Issue I– March 2017
Created by Akila Wickramathilaka & team
www.medicoolsite.wordpress.com
About the Medical Diary
Welcome to The Medical Diary, a student run independent magazine founded by Akila Wickramathilaka, which endeavours to develop interest in medicine.
The ultimate aim of the Medical Diary, is to make all topics covered as interesting as possible, in order to engage viewers, and to enhance their medical knowledge. The Medical Diary investigates a plethora of medical phenomena, and analyses in depth why such processes occur. Readers can also keep up with the most recent medical advances, which will be covered in depth and analysed. This magazine consists of high-level scientific articles compiled into a single informative booklet. I hope you enjoy reading our magazine. - Akila Wickramathilaka (Editor)
Contents Page number
Topic
4
Publishing team
5
Influenza
-Kieran
6
Gastroenteritis -Akila
8
Rabies -Sanka
10
Stem cell research -Muse
11
Plasma cell dyscrasias -Akila
13
Causes, proliferation and treatment of cancer -Mohammed
15
Kaposi Sarcoma -Akila
17
Structure of the brain -Akila
Publishing team Akila Wickramathilaka – Editor An aspiring physician with particular interest in the human genome and genetic diseases including Huntington’s chorea. Sanka Wijayarathne An aspiring veterinarian with particular interest in both animal and plant conservation.
Kieran Graham An aspiring Natural Scientist with interest in genetics and gene therapy.
Mohammed Hakimi An aspiring physician with particular interest in cancer research.
Muse Berhe An aspiring biologist with research interests in botany and the herbal medicine.
Influenza Influenza, also known as the ‘flu’, is a type of virus which causes the following symptoms: high body temperature, tiredness, weakness, headaches, coughing, aches and pains. Due to the similarity in some of the symptoms, the Influenza virus is often mistaken for the common cold which presents some of the symptoms listed (coughing, headache, elevated body temperature). However, an Influenza infection is a more serious condition than the common cold, which is evident by the fact that it killed 209 people in the UK between week 40 of 2015 to week 17 of 2016 (165 of which were from England). 1, 2 In 1918, Influenza also was the cause of the deaths of 20 million people in an epidemic so great that the death toll superseded that of the First World War. The virus is so effective since it spreads via bodily fluids, which are generally released when the host coughs or talks. When a person is about to cough, their chest muscles and diaphragm begin to contract when their throat has closed to build up pressure in the lungs. This pressure is then released when they open their throat and the infectious droplets can travel approximately 6 feet away infecting anyone who ingests the droplets. Symptoms can start to appear 1-4 days after infection however, some individuals do not present any symptoms upon infection. Yet, even though they possess no apparent reaction to the virus, there is still a risk of infection since the virus is present in their bodily fluids. 3, 4 The Influenza virus is generally regarded as a spherical virus however, it has relatively pleomorphic properties so its shape can be altered depending on the conditions the virus is present in. It has a spherical shape due to the outer lipid membrane present in its structure which was once part of the host cell it has occupied and attached to this lipid membrane is approximately 500 glycoprotein projections. These glycoprotein projections come in two types, HA (Hemagglutinin) and NA (Neuraminidase) and determine the type of strain of the Virus (e.g. H1N1 or H3N2). Just below the Lipid membrane is a viral protein called ‘M1’ which forms a shell around the inner molecule to strengthen its structure. Below this, there is a combination of RNA and Nucleoproteins which code for the glycoprotein projections present in the lipid membrane. 5, 6
(the patient stops taking the prescribed antiviral drug before the final dose) since the virus can form different strains which don’t match to the antiviral drugs as effectively. Different strains of influenza are a result of the RNA and coding proteins present in the core of the virion becoming modified. Since these RNA strands / proteins code for the glycoproteins on the external membrane of the molecule, any modification can lead to different arrangements thus, changing the virus completely. 5 Such is the case with the Influenza strains H1N1 and H3N2. The strain H1N1, is commonly referred to as ‘Swine Flu’ due to its origins in pigs where the virus would infect the respiratory tracts of the animal causing coughing, nasal secretions and decreased appetite. The virus was eventually transmitted to humans with the first identified case being in Mexico in 2009. Although the younger generation had not built up an immunity to the virus, the older generation was relatively unaffected by the virus since exposure had resulted in their immune systems producing B memory cells with antibodies specific to the virus. Although the older generation was immune to the H1N1 strain, they could still contract Influenza due to different variants of the disease (which won’t trigger the B-cells), entering the body. 7
References 'Flu - NHS Choices' (Nhs.uk, 2017) <http://www.nhs.uk/ conditions/Flu/Pages/Introduction.aspx> accessed 19 March 2017 1 'Surveillance Of Influenza And Other Respiratory Viruses In The United Kingdom: Winter 2015 To 2016' (www.gov.uk, 2017) <https://www.gov.uk/ government/uploads/system/uploads/attachment_data/ file/526405/Flu_Annual_Report_2015_2016.pdf> accessed 19 March 2017 2 S. M, 'The Ultimate Guide To Coughing – How EXACTLY Does It Work!' (MyScienceAcademy, 2017) <http:// myscienceacademy.org/2014/01/08/the-ultimate-guideto-coughing-how-exactly-does-it-work/> accessed 19 March 2017 3 'How Flu Spreads| Seasonal Influenza (Flu) | CDC' (Cdc.gov, 2017) <https://www.cdc.gov/flu/about/ disease/spread.htm> accessed 19 March 2017 4
Drugs used to treat an Influenza infection target the NA glycoprotein present in the lipid membrane but also, the ‘M2’ protein present in the membrane is targeted.
Racaniello V, 'Structure Of Influenza Virus' (Virology.ws, 2017) <http://www.virology.ws/2009/04/30/structure-of -influenza-virus/> accessed 19 March 2017 5
The drugs ‘Relenza’ and ‘Tamiflu’ target the NA glycoprotein and the drugs ‘Amantadine’ and ‘Rimantadine’ target the M2 protein however, the virus can become resistant if these drugs are not utilised correctly
'The Influenza Virus: Structure And Replication - Article In Motion' (Rapidreferenceinfluenza.com, 2017) <http:// www.rapidreferenceinfluenza.com/chapter/B978-0-7234 -3433-7.50009-8/aim/influenza-virus-structure> accessed 19 March 2017 6
Gastroenteritis Gastroenteritis refers to the inflammation of the stomach and the small intestine due to either a viral or bacterial infection. Other, more colloquial names for gastroenteritis include: “stomach flu”, “stomach bug” and “stomach virus”. There are two distinct types of gastroenteritis: the common acute gastroenteritis, and the less common chronic gastroenteritis. Acute gastroenteritis lasts for a short period of time, usually a few days to a week. It can be described as the sudden inflammation in the lining of the stomach. Conversely, chronic gastroenteritis is persistent, and will last for a long time. It may be painless and occurs slowly over time. Often associated with ulcers, and an increase in the risk of stomach cancer (most commonly adenocarcinoma), this is a condition that should not be underestimated. However, the main focus of this article will be the unexceptional acute gastroenteritis. In general terms gastroenteritis results in the inability to digest food, resulting in the expulsion of undigested food, via the oesophagus (vomiting), or through means of diarrhoea. This condition is caused by a pathogenic infection. Common viruses that may trigger this condition include the likes of rotavirus, norovirus and hepatitis A. Common bacterial causes are the Enterotoxigenic E.coli, Salmonella, Campylobacter and Shingella bacteria. Less commonly (although very common in developing countries), it can also be caused by parasites such as Giardia and Cryptosporidium. These pathogens can be found in food, water, soil, animals and in human faeces. In theory, these pathogens get into our body system via Fecal-Oral transmission. A common pathway of infection involves a lack of hygiene following the passing of a stool. If one fails to wash their hands effectively,
the pathogen will not be washed away and their hands will be contaminated. Via means of contact, this germ can spread from one place to another, until eventually it enters our body orally. Once it is in the body system, the pathogen starts to attack a region of the gastrointestinal system called the gastrointestinal wall. The wall consists of a layer called the epithelium, which is composed of specialized cells involved in digestion and absorption. Pathogens contained in the partially digested food will invade the epithelium and the specialized cells, causing apoptosis (cell death). Some of the dead epithelial cells will then break off the lining, as deposit into the “slurry” of partially undigested food. Since the presence of epithelial cells is starkly reduced, the efficiency of the digestion of food and water will deplete. Therefore, much of the important nutrients (including water) will not be absorbed, and will remain in the mixture of partially digested food. Incrementally, white blood cells near the epithelium will also be deposited into the mixture of food, leading to inflammation. This, in turn, causes a plethora of symptoms including vomiting and diarrhoea, as the partially digested food needs to be expelled from the body due to the destruction of the epithelium, meaning that food cannot be digested and absorbed. Dehydration is another symptom, since little water is absorbed into the bloodstream. If one experiences these three defining symptoms, then they may have acute gastroenteritis. Other symptoms may include stomach pain/cramps, tiredness, body aches, and a fever.
In order to confirm this, doctors will usually carry out scientific tests to find out which specific pathogen is causing the symptoms. The doctor may use a stool sample to evaluate which pathogen is contaminating the faeces. They may also carry out a blood test, which is designed to check for signs of dehydration. Marked signs include high levels of sodium (Na+) ions, or high levels of creatinine- a compound produced by metabolism of creatine and excreted in the urine. These two tests can be used to confirm whether or not a person has acute gastroenteritis. Treatment of acute gastroenteritis involves Oral Rehydration Therapy. The patient should consume vast quantities of liquid containing mineral salts and sugars. This is to combat dehydration. If the condition of the patient is severe, they can be put on an IV fluid. This is known as intravenous therapy, which involves the infusion of liquid substances directly into a vein. Dehydration is especially dangerous for babies and the elderly. If the case is caused by a bacterium, then the doctor may prescribe antibiotics. This is not a liable form of treatment if the case involves a virus, since viruses are not affected by antibiotics. Even if the case involves a bacterium, the drug may still kill other, more useful bacteria in the gastrointestinal system that aid the digestion and absorption of food. It could also be seen as a waste, because the symptoms will clear up by themselves, after a few days. Whether or not to prescribe antibiotics must therefore be derived from the condition of the patient and the nature of the pathogen. One should also try to avoid anti-vomiting or antidiarrhoeal medications unless prescribed or recommended by a doctor. In essence, there is no medicine to treat/cure acute gastroenteritis as the normal functioning of the body will eventually flush out the pathogens. To prevent gastroenteritis, one should endeavour to practise means of good hygiene.
This includes washing hands thoroughly after using the bathroom. One should also take care to drink water that has been decontaminated and is clean, and to cook food properly to ensure that it is not contaminated with pathogens, which might infect someone that eats it. The best way to combat acute gastroenteritis is to prevent it, and means of doing so are relatively easy, in comparison to most other conditions. References www.khanacademy.org
www.nhs.uk/conditions/gastroenteritis www.healthywa.wa.gov.au
Rabies
Rabies has killed more than 55,000 people in 2015 and around 100 children die every day, according to the WHO (Abraham, 2015). Rabies comes from the Latin word meaning “to rage” and was discovered by an Italian physician, Girolama Fracastoro, he discovered that this fatal disease can affect both humans as well as animals. However, it was Louis Pasteur who created the first rabies vaccine in 1885 using live rabies virus; he developed his rabies vaccine by cultivating the virus in rabbits, then by drying the affected nerve tissue to weaken the virus, to form a vaccine which is a weakened or inactive form of the pathogen. Rabies is a neurotropic virus, i.e. a virus that is capable of infecting nerve cells. Domestic dogs contribute to 99% of rabies transmission to humans, and are transmitted through the saliva of the animals (zoonotic disease).
The rabies virus belongs to the family Rhabdoviridae and genus Lyssavirus, under an electron microscope they appear bullet-shaped, measuring around 76-175nm (Sangwan). The nucleo-capsid shows helical symmetry and contains a single strand of un-segmented RNA genome and viral transcriptase. The rabies genome codes for five proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L). The rabies virus has two major structural components: a helical ribonucleoprotein core (RNP) and a surrounding envelope. In the RNP, RNA is tightly enclosed by the nucleoprotein. There are also two other viral proteins, the phospoprotein and the large protein (L-protein or polymerase) and are associated with the RNP. The glycoprotein forms around 400 trimeric spikes which are tightly packed on the surface of the virus (CDC). Figure 1: Cross section of the rabies virus (CDC)
Figure 2: Bullet-shaped rabies virus (http:// www.infectionlandscapes.org/2013/05/rabies.html’0)
When the virus envelope fuses to the host cell membrane, it starts the infection process (adsorption). The interactions between the G protein and specific cell surface receptors may be involved. After adsorption, the virus penetrates the host cell and enters the cytoplasm by pinocytosis (process of ingestion into a cell through the budding of small vesicles from the cell membrane). The portal of entry is the bite and the virus in the infected saliva is introduced into the wound or scratch contaminated by saliva. The virus multiplies in the local muscle tissues, invading the damaged nerve fibres and spreading through the peripheral nervous system to the central nervous system to reach the brain and spinal cord, once the virus reaches the brain it causes encephalitis (inflammation of the brain), it could also inflame the spinal cord producing transverse myelitis. When encephalitis occurs the mortality rate is almost 99%. The first symptoms of the disease are headache, fever, and a sense of apprehension and a feeling of irritation at the site of the bite. The patients would also have high fever, difficulty in swallowing and a fear of water (hydrophobia). During the early stages, it’s easily confused with other diseases or with general aggressiveness. The fluorescent antibody test (FAT) is used as the reference method for diagnosing rabies. Light microscopy techniques could be used to diagnose rabies in developing countries and samples of saliva, urine, and cerebrospinal fluid can be used. Cerebral inclusion bodies called Negri bodies in the hippocampus of the brain are diagnostic for rabies infection, however found only in 80% of cases.
Figure 3: FAT (http://homepage.usask.ca)
References (n.d.). Retrieved from CDC: https://www.cdc.gov/rabies/ transmission/virus.html (2014, 12 15). Retrieved from WHO: http://www.who.int Abraham, M.-R. (2015, September 15). Retrieved from BBC future: http://www.bbc.com/future/ story/20150915-indias-rabid-dog-problem-isrunning-the-country-ragged Sangwan, A. (n.d.). Retrieved from Biologydiscussion: http://www.biologydiscussion.com/essay/essayon-rabies/30860
Pre-exposure rabies prophylaxis (PrEP) is given to anyone who is at continual, frequent or increased risk for exposure to the rabies virus such as vets. An intradermal dose and an intramuscular dose is given at monthly intervals and followed by yearly boosters (WHO, 2014). For Post-Exposure Prophylaxis (PEP) the following guideline, published by WHO is used. Rabies immunoglobulin is made up of antibodies complementary to the antigens of the rabies virus. Figure 4: PEP guideline published by the WHO (15/12/2014)
Stem Cell Research ‘Stem Cell Research’ is the research into a type of cell commonly regarded as a ‘stem cell’. What gives these cells such value is that ‘Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth.’ (National Institutes of Health, 2016, Page 1). This makes them highly sought after, as they can be used to repair impaired tissues and various other structures within our bodies. Their most valuable asset is that certain types of stem cells have the ability to specialise into any other cell in the body, this means that they can be used to aid the reparation of any structure in our body, hence the high value of stem cell research. However, this isn’t the only objective of stem cell research, as the research into it ’continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms.’ (National Institutes of Health, 2016, Page 1). It furthers our understanding of the complex nature behind evolution, so we can effectively use our knowledge of stem cells to help us gain a clearer understanding of how life began on Earth. We also gain a more in depth understanding of the human anatomy and we are able to apply this new found knowledge into medicinal research. However, stem cell research is highly regarded as a controversial topic: some believe that embryos, from which stem cells can be obtained, are living organisms. Thus, by using these embryos, you are effectively murdering a human being. There are two ways in which this controversy can be avoided: ‘Deriving embryonic stem cells without destructing the foetus’ and ‘Obtaining embryonic stem cells without actually creating a foetus’. (Murnaghan, Stem Cell Controversy, 2016, Page 1). It is paramount that we place equal emphasis on obtaining stem cells from other areas in the body, such as the bone marrow, to further our understanding of the therapeutic properties of stem cells. There are three different types of stem cells: ‘Pluripotent Stem Cells, ‘Hematopoietic Stem Cells’ and ‘Mesenchymal Stem Cells’. ‘Pluripotent Stem Cells’, sometimes regarded as ‘true’ or ‘embryo’ stem cells, can differentiate into almost any cell in the body. ‘Hematopoietic Stem Cells’ are stem cells which are manufactured in the bone marrow: these have the ability to specialise into any of the cells found in the blood. And ‘Mesenchymal Stem Cells’, which are found in many different parts of the body and are typically taken from: bone marrow, skin and fat tissue. (MS Society, 2015, Page 1).
References:, National Institutes of Health, 2016, Stem Cell Basics I, https://stemcells.nih.gov/info/ basics/1.htm, Date accessed: 15/10/2016 Murnaghan, IM, 29 September 2016, Stem Cell Controversy, http://www.explorestemcells.co.uk/ StemCellControversy.html Date accessed: 17/10/2016 ABC News, 2005, Fast Facts on Stem Cells, http:// abcnews.go.com/Health/US/story?id=785936 Date accessed: 29/10/2016 Luca, ML, 1 September 2015, What diseases and conditions can be treated with stem cells?, http:// www.eurostemcell.org/faq/what-diseases-andconditions-can-be-treated-stem-cells, Date accessed: 23/10/2016 MS Society, 2015, Stem Cells, https:// www.mssociety.org.uk/ms-research/emergingareas/stem-cells#Top, Date accessed: 24/10/2016
Plasma cell dyscrasias 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.
[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.
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 3] – Electrophoresis of a sufferer
[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)
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. 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 blood- anaemia, 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. 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 isnâ&#x20AC;&#x2122;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/
Causes, treatment and proliferation of cancer 2012 saw 8.2 million deaths attributed to this genetic disease. It occurs when information in cellular DNA is corrupted, which in turn leads to abnormal expressions of genes. Alterations in the genes cause a change in its functions. Alterations can be caused by the accumulation of mutations, but also through non-mutational processes (epigenetic). These aberrant (different to the norm) gene expressions can lead to fundamental changes in the biological processes of cells. To understand the proliferation of cancer cells, one must understand the fundamental differences between a healthy cell, and one that is cancerous. This difference can be traced back to protein synthesis where transcription and translation take place. During transcription mRNA can be degraded by small non-coding RNA molecules called microRNA’s (miRNA’s) pre translation. Compelling evidence shows that in cancer cells, miRNA is dysregulated through various mechanisms. These dysregulated miRNA’s are thought to affect the hallmarks of cancer. These include resisting cell death, evading growth suppressors and activating invasion and metastasis. Metastasis is when cancer cells break away from where they first formed (primary cancer) and travel through the blood or lymphatic system to form new metastatic tumours. This new tumour is the same type of cancer as the primary tumour. When mRNA reaches the ribosome, specific protein molecules are translated due to the triplet code of bases. The phenotypic changes recognised as cancer are a result of these protein products of genes. In summation, the proliferation of cancer may be due to the miRNA molecules present during transcription, which alter the process of protein synthesis.
Furthermore, the mutation of two types of genes, oncogenes and tumour suppressor genes, are what usually result in cancer (TSG). In normal cells, these two provide an essential function. Oncogenes are a result of mutated versions of normal cellular genes, known as proto-oncogenes, which encode for proteins that function to stimulate survival, invasion/ motility, cell proliferation and apoptosis. Uncontrolled cell division occurs when proto-oncogenes are mutated. Typically, these genes expressions are carefully regulated to avoid uncontrolled cell growth. The mutated nature of these oncogenes thus results in the increased production of said proteins, leading to increased cell division, and the inhibition of apoptosis. Due to their phenotypical nature, only a single mutated copy of a proto-oncogene is required for the promotion of cancer. Therefore they are not usually associated with inherited cancer syndromes. TSG’s on the other hand are normal cellular genes which function to inhibit cell proliferation and survival. Programmed cell death (apoptosis), and cell cycle progression are both affected by TSG’. TSG’s become problematic when they are inactivated, and so don’t regulate these cellular processes. This is the opposite of oncogenes which become overly expressed. Another difference in these genes is also the fact that TSG’s are phenotypically recessive, and so both copies must be functionally altered to promote cancer. Their phenotypical nature also means they are responsible for inherited cancer syndromes. In this case, individuals inherit a germline mutation of one allele of a TSG, causing every cell in the body to be affected. As a result, there is a high likelihood of at least one cell suffering complete loss of TSG function, as only one copy has to be altered. There are various treatments for cancer; however the attention of this article will be dedicated to radiotherapy, as it is one of the most common treatments. There are in fact two types of radiotherapy: external beam radiation therapy (EBRT), and internal radiation therapy (brachytherapy). Brachytherapy involves the placement of a single or multiple radioactive sources inside the patient’s body. There are also different types of this treatment. Contact brachytherapy involves the implantation of the radioactive source in a cavity/space adjacent to the tumour
One of the main differences between EBRT and brachytherapy is that brachytherapy allows physicians to use a higher total dose in order to treat a smaller area, in a shorter space of time. The other form of this type of treatment is interstitial brachytherapy which involves the implantation of radioactive sources directly into the tumour. With interstitial there are two methods which can be applied. High-dose rate (HDR) brachytherapy involves a specific dose of radiation to be delivered to the tumour in a short burst. This is accomplished by a remote-afterloading machine which stores powerful isotopes of Iridium-192. The short bursts are used to protect workers from unnecessary overexposure. With HDR brachytherapy, thin catheters with the HDR sources are placed inside the tumour so that the radiation is focused intensely on just the tumour. Low-dose rate (LDR) brachytherapy on the other hand works by delivering radiation at a continuous rate over the course of one or two days. This also means that the patient will have to stay at the hospital overnight so the delivery device used in the procedure can remain in place throughout the treatment. With this treatment, the radiation is delivered radioactive isotope decays over time. EBRT on the other hand uses high energy X-ray beams such as photon beams, or other types of radiation such as particle beams. Unlike brachytherapy, EBRT is non-invasive. The treatment works by damaging the DNA within the cancerous cells, and by doing this the cell cannot carry out its usual functions like replication. The treatment may either damage the DNA directly, or create free radicals (charged particles) that then damage the DNA. This will ultimately lead to the cells death as the cancer cells arenâ&#x20AC;&#x2122;t able to replicate themselves due to their damaged DNA. References http://www.cancerresearchuk.org/about-cancer/ cancers-in-general/treatment/radiotherapy/external/ about-external-radiotherapy http://www.radiologyinfo.org/en/info.cfm?pg=brachy http://www.medicinejournal.co.uk/article/S1357-3039 (15)00281-9/pdf http://www.cancer.org/cancer/cancercauses/ geneticsandcancer/genesandcancer/genes-and-canceroncogenes-tumor-suppressor-genes
http://www.medicinejournal.co.uk/article/S1357-3039 (15)00270-4/pdf http://www.moloncol.org/article/S1574-7891(12)00098 -1/fulltext
Kaposi Sarcoma 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 nutrients). 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. 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. Figure 1: Electron microscope image through 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.
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. References http://journals.plos.org/plospathogens/article/file? id=10.1371/journal.ppat.1004581&type=printable 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
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.
http://www.pathologyoutlines.com/topic/ lymphnodesks.html
https://www.cancer.org/cancer/kaposi-sarcoma/causesrisks-prevention/what-causes.html
https://herpesfactorfiction.wordpress.com/kaposissarcoma-associated-herpesvirus/
https://www.youtube.com/watch?v=wtROBwDeHJ4 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.
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Structure of the brain The brain, is the most complex organ in the human body (made up of over 100 billion neurons), yet scientists still do not understand how it functions. The overall function of the brain is: to regulate non-conscious processes and to coordinate most voluntary movements. This essay will focus on the complex anatomy of the brain, and how each individual substructure contributes to the normal functioning of the brain. Figure 1
The largest part of the brain is called the cerebrum, which is composed of four lobes, as shown in figure 1. It is divided in to two cerebral hemispheres, which are connected via a structure made of nerve fibres, called the corpus callosum. The cerebrum has the iconic folded surface structure, with each individual having a unique pattern. The grooves on the surface are called sulci, and the ridges are called gyri. These patterns separate the 4 lobes, so that each lobe is distinct. To begin with, the functions of the different lobes should be understood. The frontal lobe controls movement and speech of an individual, which inevitably determines their “personality”. The parietal lobe perceives and interprets pain, pressure, temperature and sense of touch. The duty of the occipital lobe is to analyse and interpret visual information from sensory nerve signals from the eyes. Finally, the functions of the temporal lobe are to recognise sounds, and decipher the tone and loudness, and memory storage. Did you know? The brain is 75% water.
The brain consists of a plethora of inner structures, which all play different roles in the functioning of the brain. The cerebellum is the second largest part of the brain, and is located directly posterior to the brain stem (see Figure 1). It takes up one tenth of the volume of the brain, and is responsible for the balance and posture of an individual. The brainstem regulates heartbeat and respiration. It is composed of three structures: the midbrain (most superior), pons, and the medulla oblongata (most inferior). The brain is surrounded by the meninges tissue, which is composed of 3 membranes, and protects the brain and the spinal cord. The diencephalon (superior to the brainstem), consists of the thalamus, hypothalamus and pituitary gland. The thalamus is involved in relaying nerve signals to the central cerebral cortex; the hypothalamus regulates body temperature and the autonomic nervous system; and the pituitary gland (also known as the “master gland”) controls other glands in the body. The brain is 2% of an individual’s body weight (3lbs), yet it needs 20% of the blood supply. For the brain to function normally, it needs a supply of oxygen and glucose, which can only reach via the blood. Within 4-8 minutes of oxygen deprivation, major brain damage can occur, with the possibility of death. In order to prevent this 100,000 miles of blood vessels supply the brain. This abundance of blood stems from several places. The carotid arteries on the side of one’s neck, and the vertebral arteries which run alongside the spinal cord are the main suppliers of blood to the brain. References Figures 1 and 2: www.anatomy-bodychart.us The Concise Human Body Book- Steve Parker
Image provided courtesy of AAAS