TheTiffinian Journalof GeneralMedicine

2015 Gold Issue

Featured in this issue:

Phantom Limbs

Alzheimer's Disease

Psychriatry and Its Recruitment Troubles

Interview with a Consultant Neurosurgeon

MRSA and Antibiotic Resistance

Alternatives to Antibiotics

Affiliate Of

Huntarian Museum, Royal College Of Surgeons

Photo: istockphoto.com

Contents

PAGE

The Publishing Team and A Message From The Founder.......4-5

An Interview with Mr James Laban, Consultant Neurosurgeon....6

An Interview with Dr Niall Keenan, Consultant Cardiologist.....7

Phantom Limbs ......................................................................8-9

Left Ventricular Assist Device Associated Infection....................10

Alzheimer's Disease..................................................................11

Proton Beam Therapy..............................................................12

Aortic Stenosis..........................................................................13

Allergies - How TheyWork and How They're Deadly..................14

HIV - An Introduction Part I.........................................................15

MRSAAnd Antibiotic Resistance..........................................16-17

InfectiousMononucleosis (Glandular Fever)..............................18

Euthanasia...............................................................................19

Tissue Engineering and Oesophageal Atresia....................20-21

Discussion of Adult Refsum Disease Part I................................22

An Introduction toPsychiatryand itsRecruitmentTroubles.........23

Multiple Sclerosis.................................................................24-25

Obesity and Fatigue..................................................................26

Robotics inMedicine..................................................................27

Coleiac Disease........................................................................28

Xenotransplantation............................................................29

Antibiotics andNewAlternatives................................................30

Mycoplasma Pneumonia...........................................................31

About us

The Publishing Team

David CohenCo-FounderAn aspiring orthopaedicsurgeon with current interestsin Preventative Medicine,Virology (Zoonotic Diseases)and Geriatrics. Also hasinterests in the efficacy ofantibiotics and their link toCrohn's Disease.

Katya MarksEditorAn aspiring surgeon andresearcher with particularinterest in Neurology andRegenerative Medicine.

Zak MouyerEditorAn aspiring cardiothoracicsurgeon who has greatinterests in Stem Cell Researchfor organ regeneration andemergency medicine.

Zakaria AchercoukAn aspiring surgeon withcurrent interests in Embryologyand Biological Development.

SenthooranKathiravelupillaiCo-FounderAn aspiring surgeon withinterests Public Health,Neuroscience and Virology.Has current research interestsBarrett's Oesophagus and inthe early detection ofOesophageal Cancer.

Saamir MirzaEditor-in-ChiefAn aspiring neurosurgeon withinterests in the release ofneurotransmitters from cellbodies and dendrites.

Tom WilkinsAn aspiring physician withcurrent interests ingastrointestinal disorders andpsychiatry.

Hassan HussainWishes to specialise inOncology. Has specificinterests in haemato-oncology.

About Us

A Message from Senthooran Kathiravelupillai, Co-Founder

The Publishing Team

Keshi KirubaHas interests in cancerresearch, specifically stem cellstudies that allow earlydetection and treatment ofmalignancies.

Huw ChildInterested in the application ofrevolutionary technology tomedicine and surgery.

Leonardo HerreroAn aspiring pediatrician with aninterest in the application ofbiomechatronics for therehabilitation of amputees.

Jeong Hwa HongAn aspiring trauma surgeonwith an ongoing interest inGenetics and Public Health.

It has been a wonderful first year for the journal. Over the past year we have had numerous journalistsjoin the team, our journalists have won prestigious awards for their contributions and we have gainedinternational status. To add, we have received recognition from leading researchers and doctors frominstitutions such as the University of Cambridge, by which we are humbled. Over the past four issues,we have published some excellent work and so, to celebrate we have published this '2015 Gold Issue',collating all of the best pieces so far. Please do note that all sources for the pieces within this issue areavailable at www.medic-aid.co.uk.We hope that 2016 will be an even better year for us, both in terms of publishing high quality work butalso, the circulation of this studentmedical journal. I hope you enjoy reading through this issue, but alsothat you look forward to our forthcoming 2016 issues. We welcome all feedback upon our articles andare eager to hear from fellow students who wish to write for the journal.

Thank You,

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Why did you choose to study medicine?

Mr. Laban was always interested in how the body works andas a little child, he remembers flicking through variousdifferent anatomical children’s pop-up books. But mostclearly remembers looking at the abdominal organs andquestioning himself “well, what’s in between the organs, is itjust air?” Hence the main reason for going into medicine wasthat he was quite innocently curious to know how the bodyfunctioned.

Having attended ImperialCollegeLondon for yourmedicaldegree, what did you find most notable about the ICLexperience?

The college is firstly world renowned for being one of the bestuniversities and especially so for medicine. The college offersamazing academia and awide variety of facilities as well. It isalso tied in with some of the best teaching hospitals in thecountry. So to sum up, for your pre-clinical years you haveaccess to some of the best academia in theworld, and for yourclinical years you have access to the best hospitals in thecountry.

Why did you choose to study Neuroscience and Neurologyto hence become a Neurosurgeon?

After his youthful fascination within the body, he becameespecially intrigued by how themindworked in particular. Socame thedecision for him topickneurology, neurophysiologyor neurosurgery. But Mr. Laban claims to be a ‘doer’ and helikes to get answers, he also loves theatre, so this passion leadhim into neurosurgery.

What opportunities do qualified doctors have inexperiencing international medicine?

Mr. Laban, post-medical degree, went to Montreal to studyfurther epilepsy and then to Sydney to complete hisfellowship. With a medical degree, you are given anincomparable set of skillswhichcanappliedanywherearoundthe world, unlike for example country-based law. So formedicine you are unrestricted when it comes to workingabroad as you can for companies like MSF in depletedcountries suchas inwesternAfricawhere theEbola crisis tookplace. The benefits of going abroad to study, like in Mr.Laban’s case, were that you are exposed to a variety of

By Zak Mouyer

Mr James Laban, Consultant Neurosurgeondifferent institution’s cultures and hence can be thought froma different perspective which he believes is vital within thelearning process.

What responsibilities as a neurosurgeon do you have?

There are three aspects to this: the clinical one, the academiconeand themanagerialone.Hesays thathe spendshalfhis timein consultation with patients explaining managementpathways and diagnoses. And the other half is the surgicalaspect where hewould be in theatre or inward carrying out theclinical aspect.With regard to academia, there is large amountof research and teaching involved. And lastly the managerialaspect involves the patient being able to flow through thehospital smoothly and legally.

Do you believe that the act of studying and learning is stillevident within or apart of your life?

Mr. Laban strongly agrees with this and claims that this is thewhole reason he chose medicine as a career since it should bea doctor’s lifelong quest to attain knowledge and deepen theirunderstandings into the subject.

Can you give us an insight to the multi-disciplinary teamcaring for a patient in the neurosurgical department?

Anexampleof this in effect is clear post-surgeryof avery simpleprocedure such as freeing a trapped vein or fixing a slippedspinal disc. Post-surgery, a pain management team is neededandso is aphysiotherapist.There is averyclear linkbetweenhisdepartment and the oncology department, where post-op ofcranial tumour removal, an oncologist is needed to look afterand make sure the patient shows no other worrying signs.

What does a day as a consultant neurosurgeon consist of?

Mr.Labanclaims that it definitelykeepsyouonyour toesall thetime. He wakes up at 06:30 and immediately goes to ward tovisit a few patients, then there is a 08:00 meeting where theconsultants and junior doctors convene to discuss all thepatients inward. Then from there, there is either a clinic to startor surgery to get on with. Occasionally there are managerialmeetings or multi-disciplinary team meetings as well.

Do doctors have any free-time?

Generally people who choose medicine as a career have aworkaholic attitude and sort of enjoy the notion of bringingtheir work home. One of his greatest fears going into medicine

was that he wouldn’t be able to see his family enough. Mr.Laban believes that he doesn’t see his family as much as otherprofessions, but for any hardworking profession, be it workingin the city or running a business, youwon’t be able to see familyyour asmuch as someonewho doesn’t take pride in their work.

When it comes to yourwork,what ethical values do youholdas a surgeon?

The take home is that you treat your patient just as you wouldwant your family treated, with their best interests at heart. Soonemight say that you should treat your patients like your nextof kin. But you need to balance this out since your patient maynot want of have the same values as your next of kin, so deepconsideration is needed here.

What are you current standings with regard to the JuniorDoctors Crisis?

Mr.Laban firstly believes that theNHS is thebest health systemin the world with no competition, since it is internationallyrecognised for being the top medical system in the world. Butone problem is that it is in £30bn of debt, so the only way tomake it more efficient than it is, is to cut on staffing salaries,since it is not viable to cut on the actual service itself.HenceMr.Laban believes that it needs a ‘zeitgeist paradigm shift’ whichno politician would ever allow to happen. He personallybelieves that if he were to run a health service, he would do itlike theAustralians,where it is slightlyprivatisedandallows formore funding. He is still very patriotic about the NHS and hewants to protect it, but he believes there needs to be a change..

What is the most rewarding thing about being a surgeon?

Having touched upon this already, he claims it is the privilegeof being able treat the patient and help another human being,and this feeling is beyond any. Also being able to extend hisknowledge and academia is something that he loves andcherishes greatly.

What do you like to see in an aspiring medical student?

Most importantly enthusiasmandof course intelligencearekeybut determination and being self-critical are vital in the role ofdoctor. Also being personable is essential since it is a doctor’srole to be able to convey messages to other people in a friendlyand likeable manner.

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Whatwas your experience like atOxford and howdoes thiscompare or differ to other medical schools?I think the first thing is that it’s a very traditional six yearcourse and everyone does an intercalated BSc (although theycall it a BA), which is essentially a year of research, beforegoing back into the clinical course. Also, atOxford you live incollege during term so you might meet more students fromother subjects. I think the downside is there’s not very muchpatient contact in the first three years and some people missthat.

What are some of your main clinical interests?I’m interested in cardiac imaging, particularly cardiac MRIand cardiac CT, which is looking at the arteries around theheart. Echocardiography (heart ultrasound) has been aroundfor a long time but these two have only taken off in the last tenyears as we now have technology that can move fast enoughto look at amoving structure like the heart. In termsof lookingafter patients, I am personally interested in heart failure andsomething called valvular heart disease, where the valves ofthe heart either get narrowed or start to fail.

Could you tell us a little more about your research intocardiac MRI and what you’re doing at the moment?

In this department we have just finished a big genotype-phenotype study of over an thousand healthy patients. All ofour patients have had cardiacMRI scans, blood tests etc. andtheir genotypes sequenced and now thatwe are reaching largenumbers, we are beginning to see genetic trends for minordifferences in things like blood pressure and heart musclethickness. The aim is to use these findings to discover linksbetween genotype and risk of conditions such a heart failure.

What has been the process of your development as aresearcher from medical school until now?

In the holidays of medical school I spent time in a couple ofresearch laboratories inOxford,whichwasagoodexperience.Then in the clinical years ofmedical school youmight be ableto get involved in some basic research on the side. I’m not anacademic doctor but doctors who do then want to embark ona more research heavy career will do a PHD or MD and thatis a valuable period of time dedicated solely to research.

What was it that initially fascinated you about cardiology?If youknowyouwant todohospitalmedicineyouare leftwiththe fundamental choice of medicine or surgery and I chosemedicine. After that, well, the heart is a moving structure

By Katya Marks,which makes it uniquely dynamic and I think there’s alsosomething about heart patients in that there is often massivepotential with treatments to transform their lives.

Did you find that as a junior doctor you got the chance toexperience many different specialties?That is verymuch built into the course now.The course used tobe centred around the main areas, for example medicine,surgery, psychiatry, but they’ve incorporated what they callspecial study modules, where you can do almost absolutelyanything.

So what would your day be like as a cardiologist?Wehave a systemwhere youwill be in charge of patients on theward for a week. In a week like that, you do ward rounds, seeall the new referrals and make plans for each patient. On otherweeks, I see outpatients, I do cardiacMRI lists and I do a lot ofstress testingofpatients.There’s alsoa lot of time spend lookingthrough patients’ test results, supervising junior doctors andalso going on and teaching courses.

I imagine that being a consultant must entail a lot ofchallenges. We’ve been told many times that medicine is avery stressful career. How do you overcome stress?The most intense immediate stress actually comes whensomething goeswrong, the patient dies andyouhave to explainwhat happened to the relatives.More generally, I think there isa chronic stress associated with having a vast amount ofresponsibility and coping with death can be traumatising. Inshort, we cope by being well trained to handle immediatelystressful situations and having something outside of work as arelief.

Are there any other qualities you think are important for amedical student to have?I think there are many people who come into medical schoolvery focused on themedical science and sometimes the humanemotion ismissed. I think if people are thinkingaboutmedicineand they look deep in their heart to find that their keymotivation is an academic interest then they should dosomething else.

Are there any books that you would recommend?There is a great book called The Story of San Michele. It’s by adoctor, about a hundred years ago, who has looked after verylarge numbers of patients.

As a cardiologist, what minimally invasive procedures doyou normally carry out?In my training I have carried out angiograms, where you put a

tube either from the legor thewrist into the artery and thenwithx ray guidance, move it to the arteries just around the heart toinject dye and take x-ray pictures. If you see a narrowing on theartery you can insert a stent. Then there is a new procedurecalled a TAVI, which stands for transcatheter aortic valveimplantation; a new aortic valve can be put in by a catheter andjust blown up like a balloon inside a diseased valve. Thisprocedure is guided by imaging cardiologists like myself.

The junior doctor contract reforms is quite a hot topic at themoment. What do you think about that?Junior doctors are allowed to strike and my personal view isthat they wouldn’t be doing this unless they had really beenpushed into it. It’s all tied up in this thing called 7-dayworking.The main motivation for 7-day working is this statistic thatthere is a higher death rate onweekends, which has been foundto be true. However, I think the answer to that isn’t just havingmoredoctorson theweekendsbut also everythingelse;weneedthe scanners, the operating theatres and every member of theteam. I mean, personally, I think we should move towards a 7-day service but it would involve a massive expansion in thebudget.

Do you see any privatisation of the health service as likely?I don’t actually see privatisation as likely at all. Most peoplewhowork for theNHS are extremely proud of it and there isn’ta major call for privatisation.

I’ve got one last question.What has been themost rewardingpart of specialising in cardiology?When patients get better. With cardiology in particular, manypatients who come in very, very ill will respond well totreatment andwhen they comeback a year later for a followup,they have completely returned to normal. That is extremelyrewarding.

Dr Niall Keenan, Consultant Cardiologist

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Following the amputation of their arm or leg, it is acommonoccurrence that a patientmayexperience thevivid sensation that their limb remains, aphenomenon known as ‘phantom limb sensation’.What is more, this uncanny sensation is more oftenthan not accompanied by sometimes unbearablysevere ‘phantompain’. Researchers at Liverpool JohnMooresUniversity reported that 78.8%ofamputees ina study of 52, experienced phantom limb pain(Richardson et al. 2006) and a large study carried outby researchers fromGuy's Hospital and Royal SussexCounty Hospital found that of 176 amputees, 82%experienced phantom limb sensations and 78%experienced phantom pain (A D Houghton et al.1994).

The first available records of phantom limb sensationdate back to the 16th century when Ambroise Paré, aFrench military surgeon, described his experience ofamputees. Despite this longstanding awareness ofphantom limbs, until recently, there has been littlesatisfying explanation for the condition. Claims thatpatients are wishfully ‘imagining’ the limbs must bedismissed due to the overwhelming proportion ofamputees who experience phantom sensation as wellas the pain and disabilities that are often present in thephantom. The explanation that has been accepteduntil recently is that inflamed neuromas (severednerve endings in the stump), send random ‘nonsense’signals to the brain,whichare then interpreted as pain.However, this explanation does not covermany of themost startling aspects of the phenomenon, such as theability to voluntarily move a phantom limb and thevery vivid sense of form that the limb may possess

Phantom Limbs Furthermore, it does not explain the existence of pain-free phantoms.

Remapping

In order to understand the recent advances in phantomlimb research it is important to have a very basicknowledge of neuroanatomy. The primarysomatosensory cortex is located behind the centralsulcus in an area known as the post-central gyrus(Figure 1). Signals originating at the skin travel throughour sensory neurons to the sensory cortex, the leftsensory cortex receiving signals from the right side ofthe body and vice versa. The Penfield sensoryhomunculus is a map of the sensory cortex (Figure 2).It shows which region of the cortex receives signalsfrom each part of the body and therefore which regionis responsible for sensations felt in each area.

After a person undergoes amputation, sensory inputfrom the limb is lost. It is possible that as a result,‘remapping’ in the somatosensory cortex causesneurons from the region of the cortex next to the nowinactive region to invade, causing sensationsoriginating in the non-phantom area, to be felt both inthat area and in the phantom. For example, followinghand amputation, neurons from the neighbouring faceand arm regions of the cortex,may invade the dormanthand region by a process known as ‘sprouting’ andfacial and arm sensations may also be felt in thepatient’s phantom hand.

However, considering the complexity of sensorypathways in the brain, it is difficult to settle with theconclusion that ‘sprouting’ is solely responsible forphantom limb sensation. Very precise and accuratesproutingwould have to occur in order to produce suchvivid phantom sensations. It is another theory thatthere are many neural pathways in the brain, some ofwhich connect regions of the sensory cortex, that arealways present but are only active when not inhibitedby ‘genuine’ sensory input from a limb. This theorywould explain the presence of phantom limbs inpatients who were born without their arm or leg.Ramachandran argues that it is a combination ofdormant neural pathway activation and sprouting thatis responsible for phantom sensation.

Ramachandran initially used a simple experiment andavolunteerphantomhandpatient toprovehis theoryofremapping. He touched the patient’s face and arm atvarious points with a cotton swab and found that eachtime, the patient experienced the sensation not only atthat point but also at a certain point on his phantomhand.Eventually, hewas able tomapout a full handonthe patient’s face as well as on the region of his arm justabove the amputation site. This discovery has lead tothe relief of uncomfortable phantom sensations formany patients, simply by using techniques such asmassage on their face, upper arm/shoulder or theirupper leg to soothe their phantom limb.

Having discussed phantom sensation in general, I willnow turn our attention to phantom pain in particular.Firstly, an explanation for general phantom pain,according to Ramachandran, could be linked to theprocess of remapping. The complexity of neuralpathways couldmean that during this process, sensorypathways have become confused with pain pathways.As a result, light sensations on the face may lead toagonising pain in a phantom hand and the touch ofwind against a leg may lead to a burning sensation in aphantom foot. This explanation is supported byanaesthesiologist and paediatrician, Elliot Krane’sTED talk on the causes of chronic pain. He describesthe roleofglial cells atnerve synapses in themodulationof sensory experiences and how trauma can cause glialcells to begin to synthesise new proteins. Rather thanonly releasing those appropriate to the sensation, theglial cells begin to spill out many neurotransmitters,which activate other glial cells as well as nerve cells,which in turn spill out their neurotransmitters. Thisconfusion causes to inappropriate distortion of sensorysignals, which can lead to pain at the lightest touch.Perhaps a similar confusion is responsible, in part, forphantom pain. Furthermore, normally visual feedbackacts a natural form of pain amplitude control. Forexample, it may be that when you cut yourself on arock, the pain signals sent to your brain are set toproduce far more intense pain than you actuallyexperience. However, the sight of the wound sendssignals to your brain informing it of the reality of thewound’s severity, which in turn lead to its adjusting ofthe amplitude of your pain. The brain of a phantomlimb patient, on the other hand, receives no such visualfeedback from their limb, therefore their body has no

By Katya Marks

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way of controlling the severity of their pain.

The Mirror Box

With continuously improving understanding ofphantom limbs, there is increasingly abundantknowledge on which to base research into possibletreatments.While the most effective form of treatmentso far does not deal with phantom pain directly, it hasproved a great source of relief for many patients. Thedevice that I am referring to is known as themirror boxand is concerned with allowing patients to controlmovement of their phantoms.

You might ask how it is possible to move a limb thatdoes not ‘exist’ (in the regular sense of the word).Ramachandran, again, provides us with a very logicalexplanation. The cerebellum is a structure located atthe back of the brain, underneath the occipital andtemporal lobes. (Figure 1 - orange) Its role is tocoordinate movement. Taking the example of thehand, for a voluntary movement to be carried out, thecommandmustbe sent to thehand fromits regionof themotor cortex in the precentral gyrus (Figure 1).However, along the way the signal is slightly distortedand without any modulation the resulting movementwould be uncoordinated and inefficient in carrying outthe task. To overcome this complication, the signal issent simultaneously to the cerebellum, which thenholds the instructions for the perfectly coordinatedmovement. Once, the hand has received its signal fromthe motor cortex, it relays this back to the cerebellum,which compares it to the original instructions, beforesending correctional information to the hand, so that acoordinated action can be carried out. While the brainof a phantom limb patient cannot, of course, sendmotor signals to their limb, signals are still sent to thecerebellum and many patients still feel voluntarymovements accordingly.

However, often a patient whose limb has beenparalysed prior to amputation, suffers fromparalysis intheir phantom limb. This is a condition thatRamachandran refers to as ‘learned paralysis’. Hesuggests, beforeamputationeach timesignalswere sentto the limb from the motor cortex, visual feedback wassent to the brain, informing it that the limb was notmoving. As a result an inhibitory response was

developed, preventing any movement from being felt.Ramachandran theorised that following amputation,this inhibitory response remains so that sensations ofmovement are suppressed. The success of the mirrorbox in treating approximately 50% of patients could beviewed as a validation of this explanation for ‘learnedparalysis’. The box consists of two compartments, onefor thepatient’s ‘goodhand’ andone for their phantom.Thecompartments are separatedbyamirror,which thepatient views from the side of their good hand. Thepatient places their hands into the box andsuperimposes their phantomon topof themirror imageof their other hand. When they proceed to move theirgood hand and phantom together, the mirror image ofthe patient’s good hand tricks the brain and acts asvisual feedback from their phantom hand, whichovercomes the inhibitory response to motor signals.Miraculously, the patient can move their phantom.

Since its creation, the mirror box has succeeded incuring learned paralysis as well as other conditions,and, while unexplained, it has even managed to‘amputate’ aphantomarm. In thewakeof suchexcitingnewdiscovery, researchers areworking to develop newsolutions to a condition that, until recently, had littlehope of a cure.

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By Saamir Mirza

Left Ventricular Assist Device Associated Infection

A Left Ventricular Assist Device (LVAD) is a devicewhich bypasses the left ventricle of the heart to theaorta, the large artery leaving the heart, and acts as amechanical pump. Heart failure can, in the moresevere cases, render a heart too weak to pump bloodaround thebodyand this iswhere theLVADcomes in.At first, thiswasonly a temporary solution for patientswho would not survive long enough waiting for adonor for a heart transplant but with new innovationsand technological advances, hospitals can now givethese LVADs to most patients with heart failure as along term solution. The device helps the failing heartand restores normal blood flow. The installation of aLVAD requires open heart surgery and is a bigoperation. Around 80 Britons undergo this operationeach year.

This mechanical pump demands a stable, powerfulbattery since people’s lives are depending on thedevice. The battery is worn around the waist of thepatient. A cord called the driveline connects theLVAD to a controller which is in turn connected tothis externalbatterypackwhichhasa lifeofaround4-6hours. The driveline is composed of two majormaterials, silicone and Dacron fibres (Polyethyleneterephthalate). Dacron fibres are like a netted, wovensheet that areon theoutermost surfaceof the cord.Thenetted structure promotes skin growth through thelayer in order to perfectly seal the incision at thetranscutaneous region.

At the moment there are approximately 100 peopleliving in the UK with a LVAD. The quality of life ofpatients receiving LVADs is very poor prior to theoperation. They are often very weak and unable toleave the house. However, following the LVADimplant, blood flow is quickly restored and theseformerly weak patients are quickly back up on theirfeet and they can return to their normal routines.

However, there are certain problems associated withLVADs. The operation for the implantation of anLVADleaves thepatient vulnerable to infection.Post-implantation sepsis and device related infectionsaccounts for more than twice the number of deaths

than device failure does. LVAD related infections canbe split up into driveline related infections, pumppocket related infections and LVAD associatedendocarditis.Driveline infectionsoccur along the leadconnecting the LVAD to the power source. Althoughthe netted structure of the Dacron fibres are supposedto promote skin growth and facilitate a perfect seal,this is rarely the case. The transcutaneous region isgenerally an open wound, a site for many infections.Many bacteria thrive on the human skin and are oftenfound in LVAD driveline related infections. Thesebacteria can then multiply and spread to the pumppocket, the recesswhich ismadewithin theabdominalcavity in order to house the LVAD device itself. Thiscan lead to many conditions including fever,leukocytosis, abdominal tenderness, as well aspersistent purulent drainage from the driveline site. Ifthe bacteria spread further, it can lead to endocarditis.This is a very rare and potentially fatal infection of theinner lining of the heart (the endocardium).

This is clearly a very major issue and so currentresearch is using biofilms to test and examine effectivetreatment methods. Biofilms are agar platesinoculated with different bacteria. Segments of thesilicone and Dacron fibre driveline were imbeddedinto these biofilms in order to simulate what happens.A recent study used biofilms inoculated withStaphylococcus aureus, Staphylococcus epidermis,Enterobacter aerogenes, Psuedomonas aeruginosa,and Candida albicans. Then they developed aprototype of a driveline which was impregnated withchlorhexidine, triclosan, and silver sulfadiazine inorder to resist bacterial and fungal colonization. Theyrepeated the experiment with this new prototype andthen measured the zones of inhibition around thesample after 24 hours of incubation at 37oC. Aftermeasuring and compiling results, itwas found that theprototype driveline retained around 80% of micro-organismactivity.Fromthis, itwas concluded that theantimicrobial driveline worked to reduce thecolonisation of bacteria and that in this way it mightprevent early infection while still facilitating thegrowth of skin to provide protection against lateinfection.

Alzheimer’s disease (AD) is the leading cause ofdementia worldwide, and is involved in 60-70% ofdementia cases. It takes its name from the Germanneurologistwho first described it,DrAloisAlzheimer.Over 520,000 people across the UK suffer from theprogressive condition, in which neural degenerationcauses shrinking of the brain and subsequent severeloss of brain function.

In general, Alzheimer’s progresses in three phases.During the first phase, symptoms may go unnoticed,as they either gradually develop or are associatedwithwhat is perceived tobe thenatural effects of aging.Thefirst symptoms tend to be minor memory problems,such as forgetting the names of places or objects, orrecent conversations. The ability to perform tasks thatwerepreviouslyperformedwithease, suchascooking,household repairs or card games, can also be a sign ofearly stage AD. These memory problems cansometimes lead to other conditions, such as anxiety ordepression. In the second stage of AD, memory loss,particularly short-term, becomes more severe. Thepatient may also become disorientated easily withrespect to time and location.Dysphasia (a disturbancein the ability to select the correct word) may present,and the patient’s capacity to concentrate andnumerical ability also decline. Personality changescan occur, for example becoming suspicious anddemanding of others. Anxiety worsens andunpredictable mood swings are also common. In thefinal stage of AD, confusion becomes profound.Patients may also experience hallucinations,delusions and psychosis. Finally, symptomsassociated with nervous system diseases, such asabnormal reflexes, and faecal and urinaryincontinence can develop.

AD is rare in those under 60, and affects slightlymoremen thanwomen.The risk factors associatedwithADare increasing age, a family history of having thecondition, lifestyle factors commonly associated with

heart disease, and previous severe head injuries. Itfollows that those who regularly take part in contactsports such as rugby or boxing are at a higher risk ofdeveloping Alzheimer’s. Indeed, evidence was lent tothis idea by a study published in the journalNeuorlogyin 2012, which showed that former NFL players were4 timesmore likely to developADthan the generalUSpopulation. Factors associated with heart disease, forexample hypertension, increased cholesterol, poorlycontrolled diabetes and smoking increase the risk ofvascular dementia (dementia caused by impairedbloodsupply to thebrain–oftencausedbystroke), andit is thought that these factors could also contribute tothe development of Alzheimer’s. It is not knownexactly what occurs in the brain that causesAlzheimer’s to develop but in rare cases AD is causedby a dominant gene, which greatly increases risk.

People with Alzheimer’s have abnormally high levelsof two proteins, known as amyloid beta and tau. In isthought that some amyloid beta peptides misfold,causing others to do the same. This results in a build-up of amyloid plaques in neuronal synapses. Theseplaques are toxic to the neurons and so cause them todie, thus leading to neuronal degeneration. Thisfeature makes those with Down’s syndrome morelikely to develop the disease, as the extra copy ofchromosome 21 that causes Down’s syndrome alsocauses amyloidplaques to build-up in thebrain,whichin some people can lead to Alzheimer’s. The tauprotein mechanism functions in a similar way. Thisprotein is responsible for stabilising microtubules,which are abundant in neurons. These tau proteinscan become hyperphosphorylated (where a moleculewith multiple phosphorylation sites becomessaturated). This causes the protein to misfold, andwhile normal tau proteins are highly soluble, themisfolded protein is insoluble and so forms so-called‘neurofibrillary tangles within the nerve cell bodies.These interferewith cytoplasmic reactions and so leadto cell death, which leads to neural degeneration.

ADisgenerallymanagedby treating the symptoms. Inmild to moderate AD, acetylcholinesterase inhibitorssuch as donepezil, rivastigmine and galantamine canimprove symptoms. These inhibit the action of the

enzyme acetylcholinesterase, which catalyses thebreakdown of acetylcholine. Acetylcholine is aneurotransmitter, which is obstructed by amyloidplaques in AD affected synapses. Inhibiting thisenzyme causes level of acetylcholine to increase andso help relieve the symptoms presented. Howeverthese drugs have no effect on dementia brought aboutby other causes, such as head injury or stroke. Theyalso have a range of side effects, including nausea,diarrhoea, dizziness and headache. The drugmemantine canbeused to treat thosewithmoderate tosevere dementia. This drug blocksNMDAreceptors –in neurodegenerative disorders such as AD thisreceptor is overstimulated by glutamate (aneurotransmitter that plays an important role inneural activation). Treatment in this phase of thedisease is particularly important for those close to thepatient, as at this point the patient is almost entirelydependent. Therefore a treatment that reducessymptoms at this stage eases the burden on them aswell as helping to treat the patient.

While there is no known way to definitely avoiddeveloping AD, there are steps that can be taken toreduce the risk of developing it, or indeed any type ofdementia. They include stopping smoking ifapplicable, cutting down on alcohol, eating healthilyand remaining physically andmentally active into oldage.

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Alzheimer's Disease

By Tom Wilkins

Page 12

"It's incredible news. We are absolutely delighted. It hasjustified everything we have gone through because things areworking out for Ashya." Brett King

On the 13th of July 1978, in Protvino, Russia, thenuclear physicist Anatoli Bugorski was identifyingwhat was causing the U-70 Synchrotron, the mostpowerful particle accelerator at the time, tomalfunction. In doing so, he stuck his head into thepathway of the proton beam whilst the machine wasmade inactive for him. Unfortunately, the machine’ssafety mechanisms miscarried, and Bugorski had200,000 rads of radiation fired through his head.Entering through the left part of his skull and exitingthrough the left side of his nose, the protons acted asfree radicals, damaging theDNAof thebrain, skinandother cells of the tissues that the protons were firedthrough. This damage would cause apoptosis(programmed cell death) to take place. He reportedlysaw, for a very short moment, a light “brighter than athousand suns” yet didn’t feel any pain.

As a result, Bugorski was taken to a Moscow clinicwhere he was expected to die within 3 weeks and theprogression of his condition to be observed fordocumentation and research, but he survived.However, due to brain damage, over the course of thefollowing 2 years, the left side of his face becameparalysed, became deaf in his left ear and began tohave seizuresperiodically, aswell as a large increase inmental fatigue due to nerve destruction. Despite thehindrances, Bugorski managed to complete his PhD,and during the days of the Soviet Union, he served asa monument to Russian medicine.

Proton Beam Therapy is a relatively recentdevelopment in the field of nuclear medicine.Conventional radiotherapy was developed shortlyafterWilhelmRoentgen discoveredX-Rays in the late19th century, firstly as amiracle cure formany diseasessuch as SLE andTB,which laterwas focusedmore oncancer towards the mid-20th century.

It works by firing 2 types of radiation (sub-atomicparticles) towardsa tumour located inaparticularareaof the body. This can either take the form of ionisedparticles, or photons. Using photons can causeradicalisation of molecules in the cell and on theDNA, which can cause further damage. However,using ionised particles, such as protons and ions, cantransfer energy directly to the DNA chain as well asionise the atoms that constitute it, which causes it to

break at particular points. Being responsible for mostcellular functions such as replication and translation,this leads to the destruction of a cell.

Radiotherapy can be used as curative treatment,which aims to eliminate as much of the tumour aspossible to maximise the long term gains of a patientincluding life expectancy.Or it can beused apalliativetreatment, i.e. not to cure, but to reduce pain andothersymptoms, as well as to control other side effects, e.g.fatigue and swelling around the area where theradiation was fired towards, as experience byBugorski. Both of these can be conducted in 3 ways,using neoadjuvant radiation which is used to shrink atumour before surgery, which can make it easier toremove. The second is intraoperative radiation whichis used during surgery for the same purpose but also toallow the health cells to be physically protected by theuse of certain equipment by an operator. The thirdmethod is adjuvant radiation, used after to reduce thechance of the tumour reoccurring.

The advantage of radiotherapy against cancer cells isthat they go through their cell cycle relatively rapidlycompared to regular, healthy cells. As a result, cancercells are engaging in growth phasesmore often, and sotheirDNAis exposedmoreoften than ina regular cell,leaving it more prone to damage. Cells that replicatefaster e.g. skin cells, typically go through this damagephasequicklycompared toothers suchasneuroncells,as they replicate faster. Also, cancer cells arefundamentally damaged in the sense that they have aworsened ability to repair minor injuries to the DNA,so they suffer more permanent damage that morefrequently causes apoptosis.

The disadvantage of Radiotherapy is the chance ofside effects, as the photons/ionised particles couldsplash their effect onto healthy tissues/cells adjacentto cancer cells. As healthy cells usually form a highervolume of the body compared to the tumour, the lossof healthy cells and accompanied detriments couldoutweigh the benefits.

This is where proton beam therapy has an advantage.Ionised particles such as protons have mass whereas

photons do not; this causes them to have a muchsmaller scatter range upon being fired. This leads formore accurate targeting of the tumour and reduceddamage to surrounding tissues. The energydistribution pattern of proton beams can also be usedfor 3D targeting of the tumour where the beams arefocused from different directions onto the tumour tominimise damage to healthy tissues by operators.Different types of tissue can absorb different amountsof radiation safely and without much harm, thisamount is known to operators and this can be used toadjust the energy of the proton beam.

The proton beams are energised in a particleaccelerator up till they reach a certain velocity wherethey are fired out through an exit towards the patient,this determines how far into the body the beam willtravel. This is due to the protons being sloweddownasthey go through the body due to contact to particularforces. This increases the duration of exposure toelectrons on the DNA molecule, which increases theamount of ionisation that occurs compared to themethod using photons, causing more damage tocancer cells.

This makes Proton BeamTherapy very useful againstcancers in critical areaswhere if the surrounding tissueis damaged, there will be grave consequences.However, there are a few arguments against the use ofthis therapy. For one, it is considered to not be aseffective in destroying cancer cells and shrinkingtumours as conventional radiotherapy. This type oftherapy also, whilst supposedly having a reducedfrequency, triggers similar side effects to regularradiotherapy e.g. fatigue, nausea, soreness.Although,this is all dependentonmany factors including theage,health, duration and dose of radiation as well aswhether the patient has any other conditions andwhether or not the patient is also being treated withchemotherapy.

Furthermore, it is limited availability for theequipment used for Proton Beam Therapy, it isexpensive and takes time to set up, the only 2/3 inBritainwon’t be activeuntil 2017. Inparts of theworldthat use private healthcare systems such as the US,there are heavy costs for this type of therapy. Lastly, itcan’t be used effectively for all types of cancer, notenough research has gone into its effects in other partsof the body.

Evidently, this type of therapy is quite effective intreating particularly dangerous cancers, and therelatively recent incident involving the patient AshyaKing has helped support its foundation as a newsolution, but more research will have to be conductedto maintain this reputation thus far.

ZakariaAchercouk

Proton Beam Therapy

be surgery, specifically an aortic valve replacement.Normal aortic valve replacement (AVC) is arguablythe most traumatic surgery there is. The procedureinvolves splitting the chest and its sternum open andsurgically opening the pericardium around the heart.Here the heart is stopped with a dose concentrated ofpotassium and so are the lungs, hence the perfusionistwill attach the respective organs to a heart-lungmachine (this part is necessary to keep the heart andvalve stationary while the replacement occurs). Thenthe aorta is opened and the calcification is removedwith the entire valve.After amechanical, prosthetic orbiological valve has been substituted in for the oldvalve, the heart is tested, restartedwith electric shocksand is kept in rhythm with an external temporarypacemaker. Then the chest and sternum are closed.

This procedure leaves the patient with many possiblecomplications such as pericarditis, which is wherethere is fluid build-up in the pericardium, and this is aperfect place for infections to stagnate. Also there is amassive scar left on the patient’s chest, which can alsoeasily get infected. Also if there is a problem with thevalve, the freshwound on the chestmust be re-openedandoperatedonagain.Hence it is clear that thiswholeprocedure is extremely traumatising for the patientand in some cases this procedure can create moreproblems than it can solve.

An innovative andnewway to treat patientswhoneedto have their aortic valve replaced would be done byusing an Edwards SAPIEN 3 Transcatheter AorticValve. The entire procedure is completedtranscatheter and inmost cases via the femoral artery.Here a catheter is sent up the arterial side of the heart,through the aorta and into the left ventricle. Then theexisting and stenosed valve is permanently pushedapart and left open. Then a second package is sent upcontaining a wire mesh and a synthetic valve (whichare both collapsed), both ofwhich are encompassing adeflated balloon.

Then when the package is in position, the balloon isinflated, temporarily impeding any cardiac output,and causing the wire mesh to open tightly around theold valve and hence putting the new valve into its newpermanent position. From the second the balloon isdeflated, the new prosthetic valve is in completefunction.

What makes this valve replacement method so muchbetter is that the complications after for the patient are

minimised and that it also saves the healthcare systema lot of money compared to the traditional open-heartsurgery method. Also due to the fact that the valve ismade of bovine pericardial tissue, haemodynamicsare optimised and hence the longevity of this item issimilarly maximised. This method of valvereplacement is cheap, cost effective, less traumatisingfor the patient and hence is a revolutionary input intocardiac surgery.

Page 13

By Zak Mouyer

Aortic Stenosis

Theaortic valve is perhaps themost important valve inthe entire cardiovascular system.This valve is theonlybarrier between the arterial blood in the left ventriclereaching the rest of the body. Hence any impedimentto this valve could have negative effects elsewhere inthe body.

Normally, blood carrying oxygen enters the left upperchamber (atrium) of the heart. It is then pumped intothe lower left chamber. The aortic valve opens whenthe heart contracts to pump blood from the leftventricle into the aorta, the body’smain artery.Whenthe left ventricle relaxes, the aortic valve closesbecause there is a higher blood pressure within theaorta compared to the ventricle.

However, in the case of a patient with aortic valvestenosis, this process changes immensely. Aorticstenosis is the most common type of aortic valveimpediment, where due to a plethora of reasons:calcification (this iswhere calciumdeposits solidifyonthe valve preventing full movement), rheumatic heartdisease or congenital conditions (an example could bethat the aortic valve comes out to be bicuspid insteadof tricuspid at birth); the aortic valve is not allowed toopen fullywhenneeded.Hence, the fillingpressures inthe left ventricle ‘sky-rocket’ and haemodynamicvelocities across the valve increase as well; also therewill be aortic valve regurgitation where blood leaksthrough the valve. This all will in turn lead the leftventricle into having to pumpmuch harder and hencewill cause that cardiac muscle to grow more (this isknown as hypertrophy). Overtime the health of theheart will reduce and lead to complications such ascardiomegaly, arrhythmias, pulmonary oedemas andcongestive heart failure.

Therefore from the above, it is apparent thattreatment for aortic stenosis is absolutely mandatoryonce the necessary scans (echocardiographs andventriculographs) have been done. The usualmethod of treatment of severe aortic stenosis would

Page 14

By HassanHussain

Allergies - How They Work and How They're Deadly

Many people these days suffer from one or more typeofallergy,whether it is simplyhay feveroradeadlynutallergy. With the percentage of adults with allergiesincreasing by 5% each year, and 21 millions adultsaffected in theUK alone, allergies are becomingmoreand more prevalent. But what causes allergies andwhy can they be so deadly?

Lymphocytes are the main agents of the immunesystem.When they encounter a certain antigen that isconsidered to be part of a foreign body, they produceantibodies that bind to the said antigen. The 5 types ofantibodies are IgA, IgD, IgE, IgG, IgM, and these areknown as immunoglobulins. The one that causesallergic reactions is IgE. In people who don’t sufferfrom allergic reactions, IgE does not combatsubstances such as food. However in an allergicreaction the opposite occurs. The ability for the bodyto create IgE when it is not needed is inherited, so ifboth parents are allergic to substances, chances aretheir children will have allergies as well.

In order for an allergic reaction to food to occur, firstthe person must be exposed to that food substancefirst. When the food enters the body it starts to bedigested andwill eventually be digested into a protein.The person’s TH2 lymphocyte then detects thisprotein, recognises it as a foreign body and produces acytokine knownas Interleukin-4, or Il-4. The cytokineand the T-lymphocytes interact with B-lymphocytes,which begin making the immunoglobulin IgE. TheIgE binds to mast cells, which are tissue cells, andbasophils, which are a type of white blood cell. Bothare found everywhere in the body, but specifically inparts of the body that generally flare up during anallergic reaction, e.g. lungs, nose, skin, throat andgastrointestinal tract. This process is known assensitizing exposure, and takes around 7-10 days tocomplete.

When a person ingests that food again after thisprocess has been completed, and when that food isdigested into that protein again, the IgE bound to themast cell recognise the protein and binds to it, while

still staying bound to the mast cells and basophils.Proteins called complementary proteins are releasedand attach to the allergen to form a chain. The proteinchain destroys the mast cells and basophils, causingthem to release the contents, which include cytokines,histamines and other chemicals, which then lead tothe symptoms of the allergic reaction. Thesechemicals cause blood vessels to dilate, leading to adrop in bloodpressure. Fluid fills the gaps between thecells near the area affected by the reaction.

So when do allergic reactions become dangerous?Anaphylaxis is the name of a severe allergic reaction,and occurs when the process of an allergic reactiongoes out of control, leading to the body not being ableto function properly, which can cause death in theworst cases. During anaphylaxis, the histamine andother chemicals released from the mast cells and thebasophils means that fluid from the cells is dumped inthe throat, and combined with muscle contractions,results in the throat swelling andclosingup,which canlead to shortness of breath and oxygen starvation,which if not treated quickly could lead to death.Othersymptoms of anaphylaxis include hives, which is araised itchy rash all over the body.Blood pressure may decrease and fluid may be leakedfromthebloodvessels, starvingvitalorgansofoxygen,especially the brain and kidneys, and resulting inconfusion, anxiety and loss of consciousness. Too lowa blood pressure can lead to circulatory collapse,causing death.

So what can we do to counter anaphylaxis? The mainon site treatment is epinephrine,which is the chemicalin EpiPens. Epinephrine reduces the swelling in thethroat and causes vasoconstriction to stop the bloodpressure from dropping too low. Other treatmentsinclude antihistamines, adrenaline and steroids.

Allergies can appear out of nowhere and affect

people who have never been affected before, andcan range from mild to deadly. The most importantthings you can do if you have an allergy is to beprepared: stay away from your known allergens andalways carry an EpiPen if you need it.

Page 15

HIV - An Introduction - Part I of III

By SenthooranKathiravelupillai

The Human Immunodeficiency Virus (HIV) is theetiological agent of the Acquired ImmunodeficiencySyndrome (AIDS) epidemic which was responsiblefor approximately 1.5 million deaths worldwide in2013. HIV weakens the immune system bymultiplying within T-helper lymphocytes, thusdestroying them. HIV was first isolated in 1983 at thePasteur Institute in Paris, from the lymph node of apatientwith lymphadenopathy, a conditionwhere thelymph nodes have swollen due to an infection.Following electron microscopy as well as sequenceanalysis, HIV was considered to be a lentivirus, agenus of the Orthoretrovirinae sub-family and thewider Retroviridae family.

A distinct feature of the Retroviridae family is thatthey are enveloped viruses which are able to replicatewithin a host cell through the process of reversetranscription. Reverse transcription makes use of anenzyme called reverse transcriptase which creates aDNA intermediate from the viral RNA. This allowsthe genetic information to be produced by theribosomes of the host cell from theDNA intermediatefor viral replication. Viruses in the genus Lentivirus,to which HIV belongs, are characterized by theirassociation to diseases of immunosuppression and bytheir long incubation periods after infection beforesigns and symptoms of illness become obvious.Lentiviruses have also been found in many primatespecies. As well as the variants of HIV, HIV-1 andHIV-2, another example is the SimianImmunodeficiency Virus (SIV), which is found tocause Simian AIDS, a disease which develops mostcommonly if the Asian or Indian Rhesus Macaque isinfected.Notably, SIVs are able to infect up to 45 of allAfrican non-human primates [1], however, in manycases SIV infections seem to be non-pathogenic.

The two types of human retroviruses are HIV-1 andHIV-2. Amongst HIV-1, there are four subtypes,groups M, N, O and P. Group M has been identifiedas the group responsible for the HIV pandemic whichcurrently affects approximately 35 million peopleworldwide [2]. The other groups of HIV-1 are lesscommon, with Group O, identified in 1990,

representing less than 1% of global HIV-1 infections,groupN, identified in1998,with13documentedcasesand group P, discovered in 2009, with only 2documented cases.

Before studying the replication mechanism of HIV-1within cells, it is important to analyse the virus’sstructure, and how its components make it suited forentering cells such as theCD4+T-helper lymphocyte.The mature virus has a diameter of 100-120nanometres with a spherical morphology. The viralcore is a bar-shaped, electron dense core, containingtwo short strands of genomic ribonucleic acid (RNA),around 9200 nucleotide bases long, as well as theenzymes reverse transcriptase, protease, ribonucleaseand integrase. All of this is encased in an outer lipidmatrix, also referred to as anenvelope,which containskey surface antigens and glycoproteins. The envelope,which is derived from a host cell, has 72 surfaceprojections and contains the antigen gp120, which isimportant in thebindingof thevirus to target cellswithCD4 receptors as well as a co-receptor (e.g CCR5 orCXCR4). Also, there is a second glycoprotein, gp41that helps the gp120 to bind to the lipid envelope oftarget cells.

The genetic makeup of the HIV virion, also known asits genome, consists of threemajor genes, gag, pol andenv. The genes code for the production of polypeptidecomponents that will serve structural and functionalroles. For example, the enzyme reverse transcriptaseserves a crucial role in the copying of theHIV genomeinto DNA during the life cycle of the HIV virus.Amongst the genome, regulatory or accessory genessuch as tat, rev and nef are present. Regulatory genesoften code for repressor proteins, which in turnprevent RNA polymerase from transcribing RNA.Thegaggene codes for the viral capsidproteins,whichis important as it codes for the important proteinswhich will make up the viral core in which all thegenetic material of the virus is located. The pol genecodes for the production of four extremely importantenzymes, reverse transcriptase, protease, RNAse Hand integrase. Protease is the enzyme responsible forpreparing proteins made from the HIV genome, sothat they can be incorporated into newly produced,functioningHIV daughter particles. Integrase is a keyenzyme involved in a process in which the DNAreplica of the HIV’s genome is incorporated into theDNA of the host cell. The Env gene codes for theproduction of the surface glycoprotein 160 alsoreferred to as gp160. Glycoproteins are originallyproteins however; they aremodified in organelle such

as the Golgi apparatus, where carbohydrates or lipidsare added. The synthesis of gp160 is extremelyimportant since it eventually splits apart into the twotypes of surface receptor proteins or ‘spikes’ found onmature HIV virions gp120 and gp41 which actuallylies embedded in the viral membrane. The gp41protein acts as an anchor of the gp120 glycoprotein. Itshould be noted that the gag and pol gene can often beexpressed together as one, in a long strand called ‘gag-pol’. Having gained a preliminary understanding ofthe structure of the HIV virus, the pathogenesis of theHuman Immunodeficiency Virus will be explainedand discussed in the second part to ‘HIV – AnIntroduction’ in the upcoming issue.

Page 16

The invention of antibiotics could be cited as one of the mostimportant breakthroughs in medicine to this day. Antibioticsare so effective because they directly combat bacteria byaltering a specific function, causing them todie.However if allof the bacteria do not die, the surviving bacteria sometimesmultiply into resistant colonies, which will then require adifferent treatment. Thus many of the bacterial infectionsantibioticshad initiallybeendeveloped tocombatnowrequirenew and different antibiotics. As a result, we must search formore newantibiotics to supersede those that have lost efficacydue to resistance. Also, many antibiotics are being used on awide scale for all sorts of infections. Such universality of theantibiotics has led to their overuse, increasing the demand fornewer antibiotics. Studies have led to the discoveryof possiblealternatives to antibiotics, by combining natural products andcomparing their effectiveness with antibiotics with knownactivity against Methicillin-resistant Staphylococcus aureus(MRSA).Methicillin-resistant Staphylococcus aureus, morecommonly known as MRSA, is the term used to describestrains of Staphylococcus aureus (SA) bacteria, that areresistant to a number of antibiotics, including methicillin. Ingeneral, one in four people carry Staphylococcus aureus. It canbe found primarily near the nose and all over the skin’ssurface. Although Staphylococcus aureus is usually quiteharmless, once it enters the body through a cut, wound, oreven a hair follicle, it can multiply and form colonies whicheventually form an infection. In the past, many SA infectionscould be treatedwith Beta-lactam antibiotics, which includedmethicillin and penicillin. As time progressed, many Staphinfections became resistant to the Beta-lactams. This could beattributed to the fact that patients had failed to finish theirentire course of antibiotics, allowing a few bacteria to remain.The remaining bacteria would’ve only experienced a portionof the antibiotic course, and became tolerant to some of themost common antibiotics. Today, two in every one hundredpeople carry a strain of Staph bacteria that is resistant to Beta-lactams (MRSA). In Turkey, Onlen et al. found a significantbenefit from Propolis in their 2007 study, AntibacterialActivity of Propolis against MRSA and Synergism withTopical Mupirocin.

By Saamir Mirza

MRSA And Antibiotic Resistance

Conclusion

1. Dugdale III, David C., Jatin M. Vyas, and David Zieve. "MRSA - PubMedHealth."Public Medical Health. U.S. National Library of Medicine, 09 June 2011. Web. 18 Jan. 2012.

2. "Fact Sheet: The Safe Use of Antibiotics - PubMed Health."Public Medical Health. U.S. National Library of Medicine, 18 Jan. 2011. Web. 18 Jan. 2012.

3. Nordqvist, Christian. "What Is MRSA? Why Is MRSA a Concern? How Is MRSATreated?" Medical News Today: Health News. Medical News Today, 12 June 2004. Web. 17Jan. 2012. Onlen, Yusef, Nizami Duran, Esin Atik, Lutfu Savas, Enes Altug, SalvinazYakan, and Ozkan Aslantas."Antibacterial Activity of Propolis against MRSA and Synergism with Topical Mupirocin."Diss. Mustafa Kemal University Faculty of Veterinary, Hatay, Turkey, 2007.

4. Abstract. Antibacterial Activity of Propolis against MRSA and Synergism withTopical Mupirocin.Mary Ann Liebert, Inc, 11 Oct. 2007. Web. 3 Feb. 2012.

5. "WHO | Antimicrobial Resistance."WHO Fact Sheets. World Health Organization, Feb. 2011. Web. 18 Jan. 2012.

Sources

They infectedNewZealandRabbitswith strainsofMRSA,andfound that the addition of Propolis was able to reduce thebacterial cell count as well as the inflammatory responsemuchmore effectively when compared to the original medication.

Wang et al. looked past thematter of efficacy and attempted topinpoint the mechanism of how honey affects Pseudomonasaeruginosa. This could be attributed to the factthat patients had failed to finish their entire course ofantibiotics, allowing a few bacteria to remain.

The remaining bacteriawould’ve only experienced a portionofthe antibiotic course, and became tolerant to some of the mostcommon antibiotics. Today, two in every one hundred peoplecarry a strain of Staph bacteria that is resistant to Beta-lactams(MRSA).In Turkey, Onlen et al. found a significant benefitfrom Propolis in their 2007 study, Antibacterial Activity ofPropolis against MRSA and Synergism with TopicalMupirocin. They infectedNewZealandRabbitswith strains ofMRSA, and found that the addition of Propolis was able toreduce the bacterial cell count as well as the inflammatoryresponsemuchmore effectivelywhen compared to the originalmedication.Wang et al. looked past the matter of efficacy andattempted to pinpoint the mechanism of how honey affectsPseudomonas aeruginosa. Through a broth testing method,they were able to conclude two things: honey disrupts thequorum sensing (QS), and this ability has a relationship withthe sugar content of the honey.The importance of synergycomes into play when looking to the relationship betweenantimicrobials and bacteria. Each antimicrobial combats thebacteria in different ways, for example: inhibiting the quorumsensing (QS) functionof thebacteria, penetrating thewall of thebacteria, or even disrupting the energy supply for the bacteria.If just one antibiotic was being used individually, a probabilityexists such that over time, resistance will develop in thebacteria.However, if two antimicrobial agents are present, inthe case that one fails, the other agent will be able to use itsdifferent mechanism to defeat the bacteria, significantlydecreasing the probability for resistance.In this article is an account of a study done by Adeel Ahmad,a university student in Minnesota, USA, which facilitated adirect side-by-side comparison of antibiotics and naturalproducts. This was done by running culture sensitivity testsagainst a strain of MRSA (Methicillin-resistantStaphylococcus aureus) as well asMSSA (Methicillin-sensitiveStaphylococcus aureus). Each natural product was tested byitself, and in combination with the other natural products. Thecombination of propolis and garlic was thought to be the mosteffective against the Staph bacteria, for two reasons.First, theproposed activity of propolis is different than that of an

antibiotic. Antibiotics directly combat bacteria’s functions,while propolis inhibits bacterial growth by strengthening one’simmune system.The initial uses of propolis could also be datedback to the ancient Greeks and even to the ancient Egyptianeras. Similar claimshave also beenmade for garlic,whichdatesback to the ancient Egyptian era. This evidence suggests thatbacteria have yet to become tolerant to propolis and garlic.Because MRSA is resistant, the experiment had to becompleted at a Bio-Safety Level 2 lab.

Towards the end of the 1960’s, Staphylococcus aureus beganresisting the four main antibiotics that were initially made totreat them: Penicillin, Methicillin, Tetracycline, andErythromycin, leaving Vancromycine as the only effectiveantibiotic known. However in 2001, cases of VRSA(Vancromycine-Resistant Staphylococcus aureus) beganappearing in the United States, furthering the need to researchmore alternatives.The six reagents that hadbeen chosen for theproject had been confirmed to express some microbial traitsfrom either cultural significance, or parallel studies. After theculture sensitivity tests, it was clear that honey, ginger, andonion displayed no clearance zone at all. However, this doesnot allow us to conclude that these reagents aren’t effective incuring MRSA. We can only see that these reagents do notcombat the bacteria directly. On the other hand, garlic,Propolis, and olive-leaf extract proved to be effective againstboth strains of MRSA and MSSA. Different densities of thebacteria had to be tried, because the clearance zones weren’tperfectly round. Also, garlic showed a “shaded” zone, in allfour plates with a higher density of bacteria. To fix this, thedensity of the bacteriawas reduced fifty-fold, and clearer zonesthat were circular were exhibited. The new plates clearly gavethe significant data to conclude thatGarlic, Propolis and olive-leaf extract are all natural products that can be used to treatcases of both MRSA and MSSA.

Page 17

Garlic'Crushed Garlic'Extract Ginger'Extract Olive'Leaf'Extract Onion'Crushed Propolis Cefoxitin Trimetho'Sulfisoxazole VancomycinGarlic'Crushed 1.6 0 0 0 0 0.8Garlic'Extract 0 0 0 0 0 1.2Ginger'Extract 0 0 0 0 0 1Olive'Leaf'Extract 0 0 0 0 0 0.93Onion'Crushed 0 0 0 0 0 1Propolis 0.8 1.2 1 0.93 1 1.1Cefoxitin 1.14Trimetho'Sulfisoxazole 1.82Vancomycin 1.74

Practical Results

MRSA Trial 1

MSSA Trial 1

Garlic'Crushed Garlic'Extract Ginger'Extract Olive'Leaf'Extract Onion'Crushed Propolis Cefoxitin Trimetho'Sulfisoxazole VancomycinGarlic'Crushed 0 0 0 0 0 0.73Garlic'Extract 0 0 0 0 0 0.86Ginger'Extract 0 0 0 0 0 0.96Olive'Leaf'Extract 0 0 0 0 0 0.95Onion'Crushed 0 0 0 0 0 0.65Propolis 0.73 0.86 0.96 0.95 0.65 0.92Cefoxitin 2.89Trimetho'Sulfisoxazole 1Vancomycin 1.68

MRSA Trial 2

Garlic'Disc Garlic'Extract Ginger'Extract Olive'Leaf'Extract Onion'Disc Propolis Cefoxitin Trimetho'Sulfisoxazole VancomycinGarlic'Disc 0 1.43 0.75 0.91 0 1.82Garlic'Extract 1.43 0 0 0 0 1.12Ginger'Extract 0.75 0 0 0 0.68 1.1Olive'Leaf'Extract 0.91 0 0 1.86 0.74 1.08Onion'Disc 0 0 0.68 0.74 0 1.1Propolis 1.82 1.12 1.12 1.08 1.1 1.14Cefoxitin 1.13Trimetho'Sulfisoxazole 1.81Vancomycin 1.76

MSSA Trial 2

Garlic'Disc Garlic'Extract Ginger'Extract Olive'Leaf'Extract Onion'Disc Propolis Cefoxitin Trimetho'Sulfisoxazole VancomycinGarlic'Disc 2.41 2.3 0.9 0 0 1.08Garlic'Extract 2.3 0 0 0.81 0 1.02Ginger'Extract 0.9 0 0 0 0 1.07Olive'Leaf'Extract 0 0.81 0 0.72 0 0.94Onion'Disc 0 0 0 0 1.03Propolis 1.08 1.02 1.07 0.94 1.03 0.98Cefoxitin 2.91Trimetho'Sulfisoxazole 1Vancomycin 1.64

Medic&AID UK Photography

Glandular fever is a condition which effects manyyoung people, mainly caused by an Epstein-Barrinfection. Also named Infectious Mononucleosis dueto the raised count of mononuclear lymphocytes, thecondition has symptoms relating to highinflammation. Common symptoms include swollenlymphatics, including lymph nodes, extreme fatigue,raised core temperature and often headaches. Thecondition can also lead to both the enlargement of thespleen and of the liver. In addition, jaundice is seen inmore extreme cases.

The Epstein-Barr virus (human herpesvirus 4) is anextremely common virus which has found to causeglandular fever (mononucleosis) and is associatedwith the development of several varieties oflymphomas. The Epstein-Barr virus is transmitted viadroplets, often through the medium of saliva. Overninety percent of adults have a passive form of thevirus in their system, however those who have aninitial infection inadulthoodasopposed to childhood,will a fifty percent chance of suffering from thesymptoms of glandular fever. Symptoms related toglandular fever are often indirectly caused by thecondition. Symptoms are mainly due to theimmunological responses to the initial infection.Oncesomeone has contracted theEpsteinBarr virus, itswillremain in their system for life, shown by raised VCA-IgG antibodies present in the blood.

Once theEpstein-Barr virus is transmitted in to a host,it transfers across the oral epithelium and infectpresent B- Cells. A process known as proliferationthen occurs, where the B-cells rapidly multiplycausing an increase in the viral load of the Epstein-Barr virus. B-cells infected with the virus can developinto B-memory cells which act as a latent storagemedium for the virus, allowing it to remain in thebodyindefinitely. T-lymphocytes help regulate the numberof infected B cells, alongside additional assistancefrom CD8+ cytotoxic cells and natural killer cells,keeping a low but chronic count of Epstein Bar.However, in periods of immunological suppression,the viral load of the Epstein Bar virus can increasecausing bouts of glandular fever.

Being a condition associatedwith a viral infection it isextremely difficult to provide any treatment for thosewho have contracted the virus. In the majority ofcases,most patients recoverwith adequate rest and anincreased intake of fluids. Glandular fever is oftenerroneously identified as a streptococcal infectionwhich may lead to the prescription of antibiotics suchas penicillin. The use of such drugs may causedermatitis which can be mistaken as an allergicreaction.

Glandular fever can, in some cases, cause extremeswelling of the lymph-nodes leading to obstruction ofairways, which will lead to a prescription ofcorticosteroids to allow for unobstructed breathing.

Although, generally testing is not necessary it ispossible. There are two main methods for testing,which includeboth theEpsteinBarr viral antibody testand the mononucleosis spot test. The mononucleosisspot test works by identifying and determining thenumber of irregular lymphocytes present in the blood.A positive result will entail higher levels of irregularlymphocytes indicating that prevailing symptoms aremost likely mononucleosis.

In the instance where the mononucleosis spot testresults in a negative result, yet symptoms prevail, theEpstein Barr viral antibody tests will be used toidentify an infection. These more advanced series oftests allow clinicians to identify the stage of infection.Used simultaneously the VCA-IgM, VCA-IgG, EA-D, IgG, and EBNA tests determine which antibodiesare present. If a positive result occurs for both theVCA-IgM and VCA-IgG tests, then an Epstein Barrinfection is in its elementary phases. If however theVCA-IgM test shows positive and the VCA-IgG testshows negative it is likely that there has been a pastinfection. A positive result for all tests except for theVCA-IgM test indicates an activation of the latentvirus.

The Epstein-Barr virus being extremely common, isrelatively difficult to avoid. Those at greatest risk arethose who have a suppressed immune system such asHIV/AIDS patients or transplant patients and thosewho live in less developed countries. Many peoplecontract the virus from their partners, according to theNHS website most common forms of transmissionincludekissing, sharing foodordrinksandexposure tomucus and saliva.

Infectious Mononucleosis (Glandular Fever)

By David Cohen

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Euthanasia

By HassanHussain

Euthanasia is a topic that will soon be decided on. Onthe 11th of September the Assisted Dying Bill will bedebated in parliament. The process is currently illegalin the UK, in both its passive and active forms. Butgreater pressure is being put on the government forchange such as groups like Dying with Dignity.

Euthanasia is the process of ending a terminally illpatient’s life and there are two forms, active andpassive.Active euthanasia iswhenadoctorormedicalpractitioner deliberately ends a patient’s life, whilepassive is when treatment that is keeping the patientalive is stopped, allowing the patient to die. Asmentally competent patients are allowed to choosetheir treatments in theUK, passive euthanasia is legal.Other forms include voluntary, non-voluntary andinvoluntary euthanasia. Voluntary iswhen amentallycapable patient decides to end their life with the helpof another person, non-voluntary is when the patientcannot decide on their treatment due to being unableto make the decision at the current time, for exampleas a result of being in a coma. The decision is thereforeup to the patient’s next of kin based on the patient’sprevious decisions when they were mentally capable.Finally, involuntary euthanasia is when a patient iskilled against their wishes, and is considered murder.

The main argument supporting euthanasia is that apatient has the right to chooseor refuse their treatmentin theNHS (as long as they arementally capable), andwhy can this not be extended to medicines that allowmentally competent patients to end their life whichmay be full of suffering. Supporters of euthanasiaargue that legalising active euthanasia for terminallyill patients is no different from prescribing simplemedication: it relieves the patients’ symptoms. Theyargue that every person has the right to die, and factthat active euthanasia is illegal denies people theirbasic human rights.Euthanasiawouldallowpeople tochoose their fate and instead of being subjugated tointolerable pain on a daily basis, terminally ill patientswould be allowed to end their suffering earlier andsave themselves from unnecessary pain. Patients whosuffer from terminal illnesses that also lead to loss offunctions would also have access to euthanasia. Thiswould give them the ability to spare their family andfriends the emotional pain needed to care for them,and allow the patients to not feel like a burden.However, this raises worry in the following scenario.Imaginea terminally ill patient. In the timebefore theydie as a result of their condition, a treatment could bedeveloped which may have allowed them to return tofull health. If euthanasia was legal, this patient mayhave chosen it, and would not have been healed.Others argue, albeit quiet harshly, that legalisingeuthanasia will free up more hospital beds andresources for newer patients. There will not be moredeaths, as only terminally ill patients will have access

to euthanasia, but instead their periodof sufferingwillbe shorter,meaning in a givenperiodof time therewillbemore freehospital bedsallowingmorepatients tobetreated. This however leads to the worry that doctorswill be placed in positions that will cause them torecommend or even force euthanasia on their patientsin attempt to free up beds and resources.

Opponents to euthanasia argue that allowingeuthanasia raises the question of whether the lives ofterminally ill patients are worth less than that of otherpeople if they can be killed legally. Some religiouspeople oppose euthanasia on the grounds that everylife is sacred or that only God has the right to endsomeone’s life, making both suicide and murderimmoral and sinful. Some religious people argueagainst this sentiment, such as LordCarey, the formerArchbishop of Canterbury. He argues that “It is aprofoundly Christian and moral thing to devise a lawthat enables people, if they so choose, to end their liveswith dignity.” Others argue that asking doctors andother medical staff to perform the procedure ofeuthanasia goes against the role of a doctor to preservelife and heal people by asking them to do the completeopposite. This would lead to patients having less trustin their doctors if theywere toabandon their principlesof life preservation. The main worry is that legalisingactive euthanasiawould lead toacascadeofproblems.They argue that patients will feel pressurised toundergo euthanasia so they are no longer a burden tosociety or to their family and friends, leading people tomake the wrong decisions about their future. Othersfear that if euthanasia is legalised, it will be marketedand exploited by private companies for profit. Thesecompanies would not be impartial and wouldconvincepeople touse their services, leading topeoplebeing convinced to die. The argument is also madethat fewer treatments for these terminal diseases willbe researched and discovered due to there being lessdemand for them as patients suffering from them willchoose euthanasia over prolonged suffering. Thiscould hold back scientific discoveries against diseasessuch as late stage cancer. This would mean morepeople are condemned to death than treated andreturned to health. Opponents to euthanasia are alsoworried about patients being diagnosed with aterminal disease when they don’t suffer from it. Thiscould lead to them ending their life when there is noreason to, leading to unnecessary death. If euthanasiais available people fear that it will be abused by greedyrelatives to pressurise family members to end theirlives for their own personal gain.

Despite all these arguments a bill for legalisedeuthanasia is being debated on the 11th of September.It will call for the legalisation of euthanasia to be

carried out by the patient and not by the doctor. Thepatient will request the treatment and will administerit themselves, removing the need for a medicalprofessional to undertake the procedure. Thetreatment will only be available to those who aremental capable to make such a critical decision.Hundredsof terminally ill patients hangon the answerof this debate.

DiscussionThe tabled results show an encouraging extent ofdecellularisation in all three oesophageal samples(82% decellularisation average across the threeoesophagi). However, clinical standards require 90%.This is particularly important when dealing withneonates, a high risk groups. The nanodrop readingsobtained were reliable, with triplicates constantlyremaining within 1-2ng/ul of each other.PKH26 assay: The control graphs show the minimaldamage that PKH26 causes to cells. The readings inthe PE channel show a 74.55% success rate of celllabelling. Furthermore, the graphs show a high72.32% success rate of labelling with the old PKH26dye.

AlamarBlue assay: Part 1 – All graphs after 4 hoursplateau due to an excess of alamarBlue compared tocell number. This shows that the AB concentrationsare too low, even at the recommended10% tomonitorcell proliferation (and therefore tissue development)for our high cell numbers. However, a convincinglystrong positive correlation was revealed between cellnumberandABconc. for timesup to fourhoursat10%AB, suggesting a standard curve will be plausible.Anomolous results at 60000 cells suggest an incorrectmeasurement of cell suspension used for thisconcentration. Part 2 - The fluorescence readingswithscaffolds are significantly higher than those withoutscaffolds, with a range of 5000 – 25000, compared to3000 -19000. This suggests background fluorescence.Also, without scaffolds, the three graphs increase in amore coordinated way with increasing ABconcentration, suggesting that these results are morereliable.

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IntroductionIn the wake of Ciaran’s success, UCL are in theprocess of translating tracheal, oesophageal andlaryngeal tissue engineering projects into phase twotrials. Engineered oesophagi will be used in treatmentof oesophageal atresia, a congenital malformation ofthe oesophagus, which prevents normal feeding andswallowing. Autotransplantation is an excitingsolution to the problem of immunorejection and alsodecreases issues related to a lack of organ availabilityfor transplant.The engineering process:The decellularisation of a donor oesophagus providesa scaffold of extracellular proteins such a collagen.Mesoangioblasts (MABs), a type of mesenchymalstem cell (MSC) associated with muscle, are seededonto the scaffold along with fibroblasts. The scaffoldguides the proliferation and development of the cells.For phase two trials to commence the success of donordecellularisation and cell seeding must be proven toensure the clinical safety of the products.

Aims(1) Evaluate current methods of

decellularisation to ensure the numbers ofdonorHLAsonscaffoldsare reduced to therequired minimal level

(2) Develop a method of proving success of cellseeding

(3) Develop a method of quantifying cellnumbers on scaffolds in order that thedevelopment of tissue can be monitored

By Katya Marks

Tissue Engineering and Oesophageal AtresiaMaterials and methodsEvaluation of decellularisation:Threeneonatal porcineoesophagiwereobtainedandsampled. Half of the samples for each oesophagusunderwent a process of decellularisation bydetergents andDNAase.The sampleswere lysedandthe nanodropwas used tomeasure the concentrationof DNA in each sample. The difference in DNAconcentration between native and decell. scaffoldswas evaluated.Development of cell seeding proof of concept assayPKH26 dye consists of fluorescent molecules thatembed into cell membranes. Flow cytometry canthen be used to show the presence of cells. A recentassay using old PKH26 was unsuccessful. Threetubes were prepared: one containing only cells(CTV1s) and two containing cells with either old ornew PKH26. Flow cytometry was used to evaluatethe efficiency of the dye, new and old.

Development of cell quantification assay:

On entering viable cells, alamarBlue is reduced tored, fluorescent resorufin. Different concentrationsof CTV1 cells were incubated with three differentconcentrations of alamarBlue. The plates were readon the plate reader and the results used to asseswhether a standard curve can be produced offluorescence intensity against cell concentration. Asimilar experiment was then carried out with punchsamples of seeded scaffolds. For each ABconcentration, a plate was readwith andwithout thescaffold sample remaining in the well. The purposewas to identify any background fluorescence fromthe scaffold.

Left: 13#year#old Ciaran Finn#Lynch,received the first paediatric stem cellsupported trachea transplant in 2010,performed by UCL surgeons at GOSH.

Right: Illustration of oesophageal atresia

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Practical Results

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By Keshi Kiruba

Discussion Of Adult Refsum Disease Type 1: Part I

Adult RefsumType 1 is a disease linked to amutationin the PHYH gene, and causes neurological andophthalmic defects in patients due to the abnormalbuildup of phytanic acid. The gene encodes for aperoxisomal protein called phytanoyl-CoA 2-hydroxlase that is involved in the alpha-oxidation ofbranched chain fatty acids. This protein convertsphytanoyl-CoA to 2-hydroxyphytanoyl-CoA.Mutations in this gene cause the PHYH protein to beenzymatically inactive, thus resulting in a buildup ofphytanic acids and its derivatives in the plasma andtissues. The PHYH protein is normally translated inthe cytosol and uses the peroxisomal targeting signaltwo at its amino-terminus that is recognized by thePEX5-PEX7 receptor to be shuttled to theperoxisome. Recent treatments for this diseaseinvolve placing the patients on a phytanic acid-restricted diet as well as the intervention ofplasmapheresis. Meanwhile, clinical trials usingenzyme therapy to compensate for the inactivity of thePHYH gene remains strong contenders.

To begin, Adult Refsum is an autosomal recessiveneurological disease that is linked to mutations in thegene encoding for a peroxisomal protein, called thePhytanoylCoA 2>Hyroxylase Gene, or PHYH for short.The PHYH gene spans 21 kb, located on chromosome10pter>p11.2, and contains nine exons and eightintrons. (Jansen et al., 2000). As stated, the PHYH geneencodes for a peroxisomal protein; therefore it isevident that understanding the role of the peroxisomeis critical for understanding the pathology of thedisease. The peroxisome is a small; membrane>boundorganelle that contains enzymes required formetabolicpathways such as alpha>oxidation of branched chainfatty acids, synthesis of bile acids, catabolism of someamino acids and detoxification of hydrogen peroxide.The basic structure of the peroxisome is a lipid bilayermembrane enclosing the matrix with crystalloid core.Phytanic acid is a branched chain fatty acid that cannotbe metabolized by beta>oxidation due to the methylgroup at C>3. (Jansen et al., 2000). Therefore, itundergoesalpha>oxidationwithin theperoxisomeswiththe help of peroxisomal proteins such as phytanoyl>CoAhydroxlase, 2> hydroxyphytanoyl>CoA lysase, andaldehyde dehydrogenase. Now that the peroxisome isbetter understood, it is important to understand moreabout the disease, such as its symptoms. Symptoms ofAdult Refsumdisease type 1 develop progressivelywithneurologic and ophthalmic manifestations. Neurologicsymptoms include mild peripheral intermittentneuropathy, tinnitus, and anosmia. Patients will alsoexperiencesignsofprogressiveweakness, footdropand

loss of balance due to cerebellar ataxia. Ophthalmicsymptoms include failing vision, and night blindnessresulting from progressive retinitis pigmentosa.(Wierzbicki et al., 2002) It is also worth to noting thatall classic disease manifestations are rarely found in asingle affected person.As previously stated, the PHYH gene normallyencodes for the PHYH protein. This is a peroxisomalprotein involved in the initial metabolic pathway ofphytanic acid. It is found normally in the crystalloidcore of the peroxisome. Alpha-oxidation of phytanicacid in the peroxisome consists of three steps, with thefirst step being a conversion of phytanoyl-CoA to 2-hydroxyphytanoul-CoA by the PHYH protein.PHYH protein is a Fe (II) and 2-oxogluraratedependent oxygenase. It contains a double- stranded�-helix core that supports three iron-binding ligand.ThePHYH is produced initially as a protein precursorwith an N-terminal PTS2. The targeting sequence iscleaved in the peroxisome by a matrix peptide toproduce mature PHYH. Upon siredirectedmutagenesis of the PHYH gene, it is found that theP29S mutant was fully active resulting in defectivetargeting of the protein to peroxisomes. (Jansen et al.,2000) In this situation, no PHYH proteins will bepresent inside the peroxisome for the hydroxylation totake place. In another studyof three unrelatedpatientswith Refsum disease, researchers observed an 111-bpdeletion covering residues 135 to 246. (Jansen et al.,1997). This deletion resulted in PHYH lacking 37internal amino acids responsible for its enzymaticactivity. This mutant PHYH protein is unable toperform the first hydroxylation step in the breakdownof the phytanic acid, therefore potentially blocking theoxidative pathway and causing the buildup ofphytanic acid within the cell. A large amount ofphytanic acid has been found in the liver, kidney,central nervous systemandperipheral nervous systemin patients with Adult Refsum disease. Thus, most ofthe clinical symptoms of this illness could be tracedback to the toxic effect of phytanic acid.

The PHYH protein is created through translation inthe cytosol, so there is amechanism that transports theprotein into the peroxisome. This peroxisomaltransportmechanismrequires amulti-stepprocess.Asmentioned earlier, the PHYH uses the less specifictype 2 targeting signal (PTS2) to be targeted into theperoxisomal matrix. First, the PTS2-containingprotein is recognized by the cytosolic receptors PEX5and PEX7 forming a highly stable trimeric complex.

(Ma et al., 2011) The complex then interacts with thedocking/translocation machinery (DTM) at theperoxisomal membrane. This allows for the cargo-receptor complex to be inserted into the DTM viaprotein-protein interactions. PEX5 spans thetransmembrane whereas PEX7 exposes a part of itspolypeptide chain into the peroxisomal matrix. Theinsertion of the trimeric complex into the DTMinduces conformational alternations in the PEX5disrupting its interaction with the PEX7-PTS2complex. (Ma et al., 2011) This reaction triggers therelease of the PTS2 containing PHYHprotein into theperoxisomal matrix. Once inside the peroxisomalmatrix, the signal sequence is cleaved by aperoxisomal matrix peptide called TYSND1. (Ma etal., 2011)

Psychiatry is oneof twomedical specialties devoted tostudying the most complex 3lbs of organic matter inthe known universe. Officially, it is ‘the branch ofmedicine concerned with the study, prevention andtreatment of mental illnesses and emotional andbehavioural problems.’ In other words, psychiatrytreats mental disorders of all forms, which are dividedinto three broad groups: mental illness, learningdisabilities and personality disorders.

In the UK, there are a variety of subspecialties forpsychiatrists: Child and Adolescent Psychiatry,Forensic Psychiatry, General Psychiatry, LearningDisability Psychiatry, Liaison Psychiatry, Medicalpsychotherapy, Old Age Psychiatry, RehabilitationPsychiatry, and finally Substance Misuse Psychiatry.While all fall under the umbrella term of psychiatry,each has its own unique challenges. For example, anOld Age psychiatrist made find themselves dealingwith many bereavement cases, while a liaisonpsychiatrist will often be called into A&E to assess apatient who has attempted to commit suicide.

When translated from Greek, psychiatry literallymeans ‘medical treatment of the soul’. In the last 100years however, psychiatry has shifted from a ratherspiritual, social field to a more biologically,scientifically based field, thereby aligning itselfsimilarly to the majority of other medical fields. Thischange has arguably come from the great leaps inscientific knowledge in the past century. Due totechnological advances, psychiatrists can nowpinpoint exactly which part of the brain ismalfunctioning and use this to diagnose – a huge stepforwards from diagnosis merely based on a clinicaldescription of symptoms.

Psychiatry has a major recruitment problem. Thereare a myriad of reasons for this: misconceptions suchas ‘psychiatric patients don’t get better’ or ‘psychiatryisn’t a scientific field’ – psychiatric patients do getbetter, however it’s often amuch longer process that inmost other fields, and psychiatry is as scientific as thenext field. Professor Sir Simon Wessely, president ofthe RCPsych, puts this particular misconceptiondown to psychiatry having a much lesser reliance ontechnologycompared toother fields, but asmentionedbefore, this is set to change.

Other reasons for the lack of recruitment include theemphasis on early specialisation; most young doctorsbegin specialisation training after their FoundationYears, however until recently Foundation doctors didnot have the option to practice psychiatry.

Yet another reason is the extra training involved inspecialising in psychiatry. A GP is required to haveonly 3 years of specialist training; a psychiatricconsultant must spend at least 6 years training,sometimes more depending on the subspecialtychosen.

So what is the Royal College of Psychiatrists doingabout this? In 2011 the Royal College formed acommittee, aptlynamed ‘PromotingRecruitment intoPsychiatry’ (PRIP). Dr Tom Brown, AssociateRegistrar for Recruitment for the committee,developed a recruitment strategy, with the aim ofincreasing recruitment into the CT1 grade of CorePsychiatry training (the first year of specialisttraining). This strategy aims to increase applicationsto CT1 posts by 50% and to achieve a 95% fill rate inCT1 posts by the initiative’s projected end in 2016.

The strategy is split into three different sections. Thefirst section targets students still in secondaryeducation, the second targetsmedical students and thethird targets Foundation Years trainees. In order toattract students who are still in school, the RCPsychencourages the organisation of work experienceplacements so that these students canhaveexposure topsychiatry in such a way that would also be beneficialto an application tomedical school. Furthermore, theCollege has outlined how organisations should co-ordinate work experience placements in such a waythat allows the process to run smoothly, and thestudent to gain the most from the experience.

An initiativeopen toboth school andmedical studentsis the running of summer schools by medical schoolsaround the country.These generally involve amixtureof work experience placements andworkshops run bypracticing psychiatrists who aim to attract medicalstudents while informing them of the realities ofworking in psychiatry. As of 2014, there were 12summer schools running throughout the country, 9more than at the programme’s outset in 2011.

In order to gain influence within medical schools, thecollege has encouraged the founding of psychiatricsocietieswithin universities tomatch societies alreadycommonly found in universities, such as orthopaedicsocieties. To this end the college has been verysuccessful – 30 of the UK’s 33 medical schools nowhave a psychiatric society.

So that the college can attract medical students beforethey start their Foundation Years, the so-called‘PathfinderFellowships’were created.Theseareopento any medical student in their penultimate year ofstudy, and last for three years. Successful applicantsreceive aplethoraof benefits, includingbutnot limitedto: a mentor to advise and support them throughoutthe three years of the fellowship; a grant of up to £1500to help fund either an elective, a research project or anSSC in psychiatry, either in the UK or overseas; freeregistration and subsidised accommodation for theInternational Congress of the RCPsych for the threeyears the fellowship runs; and free subscriptions tojournals published by the RCPsych. In 2014 thecollege awarded 29 Pathfinder Fellowships, selectingfrom a body of 70 applicants.

The Student Associateship Scheme was in placebefore the scheme started, but was popularised in anattempt to attract psychiatrists. Aimed at medicalstudents and Foundation doctors, being a StudentAssociate of the RCPsych means potentialpsychiatrists get free newsletters from the College,discounts on RCPSych publications, and freesubscriptions to various psychiatric journals and freeadmission to events run by the college. By 2014, therewere roughly 4000 student associates, a clear increaseon the 2011 total of 2500.

Lastly,what is heldby some tobe themostworthwhileaction of the whole campaign is the introduction ofpsychiatry placements for doctors completing theirFoundation Years. This is essential as it givesFoundation doctors full clinical exposure topsychiatry, and has on thewhole been successful. Thecollege aims for 7.5% of F1 and F2 to be in psychiatryby2017,meaning that 45%ofFoundationdoctorswillexperience psychiatry during their FoundationYears.

In conclusion, itwill be hard to judge the success of thecollege’s scheme until it has run its full course. In anycase, there seems tobeclear improvementsmade,withthe number of CT1 posts filled increasing to 87% in2014 from the 2011 level of 83%. However, this is stillshort of the college’s target of 95%. Nevertheless, thescheme seems to have laid the foundations required tohelp alleviate the recruitment crisis into psychiatry.

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Tom Wilkins

An Introduction to Psychiatry and Its Recruitment Troubles

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Multiple SclerosisBy Zak Mouyer

Multiple Sclerosis is an example of an autoimmunediseasewhich affects the brain, specifically its neuronsby damaging the insulating layer known as myelinaround it. By being autoimmune, multiple sclerosis(MS) works by using the body’s immune system todirectly degrade the myelin layer. Hence it is fairlyobvious that MS presents through a variety ofsymptoms with neurological roots.

When looking for MS, there are some tell-tale signsand symptoms to lookout for. For example thepatientoften presents with impaired or weakened visionwhere distant object cannot be seen and double visionis common. And since this condition directly affectstheCNS, there isoften stuttered speechandadifficultyin breathing.Also in theperipheral extremities like thehands, there is often a lack of sensation or evenparaesthesia present. In some cases as well, there ismuscularparalysisor spasticity, and it is verycommonthat there is a lackof bladder control and in some casesit is difficult to maintain sexual arousal. Lastlyassociated with MS is cognitive dysfunction, wherethings like paying attention, the working memory ordecision making are significantly impaired.

Diagnosis:

Having the above signs and symptoms are not enoughwhen it comes to giving a full diagnosis ofMS, insteadsignificant testing is needed. The first and mostcommon test is an MRI scan. In the MRI scan, it isvery clear that MS could be present when lesions areseen in the white matter of the brain. As shown inimage above, these lesions/plaques are the whitespots where damage has occurred from the MScondition. Also the white matter shown is mainly justthe axons covered in the myelin insulator, so theselesions tell us thatMScauses damage to the axons, butspecifically to the myelin layer.

The next diagnostic test for MS is to take a LumbarPuncture (LB) which is where a sample of thecerebrospinal fluid is taken and tested by doing a gelelectrophoresis. Since the cerebrospinal fluid is stillpart of theCNS, it is still verymuchprone to the effectsof MS. And also since MS is autoimmune, the LBcontains immune system remnants like antibodieswhich can, if elevated, show the presence ofMS.Withregard to the gel electrophoresis test, it will help

separate and visualise the contents of the LB. Theresults of this, as shown in the image on the left, depicta set of lines. In the normal patient, the thin linesindicate proteins. In the MS patient, the thicker lines(oligoclonal bands) indicate a higher protein presencefrom antibodies; this hence directly points towardsMS.

The last diagnostic test, which is more confirmatorythan anything else, is a visual evoked potential test.Here the patient has some electrodes placed on hisscalp where lesions have been seen on their MRI anda lit chequered screen is placed in front of them. Thisscreen alternates the black area into white by lightingthem rapidly. This should induce a detectable amountneural activity to which can be plot on voltage-timegraph. If there was a lesion on one of the optic nervesfor example, the voltage-time graph should show adelay for the output of an electrical impulse from thedamaged neuron. And sinceMS damages themyelin,all electrical impulses from neurones that havedegradedmyelin will not be able to transmit impulsesas well as normal neurones.

Risk Factors:

When it comes to putting a cause of MS on the table,it is very difficult since there isn’t one. However thereare some very clear risk factors that put you moreprone to MS than others. MS is not a genetic diseasebut definitely has genetic components leading to itsarrival in a patient. In twin studies, where identicaltwins (sameDNA) are compared with fraternal twins(different DNA), there is a clear link to the passingdownofMS.Recent studies have shown that there arearound fifty genes related to the cause ofMS. But onethat is very prevalent in MS patients is theautoimmunity gene in chromosome 6, namely HLA-DRB1. The HLA stands for Human LeukocyteAntigen, and since this antigendetermineswhat is andwhat isn’t meant to be in the body, inMS patients theHLA-DRB1 gene is damaged.

Aside fromgenetic risk factors forMS, therehavebeenstudies to show that there are environmental factors aswell. For example formostMS cases, people who live

north of the equator are much more likely to get thisdisease.And since as you go further and further north,you are exposed to less sunlight. And sunlight on theskin is what produces vitamin D which is thought tolead to autoimmunity. There is also a correlation ingetting MS as an adult when in your childhood hadone of the following viruses: Epstein-Barr, herpes,mumps or measles. Lastly it is evident in people whohave MS and smoke, that when they quit smoking,their treatment works a lot better.

Pathophysiology:

MSat its heart is the degradation of themyelin aroundthe axon of a neuron caused by the body’s ownimmune system.But howdoes the immune systemgetto the neurons in the first place since there is a bloodbrain barrier to prevent this from happening.Normally the blood brain barrier (BBB) prevents anyviruses or immune system components from enteringthe brain since the endothelial cells are joined togethervery well at points called tight junctions. In MShowever, parts of the immune system are able to enterthe brain and slip through the BBB. Inmost cases a T-cell breaches the barrier and when it reaches neurons,it detects the protein structures coming out of themyelin and hence it releases a chemical known ascytokines. Cytokines can do a number of three things.Firstly they degrade the BBB further such that itbecomes more permeable. It also calls for otherimmune system components like macrophages or Bcells which both are able to break down the myelinfurther. And lastly the cytokines are directly toxic tothemyelin and can actively degrade it themselves. Allof this attacking and the presence of the immunesystem in the brain leads to an increased amount ofinflammation called neuro-inflammation.

The body does however have its own recovery systemwhere cells come to the damaged myelin and are ableto replenish the degraded sheath around the neuron.These cells are not neurons themselves and are knownas oligodendrocytes. And the process which allowsthem to replenish the myelin on the neurons is calledremylelination. However since immune system is sostrong, theoligodendrocytes are in a losing battle fromthe start since theamountofmyelinedegradationendsup being so great that they are incapable of healing thedamaged neurons.

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Treatment:

Unfortunately, since there is no known cause to MS,there is no single cure to it as well. However there is atreatement where the patient can take drugs known as‘disease-modifying drugs’. Themost common type ofMS, relapse-remitting MS, is the type of MS thatresponds best to treatment. And since the drug is‘disease-modifying’, it decreases the replase time andalso the remission but it greatly increases the time inwhich the next relapse begins. This is why the lifeexpectancy of a person with MS is only shortened bya few years at most.

When it comes to the drugs used there are two types.One being an immunosuppressant like corticosteroidsand the other are Beta Inerferons which suppressesinflamation. The mmunosuppressants are veryeffective as they are able to initially prevent anyT-cellsfromleaking through theBBBinto thebrain.Also theyare able to stop anyT-cells from reacting vigorously atthe presence of proteins on the myelin and hencerelease cytokines. With a reduced amount ofcytokines released, fewer macrophages and B-cellscome to further degrade the myelin. This treatmentspecifically targets theautoimmuneresponseofMSbydampening the immuneactivity in thebrain.Butwhenit comes to treating the presenting symptoms, not onlythe pathophysiological ones, a lot of therapy isneeded.Whether it bephysio for themusclenumbnessor pains or cognitive stimulaiton to maintain areasonable amount of cognitive activtity, thetreatment for these symptoms for MS is extremelysubjective to the case of each patient.

Epideomology of MS:

There are currently 2.3 million people who have MSbut it is difficult to count the exact number sinceMS isa non-reportable disease whichmeans that doctors do

not have to tell the government that their patient hasMS, unlike HIV. In the general poplulation there is a0.1% chance of havingMS butwhen it comes to beingdirectly related to a MS patient, this chance increasesto 2.5%-5%. However, even if you have an identicaltwinwithMS, chanceswhich should increase to 100%only go up to 25% which suggestS that it is not anentirely genetic disease. MS is most common incausasians around the world and there is a slighttendancy towards females than males within thetwenty to fifty year old age range.

With the increase in the morbidity rate of beingoverweight, or as some would term it, “The ObesityCrisis”, many public healthcare systems are facingan already substantial problem become a lot morelong-term with many more issues down the line.Many experiments have been conducted, what isthe most effective way to reduce weight. At thesource we find many factors. Some areuncontrollable, like genetics, many people arepredisposed to have diabetes (types 1 and 2) and itcould even be racial (Afro-Caribbean’s have higherfat retention that most other races). Some are,however, controllable, some boil down topsychology like society and its stigma towardsobesity. But oneof the largest issues that havebeenraised as a cause for this “epidemic” is the lack ofexercise. Why are people reluctant to do physicalactivity?

A correlation has been found between a person’sBMI and their activity level, which incompletelyshows a correlation in choice, themore fat a personcarries, the more sedentary their lifestyle. Anexperiment conducted at UCLA on rats with twodiets, one was a standard diet, and one with fat-richjunk food and got the rats to perform particularactivity tests. They concluded that the diet itself cancause fatigue as well as obesity, which itself alsocauses fatigue.Theconsequencesof this, includinggenes, involve effects on the endocrine andnervous system, our energy and fitness levels,which all impact willingness to be physically active.

Three mechanisms are involved in this process, ofobesity to inactivity. One mechanism involvesdopamine, a key mediator of the reinforcementphenomenon. Dopamine is a product of exerciseand eating particular kinds of food, and food beingreadily available in society means that it is moredesirable than exercise, which includes the risk ofinjury and pain. Also, studies have shown obesepeople to have a decrease in the expression of theDopamine 2Receptor i.e. a resistance to dopamineand thereforeneedagreater stimulus toachieve thesame level as pleasure than a person with normaldopamine sensitivity, which may make exercise asan unfavourable option.

The 2nd mechanism revolves around leptin, ahormone produced by fat tissues and received bythe hypothalamus. The hypothalamus maintains anegative feedback loop of this hormone bydecreasing energy expenditure and increasedappetite when leptin is low and vice versa. Aninvestigation at the University of Cambridgehowever has shown an inverse relationshipbetween plasma leptin concentration and energyexpenditure in physical activity. The theory behind

this is that the resulting hyperactivity from low leptinstimulated our hunter-gatherer ancestors to hunt forfood, rather than be left to starve and vice versa.Though, this isn’t always the case. Moreover,evidence has been shown for a reduced response toleptin when it reaches the receptors in thehypothalamus, another increased tolerance, so thebrain perceives the body as being “lighter” than itactually is.

The 3rd mechanism is chronic low-gradeinflammation. A consequence of having larger fat (oradipose) tissues results in higher inflammatorymediators in the bloodstream, as they produce themand their levels are particularly high after ameal. Thiscauses tiredness and fatigue, an overall decrease inphysical performance due to slow damage to the bodyover time.

Exercise is contraction of muscle(s). The brain sendsan electrical impulse to an effector muscle, whichtriggers the release of calcium ions, which causes themuscle to contract. The strength (or “frequency”) ofthe signal affects the power of the contraction. Themore unable a nerve is to maintain a high frequencysignal, the shorter the length of time the maximumcontraction is maintained, or the maximum possiblecontraction the nerves can effect. It reaches a pointwhere the signal declines and stops. This is nervousfatigue, but once this has been trained to contract themuscle to its physical limit, then the muscle begins toexperience Metabolic Fatigue.

This fatigue can be caused by exhaustion of substratesto metabolise to produce the energy in the musclerequired for it to contract. It can also be due to theproducts andmetabolites involved in the contractionse.g. lactic acid reducing the sensitivity of proteinsresponsible for contraction to calcium ions andpotassium build-up leads to an increase in themembrane potential, reducing the release of calciumions, decreasing the contraction.

Fatigue in the obese could be a result of nervousfatigue that hasn’t been trained enough to be reduced.But being obese affects your body’s physiology. Lackof exercisepromotesCoronaryArtery/HeartDisease,whereby further exercise cancauseangina, a relativelystrong disincentive to exercise. A common symptomof obesity is sleep apnea, where throat muscles relaxwhilst sleeping, narrowing your airway, reducingoxygenabsorption into thebloodand leading toa tiredmorning feeling.

However, the endocrine system, where the processes

for metabolism are maintained and musclecontraction is controlled, is where a major concernlies. A function of the pancreas is to produce insulin,which is responsible for the uptake of glucose bytissues. Fat in the form of adipose tissues found inmuscle and fat in liver cells secrete a protein calledpigment epithelium-derived factor, which increasesinsulin desensitivity. Another similar proteinproduced by fat tissues includes resistin. Excess fat incells itself adds stress to the endoplasmic reticulumorganelle, which signals insulin receptors to becomeunresponsive to insulin aswell. If these conditions aremaintained, cells can lose their ability to respond toglucose, which then causes them to no longer absorbglucose. Other conditions like Cushing’s disease andHyperthyroidism can also cause fatigue.

As a result, these cells rely on creatine phosphateswhich contain enough energy for about 10 seconds ofhigh level energy expenditure. Once this has beenexhausted, cells turn to glycogen, the polymerisedform of glucose. But if the cells are insulin insensitive,then they would be unable to absorb glucose andmetabolise it to produce energy.Without energy, youcan’t contract muscles and you become tired.

However, significant exercise has been shown toincrease sensitivity to insulin, it can reduce the risk ofcoronary artery disease and decrease nervous fatigueas well as release dopamine to reinforce it as a benefit.Fatigue is a mental restriction that warns of pain, andsure, acute pain signals muscle damage and tearing.This should beunderstoodas a largedisincentive fromexercise in order to help the large demographic ofpeople who are overweight/obese to attain a betterstate of physical health, starting with their state ofmind.And a 4-word slogan popularising a feeling thatothers experience more than us isn’t going to help.

By ZakariaAchercouk

Obesity and Fatigue

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Robotics In MedicineBy Leonardo Herrero

The role robots will play in the modern medical field,is perhaps themost critical factor of future healthcare.Robots will be present in nearly all sectors of publichealth. In the surgical field, robots will allow high-precision surgical operations to be carried out as wellas remote surgery to be performed if a human surgeonmight not be physically present. Rehabilitation robotscan aid lives of the elderly, people with dis-functionalbody parts that affect movement or ease childrenduring hospital stays. Procedures related to therapycan be performed by robots to speed up recoveryefficiency and speed. The automation of thepharmaceutical distribution of drugs, measurementand mixing of compounds along with trackingcustomer information and inventorymanagement areareas where robots have proven to be competent.Robots have the capability to automate disinfection,using ultraviolet light, leaving an entire room sterilewithinminutes.Robots that simulate patients areusedto teach the next generation of doctors, dentists andnurses.An example of robotically assisted surgery is the daVinci Surgical System. Since the year 2000more thantwo million operations worldwide have been carriedout. It is able to perform minimally invasive surgerythrough its: “superior visualization, enhanceddexterity, greater precision, and ergonomiccomfort” [1]. Complex procedures such as open-heartsurgery may be executed through incisions of only 1centimetre. This system reduces hospital stay by half,reduces cost by a third by causing less pain and theneed for painkillers post-operation, and therefore amore rapid recovery time. Its precision isdemonstrated by the ability to perfectly peel a grape aswell as stitching it back together. It can also fold swanorigami down to the size of a penny.

Themost prominent goal of robotic rehabilitation is todevelop applicable technology that can easily beemployed by patients, therapists enhancing theefficacy of clinical therapy in addition to increasingthe ease of activities in the daily lives of patients.Robotic rehabilitation can take many forms, fromrobotic limbsaidingamputees, toexoskeletons to trainand exercise those suffering from paralysis. One suchexample is the ReWalkTM Personal 6.0 [2]exoskeleton demonstrated by a paraplegic manstrolling effortlessly through New York. This is thefirst instance of robotic exoskeleton to be cleared forclinical and personal use.

With the aging population, an increasing amount ofstress has been put on care for the elderly. Yet robotslike ‘Robear’[3]will lead themarch in aiding of care forthe elderly. This robot has intelligent vision, flexiblemovementandgiant arms,whichare strongenough tolift a human right off the ground.Robear is designed toperform tasks such as helping elderly patients standupor lifting them froma bed into awheelchair. The lattertask canbe severely strenuous for careworkerswhodoit an “average of 40 times a day”. Its friendly designmakes for a relation between patients and the robot.While it is still not commercially viable, as prices andaccessibility go down it will not take long before suchrobots become the norm in elder care.

With the automation of pharmacy there will comeseveral advantages, such as reducedmedication errorsthanks to bar code scanning, vision systems andweight confirmation help identify final products.Through these digital charting mechanisms, it ispossible to sort out medication for each patientwithout any mistakes, which in turn enablesphysicians to spend time communicating withpatients and explaining medications, rather thanperforming routine tasks. These robot-based systemsprepare intravenous products in syringesconsequently encouraging long-term hospital costsavings.

The use of robots is not uncommon to teach doctors,nurses and dentists. Robots can “feel” pain and reactif improperly handled, which is especially important

when medical students learn how to perform routineprocedures on patients.

Any medical robot is only as good as it is safe.Naturally there are some safety concerns, as robotsused in the medical field behave much morecomplicated and differently than their industrialcounterparts. As medical robots will always be inhumanpresence, theyneed to performwell in chaotic,time-varying environments. Theunpredictable natureof accidents and complications may not bode well ifthe medical robot does not have rich sensory andreasoning capabilities. While robots will not fullyreplace human doctors for a long time, they may verywell be of utmost importance for the future ofmedicine.

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Coeliac disease is an autoimmune disorder where thelining of the small intestine is damaged due to ahypersensitivity to gluten.

Gluten in found in grains of the tribe Triticeae, theprincipal grains eaten by humans in this family beingwheat, barley, and rye. It is the body’s reaction withthe protein gliadin, found in gluten that damages theintestinal wall and the bowel of a coeliac-affectedindividual.

Coeliac disease occurs in genetically predisposedindividuals (roughly 1% of the western population)and varies in severity. As such, it tends to run infamilies. Indeed, having a primary family member(parent, child or sibling) with the disease leaves andindividual with a 10% chance of developing itthemselves at some stage. It canpresent in both infantsand adults and symptoms vary accordingly. Anothermajor risk factor for coeliac disease is the presence ofthe protein HLA-DQ2. Commonly found inpopulations inWestern Europe, Northern Africa andEastern Africa, 95% of coeliacs have the HLA-DQ2protein, 30%ofwhomhave twocopies of the gene thatcodes for it. For homozygotes carrying theHLA-DQ2gene there is a 20-40% chance of developing coeliacdisease.

In children, coeliac symptoms include listlessness andirritability, vomiting, acute diarrhoea, anddehydration, and usually presentwithin sixmonths ofthe introduction of gluten to the diet. In adults,symptoms generally include tiredness, breathlessness,abdominal pain, diarrhoea, vomiting, and swelling ofthe legs. Sufferers may also develop Dermatitisherpetiformis, a chronic rash consisting of tiny, red,

itchy blisters commonly found on the back, elbows,knees, buttocks and scalp. Often coeliac disease canlead to steatorrhea, or a presence of excess fat in thefaeces. This leads to faecal matter being grey, greasyand foul smelling.

The malabsorption caused by damage to the villifrequently leads to complications. These include, butaren’t limited to, iron and folate anaemia, stuntedgrowth, reduced fertility in both sexes and increasedrisk of developing osteoporosis, type 1 diabetes,Sjörgen’s syndrome (a condition where the nasalcavityandeyesare excessivelydry),Addison’sdisease(a chronic condition in which there is a deficiency inthe corticosteroid hormones hydrocortisone andaldosterone, which can lead to tiredness, weaknessand abdominal pain), multiple sclerosis and manyforms of gastrointestinal cancer. The chance ofdeveloping complications depends on the age ofdiagnosis of coeliac disease. For those diagnosedbetween the ages of 2-4, there is a 10.5% chance ofdeveloping a further condition. For 4-12 year olds, thechance is 16.7%, for 12-20 year olds the chance is 27%and for those older than 20, there is a 34% chance ofdeveloping further complications.

Diagnosis is performedby blood tests and involves thedetection of antibodies known as ‘anti-endomysialantibodies’, which bind to proteins found in the

endomysium (connective tissue that surroundsindividual muscle fibres). This test has a 98% successrate and positive tests, which require 5-7 days, arenormally followed up by a jejunal or duodenalendoscopy to confirm. Endoscopy involves aphysician taking samples from roughly 8 separatelocations in the bowel. The physician performing theendoscopy looks for signs including scalloping of thesmall bowel folds, a scarcity of the folds themselves, a‘cracked-mud’ pattern in the mucus membrane and aprominence of sub-mucosa blood vessels. In the pastjejunal biopsy was performed, and when viewedunder a microscope blunted villi were indicative ofcoeliac disease. This practice was discontinued infavour of endoscopy due to its greater sensitivity andlower error rate.

At present, the only known treatment for coeliacdisease is a gluten free diet. No drugs exist to protectthe patient if gluten is found in the diet, meaningchecking the ingredients of food is essential if one is toavoid relapse. A gluten free diet generally relievessymptoms within weeks of introduction, and iseffective in 95% of patients. The remaining 5%experience what is known as ‘refractory disease’,whereby they do not improve upon introduction of agluten free diet. This ismainly because the disease hasbeen present for so long that the small intestine ispermanentlydamagedandsocannot recover.Patientswith this conditions are treated with steroids andimmunosuppressants, assuming othergastrointestinal disorders, such as Crohn’s disease,microscopic colitis, andulcerative colitis have alreadybeen discounted.

Coleiac Disease

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Tom Wilkins

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XenotransplantationBy Huw Child

Xenotransplantation, the process of transplantingcells, tissuesororgansbetweendifferent species, is oneof the fastest growing areas of medical research andhas significant potential in solving many of thecomplex issues that arise when performing andpreparing transplants. However, this topic of medicalresearch is considered to be very controversial andraises many issues such as whether or not it is ethical.

There are several advantages to xenotransplantationwhen compared to allotransplantation. All animalorgans will be optimal for transplantation, unlikecurrently when it has become normal to accept non-optimal human organs for transplant. This is due tothere being a shortage of available human organs.Furthermore, patients would not have to wait verylong to receive their organs and they would beavailable on demand. In addition, since the time oftransplantation would be able to be prescheduled, thepatient would be able to undergo pre-treatment withimmunosuppressive agents. This greatly reduces thechance of organ rejection.

The first ever xenotransplantation performed on ahumanwas in1982,whereababygirlwithhypoplasticleft heart syndrome (a rare condition where the leftventricle is severely underdeveloped), was therecipient of a baboon heart. This procedure was onlymeant to be a temporary solution to the issue, while areplacement human heart was being found.Unfortunately, no heart could be found and she died21 days later due to graft rejection (mainly due toamismatch of blood types).

All types of transplantation, especiallyxenotransplantation, carry a risk of transferring

pathogens from the donor to the patient. Whilst thisissue can be solved with pathogens by using animalsthat have been kept in sterile environments, it will notwork with porcine endogenous retroviruses (PERV).All mammalian species carry these viruses as part oftheir genome. This means that PERV could betransmitted by transplantation. Under normalconditions thesevirusesdonot causedisease,howeverit is believed that they could become pathogenicwhentransferred into another species due to the change inenvironment. An example of this was in 1990 whenPERV was seen to be transmitted from pig cells intohuman cells while the cell were being kept in tissueculture. While PERV transmission has never beenobserved in 160 examples of pig to humanxenotransplantation, patients still need to be heavilymonitored for the viruses.

So far, no trials of xenotransplantation have beencompletely successful mainly due to the immuneresponse that xenotransplantation provokes in thereceiving organism. Xenotransplantation normallycauses a more severe response than the responsecaused by allotransplantations (inter-speciestransplantation) due to the significant differencesbetween the tissues. These rejections canoccur almostinstantly and can cause death in the receivingorganism within a few hours. One of the main causesof rejection is due to XNAs (xenoreactive naturalantibodies). These antibodies begin to circulate in theblood and activate the complement system (part of theimmune system that aids antibodies in clearingpathogens from the body). This can lead to celldamage,haemorrhaginganddeath in the transplantedorgan. Whilst this severe response can be overcomeusing a variety of drugs and treatment, there are othermore complex forms of rejection that are not fullyunderstood such as acute vascular rejection. Thebody’s natural response means that whole organxenotransplantations are not currently safe or viableoptions and are mostly not used. Instead,xenotransplantations are currently used for muchsmaller procedures such as replacing valveswithin theheart using valves taken from pigs.

Whilst direct whole organ xenotransplantations are

not possible, research has begun on applyingdecellularisation to make pig hearts suitable fortransplantation in humans. Decellularisation is theprocess of taking an organ and stripping it of all itscells, leavingonly theextracellularmatrix.Thiswouldbe particularly useful for xenotransplantation since itwould allow you to take the basic structure of a pig’sheart (orotherorgan/bloodvessel),which is veryeasyto obtain and structured very similarly to a humanheart, and rebuild the heart tissues using cells takenfrom the patient. This would mean that the issues ofrejection would be almost completely negated sinceyou are transplanting the patient’s own tissues.However, due to the complexityofhumanorgans, thisprocess is only currently available for some donortissues such as veins. This means that it will bepotentially several decades before this procedure isavailable for complex transplantations such as theheart.

There are several moral and religious issuessurrounding the topic of xenotransplantation. One ofthese is the way that animals would be treated beforetransplantation; they would have to be kept in acontrolled and sterile environment before organdonation. Many people consider this a cruel andunfair act, especially since animals lack the ability togive permission. Another cause for discussion arepeople’s religious views. Many religions consider theconsumption of certain animals, such as pigs or cows,to go against their religious teachings. Thismeans thatxenotransplantation would not be appropriate inseveral countries and cultures.

To conclude, I believe that xenotransplantation is aparticularly interesting area of medical research anddevelopment, which has been proven to work onseveral occasions. However, as an area of medicine itis still in its infancyandhas several problems includingrejection, ethics and the transfer of pathogens. Due tothese issues, even at the current rate of development,it could be decades before we see xenotransplantationbeing used more widely.

Antibiotics: the medicine that signalled the end of theera of folk law treatments and hailed the beginning ofeffective care for the ill. They were first discovered bythe scientist Alexander Fleming in 1928, when heobserved themould Penicillium that had been left in aPetri dish full of bacteria produced a bacteria free haloaround itself. Since then, antibiotics haverevolutionisedhealthcarearound theworld.Howeverour obsessive and careless use has led to the worstscenario feared by doctors and scientists: bacteria arebecoming resistant.

An antibiotic can work in many different ways,depending on its classification. The two mainclassifications of antibiotics are those that arebactericidal; they kill bacteria, and those that arebacteriostatic; they stop bacteria from multiplyinguncontrollably. Bactericidal antibiotics mainly workby inhibiting the biochemical pathway inside thebacterium cell that makes or attaches to one of themain parts of the cell wall. This then makes the cellwall of the bacterium weaker, so after many celldivisions, the cell wall of the daughter cells are veryweak. They cannot strengthen their cell wall as themolecules required are being inhibited. The cell wallcollapses, the cell undergoes lysis and the bacteriadies.

Some bactericidal antibiotics attack the cellmembrane instead of the cell wall, which then allowsthe content of the cells to leakout, suchasmineral ionsand other molecules the bacterium would use forgrowth, repair and general function. Molecules thatareessential for thebacteriumtosurvive, suchasDNAandRNAare also lost, contributing to the bacterium’sdeath. Other types of bactericidal bacteria work byaffecting the important internal processes of the cell.For example somebind to the bacteria’s ribosomes, sothe bacteria are unable to produce vital proteins, andtherefore die.

Bacteriostatic antibiotics work by stopping thebacteria from dividing uncontrollably, allowing thebody’s immune system to fight them off easier. Forexample, by binding to ribosomes, but in this case lessimportant ones, means that the bacteria affected willstill be able to survive, butwill not be able to reproduceand create daughter cell to overwhelm the patient’simmune system.

One of the main worries of medicine currently is theresistance of dangerous bacteria to antibiotics, ourmain method of treatment. Antibiotic resistance inbacteria is simply due to natural selection. If onebacterium mutates, and then becomes resistant to acertain antibiotic, when that antibiotic is used to treatthat bacterium, the bacteria without the mutations

will die, but the mutated bacterium will survive, andthen replicate to produce many other resistantbacteria, that cannot be treatedwith that antibiotic.Tomake matters worse, bacteria can transfer the gene orgenes that makes them resistant to antibiotics to otherbacteria by horizontal gene transfer,which can lead tothe spread of resistance even faster.

The creation of resistant bacteria can be caused bothby too long or too short courses of antibiotics. Tooshort courses can mean the bacteria are in anenvironment of low antibiotic concentration. Notenough to kill them, but enough for them to develop aresistance to the antibiotic, rendering it useless. Toolong a course has also been shown to increase the riskof antibiotic resistance. To make matters worse,bacteria have been becoming immune to antibioticsdue to doctors over-prescribing antibiotics to peoplewho are demanding them to help fight viruses, such asthe common cold, even though antibiotics don’t affectviruses, so the antibiotics have no affect apart fromcausing resistance in the small levels of bacteria thatmay be in the patients body at the time.

Evenour food is contaminatedwith resistant bacteria.Farmers add antibiotics to the food they feed theirlivestock, regardless of the condition of theirlivestock’s health, to prevent an outbreak before itbecomes toomuchof a threat and therefore increasingtheir profit. The farmers therefore unwittingly createmore antibiotic resistant bacteria that will be carriedon by their livestock, and if the meat from theirlivestock is not cooked properly, it could causesickness in humans.

So what do we do now? How can we curb the rate ofresistance? What are our alternatives? The rate ofbacteria resistance can be lowered significantly ifdoctors stop prescribing antibiotics to patientsunnecessarily, and if patients stop taking antibioticswhen they aren’t required. Patients completing theircourse of antibiotics fully even if they feel fine willhelp, as there may be some bacteria still left in theirsystem.

Phage therapy could be a reliable treatment for thosesuffering from bacterial infections. Phage therapyworksby selectingabacteriophage, a virus that attacksbacteria, and administering it to the patient. The viruswill not cause harm to the patient, but will attack thebacteria and use them as hosts to multiply, therebydestroying the bacterial infection. As the viruses onlyaffect bacteria, there are little to no side effects for thepatient, and the virus can be taken orally or applied

straight onto wounds.

New treatments for dangerous bacteria are beingdeveloped all the time. Scientists from the GenevabasedcompanyLasccohavedevelopedsmall particlesthat are made of lipids that are similar to thephospholipids in the cell membranes of the patient’scells. The bacteria’s toxins therefore become attachedto the lipid particles instead of the membranes of theimmunecells; the immunecells canattackanddestroythe bacteria cell with little to no repulsion from thebacterial toxins. This allows the body’s immunesystem to fight off the attack without any extra help.This treatment doesn’t attack the bacteria in the gutflora, which is affected by antibiotics.

TheDutch biotech companyMicreos has developed anew drug that contains enzymes produced bybacteriophages that are used to cut through the cellwall of the bacteria. In this drug the enzymes tear apartthe cell wall of the bacteria, causing it to die. Theseenzymes are specific to different parts of the cell wall,so in order for the bacteria to become resistant, itwould require manymutations combined for the newdrug to become ineffective.

So although bacteria becoming resistant to antibioticsmay be a terrifying prospect, new and even saferalternatives are coming around the corner to curemore illnesses and save more lives.

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Antibiotics and New AlternativesBy HussanHussain

Mycoplasma Pneumonia, also known as ‘WalkingPneumonia’, is, like all forms of pneumonia an upperrespiratory infection. It is the smallest known freeliving bacteria, and is very dependent on its hostorganism for ‘life support’ .The mycoplasmapneumoniamicrobe is an atypical bacterium, aswhenit was first discovered it was thought to be a viruspathogen, due to its apathetic response to �-lactamantibiotic treatment. However, with the developmentof modern antibiotics, it has recently been found thatsome antibiotics can treat Mycoplasma pneumoniabased infections. This caused a change inclassification since a virus could not viably be treatedby antibiotics. Understanding the function of BetaLactam antibiotics is key when trying to understandthe structure of mycoplasma pneumonia. BetaLactam antibiotics act as enzyme inhibitors for cellwall synthesis. They have many early variantsincluding Penicillin. Beta Lactam antibiotics at thetimewere revolutionary since they allowed doctors toprescribe adrugwhichwouldnot attack the cells of theperson who was being treated. The antibiotic wouldnot destroy animal cells, since they are notencapsulated by a cell wall. This idea, thatmycoplasma was unresponsive to Beta-lactamantibiotics but was susceptible to alternativeantibiotics, suggested a fundamental deviation fromtypical cell structure. Clearly, mycoplasmapneumonia does not have a cell wall.

The lack of a cell wall means that the state ofmycoplasma pneumonia’s surrounding environmentis imperative, mycoplasma is by no means andextremophile. This limits the bacterium to warm,moist environmentswithminimal changes in osmoticconditions and is only really transmitted through thedroplet medium. To add to that, the fact thatMycoplasma pneumonia is so imperceptible meansthat it can surpass regular immune defences. Thisallows the bacterium to evade the body’s naturaldefences, allowing it to thrive off the conditions. Itssize also contributes to its elevated difficulty ofdetection, as it cannot be seen by standard resolutionlight microscopes.

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Mycoplasma Pneumonia

By David Cohen Two methods of detecting mycoplasma pneumoniaare used today, DNA staining and Lab culture tests.DNA staining is a faster and more common processwhen it comes to narrowing down the possibility of amycoplasma infection. Staining will take up to twodays whereas a lab culture test will take up to 30 days.This is due to the fact that in the space of time thatmycoplasma is in the culture medium, there is apossibility it could remain dormant. This in turnmeans that 3 – 4 weeks are needed to rule out thepossibility that there could be a development of thebacterium.

Symptoms of the infection are not localised to thepulmonary system, however the majority of patientsdiagnosed with mycoplasma tend to have a mild,developing cough or wheeze. To add to that manypatients will feel lethargic, with a headache and fever.According to the Centres for Disease Control andPrevention, “a third of all mycoplasma cases willdevelop into pneumonia”.Mycoplasmapneumonia’srelatively difficult detection, difficulty to treat withconventional antibiotics and seemingly commonmedium of transmission means that it is problematicto contain and avert. Its tendency to stay dormant inmany patients, will lead to chronic outbreaks. Themajority of cases are usually found in the tropics, dueto the suitable conditions.

Mentioned earlier, conventional antibiotics such asBeta-Lactams are unreactive with mycoplasmapneumonia, which means that alternatives have to beused. These alternatives include the sub group ofantibiotics are calledmacrolides and includeKlaricid,better known as Clarithromycin or Erythromycins.

These specific groups of antibioticswork by hinderingthe replication of the mycoplasma’s D.N.A, meaningthat protein synthesis cannot occur. The macrolidesare not bactericidal, rather they are part of thebacteriostatic groups. A common issue withprescription of antibiotics is that bacteria will developa resistance to them, through genetic mutations.Therefore, it is vital that prescribers take into accountboth the event of overmedication andundermedication of patients, especially in this casewith the macrolides group. According to Medscape,“Since 2000, macrolide-resistant M pneumoniacaused by point mutations in domain V of 23Sribosomal RNA has emerged in Asia and has nowbeen reported in Europe and North America. Recentsurveillance conducted primarily in paediatricpopulations has documented resistance rates of46%-93% in Japan, 69%-97% inChina, 12.3%-23% inTaiwan, 61.3% in SouthKorea, 30% in Israel, 9.8% inFrance, and 8.2% in the United States.” These

statistics show that amongst the observed nations, theEast Asian states had the largest proportion of caseswhere Mycoplasma was unresponsive to macrolidetreatment due to adeveloped resistance. Mycoplasmapneumonia’s increasing antibiotic resistance isleading to an increased rate of chronic reinfection, andthere is no evidence to show that an infection ofmycoplasma will lead to any form of immunity.

To conclude, a mycoplasma pneumonia infectiondoes not share the same fatality rate as other relevanttropical diseases however, it can act as a ‘gateway’ tofar more serious conditions such as pneumonia.Although it is important to notwithholdmedications,it is important to be ethical when coming toprescribing antibiotics, as the under and overmedication can lead to serious consequences for boththe patient and society.

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