain uses neurotransmitters, chemicals used by nerve cells to communicate with one another. Depression is associated with disruption in the neurotransmitters, serotonin, norepinephrine, and dopamine levels in the brain. Research suggests that depressed people have lower amounts of one or more of these neurotransmitters in the synapse between nerve cells than do people w h o aren't depressed.

Antidepressants such as cyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and newer, more receptor-specific agents such as venalfaxine (Effexor) and mirtazapine (Remeron) all work by influencing the activity of these neurotransmitters.

Another commonly used treatment for depression is counseling or psychotherapy. There are m a n y forms of psychotherapy, such as group therapy, interpersonal therapy (IPT), and cognitive behavior therapy (CBT), however, they all generally involve a mental health professional assisting the depressed person recover psychologically by talking, listening, dealing with thoughts and emotions, and changing behaviors.

Exactly h o w psychotherapy works to improve depression isn't known.

In extreme cases of depression, antidepressants and psychotherapy aren't very effective. In these circumstances, electroconvulsive therapy (ECT) is used. In this therapy, precise amount electrical current is passed into one's brain, causing a brain seizure that lasts 30 to 60 seconds. It is not known for certain h o w E C T helps treat depression. It is known, though, that m a n y chemical aspects of brain

Issue 2 I March 2003

18 functioning are altered during and after the seizure activity. This treatment works quickly than medication or psychotherapy, however, it can cause side effects such as memory impairment. The main benefit of this treatment is that it's often effective when other treatments aren't helpful.

N e w treatments for depression are continually being researched, and currently treatments such as transcranial magnetic stimulation and vagal nerve stimulation are being investigated.

Depression is one of the most prevalent diseases in the world today. Thanks to improved medications and treatments, depression is

treatable. With appropriate treatment, approximately eight out of 10 people with depression will improve and can return to their normal lives. Unfortunately, too many people often don't seek treatments, either because they are unaware that they have depression, or because of misconceptions that depression isn't a real illness and admitting depression is a sign of weakness. It is crucial to treat depression as it can interfere significantly in one's physical and social functioning, and too often, untreated depression is associated with suicide. â&#x20AC;˘

AFTER THE STORM

Pouo AND POST Pouo SYNDROME KLABHLWEK

RAUT

It was not before 1916 that Polio first took center stage in international awareness. In that year, the first major U S epidemic occurred. In N e w York City alone, the number of cases of Poliomyelitis were upwards of 9000 and resulted in 2400 deaths. Because the vast majority of those affected were under the age of five years, Polio was also known as Infantile Paralysis. During the 1930s, 1940s and 1950s, the Polio epidemics grew to unimaginable proportions.

Almost 60 000 cases were reported during 1952 making it the largest epidemic year on record. O n April 12, 1955, the nightmare w a s finally over. The Salk vaccine was deemed both safe and effective.

Together, the Salk and Sabin vaccines m a d e Polio almost completely disappear. But for those w h o faced the nightmare of Polio and survived, it seems that their troubles are still far from over.

The Stages of Polio

collectively as a syndrome. T h e table below s h o w s the percentage of people with Post Polio Syndrome that are affected by the various symptoms.

Symptom (Range) Fatigue Muscle pain Joint pain Weakness in muscles Cold intolerance Atrophy * Statistics from "Managing Post-Polio" Halstead.

Causes of Post Polio Syndrome

Percent 86-87 71-86 71-79 69-87 29-56 28-39

The word poliomyelitis comes from the Greek words polios (grey), and myelos (marrow) with the English word itis Previously, Polio had been divided into three distinct stages: acute illness, period of recovery, and stable disability. W e now understand (inflammation). T h e poliovirus produces an inflammation of that there is one more stage which brings on a new set of symptoms the gray marrow portion of the spinal cord. More specifically, it affects the motor nerve cells in the anterior horn of the spinal related to the original Polio attack. This stage has various terms including Post-Polio Sequelae, Post-Polio Muscular Atrophy, Post- cord. This results in a variable amount of paralysis to the infected person. The virus is widely distributed and infects Polio Muscle Dysfunction, or Post-Polio Syndrome. Acute Illness over 95 percent of the motor neurons in the spinal cord and (Stage 1) is begins with a mild fever, headache, sore throat, diarrhea other cells in the brain as well. After the infection, the affected or vomiting, and malaise. To the majority of people affected, these cells either die or shed the virus and regain a near normal symptoms will disappear after about three days. However, in a appearance.

Since m a n y of the neurons die, the ones that minority in the range of 5%, the virus invades the central nervous survive can develop additional terminal axon sprouts. This is system resulting in high fever, stiff neck, severe headache, and done to reconnected nerves to muscle fibers which are muscle pains. The infection can spread even more producing muscle paralysis or weakness in the limbs, trunk, face and neck. Stage 2 is disconnected from the rest of the body due to the death of their original motor neurons. This additional growth of axon sprouts the recovery phase, and begins as soon as the patient's temperature returns to normal. Children take the longest time to recover with an is the body's way of keeping as many muscle cells in working condition as possible. This compensatory process allows a average length of eight years. Stage 3 begins when the person recovered motor neuron to adapt up to ten additional muscle reaches a plateau of m a x i m u m recovery. In this stage, the patient fibres for every muscle cell stimulated originally. This m e a n s believes he/she has m a d e a full recovery, and it really does seem that a motor neuron that w a s designed to supply 1000 muscle this w a y considering that this stage usually lasts about 25 years. fibres might take on the function of supplying as many as 10 However, Stage 4 begins with an onset of new weaknesses, and is accompanied by fatigue, pain in muscles and joints, and decreased 000 fibers. The size of these motor units increase significantly function. Pain in thejoints and the muscles is also noted. Symptoms after acute polio, and are known as 'giant motor units'. This can include muscle atrophy, breathing and swallowing difficulties, makes it possible for a few motor neurons to do the work of many more. However, this process is a temporary solution at and cold intolerance. Stage 4 begins on average about 33 years best. Any cell which is overworked to nine times its original after the initial polio illness, and lasts for the entire life of the function will malfunction at a m u c h quicker rate than a normal individual. Because these symptoms occur together, they are labeled

Issue 2 | March 2003

19

cell. And thus, the greatly enlarged motor units which labour for decades under an increased burden eventually result in degradation. And so the onset of Post Polio Syndrome begins Research into Post Polio Syndrome is quite recent, and has still much greater lengths to go before the lives of

Polio victims can reach normality However, like all research, scientists will trudge on in the darkness, searching for treatments to alleviate the suffering that is felt once more by the victims of Polio. •

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Issue 2 | March 2003

20

SHEDDING SOME I<IGHT ON GLAUCOMA - DR. ALEXANDER K BALL'S RESEARCH AT MCMASTER BY: JONATHAN M. NG Do not go gentle into that good night.

Rage, rage against the dying of the light.

- Dylan Thomas (1952)

Dr. Alexander K. Ball, McMaster professor in the department of Pathology and Molecular Medicine

(BDNF), show promising results. After As the second leading cause of blindness worldwide, glaucoma's cape two weeks, the drugs of darkness covers more than 6.4 million sufferers across the globe successfully protect ( W H O , 1997). The dominant form of the disease is a silent stalker; it 2 4 % and 3 4 % of the usually progresses into the severe, late stages without any obvious cells that would have symptoms. By progressively obliterating neurons of the retina, it otherwise died in salineeventually leaves sufferers fumbling in the dark, dissociated from the injection control trials, vivid colours that paint our reality. To conquer the beast in the midst of respectively. However, such tenebrous times, vision researchers step forward with their wellBall and others have already documented such successes designed experiments and powerful evidence. Shedding some light on in the literature (Klockeretal., 1997; Koeberle& Ball, 1998; the situation here at McMaster, Dr. Alexander K. Ball showcases his Yan et al., 1999). The revolutionary n e w findings arise exciting findings on neuroprotective drugs and their potential use in retinal from Ball's recent publication in Neuroscience. Here, he diseases like glaucoma. pioneers into unchartered land with the first-ever testing Glaucoma - The Mechanism of Destruction of neurturin's neuroprotective abilities in an animal glaucoma model (Koeberle & Ball, 2002). At first, In the healthy eye, light enters and is first detected by photoreceptor neurturin's protective effects seem weak in comparison, neurons. From here, the signal is quickly relayed through processing producing only 1 9 % protection.

However, seeing further bipolar cells and is passed on to retinal ganglion cells (RGC's) [See potential in the drug, Ball hypothesized that the three drugs Figure 1]. The bundles of protruding R G C axons form the optic nerve, acted through different cellular pathways. H e rationalized the critical bridge linking eye and brain, reception of light at the retina and perception of the signal. Glaucoma exacts its wrath upon this link. that if such a hypothesis were true, synergistic protective effects would be observed. Putting the theory to the test In most cases of the disease, high pressures within the eye accumulate and compress the optic nerve head. The resulting constriction is believed and combining neurturin with B D N F injections, the novel to cut off the RGC's vital supply of nutrients from the brain, effectively concoction elicits an astonishing 7 6 % R G C protection rate [See Diagram 2 & 3]. If such results were reproducible in starving the neurons to death. Failure to receive this cocktail of target derived growth factors (TdGF's) causes them to initiate apoptosis: cell- human cases of glaucoma, almost three fourths of the suicide. To further complicate matters, RGC's have no means to replace individual's sight would be protected!

Current Research Direction: Making the right themselves. They do not arise from neuronal stems cells and cannot connections divide to proliferate. O n the patient's level, this permanent loss of cells Unfortunately, neuroprotection is not so simple. Although is the direct cause of the partial or complete loss of sight that s/he these growth factors are able to sustain R G C survival two experiences (Margolis & Schachat, 1999). weeks after axotomy, cell survival characteristics beyond Dr. Ball's Research: The magic of target derived growth factors this time period are unknown.

It remains an untested theory Dr. Ball's research pursuits aim to stop RGC apoptosis in glaucoma that, once damaged, RGC's cannot escape their inevitable and other retinal diseases. By using what he affectionately calls the apoptotic fate. Although this phenomenon has not yet been "Magic Juice", concoctions of various TdGF's, he protects RGC's from thoroughly Figure I: examined, the sheer complexity of the central their suicidal fate. To test the mixture, Ball uses a sound and solid research design. First, the optic nerve is severed in anaesthetized rats. The 3 primary cells involved in This stops the flow of TdGF's and simulates the pathology of glaucoma. neurotransmission from the eye to the Next, varying amounts of TdGF's are injected into the vitreous humour brain [photoreceptors, bipolar cells of the eye to replace the missing growth factors. Finally, after measured and retinal ganglion cell (RGC)] with periods of time, the effects of the various growth factors are determined the typical location of glaucomatous damage labelled. by counting the surviving cells.

T w o of these tested growth factors, glial cell line-derived Modified from http://137.222.

110.150/calnet/Visual2/page2.htm neurotrophic factor ( G D N F ) and brain-derived neurotrophic factor Introduction to G l a u c o m a

Issue 2 | March 2003 nervous system is enough to give credibility to this claim. To circumvent these potential problems, Ball hopes to take a novel approach to the rescue and regeneration of these neurons. By reconnecting RGC's to their respective brain centres after damage, he hopes to provide lasting protection that closely simulates normal physiology. Consequently, his current research is moving towards the study of neuronal dendrite and axon regrowth. With preliminary findings that the TdGF's used in his experiments produce axonal regrowth, Ball is switching to a new model of rat glaucoma that doesn't sever the guiding myelin sheath surrounding the R G C axons. T h e use of endothelin-1, a potent vasoconstrictor, to kill these cells would leave a guiding path for the RGC's to return to their h o m e in the brain. The results of this experiment would have far reaching implications that extend well beyond the pathology of the eye Successful regrowth of these neurons would imply a healing process for the numerous afflictions of the central nervous system that plague humankind.

A Candle in the Night: With such developments now on the horizon, the future of neurological research looks exciting. For the scientific community, these contributions help m a p nature's hidden mysteries of neuronal protection and regeneration. Laying the

groundwork for the growth knowledge worldwide, it is planting the seed for further groundbreaking discoveries. For the millions of future glaucoma sufferers, such findings offer hope for miracle drugs of the future and restoration of the gift of sight - a return to the world of vivid colour. Leading the new discoveries here at McMaster, Dr. Alexander Ball is holding a candle of hope in the night!

Figure 3: Typical fluorescence c o n f o c a I micrograph images of surviving RGC's after various administration of various target derived growth factors I A days after axotomy.

(Koeberle & Ball, 2002)

Effects ofComhlnertAifrnlntHtration of Neurotropic Factors on R O C Survival at 14 Days Fostaxotomy

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Figure 2: Graph showing RGC survival after administration of various target derived growth factors (TdGF) IA days after axotomy.

(Koeberle & Ball, 2002)

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Issue 2 | March 2003

22

HIV: TERROR OF OUR TIMES RY TERRY NG acquired immunodeficiency syndrome (AIDS) if they present one "The AIDS epidemic claimed more than 3 million lives in 2002, and an or more of the 25 AIDS-indicating conditions (such as Kaposi's estimated 5 million people acquired the human immunodeficiency virus (HIV) in 2002—bringing to 42 million the number of people globallysarcoma or any mycobacterial disease) if they are HIV-positive and if they have a C D 4 + T cell count less than 200 cells per cubic living with the virus." millimeter ( m m 3 ) of blood ( C D C , 1987a; C D C , 1992). A I D S - UNAIDS/WHO AIDS Epidemic Update 2002 diagnosis for children under 13 also includes lymphoid interstitial pneumonitis and recurrent bacterial infections (CDC, 1987b).

Last year, the National Institute of Health, poured over 1.7 billion dollars The C D 4 + T cells that define A I D S diagnoses are immune cells (known as lymphocytes) that mature in the thymus into researching the causes, manifestations and treatments of HIV/ gland (hence "T" cells), and have C D 4 molecules that can act as AIDS in order to put an end to HIV's terror. Since the 1980s, there has cell-surface receptors for HIV. The HIV virion (the virus particle been an increasing need to find some method to prevent the spread of itself) is surrounded by an outer coat known as the viral envelope.

HIV infection among individuals and populations.

Freshly assembled in the cell, the HIV virion carries with it s o m e Currently, the main form of HIV treatment employs a combination of of the cell's lipid bi-layer membrane as it exits the cell. Protruding drugs to target different stages of HIV infection. This therapy, known through the actual virus particle (virion) and the envelope are as Highly Active Antiretroviral Therapy (HAART), slows HIV spread by approximately 70 copies of a complex HIV protein known as env reducing a victim's "viral burden" to very low or undetectable levels. proteins, which consists of a cap m a d e of three molecules called (Kimball 2000, NIAID 2001). However, they are only temporary glycoprotein (gp) 120 and a stem consisting of three gp41 solutions. H A A R T and such therapies are costly, and are inaccessible molecules that anchor the glycoprotein structure in the viral to most people living in developing nations - which comprise envelope. The gp120 molecules are the active sites that have high approximately 9 0 percent of HIV-infected individuals worldwide affinity for and bind to the C D 4 molecule(s), which as previously (UNAIDS, 2002). This is why researchers are still in search of the mentioned, characterize the cell's surface (Dalgleish et al., 1984; ideal vaccine that is safe, inexpensive, easy to store and administer, Klatzmann et al., 1984; McDougal et al., 1985, McDougal et al., would elicit strong immune responses that confer long-lasting protection 1986). This binding results in a conformational change in the gp120 against HIV infection by exposure to infected blood and by sexual molecule, allowing it to bind to a second molecule on the cell contact, and would also protect against exposure to m a n y different surface known as a coreceptor. (Fig. 1) The envelope of the virus strains of HIV. and the cell membrane then fuse and allow the virustoenter the Before delving into the intricacies involved in HIV vaccine cell (Janeway et al., 2001; NIAID, 2001). development, one must have a basic understanding of the nature of In the cytoplasm of the host cell, an enzyme, found in HIV. It is a retrovirus that infects immune cells of the body, causing HIV, known as reverse transcriptase, converts viral genomic either death or dysfunction of these cells. Most accept that HIV is the ribonucleic acid (RNA) into deoxyribonucleic acid (DNA) so that cause of AIDS. Once HIV depletes the body's immune system, the another enzyme, known as integrase, can incorporate or splice body's immune system awaits death helplessly at the mercy of minor infections that previously had no effect on a healthy body (Clark et al., the viral D N A into the host cell's D N A . This newly integrated viral 1991; Cooper et al., 1985; Daar, Moudgil, Meyer, and Ho, 1991; D N A is n o w called a provirus. For a provirus to produce n e w viruses, transcription must occur to convert the provirus into Pantaleo, Graziosi, and Fauci, 1993; Tindall and Cooper, 1991). messenger R N A (mRNA). After HIV m R N A is processed in the The virus is mainly spread through sexual intercourse, contaminated needles used for intravenous drug delivery, and cell's nucleus, it is transported to the cytoplasm. In the cytoplasm, the viral m R N A works with the cell's protein-making machinery therapeutic use of infected blood or blood products. In occasional including structures called ribosomes - to m a k e long chains of viral instances, an infected mother can also transmit the virus to her baby at proteins and enzymes by acting as a template for translation into birth or through breast milk feeding (Janeway, Travers, Walport, and different proteins. Newly m a d e HIV core proteins, enzymes and Shlomchik, 2001). A n individual 13 years or older is diagnosed with genomic R N A gather just inside the cell's m e m b r a n e to form a Figure 1 new HIV virion, while the viral envelope proteins aggregate within Organization of t h e HIV-1 Virion the membrane. Proteins encoded by the env gene from the A pictorial diagram of the provirus become the viral envelope, which includes the protruding basic organization of the gp120 molecules. The gag and pol genes encode one single main components of the HIVprotein molecule, (fig. 2)Protease then cleaves it into the capsid 1 virus. The protein gpl 2 0 is the active site that binds proteins that form the RNA-containing capsule, reverse f $\ C D 4 molecules and is the transcriptase, integrase, and protease itself, thus forming another target of many current HIV-1 mature and infectious HIV molecule (Janeway et al., 2001 • Kimball 1 /f"-"+!. ] vaccines.

T h e lipid 2000; NIAID, 2001). m e m b r a n e is derived from Once inside the body, HIV infects a large number of C D 4 + the host cell in which it was cells and replicates rapidly, causing the blood to spread the viral created. Reverse transparticles into various organs, particularly lymphoid organs, which criptase is responsible for store and produce lymphocytes. The initial infection, approximately conversion of viral R N A into Image courtesy of the Na ional Institute of viral D N A , which is also two to four weeks after exposure to the virus, results in an abrupt

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Issue 2 | March 2003 decline in the number of lymphocytes. Up to 70 percent of HIVinfected individuals suffer flu-like symptoms during this period.

The body's immune system soon fights back with its soldiers, which mainly consist of killer or cytotoxic T cells (CD8+ T cells) and B cells (or B lymphocytes). Each T cell or B cell "knows" that a specific invader has breached into the immune system because it presents a specific antigen or epitope at its surface that marks it as "foreign". B cells secrete Y-shaped antibodies, which are molecules that attach to free floating viruses in the bloodstream and prevent them from infecting other cells. T cells consist mainly of helper T cells and killer T cells. Helper T cells, which comprise C D 4 + T cells, orchestrate the immune response by bringing in other i m m u n e defense cells. Killer T cells or cytotoxic T lymphocytes (CTLs) (also known as C D 8 + T cells) directly or indirectly kill actual cells that have been infected by viruses. These adaptive immune preventative measures dramatically reduce HIV levels. The number of C D 4 + T cells in an infected individual m a y rebound and even approach its original number. Because of the activated i m m u n e system, the individual m a y remain free of symptoms for many years.

Unfortunately, s o m e of the HIV invariably escapes by hiding in the lymphocytes themselves. Inside the host lymphocyte, latent HIV provirus replicates whenever the lymphocytes themselves replicate to fight those invading molecules, including HIV, that remain in other parts of the body (NIAID, 2001). To illustrate this manifestation in a different way, HIV "terrorists" hide, feed, and grow in numbers inside the lymphocyte camp, while the lymphocyte soldiers are fighting other HIV terrorists that seem to persist no matter h o w many they kill. Eventually, the lymphocyte soldiers become exhausted and are no longer able to suppress the number of HIV terrorists. The terrorists then take over, and completely destroy the body's immune system, which leads to the inevitable result of AIDS. HIV takes the upper hand even w h e n faced against lymphocytes because it has all the time to grow strong in numbers while it is hidden and under protection inside the host cell Meanwhile, lymphocytes have to expend themselves continually to hunt down the remaining "visible" HIV molecules. Eventually, the lymphocyte army weakens so much that they soon become helpless when faced with even the most c o m m o n of intruders that would not have a single effect on the body normally The chances of finding a way to stop this do not look too optimistic. However, while there are lymphocytes designed to attack, other cloned B or T cells remain in the body as memory cells so that a more rapid and more powerful immune response m a y occur on subsequent encounters with the s a m e antigen (Janeway et al., 2001; Keeton and Gould, 1986; Kimball, 2002; NIAID, 2001). Therefore, there is a good chance that by administering a vaccine that presents the antigenic properties of a weakened or killed virus to the body, the body's immune system will be more prepared to attack or kill the virus before it can spread or do any d a m a g e to the body.

There are m a n y reasons that m a k e HIV vaccine development uniquely challenging for researchers. As discussed previously, HIV is shielded from the T lymphocytes and B-cell antibodies by existing as a provirus within the cell. The resultant proliferation of proviral D N A that happens during lymphocyte proliferation results in more cells with proviral HIV and therefore increased HIV replication HIV also leads to chronic immune system activation of B cells (NIAID, 2001). The exhaustion of these cells impairs their ability to synthesize antibodies against other pathogens (Kimball, 2000; NIAID, 2001). Furthermore, HIV

23 Figure 2 HIV enters the cell by binding the CD4 molecule and coreceptor at the cell surface. O n c e in the cell cytoplasm, the m e m b r a n e proteins disintegrate.

The viral R N A , which has been released is transcribed into D N A by reverse transcriptase. Splicing into the host cell's D N A is then mediated by integrase enzymes. The viral D N A can then have a chance to synthesize new HIV molecules during protein synthesis from the infected host cell's "new"

DNA. image courtesy of the National Institute of Allergy and Infectious Diseases, Notional Institutes of Health (200I)

impairs C D 4 + T cell function, which is crucial to coordinating the combat against HIV (NIAID, 2001).

Although the normal immune response is usually sufficient to clear most viral infections, it is unable to do so for HIV because T cells and B-cell secreted antibodies are antigen-specific. A high rate of mutations occurs during the process of HIV replication (Connor and Ho, 1994; Kimball, 2000; Richman and Bozzette, 1994). Consequently, the immune system cannot produce enough lymphocytes to combat the rapidly evolving strains of HIV Because HIV can exist as a free virus or as integrated D N A in host cells, vaccines must be able to induce not only antibody-mediated immunity (or B cell-mediated immunity), but also cell-mediated immunity, which comprises the action of C D 8 + T cells destroying HIV infected cells.

In addition to the complications related to HIV, vaccine testing is also a drawn out process. Vaccine trials must first be tested on animals because of undue risk to humans. For example, animals can be inoculated with an experimental vaccine and then exposed to a virus to test the vaccine's effectiveness - a study that would be unethical to conduct in humans. Each candidate vaccine must undergo extensive pre-clinical evaluation in the laboratory, in small animal models, and in non-human primates before it is tested in humans. There are three phases of clinical (i.e. human) testing, which can take at least 8-10 years to complete.

S o m e of the most recent vaccine trials use a prime-boost combination, which consists of an antigen and an adjuvant, which can stimulate a strong cellular immune response, including persistent killer C D 8 + T cells, as well as antibodies that neutralize the virus (NIAID, 1998). This type of vaccine is being developed in Kenneth Rosenthal's research lab at McMaster University (Meducator Issue #1 - A Vaccine for HIV). Rosenthal and his team showed that administering a gp120 depleted, whole-killed HIV-1 virus with a short D N A strand adjuvant known as C p G oligodeoxynucleotide at the mucosal surface of mice

Issue 2 | March 2003

24

can significantly increase HIV-specific mucosal antibodies and T cells, small phase I clinical trialtotest in humans. If successful, the allowing protection from genital infection (Dumais, Patrick, Moss, Davis, same preparations will proceed to larger phase II and phase III clinical trials in Canada and Africa to further confirm their safety and Rosenthal, 2002). The vaccine is significant because it has a high and effectiveness (CANVAC, 2002). Needless to say, vaccine potential of preventing infection at the mucosal surface, especially the development is an expensive and long drawn process with many genital mucosa which is the first target following sexual transmission unclear paths ahead. It is especially difficulttodesign a vaccine of HIV. The mucosal surfaces are thin and permeable barriers to the that,tobe effective, needs to activate the very cells that the virus interior of the body because of their function in gas exchange in the infects. Although there m a y not be a complete preventative lungs, food absorption in the gut, sensory activities in the eyes, nose, measure for HIV/AIDS at present time, it is the hope of many mouth, and throat, and reproduction in the uterus and vagina (Janeway researchers that a vaccination that stays true will arise by the end et al., 2001). Thus, the necessary permeability of the mucosal surface lining these sites creates obvious vulnerability to infection. of this decade. â&#x20AC;˘ The vaccine preparation or combination of vaccine preparations that best protect the mice from infection will go on to a

GREETINGS FROM THE EXECUTIVE

Missing Karen Ho Zain Kassam

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