The Tiffinian Journal of General Medicine - Autumn/Winter 2017

The Tiffinian Journal of General Medicine Issue 4—Autumn/Winter 2017 Created by Zak Mouyer

Made in association with www.tbsmb.co.uk/

A Message from the Editor-in-Chief The Tiffinian Journal of General Medicine is a termly medical publication directed at, but not limited to, aspiring medical students and human biologists. The aim is to provide informative and thoroughly researched articles on a variety of clinical and biological cases. Since the magazine was first published, the publishing team have focused on conveying undergraduate knowledge to A– Level students in wellwritten, coherent articles. Every term we receive thirty-five articles, however only the most intriguing are selected for the final edition.

To maintain the high quality of our published material, our journalists are advised to utilise and quote data from reliable sources such as research papers and other renowned medical journals.

I hope that you enjoy reading through our articles and other material. The Publishing Team and I are extremely grateful for your support by reading our journal and I hope you are eager for the upcoming issues. This journal was made in association with the The British Students’ Medical Blog (www.tbsmb.co.uk), an online medical blog which highlights current advances and hot topics in the medical field.

Thank you, Zak Mouyer Editor-in-Chief and Head of the Tiffin Anatomical Society

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Contents: The Publishing Team.................................................4 Tiffin Anatomical Society...........................................6 Mr James Laban........................................................7 Neuroglia and Gliomas…………………………..........8 Crunchy Toast………...............................................10 Aortic Stenosis and Valve Replacement.....................12 Oesophageal Achlasia...............................................13 Hashimoto’s Thyroiditis...........................................14 Ataxia-Telangiectasia ..............................................15 Thalassemia.............................................................16 Abdominal Aortic Aneurysm....................................17 Duchenne Muscular Dystrophy…………..................18 Sickle Cell Anaemia……….......................................19 Human Blood Types..................................................20 Plasma Cell Dysrasias...............................................21 Kaposi-Sarcoma…....................................................22 Spinal Muscular Atrophy...........................................23 Cardiac Septal Defects...............................................24 COPD………............................................................25 Pneumonia………....................................................26 Hydrocephalus..........................................................27 Transverse Myelitis....................................................28 Mucocutaneous Lymph Node Syndrome.....................29 Anaesthesia………...................................................30 Insomnia……….......................................................31 Gout………..............................................................32 Asystolic Cardiac Arrests and CPR……….................33 Acute Myeloid Leukaemia.........................................34 Epilepsy……….........................................................35

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The Publishing Team

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Zak Mouyer Editor-in-Chief and Journal Designer

Malachi Saccomani

Vith Ketheeswaranathan

James Hong

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Neil Narayan

Yunis Fazaldin

Abhijeet Neeti

Akila Wickramathilaka

Denis Efovi

Rohan Vijjhalwar

Rohit Vijjhalwar

Rajan Patel

Narmathan Rajeswaran

Maciek Lamejko

Ajay Krishna

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The Tiffin Anatomical Society

By Zak Mouyer The Anatomy Society has seen a lot of change this past term. Be it the hand-over of leadership from outgoing Head Senthooran to myself or the new influx of members from Year 12. Among other things, we have seen a change in the syllabus , where each term focuses on the anatomy and pathology of only two bodily systems; this allows for greater detail and more content to be covered over the year. Also the teaching style has evolved, very much emulating the Oxbridge tutorial system. Perhaps our greatest triumph (pictured above) was the ox heart dissection, which attracted great attention across this year’s cohort of biology students. Hopefully many more dissections are to come!

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Mr James Laban, Consultant Neurosurgeon

By Zak Mouyer

What responsibilities as a neurosurgeon do you have?

The below is the transcript of an interview we gave to Mr Laban:

There are three aspects to this: the clinical one, the academic one and the managerial one. He says that he spends half his time in consultation with patients explaining management pathways and diagnoses. And the other half is the surgical aspect where he would be in theatre or in ward carrying out the clinical aspect. With regard to academia, there is large amount of research and teaching involved.

And lastly the managerial aspect involves the patient being able to flow through the hospital smoothly and legally.

Why did you choose to study medicine?

Mr. Laban was always interested in how the body works and as a little child, he remembers flicking through various different anatomical children’s pop-up books. But most clearly remembers looking at the abdominal organs and questioning himself “well, what’s in between the organs, is it just air?” Hence the main reason for going into medicine was that he was quite innocently curious to know how the body functioned.

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

After his youthful fascination within the body, he became especially intrigued by how the mind worked in particular. So came the decision for him to pick neurology, neurophysiology or neurosurgery. But Mr. Laban claims to be a ‘doer’ and he likes to get answers, he also loves theatre, so this passion lead him into neurosurgery.

What part of surgery, if there is one, takes the greatest toll on you?

Of course, surgery requires hours of arduous and intense concentration but this isn’t the hardest part. He believes that, from his experience in theatre, the hardest part of the surgical process is the decision-making. He claims this since, whilst under immense pressure, you need to accumulate all of your knowledge about the situation and make a decision which will bring out the greatest good for the patient.

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

An example of this in effect is clear post-surgery of a very simple procedure such as freeing a trapped vein or fixing a slipped spinal disc. Post-surgery, a pain management team is needed and so is a physiotherapist. In some cases an occupational therapist is needed which tries to optimise and make as painless as possible the home living experience. There is also a very clear link between his department and the oncology department, where post-op of cranial tumour removal, an oncologist is needed to look after and make sure the patient shows no other worrying signs.

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

Most importantly enthusiasm and of course intelligence are key in a medical student. But determination and being self-critical are vital in the role of doctor, hence he expects to see this. Also being personable is essential since it is a doctor’s role to be able to convey messages to other people in a friendly and likeable manner.

Neurglia and Gliomas tude of adhesion molecules which help preserve connections between nerve cells.

Another astrocyte function is CNS Homeostasis1.

Between each astrocyte are small gap junctions which form a syncytium which allows ions and small molecules to diffuse across the brain parenchyma. These processes around the nervous synapses contain transport proteins specific to neurotransmitters such as glutamate and allow the reabsorption of such molecules after an electrochemical synapse. The astrocytes then metabolise glutamate into glutamine, which is then released into the extracellular fluid and absorbed back by neurones. It is used as a precursor molecule for both glutamate and GABA.

By Zak Mouyer Neuroglia: Glial cells are often unheard of despite having a vital function within the CNS and outnumbering neurones ten to one. The word ‘glia’ originates from Ancient Greek and means ‘glue’. Initially their purpose was thought to merely keep the brain together, it is now known that their function is much more intricate and a lot more delicate. Generally speaking, ‘glia’ is the universal term given to the non-neuronal microbiology of the CNS. There are several types of glial cells, with drastically differing functions and morphology, but they can be divided into two major groups: macroglia and microglia of which each can be further subdivided.

Macroglia comprises of astrocytes, oligodendrocytes and ependymal cells (whose function serves no known physiological role1). Astrocytes have a distinct, irregular star shape with long processes; they also make up between 20% and 50% of the CNS by volume. Astrocytes can be further divided into fibrous astrocytes which are located among myelinated fibres of the white matter and protoplasmic astrocytes which are found around cell bodies, dendrites and synapses in the grey matter. As for their functions, there are many.

Their most notable function is ‘isolation of the brain parenchyma’1. The glia limitans is formed by long processes going into the pia mater (the deepest layer of the meninges) and astrocyte processes ensheathing capillaries and the Nodes of Ranvier. Though astrocytes do not individually

Figure 1: Glial Cells

form the blood-brain barrier, they do however induce and maintain tight junctions between the endothelial cells. They also to produce a multi-

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Astrocyte processes come into close proximity to the axonal membrane at the Nodes of Ranvier and coincidentally astrocytes appear to have excellent K+ permeability. Simply put, astrocytes are able to buffer K+ and after high neuronal activity; they can balance the K+ concentration by extruding it out of their end-feet. They can distribute K+ all along their bodies, and hence similarly distribute K+ along the axons and neighbouring capillaries. Having a raised K+ concentration near blood vessels stimulates vasodilation, therefore the absorption of ions by astrocyte end -feet provides an autoregulation mechanism for optimum blood flow to maintain nutrient delivery to neurones.

The final two functions of astrocytes include ‘responses to infection and injury’1 and ‘production of growth factors’1. Astrocytes react with T lymphocytes, which they are able to stimulate or suppress and hence they graduate with inducible, facultative and antigen-presenting qualities. In addition they help microglia remove neuronal debris and on case of physical injury, they can seal off damaged brain tissue. Their function of producing growth factors is another part of microbiology which is poorly understood.

Astrocytes debunk the common misnomer of the CNS being irreparable, when in fact, the astrocytes play a vital role in the regenerative capacity of the CNS (in areas like angiogenesis and cellular proliferation) along with oligodendrocytes.

Oligodendrocytes are the second type of macroglia which serve similar functions to the Schwann cells of the PNS. They form lipoprotein, myelin sheaths around nerve axons, but unlike Schwann cells and due to the pressure for space in the CNS, a single oligodendrocyte can sheathe many axons. Around larger diameter axons, the axon is sheathed at one millimetre intervals to increase the speed of neuronal transmission via salutatory conduction.

Microglia develop from bone-marrow monocytes that enter the brain parenchyma at early stages of CNS development. Their structure involves numerous processes extending symmetrically from a small rod-shaped body with an elongated nucleus. Their primary function is to act as immune-response coordinators of the CNS. They retain the monocyte and macrophage functions

they acquire in early CNS development and hence are involved in immune responses and collecting debris from damaged cells. They are also thought to secrete cytokines and growth factors which are needed for fibre-tract development, gliogenesis and angiogenesis.

Gliomas: A glioma is a brain tumour which broadly covers the cancerous growth of neuroglial cells. The most common and most aggressive primary brain tumour*in adults are Grade IV astrocytomas or more commonly called glioblastoma multiforme; it is this type of astrocytoma that will be the main concern of this study.

The less malignant types of astrocytoma vary from Grades I to III, where Grade IV is most malignant. Grade I astrocytomas are known as pilocytic and are benign as they grow slowly. Grade II astrocytomas are called diffuse as they begin to infiltrate neighbouring tissue with some force, again these are slow growing and are relatively easy to excise. Grade III astrocytomas show some malignancy and present with seizure and neurological deficits, this is why they are referred to as being anaplastic since the astrocytes lose some of their morphological function. Finally Grade IV astrocytomas show very fast growth and are the most invasive. Secondary glioblastomas are very rare since the astrocytoma is often caught in its early stages as Grade II or III; the majority (90%) of Grade IV glioblastomas are detected as primary glioblastomas.

Analysing the aetiology of glioblastomas exposes a weak understanding where the causes are somewhat idiopathic and genetic. Generally it can be detected that certain cellular inhibitors are inactivated whilst some growth signals are overstimulated. In the cases of glioblastomas, 70-80% of patients acquire monosomy of chromosome 10 and trisomy of chromosome 7. Due to increased methylation on template strands of DNA, transcription factors do not bind. This in turn causes inhibition of vital cellular checkpoint inhibitors such as: TP53, PTEN, NF1 and p16-INK4A3. More commonly associated with the monosomy and trisomy, is increased acetylation of growth stimulating genes like EGFR (epidermal growth factor receptor). This leads to over-stimulation of this gene and hence causes excess astrocyte growth.

The amplification of EGFR is most commonly associated with this genetic defect4. Patients present with the MGMT (O (6)-methylguanineDNA methyltransferase) gene are often not as responsive to chemo-radiation. This is because the MGMT protein is responsible for cellular DNA repair, hence the patients who receive chemoradiation will actively fight against the treatment at a cellular level. Patients who have a methylated (inactivated) MGMT respond much better to treatment 3.

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Figure 4: Agent distribution improvement in CED (left) compared with Diffusion-mediated-delivery (right) Presenting symptoms of astrocytomas are few, as with many brain tumours, however these few symptoms give good cause for serious further investigations. Common symptoms include anything deriving from intracranial hypertension, such as intense headaches, seizures or inflamed optic discs. Confirmatory tests however must be done to categorically conclude that an astrocytoma is the underlying pathology. Initially a full neurological exam is given to assess aspects such as vision, audition, alertness, motor capacity, cognition and cranial nerve function3. When neurological deficits confirm lesions to the nervous tissue, scans must be done. A computerised tomography or MRI scan is often sought after to determine size and location of the tumour. The best way however to determine the morphology of the tissue and hence the grade of the astrocytoma is via surgical biopsy. Neuropathology can then confirm the grade of the tumour and any genetic deficiencies that could have caused the astrocytoma; after this a treatment plan can be established. Normal prognosis for a Grade IV astrocytoma is poor, with regular malignant recurrences, hence dwindling the life expectancy to 12-18 months where only 3% of cases live longer than 36 months3.

For Grade IV astrocytomas, chemo therapy and radiation are the first port of call for treatment.

This is used in combination with surgical resection, if the tumour is operable that is. On surgical resection, the patient can be given a 5-ALA3 (5amino-luvenlinic acid) drink. The drink itself is colourless, it however causes the cancerous astrocytes in the brain to glow pink under UV light.

This aids the neurosurgeon in their excision and identifying of the tissue.

Figure 3: 5-ALA under UV light

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Some glioblastomas are not operated on, be it because the case is initially inoperable, or there is a complication during surgery or because the patient refuses invasive procedures. Standard chemotherapy and radiation alone are not enough to tackle the intense belligerence of a glioblastoma. This is due to the extremely beneficial, but in this case troublesome, blood-brain barrier (BBB). Most (98%) standard dosages of chemotherapy cannot pass through the BBB since it usually does not allow molecules of molecular weights greater than 180 kDa to pass through it. To overcome this obstacle, intraparenchymal delivery of therapeutic agents has been investigated. An example of an invasive drug therapy includes convection-enhanced delivery (CED) through rigid cannulas and/or soft catheters. In other words, the glioblastoma would directly be accessed by drugs, via a bur hole and catheters, in order to avoid the BBB. Initial research in 1994 used diffusion-mediated delivery; this method came with many drawbacks. A compound’s diffusion in a given tissue depends on its free concentration gradient and its diffusivity in the tissue. Therefore, highmolecular-weight compounds like enzymes and antibodies are unable to diffuse over large distance. To put things into perspective, it may take as long as three days for an immunoglobulin to diffuse 1mm from its delivery site5.

CED which was initially conceptualised by Bobo et al. in 1994 can overcome the drawbacks of diffusion-mediated-delivery along with the nuisance that is the BBB. CED involves strategically inserting one or more rigid cannulas with soft catheters directly into the tumour via bur holes.

The catheters are proximally connected to a syringe pump containing the infusate while the distal ends infiltrate into the target tumour area.

CED is initiated by bulk-flow kinetics and pressure gradients, as opposed to the concentration gradients of diffusion delivery. Advantages of CED include an improvement of intratumoural spatial distribution since the pressure gradient allows agents to be spread over larger volumes, more evenly and a higher amounts. Also CED

does not depend on steep concentration gradients so less toxic doses can be used. Lastly CED is not as selective about the agent used since the agent’s molecular weight or diffusivity are irrelevant5.

Of all clinical trials between 1997 and 2010 which tested the efficacy of the CED treatment, eight involved using astrocytoma specific conjugated toxins, one using viruses, and five using conventional chemotherapies usually unable to pass the BBB. Challenges that have faced CED in these trials are numerous. The first and most obvious is the choice of agent used. Another controversial issue is of cannula design and placement. The latter issue is particularly difficult since each tumour is different so each design has to be tailored to the patient which is time-consuming, resource-consuming and costly. A common inaccuracy of CED is that it is an easier treatment compared to surgery. CED itself requires an operating room, an MRI, 3-D navigation systems, a full operating team and neuro-pathophysiologists for agent concoction.

The future for glioblastomas certainly is bright, especially in the light of CEDs. Current trials look forward to installing permanent cannulas into the patient so each time the patient requires a dose, a full surgery is not necessary rather only a syringe.

References: 1. Neuroanatomy and Neurophysiology - Chapter 11 - Oxford Handbook of Medical Sciences 2nd Edition – Oxford University Press 2.Space-occupying lesions – Neurology - Oxford Handbook of Clinical Medicine 9th Edition – Oxford University Press 3.Glioblastomas – The Brain Tumour Charity Fact Sheet pdf.

4.Association of chromosome 7, chromosome 10 and EGFR gene amplification in glioblastoma multiforme.

C. Lopez-Gines, M. Cerda-Nicolas, R. Gil-Benso, A. Pellin, J. A. Lopez-Guerrero, R. Callaghan, R. Benito, P. Roldan, J. Piquer, J. Llacer, et al. - Clin Neuropathol. 2005 Sep-Oct; 24(5): 209– 218.

5.Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies - Arman Jahangiri, BS, Aaron T. Chin, BS, Patrick M. Flanigan, BS, Rebecca Chen, BS, Krystof Bankiewicz, PhD, and Manish K. Aghi, MD, PhD - Journal of Neurosurgery - Jan 2017 / Vol. 126 / No. 1 / Pages 191-200

Crunchy Toast

Amino Acid*

Level of Acrylamide Formation After Combination with Sugar and Application of Heat

Alanine

<50 ppb

Asparagine

9270 ppb / 9.27 ppm

Aspartic Acid

<50 ppb

Cysteine

<50 ppb

Glutamine

156 ppb

Lysine

<50 ppb

Methionine

<50 ppb

Threonine

<50 ppb

By Zak Mouyer

A carcinogen is any kind of substance, radionuclide or form of radiation that is directly involved in causing an abnormal growth known as cancer.

Reasons for this may be due to substantial or irreversible damage to the genome or disruption to the cellular metabolic or growing processes.

Some radioactive substances are considered carcinogenic, such as gamma rays and alpha particles. Familiar non-radioactive carcinogens include: inhaled asbestos, dioxins and tobacco smoke. Cancer is any disease where normal cells which are damaged do not go through the normal, programmed cell death process as fast they are able to divide via mitosis. From this, food is perhaps the last place one would go in search for possible carcinogens.

Acrylamide, or prop-2-enamide, is a toxic and potentially carcinogenic substance naturally present, in very small amounts, in uncooked foods. It is a colourless crystalline solid which readily forms water-soluble polymers with the chemical formula C3H5NO. However for this chemical to pose as a risk, it must be in a higher quantities, such as that found in cooked foods.

Non dietary exposure to acrylamide is evident in cigarette smoke and cosmetics. The United States Environmental Protection Agency (EPA) has estimated that the average adult in the developed world intakes 0.4 micrograms of dietary per kilogram of body weight each day. In perspective, an average male would consume approximately 27 micrograms a day, this is 19% of the maximum allowable exposure to acrylamide from dietary intake.

At the moment acrylamide is a Group B2, â&#x20AC;&#x2DC;possible to likelyâ&#x20AC;&#x2122; human carcinogen. The EPA primarily base this result on acrylamide research conducted on animals, since a large-scale epidemiologic study on humans is simply not available.

This chemical has also been shown as a neurotox-

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in that hinders the nervous system function, by disrupting the impulse that gets transmitted by nitric oxide at the onset of the nerve firing process. Hence the neurotoxic and probable carcinogenic aspects of acrylamide make it clear that we do not want to be exposed to it in excess amounts.

But how does this chemical relate to food? In food, acrylamide can be formed in two ways.

First, the chemical is formed when amino acids interact with sugars in the presence of heat.

Many different sugars and amino acids can interact to produce acrylamide in this way. However, an amino acid called asparagine has a far greater tendency to interact with sugars to form the named chemical. The chart above shows how different amino acids react to produce different amounts of acrylamide. Note how asparagine produces a huge amount so much so it can be written in ppm, where ppm is one thousand times greater than ppb.

Secondly it is possible to produce acrylamide without the presence of saccharides. As fats are oxidised, unique 3-carbon molecules (specifically

Food

acrylic acid and acrolein) can be made. When heated, the 3-carbon molecules are able to make interactions with asparagine to from acrylamide.

This process is extremely common in fried foods, even if there is little to no sugar found in the food originally.

A very common example where acrylamide is formed is during the production of potato crisps.

In raw potatoes, there are small amounts of asparagine present. And whilst being fried, the fats are oxidised and can be converted into acrolein and acrylic acid. The starch prevalent throughout the whole of the potato can also be changed into sugars. The distinctive blend of substances can interact in a way which results in unusually high amounts of acrylamide being formed. One small one ounce packet of potato crisps would represent 28 micrograms of acrylamide, this amount is already higher than the recommended daily exposure of an adult male.

Below is a table showing the foods with highest amounts of acrylamide known to modern research completed this year:

Highest Research Finding for Acrylamide Content

Grain-based coffee substitutes

5.399 ppm

Potato crisps

9.270 ppm

Chips

1.325 ppm

Dehydrated onion soup mix

1.184 ppm

Toasted wheat cereal

1.057 ppm

Cookies

0.995 ppm

Cocoa

0.909 ppm

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Food

Acrylamide level in parts per billion (ppb)

Asparagine level in milligrams per gram

Asparagus

<10 (frozen, canned, grilled) 41-820 (raw)

Carrots

61 (grilled)

3.2 (raw and dehydrated)

Onions

70 (grilled)

3-5 (raw)

Potatoes

114 (roasted)

6.6-16.0 (raw)

Broccoli

235 (canned)

179-393 (raw)

Plums and Prunes

31-188

16-116 (raw)

Coffee beans

179-351 (roasted)

0.33-0.97 (raw and dried)

Cocoa beans/ Chocolate

24-909

9-31 (both raw powder and roasted beans)

Wheat/breads

27-364

20-215 (fresh wheat) 2-5 (fermented and non-fermented wheat dough)

The table indicates that foods must have some amount of asparagine in them in order for substantial amounts of acrylamide formation. Nevertheless the amount of acrylamide made cannot be predetermined by the amount of asparagine present. This is shown in asparagus, where asparagine levels are relatively high yet there are very low levels of acrylamide formed (this amino acid asparagine initially got its name from asparagus since it was first detected in asparagus juice).

Hence it is evident that heating foods can result in unwanted amounts of acrylamide (as shown by the above table). However, this always is not the case, even if the food contains high amounts of asparagine (again as shown above). When all factors of forming acrylamide are present, it approximately takes 121°C for a noticeable formation of acrylamide to take place. Research interestingly shows a peak of acrylamide formation in roasting temperature ranges (121-191° C). Finally relating this all to toast which is too crunchy (by which the bread is toasted at the latter temperatures), extensive research has shown that the amount of acrylamide present increases as the level of crunch increases on the toast. Despite all this it is important to remember that heating foods to the mentioned temperatures does not automatically mean that acrylamide will be formed. It takes the vital combination of asparagine with a sugar, or the oxidation of fat into smaller 3-carbon molecules, or both for substantial formation of acrylamide.

Metabolically, acrylamide can be detoxified in the body, providing it is processed through the cytochrome P450 enzyme system and then converted into glycidamide, or if it is attached with the sulphur-containing antioxidant glutathione. Despite our metabolic pathways being able to de-

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toxify acrylamide, we are still able to overload the detox ability of these pathways and put ourselves at risk from excessive exposure. However, since there is a capacity to the detox pathway, it means that we can lower the risk of excessive toxicity if keep plenty of glutathione in our metabolic reserves. Eating a lot of sulphur containing foods will do this job excellently (like garlic, onions and other cruciferous vegetables).

Also consuming a high amount of the sulphur containing amino acid cysteine will help too.

Hence if you would like to reduce the amount of acrylamide in your diet, consuming less of the following is highly advisable: fried processed starches, baked snacks containing wheat and sugar, overly toasted breads and grains and lastly roasted grain-based coffee substitutes. Eating a large amount of cruciferous vegetables is a brilliant way to battle against a high amount of acrylamide, and by doing so you are aiding your detox system in the detoxification metabolic pathway of acrylamide.

References: 1. http://www.telegraph.co.uk/news/health/ news/11996554/Crunchy-toast-could-give-youcancer-FSA-warns.html 2. https://www.google.co.uk/webhp? sourceid=chromeinstant&ion=1&espv=2&ie=UTF-8#q=how% 20much%20acrylamide%20is%20in%20toast https://en.wikipedia.org/wiki/Carcinogen 3. http://www.who.int/foodsafety/publications/ chem/en/acrylamide_full.pdf 4. Elmore JS, Koutsidis G, Dodson AT et al. The effect of cooking on acrylamide and its precur-

sors in potato, wheat and rye. Adv Exp Med Biol.

2005;561:255-69.

5. Carere A. Genotoxicity and carcinogenicity of acrylamide: a critical review. Ann Ist Super Sanita.

2006; 42(2):144-55.

Aortic Stenosis and Edwards SAPIEN 3 Transcatheter Aortic Valve Replacement Procedure

By Zak Mouyer The aortic valve is perhaps the most important valve in the entire cardiovascular system. This valve is the only barrier between the arterial blood in the left ventricle reaching the rest of the body. Hence any impediment to this valve could have serious consequences elsewhere in the body.

Normally, blood carrying oxygen enters the left upper chamber (atrium) of the heart. It is then pumped into the lower left chamber. The aortic valve opens when the heart contracts to pump blood from the left ventricle into the aorta, the largest artery in the body. When the left ventricle relaxes, the aortic valve closes because there is a higher blood pressure within the aorta compared to the ventricle. However, in the case of a patient with aortic valve stenosis, this process changes immensely.

Aortic stenosis is the most common type of aortic valve impediment, where due to a plethora of reasons: calcification (this is where calcium deposits solidify on the valve preventing full movement), rheumatic heart disease or congenital conditions (an example could be that the aortic valve comes out to be bicuspid instead of tricuspid at birth); the aortic valve is not allowed to open fully when needed. Hence, the filling pressures in the left ventricle ‘sky-rocket’ and haemodynamic velocities across the valve increase as well; also there will be aortic valve regurgitation where blood leaks through the valve. This all will in turn lead the left ventricle into having to pump much harder and hence will cause that cardiac muscle to grow more (this is known as hypertrophy). Overtime the health of the heart will reduce and lead to complications such as cardiomegaly, arrhythmias, pulmonary oedemas and congestive heart failure.

and its sternum open (sternotomy) and surgically opening the pericardium around the heart. Here the heart is stopped with a dose concentrated of potassium and so are the lungs, and the perfusionist will attach the respective organs to a heart-lung machine (this part is necessary to keep the heart and valve stationary while the replacement occurs). Then the aorta is opened and the calcification is removed along with the entire valve. After a mechanical, prosthetic or biological valve has been substituted in for the old valve, the heart is tested, restarted with defibrillation and is kept in rhythm with an external temporary pacemaker. Then the chest and sternum are closed.

This procedure leaves the patient with many possible complications such as pericarditis which is fluid build-up in the pericardium; this is a perfect place for infections to stagnate. Also there is a massive scar left on the patient’s chest which can also easily get infected. If there is also a problem with the valve, the fresh wound on the chest must be re-opened and operated on again.

Hence it is clear that this whole procedure is extremely invasive for the patient and in some cases this procedure can create more problems than it can solve.

An innovative and new way to treat patients who need to have their aortic valve replaced would be done by using an Edwards SAPIEN 3 Transcatheter Aortic Valve. As by its name, the entire procedure is completed transcatheter and in most 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 the existing and stenosed valve is permanently pushed apart and left open. Then a second package is sent up containing a wire mesh and a synthetic valve (which are both collapsed), both of which are encompassing a deflated balloon. Then when the package is in position, the balloon is inflated, temporarily impeding any cardiac output, and causing the wire mesh to open tightly around the old valve and hence putting the new valve into its new permanent position. From the second the balloon is deflated, the new prosthetic valve is in complete function.

Therefore from the above, it is apparent that treatment for aortic stenosis is absolutely mandatory once the necessary scans (echocardiographs and ventriculographs) have been done. The usual method of treatment of severe aortic stenosis would be surgery, specifically an aortic valve replacement. Normal aortic valve replacement is considered to generally be a very traumatic surgery. The procedure involves splitting the chest

Figure 1 shows an Edwards SAPIEN

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What makes this valve replacement method so much better is that there are few post-operative complications, and that it is cheaper. Also due to the fact that the valve is made of bovine pericardial tissue, haemodynamics are optimised and hence the longevity of this item is similarly maximised. This method of valve replacement is cheap, cost effective, less traumatising for the patient and hence is a revolutionary input into minimally invasive cardiac surgery.

References: 1.

Ventricular Fibrosis Suggested by Cardiovascular Magnetic Resonance in Adults With Repaired Tetralogy of Fallot and Its Relationship to Adverse Markers of Clinical Outcome —Sonya V. BabuNarayan, Philip J. Kilner, Wei Li, James C. Moon, Omer Goktekin, Periklis A. Davlouros, Mohammed Khan, Siew Yen Ho, Dudley J. Pennell, Michael A. Gatzoulis—American Heart Association Journal January 2006

2.

Holoshitz, Noa, Clifford J. Kavinsky, and Ziyad M. Hijazi. “The Edwards SAPIEN Transcatheter Heart Valve for Calcific Aortic Stenosis: A Review of the Valve, Procedure, and Current Literature.” Cardiology and Therapy 1.1 (2012): 6. PMC. Web. 19 Mar. 2017.

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Oesophageal Achalasia and Heller’s myotomy

By Rohit Vijjhalwar Polycystic Oesophageal Achalasia is an uncommon oesophageal motility disorder characterised by the loss of oesophageal peristalsis (aperistalsis) and the impairment in the lower oesophageal sphincter (LOS) relaxation. Most recent reports indicate that this disorder affects approximately 1.6 individuals per 100,000 individuals. [2]Currently, there is no cure.

Whilst its pathophysiology is not fully understood, it is believed to be a multistep process distinguished by the initial degeneration of the inhibitory nitrergic neurones in the myenteric plexus (major nerve controlling gastrointestinal motility).[3] These neurones are shown to contain inhibitory neurotransmitters such as neuronal nitric oxide synthase and vasoactive intestinal peptide responsible for the coordination of the lower oesophageal sphincter relaxation and peristaltic contractions of the oesophagus. As a result of the degeneration of these inhibitory ganglia, high amplitude nonperistaltic contractions of the LOS occur due to unopposed action of excitatory neurotransmitters such as Acetylcholine and Tachykinins. [3] The initial degeneration is as a result of a cell-mediated and antibody-mediated immune response involving the cytotoxic T-lymphocytes due to an unknown self-antigen.

The primary symptom of Achalasia is dysphagia (difficulty in swallowing), bland regurgitation of undigested food and sharp chest pains behind the sternum.

[2] In addition to this, some contents may enter the lungs (tracheobronchial aspiration) which can lead to the contraction of aspiration pneumonia. The progressive degeneration of the myenteric plexus will lead to worsening symptoms of Achalasia, especially dysphagia.

Furthermore, long-term Achalasia can also lead to the formation oesophageal adenocarcinoma due to the neoplasia of the oesophageal epithelial cells. Also, long term suffers will suffer from a permanent dilation of the oesophagus which leads to the requirement for either a partial Oesophagectomy or full Oesophagectomy which has extremely poor clinical efficacy rates currently involving the surgical removal of entire or parts of the oesophagus.

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It is clear that without early intervention, this disease can lead to the contraction of other fatal diseases and ultimately, death. There are multiple methods by which this disorder can be treated. The most common method of treatment of primary Achalasia is Heller’s myotomy with partial fundoplication treating over 90% of Achalasia sufferers with the best clinical efficacy rates. [4] This is an aseptic and minimally invasive procedure with the primary objectives of eliminating the obstruction of the non-relaxing sphincter as well as maintaining a barrier against gastroesophageal acid reflux. However, there are other non-invasive methods of treating Achalasia.

Calcium antagonists are the primary form of noninvasive treatment that act by inhibiting the cellular uptake of calcium ions which coordinate the contraction of the lower oesophageal sphincter muscles. As a result, there is a relaxation of the lower oesophageal muscle.

However, according to research carried out in 2011, the efficacies of the calcium antagonists were as low as 50% indicating induced tolerance against the drug causing the diminishing effect of the drug with a progression of the disease. [7] The surgery offers long-term and a more permanent solution to clinical Achalasia. This multistep laparoscopic surgery is characterised by the initial small incision made just above the umbilicus followed with a trocar being inserted (a hollow tube.) [5] Consequently, four more incisions are followed with trocars being inserted exposing the anterior gastroesophageal junction allowing the surgeon to begin to surgically weaken the muscles to allow the lower oesophageal sphincter to remain open. The anterior and posterior muscle fibres of the lower oesophageal sphincter are incised (approximately 4-6cm of musculature is incised) [5] without disrupting the mucosal layer of the oesophagus in order to weaken the muscles allowing the lower oesophageal sphincter to remain open. In previous years, this would be the extent of the laparoscopic surgery in order to treat Achalasia. This often resulted in many individuals reporting postoperative gastroesophageal reflux. According to a clinical trial consisting of twenty-one individuals that Heller’s myotomy, 47.6% reported pathological gastroesophageal reflux. [6] Furthermore, another postoperative symptom is oesophageal perforation as a result of a puncture in the oesophagus during the Heller’s myotomy which is common in patients of Heller’s myotomy.

However, in recent years, improvements in laparoscopic surgeries have led to a decrease in postoperative symptoms of surgical procedures such as Heller’s myotomy.

Following the myotomy of the anterior and posterior muscles of the gastroesophageal junction, the recent inclusion of a partial Fundoplication has led to a reduced number of reported gastroesophageal reflux cases. The addition of partial Fundoplication involves the suturing of the fundus of the stomach to the front of the oesophagus in order to reduce the postoperative gastroesophageal reflux. According to clinical research published determining the impact of the addition of the partial Fundoplication, there was a decrease of 38.5% in the reported cases of pathological gastroesophageal reflux indicating increased clinical efficacies in the treatment of Achalasia. [6]

ReferencesImage provided by- https://www.jhmicall.org/ GDL_Disease.aspx?

CurrentUDV=31&GDL_Cat_ID=83F0F583EF5A-4A24-A2AF0392A3900F1D&GDL_Disease_ID=0E11DE8 C-7FB7-47AE-BC76-766AC830F7BA O’Neill, O.M. (2013) ‘Achalasia: A review of clinical diagnosis, epidemiology, treatment and outcomes’, .

Ghoshal, U.C. (2012) ‘Pathogenesis of achalasia cardia’, .

Kaufman, J.A., Lal, D.R. and Oelschlager, B.K. (2006) ‘Surgical treatment for achalasia’, GI Motility Torres-Villalobos, G. (2013) ‘Surgical Treatment for Achalasia of the Esophagus: Laparoscopic Heller Myotomy’, Gastroenterology Research and Practice, 2013.

Richards, W.O. (2004) ‘Heller Myotomy versus Heller Myotomy with Dor Fundoplication for Achalasia’, Dughera, L. (2011) ‘Management of achalasia’, .

Hashimoto’s Thyroiditis

By Rohit Vijjhalwar Hashimoto’s thyroiditis, otherwise known as chronic lymphocytic thyroiditis, is an autoimmune disorder where lymphocytes cause the gradual destruction of the thyroid parenchymal tissue. The true incidence of this disease is unknown but is believed to be approximately 1.5 cases per 1000 population per year making it the most common autoimmune disease to cause hypothyroidism in countries like the U.S. [1]Currently, it is an incurable disease.

The development of the autoimmune failure of the thyroid is a multistep process characterised first by the breakdown of the immunological tolerance. This leads to the suppression in the peripheral tolerance which controls the activation-induced T-cell apoptosis regulating the process of clonal deletion to prevent autoantigens being presented on the lymphocytes. [2] The alteration in this process allows autoreactive T cells to escape clonal deletion and becoming antigen presenting cells that show thyroid specific autoantigens. In the latter, it leads to activation and clonal expansion of autoreactive CD4+, CD8+ cytotoxic T cells and autoantibodies leading eventually to the depletion of the thryocytes via the apoptotic mechanics of cytotoxity. As a result, the principal biochemical marker of this disease is the elevated presence of the thyroid peroxidase antibodies and thryoglobulins in the serum of the blood. [2] Hashimoto’s thyroiditis leads to a disorder called Hypothyroidism. [2] Hypothyroidism is a disorder that occurs when the thyroid gland is not secreting enough thyroid hormones (triiodothyronine and its precursor hormone called thyroxine) as a result of the destruction of the thyroid parenchymal tissue.

The main symptoms attached to the thyroid functional decline include a decrease in the basal metabolic rate which leads to weight gain, fatigue and weakness in muscles. However, in certain cases, the patient might also suffer from a multinodular goitre as a result of the inflammation of the thyroid gland caused due to the inflammatory response of the autoreactive lymphocytes. This can lead to the constriction of the airways and the oesophagus leading to a difficulty in breathing and swallowing. [2] Often, as a result, it could lead to the need for surgical intervention through either total or partial thyroidectomy.

Therefore, from above, it is apparent that this disease has severe clinical consequences. The current treatment for Hashimoto’s thyroiditis is the prescription of Levothyroxine, a synthetic thyroid hormone. [3] Levothyroxine is a compound that is indistinguishable both chemically and structurally from the natural thyroxine hormone administered when the body is deficient of the natural hormone. The administration of the drug can lead to a

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reduction in the presence of thyroid peroxidase antibodies and thryoglobulins in the serum of the blood as well as alleviating any symptoms attached to hypothyroidism. According to a long term study ( five years of continuous inspection) carried out by the University of Cologne in 2008, there was a 70% decrease in the concentration of thyroid peroxidase antibodies and thryoglobulins in the serum of the blood after five years of usage of Levothyroxine. [3]However, despite the drug causing a decrease in the rate of destruction of the thyroid parenchymal tissue, there can be adverse effects to this drug. It can also lead to hyperthyroidism as a result of overprescribing which leads to weight loss, arrhythmias and excessive sweating. It can be fatal in some cases leading to death. [3] However, in recent years, John Hopkins University have found an alternative to Levothyroxine drug in plants. [4] The compound in question is called Anatabine which is a naturally occurring alkaloid found in Nightshade plant family. It is believed to have anti-inflammatory and immunomodulatory properties hence can reduce the expression of cytokines associated with the clonal expansion of autoreactive leukocytes. A recent study carried out by a research team found a decrease of 40% in the presence of thyroid peroxidase and thryoglobulins in the serum of the blood across a sample of 165 individuals over the period of only twelve weeks. [4] Furthermore, the patients noted only for minor symptoms such as dizziness (38%) and nausea (8%) hence has fewer side effects compared to that of Levothyroxine. [4] Lastly, it also leads to a reduction in the goitre size (if the patient is suffering from it) hence reducing the pressure on the larynx and preventing the constriction of airways. As a result, it is safer, more effective and a more robust therapeutic agent in treating Hashimoto’s thyroiditis hence can be a future drug used in the treatments. Currently, it is awaiting further drug trials. [4]

ReferencesHashimoto’s Thyroiditis (2015) Available at: http:// patient.info/doctor/hashimotos-thyroiditis.

Zaletel, K. and Gaberšček, S. (2011) ‘Hashimoto’s Thyroiditis: From genes to the disease’, .

Schmidt, M. (2008) ‘Long-term follow-up of antithyroid peroxidase antibodies in patients with chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) treated with levothyroxine’, Thyroid : official journal of the American Thyroid Association., .

Schmeltz, L.R., Blevins, T.C., Aronoff, S.L., Ozer, K. and Leffert, J.D. (2014) ‘Anatabine Supplementation decreases thyroglobulin antibodies in patients with chronic lymphocytic autoimmune (Hashimoto’s) Thyroiditis: A Randomized controlled clinical trial’, The Journal of Clinical Endocrinology & Metabolism, .

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Ataxia-Telangiectasia (A-T)

By Rohan Vijjhalwar Ataxia-Telangiectasia (AT) is a congenital neurodegenerative, autosomal recessive disease. This is an early onset condition from ages of eight and above which is extremely rare with an incidence rate of 1 in 40,000100,000. There are expected 100,000 sufferers. AT is caused by a mutation of the ATM gene located on the 11th chromosome with locus at 11q22.3[1]. The ATM gene is responsible for signalling repair mechanisms for the DNA during errors. As a result of the mutation, there will be a loss of functionality of the proteins coded by ATM. This results in multiple problems such as increased risk of cancer, infertility, neurologic problems among others. Extensive epidemiological studies show no particular ethnicity or group to be significantly afflicted with this illness [2].

AT arises from the loss of functionality of ATM gene which is responsible for regulation of repair mechanisms when DNA is damaged. To elaborate, ATM codes for a protein which exists within the nucleus which phosphorylates several proteins which activates the cell cycle checkpoints, DNA repair cycles and proteins which regulate cell apoptosis. [3] The activated proteins are also effective tumour suppressors as they induce apoptosis in cancerous cells. ATM as a result is a highly important protein during cell cycle and regulation of DNA. The mutation of ATM as a result leads to defective response to double strand breaks (DSB), mitotic\meiotic activity.

This results in formation of tumours and death of cells.

Infertility also arises due to the fact that DSBs occur frequently during meiosis in order to allow for genetic diversity but since ATM is defective, the gametes are often malformed. Furthermore, a distinct feature of AT is a progressive neurological degeneration. The cause of this is debated among neurologists however the current hypothesis is that it is caused due to defective DNA repair mechanisms in the neurons. [4] This leads to malfunctioning neurons which die as a result thus causing the neurological functional decline which is observed.

Furthermore, another hypothesis for the cause is that when neurons form they enter the post-mitotic stage inappropriately thus causing early\rapid apoptosis of the neurons. The mass death of neurons in areas such as Basal Ganglia leads to an inability to learn, seizures and a loss of motor control. In latter stages, it can also be fatal to the sufferer.

The early detection of AT is preferable due to its rapid progressive nature. Unfortunately, AT is difficult to diagnose due to its rarity and its symptoms being mutual to other illnesses. Initially, a physician will observe discoloration of skin affected by sun light due to the cells in the affected regions dying but not being regenerated correctly because of problems with mitosis. Further-

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more, AT is also evidenced through ocular telangiectasia (dilated blood vessels over the sclera). In addition, the growth of the child might also be severally hindered even in a high caloric environment due to inability for cells to go through mitosis. Once AT is suspected, the physicians will then take a blood test of the suspected patient. A biochemical marker of AT is low levels of immunoglobulins, chromosomal pieces, and elevated Alpha-fetoprotein (AFP) levels.[5] The patient will then have a MRI scan as high AFP is not only common for tumours but also for neurological illnesses. The MRI of a patient will be shown to have cerebellar atrophy. The physician will then perform a genetic analysis on the patient which will show the absence of ATM gene thus clearly indicating AT. Genetic illnesses, are by nature extremely difficult to cure or treat however there are methods of slowing the progression of the illness. Currently, the most effective method is through replacement gamma-globulin infusions however if patient is also undergoing cancer treatments then administration of prophylactic, antibiotics is also advised.[6] Furthermore, patients are also recommended to physiotherapy and speech therapy to counter the neurodegenerative effects associated with the illness. Unfortunately, the illness being genetic means that current treatments cannot reduce the speed of neural degeneration. The current research into treatment is in its open-label phase 2 of clinical testing.

The test involves patientâ&#x20AC;&#x2122;s native erythrocytes being infused with dexamethasone to deliver the medicine across the body. The researchers (Chess et al) found the treatment to be reducing the neurological symptoms due to AT. The research also concluded that the treatment was more effective on those who were in later stages of AT. This implies that those who are severely afflicted by this illness can see considerable improvement in lifestyle and treatment will become more effective with progression of the illness.[7]

Thalassemia natal development results. [4] This unfortunately caused as a result of the fact that less oxygen is acquired by Haemoglobin hence it results in tissue cells receiving less oxygen which leads to oxygen deprivation in tissue cells hence inhibiting mitotic activity.

By Rohan Vijjhalwar Thalassemia is an autosomal recessive hematologic illness, which is characterised by the abnormal formation of haemoglobin. Unlike most genetic diseases, Thalassemia has a high incidence rate of over 203 million individuals globally. Epidemiological studies reveal that the illness has a larger prevalence among the Italian, Greek, Middle Eastern, South-Asian and African population.

Interestingly, prevalence of Thalassemia trait among specific population is due to the trait curtailing malaria (to a certain extent) thus the trait is common in areas that were at risk of malaria. There are 3 variants of Thalassemia: α Thalassemia, β Thalassemia, deltaThalassemia. Alpha-Thalassemia is caused by the deletion of 2 genes: HBA1, HBA2 which are located on chromosome 16 within the Alpha-Globin locus. BetaThalassemia is caused due to the mutation\deletion of the HBB gene, located on chromosome 11. DeltaThalassemia is caused by mutation of HBD which codes for delta proteins which are present in minor forms of haemoglobin. Delta-Thalassemia is extremely rare and so will be beyond the realms of this article. [1] Haemoglobin consists of two haemoglobin alpha-1 proteins and two haemoglobin beta-1 proteins. These proteins interact in such a way to enable oxygen to bond to it. The interaction between these proteins allow for mass transport of oxygen across the body. In AlphaThalassemia, genes coding for alpha-1 protein (HBA1 & HBA2) are deleted which results in a formation of malformed alpha-1 protein. The malformation of alpha protein leads to further misfolded quaternary structure leading to having low affinity for Oxygen. Consequently, in many cases oxygen is unable to bind to the misfolded haemoglobin protein leading to a failure of red blood cell. Similarly, Beta-Thalassemia is a result of a mutation\deletion of HBB gene which codes for beta-globin protein. Once again malformed haemoglobin molecules are synthesized thus same consequences follows. Thalassemia, albeit a hematologic disorder, presents its symptoms by affecting variety of body systems. To begin, women suffering with Thalassemia (TASM) are at high risk of miscarriages. [2] This symptom is presented as the Haemoglobin is unable to function correctly, leading to foetal blood being unable to load oxygen which kills the foetus. In addition, TASM also can in some lead to increased iron levels within the body due to the failure of the genes to synthesise haemoglobin. As haemoglobin contains Fe(II) molecules as a prosthetic group, a failure to synthesise correct haemoglobin can lead to a iron overload or iron crisis. For unknown reasons, iron overload is most commonly presented. [3] Iron overload, or otherwise known as haemochromatosis, leads to haemosiderosis whereby excess iron is deposited in various organs, joints. The increased volume of iron within organs means that through reactions within the body such as Fenton reaction, Fe (II) catalyses formation of free radicals. Undoubtedly, this increases risk of multisystem organ failure, tumours forming. Interestingly, TASM leads to Splenomegaly (enlargement of spleen) due to the fact that TASM leads to malformed blood cells which are later removed by spleen. The continuous hyperactivity by spleen leads to spleen invoking replication of more spleen cells causing enlarged spleen. In case of low iron variation of TASMs the slowing of neo-

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TASM presents itself very early due to the observable symptoms such as stunted growth, pain in abdomen (due to spleen enlargement) and miscarriages. In addition, the high incidence rate of this illness in human population makes it prone to detection. A common examination prescribed by a physician after noting history of patient is a blood test. Blood tests are universally prescribed and taken due to the vast amount of information it can reveal about a patient. This is a result of cell waste products being taken out through blood also due to various cells moving through it. As a result identifying any infections, illness can be done through seeing blood. Once a blood sample is taken, it tested for various concentrations of various items within blood. In TASM blood test often shows increased\decreased level of iron, low levels of haemoglobin (mean corpuscular haemoglobin) and low level of volume of red blood cells. These symptomatic traits which are indicative of TASM result in a progressive DNA check-up whereby patients DNA is captured and analysed. Gene mapping of the patient is focused on the HBB, HBA1, HBA2 and HBD. The mutation of any of these genes is a direct proof for diagnosis of TASM. The severity of the illness, however, depends on how many of those 4 genes are mutated. In severe cases all 4 are mutated leading to exhibition of severe symptoms often resulting in early death. [5] Like many genetic illnesses, this disease is incurable however there are methods available to reduce the effect of this illness. Firstly, blood transfusions are administered throughout patient’s life to allow for normal function. Blood transfusions are accompanied by the prescription of chelating agents (Deferoxamine, Deferasirox etc). This is counter-acting the increased iron levels due to blood transfusion treatment. In addition, surgery is also a plausible method to reduce impact of the illness. Splenectomy is often done to remove enlarged spleen to reduce risk of internal haemorrhaging. Finally, bone marrow transplants are also considered to reduce symptoms however lack of matched donors lead to inability to use this treatment. Over 90% success rate has been demonstrated through bone marrow transplants. [6] References [1] Α +-Thalassemia and protection from malaria (2006) 3(5).

[2] (Available at: https://www.rcog.org.uk/globalassets/ documents/guidelines/gtg_66_thalassaemia.pdf (Accessed: 5 March 2017).

[3] MISHRA, A.K. and TIWARI, A. (2013) ‘Iron overload in beta Thalassaemia major and Intermedia patients’, 8(4).

[4] Beta Thalassemia - NORD (national organization for rare disorders) (no date) Available at: https:// rarediseases.org/rare-diseases/thalassemia-major/ (Accessed: 5 March 2017).

[5] How are Thalassemias diagnosed? - NHLBI, NIH (2012) Available at: https://www.nhlbi.nih.gov/health/ health-topics/topics/thalassemia/diagnosis (Accessed: 5 March 2017).

[6] How are Thalassemias treated? - NHLBI, NIH (2012) Available at: https://www.nhlbi.nih.gov/health/healthtopics/topics/thalassemia/treatment (Accessed: 5 March 2017).

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Abdominal Aortic Aneurysm

By Narmathan Rajeswaran Abdominal aortic aneurysm (AAA) is a swelling of the main blood vessel that leads away from the heart, called the aorta, down through the abdomen to the rest of the body. The abdominal aorta is the largest blood vessel in our body with a diameter of 2cm however, it can swell to over 5.5cm and this is referred as abdominal aortic aneurysm (AAA). [1] The abdominal aorta is extremely important as it has branches that supplies blood to the liver, spleen, gut and kidneys, and then the single abdominal aorta divides into two arteries that supply blood to the legs. [2] An aneurysm is a bulge in a blood vessel caused by a weakness in the blood vessel wall. As blood passes through the weakened blood vessel, the blood pressure causes it to bulge outwards. Aneurysms can occur anywhere in the body, but the two most common places for them to form are in the abdominal aorta and the brain. An aneurysm usually causes no symptoms unless it ruptures which is often fatal. [3] A rupture of the aorta will lead to massive bleeding, and will quickly result in death. AAA's are the tenth leading cause of death in men over 50 in the US, with ruptures accounting for approximately 20,000 deaths each year. [4] Even if the aneurysm doesn't rupture, sometimes a blood clot can form inside the abdominal aorta at the site of the aneurysm and this can interfere with the blood supply to the legs.

What is the cause of AAA? Unfortunately, it’s not known exactly what causes the aortic wall to weaken, although increasing age and being male are known to be the biggest risk factors. A normal healthy artery has three layers: a thin inner layer lined with endothelial cells, a middle layer composed of smooth muscle cells and elastic tissue made of tissues called elastin and collagen, and an outer layer of supporting tissues. But the middle layer of the aorta distinguishes it from other arteries; it is composed of layer upon layer of elastic tissue, which makes it very thick and strong thus able to withstand the high pressure of blood flow. Research has shown that elastin concentration within the aorta decreased with age as well as that age could have altering effects on the amino acid structure of elastin. It showed that the contents of the elastin cross-linking amino acids, desmosine and isodesmosine, decreased after the age of 63. Therefore, the loss of elastin content and decrease in crosslinking could explain the formation of aneurysms. [5] Atherosclerosis is also believed to a major risk factor for AAA. Atherosclerosis is the narrowing, hardening and loss of elasticity in an artery or arteries resulting from the accumulation of fat, cholesterol, calcium, and lowdensity lipoproteins (LDL) in the vessel wall. The plaque accumulates in your blood vessels leasing them to be narrowing the arteries and impeding the flow of blood.

An AAA is thought to develop because plaques cause the aorta to widen in an attempt to keep blood flowing through it. As a result, it weakens the aorta.

Finally smoking also seems to play an important role for AAA. Research has shown that current smokers are more than 7 times more likely to have an AAA than agematched non-smokers, ex-smokers are 3 times more likely to have an AAA compared with non-smokers and an increased duration of smoking was significantly associated with an increased risk of AAA. [6] The reason being was due to tobacco smoke contains harmful substances that can damage and weaken the wall of the

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aorta.

Abdominal aortic aneurysms often grow slowly and usually without symptoms, making them difficult to detect. Some aneurysms will never rupture. Most AAA’s are found by chance during an imaging test performed for another reason, such as an ultrasound to examine the gallbladder or an MRI to evaluate a spinal problem.

Symptoms of an unruptured AAA may include a pulsating feeling in your stomach, persistent back pain, and persistent abdominal pain. If an aortic aneurysm ruptures there would be a sudden and severe pain in the middle or side of your abdomen, dizziness, sweaty and clammy skin, rapid heartbeat (tachycardia), shortness of breath, feeling faint, and loss of consciousness. As mentioned before, a ruptured aneurysm is fatal and can needs immediate medical attention. Around 80% of people with a rupture die before they reach hospital or don’t survive emergency surgery. It is for this reason that the NHS offer all men who are over 65 an ultrasound scan to check for AAAs. [1] Treatment for AAA is dependent on several factors: age, health and aneurysm size. In general if one had a large aneurysm it would be advisable to have surgery since large aneurysms are more likely to rupture. A small aneurysm will normally be regularly monitored to check its size. There are two surgical techniques used to treat a large aneurysm: endovascular and open surgery.

Open surgery is the traditional surgery used to repair an aneurysm in the aorta. It involves removing the section of the abdominal aorta that is dilated and replacing it with a graft, a prosthesis made of synthetic material. It's an effective procedure, but it's a big operation with substantial risk of complications, including infection, bleeding, and even death. [1] Endovascular surgery is a type of "keyhole" surgery where the surgeon makes small cuts in your groin and threads the graft up into the aorta through a thin catheter that has been inserted into the femoral artery in the groin. X-rays are used to monitor the progress of the catheter on a video screen; when the stent is in place, doctors expand it and then withdraw the catheter. This reinforces the aorta, reducing the risk of it bursting.

Unlike open surgery, endovascular surgery can be done under local anaesthesia. Moreover, endovascular surgery is safer than open surgery since around 98-99% of patients make a full recovery, and recovery time from the operation is shorter than if you have open surgery.

However, the way the graft is attached is not as secure as open surgery. In open surgery the doctor stiches on the graft however in endovascular surgery regular scans are needed to make sure the graft has not moved. [7] To conclude, most people with AAA live healthy, symptom-free lives. The decision to undergo surgery involves weighing the risk of aneurysm rupture versus the risks of a surgical procedure.

[1] NHS Choices, 2015. Abdominal Aortic Aneurysm [Online] Available at: http://www.nhs.uk/conditions/ repairofabdominalaneurysm/Pages/Introduction.aspx [Accessed 5 February 2017].

[2] NHS Cambridge University, 2016. Abdominal Aortic Aneurysm [Online] Available at: Hospitals http://www.cuh.org.uk/vascular-surgery/ abdominal-aortic-aneurysm-aaa [Accessed 5 February 2017].

[3] Patient 2015. Abdominal Aortic Aneurysm [Online] Available at: http://patient.info/health/abdominal-aortic-aneurysm [Accessed 5 February 2017].

[4]University of Michigan, 2016. Abdominal Aortic Aneurysm [Online] Available at: http:// surgery.med.umich.edu/vascular/patient/diseasespecific/abdominal_aortic_aneurysm.shtml[Accessed 5 February 2017].

[5]NCBI, 2013. Elastin and collagen fibre microstructure of the human aorta in ageing and disease [Online] Available at: https://www.ncbi.nlm.nih.gov/pmc/

articles/PMC3645409/ [Accessed 5 February 2017].

[6]Journal of Vascular Surgery, 1999. The association between cigarette smoking and abdominal aortic aneurysms. [Online] Available at: http://www.jvascsurg.org/article/S0741-5214(99)70049 -2/fulltext [Accessed 5 February 2017].

[7] Harvard Health Publication, 2013. Abdominal aortic aneurysms: Triple A, double trouble. [Online] Available at: http://www.health.harvard.edu/heart-health/ abdominal-aortic-aneurysms-triple-a-double-trouble [Accessed 5 February 2017].

Duchenne Muscular Dystrophy gene is a locus of DNA, which is made from a specific sequence of nucleotides that contains the coded information for making a polypeptide. Thus a mutation can lead to lack of proteins being formed and this lack of dystrophin leads to muscle fibre damage and a gradual weakening of the muscles. [5]

By Narmathan Rajeswaran Duchenne muscular dystrophy (DMD) is one of the nine types of muscular dystrophy. [1] In short, DMD is a genetic disorder that causes progressive muscle degeneration and weakness. DMD is one of the most common and severe forms of muscular dystrophy usually affecting boys in their early childhood however, men who are affected will usually only live around the age of 20 or 30.

In the UK, about 100 boys are born with DMD each year, and there are about 2,500 boys living with the condition in the UK at any one time. [2] Children with DMD usually start to have noticeable symptoms between one and three years of age. The muscles around their pelvis and thighs tend to be affected first and often appear bulkier than normal. A child with DMD may have difficulty walking, climbing, standing up, learning to speak and have behavioural or learning difficulties. As DMD is a progressive condition, the symptoms get worse. By the age of 8-14, children with DMD may need a wheelchair as their muscles weaken and they lose the ability to walk. They can also develop scoliosis, where the spine begins to curve sideways leading to one shoulder or hip being higher than the other. Moreover, by their mid-teens, some people with DMD will develop dilated cardiomyopathy. This condition affects the heart muscles, causing the heart's chambers to enlarge and the walls to get thinner making the heart weaker and less able to pump blood out to the rest of the body. By their late-teens or early 20s, people with DMD may start to have breathing problems. This is because the intercostal muscles the diaphragm becomes affected. These muscles are integral for inhalation and exhalation meaning that those with DMD struggle to breathe and provide the body with enough oxygen or remove the carbon dioxide produced in the body. Once the heart and respiratory muscles are damaged, DMD becomes life-threatening. With medical care, most people with DMD die from heart or respiratory failure. [3] Most boys with DMD are not diagnosed until they start displaying symptoms, unless there is someone else in the family with the condition. DMD can be confirmed by genetic testing usually on a blood sample. Boys with DMD will usually have high levels of creatine kinase.

Creatine kinase is normally found in muscle but when muscles are damaged, such as in DMD, it leaks into the bloodstream. Muscle biopsy may also be recommended.

A muscle biopsy involves removing a small sample of muscle tissue through a small cut (incision), or using a hollow needle, so it can be examined under a microscope and tested for proteins. The sample will usually be taken from the leg or arm. Analysing the protein in the muscle can help to determine which gene is causing MD and therefore which type of MD you have. For example, people with DMD and Becker MD have too little of the protein dystrophin in their muscles. [4] Until the 1980s, little was known about the cause of any of the forms of muscular dystrophy. It was only in 1986, researchers identified a gene on the X chromosome that, when mutated, caused Duchenne muscular dystrophy.

Muscles contain a protein called dystrophin, which is necessary for muscles to function properly. People with DMD have a shortage of dystrophin in their muscles due to the mutation on the gene on the X-chromosome. A

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As DMD affects the sex chromosome it is a sex-linked disorder. DMD is inherited in a pattern called 'X-linked recessive inheritance'. Usually, when the DMD gene when carried by a women it does not cause problems in girls or women (with rare exceptions) because women have two X chromosomes, if one X chromosome has the 'faulty' DMD gene and the other X chromosome has a normal gene, the normal one will compensates for the faulty one. In contrast, boys with the DMD gene do not have a second X chromosome and so they cannot compensate for the faulty gene thus always have symptoms of the disease.[6] Although DMD often runs in a family, it's possible for a family with no history of DMD to suddenly have a son with the disease; the child with DMD has a new genetic mutation that arose in one of his mother’s egg cells.

Since this mutation isn’t in the mother’s blood cells, it’s impossible to detect by standard carrier testing. [2] Although usually, girls and women who carry the DMD gene have no symptoms of DMD themselves, the DMD gene might rarely affect them. If women have the DMD gene they are carries and can pass it on to her children, normally there will be a 1 in 2 chance that the gene will be passed on to their child . A small number of women carrying the DMD gene may develop some muscle weakness. This probably occurs in about 3 in 100 women carrying the gene. The muscle weakness is usually mild but there is a lot of individual variation. Rarely, there can be a muscle weakness similar to that in boys with DMD. If there is a weakness, it may increase (progress) slowly over time. [5] At the moment, DMD cannot be cured however, continuous research is being done in order to find some sort of medication to cure the disease or reduce the symptoms. For example, in 2015 Scientists have discovered that eplerenone, a drug traditionally used for high blood pressure and late stage heart failure could slow the decline of heart function in Duchenne muscular dystrophy. [7] [1] Muscular Dystrophy Association, 2015. Duchenne Muscular Dystrophy. [Online] Available at: https:// www.mda.org/disease/duchenne-muscular-dystrophy [Accessed 05 February 2016].

[2]NHS Choices, 2015. Muscular Dystrophy. [Online] Available at: http://www.nhs.uk/conditions/Muscular-dystrophy/ Pages/Introduction.aspx [Accessed 05 February 2016].

[3] Patient Info, 2012. Duchenne Muscular Dystrophy.

[Online] Available at: http://patient.info/health/ duchenne-muscular-dystrophy-leaflet [Accessed 05 February 2016].

[4] Lancet Neurol, 2010. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management.

[Online] Available at: http://www.treat-nmd.eu/ downloads/file/standardsofcare/dmd/lancet/ the_diagnosis_and_management_of_dmd_lancet_com plete_with_erratum.pdf [Accessed 05 February 2016].

[5] Muscular Dystrophy UK, 2014. Duchenne Muscular Dystrophy Factsheet. [Online] Available at: http:// www.musculardystrophyuk.org/app/uploads/2015/05/ DMD-factsheet.pdf [Accessed 05 February 2016].

[6] Muscular Dystrophy Association, 2015. Duchenne Muscular Dystrophy. [Online] Available at: https://

www.mda.org/disease/duchenne-muscular-dystrophy/ causes-inheritance [Accessed 05 February 2016].

[7] Muscular Dystrophy UK, 2015. A new drug could slow heart damage in Duchenne muscular dystrophy. [Online] Available at: http://www.musculardystrophyuk.org/ news/news/a-new-drug-could-slow-heart-damage-induchenne-muscular-dystrophy/ [Accessed 05 February 2016].

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Sickle Cell Anaemia stretch, which in turn creates the sickle shape.

By Malachi Saccomani Sickle cell anaemia is the most common of the sickle cell diseases, and is an autosomal recessive disease; someone has to have two copies of the sickle cell causing allele in their DNA for them to be affected, one from each parent. People of African, Caribbean and Asian heritage have the greatest likelihood of being a carrier in the UK about 1 in 10 of this demographic are believed to be carriers [1], and in the US it is estimated that 1 in 13 African-Americans are carriers [2]. One theory of why sickle cell anaemia is more common in these areas is because malaria is also more common, and sickle cell anaemia carriers are better suited to fighting the parasite. Thus, due to natural selection, sickle cell anaemia will be found in more people.

Sufferers of sickle cell anaemia have abnormal red blood cells due to clumping of haemoglobin to form rods. This causes the characteristic ‘sickle’ shape as shown above.

The genetic mutation that causes the clumping of the haemoglobin is a simple one, and yet has severe consequences. A substitution occurs on each of the 11th chromosomes, on the β-globin gene at position p15.5. The 17th base, thymine, is substituted for adenine. When this allele is transcribed by RNA polymerase during protein synthesis, mRNA is still produced; however its sixth codon will be GUG, as opposed to GAG, leading to the

Sickle cells can cause a variety of problems in the body, and these are generally known as crises. A vasoocclusive crisis is caused by a deficiency of oxygen and/ or glucose in a tissue, and is caused due to sickle cells clotting and blocking off blood vessels, restricting the blood flow. These are typically a sudden and acute pain and can last for up to a week; blood transfusions can be used in severe cases where hydration is not enough to help treat it. Blood transfusions are often necessary for other crises, such as the haemolytic crisis in which a person’s red blood cell count drops due to haemolysis (spontaneous destruction of red blood cells). Another type is the aplastic crisis, which results in the sufferer being paler and more fatigued, as well as having a faster heartrate because of fewer red blood cells. This is similar to a haemolytic crisis, however the cause is not a death of cells, but instead a halt of production. It’s made particularly worse because sickle cell anaemia sufferers’ red blood cells have a life of only 10-20 days (90-120 is the length for a normal adult)[3].

Diagnosis is relatively simple for sickle cell anaemia as a complete blood count will be sufficient. Haemoglobin levels are typically around 15 g/dl in a healthy adult [4], whilst for a sickle cell anaemia sufferer it might be as low as 6-8. Other signs such as a higher count of reticulocytes (immature red blood cells) will also help diagnose because the bone marrow has to produce cells at a higher rate.

Life expectancy has increased dramatically in the past decades due to advancements in medicine; in 1973, the average lifespan of a sickle cell anaemia sufferer was just 14 years, yet it has increased to 40-60 years in developed countries.

References: 1. http://www.nhs.uk/Conditions/Sickle-cell-anaemia/ Pages/Carriers.aspx 2. https://www.cdc.gov/ncbddd/sicklecell/data.html 3. https://www.nhlbi.nih.gov/health/health-topics/ topics/sca 4. https://www.disabled-world.com/calculators-charts/ hemoglobin-iron.php

amino acid glutamic acid being replaced by valine during translation.

Despite this change, haemoglobin can still be formed.

The quaternary structure of haemoglobin A (the dominant haemoglobin type) consists of two α-globin chains and two β-globin chains. However, when a haemoglobin protein is formed with the abnormal β-globin chains, it is known instead as haemoglobin S. Haemoglobin S is still functional in that it is able to bind to oxygen and thus allows red blood cells to transport it, but it can cause its carrier blood cell to become sickle-shaped. This happens because, unlike glutamic acid, valine’s R group is hydrophobic and therefore associates with a hydrophobic patch elsewhere in the haemoglobin. However, this occurs only in low oxygen concentrations because the hydrophobic patch is not normally exposed. This causes the haemoglobin to collapse in on itself and aggregate with others, which eventually will cause a fibrous rod to form. These fibres press out on the cell and cause it

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Human Blood Types

By Malachi Saccomani Although there are many types of antigens on human red blood cells, many of them are considered almost irrelevant for identification purposes, and so human blood types are generally comprised of two main systems.

The ABO blood group system is used to identify whether the blood cells display A antigens, B antigens, both, or neither; in the case where there is neither, the blood type is said to be O. This also indirectly describes the blood plasma antibodies. If a person has A blood, they have anti-B antibodies; B blood has anti-A antibodies; AB has neither; O has both. Anti-A antibodies bind to A antigens on red blood cells and collectively kill the cells.

The Rh blood group system is comprised of around fifty antigens, however antigen D is the only antigen displayed on a standard blood type (A/B/AB/O +/-) and is referred to by the + or -; + shows that the D antigen is present, - shows that it is absent. This D antigen has particular significance during child birth.

Blood type is entirely genetic and for the ABO system, there is one gene that depicts the antigen; 9q34.2 has three alleles, i, IA and IB. In order to have type O blood, someone must inherit two i alleles as IA and IB are both dominant. However, they are codominant and so although they will be expressed in the phenotype over i, possession of both IA and IB will lead to AB blood type.

The gene codes for a glycosyltransferase enzyme which modifies the carbohydrate on the antigen, thus making it either A, B or nil.

To be Rh+ one must possess a single allele that codes for the production of the RhD antigen. It is a dominant allele and it is situated on the first chromosome, at locus p36.11. As is often the case with genetics, certain populations have a much higher possession rate of the D+ allele; 84% of Europeans are D+, whilst almost 100% of Africans and Asians are.[1] There are numerous blood tests to deduce someone’s

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blood type. ABO is tested in an agglutination test. The patient’s blood is taken and split into two, before anti-A antibodies are added to one part, and anti-B antibodies are added to the other. If there are complimentary antigens for the antibodies to bind to, then the blood cells will agglutinate and the solution will turn from thick red, to clear with red clumps. Agglutination in A shows the patient possesses antigen A; agglutination in B shows antigen B; agglutination of both shows AB; no agglutination shows O. Agglutination occurs because the antibodies have many binding sites on them and so numerous cells connect to them, forming a large mass.

The Coomb test is used to see if someone is RhD+ or RhD-.

It is important to know someone’s blood type for many reasons. One reason is for blood transfusions. For example, if somebody is in an accident they may suffer a serious injury and lose a lot of blood. To stop them dying from blood loss, doctors may provide a blood transfusion. The blood is taken from donors (to the NHS in the UK, although in countries such as the USA it can be sold) and is sorted into blood components, such as red blood cells, platelets and plasma. However, because of the antibodies anti-A and anti-B, the recipient and donor must be compatible. O- has the fewest antigens and so can be given to any recipient because they will have no complimentary antibodies that would destroy the cells; people with O- blood are known as ‘universal recipients’. AB+ people have the A antigen, the B antigen and the D antigen, and so would cause an immune response in any recipient who isn’t AB+ because their antibodies would attack the blood cells. However, because AB+ people have fewer antibodies in their blood, they can receive blood from anyone and so are known as ‘universal recipients’.

Haemolytic disease of the new-born is caused by the mother’s antibodies passing through the placenta into the foetus’ blood system and attacking its cells. This can cause child death. RhD is the main antigen that can cause this, however, there are several others, including the main Rhesus antigens – C, c, E and e – as well as other blood type antigens that can cause it also. In the case of RhD, it’s caused by the mother being RhD- and her foetus being RhD+ (this can occur if the father is RhD+). Foetal-maternal haemorrhage is the breakage of the embryonic chorion in the placenta, which is the blood barrier that stops blood cells passing between the mother and foetus. This causes RhD+ red blood cells to enter the mother’s blood stream which triggers an immune response. Plasma B cells with complimentary antigens are activated and produce anti-D antibodies.

This is known as the mother’s sensitisation. However, in the first exposure/the sensitisation, the antibodies produced are all immunoglobulin M type which are too large to cross the placenta and so cannot affect the baby. However, in the mother’s second pregnancy, immunoglobulin G type antibodies are produced, which are small enough to pass through the placenta and attack the baby’s red blood cells.

Fortunately, haemolytic disease of the new born caused

by RhD can be prevented. If the mother is unsensitised, then an injection of anti-D immunoglobulin should be

given at 28 weeks and 34 weeks. These times are used because at 28 weeks, the foetus’ red blood cells wills start to present D antigens if they are RhD+ and at 34 weeks, labour is likely to happen within weeks and a foetal-maternal haemorrhage is more likely to occur in labour.

Reference: 1. Steve Mack, 21/03/2001 http://www.madsci.org/ posts/archives/mar2001/985200157.Ge.r.html

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Plasma Cell Dyscrasias

By Akila Wickramathilaka Plasma cell dyscrasias can be defined as disorders of the plasma cells in one’s immune system. A plasma cell is a type of antibody-producing lymphocyte (white blood cell). Lymphocytes are involved in the adaptive (specific) immune system, dealing with intruding pathogens and other chemicals. T-cells involved in cell mediated responses, and B-cells involved in humoral responses both have the ability to multiply into plasma cells, which in turn carry out their function by producing antibodies to destroy the foreign pathogens. By inference, one can assume that the disorder of plasma cells will result in the individual’s immune system being unable to defend against threats. Examples of plasma cell dyscrasias are: multiple myeloma, monoclonal gammopathy of undetermined signicifance (MGUS), Walderstrom macroglobulinemia, and Langerhans cell histiocytosis. Multiple myeloma is caused problems with the functioning of antibodies, whereas MGUS and the other dyscrasias are caused by changes in blood concentration and type of antibodies. This essay will focus on MGUS, and how it is a precursor to multiple myeloma.

Monoclonal gammopathy of undetermined significance starts in the bone marrow of an individual. Bone marrow is the interior part of a bone, which is responsible for the production of blood cells: erythrocytes, thrombocytes and white blood cells. Bone marrow contains precursors of these cells, and this is where the problem begins. Due to an unidentified reason, a dysfunctional precursor which produce plasma cells begin to multiply in a process known as monoclonal expansion. Monoclonal expansion implies that the cloned cells have been derived from one cell (see Figure 1).

[Figure 1] - Monoclonal expansion This replication is unregulated, and hence an exponential amount of the same, dysfunctional, antibody-producing plasma cells are produced. Some of the dysfunctional plasma cells may produce more antibodies than normal.

This is where the “monoclonal” part of MGUS originates.

Antibodies are proteins. They can be measured in the blood using a process called protein electrophoresis.

Electrophoreses depict the different types of proteins that they measure (see Figure 2)

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[Figure 2] – Electrophoresis for a non-sufferer Gamma proteins relate to antibody function. Since monoclonal expansion produces large quantities of the same antibody, there will be significantly more gamma proteins observed in the electrophoresis. Therefore, a person suffering from MGUS will have produce an electrophoresis with a different shape, displaying an “m -spike” (see Figure 3). This is where the “gammopathy” part of MGUS originates.

Like MGUS, multiple myeloma is caused by the monoclonal production of immunoglobulins. Immunoglobulins are proteins which can be deposited in the kidneys, causing renal failure. Increased bone turnovers are another symptom. The malignant cells release factors that cause the bones to form lytic bone lesions, which starkly increase the chance of bone fractures, especially in the spinal column. As the bone is broken down, calcium ions are released into the bloodstream, causing hypercalcemia. Thirdly, as discussed earlier, monoclonal expansion creates lots of clones of malignant cells which overcrowd the bone marrow. This can have two effects: there could be a low level of red blood cells in the bloodanaemia, and/or there could be a low level of platelets in the blood- thrombocytopenia. Finally, there will also be a decreased production of normal immunoglobulins, and hence people with multiple myeloma will have an increased chance of infection.

These problems caused by the malignancy can be related to the symptoms one may display. Hypercalcemia causes gastrointestinal problems, renal failure can cause thirst, anaemia can cause fatigue and pallor, lytic bone lesions cause back pain.

[Figure 3] – Electrophoresis of a sufferer The same process occurs in multiple myeloma, apart from one key difference: the monoclonal expansion of the dysfunctional cells is more unregulated. This causes the bone marrow to become overpopulated with dysfunctional precursors that produce plasma cells. This in turn, inhibits the production of other cells by other precursors- erythrocytes and thrombocytes. Multiple myeloma shows symptoms, whereas MGUS is asymptomatic. MGUS can lead to multiple myeloma, once symptoms start to show. In this sense, MGUS is a precursor to multiple myeloma (discussed later), and is often referred to as “pre-myeloma”. However, the probability of an individual with MGUS developing multiple myeloma is incredibly slim. In perspective, 3-5% of individuals over the age of 60 develop MGUS. Of that small percentage of individuals, only approximately 1% develop multiple myeloma per year. This is where the “undetermined significance” part of MGUS is derived from.

Multiple myeloma is the cancer of plasma cells. As aforementioned, multiple myeloma causes cancer cells to accumulate in the bone marrow, causing them to crowd around healthy cells. Common symptoms of multiple myeloma are: gastrointestinal problems, thirst, fatigue, pallor, back pain. These symptoms are reasonably telling that the individual has multiple myeloma, as they can be directly related to the progression of the malignancy.

Diagnosis of multiple myeloma is based upon the problems aforementioned. Renal failure can be detected through blood tests checking for BUN and creatinine, or through electrophoresis which can be done on the serum or the urine. Lytic bone lesions can be detected using bone scans. Hypercalcemia can be detected using blood tests. Anaemia and thrombocytopenia can be diagnosed via a complete blood count, or by checking for overcrowding in the bone marrow on a bone marrow biopsy.

There are two general approaches to treating multiple myeloma. The first pathway is to treat the symptoms of the disease and cause disease regression, which is accomplished via chemotherapy and a plethora of different medicines. The second pathway is the actual curation of the disease, which can only be achieved via a bone marrow transplant. However, this is seen as unfavourable. This is because most of the sufferers are old aged, and hence may not be able to cope with the effects of such an operation. Furthermore, there isn’t a surfeit quantity of bone marrow donors, hence making the whole process very slow and often agitating for sufferers.

References www.khanacademy.org www.nhs.uk http://www.cancerresearchuk.org/

Kaposi—Sarcoma

By Akila Wickramathilaka Kaposi’s sarcoma is a rare type of cancer, affecting the skin and the mouth. Unusually, it is caused by a virus called the human herpesvirus 8 (HHV-8) - a gamma herpesvirus. It is a very common virus, but dormant in most people. It is activated only in immunocompromised people, e.g. those who suffer from Acquired Immune Deficiency Syndrome (AIDS), and those who are donor organ recipients, who have been under immunosuppressant drugs. Both the aforementioned result in a weakened immune system, which allows the HHV-8 virus to cause damage. The discovery of this disease some 150 years ago is truly magnificent, and currently scientists are only a few steps away from making a breakthrough for a cure. This article will focus on the history, causes, symptoms, and treatment of this rare phenomenon.

Kaposi’s sarcoma, was discovered in 1872, by a Hungarian dermatologist by the name of Moritz Kaposi. Initially, he reported multiple idiopathic and pigmented nodules, of purple colouration, on the skins of five of his patients.

145 years later, scientists can now classify Kaposi’s sarcoma into four categories. Classic Kaposi’s sarcoma is a hereditary form, which affects middle-aged, and elderly men of Mediterranean or Jewish descent. Scientists believe that individuals with classic Kaposi’s sarcoma were born with a greater vulnerability to the HHV-8 virus. Very much unlike the other forms of this disease, the classic type is indolent and progresses slowly over many years. It is not metastatic so is localised in the skin.

The second type is transplant-related Kaposi’s sarcoma, which occurs as a result of the immunosuppressant medication given to organ donor recipients. In stark contrast, the transplant-related type is frightfully aggressive, and often requires immediate treatment. The third type is HIV-related Kaposi sarcoma- the most aggressive form of the disease, with a dissemination probability greater than 60%. Combination antiretroviral therapy (cART) is often used to prevent HIV from proliferating and hence assists the immune system to control the levels of HHV-8. The final type is endemic African Kaposi sarcoma, the most widespread form of the disease.

Clinically, it is very similar to the classical form, but may be more locally invasive. Also it is often associated with HIV-related Kaposi sarcoma, which is prevalent in many parts of Africa. It is very important to note that all four types of KS have a common histology. Under the microscope, the only distinct differences between them are their distribution and their tropisms for different organs.

Otherwise, they are virtually indistinguishable.

The progression of the classical form can be mapped.

Initial signs of Kaposi sarcoma are visible lesions on the skin. These lesions progress slowly over time, developing into bigger, more vascular nodules. They first start off as prominent, inflammatory components on the skin (quite like a rash), particularly in the lower body. If a biopsy was to be carried out, inflammatory cells such as T lymphocytes, B lymphocytes, monocytes and macrophages would be found alongside the tumour cells. Over time, the lesion develops into a plaque like form, where it becomes elevated, indurated and oedematous. They then evolve into nodules, which are dome shaped masses. They are distinctly coloured red and purple, indicating regions of angiogenesis (the formation of new blood vessels to supply the cancerous cells with nutri-

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ents).

References:

AIDS-related Kaposi sarcoma results in dozen more lesions forming, often across the entire body. A biopsy would, however, show that the two types of lesions are indifferent. The worst case scenario that could happen to a sufferer is if the cancer were to disseminate. Metastasis often results in the spread of the tumour to the lungs (visceral involvement), or to the gastrointestinal tract. As aforementioned, KS on its own is an indolent disease, meaning people can live with it. A popular phrase in medicine used to describe this is: “KS is something one dies with, not of”. However, once the tumour spreads to vital organs, and starts to proliferate, it causes a plethora of serious problems, which will inevitably cause death.

http://journals.plos.org/plospathogens/article/file? id=10.1371/journal.ppat.1004581&type=printable

Kaposi sarcoma is a very atypical sarcoma. KS tumours are not monotonous, but rather are made up of a diverse community of cell types. A typical KS tumour consists of: spindle cells, which are of endothelial origin (as they express CD34 and CD31 markers, and are heterogeneous), inflammatory cells (such as phagocytes and lymphocytes), and neovascular spaces caused by the widespread angiogenesis. Below is a photomicrograph of a skin lesion.

This photomicrograph shows that KS occurs below the surface of the skin (epithelial cells are unaffected). KS affects the dermis, particularly the connective tissue.

The red pigmentation shows the presence of many red blood cells in newly formed blood vessels (angiogenesis).

So how does KS actually occur? Kaposi sarcoma occurs when HHV-8 viruses come into contact with the endothelial cells of lymphatic vessels. The virus brings genetic information into these which causes them to divide uncontrollably by mitosis. This eventually results in the formation tumours/lesions.

KS can be diagnosed in several ways. Firstly, any distinct lesion present on the skin will be a tell-tale sign that the patient has Kaposi Sarcoma. The most common way of diagnosing KS is via a biopsy, which is almost always correct. Since KS may affect the pulmonary vessels and the lungs, bronchoscopy can be used to detect respiratory symptoms caused. Likewise, endoscopy can be carried out to detect gastrointestinal problems caused

by KS. Computerised tomography scans (CT scans) and magnetic resonance imaging (MRI) may also be used if the cancer disseminates to parts such as the lymph nodes.

Regular methods of treating KS includes the typical cancer treatments: surgical removal, chemotherapy and radiotherapy. Another form of treating KS is through cryotherapy (freezing off the lesions). For those suffering from transplant-related KS, adjusting the concentrations of immunosuppressant drugs taken will allow time for the immune system to recover following surgery, ensuring that the HHV-8 virus is not activated. Moreover antiretroviral therapy is another option.

Recent research has found new ways of treating KS. Scientists at the University of Leeds have recently identified a human protein which may control replication of the virus, and therefore control the spread of the cancer. They explained that if they could find a compound which blocked the function of the protein, then this may offer a strategy to treat the disease. Through testing various molecular targeted drugs in virtual high throughput screening, excitingly the scientists found a drug that exactly attaches to the virus. The compound is now being optimised to improve its effect against the virus and to reduce the potential for side effects, with the aim of developing a drug which can be used therapeutically in humans.

https://en.wikipedia.org/wiki/Kaposi's_sarcoma http://www.nhs.uk/Conditions/Kaposis-sarcoma/Pages/ Introduction.aspx https://www.youtube.com/watch?v=D7J9dm1d3dQ http://www.pathologyoutlines.com/topic/ lymphnodesks.html https://www.cancer.org/cancer/kaposi-sarcoma/causesrisks-prevention/what-causes.html

https://www.youtube.com/watch?v=wtROBwDeHJ4

https://www.futurelearn.com/

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Autosomal Recessive Proximal Spinal Muscular Atrophy Part 1/2: The Background and Cause

By Abhijeet Neeti Spinal muscular atrophy (SMA) is an autosomal recessive muscular disease that is very common, second only after cystic fibrosis. It results in the loss of motor neurones and progressive muscle wasting. The phrase ‘autosomal recessive’ means that the disease is transferred only if both the parents have the defective gene (the SMN1 ‘survivor motor neurone gene’) and it is not carried in an allosome (which is another name for sex chromosome).

It has an incidence rate of around 1 in 7500 [1] (the frequency of those who are carriers is around 1 in 50 [2]), classifying it as a rare disease as the prevalence rate is lower than 1 in 2000 [3]. Although SMA is hereditary, it can appear ‘de novo’ (i.e., without any hereditary causes) in around 2-4% of cases. SMA is categorised into 4 types, with the prognosis of the first type usually being death in the first year of the sufferer’s life, and no mortality, but mild to severe disability for the chronic and later onset forms.

Firstly, a distinction between atrophy and dystrophy must be made to fully understand SMA. Dystrophy is a wasting in the muscle tissue, without any visible loss in the mass of the muscle itself, meaning the problem is more deeply rooted in the muscle, affecting things like the production of essential muscle proteins (like dystrophin). Atrophy is muscle wasting as a result of loss of tissue due to a prolonged non-use of the muscle (even for a few days) or another neurogenic reason. Non-use can occur to those who are bedridden, those who work in zero gravity environments like astronauts etc. Neurogenic atrophy happens when there is injury to the nerve supplying a set of muscles, so the atrophy is seen in that group of muscles [4], as they cannot be used. Spinal muscular atrophy is a form of neurogenic atrophy where the muscle cannot be used due to a loss of function to the motor neurones.

Symptoms of SMA can include hypotonia associated with areflexia/hyporeflexia (loss of/decreased reflexes), especially in the extremities and a difficulty in achieving physical developmental milestones like standing, sitting, walking etc., a bell shaped torso (caused by using only abdominal muscles for respiration, on the left). Also, an electromyogram will show fibrillation and muscle denervation and the serum creatine kinase may be increased in those with SMA. However, many similar diseases do exist and it can be hard to differentiate between them, so doctors look for ‘differentiating symptoms’ and confirmation of an SMA diagnosis can only happen through genetic testing for bi-allelic deletion of exon 7 of the SMN1 gene. Carriers do not present any symptoms of SMA or other diseases, so SMA cannot be predicted unless the parents know that they are carriers. They can undergo carrier analysis using a blood or saliva sample and the American College of Obstetricians and Gynecol-

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ogists recommends all people thinking of becoming pregnant be tested to see if they are a carrier. Prenatal testing for SMA is possible through chorionic villus sampling, cell-free foetal DNA analysis and other methods and preimplantation genetic diagnosis can be used to screen for SMA-affected embryos during in-vitro fertilisation. However, routine prenatal/neonatal screening for SMA is ethically controversial, because the disease is so severe. A cost of $5,000,000 per case can be averted if the population is not screened. On the other hand, it can be argued that SMA meets all the required criteria for screening programs and that the testing should be administered to all couples.

The cause of this disease is found out to be a deletion mutation in the 7th exon of the SMN1 gene [5] (which is near the telomere), meaning that the survival of the motor neurone protein cannot be properly made and the death of motor neurone occurs. Another gene, SMN2 also exists, but only 10%-20% of the required SMN protein is produced viably as there is a variation in a single nucleotide. As a result of cytosine being thymine, the other 80%-90% of SMN protein formed (a truncated protein compound SMNΔ7) by SMN2 rapidly degrades in the cell [7]. This deletion mutation occurs as a result of an error in RNA splicing and that particular exon is read as an intron and is removed [6]. The SMN1 gene is therefore unable to correctly code the SMN protein and not enough is made (even when including the SMN protein produced by the SMN2 gene) for the survival of enough motor neurones.

The reduced amount of the SMN protein leads to the gradual death of motor neurones and there will be a progressive wasting of muscle (atrophy). This is because decreased impulse transmission through the dying motor neurons leads to decreased contractile activity of the denervated muscle. Proximal muscles are usually more affected to a greater degree than distal ones, although the cause of this is generally unknown. The severity of the disease, then, relies on the amount of SMN protein present. For those with SMA therefore, severity is related to how well the remaining SMN2 genes can make up for the loss of function of SMN1. As the number of copies of SMN2 present increases, the severity of SMA decreases. However, the correlation between symptom severity and SMN2 copy number is not absolute; there seems to exist other factors affecting the disease phenotype [8].

The prognosis of those with SMA, especially the more severe types isn’t very good. Those with Type 0/1 do not survive until the age of 4, recurrent respiratory problems being the primary cause of death [9]. Those with Type 2 die before 20 and those with Types 3 and 4, although usually not having a decreased life expectancy; their mobility will be decreased, with the disability being mild to severe, again depending upon each individual case.

This article has only discussed the background, cause of SMA and diagnosis/prognosis. In the next part, we will be discussing treatment, management and further research.

References: [1] Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB: Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002, 110: 301-07.

10.1002/ajmg.10425.

[2] Prior TW, Snyder PJ, Rink BD, Pearl DK, Pyatt RE, Mihal DC, Conlan T, Schmalz B, Montgomery L, Ziegler K, Noonan C, Hashimoto S, Garner S: Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A. 2010, 152A: 1605-1607. 10.1002/ajmg.a.33519.

[3] Alliance, G. (2016) What is a rare disease? Available at: http://www.raredisease.org.uk/what-is-a-raredisease/ (Accessed: 4 March 2017).

[4] Rachita (2014) Difference between atrophy and dystrophy. Available at: http:// www.differencebetween.net/science/health/diseasehealth/difference-between-atrophy-and-dystrophy/ (Accessed: 5 March 2017).

[5] Brzustowicz, L. M.; Lehner, T.; Castilla, L. H.; Penchaszadeh, G. K.; Wilhelmsen, K. C.; Daniels, R.; Davies, K. E.; Leppert, M.; Ziter, F.; Wood, D.; Dubowitz, V.; Zerres, K.; Hausmanowa-Petrusewicz, I.; Ott, J.; Munsat, T. L.; Gilliam, T. C. (1990). "Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3". Nature. 344 (6266): 540–541.

[6] ColdSpringHarborLaboratory (2016) SMA and the drug that fights it, explained. Available at: https:// www.youtube.com/watch?v=YLluIVwg_y4&t=67s (Accessed: 5 March 2017). (6.1 – 2.10, [7] Spinal muscular atrophy (2017) in Wikipedia. Available at: https://en.wikipedia.org/wiki/ Spinal_muscular_atrophy (Accessed: 5 March 2017).

[8] Jędrzejowska, M.; Milewski, M.; Zimowski, J.; Borkowska, J.; Kostera-Pruszczyk, A.; Sielska, D.; Jurek, M.; Hausmanowa-Petrusewicz, I. (2009). "Phenotype modifiers of spinal muscular atrophy: The number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease". Acta Biochimica Polonica.

[9] Yuan, N.; Wang, C. H.; Trela, A.; Albanese, C. T. (2007). "Laparoscopic Nissen Fundoplication During Gastrostomy Tube Placement and Noninvasive Ventilation May Improve Survival in Type I and Severe Type II Spinal Muscular Atrophy". Journal of Child Neurology.

Images Available at: http://www.in.gov/isdh/files/ Autosomal_recessive_inheritance.jpg (Accessed: 5 March 2017).

Available at: http://ehealthwall.com/wp-content/ uploads/2012/03/Spinal-Muscular-Atrophy-images.jpg

Cardiac Septal Defects fied using a stethoscope as a splitting S2 sound.

References:

The ASD has the potential to become extremely dangerous if an embolus (maybe broken off from a clot if the person has deep vein thrombosis) and travels through the defect and be caught up within the systemic circuit and lodge in the brain (and cause a stroke) or a coronary artery (and cause cardiac arrest). This is called a paradoxical embolism due to the fact that the embolus begins in the right side and travels to the left.

The University of Nottingham (no date) The S wave sinus rhythm - normal function of the heart - Cardiology teaching package - practice learning - division of nursing - the university of Nottingham. Available at: http:// www.nottingham.ac.uk/nursing/practice/resources/ cardiology/function/s_wave.php (Accessed: 5 February 2017).

By Abhijeet Neeti

VSD - Ventricular Septal Defect

A septal defect is abnormality in the heart that means the sufferer has an opening or a hole in the septum (the wall that separates the left and right side of the heart).

The two major septal defects that will be discussed in this article are the Ventricular Septal Defect (VSD) and the Atrial Septal Defect (ASD) which account for more than 30% of all congenital heart defects. Quite intuitively, they involve defects in the ventricular septum and the atrial septum, respectively.

Firstly, to understand how the conditions above arise, we need to firstly need to understand how the development of the heart occurs. In the heart of the human embryo there is a subset of cells that play a vital role in the development of the septa, between both the atrial and ventricular chambers of the heart, called the endocardial cushions that are in the central portion of the heart. They also give rise to the heart valves and form a proper functioning four chambered heart.

During development, a muscular ridge begins to form from the apex of the heart growing upwards to form the lower part of the ventricular septum. Meanwhile, a membranous region forms from the endocardial cushions (similar to the above), growing downwards, likewise, forming the upper part of the ventricular septum.

In healthy development, these close and form a sealed wall, but in VSD, the two growths don’t fuse, leaving a hole.

ASD – Atrial Septal Defect In the atria, a tissue called the ‘septum primum’ is formed, growing downwards, towards the endocardial cushions, from the top of the heart, slowly creating two distinct chambers (the left and right atria). The hole that exists between the septum primum and the endocardial cushions is called the ‘ostium primum’. In a regular, healthy heart, this is ‘ostium’ (hole) is closed when the septum primum fuses with the endocardial cushions.

While this happens, another hole, the ‘ostium secundum’ forms in the upper region of the atrial septum.

Then, another septum, the ‘septum secundum’ is formed, to the right of the septum firstum, covering the ostium primum. Another opening is formed, called the foramen ovale (right). This acts as a valve to allow blood to flow one way from the right atrium to the left atrium.

This is not harmful however as before birth, oxygenated blood from the placenta from the umbilical vein can bypass the pulmonary circulation and move directly to the systemic circulation, providing oxygen to the body of the foetus.

During the development, the septum secundum and the septum primum fuse together, closing the foramen ovale, creating the full, healthy atrial septum. However, in the case of ASD (Atrial Septal Defects), the fusing shut action doesn’t occur, leaving the ostium secundum (90% of cases) or the ostium primum (10% of the cases) open, allowing blood to pass between the septum. As there is normally higher blood pressure in the left side of the atrium, the blood ‘shunts’ to the right atrium, mixing with the deoxygenated blood. This is called an acyanotic heart defect and the extra volume of blood in the pulmonic circulation leads to a delayed pulmonary valve closure (relative to the aortic valve), which can be identi-

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The oxygenated blood flow, due the defect, shunts from the left ventricle to the right ventricle (flowing from high to low pressure) and can be heard as a ‘holosystolic murmur, at the lower left sternal border’. The severities of the symptoms of a VSD tend to correlate positively with the size of the defect. This again (similar to ASD) can cause an increase in the blood volume of the pulmonic circulation, causing higher pressure there. This could lead to pulmonic hypertension which has various symptoms such as shortness of breath, dizziness, leg swelling, fainting and many others. In some extreme cases, the blood flow can be from the right the left, a condition known as Eisenmenger syndrome. Eisenmenger syndrome is incredibly dangerous, most people with a pressure differential small enough to reverse the shunt have an incredibly high mortality rate post treatment. This can mean less blood is being getting the rest of the body, leading to cyanosis. Cyanotic heart defects involve deoxygenated blood mixing with the oxygenated blood in the left side of the body and enter the systemic circulation. The can cause a bluish (cyan) tinge to the skin, especially around the lips and fingertips. The heart will also need to pump much faster to deliver the same amount of oxygen, which could lead to valve stenosis, decreased lifespan due to earlier heart failure and the feeling of dizziness and tiredness when completing simple tasks.

Causes and Treatment Although a lot is still misunderstood about what exactly causes septal defects, but some factors which have shown to increase occurrence include: Fetal alcohol syndrome, Downs Syndrome, Other cardiac deformities and defects, Holt–Oram syndrome. A common method is the catheter procedure, in which where the doctor inserts a thin flexible tube into a vein in the groin. The umbrella-like device on it reaches the septum and the device is pushed out of the catheter and positioned so that it plugs the hole between the chambers, closing up the hole. A recent (post early 1990s) common method to fix these septal defects is surgical closure of an ASD involving the opening up at least one atrium and closing the defect with a patch under direct visualisation. The prognosis is usually better with surgical treatment.

Atrial septal defect (2016) in Wikipedia. Available at: https://en.wikipedia.org/wiki/Atrial_septal_defect (Accessed: 5 February 2017).

CHD-UK, 2017 (2007) Ventricular Septal defect (VSD).

Available at: http://www.chd-uk.co.uk/types-of-chd-and -operations/ventral-septal-defect-vsd/ (Accessed: 5 February 2017). syndrome, H.-O., Reference, G.H. and Health, N.I. of (2017) ‘Holt–Oram syndrome’, in Wikipedia. Available at: https://en.wikipedia.org/wiki/Holt%E2%80% 93Oram_syndrome (Accessed: 5 February 2017).

Pathophysiology, O. (no date) Cardiac Septal Defects.

Available at: https://www.youtube.com/channel/ UCNI0qOojpkhsUtaQ4_2NUhQ (Accessed: 5 February 2017).

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COPD become inflamed and be invaded by inflammatory cells.

As the disease progresses, the inflammation is replaced by scarring and constriction of the airways.

(Figure 2: An overview of the pathophysiology of COPD.)

Pharmacological management of COPD starts with the use of inhaled bronchodilators, which act to widen the bronchi and bronchioles. There are two types of bronchodilators: beta-2 agonists and anticholinergics. Beta-2 agonists activate beta-2 adrenergic receptors to relax the smooth muscles in the lungs. Both bronchodilators are available in long- and short-acting forms. Another form of treatment which also reduces the frequency and severity of exacerbations are corticosteroids. However, these are less commonly used as they are known to cause side-effects such as non-fatal pneumonia. Pneumococcal and annual influenza vaccinations should also be offered to every patient with COPD, as they are more vulnerable to infections and diseases such as pneumonia, sepsis and meningitis.

By Neil Narayan Introduction Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease commonly characterised by breathing difficulties. The disease affects an estimated 3 million people in the UK and is prominent around the world, with as many as 329 million cases. The two main types of COPD are chronic bronchitis and emphysema.

Signs & Symptoms The usual symptoms include dyspnoea (difficulty breathing) in addition to a chronic, productive cough. This cough is identified by sputum (mucus) production and persists for at least 3 months over a 2-year period.

Patients also experience frequent wheezing and tightness in the chest. As the disease progresses, individuals are seen to adopt a ‘tripod position’ (Figure 1). This is where the person leans forward and supports their upper body by placing their hands on their knees. COPD patients can experience a sudden deterioration of their symptoms: worsening cough, increased sputum production and shortness of breath. This is referred to as an acute exacerbation of COPD. (Figure 1: The tripod position) Risk Factors The risk factors of COPD can be largely divided into two groups: environmental and genetic. The major risk factor for COPD is cigarette smoking.

Approximately one fifth of people who smoke will go onto develop COPD whilst the figures are higher for lifetime smokers. In the UK and America, 80-95% of patients with the disease are current or former smokers. Other environmental factors include economic deprivation and the use of cooking and heating equipments that utilise coal, wood and animal dung. People working in the mining industry are exposed to high levels of dust and fumes and have a higher chance of developing the condition. Genetics also has a role in the onset of COPD. It has been shown that alpha1 antitrypsin (A1AT) deficiency can cause COPD. This is because A1AT normally inhibits the enzyme elastase. A deficiency in A1AT results in the breakdown of elastin, a major protein in the connective tissue of lungs.

Pathophysiology In COPD there is chronic, irreversible airflow obstruction.

This arises due to constriction of the small airways (chronic bronchitis) and damage to the lung parenchyma (Figure 2), better known as emphysema. Emphysema affects the elasticity of the airways and damages to the lung tissue results in air trapping. The most common pathological observation seen in COPD is an increase in the number of mucus-producing goblet cells in the lining of the airways. The bronchi also have the capacity to

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symptoms and improve overall exercise tolerance.

Counselling has also been shown to have beneficial results and helped patients in managing their day-to-day lives and psychological conditions, such as anxiety and depression, that can arise secondary to COPD.

Diagnosis COPD is diagnosed in patients who present with the symptoms mentioned above and have risk factors for the condition. After the patient is given bronchodilators to widen the airways, a spirometer is used to confirm the diagnosis. Spirometry measures two parameters: FEV1 (forced expiratory volume in one second): the largest volume of air expelled in one second FVC (forced vital capacity): the total volume of air expelled These two measurements can be used to calculate the FEV1/FVC ratio. A ratio below 70% together with symptoms confirms the diagnosis.

A chest x-ray can be invaluable in disregarding other possible diagnoses such as pneumonia and pulmonary oedema. In patients with advanced COPD, the x-ray may show a flattened diaphragm and abnormal air collections within the lung which are called bullae. Finally a full blood count (FBC) can be used to diagnose conditions that give rise to similar symptoms including polycythaemia (high concentration of red blood cells) and anaemia (low haemoglobin in the blood).

Management

Severe cases of COPD may require surgery including lung transplantation and lung volume reduction surgery. The latter technique involves removing parts of the lung most damaged by emphysema. As a result, less air is trapped within the chest, the diaphragm is allowed to relax and patients experience more comfortable breathing.

In conclusion, COPD is a leading cause of mortality that is associated with other conditions such as diabetes, heart disease and cancer. The condition has economical, financial and social implications. In spite of this, research is being conducted with the aims to improve current therapies whilst also exploring novel approaches such as stem cells.

References: http://www.nhs.uk/Conditions/Chronic-obstructivepulmonary-disease/Pages/Introduction.aspx http://www.nhs.uk/Conditions/Chronic-obstructivepulmonary-disease/Pages/Diagnosis.aspx https://en.wikipedia.org/wiki/ Chronic_obstructive_pulmonary_disease https://biology-forums.com/index.php? action=gallery;sa=view;id=8024

Although there is currently no cure for COPD and no medications which decisively inhibit the decline of lung function, there are still a number of measures that doctors use to treat symptoms and delay disease progression. Management of COPD can be divided into three groups: conservative, medical and surgical.

https://en.wikipedia.org/wiki/ Acute_exacerbation_of_chronic_obstructive_pulmonary _disease

Minimising exposure to risk factors is the main target in the prevention and treatment of COPD. As smoking is the most pertinent risk factor of COPD, patients are strongly urged to quit smoking. Government policies and smoking cessation campaigns have been influential in persuading people to desist from smoking. The use of nicotine replacement therapy and other medications such as bupropion can also increase chances of longterm abstinence from smoking. It has been recommended that an overall reduction in contact with noxious fumes, gases and dusts as well as air pollutants may improve indoor and outdoor air quality. However, this goal is difficult to achieve in developing countries.

Increased industrialisation plus poorly ventilated cooking and heating equipment has led to higher levels of air pollution. Another conservative measure of treatment involves exercise and regular physical activity, which has been shown to minimise the number of acute exacerbations and reduce length of stay in hospital. It is part of a broader therapeutic measure known as pulmonary rehabilitation. The aims of this therapy are to reduce

Kumar & Clark’s Clinical Medicine: 8th Edition, pg. 812816

https://en.wikipedia.org/wiki/Alpha_1antitrypsin_deficiency

http://www.webmd.com/lung/copd/chest-x-rays-forchronic-obstructive-pulmonary-disease-copd http://www.atsjournals.org/doi/full/10.1164/ ajrccm.163.5.2101039 https://www.nice.org.uk/guidance/CG101/chapter/1Guidance#diagnosing-copd https://en.wikipedia.org/wiki/Pneumococcal_vaccine https://www.blf.org.uk/support-for-you/copd/ treatment/surgery https://en.wikipedia.org/wiki/Pulmonary_rehabilitation

Pneumonia term heart, lung and kidney diseases are also more likely to contract the disease. Poor lifestyle choices such as smoking or drinking alcohol excessively can make a huge negative impact on the lungs. Furthermore, immunodeficiency caused by HIV or treatment involving immunosuppressant drugs is a prominent factor as the human body becomes vulnerable to infections. A less common factor involves people with cancer, who may get pneumonia as chemotherapy treatment may cause inflammation of the lungs. Viral pneumonia is most likely to occur in cold weather as this is when influenza spreads more easily (BLF, 2016).

By Neil Narayan ABSTRACT Pneumonia is an infection of the lung tissue, causing an inflammatory response in one or both of the lungs inside the body. The response refers to the inflammation of alveoli, which are filled with fluid and causes difficulty in breathing. It is one of the leading causes of death worldwide. In the UK, approximately 5 to 11 out of every 1,000 individuals get the disease annually (BLF, 2016).

CLASSIFICATION The disease in question is firstly classified by location: community-acquired (CAP) or hospital-acquired. CAP occurs in people who have not been in hospital recently and is the most common type of pneumonia. Many cases of this type of the disease are bacterial and involve the interaction of Streptococcus pneumoniae and Haemophilus influenzae. Hospital-acquired pneumonia develops during (or straight after) a hospital stay while being treated for another condition or having a procedure. A subsection of this type of disease is ventilatorassociated pneumonia (VAP). This occurs in patients in the intensive care unit (ICU) who are put on a mechanical ventilator. Pneumonia develops because bacteria are able to flow freely through the endotracheal tube.

Classification then occurs by the cause of the disease.

This can be chemical pneumonia, where one inhales harmful toxicants such as pesticides or aspiration pneumonia. This involves the ‘aspiration’ of foreign objects such as contents from vomiting or even dust. Dust settles on the epithelial lining of the alveoli and prevents the cilia from moving harmful pathogens which may cause pneumonia. Opportunistic pneumonia may develop in people with weakened immune systems (Wikipedia, 2017).

CAUSES Pneumonia is primarily caused by bacterial or viral infection and more rarely by fungi or parasites. There are many types of bacteria which can stimulate the disease but the most typical one is Streptococcus pneumoniae. It causes a pneumococcal infection which, in the case of pneumonia, is invasive as it occurs inside the lungs and is more severe (NHS, 2016). This type of pneumonia generally begins in the lower lobes or posterior segments of the upper lobe of the lungs (Brant and Helms, 2012). It is responsible for 50% of CAP cases. Viral pneumonia is typically brought about by the respiratory syncytial virus (RSV) and sometimes influenza type A or B (NHS, 2016). Viruses reach the lung after a person touches a contaminated object and touches their eyes or nose. They attack the lung parenchyma and alveoli, resulting in an inflammatory immune response. Viral infection could also provide a pathway for bacterial infections, creating co-morbidity, i.e. illnesses occurring together (Wikipedia, 2017).

RISK FACTORS The disease can occur in all age groups but rates are highest in the extremes, i.e. babies and young children as well as elderly people over the age of 65, as they have weaker immune systems and are more susceptible to pneumonia. People who have a medical history of long-

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SIGNS & SYMPTOMS People with pneumonia often have a dry or productive cough (where phlegm is formed). Other very common symptoms include chest pain, dyspnoea (shortness of breath) and a fever. The chest pain becomes worse as one breathes or coughs, as patients may feel sharp or stabbing pains, while breathlessness causes the person to develop more rapid and shallow breathing even at rest. Fever occurs at a temperature of 38oC with sweating and shivering after a feeling of coldness, chills (NHS, 2016). As a result, the person may present with a higher respiratory rate and a high heart rate on examination by a doctor (Hoare, 2006). Less common symptoms involve haemoptysis, the act of coughing up blood, and wheezing, again showing the discomfort and difficulty in breathing that is experienced. The general wellbeing of the patient deteriorates, as they may lose their appetite, feel nauseated and in some extremes, vomiting might occur. As the patient develops a productive cough, they may also feel fatigued with pain in their muscles and joints. Sometimes patients start to have headaches and feel confused or disorientated as a secondary symptom, particularly elderly people (NHS, 2016).

DIAGNOSIS Diagnosis generally involves a combination of a physical examination and a chest X-ray, which is only used for severe cases. The former involves the doctor asking about the patient’s symptoms and examining their chest. Usually, the doctor will perform auscultation, i.e. listen to the chest with a stethoscope (Wikipedia, 2017).

For a person with the disease, there may be cracking and rattling sounds when breathing in as well as harsh breath sounds indicating bronchial breathing. Percussion on the chest is done and the sign for pneumonia is a dull sound. This occurs because the lung full of fluid produces a different sound to a normal, healthy lung (NHS, 2016). A chest radiograph is carried out when the person is hospitalised, within 4 hours, according to NICE guidelines. There are a few certain patterns on the X-ray that can classify different types of pneumonia based on the location and extent of the effect of the disease. The first is lobar pneumonia, where several opacities are seen, indicating that inflammation has spread through the entire lobe of the lung. Bronchopneumonia is the most common presentation where inflammation is focused around lobular bronchi. This inflammation forms a ‘patchwork quilt’ appearance as normal and diseased lobules are interwoven (Brant and Helms, 2012). For patients who do not respond to treatment and thus have quite a high severity of pneumonia, microbiological tests can be carried out to plan the net course of action. This involves taking blood and sputum cultures, which are both indicators of a productive cough. The doctor may also consider urinary tests which detect antigens for Legionella and Streptococcus pneumonia (NICE, 2014).

PREVENTION/MANAGEMENT There are many preventative measures a person with pneumonia can take to reduce symptoms. The most effective of these are vaccinations, especially the pneumococcal vaccine and the influenza vaccine. Vaccina-

tions have been strongly recommended to people most at risk of getting the disease, i.e. children under the age of 5 and elderly people over the age of 65. Environmental solutions involve smoking cessation and improving indoor air quality in order to reduce the risk of aspiration and pneumococcal forms of the disease. Hand hygiene and covering one’s mouth when coughing are extremely important to stop spread of the disease (NHS, 2016).

People with mild pneumonia generally require minimal treatment. Nevertheless, one needs to rest, drink ample fluids, and take oral antibiotics and analgesics (painkillers) such as paracetamol or ibuprofen (NHS, 2014). For low severity community-acquired pneumonia, a five-day course of antibiotic therapy is needed. Antibiotics are the first line of treatment in managing bacterial pneumonia, where amoxicillin is given to treat CAP (NICE, 2014). They are also used to treat aspiration pneumonia and the foreign object inhaled has to be removed. Stronger and more effective antibiotics such as fluoroquinolones are given for cases of hospital-acquired pneumonia. This is because the forms of bacteria causing the disease are drug-resistant. Neuraminidase inhibitors including oseltamivir may be given to treat viral infections by the influenza virus. They work by preventing viral reproduction (Wikipedia, 2017).

References BLF, (2016). Pneumonia. [online] British Lung Foundation.

Available at: https://www.blf.org.uk/support-foryou/pneumonia [Accessed 5 Mar. 2017].

Brant, W. and Helms, C. (2012). Fundamentals of Diagnostic Radiology. 4th ed. Philadelphia: Wolters Kluwer, p.435.

Hoare, Z. (2006). Pneumonia: update on diagnosis and management. BMJ, 332(7549), pp.1077-1079.

Medscape, (2015). Image in a 49-year-old woman with pneumococcal pneumonia. The chest radiograph reveals a left lower lobe opacity with pleural effusion.. [image] Available at: http:// emedicine.medscape.com/article/360090-overview [Accessed 5 Mar. 2017].

NHS, (2014). Pneumococcal infections - NHS Choices. [online] Nhs.uk. Available at: http://www.nhs.uk/ conditions/Pneumococcal-infections/Pages/ Introduction.aspx [Accessed 5 Mar. 2017].

NHS, (2016). Pneumonia - NHS Choices. [online] Nhs.uk.

Available at: http://www.nhs.uk/Conditions/ Pneumonia/Pages/Introduction.aspx [Accessed 5 Mar. 2017].

NHS, (2016). Pneumonia - Treatment - NHS Choices. [online] Nhs.uk. Available at: http://www.nhs.uk/ Conditions/Pneumonia/Pages/Treatment.aspx [Accessed 5 Mar. 2017].

NICE, (2014). Pneumonia in adults: diagnosis and management | Key-priorities-for-implementation | Guidance and guidelines | NICE. [online] Nice.org.uk.

Available at: https://www.nice.org.uk/guidance/ cg191/chapter/Key-priorities-for-implementation [Accessed 5 Mar. 2017].

NICE, (2014). Pneumonia in adults: diagnosis and management | 1-Recommendations | Guidance and guidelines | NICE. [online] Nice.org.uk. Available at: https://www.nice.org.uk/guidance/cg191/ chapter/1-Recommendations [Accessed 5 Mar. 2017].

NIH, (2016). Lobar bacterial pneumonia. This figure shows pneumonia affecting the single lower lobe of the left lung. Figure A shows the location of the lungs and airways in the body. Figure B shows normal alveoli. Figure C shows infected alveoli or air sacs.. [image] Available at: https://www.nhlbi.nih.gov/ health/health-topics/topics/pnu/causes [Accessed 5 Mar. 2017].

Wikipedia, (2017). Classification of pneumonia. [online] En.wikipedia.org. Available at: https:// en.wikipedia.org/wiki/Classification_of_pneumonia [Accessed 5 Mar. 2017].

Wikipedia, (2017). Pneumonia. [online] En.wikipedia.org.

Available at: https://en.wikipedia.org/wiki/ Pneumonia [Accessed 5 Mar. 2017].

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Hydrocephalus cephalus”.(5)

By Denis Efovi Hydrocephalus is a condition characterised by excessive cerebrospinal fluid (CSF) buildup in the brain. The excessive accumulation of CSF results in an abnormal widening of the lateral ventricles present on each hemisphere of the brain. This widening creates potentially harmful pressure buildup within the cranium, which can lead to intracranial hematoma, cerebral oedema, crushed brain tissue or herniation.(1) The cerebral ventricular system is a set of four interconnected cavities (ventricles) in the brain, where cerebrospinal fluid is produced. Each ventricle contains a region of choroid plexus, an arrangement of ependymal cells involved in the production of CSF. The ventricular system is connected to the central canal of the spinal cord, in order to allow for proper fluid drainage.(2) Hydrocephalus arises when the ventricular system is blocked or fluid drainage is impaired by a range of causes.

There are three types of hydrocephalus: acquired, congenital and normal pressure hydrocephalus (NPH).

Regardless of the type, the condition is diagnosed by using ultrasonography, CT, MRI, or pressure-monitoring techniques.

Acquired hydrocephalus occurs when the condition manifests itself after birth; usually caused by a tumour, injury or disease which blocks the original path of CSF in the brain. One of the most common causes is aqueductal stenosis (3), a form of non-communicating hydrocephalus. The cerebral aqueduct is part of the Sylvius, a narrow tube connecting the third ventricle to the fourth ventricle. Since the Sylvius is naturally thin, CSF flow can be easily blocked by blood following a haemorrhagic stroke. This, paired with the continuous CSF production causes the excess fluid to be redirected to the lateral ventricles, which leads to an increase in pressure of CSF against the brain tissue. Communicating hydrocephalus is caused by impairment of resorption of CSF into the venous system, unlike non-communicating hydrocephalus which is as a result of direct obstruction. Symptoms associated with acquired hydrocephalus include: headaches, neck pain, nausea, vomiting, drowsiness and confusion.

Another type of hydrocephalus, which occurs at birth, is congenital hydrocephalus. The increased pressure can be very detrimental to the infant’s brain tissues as it could cause permanent physical or mental damage. It is caused similarly to acquired hydrocephalus, by blockage of the ventricles concerned with the correct resorption of CSF. This form of hydrocephalus can occur from genetic defects as well as other conditions such as spina bifida (undeveloped spine). Congenital hydrocephalus occurs once per 1000 infants born, which makes it as common as Down’s syndrome.(4) Normal pressure hydrocephalus was first theorised by Hakim in 1964. Upon performing autopsies on patients whom had died from central nervous system neurodegenerative diseases, such as Alzheimer’s; he observed that in many cases the cerebral ventricles were enlarged without the destruction of the brain cortex. When he found a 16-year-old living patient with this unknown condition, he described it as “normal pressure hydro-

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Prevalent in the elderly, normal pressure hydrocephalus is also the buildup of cerebrospinal fluid, which is associated with a gradually degenerative disorder. The classic triad is composed of abnormal gait, urinary incontinence and dementia. 50% of cases have no prior cause (idiopathic NPH), while the rest may be secondary to head injuries, meningitis or subarachnoid haemorrhage.(5) The abnormal gait is due to the enlarged lateral ventricles distorting the corona radiata in the brain, which affects the manner of walking by interfering with the sacral motor fibers. The movement patterns are often confused with Parkinson’s, with the exception being that NPH exhibits less rigid tremors. Urinary incontinence appears later on in most individuals and can lead on to become bowel incontinence. Dementia derived from normal pressure hydrocephalus accounts for 6% of all dementia cases and is due to traction on the frontal and limbic fibers by the enlarged lateral ventricles, the traction causes a distortion of the periventricular system which leads on to frontal lobe dementia (predominantly).(7)(8) Symptoms include slow cognitive function and physical movement and a lack of attention or concentration. In these cases, dementia progress at a slower rate when compared to Alzheimer’s.

Due to the lack of medical therapies for hydrocephalus, the most effective treatment is surgery. One type of surgery is shunt implantation. Also known as CSF diversion devices, shunts are long, silicone tubes, with valves attached, which divert excess CSF in the ventricles or the subarachnoid spaces around the brain to another part of the body where it can be safely absorbed. This creates an alternative route for the cerebrospinal fluid, which is constantly being produced, therefore preventing buildup in one area. This usually restores physiological balance between CSF production, flow and absorption when one of these functions has been impaired. Valves are also present in the shunt to maintain a regular drainage rate and to keep the flow unidirectional. For example, to prevent over-drainage when a person stands up, the valve opens when the pressure difference across the valve exceeds the valve’s opening pressure.(9) An alternative surgical procedure, mainly carried out on patients with non-communicating hydrocephalus is endoscopic third ventriculostomy (ETV). It involves the surgeon creating an opening in the floor of the third ventricle using an endoscope; which is subsequently inserted through a burr hole. If carried out correctly, the process results in cerebrospinal fluid being diverted to the basal cisterns. The fluid bypasses the obstruction present, relieving the pressure, however, the operation does not prevent future CSF buildup, which makes it an alternative treatment instead of a cure. ETV is preferred in specific cases as shunts may have complications such as blockages and infections which require multiple surgical revisions. (10) Hydrocephalus has been a concern for over 50 years, with no further improvements in the treatment or prevention of it since. This is mainly due to a lack of funding (approximately $1 million provided annually by the National Health Institute) relative to the amount of money spent on treating it annually, which is over $1 billion in the US alone. The current treatments are not very reliable, seeing as over 60% of patients need to be reviewed after the first operation. Hydrocephalus is the main cause of brain surgery in children and 80% of adults remain undiagnosed and untreated, according to a recent study conducted by the Hydrocephalus Association. Conclusively, more research is needed in order to improve reliability of treatments and perhaps even lead to the discovery of a cure.(11)

References: () Hydrocephalus, Available at: https:// www.headway.org.uk/about-brain-injury/ individuals/types-of-brain-injury/ hydrocephalus/.

Crisan, E. () Ventricles of the Brain, Available at: http://emedicine.medscape.com/ article/1923254-overview. () Aqueductal Stenosis, Available at: http:// neurosurgery.ucla.edu/aqueductal-stenosis.

Mohan, S. () Hydrocephalus, Available at: http:// www.slideshare.net/NeurologyKota/normal -pressure-hydrocephalus-39338545.

Sussman, M. () Dr. Salomon Hakim – a Giant in the Field of Hydrocephalus, Available at: http:// www.hydroassoc.org/dr-salomon-hakim-agiant-in-the-field-of-hydrocephalus/.

Younger, D.S. (2005). Adult Normal Pressure Hydrocephalus. In Younger, D.S. (Ed.), Motor Disorders (2nd edition) (pp. 581584). Philadelphia, PA: Lippincott Williams & Wilkins Tidy, C. and Knott, L. () Normal Pressure Hydrocephalus, Available at: http://patient.info/ doctor/normal-pressure-hydrocephalus.

Ropper, A.H. & Samuels, M.A. (2009). Adams and Victor’s Principles of Neurology (9th edition). New York, NY: McGraw-Hill Medical.

The Shunt Book. Drake and St. Rose 1996.

Drake, J. and McLone, D. () Endoscopic Third Ventriculostomy, Available at: http:// www.hydroassoc.org/docs/ FactSheet_Third_Ventricular_Endoscopy.pdf. () Concerns with Hydrocephalus, Available at: http://www.hydroassoc.org/about-us/ newsroom/facts-and-stats-2/.

Transverse Myelitis for some patients (for example those with pacemakers), so doctors may opt for a CT scan with the use of myelography. This is when a dye is injected into the spine and spread along it by tilting the patient up and down.

The dye will then be detected on the CT and give a clearer image of the spinal cord.

By Vith Ketheeswaranathan Transverse myelitis is a neurological disorder, where here is inflammation across the width of one section of the spinal cord. The inflammation may damage the myelin sheath, which is an insulating layer covering nerve cell fibres which in turn disrupts signals sent from the spine to other body parts.

It is common for the first symptoms to be paraesthesia, which is numbness, pins and needles, or heightened sensitivity to temperature and pressure, in the legs. In some cases this can be so severe that patients experience from allodynia, which is great discomfort caused simply by the feeling of clothing. Other symptoms include incontinence, which is the loss of control over the bowel. Any muscle weakness felt in the legs usually quickly evolves into more serious symptoms such as paralysis.

The cause of 60% of TM cases remain unknown, and this is identified as idiopathic transverse myelitis. In the majority of cases, it develops after a viral or bacterial infection, which triggers an autoimmune response. This is when the immune system, instead of attacking and destroying pathogens within the body, mistakenly attack the bodyâ&#x20AC;&#x2122;s own tissue and when this occurs at the spinal cord it may trigger TM. Although the exact cause remains unknown, scientists have suspected viruses such as varicella zoster, influenza, rubella, herpes simplex and many others. Some scientists have also suspected that certain vaccinations may trigger the autoimmune response where the immune system mistakenly attacks the spinal cord instead of the pathogen within the vaccination. It is highly recommended that all patients with TM are also evaluated for multiple sclerosis and neuromyelitis optica, as it could an indication of these disorders, and so the patient will require a different set of treatments.

Transverse Myelitis is a relatively rare disorder, and it is estimated that there are approximately 300 cases in the UK, and 1,400 cases in the U.S per year. It is unbiased in the sense that it can affect anyone in any age range however, there seems to be a high number within the ranges of 10-19 and 30-39.

Diagnosis TM can be either acute (develops over a short period of time), or subacute (develops over a longer period of time). Those with acute transverse myelitis normally go straight to a hospital, and those with subacute transverse myelitis may see a GP, who will then refer them to a neurologist. The first step of the diagnosis is to eliminate other causes and conditions. If a patient presents the symptom of muscle weakness or paraesthesia, conditions which may cause pressure on the spinal cord such as a slipped disk, tumour, abnormal blood vessel collection and stenosis (narrowing of the canal which holds the spinal cord) must be ruled out.

The go-to option in order to detect TM is an MRI. This should indicate any lesions or inflammation present in the spinal cord. However, an MRI may not be an option

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Alternatively, a lumbar puncture procedure is when a needle is inserted between two vertebrae in the lumbar area of the spine. Cerebrospinal fluid, which surrounds the spinal cord, may contain abnormalities such as an increased amount of white blood cells and protein in those with TM, and these can be detected by analysis in a lab. The procedure is known to be painful and so the patient is given a local anaesthetic.

If the doctor is unable to come to a conclusion regarding TM after these tests and procedures but is sure that the patient has TM, then it will be classified as idiopathic transverse myelitis.

Despite there being no successful cure for TM, there are a number of methods used to manage the symptoms and their after effects, as well as coping with the severity of it.

Corticosteroids is the most common cause of treatment, and are prescribed to reduce the inflammation within the spinal cord, as well as suppressing the immune system in order to reduce any further damage. Methylprednisolone is given on a 3-5 day course intravenously and may be followed by an oral course.

When a patient shows no positive response to corticosteroids, they may have to undergo other forms of therapy such as plasma exchange (PLEX), or plasmapheresis. A colourless liquid within the blood, known as plasma, may contain antibodies which are responsible for the damage to the spinal cord and the myelin sheath, as a result of the autoimmune response. PLEX is when the patientâ&#x20AC;&#x2122;s blood is passed through a machine, where centrifugation takes place. This is when the different components of the blood are separated, and the plasma is then replaced with donor plasma meaning these antibodies are no longer within the circulatory system, hence are unable to cause any further damage to the spinal cord.

If a patient is unresponsive to PLEX and corticosteroids, and further inflammation occurs, cyclophosphamide intravenously. This is a very strong immunosuppressant and is used in chemotherapy for the treatment of leukaemia. AN experienced oncology team must be consulted before the administration of such a drug, and the patient should be constantly monitored while theyâ&#x20AC;&#x2122;re immune system is compromised.

One-third of those who have suffered from TM make a full recovery however, a further third may also suffer from long-term effects such as difficulty walking due to muscle weakness, and permanent paraesthesia in the legs. Physiotherapy and rehabilitation have shown to be exceedingly effective during the recovery period when adhered to strictly. As the myelin sheath has the ability to recover from any damage caused, and some parts of the spinal cord may be only temporarily damaged, there is a chance that a patient with acute transverse myelitis may make a very reasonable recovery.

References: https://www.ninds.nih.gov/Disorders/Patient-Caregiver -Education/Fact-Sheets/Transverse-Myelitis-Fact-Sheet https://issuu.com/brainandspinefoundation/docs/ bsf_transverse_myelitis_a5_booklet/4? ff=true&e=1177223/39172753

https://www.hopkinsmedicine.org/ neurology_neurosurgery/centers_clinics/ transverse_myelitis/about-tm/what-is-transversemyelitis.html http://www.myelitis.org.uk/symptoms-anddiagnosis.html

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Mucocutaneous Lymph Node Syndrome heart, which would be irreparable.

By Yunis Fazaldin Kawasaki disease (mucocutaneous lymph node syndrome) was first described by Tomisaku Kawasaki in 1967. It is a vasculitis, an inflammation of blood vessels.

It is an idiopathic, self-limited condition that usually resolves itself within 6-8 weeks, but in 20-25% of cases without treatment, there may be more serious consequences such as aneurysms in the coronary arteries, ischemia of the heart muscles and therefore the possibility of a myocardial infarction.

The disease is thought to occur as the result of a combination of factors such as genetic predisposition, autoimmune reactions and infection, but its cause is not fully known. When the endothelial cells in the blood vessels are damaged, the collagen and tissue factor in the tunica media are exposed. This increases the chance of a thrombus forming due to blood coagulation in the lumen of the vessel. The clot in the artery reduces the blood flow in the vessel. Furthermore, to repair the damaged walls, fibrin builds up on the wall of the vessel allowing platelets to coagulate over the damaged areas. This also reduces the blood flow, and in tandem with a clot forming, could lead to ischemia. Arteries are more likely to be affected, as the pressure in them is higher than that of veins. In addition to clots forming, the weakened walls of the vessel sometimes bulge out as they can no longer withstand the pressure of blood as well as they could prior to the damage to the endothelium. Moreover, considering LaPlace’s Law, as the diameter of the lumen increases, the pressure on the wall increases, leading to further bulging of the cell wall. Therefore, another consequence of the vasculitis is that an aneurysm may form. If the aneurysm was to rupture, the blood flow would decrease drastically, further increasing the chance of ischemia.

The vasculitis in Kawasaki disease mainly affects the coronary arteries. These means that coronary aneurysms form, clots build in the coronary vessels, and the reduced blood flow means there is ischemia of the heart muscles, which leads to a myocardial infarction. These could occur as a result of Kawasaki disease if left untreated, but there are symptoms that could help diagnose the disease.

The symptoms can be remembered with the mnemonic ‘CRASH and burn’. Conjunctivitis may be observed, which is inflammation of the conjunctiva layer on the surface of the eye. The eye may appear red and bloodshot, but the conjunctivitis would be limbus sparing. Patients would have a Rash present, which could present on any part of the body. The rash is initially polymorphous but later desquamates (flakes off). Another symptom is Adenopathy, which is the enlargement of the lymph nodes, especially the cervical lymph nodes (found in the neck). Strawberry tongue is a symptom that means the tongue is very red, swollen, and there are bumps present on the surface of the tongue. In addition, the patient’s Hands and feet may be very red and swollen on the palms and soles, and their hands and feet could have a rash on them. Hence, desquamation would happen on the hands and feet if there is a rash present. If 4 of these 5 symptoms are present, as well as a fever (present for longer than 5 days, the ‘burn’ part), then treatment is started immediately to prevent any damage to the

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Some patients may only have a few of these symptoms.

If the patient has 3 or less of these, they may have atypical or incomplete Kawasaki disease. To ascertain a correct diagnosis, an ESR (Erythrocyte Sedimentation Rate) and a CRP (C-Reactive Protein) would be obtained.

ESR measures the rate at which red blood cells sediment. When there is inflammation, fibrinogen causes red blood cells to stack together to form rouleaux, which sink faster. Therefore, the patients ESR would be elevated (to above 40mm/hour) with Kawasaki disease as it is a vasculitis. CRP is a protein of hepatic origin, which increases in the blood plasma when there is inflammation, so its levels would be elevated to above 3mg/dL. There are also supplemental tabs that may be observed, such as an increase in platelet count or the presence of mononuclear white blood cells in the urine without any evidence of bacteria. An echocardiogram may also be used to see whether aneurysms have formed in the coronary arteries, and if any have been ruptured, blood may collect in the pericardial sac (pericardial effusion).

As the cause of the disease is unknown, and it is a selflimiting disease, treatment is used to prevent cardiac issues and to reassure the diagnosis that the condition was Kawasaki disease (if the medication works). Patients are usually injected with intravenous immunoglobulins (IVIG), but the way they help when given to a patient with Kawasaki disease is unknown. It is thought that the IVIG reduce the likelihood of white blood cells from attaching to activated Kawasaki antibodies that are responsible for the breakdown of the endothelium.

However, the increase in antibodies may mean that more antibodies are removed from the system, both the IVIG antibodies and the Kawasaki antibodies. Another way to treat mucocutaneous lymph node syndrome is by using acetylsalicylic acid (ASA or aspirin). Aspirin inhibits cyclooxygenase, which prevents platelet aggregation and clots forming. However, Kawasaki disease mainly presents in children under 5 years old, and giving aspirin to children means they may develop Reye’s syndrome (encephalopathy and serious liver injury). On the other hand, the Kawasaki disease may lead to a myocardial infarction, so there is a risk taken when giving aspirin to children, and they are monitored very carefully.

Reference: https://www.youtube.com/watch?v=sTyDHTUCw48 http://www.chfed.org.uk/how-we-help/informationservice/heart-conditions/kawasaki-disease/ https://www.khanacademy.org/science/health-andmedicine/circulatory-system-diseases/vasculitis/v/ kawasaki-disease https://www.khanacademy.org/science/health-andmedicine/circulatory-system-diseases/vasculitis/v/ kawasaki-disease-diagnosis-and-treatment https://www.britannica.com/science/fibrin https://www.youtube.com/watch?v=FgcHtmry3iA

Anaesthesia overdosed. Due to the nature of local anaesthetic, the patient often needs to be intubated as the drugs often interfere with breathing, causing the airway in the trachea to close.

By Rajan Patel Anaesthetics are something that we take for granted today: if we need any major surgery we are able to be put to sleep through the painful parts and we’ll barely remember anything when we wake up, but how does anaesthetic work?

Before the mid-1800s, whenever a surgery was necessary the only thing to numb a patient’s pain would have been strong alcohol and opium. Although these substances would have numbed the patient somewhat, it would not have completely eliminated the pain during the operation and the patient would still remember the pain afterwards. Over time anaesthetic has become much more effective at reducing our pain, relaxing our muscles and preventing us from remembering any surgery through combinations of drugs. We now have two primary forms of anaesthetic: local and general anaesthetics.

Local anaesthetics (as the name implies) are applied directly to the point that requires the doctor’s attention.

This type of anaesthetic blocks the nerves that connect the part of the body near the injection site and so prevents any impulses from being sent to or from the brain.

This means that any pain will not be felt as the brain will not register it. Due to its effectiveness in small areas of the body, local anaesthetics such as novocaine are used by dentists when removing a tooth or to perform root canal surgery. Other local anaesthetics are also used to perform epidurals, allowing for more painless childbirth by blocking the nerves at the base of the spinal cord which serve the pelvis.

For major surgery, general anaesthetic is used. This form of anaesthetic is used as it renders the patient completely unconscious and leaves them with no perception of the occurring surgery, however pain will be apparent following the surgery and so often patients are left on some form of pain killer. General anaesthetic also limits the body’s physiological responses, limiting the reaction to surgical cuts and therefore keeping the body’s blood pressure, hormone levels and heart rate constant during the procedure. Early forms of general anaesthesia include chloroform and ether, although these drugs were applied through a cloth soaked in them, providing a very uncontrolled dose to the patient and therefore causing death due to overdosing in some cases. Chloroform was made popular as an anaesthetic after Queen Victoria used it. Today we are able to provide much more controlled doses of anaesthetic in gas form using much more complex drugs. Anaesthesiologists provide the precise dosage of anaesthetic required to keep the patient under for long enough to complete the procedure but not

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so much that the patient is

General anaesthetic can also be used to put a patient into a medically induced coma. A medically induced coma is when a patient is put into a controlled temporary coma (often after a severe accident or head trauma) via the use of anaesthetic such as propofol, pentobarbital, or thiopental. This method is used to prevent the brain from swelling by reducing the metabolic rate of the brain tissue and by slowing the cerebral blood flow, preventing any serious brain damage from occurring before any surgery can take place. Doctors often opt for a medically induced coma is a patient has brain swelling that does not react to other methods of treatment. In this comatose state the patient’s brain tissue rests and any swelling should reduce, reducing pressure on the brain which would otherwise cut off the blood supply and destroy brain tissue.

Although anaesthetic is vital to the medical industry, we do not fully understand the mechanism by which it works. The best theory that we have at the moment is that the chemicals dissolve in some of the fat present in the brain cells, changing the activity in the cells and hindering the physiological responses usually present, however this is still only a theory.

References: How Does Anesthesia Work? By Brooke Borel, Life's Little Mysteries Contributor, February 23 2012 What It's Like Being in A Medically Induced Coma, According To A Girl Who's Lived It. by Justin Caba, June 29 2015

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Insomnia

By Rajan Patel Insomnia is well known as a psychiatric condition which results in difficulty falling asleep (onset) or staying asleep (maintenance), but it is a less well known fact that there are two main types of insomnia and that most people have been effected by it at some point.

Insomnia is described as 1“difficulty falling asleep or staying asleep, even when a person has the chance to do so.” Symptoms of the condition include “fatigue, low energy, difficulty concentrating, mood disturbances and decreased performance in work or school.” (What is Insomnia?, National Sleep foundation, 2017) Insomnia is categorised based on the duration of the problem. Short term or acute insomnia only lasts a few days and is often brought about through stress or other life circumstances, for example: exams, following the receival of bad news or even jet lag. Most people have experienced this form of insomnia and it often subsides without any treatment.

The form of insomnia most commonly related to the condition is chronic. Chronic insomnia is defined as occurring at least three nights a week for at least three months. There are many different causes for chronic insomnia, including shift work, bad sleep habits, changes in environment and even other clinical conditions or medications. Due to the numerous possibilities of causes for chronic insomnia, it is very difficult to trace the main cause and repair it. Chronic insomnia can also be comorbid, meaning it could be linked to another medical issue, making it very difficult to determine the relationship between these afflictions. Many people who suffer from chronic insomnia benefit from outside treatment to get them back to a regular, healthy sleeping pattern.

Insomnia is now thought to not only be a problem during sleep, but also while awake. Our brains have a sleep cycle and a wake cycle and it is thought that insomnia could be a problem with either part of this cycle. This has led to the idea that insomnia could be caused by either too much wake drive or too little sleep drive.

2 These cycles have been linked to an inhibitory neurotransmitter called gamma-aminobutyric acid (or GABA).

It has been found that people affected by insomnia produced, on average 20-30 percent less GABA than normal sleepers. GABA is known to help the brain slowdown in activity by reducing the electrical impulses in most regions of the brain and so most sleeping pills work by helping receptors in synapses to receive the neurotransmitter more efficiently. Further GABA measurements taken during the day also indicated that insomnia is not simply a nightly disease but a 24-hour problem, extending to the waking hours of the day and further crediting the theory of insomnia as a “state of hyperarousal”. Due to the nature of insomnia and its relation-

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ship to other psychiatric or medical conditions, it is difficult to isolate the effects of GABA on the disease, however around a quarter of people who suffer from the disease are unaffected by any other conditions and so, with these participants, it was possible to test for the effects of GABA on insomnia. The result of the study showed that the amount of time spent awake at night was inversely proportionate to the levels of GABA in the participant’s brain, indicating a correlation between the disease and levels of GABA, however it is still unclear whether insomnia is caused by low levels of GABA in the brain, low levels of GABA are caused by insomnia or both are symptoms of a separate hyperarousal disorder; the link between them is simply unclear so far.

Although insomnia is usually linked to the chronic form of the disease, it is experienced by most people, although in a less serious form. The disease can be caused by an irregular sleep pattern or an unhealthy diet and can be controlled if this is the case, however it can also be linked to a different disease such as sleep apnea and can therefore be difficult to control without treatment.

In some cases, the disease can be due to a fault in neurotransmitters in the brain, causing the brain to remain active when electrical impulse activity should reduce. It has also been indicated that the disease is not only a night-time issue but an ongoing problem in the brain, however it is still unclear what the link between insomnia and the neurotransmitter is.

References



Insomnia Tied to Lack of Brain Chemical, Aalok Mehta, Dec 24 2008



What is Insomnia?, National Sleep foundation, 2017

Gout The inflammation process breaks down the crystals that have become loose inside the joint, and the attack gradually settles over a few days or weeks, depending on how many crystals spilled out. Tophi can grow and cause pressure damage to your cartilage and bone. The damage can cause more regular, daily pain when you use the affected joints. At this stage the condition is often called chronic tophaceous gout. Some tophi may be seen and easily felt under the skin, but by this time the unseen part of the tophi in your joints and deeper tissues are usually quite extensive.

By James Hong Gout is a common inflammatory arthritis. Small crystals are formed inside around the joint and are usually sudden attacks, which cause severe pain, and swelling and multiple symptoms are known as an acute attack.

Symptoms of gout include intense and rapidly developing pain in the affected joint, hot and swollen joints that feel very tender to the touch, and shiny and often red skin, which can cause the skin over the joint to peel.

Attacks usually start at night. The symptoms develop quickly and are at their worst within 24 hours of first noticing anything is wrong and last for 3 to 10 days.

Urate crystals (a combination of calcium and urate, substances normally found in urine) cause this and areas where gout would appear are usually the big toe. However, it may appear in other joints such as ankles, knees, elbows, wrists, fingers and other joints in the feet. Multiple inflammations (polyarticular gout) may occur. It can appear in other areas of the body towards the centre such as the spine, shoulders and hips but this is extremely rare (arthritisresearchuk.org, 2012). Urate crystals form small, firm white lumps called tophi. These aren’t usually painful but sometimes they break down and discharge pus-like fluid containing gritty white material, the urate crystals themselves. Gout can lead to further problems such as kidney stones and permanent joint damage.

Around 2 in 100 people in the UK are affected by gout.

The condition mainly affects men over the age of 30 and women after the menopause. Overall, gout is more common in men than women. Gout can be extremely painful and debilitating, but treatments are available to help relieve the symptoms and prevent further attacks.

It occurs more commonly as people get older or become overweight or obese (nhs.uk, 2015). It most commonly occurs in people who are suffering from obesity, high blood pressure/diabetes, relative having gout (genetic), kidney problems and eating food that causes the build up of uric acid e.g. red meat, seafood and drinking too much alcoholic drinks.

The 2 main methods of treating gout are non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. Acute attacks of gout are often treated with oral NSAIDs, which can ease pain and possibly reduce some of the inflammation (an example is ibuprofen) and there are side effects (nhs.uk, 2015).

NSAIDs are more effective the closer you take them to the onset of an attack of gout.

NSAIDs can cause digestive problems (stomach upsets, indigestion, or damage to the lining of the stomach) so NSAIDs should be prescribed along with a drug called a proton pump inhibitor (PPI), which will help to protect your stomach and can carry the risk of stroke and heart attack. If other medication is being taken, including water tablets or warfarin, or has other medical conditions, such as chronic kidney disease, NSAID should not be taken (arthritisresearchuk.org, 2012).

Colchicine is made from the crocus plant. It's not a painkiller but it's often very effective at damping down the inflammation caused by the crystals touching the joint lining. Colchicine tablets should be taken as close as possible to the beginning of an attack, and certainly within the first 24 hours of the attack starting, otherwise it may not be effective. Side effects include nausea, vomiting or diarrhea (arthritisresearchuk.org, 2012).

You shouldn't take colchicine at the same time as NSAIDs.

It's also important to consider other ways of reducing your urate levels. Its important to lose weight if you're overweight by regular exercise, avoid foods, which are high in purines.

References: http://www.arthritisresearchuk.org/arthritisinformation/conditions/gout.aspx http://www.nhs.uk/conditions/Gout/Pages/ Introduction.aspx

About two thirds of the urate in our bodies comes from the breakdown of purines which are naturally present in the cells of our bodies. The other third comes from the breakdown of purines in some foods and drinks. Having urate in your blood doesn’t mean you’ll definitely develop gout but it’s normal and healthy to have some urate in the bloodstream. When urate levels start to build up, your body usually gets rid of any excess urate through your kidneys into your urine; however, if your body is making too much urate or your kidneys are unable to remove enough urate, then urate levels start to rise. If the level goes above a certain point (the saturation point), it’s possible for urate to form crystals of sodium urate. These crystals mainly form in and around joint tissues.

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Asystolic Cardiac Arrests and CPR

By Maciek Lamejko

can not get to parts of the body such as the brain.

“Hello, can you hear me?”

Aetiology

“Open your eyes!”

The main causes of asystole are:

Any first aider could tell you that this question and command are the first sentences you use to identify if someone is having a cardiac arrest. If there is no response, the next step would be to pinch the patient’s ear lobes to find out whether they respond to pain, if there is still no response the patient can be classed as ‘unresponsive’. In a situation were this would be occurring outside of a hospital, the attendee would call for help so someone can assist by calling an ambulance. The next step would be to check their breathing by first tilting back the head of the patient to open their airway, then moving close to the patient’s mouth to hear and feel their breaths and check whether their chest is rising or not. If the patient is not breathing or breathing abnormally it’s likely they are having a cardiac arrest and the person on the phone to the operator should notify them of this, so that paramedics can be informed en route.

Causes are various and include a variety of different heart ‘rhythms’: asystole, ventricular fibrillation, pulseless electrical activity, pulseless ventricular tachycardia (and others). This article limits focus to asystole: how it causes a cardiac arrest and common treatment methods.

What causes an asystolic cardiac arrest?

The answer lies in the basics of heart’s electrical system.

Within the wall of the right atrium of the heart is a group of specialised cells called the sinoatrial node (SAN). The SAN emits electrical pulses across both atria and cause the cardiac muscle tissue to contract. This is one part of the cardiac cycle.

The atrioventricular septum which is a layer of nonconductive tissue that stops the wave from causing the ventricles below to contract at the same time. Instead it enters a different group of cells, located in the floor of the right atrium, known as the atrioventricular node (AVN). After a short delay the AVN re-transmits the wave of electrical excitation. This passes through a structure of muscle fibres known as the ‘bundle of His’. The bundle of His conducts the wave through the ventricular septum to the base of the ventricles and then the wave is passed through smaller fibres known as Purkinje tissue. The wave is then released from the Purkinje tissue causing the ventricles to contract. This is the second part of the cardiac cycle.

It is now possible to understand that any interference to the nodes will have a massive impact on the heart’s ability to perform its primary function: delivery of oxygenated blood to body tissue.

Pathophysiology Asystole occurs when the nodes fail to emit a wave of electrical excitation, therefore preventing the muscular tissue from contracting and blood can’t be pumped around the body.

In severe cases, such as in a asystolic cardiac arrest the cellular activity in the heart stops because the nodes completely fail to emit any waves of electrical excitation.

In more mild cases were theses waves of electrical excitation are delayed, the patient may have bradycardia. This is a condition in which a person has a slow effective heart rate, under 60 beats per minute.

As previously mentioned, anyone having a cardiac arrest will be unresponsive. This is due to the fact that the cerebrum (part of the brain) is not receiving enough oxygen (cerebral hypoxia) or not receiving any oxygen at all (cerebral anoxia). This is because blood is not circulating around the body meaning that oxygenated blood

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Cardiac ischaemia (insufficient oxygen supply to the heart).

Degeneration of the nodes (SAN and AVN) due to conditions such as sclerosis.

In the case of ischaemia, the ‘pacemaker’ cells which make up the SAN can no longer generate an electrical impulse due to a lack of adenosine triphosphate (ATP) and certain ions such as potassium which allow them to emit electrical impulses.

In the case of sclerosis, hardening of tissue, mostly from inflammation, may occur due to the deposition of fibrous tissue or fatty plaques. This causes the tissue which makes up the nodes to degenerate. Eventually the nodes may degenerate to a stage at which they can no longer emit waves of electrical excitation and therefore can no longer cause successful systole to occur.

A cardiac arrest can also be caused by an occlusion of any coronary artery (myocardial infarction, more commonly known as a heart attack), this can cause ischaemia in the SAN and AVN. Other causes include: idiopathic degeneration of the nodes, a tumour, cardiac trauma, suffocation and even lighting strikes.

Cardiac Arrest – Immediate Steps and Treatment Cardiopulmonary resuscitation(CPR) should be carried out immediately, rescue breaths should only be carried if the person carrying out the CPR has been trained on how to carry them out.

CPR manually pumps blood around the body. Rescue breaths provide oxygen, ultimately delaying tissue death due to oxygen deprivation. A bystander can do little other than CPR and call 999. Even if available an automated external defibrillator (AED) would be initially ineffective as asystole is regarded as ‘non-shockable’.

The purpose of a shock is to reorganise an unorganised rhythm (unorganised contractions of the cardiac muscle tissue). Asystole is a lack of a rhythm, therefore shocking the tissue will have no effect. Standard treatment algorithms include use of AEDs as they can recognise the type of rhythm present and therefore asses whether a shock is necessary. If a bystander was to successfully change the rhythm the AED could be used to deliver a shock.

When paramedics arrive on scene they can use an endotracheal tube to keep the airway open, use oxygen canisters to then pump oxygen into the patient’s lungs and they will also have an AED of their own if one is not already being used. They then follow an algorithm which mainly involves CPR and administering adrenaline (epinephrine). Epinephrine is used as it increases cardiac output by increasing cardiac muscle contractility and improving conductivity through the AVN. Their whole objective is to change the rhythm so that it becomes a shockable rhythm.

Within a hospital, given they have more equipment, the procedure is slightly different. For example, waveform capnography helps resuscitation teams to asses the quality of the CPR being done. CPR can be assessed as the wave capnograph machine measures ventilation in the lungs, and it also indirectly measures metabolism and circulation. For example, a decrease in perfusion (cardiac output) will lower the delivery of carbon dioxide to the lungs. This will cause a decrease in CO2 exhaled from the lungs and will be observable on the waveform capnography machine.

The algorithm used by healthcare professionals during an arrest is presented below. The drug amiodarone, mentioned within, would not be used in the case of asystole. However, it would be used if the rhythm changed from asystole to a different shockable rhythm.

If someone survives a cardiac arrest the road to recovery will be arduous and almost definitely requiring surgery; in the case of an asystolic cardiac arrest caused by myocardial infarction, a stent may be placed in the appropriate coronary artery. Fatality rates for cardiac arrests are high, according to the ‘American Heart Association’ only 11% of people who had a cardiac arrest outside of hospital survived it (2015). The algorithm for treatment is modified frequently with new drugs being used and some drugs being removed from the algorithm. New technological developments and improvements have led to the creation of devices such as pocket AEDs making AEDs more convenient to carry and therefore making them more available (increasing the chances of someone having one in their possession). Many busy public places also now have AEDs available. The future for treating cardiac arrests is looking promising and hopefully someday there will be a greater chance of surviving one than not.

References https://acls-algorithms.com [2017] “Asystole and Its Treatment in ACL”, “Quantitative Waveform Capnography” and “ACLS and Epinephrine”. http://emedicine.medscape.com/article/757257overview#a2 [2015] “Asystole” by Sandy N Shah http://www.sja.org.uk/sja/first-aid-advice/loss-ofresponsiveness/unresponsive-not-breathing/adult.aspx [2015] “Unresponsive and not breathing adult – CPR” https://www.evidence.nhs.uk/formulary/bnf/current/2cardiovascular-system/27-sympathomimetics/273cardiopulmonary-resuscitation “2.7.3 Cardiopulmonary resuscitation” “AQA Biology A Level 2nd Edition” [2015] “Control of heart rate” Pages 340-341 by Glen Toole and Susan Toole http://health.howstuffworks.com/human-body/ systems/circulatory/heart4.htm [2000] “How Your Heart Works” by Carl Bianco

Acute Myeloid Leukaemia

By Maciek Lamejko Acute Myeloid Leukaemia (AML) is a malignant disease of the bone marrow in which haematopoietic precursors are stopped at an early stage of development and not fully matured myeloid stem cells are released into the blood stream as a result. It is the most common acute leukaemia among adults; acute meaning rapidly developing. AML is also frequently referred to as acute myelogenous leukaemia, acute myeloblastic leukaemia, acute granulocytic leukaemia, and acute nonlymphocytic leukaemia. This disease mainly occurs in long bones (for example the femur or the humerus) but is also found in flat bones (such as the hip bone).

Long Bone Physiology A typical bone is constructed from: cortical (compact) bone, cancellous (spongy) bone and bone marrow.

Cortical bone is the outer layer of the bone, cancellous bone makes up the interior of the epiphysis and the spaces between the cancellous bone contain red bone marrow, both yellow and red bone marrow are found at the core of the diaphysis; in the marrow cavity. Red marrow contains blood stem cells, which will eventually mature into red blood cells, white blood cells or platelets. Yellow marrow on the other hand is constructed mainly out of lipids, its primary function: to store adipocytes whose triglycerides can serve as a source of energy.

The red bone marrow will produce blood stem cells which will mature into either myeloid or lymphoid stem cells. Lymphoid stem cells will mature into: plasma cells, t-lymphocytes and natural killer cells. On the other hand, myeloid stem cells develop into red blood cells, platelets and granulocytes. The red blood cells primary function is to carry oxygen to tissue around the body, white blood cells function as a defence mechanism against pathogens and platelets are used to form clots and therefore reduce bleeding.

Pathophysiology In AML, the blood stem cells stop maturing when it reaches the myeloid stage, therefore they are unable to function as a normal blood cell. These immature cells (frequently referred to as blast cells) are then released into the blood stream. The reason behind this maturational defect is still under investigation however, it appears that the in most cases it is because of genetic abnormalities, such as chromosomal translocations. One of the main ways of differentiating different subtypes of AML is by looking at which chromosomes have been translocated.

The impact of this is a major reduction in the healthy blood cells which leads to conditions such as anaemia, thrombocytopenia and due to a reduction in the number of granulocytes the body becomes vulnerable to pathogens. These cells accumulate quickly in the bone marrow as they are unable to undergo apoptosis due to the genetic abnormalities. From this point the leukaemia cells may begin to spread to other parts of the body and will invade tissue, hence why it is referred to as malignant.

Aetiology Many factors are thought to contribute to the development of AML however, most patients suffering from AML have no identifiable risk factor.

The most common risk factor is the presence of an antecedent haematological disorder such as myelodysplastic syndrome (MDS). It is a disease that usually develops as a result of radiation exposure and causes cytopenia (thrombocytopenia, anaemia and neutropenia). In severe cases this condition frequently leads to the development of AML. Some congenital diseases also predispose people to AML. These conditions include: Down syndrome other-

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wise known as trisomy 21 (genomic instability is one of the effects of this syndrome and predisposes people to AML), Bloom syndrome otherwise known as congenital telangiectatic erythema (also causes genomic instability), Fanconi anaemia (deficiency of blood cells) and congenital neutropenia (deficiency of neutrophils).

Usually these types of patients develop AML early in their childhood.

tients involves the use of two drugs known as cytarabine and daunorubicin or idarubicin. This process usually lasts a week. These drugs cause bone marrow suppression and stop or slow the release of blast cells.

Environmental exposures can also increase the chance of someone developing AML. Studies have shown that there is a correlation between radiation exposure and the chance of developing AML. In the past radiologists were found to have an increased chance of developing AML possibly due to the fact they did not have the appropriate shielding. Studies have proven that smoking and exposure to benzene (can be found I dyes, pesticides and synthetic fibres) also increases the chance of developing AML.

Induction reduces the number of normal bone marrow cells as well as the blast cells. At this stage a patient may have very low blood counts, may require a blood transfusion, and will be on antibiotics to eliminate common pathogens. After one to two weeks, a bone marrow biopsy will be done to assess the success of the chemotherapy. At this stage either more chemotherapy will be recommended, a bone marrow transplant could be preformed or the patient may continue to be assessed until remission is reached (when blast cells make up less than 5% of all bone marrow cells).

More patients are being cured from cancer than ever before. However, this has complications as the intensive exposure to chemotherapeutic agents that many patients receive has been shown to increase the risk of AML. For example, a study looking at the incidence of AML in patients with breast cancer, who were given the drugs doxorubicin and cyclophosphamide as part of their chemotherapy, showed that a significant number of the breast cancer patients developed AML after 1- 5 years of receiving the chemotherapy.

Presentations of AML Those who have AML may present with the following symptoms: Fever, Shortness of breath, Easy bruising or bleeding, Petechiae (flat, pinpoint spots under the skin caused by bleeding), Frequent tiredness and an unusual sense of weakness, Weight loss and a loss of appetite.

Investigations An initial investigation should include a simple physical examination and the patient’s medical history should be obtained. Further tests are carried out if AML is suspected.

One such test is a full blood count (FBC). A blood sample is collected and sent away to a laboratory. There the number of platelets, red blood cells and white blood cells can be counted. In the case of AML, a patient would have a considerably low number of blood cells.

Generally, if a FBC shows there is an abnormal number of blood cells a blood film would be carried out. This is done by placing a blood sample on a slide and ‘smearing’ it across using a spreader slide. A dye is then used to stain the cells. They are then studied under a microscope, the person studying the cells will look for any abnormal looking cells as they may indicate the patient has AML. Bone marrow aspiration and biopsy is a way to obtain bone marrow to analyse in the laboratory. When the area around the hip bone has been numbed using a local anaesthetic, a hollow tube is inserted into the hip bone and samples of blood, bone and bone marrow are extracted.

Within a laboratory, tests such as cytogenetic analysis can be carried out to determine whether a patient has AML or not. The samples of blood and bone obtained can be studied under an electron microscope to identify any significant changes within the chromosomes of the cells in the sample.

Treatment Treatment of AML is usually divided into two phases of chemotherapy: remission induction and consolidation (post remission).

The aim of the induction stage is to get rid of as many blast cells as possible. Current guidance for most pa-

If the blast cells have spread to the brain or spinal cord these drugs may be injected into the cerebrospinal fluid (CSF) and radiation therapy may also be used.

Consolidation therapy, is next. In this therapy, only cytarabine is used. The drug is given in high doses, typically over five days. This is repeated every four weeks for a total of three to four cycles. Another approach is to use stem cell transplants, a autologous (using patient’s own stem cells) or allogeneic (using stem cells from a donor) stem cell transplants may be carried out. While successful recovery is more likely with a stem cell transplant, the risks posed are significant and could even lead to the patient’s death.

Prognosis The prognosis (chance of recovery) is very different depending on the type of patient. The following must be considered: The age of the patient The subtype of AML Whether the cancer has recurred Whether previous chemotherapy has been carried out for a different form of cancer Whether the cancer has spread to the central nervous system The fragility of the patient The Future of Treatment There have been vast advances in the treatment of AML in recent years, especially in chemotherapy. For example, bortezomib, a proteasome inhibitor (blocks actions of proteasomes, cellular complexes that break down proteins), which is known to treat multiple myeloma, a cancer which affects plasma cells. A recent study which considered adding this drug to chemotherapy has led to promising results. With advances such as these, there is a hope that a cure for AML will be found in the lifetimes of the current economically active population.

References NATIONAL CANCER INSTITUTE. Adult Acute Myeloid Leukaemia Treatment (PDQ®)–Patient Version [online] National Cancer Institute, July 28, 2016 [viewed 02/16/2017] Available from: https://www.cancer.gov/types/leukemia/patient/adult-amltreatment-pdq BBC. Bone growth [online] BBC Bitesize, September 15, 2006 [viewed 03/04/2017] Available from: http://www.bbc.co.uk/schools/ gcsebitesize/pe/ appliedanatomy/2_anatomy_skeleton_rev4.shtml AMERICAN CANCER SOCIETY. What’s New in Acute Myeloid Leukaemia Research and Treatment? and Typical Treatment of Most Types of Acute Myeloid Leukaemia (Except Acute Promyelocytic M3) [online] American Cancer Society, February 22nd 2016 [viewed on 02/16/2017] Available from: https:// www.cancer.org/cancer/acute-myeloid-leukemia/about/newresearch.html and https://www.cancer.org/cancer/acutemyeloid-leukemia/treating/typical-treatment-of-aml.html CONVERSANT BIO. Red Bone Marrow vs. Yellow Bone Marrow: What is the Difference [online] Luke Doiron, December 16 2014 [viewed on 02/16/2017] Available from: http:// www.conversantbio.com/blog/red-bone-marrow-vs.-yellowbone-marrow-what-is-the-difference MEDSCAPE. Acute Myelogenous Leukaemia (AML) [online] Karen Seiter, September 29 2016 [viewed on 02/16/2017] Available from: http://emedicine.medscape.com/article/197802overview#a1

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Epilepsy

By Ajay Krishna Epilepsy is a brain disorder that results in the repeated occurrence of seizures, which are caused by abnormal electrical discharges in the brain. This condition affects about 50,000 people in the UK and about 181,000 cases are diagnosed each year worldwide (MayfieldClinic, 2016). Epilepsy can be categorised as idiopathic (primary) or symptomatic (secondary). The electrical fault in the brain results in seizures and the most common seizure types can be classified as either partial (focal) or generalised (Epilepsy Causes, 2014).

The effect of a seizure on a person depends on which part of the brain is affected, as each section of a brain controls a different function of our body. Some of the common seizures are: Temporal lobe epilepsy - about two-thirds of the seizures are partial and one-third is generalised. It usually begins in childhood from around 6 - 10 years and the seizures last from 30 seconds to 1 minute. As the temporal lobe is mainly responsible for hearing, speech, memory, emotions and learning, the seizure will result in the person having confusion, amnesia and short-term speech problems. (Focal Seizures, 2014) Frontal lobe epilepsy - these have a sudden onset and a short duration period, most of the time it is a partial seizure and more common during sleep.

The frontal lobe is responsible for making decisions, solving problems, behaviour, consciousness and emotions. The symptoms include difficulty in speaking, unaware of the surroundings and screaming, swearing or laughing. These symptoms can be mistaken for a mental health condition or a sleeping disorder. (Focal Seizures, 2014).

Reflex epilepsy - this is the most known type of epilepsy. The seizures are triggered by the environment; the main reason is photosensitivity (seizure as a response due to flashing lights, strobe lights and video games). It begins in childhood and is often outgrown before adulthood.

(MayfieldClinic, 2016).

There are also other types such as Juvenile myoclonic epilepsy, benign rolandic epilepsy and Lennox-Gastaut syndrome, but these are the rare types epilepsy.

(MayfieldClinic, 2016).

Approximately, for 70% of patients with epilepsy, the cause is unknown, these types of epilepsy are known as idiopathic epilepsy. The reason behind this is that the equipments used are not advanced enough to detect the damage done by epilepsy or it is a genetic defect in the genes that leads to abnormal discharges of electrical impulses. However, for symptomatic epilepsy, some of the causes can be identified, such as head trauma, stroke, birth injury, brain tumours, infection, drug abuse and alcohol misuse. Although some of these problems can cause childhood epilepsy, people over the age of 60 are more prone to symptomatic epilepsy. Moreover, people with epilepsy can have seizure triggers such as stress, lack of sleep, some medications, drugs, flashing lights e.t.c. but seizures can also occur without any obvious triggers. (Epilepsy Causes, 2014).

Diagnosis When presented with the symptoms (i.e. seizures), a detailed neurological examination is required, which tests specific functions of the central nervous system.

Electroencephalogram (EEG) is a commonly used test for epilepsy. This detects electrical patterns in the brain called brain waves. Electrodes are placed on the scalp which is connected to an EEG machine. The machine detects and amplifies electrical signals which the com-

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puter will be able to record and display. The brain waves of a normal person are different to a person with epilepsy, so the displayed reading can not only show abnormal EEG patterns but also can indicate the type of epilepsy. However, a positive and negative result of EEG can only show a likelihood of the person being epileptic or not. To confirm the diagnosis of epilepsy further tests like blood tests or Magnetic resonance imaging (MRI) to rule out other possibilities like infections, chemical imbalances or brain tumours. (Kenny, 2015).

Treatment The first line of treatment includes anti-epileptic medications and the main aim of this is to control the seizures; some of the drugs are Phenytoin (Dilantin), Felbamate (Felbatol) and Tiagabine (Gabitril). However, these medications can result in lots of side effects, including fatigue, drowsiness, nausea, weight gain e.t.c., moreover about 30% of the patients under medications will not show much improvement so invasive surgery is the next option but for children a ketogenic diet, which contains high-protein/fat, may be introduced.

(MayfieldClinic, 2016).

Vagus nerve simulation (VNS) is used to prevent seizures by sending mild, regular electrical current to the brain via the vagus nerve. The device is usually powered by a pacemaker. There might be some small side effects such as tingling or a change invoice during stimulation.

Another treatment option is Epilepsy surgery. This will remove the part of the brain that generates seizures. To be eligible for this treatment the person has to have partial seizures and the focal point of the seizures needs to be in a part of the brain that can be isolated. This is the most effective surgery as 50-80% will be seizure free and is beneficial for those with temporal lobe epilepsy.

(MayfieldClinic, 2016).

Bibliography Autism and Epilepsy Resources. (n.d.). Retrieved 03 04, 2017, from Autism Speaks: https:// www.autismspeaks.org/ Epilepsy Causes. (2014, 11 25). Retrieved 03 04, 2017, from NHS: http://www.nhs.uk Epilepsy Health Center. (2016, 05 25). Retrieved 03 04, 2017, from WebMD: http://www.webmd.com Epilepsy society Treatment. (n.d.). Retrieved 03 05, 2017, from Epilepsy society: https:// www.epilepsysociety.org.uk Focal Seizures. (2014, 06). Retrieved 03 04, 2017, from Epilepsy in action: https://www.epilepsy.org.uk Kenny, D. T. (2015, 12 23). Electroencephalograph.

Retrieved 03 04, 2017, from Patient: http://patient.info MayfieldClinic. (2016, 04). Epilepsy. Retrieved 03 04, 2017, from Mayfield Clinic: http:// www.mayfieldclinic.com

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