Or is it?
So far, 1424 syndromes, 18 different categories of diseases or disorders adding up to over 100,000 known diseases with 42 of them currently deemed incurable and 135 types of cancers have been identified. Diseases can include cancers, cutaneous conditions and originate possibly from the eye, intestines, heart, liver, voice, vulvavaginal area, brain or the environment such as infectious viruses, pathogens and harmful bacteria. I won’t be listing all of the known syndromes, cancers, diseases and disorders but you can check them out via the links below.
https://en.wikipedia.org/wiki/Lists_of_diseases
https://en.wikipedia.org/wiki/List_of_incurable_diseases
https://en.wikipedia.org/wiki/List_of_cancer_types
https://en.wikipedia.org/wiki/List_of_syndromes
For simplicity’s sake, I’ll be discussing the most common diseases, cancers, disorders and syndromes that affect the majority of us. You’ll hear doctors, medical researchers and scientists use the terms ‘disease’, ‘disorder’, ‘morbidity’, ‘illness’, ‘sickness’ and ‘syndrome’ interchangeably, but do they have any differences or similarities? A disease is an abnormal condition affecting part or all of an organism not caused by an external source which consists of a disorder of a structure or function, which usually serves as an evolutionary disadvantage. The study of diseases or specifically cause of diseases is called pathology. The study of the factors that cause or drive the pathogenesis of diseases is called epidemiology. Diseases are often construed as medical conditions associated with multiple specific signs and symptoms. They can be caused by external forces such as pathogens or by internal dysfunctions such as immunodeficiency or hypersensitivity, including allergens and autoimmunity. When humans are afflicted by diseases, they display conditions that cause them pain, dysfunction, distress, social problems or death. Broadly speaking, it may include injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviours and atypical variations of structure and function. Diseases may also affect victims emotionally by affecting their perspective on life whilst living with it. When you hear a person die by natural causes, they refer to diseases as their cause of death. There are different categories of diseases: Infectious, Deficiency, Genetic (both hereditary and non-hereditary) and Physiological. It’s easy to get the concepts of disease discombobulated because of the way it’s loosely used in medical prose, scientific literature and general conversations. Hence I’ll try to clarify and distinguish each and every one of the following phrases.
- Disease = Any condition impairing the normal functioning of an organism’s body. They are associated with dysfunction of the body’s normal homeostatic processes. In epidemiology, researchers refer specifically to infectious diseases that result from the presence of pathogenic microbial agents, including viruses, bacteria, fungi, protozoa, multicelullar organisms and aberrant proteins known as prions. Infections that doesn’t or won’t produce clinical evidence of impairment of normal functioning such as normal bacteria and yeast in the gut or passenger viruses aren’t considered as diseases. In fact, infections that are asymptomatic during its incubation period, but are expected to produce symptoms later are often considered as diseases such as HIV. Non-infectious diseases account for all other diseases including cancers, heart disease and genetic disease.
- Acquired Disease = Diseases beginning at some point during your lifetime, as opposed to diseases that were already present at birth.
- Acute Disease = Diseases of short-term (fulminant) nature
- Chronic Disease = Diseases of long-term nature
- Congenital Disease = Diseases present at birth. The causes are often genetic and can be inherited by the parents. It can also be the result of vertically transmitted infection from the mother such as HIV / AIDS.
- Genetic Disease = Diseases caused by genetic mutations that are often inherited but sometimes occur randomly and de novo.
- Hereditary or Inherited Disease = A type of genetic disease caused by mutations that are hereditary meaning it can run in families.
- Latrogenic Disease = Disease conditions caused by medical intervention
- Idiopathic Disease = Diseases with unknown causes. However medical science advances, there’s hope we can find plausible and rational explanations to diseases that were once complete mysteries. e.g. Some Diabetes Mellitus Type 1 are the cause of autoimmunity but the molecular basis involved is not yet understood.
- Incurable Disease = Diseases that currently don’t have a cure
- Primary Disease = Diseases that come about as a root cause of illness
- Secondary Disease = Diseases that is a sequela or complication of other disease or underlying causes (root cause). e.g. Bacterial infections can either be primary (healthy prior to arrival of bacteria) or secondary to a viral infection or burn, which predisposed by opening up a wound or weaken the immune system (otherwise the bacteria wouldn’t have been established).
- Terminal Disease = Diseases that inevitable will end an organism’s life
- Illness = By definition, it’s a synonym for disease. However patients occasionally use this term to refer specifically to their personal experience of the same disease and this interchangeable use of terms can create a paradox. You can be suffering from a disease without being ill, in the case of objectively definable but asymptomatic medical condition such as subclinical infections. You can also be ill without suffering from any disease, in the case of a patient perceiving a normal experience as a medical condition or medicalising a non-disease situation in their life. e.g. People feeling unwell as a result of embarrassment which can be interpreted as sickness rather than normal emotions. Symptoms of illnesses aren’t often directly the result of infection, but an accumulation of evolved responses like sickness behaviour by the body to help clear the infection. Examples of such illnesses include lethargy, depression, loss of appetite, sleepiness, hyperalgesia and inability to concentrate.
- Disorder = A functional abnormality or disturbance of the body biological mechanisms, structure and function. They can be categorised into Mental, Physical, Genetic, Emotional and Behavioural, and Functional. This term is often considered more value-neutral and less stigmatising than other terms ‘disease’ or ‘illness’, therefore it is the preferred terminology in some circumstances. In mental health, mental disorder is a term that acknowledges the complex interaction of the biological, social and psychological factors in psychiatric conditions.
- Medical Condition = A broad term including all diseases, lesions, disorders, or non-pathological condition that normally receive medical treatment such as pregnancy. In some contexts, this term is used specifically to denote any illness, injury or disease except for mental illnesses, unless used in a general sense. The Diagnostic and Statistical Manual of Mental Disorders (DSM) uses the term ‘general medical condition’ to refer to all diseases, illnesses and injuries except for mental disorders. As it is more value-neutral term, it is often preferred by people with health issues that they don’t consider deleterious. If the medical nature of the condition needs to be emphasised, other terms are used. It is also a synonym for ‘medical state’, which describes an individual patient’s current state from a medical standpoint. You’ll hear news bulletins describing the condition of patients and victims as being in critical or stable condition.
- Morbidity = Derived from the Latin morbidus, meaning ‘sick, unhealthy’, it is defined as a diseased state, disability, or poor health due to any cause. It may refer to the existence of any form of disease, or to the degree that the health condition greatly affects the patient. Patients who are severely ill have a level of morbidity measured by ICU scoring systems. Comorbidity is the simultaneous presence of 2 or more medical conditions, such as Schizophrenia and Substance Abuse. In epidemiology and actuarial science, the term “morbidity rate” refers to either the estimated incidence rate of a certain disease or the prevalence of a disease or medical condition. On the other hand, "mortality rate” refers to the proportion of people dying during a given time interval. In actuarial professions such as health, life and long-term insurances, 'morbidity rate’ is used to determine the correct premiums to charge to customers. It helps insurers predict the likelihood that an insured people will contract or develop any number of specified diseases.
- Pathosis or Pathology = These terms are synonymous with ‘disease’.
- Syndrome = An association of several medical signs, symptoms, or other characteristics that often occur concurrently. e.g. Down Syndrome has only 1 cause, whereas Parkinsonian syndrome has multiple causes.
- Pre-disease = A subclinical or prodromal vanguard of a disease state. e.g. Prediabetes and Prehypertension. The nosology or epistemology of pre disease is a contentious topic because there is “seldom a bright line differentiating a legitimate concern for subclinical / prodromal / premonitory status on one hand and conflict of interest—driven disease mongering or medicalisation on the other hand. Nevertheless, if doctors and scientists can identify legitimate pre-disease, this would certainly result in useful preventive measures such as motivating the patient to perform and maintain a healthy amount of physical exercise. However, precaution must be taken when labelling a healthy person with an unfounded notion of predisease. This increases the risk of overtreatment, hence a drug overdose which would normally help people with severe disease or paying for drug prescription instances whose benefit-cost analysis is minuscule.
- Mental Illness = A broad, generic label for category of illnesses including affective or emotional instability, behavioural dysregulation, cognitive dysfunction or impairment. They can be of biological (e.g. anatomical, chemical or genetic) or psychological (e.g. trauma or conflict) origin. Having a mental illness can impair a person’s ability to work or study and can harm interpersonal relationships. Examples include Major Depression, Generalised Anxiety Disorders, Schizophrenia and Attention Deficit Hyperactivity Disorder (ADHD).
- Organic Disease = Diseases caused by a physical or physiological change to some tissue or organ of the body. This includes emotional and behaviour disorders if they are due to changes to the physical structures of functioning of the body, such as after a stroke or a traumatic brain injury, but not if they are due to psychosocial issues.
- Clinical Disease = The stage of the disease that produces characteristic signs and symptoms of that disease. e.g. AIDS is the clinical disease stage of HIV infection.
- Cure = This stage marks the end of a medical condition or a treatment that is likely to end it. - Remission refers to the disappearance, possibly temporarily, of symptoms. Complete remission is the best possible outcome for incurable diseases.
- Flare-up = Refers to either the recurrence of symptoms or an onset of more severe symptoms.
- Progressive Disease = A disease whose typical nature course is the worsening of the disease until death, serious debility, or organ failure occurs. Slowly progressive diseases are also called chronic diseases, many of which are degenerative diseases like Parkinson’s Disease & Alzheimer’s Disease. The antonym of progressive disease is Stable or Static Disease meaning an existing medical condition that doesn’t improve or worsen.
- Subclinical Disease = Silent Disease, Silent Stage, Asymptomatic Disease. A stage in some diseases before the first symptoms are noted.
- Terminal Phase = The stage between the earlier disease process and active dying. This means a person will die soon from a disease, regardless of whether that disease typically causes death.
- Localised Disease = A disease that affects only 1 part of the body, such as athletes’s foot or an eye infection.
- Disseminated Disease = A disease that has spread to other parts of the body. Cancer is classified as a metastatic disease.
- Systemic Disease = A disease that has affected the entire body e.g. Influenza or hypertension.
- Airborne Disease = Diseases caused by pathogens and transmitted through the air.
- Foodborne Disease = Food poisoning, any illness resulting from the consumption of food contaminated with pathogenic bacteria, toxins, viruses, prions or parasites.
- Infectious Disease = Transmissable or Communicable Diseases, comprises of clinically evident illness (i.e. characteristic medical signs or symptoms of disease) resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism. This includes contagious diseases like infections such as influenza or the common cold which commonly spreads from one person to another. - Communicable Diseases doesn’t require everyday contact to spread from one person to another.
- Lifestyle Disease = Diseases that appear to increase in frequency as countries become more industrialised and people living longer lives, especially if the risk factors include behavioural choices like a sedentary lifestyle or a diet high in unhealthful foods such as refined carbohydrates, trans-saturated fats or alcoholic beverages.
- Non-communicable Disease = Diseases that are non-transmissable meaning they don’t spread directly from one person to another. e.g. Heart Disease & Cancer
- Disease Burden = Impact of a health problem in an area measured by financial cost, mortality, morbidity or other indicators.
https://en.wikipedia.org/wiki/List_of_epidemics
https://en.wikipedia.org/wiki/Epidemic
https://en.wikipedia.org/wiki/Ebola_virus
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495366/
https://www.youtube.com/watch?v=sRv19gkZ4E0&t=210s
1. The virus begins its attack by attaching to host receptors through the Glycoprotein Surface Peplomer, on Dendritic Cells for instance.
2. This is then endocytosed into Macropinosomes in the host cell.
3. It then penetrates the cell by fusing its viral membrane with the vesicle membrane and the nucleocapsid is released into the cytoplasm.
4. Now encapsidated, the RNA virus is used as a template for synthesis of polyadenylated, monocistronic mRNAs and, using the host cell’s ribosomes, tRNA molecules etc., the mRNA is translate into individual viral proteins.
5. These viral proteins called Glycoprotein precursors (GP0) become cleaved to form GP1 and GP2, which are then heavily glycosylated using the host’s cellular enzymes and substrates.
6. GP1 and GP2 assemble together, first into heterodimers, and then into trimers to give the surface peplomers.
7. Secreted Glycoprotein precursors (sGP) are then cleaved to sGP and δ peptides, which would be released from the cell.
8. As the level of viral protein increases, there is a switch from translation to replication.
9. Using the negative-sense single-stranded genomic RNA as a template, a complementary positive-sense single-stranded RNA is synthesised to be then used as a template for the synthesis of new viral RNA strands.
10. The above steps are repeated continuously for a infinite amount of time until it kills the crucial immune cells and other bodily cells causing the person’s death.
Because Dendritic Cells are infected by the Ebolavirus, they aren’t able to perform its usual adaptive immune functions like producing and secreting cytokines, including type-I Interferons (IFN), and undergoing a correct maturation process, perform effector functions by activating Macrophages and Monocytes when it detects a foreign pathogen. Furthermore viral proteins impair 1 of 3 signals required for CD4 T-Cell activation by inhibiting CD80 and CD86 ligands, which impairs B-Cell help and CD8 T-Cells, leading to apoptosis of T-Cells and undifferentiated mature B-Cells. The B-Cells’ antibodies have their BCR, surface Ig or antibodies blocked by sGP or GlycGP causing misdirection and prohibition of opsonisation and capturing the virion to be presented to healthy Dendritic Cells. In the peripheral bloodstream, Natural Killer Cells (NK) can lend a hand in killing the virus but it is vulnerable to being infected by the virus hence their numbers will eventually dwindle, failing to mediate direct protective cytotoxicity and drive adaptive immune system by helping DC maturation.
https://en.wikipedia.org/wiki/Cocoliztli_epidemics
However that wasn’t the worst epidemic. A notable but forgotten epidemic dates back to 1545 & then again in 1576 when 5-15 million (80% of the population) and then a further 2 - 2.5 million people (50% of the population) respectively died of Viral Haemorrhagic Fever in Cocoliztli, Mexico. The cause of this epidemic remains unknown to this day. There are speculations that it might have been an indigenous viral haemorrhagic fever, probably exacerbated by the worst droughts to affect Cocolizti in 500 years and miserable living conditions for indigenous Mexicans in the wake of the European invasion circa 1519. In 2018, there was news of a discovery of DNA recovered from the teeth of 29 skeletons that belonged to a rare strain of a bacterium called Salmonella enterica subsp. enterica. This may have caused paratyphoid fever but research is still ongoing as you read this.
https://en.wikipedia.org/wiki/1918_flu_pandemic
- 17 million Indians including 13.88 million of those living in its British-ruled districts
- 390,000 Japanese
- 1.5 million Dutch East Indies (now known as Indonesian)
- 38,000 Samoans
- 13% of Tahiti’s population
- Between 902,400 and 2,431,000 Iranians
- Between 500,000 and 675,000 Americans especially those living in Native Americans tribes and Alaska
- 50,000 Canadians
- 300,000 Brazilians including president Rodrigues Alves
- 250,000 Britons
- More than 400,000 French
- At least 100,000 Ghanians
- 7% of British Somaliland’s population
- 5,000 to 10,000 Ethiopians living in their capital city, Addis Ababa
- 8% of Tongans
- 16% of Nauruns
- 5% of Fijians
- 62% of German Samoans (known now as the independent state of Samoa)
- 8,573 New Zealanders
- 10% of Irish population
- 12,000 Australians
Places that miraculously escaped the outbreak with not a single death reported were American Samoa, French colony of New Caledonia, the island of Marajó in Brazil’s Amazon River Delta and Saint Helena.
The percentage of deaths were disproportionately distributed across juvenile, elderly, already immunologically weakened patients and surprisingly healthy young adults. In 1918-1919, 99% of the influenza pandemic deaths in the USA alone, were people under the age of 65, and nearly 50% of the deaths were young adults aged 20 to 40. These death toll statistics were unusual since influenza was usually fatal to immunologically weak individuals, such as infants under the age of 2 and the elderly over the age of 70, and the immunocompromised.
In August 1918, a much deadlier second wave of the influenza pandemic struck France, Sierra Leone and the United States of America, which lead to the realisation that the virus had mutated to a form our bodies’ immune systems wasn’t prepared for considering it was still trying to clear out the first wave of influenza virus.
- Where did the virus come from?
- Who were the first to be infected?
- How and why did this virus strain spread across Earth so quickly and infected so many people?
- How and why did it claim so many lives in a short space of time?
- How come doctors, virologists and immunologists at the time struggled find a strategy and develop a cure to eliminate this virus completely from our systems?
Initial reports by Alfred W. Crosby and then John Barry hypothesised Haskell County in the US state of Kansas as the point of origin. But investigative work in 1999 by a British team led by virologist John Oxford of St Bartholomew’s Hospital and the Royal London Hospital refuted earlier hypotheses and identified a hospital camp in Étaples, France as the centre of pandemic. The camp housed wounded soldiers who were been hospitalised by many nurses and medical staff. You ask why there are soldiers here in the first place, it is because the pandemic occurred during World War 1 when France & Britain declared war against Germany following the assassination of Austrian Archduke Franz Ferdinand on 28 June 1914. I’ll delve into the world wars and other battles in another post. Because the hospital camp was overcrowded with as many as 100,000 wounded soldiers admitted there every day, it was the perfect site for the spreading of a respiratory virus. The camp was also home to a live piggery, and poultry was regularly transported in from surrounding villages to feed the wounded soldiers. Oxford and his team postulated a significant precursor virus, harboured in birds, mutated so it could migrate to pigs that were stored near the front of the camp. This debate about the exact origins of the influenza virus is still ongoing and no one can unanimously agree on it, which is frustrating for scientists and human civilisation.
https://news.nationalgeographic.com/news/2014/01/140123-spanish-flu-1918-china-origins-pandemic-science-health/
— The source of the influenza virus were at the World War I trenches in Aldershot, UK and Étaples, France.
— In 1917, the first stirrings of the flu showed the first signs of the respiratory disease outbreak in the Shanxi Province of China.
— 48 soldiers at Camp Funston in the US state of Kansas were believed to be the first fatalities just ahead of the outbreak.
Are any of these theories true? Can any of them be proven correct?
According to Jeffrey Taubenberger, of the National Institute of Allergy and Infectious Diseases, several burial samples of the virus are required across different continents in order to find preserved samples of the virus in the victims of the outbreak. The aim for scientists is to find a genetically identified sample of the H1N1 Influenza Virus taken from a victim who died before the first widespread outbreak of the pandemic in the spring of 1918. If they successfully find this victim, it would help narrow down its possible origins and point to a time and place as the likely origin point of the pandemic.
https://www.youtube.com/watch?v=T_me5EF0ne4
https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H1N1
If an Influenza virion enters your body, you will feel symptoms after 1 or 2 days onset. Those symptoms commonly include high fever, runny nose, , sore throat, muscle pains, headache, coughing, fatigue, nasal congestion, sneezing, hoarseness, ear pressure, earache, muscle aches, irritated or watery eyes, reddened eyes, skin (esp. face), mouth, throat and nose, petechial rash. In children, gastrointestinal symptoms are observed such as diarrhoea, vomiting and abdominal pain. Those early-stage symptoms are almost identical to those of the common cold, making it difficult to distinguish it from the influenza. Influenza, in fact, is a combination of symptoms of common cold and pneumonia, body ache, headache and fatigue.
Influenza virus are RNA viruses that make up 3 of the 5 genera of the family Orthomyyoviridae.
Influenzavirus A:
This genus has 1 viral species, influenza A virus. It’s known that wild aquatic birds are the natural hosts of a variety of influenza A viruses. Occasionally they are transmitted it other animal species and may then cause devastating outbreaks in domestic poultry giving rise to human influenza pandemics. According to history, Influenza A is wildly known as the most virulent human pathogens among the 3 influenza types causing the severest disease. It is subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans are:
H1N1: Caused the 1918 Spanish Flu and 2009 Swine Flu
H2N2: Caused the 1957 Asian Flu
H3N2: Caused the 1968 Hong Kong Flu
H5N1: Caused the 2004 Bird Flu
H7N7
H1N2
H9N2
H7N2
H10N7
H7N9
Influenzavirus B:
This virus types almost exclusively infects humans but is less common than influenza A. Other susceptible animals are seals and ferrets. Influenza B mutates at a rate 2 to 3 times slower than type A and consequently is less genetically diverse, with only 1 serotype. This lack of antigenic diversity acquires a degree of immunity to this virus type at an early age. However its mutation rate is adequate for lasting immunity to not be possible.
Influenzavirus C:
This virus type infects humans, dogs and pigs causing both severe illness and local epidemics. It’s less common than the other types and usually only causes mild disease in children.
— Haemagglutinin (HA)
— Neuraminidase (NA)
— Nucleoprotein (NP)
— M1, M2, NS1, NS2 (NEP, Nuclear Export Protein)
— PA, PB1 (Polymerase Basic 1), PB1-F2 and PB2.
Haemagglutinin (HA) and Neuraminidase (NA) are the 2 large glycoproteins that make up the surface of viral particles. HA is a Lectin that mediates the binding of the virus to target cells and entry of the viral genome into the target cell. NA is involved in the release of progeny virus from infected cells by cleaving carbohydrates that bind the mature viral particles. These glycoproteins are antigens to which antibodies can be raised but antibody responses vary which is why there are different subtypes of Influenza A viruses. These different types of HA and NA form the basis of the H & N distinctions. e.g. H5N1 vs H1N1. So there are 16 H and 9 N subtypes known, but only H1, 2 & 3 and N1 & 2 are commonly found in humans.
2. After the Hemagglutinin is cleaved by a Protease, the cell imports the virus by endocytosis.
3. The intracellular details are still being elucidated. Virions then converge to the Microtubule organising centre, interact with acidic Endosomes and finally enter the target Endosomes for genome release. Once inside the cell, the acidic conditions in the Endosome causes 2 events to occur:
4. Part of the Hemagglutinin fuses the viral envelope with the Vacuole’s membrane.
5. The M2 ion channel allows protons (H+ ions) to move through the viral envelope and acidify the core of the virus.
6. This causes the core to disassemble and release the viral RNA and core proteins.
7. The viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA Polymerase are then released into the cytoplasm.
8. These core proteins and vRNA form a complex that is then transported into the cell nucleus.
9. Inside the cell nucleus, RNA-dependent RNA Polymerase begins transcription of complementary positive-sense vRNA.
10. The vRNA is either exported to the cytoplasm and translated or remains in the nucleus.
11. Newly synthesised viral proteins from the vRNA genome are either secreted through the Golgi apparatus onto the cell surface (via NA & HA) or transported back into the nucleus to bind vRNA and form new genome particles.
12. Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.
13. Negative-sense viral RNAs that form the genomes of future viruses, RNA-dependent RNA Polymerase and other viral proteins are assembled into a virion.
14. HA & NA molecules then cluster into a bulge in the cell membrane.
15. vRNA and viral core proteins leave the nucleus and enter this membrane protrusion.
16. Mature virus buds off from the cell membrane in a sphere of host phospholipid membrane, acquiring HA and NA with this membrane coat.
17. Viruses adhere to another cell through HA and mature viruses detach once their NA has cleaved Sialic Acid residues from the host cell.
18. After the release of new influenza viruses, the host cell will die.
Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the viral genome makes an error every 10,000 nucleotides. Therefore the majority of newly manufactured influenza viruses are mutants. This causes a phenomenon called antigenic drift, which is a slow change in the antigens on the viral surface over time. The separation of the genome into 8 separate vRNA segments allows reassortment or mixing of vRNAs if more than 1 type of influenza virus infects a single cell. As a result, the rapid changes in viral genetics would produce antigenic shifts, which are sudden changes from 1 antigen to another. These antigenic shifts allow the virus to infect new host species and quickly overcome their protective immune systems. This poses significant challenges for immunologists and virologists to procure a vaccine for each mutant of influenza virus. A few questions spark to my mind:
- Where did these virus particles come from?
- Why do viruses exist?
- If you need an RNA-dependent RNA polymerase to transcribe and translate the viral RNA genome into viral proteins, then what created the RNA-dependent RNA polymerase since it’s a protein itself?
- How did viruses evolve to create their own genetic instructions to invade, infect specific host organisms in order to survive?
- Are viruses conscious?
I’ll try to look deep into viruses in another post.
https://en.wikipedia.org/wiki/Black_Death
The worst ever epidemic so far dates back to 1346-1350 when 75 - 200 million people, roughly 30-60% of the world’s population at the time, died across Europe, Asia and North America. That epidemic is famously known as ‘The Black Death’. It was caused by a plague of a harmful bacteria called Yersinia Pestis. The plague disease is enzootic (commonly present) in populations of fleas carried by ground rodents in various areas including Central Asia, Kurdistan, Western Asia, Northern India and Uganda. Due to climate change in Asia, rodents flee the dried out grasslands to more populated areas, hence spreading the disease. The first references of the plague were discovered in Nestorian graves dating back to 1338 - 1339 near Lake Issyk Kul in Kyrgyzstan. Epidemiologists believed these inscriptions marked the outbreak of the epidemic, from which it may have spread to China and India. It’s estimated about 25 million Chinese and other Asians died 15 years before the Black Death reached Constantiopole in 1347. The disease may have travelled along the Silk Road with Mongol armies and traders or via ship. By the end of 1346, reports of plague had reached the seaports of Europe stating: “India was depopulated, Tartary, Mesopotamia, Syria, Armenia were covered with dead bodies. In 1346, Genoese traders working at the port city of Kaffa in the Crimea were reportedly the first infected by the plague. After a protracted siege during which the Monogol army under Jani Beg was also suffering the disease, the army catapulted infected corpses over the city walls of Kaffa to infect the inhabitants. This forced Genoese traders fled, taking the plague with them by ship into Sicily and south of Europe, whence it spread north. This hypothesis is yet to be proven but it’s clear several existing conditions like war, famine and climate contributed to the severity of the Black Death.
When 12 Genoese galleys reached Sicily in October 1347, the plague spread all over the entire island. In January 1348, other Genoese galleys reaches Genoa and Venice but it was the outbreak in Pisa a few weeks later that became the plague’s entry point to northern Italy. Towards the end of January, one of the galleys expelled from Italy arrived in Marseille. From then, the disease spread northwest from Italy across Europe towards France, Spain, Portugal and England by June 1348, then turned and spread east through Germany and Scandinavia from 1348 to 1350. In 1349, a ship also the disease landed at Askøy, Norway, then spread to Bjørgvin (modern Bergen) and Iceland. Finally in 1351, it had spread to northwestern Russia. Countries and communities with smaller trade relations with their neighbours reported less cases of the plague including the majority of the Basque Country, isolated parts of Belgium and the Netherlands, and isolate alpine villages throughout Europe.
The plague also struck various regions in the Middle East during the pandemic, leading to serious depopulation and permanent change in both economic and social structures. As the disease spread from China with the Mongols to a Chinese trading post in Crimea, called Kaffa, used by the Republic of Genoa. From there the disease infected rodents which infecting new rodents and then those rodents entered the region from southern Russia also. By autumn of 1347, the plague reached Alexandria in Egypt, through the port’s trade with Constantinopole, and ports on the Black Sea. During 1347, the disease then travelled eastward to Gaza, and north along the eastern coast to cities in Lebanon, Syria and Palestine, including Ashkelon, Acre, Jerusalem, Sidon, Damascus, Homs and Aleppo. In 1348 - 1349, the disease reached Antioch. Those residents fled to the north, however most of them succumbed to the disease during the long and arduous journey north on foot. In 1349, the cities of Mecca, Mawsil (Mosul) and Baghdad also experienced massive epidemics.
The most common symptoms of the Black Death included buboes (or gavocciolos) in the groin, neck and armpits, which oozed pus and bled when opened. This was followed by acute fever and vomiting of blood. Most victims died within 2 to 7 days of being infected with Yersinia Pestis. Freckle-like spots and rashes caused by flea-bites were also identified as another potential sign of the plague.
In 1894, a team of scientists investigated a similar plague presumably caused by the same pathogen. Among whom was the French-Swiss bacteriologist Alexandre Yersin, after whom the pathogen was named Yersinia Pestis. In 1898, Paul-Louis Simond established the mechanism by which this pathogen was usually transmitted. It was found to involve the bites of fleas whose midguts had become obstructed by replicating Yersinia Pestis several days after feeding on an infected host. This blockage resulted in starvation and aggressive feeding behaviour by the fleas, which repeatedly attempt to clear this blockage by regurgitation, resulting in 1000s of plague bacteria being flushed into the feeding site, infecting the host. The bubonic plague mechanism was also dependent on 2 populations of rodents: 1 resistant to the disease, which act as hosts, keeping the disease endemic and another that lack resistance. When the 2nd population dies, the fleas move on to other hosts, including humans, thus creating a human epidemic.
Now we have access to antibiotics that can kill or eliminate Yersinia Pestis successfully and decrease the mortality rate for the modern bubonic plague to about 11%, though it may be higher in underdeveloped regions. If you are infected by Yersinia Pestis, you will have a fever of 38 - 41 oC (100 - 106 oF), suffer from headaches, painful aching joints, nausea and vomiting, and a general feeling of malaise. If you remain untreated within 8 days, death is inevitable.
https://en.wikipedia.org/wiki/Epidemic
https://en.wikipedia.org/wiki/Pandemic
https://en.wikipedia.org/wiki/Vaccine
https://en.wikipedia.org/wiki/Vaccination
- Occasionally immune protection fails because a host’s immune system doesn’t adequately respond to the vaccine at all possibly from clinical factors such as Diabetes, Steroid Use, HIV infection and age.
- Moreover there may be a lack of B-Cells strains that could generate antibodies suited to reacting effectively and binding to the antigens associated with the pathogen.
- Even if the host does develop antibodies, protection mightn’t be adequate and immunity develops too slowly to be effective in time to fit the vaccination schedule.
- Antibodies mightn’t disable the pathogen completely or there are multiple strains of pathogen, and not all of which are equally susceptible to the immune reaction.
There are different types of vaccines currently in use.
(a) Inactivated: These vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat or radiation
e.g. Polio, Hepatitis A, Rabies and some Influenza vaccines
(b) Attenuated: These vaccines contain live, attenuated micro-organisms. Many of which are active viruses that have been cultivated under conditions that disable their virulent character or that use closely related but less dangerous organisms to produce a broad immune response. They can be viral or bacterial in nature
e.g. Yellow Fever, Measles, Mumps, Rubella and Typhoid Vaccines. However there are some exceptions. The live Mycobacterium Tuberculosis vaccine isn’t made of a contagious strain but contains a virulently modified strain called “BCG”, which is used to elicit an immune response to the vaccine. The live Yersinia Pestis EV vaccine is used for plague immunisation.
(c) Toxoid: These are made from inactivated toxic compounds that cause illness rather than the micro-organism.
e.g. Tetanus and Diphtheria. They are known for their efficacy. However, not all toxoids target micro-organisms such as the Crotalux Atrox toxoid used to vaccinate dogs against rattlesnake bites.
(d) Subunit: Better known as Protein Subunits, they are fragments of inactivated or attenuated micro-organisms to elicit an immune response.
e.g. Hepatitis B virus subunit vaccine composes of only the surface proteins of the virus which was previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast.
e.g. Virus-like Particle (VLP) vaccine against HPV (Human Papillomavirus) composes of the viral major capsid protein
e.g. Hemagglutinin & Neuraminidase subunits of the Influenza virus.
(e) Conjugate: These vaccines contain poorly immunogenic polysaccharide outer coats found on certain bacteria that are linked to proteins. This will lead to the immune system recognising the polysaccharide as if it were a protein antigen.
e.g. Haemophilus Influenzae Type B vaccine
(f) Experimental: These innovative vaccines are currently in development or in use:
- Dendritic Cell Vaccines = These vaccines combine Dendritic Cells with antigens in order to present the antigens to the body’s White Blood Cells (WBC), thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumours and malignant melanoma.
- Recombinant Vector = These vaccines are a combination of the physiology of 1 micro-organism and the DNA of another in order to generate immunity against diseases that have complex infection processes.
- DNA Vaccination = These vaccines are still under development, though it is created from an infectious agent’s DNA. The proposed mechanism is inserting (and expressing, enhanced by the use of electroporation which triggers an immune system recognition) viral or bacterial DNA into human or animal cells. Some immune cells will recognise these expressed proteins and then launch an attach against these proteins and the cells expressing them. Because these cells have a longer half-life, if the pathogen that normally expresses the same proteins is encountered at a later time, they will be attacked instantly by the immune system.
- T-Cell Receptor Peptide Vaccine = These vaccines are still under development for several diseases using models of Valley Fever, Stomatitis and Atopic Dermatitis. These peptides vaccines have been shown to modulate cytokine production and improve cell-mediate immunity.
Whilst most experimental vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly of synthetic peptides, carbohydrates, or antigens.
(g) Valence: Vaccines can be monovalent (univalent) or multivalent (polyvalent). Monovalent vaccines are designed to immunise against a single antigen or a single micro-organism. Multivalent vaccines are designed to immunise against 2 or more strains of the same micro-organism or against 2 or more micro-organisms.
(h) Heterotypic: Also known as heterologous or “Jennerian” vaccines, these vaccines are pathogens of other animals that either don’t cause disease or cause mild disease in the organism being treated.
e.g. A classic example is Jenner’s use of cowpox to protect against smallpox.
e.g. Current example is the use of BCG vaccine made from Mycobacterium Bovis to protect against human tuberculosis.
Nonetheless a wide array of vaccine critics oppose vaccinations since the earliest campaigns of compulsory vaccinations in the 19th century. Although the benefits of preventing serious illness and death from infectious diseases far outweigh the risks of rare serious adverse effects following immunisation, disputes have arisen over the morality, ethics, effectiveness, and safety of vaccination. Those critics include political groups, religious groups and overprotective parents, known as anti-vaccinationists (anti-vaccs). They claimed that vaccinations would cause autism in their children, despite the lack of scientific evidence to support this myth. Is this myth theoretically and scientifically true? In 1988 a paper was published by Andrew Wakefield in The Lancet regarding the MMR vaccine controversy. It was discovered that the paper presented false evidence that the MMR vaccine was linked on the onset of Autism Spectrum Disorders. MMR vaccines normally immunise against Measles, Mumps and Rubella (MMR) in children shortly after their first birthday. It was widely criticised for a lack of scientific rigour and the paper was retracted by The Lancet in 2010. As a result, Wakefield was struck off the UK’s medical registry and subsequently stripped of his medical licence under fraud charges. However, this myth still lingers around the anti-vaccination movement with 1 in 4 parents (especially in USA) still believe that vaccines can cause autism. As a result, a large percentage of measles cases along with subsequent cases of permanent hearing loss and death caused by measles were American people who refused to be vaccinated under non-medical reasons. In 2010, California experienced the worst whooping cough outbreak since 1960 with majority of patients unvaccinated children.
https://en.wikipedia.org/wiki/Causes_of_autism
https://en.wikipedia.org/wiki/Autism
Autistic children demonstrate a characteristic triad of symptoms such as impairments in social interaction, impairment in communication and restricted interests and repetitive behaviour. They have social impairments and often lack the intuition about others that many people take for granted. Autistic infants show less attention to social stimuli, smile and look at others less often, and respond less to their own name. Autistic toddlers differ more resoundingly from many social norms.
— Reduce eye contact and turn-taking
— Inability to use simple movements to express themselves such as pointing at things.
When autistic children turn 3, 4 or 5, they are less likely to exhibit social understanding, approach others spontaneously, imitate and respond to emotions, communicate non-verbally, and take turns with others. Nonetheless, they form attachments to their primary caregivers. When autistic children mature into adulthood they perform worse on tests of face and emotion recognition.
Children with high-functioning autism suffer from intense and frequent loneliness, despite the common belief that autistic children are introverted i.e. prefer to be alone. They often have difficulty making and maintaining friendships, thus for them, the quality of their friendships predicts how lonely they feel rather than the number of friends they have. Functional friendships, such as those resulting in invitations to parties, may affect their quality of life even more deeply. There are hypotheses that children suffering from ASD may be prone to aggression, violence, destruction of property and throwing tantrums but research is limited.
About a 3rd to a half of autistic people don’t develop adequate natural speech to meet their daily communications needs. This includes:
— Delayed onset of babbling
— Unusual gestures
— Diminished responsiveness
— Vocal patterns that aren't synchronised with their caregiver.
Later on, this manifests into:
— Infrequent and limited babbling, consonants, vocabulary and word combinations, — Gestures are less often integrated with their words
— Less likelihood to make requests or share experiences
— More likelihood to simply repeat others’ words aka Echolalia or Reverse Pronouns.
Because joint attention is necessary for functional speech, deficits in it would distinguish autistic infants from non-autistic infants.
— They would look at a pointing hand instead of the object being pointed at.
— Consistently fail to point at objects in order to comment on or share an experience.
— Having difficulty with imaginative play and with developing symbols into language.
A pair of studies that included high-functioning children with autism aged 8-15 performed equally well as, and as adults better than, individually matched controls at basic language tasks involving vocabulary and spelling. However, both autistic groups performed worse than the controls at complex language takes such as figurative language, comprehension and inference. The findings from these studies suggest that people speaking to autistic individuals are more likely to overestimate what they comprehend.
Autistic individuals can demonstrate many forms of repetitive or restricted behaviours. The Repetitive Behaviour Scale-Revised (RBS-R) has labelled them into the following categories:
— Stereotyped Behaviours = Repetitive movements
e.g. Hand flapping, head rolling, or body rocking
— Compulsive Behaviours = Time-consuming behaviours intended to reduce anxiety that an individual feels compelled to perform repeatedly or according to rigid rules
e.g. Placing objects in a specific order, checking things, or hand washing.
— Sameness = Resistance to change
e.g. Insisting that furniture shouldn’t be moved or refused to be interrupted
— Ritualistic Behaviour = Unvarying pattern of daily activities. This is closely associated with sameness.
e.g. Unchanging menu or dressing ritual
— Restricted Interests = Interests or fixations that are abnormal in theme or intensity of focus
e.g. Preoccupation with a single television, program, toy, or game.
— Self-Injury = Behaviours that cause self-harm
e.g. Eye-poking, Skin-picking, Hand-biting, Head-banging
Note that no single repetitive or self-injurious behaviours is specific to autism. Only elevated patterns of occurrence and severity of these behaviours are indicative of autism.
Autistic individuals may have other symptoms that are independent of the diagnosis, but can affect the individual or the family. It’s estimated about 0.5% to 10% of individuals with ASD gain unusual abilities ranging from splinter skills such as memorisation of trivia to the extraordinarily rare talents of prodigious autistic savants.
Many ASD individuals display superior skills in perception and attention, relative to the general population, but also show sensory abnormalities. Differences are greater for under-responsivity (e.g. Walking into things) than for over-responsivity (e.g. Distress from loud noises) or for sensation seeking (e.g. Rhythmic movements). It’s estimated about 60 - 80% of autistic people have motor signs that include poor muscle tone, poor muscle planning, and toe walking, which are deficits are motor coordination. About 75% of ASD children show unusual eating behaviours with selectivity being the most common problem along with eating rituals and food refusal. However these behaviours don’t result in malnutrition. It’s unclear whether there’s a strong correlation between autism and gastrointestinal problems with a few published papers stating contradiction conclusions.
Unlike many other brain disorders, such as Parkinson’s Disease, scientists have yet to identify the underlying mechanism at either the molecular, cellular or systems levels that causes autism. Although there’s a high likelihood that heritability drives autism and ASD, most of the mutations that increase autism risk can’t be traced to a Mendelian (single-gene) mutation or a single chromosome abnormality. To further compound the dilemma, none of the genetic syndromes associated with ASDs have shown to selectively cause ASD. A large number of autistic individuals live amongst non-autistic family members which may suggest the cause is due to spontaneous structural variations of DNA such as deletions, duplications or inversions in genetic material during meiosis. Several studies have revealed evidence to synaptic dysfunction caused by rare mutations, such as malfunction with cell adhesion. Gene replacement studies in mice suggest that autistic symptoms correlate with latter developmental steps dependent on synaptic activity and on activity-dependent changes. All known teratogens (agents that cause birth defects) contributing to the risk of autism appear to act during the first 8 weeks after conception. Just after birth, the brains of some autistic children appear to expand faster than usual, followed by normal or relatively slower growth in childhood. This occurs mostly in brain areas that are responsible for the development of higher cognitive specialisation. A number of hypotheses for the cellular and molecular bases of pathological early overgrowth include:
— Excess number of neurons causing local over-connectivity in key brain regions such as Cerebral Cortex, Amygdala, Basal Ganglia, Hippocampus, Brainstem, Cerebellum & Corpus Callosum.
— Disturbed neuronal migration during early gestation
— Unbalanced excitatory-inhibitory networks
— Abnormal formation of Synapses and Dendritic Spines. e.g. By modulation of Neurexin-Neuroligin Cell-Adhesion system, or by poorly regulated synthesis of synaptic proteins. If synaptic development is disrupted, it may contribute epilepsy which may explain why the 2 conditions are associated.
The immune cells in our brains called Microglia are thought to play an important role in autism. Inflammation of both the peripheral and central immune system as indicated by increased levels of pro-inflammatory cytokines and significant activation of Microglia. Biomarkers of abnormal immune function is found to be associated with increased impairments in behaviours characteristic of the core features of autistic behaviour such as deficits in social interactions and communication. Interactions between the immune system and the nervous system begin early during the embryonic stage of life, and successful neurodevelopment depends on a balanced immune response. It’s believed that activation of a pregnant mother’s immune system by environmental toxicants or infections can contribute to increased risk of autism, which causes a disruption of brain development. The relationship between neurochemicals and autism isn’t well understood but several studies have investigated the role of Serotonin and of genetic differences in its transport. The most common identified genetic cause of autism to date is Group I(1) Metabotropic Glutamate Receptors (mGluR) in the pathogenesis of Fragile X Syndrome. Data suggests neuronal overgrowth potentially relates to an increase in several growth hormones or to impaired regulation of growth factor receptors but we don’t know which ones specifically.
Several theories have been proposed in an effort to explain the cause of autism:
(a) Mirror Neuron System Theory (MNS)
This theory hypothesises that distortion of the MNS interferes with imitation and leads to the core features of social impairment and communication difficulties. Normally the MNS is stimulated when an animal performs an action or observes their behaviour via an embodied simulation of their actions, intentions, and emotions. It’s demonstrated that there are structural abnormalities in MNS brain regions of individuals with ASD, a delay in the activation of the core circuit for imitation in individuals with Asperger’s Syndrome and a correlation between reduced MNS activity and severity of Asperger’s Syndrome in children with ASD. However, this theory fails to explain why some autistic individuals elicit abnormal brain activation in many neural circuits outside the MNS and the perform normally on imitation tasks involving a goal or object.
(b) Underconnectivity Theory
This theory hypothesises that autism is marked by under-functioning high-level neural connections and synchronisation, along with an excess of low level processes. Evidence supporting this theory has been discovered in functional neuroimaging studies on autistic individuals and by a brainwave study that suggested that adults with ASD have local over-connectivity in the Cortex and weak functional connections between the Frontal Lobe and the rest of the cortex. Other evidence suggests that under-connectivity is mainly within each hemisphere of the cortex, hence autism might be a disorder of the Association Cortex.
ASD-related patterns of low function and aberrant activation in the brain differ depending on whether the brain is performing social or non-social tasks. There is evidence of reduced functional connectivity of the default network and intact connectivity in the task-positive network. A default network is a large-scale brain network involved in social and emotional processing, whilst a task-positive network is involved in sustained attention and goal-directed thinking. These 2 networks aren’t negatively correlated in time in autistic people, which suggests an imbalance in toggling between the 2 networks, possibly reflecting a disturbance of self-referential thought.
According to studies based on event-related potentials, there is evidence for differences in autistic individuals with respect to attention, orientation to auditory and visual stimuli, novelty detection, language and face processing, and information storage. Event-related potentials are transient changes to the brain’s electrical activity in response to stimuli.
2 cognitive theories have been proposed in an attempt to explain the links between autism and behaviour:
(c) Empathising-Systemising Theory
Proposed by Simon Baron-Cohen, this theory postulates that autistic individuals can systemise i.e. develop internal rules of operation to handle events inside their brain, but are less likely at empathising by handling events generated by other agents. It focuses on deficits in social cognition. The extreme male brain theory extends this postulate by hypothesising that autism is an extreme case of the male brain, which is defined psychometrically in individuals who systemise better than empathise. These theories are related to Baron-Cohen’s earlier Theory of Mind approach. The theory of mind hypothesis infers that autistic behaviour arises from an inability to ascribe mental states to oneself and others. This is supported by the atypical responses of autistic children to the Sally-Anne Test for reasoning about others’ motivations, and the MNS theory. However most studies failed to find evidence of impairment in autistic individuals’ ability to understand other people’s basic intentions or goals. Instead they suggested that impairments are found in understanding more complex social emotions.
https://en.wikipedia.org/wiki/Sally–Anne_test
Sally-Anne Test
Imagine 2 little girls named Sally and Anne playing in a room. In the room with them is a basket, a box and a cookie. Sally puts the cookie into the basket and then strolls out of the room. Having witnessed where the cookie was placed, Anne takes the cookie out of the basket and places into the box. When Sally returns to the room, where will she look for the cookie, the basket or the box?
(d) Weak Central Coherence Theory
This theory hypothesises that a limited ability to see the big picture underlies the central disturbance in autism. It focuses on non-social or general processing responsible for the executive functions of the brain such as working memory, planning and inhibition. Kenworthy states in his review that “the claim of executive dysfunction as a causal factor in autism is controversial”, however “it is clear that executive dysfunction plays a role in the social and cognitive defects observed in individuals with autism.” Tests of core executive processes such as eye movement tasks give an indication whether an autistic child shows improvement from late childhood to adolescence. One strength of this theory is the prediction of special talents and peak performance in autistic individuals. Another strength is predicting stereotyped behaviour and narrow interests. Nonetheless, 2 weaknesses of this theory include the difficulty to measure executive function and that executive function details are yet to be discovered in autistic children. A related theory concerning enhanced perceptual functioning focuses more on the superiority of locally oriented and perceptual operations in autistic individuals. Monotropism is a typical feature of autism that describes a child’s restricted range of interests and selective attention. It posits that autism stems from a different cognitive style which tends to focus attention (or processing resources) intensely, whilst excluding stimuli outside of their attention tunnel.
Currently, diagnosis of autism is based on behaviour rather than cause or mechanism because scientists have yet to uncover the scientific cause of autism. Under the DSM-5, if your child is characterised by persistent deficits in social communication and interaction across multiple contexts and demonstrated by restricted, repetitive patterns of behaviour, interests, or activities, they are more likely to be autistic. Sample symptoms include lack of social or emotional reciprocity, stereotyped and repetitive use of language or idiosyncratic language, and persistent preoccupation with unusual objects. However we are a long way from discovering the actual biological cause before we can develop innovative treatments to cure autism and I hope geneticists and neuropsychologists alike find that golden watch moment as soon as possible.
Once you’ve survived a majority of life’s and nature’s greatest challenges and successfully reached into your 60s, give yourself a round of applause. But there’s one last obstacle you have to face that no one has been able to survive so far. It’s called cancer. Cancer accounts for 13% of the total deaths every year. The number of people diagnosed and then dying from cancer 6 years later is increasing every year as society matures with more people are living longer than ever before thanks to higher living standards. The most common cancers are lung cancer, stomach cancer, liver cancer, colorectal cancer and breast cancer. This makes invasive cancer the most common cause of death in the developed world and the 2nd leading in the developing world. Although cancer can affect anyone at any age, most cancer patients with invasive cancer are over the age of 65. By definition, cancer is a group of diseases involving abnormal cell growth with the potential to invade and spread to other parts of the body. These contrast with benign tumours which don’t spread to other parts of the body. They form a subset of neoplasms or tumours, which are a group of cells that have undergone unregulated growth and often form a mass or lump but may be distributed diffusely. All tumour cells display the 6 hallmarks of cancer which are required to produce a malignant tumour. They include:
— Cell growth and division in the absence of proper cell signals
— Continuous growth and division even if they are given contrary cell signals
— Avoidance of programmed cell death
— Limitless number of cell divisions
— Promotion of blood vessel construction (Angiogenesis)
— Invasion of tissue and formation of Metastases
Cancers are often described by the body part that they originated in. However some body parts contain multiple types of tissue, so cancers are additionally classified by the type of cell that the tumour cells originated from for greater precision. These types include:
— Carcinoma = These cancers are derived from epithelial cells which includes many of the most common cancers affecting mostly older adults. Virtually all carcinomas develop in the breast, prostate, lung, pancreas and the colon.
— Sarcoma = These cancers arise from connective tissue i.e. bone, cartilage, fat and nerve. Each of which develop from cells originating in Mesenchymal Cells outside the bone marrow.
— Lymphoma (Leukamia) = These classes of cancer arise from cells that make blood. Leukamia is the most common type of cancer in children accounting for about 30%. However, a greater proportion of older adults develop both Lymphoma and Leukamia.
— Germ Cell Tumour = These cancers are derived from pluripotent cells, most often presenting in the testicles or ovaries (better known as Seminoma and Dysgerminoma, respectively.
— Blastoma = These cancers are derived from immature “precursor” cells or embryonic tissue. They are common in children than in older adults.
Cancers are usually named using -carcinoma, -sarcoma, or -blastoma as a suffix, combined with the Latin or Greek etymology for the organ or tissue of origin as the root. For example:
- Cancers of the liver parenchyma arising from malignant epithelial cells are called Hepatocarcinoma.
- Maligancies arising from primitive liver precursor cells are called Hepatoblastoma.
- Cancers arising from fat cells are called Liposarcoma.
For some common cancers, the English organ name is used. For example:
- Breast Cancer is also called Ductal Carcinoma of the Breast — ‘Ductal’ refers to the appearance of the cancer under the microscope, which suggests that the cancer has originated in the milk ducts.
Benign Tumours (which aren’t cancers) are usually named using -oma as a suffix combined with the organ name as the root. For example:
- Benign tumours of smooth muscle cells are called Leiomyoma — In the Uterus, it’s commonly called a Fibroid.
Confusingly, some types of cancer use the suffix -noma, examples include Melanoma and Seminoma. Some other types of cancer are named of the size and shape of the cells under a microscope such as Giant Cell Carcinoma, Spindle Cell Carcinoma and Small Cell Carcinoma.
Cancer symptoms aren’t visible at the beginning of malignant cell progression. They could appear anywhere on the body as the mass grows or ulcerates. Local symptoms can be:
— Lung Cancer: Mass effects blocking the Bronchus results in cough or pneumonia
— Oesophageal Cancer: Narrowing of the Oesophagus, making it difficult or painful to swallow.
— Colorectal Cancer: Narrowing or blockages in the bowel, affecting bowel habits.
— Breast & Testicular Cancers: Masses would produce observable lumps.
If ulceration that causes bleeding occurred in the:
— Lungs: You will cough up blood
— Bowels: It will lead to anaemia or rectal bleeding
— Bladder: Blood will enter your urine
— Uterus: In girls only, blood will enter their vagina.
Initial swelling is painless but may worsen to localised pain in advanced cancer. This may be caused by a buildup of fluid within the chest or abdomen.
Over time general symptoms may occur due to effects unrelated to direct or metastatic spread of cancerous cells. These include:
— Unintentional Weight Loss
— Fever caused by Hodgkin Disease, Leukaemias and Liver & Kidney Cancers
— Excessive Fatigue
— Changes to the skin
Some cancers may cause specific groups of systemic symptoms, termed Paraneoplastic Syndrome. e.g. Myasthenia Gravis in Thymoma and Clubbing in Lung Cancer.
About 90-95% of cancers are due to genetic mutations from environmental factors. The remaining 5-10% are due to inherited genetics. When cancer researchers use the term “environmental”, they are referring to any cause that isn’t inherited genetically, such as lifestyle, economic and behaviour factors and not merely pollution. The common environmental factors that contribute to cancer death include: — Smoking tobacco (25-30%)
— Poor diet and obesity (30-35%)
— Infections (15-20%)
— Both ionising and non-ionising radiation (10%)
— Stress
— Lack of physical activity
— Pollution
http://www.quitsmokingsupport.com/whatsinit.htm
(A) Smoking
Exposure to particular substances that are linked to specific types of cancers are called Carcinogens. For instance, tobacco smoke is responsible for 90% of lung cancer cases. Tobacco is responsible for 1 in 5 cancer deaths worldwide and 1 in 3 in the developed world. It also causes cancer in the larynx, head, neck, stomach, bladder, kidney, oesophagus and pancreas. Tobacco smoke is known to contain over 4000 chemicals including 50 known carcinogens, including Nitroamines, Benzene and Polycyclic Aromatic Hydrocarbons like Benzo[a]pyrene and 400 other toxins. More ingredients: Nicotine, Tar, Carbon Monoxide, Formaldehyde, Ammonia, Hydrogen Cyanide, Arsenic, DDT, Fungicides, Pesticides, Cadmium, Nickel, Butane, Ethyl Furoate, Lead, Methoprene, Megastigmatrienone, Maltitol, Napthalene, Methyl Isocyanate, Polonium, Phenylacetic Acid and the oil of the East Indian mint Patchouli. According to American tobacco company Liggett Group Inc, some cigarettes like L&M also contain additives like yeast, wine, caffeine, beeswax, chocolate, high fructose corn syrup, sugar, natural and artificial liquorice flavour, menthol, artificial milk chocolate, valerian root extract, vanilla, molasses, cedarwood oil, Glycerol, Propylene Glycol, Isovaleric Acid, Hexanoic Acid and 3-Methylpentanoic Acid.
— Nicotine is a highly addictive substance when inhaled it reaches your brain in just 6 seconds. In small doses, it acts as a stimulant to then brain. In larger doses, it acts as a depressant, which inhibits the flow of electrical signals between nerve cells. In insurmountable doses, it acts as a lethal poison that affects the heart, blood vessels and hormones. Nicotine in your bloodstream would act to calm you.
— Carbon Monoxide is a poisonous gas that displaces Oxygen in Haemoglobin of Red Blood Cells which increases the amount of tar into your lungs and deliver less deoxygenated blood throughout your body to nourish your cells.
— Tar is a mixture of substances that together form a sticky mass in your lungs.
— Fungicides and Pesticides are known to cause many types of cancers and birth defects when inhaled.
— Cadmium is used in batteries that is linked to lung and prostate cancers
— Benzene is linked to Leukamia
— Formaldehyde is linked to lung cancer
— Nickel increases your susceptibility to lung infections causing pneumonia.
— Ammonia is a common household cleaner to clean toilets
— Angelica Root Extract is known to cause cancer in animals
— Arsenic is an element used in rat poisons
— Benzene is an organic cyclic compound used in making dyes and synthetic rubber
— Butane is a natural gas used in lighter fluid
— DDT is a banned insecticide
— Ethyl Furoate causes liver damage in animals
— Lead is a neurotoxin poisonous in high doses
— Formaldehyde is used to preserve dead specimens
— Methoprene is an insecticide
— Megastigmatrienone is a chemical natural found in grapefruit juice
— Maltitol is a sweetener for diabetics
— Napthalene is an ingredient used in mothballs
— Methyl Isocyanate is the chemical accidentally released from a chemical factory that stored phosgene which killed over 2000 people in Bhopal, India in 1984.
— Polonium is a cancer-causing radioactive element
(B) Diet and Exercise
Dietary factors are recognised as having a significant effect on the risk of cancers, with different dietary elements both increasing and decreasing that risk. Poor diet and obesity is related to up to 30-35% of cancer deaths, whilst physical inactivity is related to 7% risk of cancer deaths. Many studies have concluded that obesity, alcohol consumption and beverages sweetened with sugar are linked to rise of cancer. Other studies have linked eating red or processed meat to an increased risk of breast cancer, colon cancer, prostate cancer, and pancreatic cancer, due to the presence of carcinogens in food cooked at high temperatures.
— Aflatoxin B1 is a frequent food contaminate , which causes liver cancer.
— Chewing Betel Nut causes oral cancer.
— Pickled vegetables are directly linked to increased risk of several cancers.
The differences in dietary practices partly explain the differences in cancer incidence in different countries. e.g. Stomach cancer is more common in Japan due to its high-salt diet and colon cancer is more common in the USA. You often hear nutritionists, health experts and doctors provide dietary recommendations for cancer prevention like weight management, consuming mainly vegetables, fruit, whole grains and fish and a reduced intake of red meat, animal fat and refined sugar. These so-called anti-cancer diets include the Breuss Diet, Gerson Therapy, Budwig Protocol and the Macrobiotic Diet. But none of these are proven to be effective due to their manifesting harmful side-effects.
According to the International Agency for Research on Cancer (IARC), Alcoholic beverages are classified as a Group 1 Carcinogen i.e. carcinogenic to humans. It classifies consumption of alcoholic beverage as a cause of cancers of the female breast, colorectum, larynx, liver, oesophagus, oral cavity, pharynx and pancreas. As your liver breaks down ethanol, it produces Acetaldehyde. Normally the liver then eliminates 99% of the Acetaldehyde as it processes 7g of ethanol every hour. Studies suggest that exposure to more Acetaldehyde than normal through a defect in the gene for Alcohol Dehydrogenase are at greater risk of developing cancers of the Upper Gastrointestinal Tract and Liver. Scientists don’t know the real mechanism behind alcohol causing cancer but many theories have been put forward which include:
— Production of Acetaldehyde, which is a weak mutagen and carcinogen
— Induction of Cytochrome P450 2E1 and associated oxidative stress and conversion of pro-carcinogens to carcinogens.
— Depletion of S-Adenosylmethionine and, consequently, induction of global DNA hypomethylation.
— Induction of increased production of inhibitory Guanine Nucleotide Regulatory Proteins and components of extracellular signal-regulated Kinase-Mitogen-activated Protein Kinase Signalling
— Accumulation of Iron and associated oxidative stress
— Inactivation of the tumour suppressor gene BRCA1 and increased Oestrogen responsiveness (primarily in breast)
— Impairment of Retinoic Acid metabolism
— Production of Reactive Oxygen species and Nitrogen species
— Changes in Folate metabolism.
Over the past several decades, many investigations have highlighted the defects in the Methionine metabolism pathway as a possible cause of carcinogenesis. e.g. Deficiencies of the main dietary sources of Methyl donors, Methionine and Choline, lead to the formation of liver cancer in rodents.
— DHF (Dihydrofolate)
— dSAM (decarboxylated S-adenosylmethionine)
— hCys (homocysteine)
— ME (Methyl group)
— MetTR-1-P (5-Methylthioribose-1-Phosphate)
— MT (Methyltransferase)
— MTA (Methylthioadenosine)
— MTHF (Methylenetetrahydrofolate)
— SAH (S-Adenosyl-L-Homocysteine)
— SAM (S-Adenosyl Methionine)
— SUB (Substrate)
Methionine is an essential amino acid meaning our bodies can’t produce it naturally through intrinsic processes. Hence we have provide Methionine by dietary intake of proteins or Methyl donors like Choline and Betaine found in beef, eggs and some vegetables. Assimilated Methionine is transformed in SAM, which is a key metabolite for polyamine synthesis e.g Spermidine and Cysteine formation. Methionine breakdown products are also recycled back into Methionine by Homocysteine remethylation and MTA conversion. Vitamins B6, B12, Folic acid and Choline are essential co-factors for these reactions. SAM is the substrate for methylation reactions catalysed by DNA, RNA and Protein Methyltransferases.
The products of these reactions are methylated DNA, RNA or proteins and SAH. SAH has a negative feedback on its own production as an inhibitor of Methyltransferase enzymes. Therefore the SAM: SAH ratio directly regulates cellular methylation, whereas the levels of Vitamins B6, B12, Folic acid and Choline regulates indirectly the methylation state via the Methionine metabolism cycle.
A ubiquitous features of cancer is a maladaption of this Methionine metabolic pathway in response to genetic or environmental conditions resulting in the depletion of SAM and/or SAM-dependent methylation. The maladaptations include:
— Deficiency of enzymes such as MTA Phosphorylase,
— Methionine dependency
— High levels of polyamine synthesis
— Induction of a diet deprived of extrinsic Methyl donors or enhanced in Methyl inhibitors
It’s evident of a strong correlation between tumour formation and decreasing levels of SAM in mice, rats and humans.
(C) Infections
About 16% of cancers worldwide are caused by infectious diseases. A large proportion of these cases occur in developing countries especially in sub-Saharan Africa (as high as 32.7%) compared to less than 10% in the developed world countries like Australia and New Zealand. Oncoviruses are the usual infectious agents that manifest cancer. Examples of oncoviruses include:
— Human Papillomavirus (HPV)—> Cervical Cancer
— Epstein-Barr Virus —> B-Cell Lympholiferative Disease & Nasopharyngeal Carcinoma
— Kaposi’s Sarcoma Herpesvirus —> Kaposi’s Sarcoma and Primary Effusion Lymphomas
— Hepatitis B & C viruses —> Hepatocellular Carcinoma
— Human T-Cell Leukemia Virus-1 —> T-Cell Leukemias
Bacterial infections also increase the risk of cancer, for instance, Helicobacter Pylori induces Gastric Carcinoma. Parasitic infections associated with cancer include Schistosoma Haematobium (Squamous Cell Carcinoma of the Bladder), Opisthorchis Viverrini (Liver Flukes) and Clonorchis Sinensis (Cholangiocarcinoma).
(D) Radiation
Up to 10% of invasive cancers are related to exposure to both ionising and non-ionising radiation Nonetheless, the majority of non-invasive cancers are non-melanoma skin cancers caused by non-ioninsing ultraviolet radiation, mostly from the sun’s ultraviolet rays. Other common sources of ionising radiation including medical imaging apparatus and radon gas. Radon gas is often found from natural sources that accumulate in buildings especially in confined areas areas such as attics and basements. It can also be found in spring waters and hot springs. There is epidemiological evidence for radon inducing lung cancer, 2nd only to cigarette smoking, according to the United States Environmental Protection Agency.
In industrialised countries, Medical imaging contributes almost as much radiation dose to the public as natural background radiation. Since the invention of 3D scanners in the 1990s, people are exposed to 6 times more radiation than traditional radiographs. CT scans (Computer Tomography) account for about half of the medical imaging dose to the public which is responsible for 0.4% of current cancers in the USA. Other nuclear medicine techniques like PET scans involve the injection of radioactive pharmaceuticals like Telirium directly into the bloodstream, and radiotherapy treatments deliberately deliver lethal doses (on a cellular level) directly to tumours and surrounding tissues.
Nuclear energy workers or people who work near nuclear power plants are permitted to receive 20 times more radiation dose than the general public normally does, according to ICRP recommendations. Higher doses are usually permitted when responding to an emergency like a nuclear meltdown. Every day, nuclear workers are routinely kept well within regulatory limits, whilst essential technicians routinely approach their maximum dose each year. However, accidental overexposures beyond regulatory limits still occurs globally several times a year. Astronauts who participate on long missions are exposed to cosmic radiation which increases their risk of cancer. Airline crews are exposed to similar levels of cosmic radiation due to reduced atmospheric shielding at higher attitudes during flights. Miners working deep underground in Uranium mines ;and Granite mines are exposed to Radon. Some of you have heard about the Chernobyl Nuclear Disaster in 1986 that occurred in Chev, Ukraine. In addition to conventional fatalities and acute radiation syndrome fatalities, 9 children died of Thyroid Cancer, and it’s estimated that up to 4000 excess cancer deaths among the 600,000 highly exposed people. Of the 100 million curies (4 exabecquerels) of radioactive material, the short half-life radioactive isotopes such as Iodine-131 Chernobyl released were initially the most dangerous. Due to their short half-life of 5 - 8 days they now have decayed, leaving the more long-lived Caesium-137 (half-life of 30.07 years) and Strontium-90(half-life of 28.78 years) as the main dangers.
In March 2011, an earthquake and tsunami caused damage to the Fukushima I Nuclear Power Plant in Japan, which led to explosions and partial nuclear meltdowns. Significant release of radioactive material like Iodine-131 took place following Hydrogen explosions at 3 reactors, as technicians desperately pumped in seawater to keep the Uranium fuel rods cool and bled radioactive gas from the reactors in order to vacate room for the seawater. Now there is a 20km exclusive zone set up around the Fukushima plant and anyone situated within the 20-30 km zone are advised to stay indoors. We don’t know exactly how long will it be before it is safe to walk in the exclusive zones without protective suits. I’ll discuss radioactivity and the day when humans can walk into the exclusive zones unprotected in another post.
Cancer is a stochastic effect of radiation. Stochastic means that the probability of occurrence increases with effect radiation dose, but the severity of cancer is independent of dose. The speed at which cancer progresses, the prognosis, the degree of pain, and every other feature of the disease aren’t functions of the radiation dose to which the person is exposed. This contrasts with the deterministic effects of acute radiation syndrome which increase in severity with dose above a threshold. A normal cell becomes cancerous if its operations is disrupted. Normal cell operation is controlled by the chemical structure of DNA molecules coiled around Histone proteins called Chromosomes. When radiation deposits enough energy in organic tissue to cause ionisation, this breaks apart covalent molecular bonds and thus alter the molecular structure of the irradiated molecules. Less energetic radiation, such as visible light, only cause excitation, not ionisation, which is usually dissipated as heat with relatively minimal chemical damage. Ultraviolet light like sunlight is categorised as non-ionising, but it is in the intermediate range that produces some ionisation and chemical damage which leads to the carcinogenic mechanism of UV radiation. Unlike chemical or physical triggers for cancer, penetrating radiation hits molecules within cells randomly. Molecules disintegrated by radiation can become highly reactive free radicals that cause further chemical damage. Some of this direct and indirect damage will eventually impact chromosomes and epigenetic factors that control gene expression. There are cellular mechanisms that repair most of the damage, but some repairs are done incorrectly and some chromosome abnormalities will turn out to be irreversible.
The most biologically significant lesion by which ionising radiation causes cancer is DNA double-stranded breaks (DSBs). In vitro experiments have found that every Gray (Gy) of ionising radiation causes 35 DSBs per cell, removes a portion of epigenetic markers of the DNA, which regulate gene expression. Most of the induced DSBs are repaired within 24 hours after exposure, however, 25% of the repaired strands are done incorrectly and about 20% of fibroblast cells die within 4 days after exposure to 200mGy of ionising radiation.
Major damage normally results in the cell dying or being unable to reproduce or replicate. This effect is responsible for acute radiation syndrome, thus these heavily damage cells can’t become cancerous, especially if tumour suppressor genes are damaged. Research suggests that mutagenic events don’t occur immediately after irradiation but rather when surviving cells acquire a small genomic instability which causes an increased rate of mutations in future generations. These cells will then progress through multiple stages of neoplastic transformation that culminate into a tumour mass after years of incubation. This neoplastic transformation can be divided into 3 major independent stages:
— Morphological changes to the cell
— Acquisition of cellular immortality i.e. Losing normal, life-limiting cell regulatory processes
— Adaptations favouring formation of a tumour
Prolonged exposure to UV radiation mainly from the sun can lead to Melanoma and other skin malignancies like most non-melanoma skin cancers. Skin cancer may occur following ionising radiation exposure following a latent period averaging 20 - 40 years. Various malignancies may develop like Basal-Cell Carcinoma followed by Squamous-Cell Carcinoma, but the conclusions of several studies regarding the carcinogenic risk arising from low levels of ionisation radiation exposure is still contentious.
(E) Heredity
The vast majority of cancers are non-hereditary or sporadic. But the minority of cancers are primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic mutation that exhibits a large effect on cancer risk and is responsible for 3-10% of cancer cases. Some of these cancer syndromes include certain inherited mutations in the BRCA1 and BRCA2 genes with more than 75% risk of breast cancer and ovarian cancer, and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, which is present in 3% of people with colorectal cancer. Statistically, for cancers with high mortality rates, the relative risk of developing colorectal cancer when a first-degree relative (parent, sibling or child) has been diagnosed with it is about 2; 1.5 for lung cancer, 1.9 for prostate cancer, 1.8 for breast cancer if the first-degree relative has developed it at 50 years or older, and 3.3 if the first-degree relative has developed it younger than 50 years.
(F) Physical Agents
You all hear people mention asbestos as a cancer-causing agent right? If you don’t know what is it, asbestos is a naturally-occuring mineral fibre that when inhaled would cause Mesothelioma (cancer of the serous membrane surrounding the lungs). Other cancer-causing naturally-occuring and synthetic asbestos-like fibres include powdered metallic Cobalt and Nickel and Crystalline Silica (Quartz, Cristobalite and Tridymite). Here are some burning questions for you to think about:
- Do you think physical trauma causes cancer?
- Can frequent, long-term application of hot objects to the body cause skin cancer?
- Can frequent consumption of scalding hot tea cause oesophageal cancer?
(G) Hormones
It’s known some hormones play a role in promoting cell proliferation which is a hallmark of cancer. For example, Insulin-like Growth factors and their binding proteins play a key role in cancer cell proliferation, differentiation and apoptosis, which suggests they are involved in carcinogenesis. Hormones are also important agents in sex-related cancers, such as breast cancer, endometrium cancer, prostate cancer, ovarian cancer, testicular cancer and also thyroid cancer and bone cancer. Studies have found that daughters of women afflicted with breast cancer have significantly higher levels of Oestrogen and Progesterone than daughters of women without breast cancer. This findings may explain their increased risk of breast cancer, even in the absence of a breast-cancer gene. Similarly, men of African descent have significantly higher levels of Testosterone than men of European descent and have a correspondingly higher level of Prostate cancer. Men of Asian ancestry have the lowest levels of Testosterone-activating agent Androstanediol Glucuronide, hence they have the lowest levels of prostate cancer.
Obesity caters for the higher levels of some hormones associated with cancer and higher rates of those cancers. Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones. On the other hand, people who exercise more than the average person have lower levels of these hormones thus reducing their risk of cancer. Osteosarcoma may be promoted by growth hormones but further research needs to be conducted.
(H) Autoimmune Disease
These is an association between celiac disease and an increased risk of all cancers. However this risk decreases with time after diagnosis and strict treatment, possibly due to the adoption of a gluten-free diet, which seem to play a protective role against development of malignancy in people with celiac disease. People with Crohn’s Disease and Ulcerative Colitis have an increased risk of gastrointestinal cancers, due to chronic inflammation.
So what really causes cancer?
— Large-scale mutations involve the deletion or gain of a portion of a chromosome.
— Genomic amplification occurs when a cell gains copies of a small chromosomal locus, usually containing 1 or more oncogenes and adjacent genetic material.
— Translocation occurs when 2 separate chromosomal regions become abnormally fused, often at a characteristic location. e.g. Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukaemia and results in the production of the BCR-abl fusion protein, which is an oncogenic Tyrosine Kinase.
— Small-small mutations include point mutations, deletions, and insertions, which may occur in the promoter region of the gene and affect its expression, or in the gene’s coding sequence and alter the function of stability of its protein product.
— Disruption of a single gene may result from integration of genomic material from a DNA virus or a Retrovirus. This lead to the expression of viral oncogenes in the affected cell and its descendants.
— Replication of the data contained within the DNA of living organisms will probably result in some errors (in mutations). Complex error correction and prevention is built into the process and safeguards the cell against cancer. If a significant error occurs, the damaged cell self-destructs through programmed cell death called apoptosis. If the error control processes fail, then the surviving mutations will prosper and be passed along to daughter cells.
Some environments make genomic errors more likely to arise and propagate like the presence of carcinogens, repeated physical injury, heat, ionising radiation or hypoxia. The errors that cause cancer are self-amplifying and compounding, for example:
- A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors swiftly.
- Further mutations in oncogenes might cause the cell to reproduce rapidly and more frequently than its normal counterparts.
- Further mutations may cause the loss of a tumour suppressor gene, which then disrupts the apoptosis signalling pathway and immortalising the cell.
- Further mutations in the signalling machinery of the cell might send error-causing signals to nearby cells.
The transformation of a normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors. With each accumulating error, this progressively allows the cell to escape more controls that limit normal tissue growth. This rebellion-like scenario is an undesirable survival of the fittest, where the driving forces of evolution work against the body’s design and enforcement of order. Once cancer has begun to develop into your body, an ongoing process called clonal evolution takes place. This drives the progression towards more invasive stages. Clonal evolution leads to intra-tumour heterogeneity that complicates designing effective treatment strategies. Intra-tumour heterogeneity refers to cancer cells with heterogeneous mutations. Cancers develop characteristic abilities to ensure their survival such as:
— Evasion of apoptosis
— Self-sufficiency in growth signals
— Insensitivity to anti-growth signals
— Sustained angiogenesis
— Limitless replicative potential
— Metastasis
— Reprogramming of energy metabolism
— Evasion of immune destruction
I’ll discuss the hallmarks of cancer in another post because the microbiology of cancer is quite complex to understand.
https://en.wikipedia.org/wiki/Metastasis
(I) Metastasis
How and where does cancer metastasise?
When a pathogenic agent metastasises, it spreads from an initial or primary site to a different or secondary site within the host’s body. These newly pathological sites are then called metastases (mets). This uncontrolled proliferation by mitosis produces a primary heterogeneic tumour. The cells which constitute the tumour eventually undergo metaplasia, followed by anaplasia then dysplasia, resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a secondary site for tumorigenesis. Some cancer cells known as circulating tumour cells acquire the ability to penetrate the walls of lymphatic or blood vessels, after which they are able to circulate through the bloodstream to other sites and tissues in the body. This is process is known respectively as lymphatic or hematogenous spread. After the tumour cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiple, eventually forming another tumour. This new tumour is known as a metastatic (or secondary) tumour. e.g. When breast cancer cells metastasises to the lungs, the secondary lung is made up of abnormal breast cells, not of abnormal lung cells. The tumour in that lung is then called metastatic breast cancer, not lung cancer.
Initially, nearby lymph nodes are struck early with cancer cells. Then cancer cells commonly metastasise to the lungs, liver, brain and bones.
— Lymph Nodes: Lymphadenopathy
— Lungs: Cough, Hemoptysis and Dyspnea (shortness of breath)
— Liver: Hepatomegaly (Enlarged liver), Nausea and Jaundice
— Bones: Bone pain, fracture of affected bones
— Brain: Neurological symptoms such as headaches, seizures and vertigo.
Malignant cells break away from the primary tumour and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumour from adjoining tissues.
This allows cancer cells to breach the ECM and escape.
The location of the metastases isn’t necessarily random because different types of cancer tend to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone.
e.g. Breast Cancer often tends to metastasise to the bones and lungs. This specificity is mediated by soluble signal molecules called Chemokines and Transforming Growth Factor-Beta (TGF-β).
The body initially resists metastasis by a variety a mechanisms through the actions of a class of proteins known as Metastasis Suppressors.
Human cells exhibit 3 kinds motion: Collective motility, Mesenchymal-type movement and Amoeboid movement. Cancer cells often switch between all 3 kinds of motion when given the opportunity. Cancer researchers are currently developing treatments that aim to stop or slow down the spread of cancer by blocking some necessary step in 1 or more kinds of motion. It’s known several different cell types are critical to tumour growth. In particular, Endothelial Progenitor Cells (EPCs) have been shown to influence the growth of Tumour Blood-Vessels, be critical for metastasis and angiogenesis. EPCs can be marked using the Inhibitor of DNA Binding 1 (ID1). This marker helps researchers track EPCs from the bone marrow to the blood to the tumour-stroma. It even becomes incorporated in tumour vasculature, which suggests that EPCs in blood-vessel development is important in a tumour setting and metastasis. Ablation of the EPCs in bone marrow can lead to a significant decrease in tumour growth and vasculature development.
— NFAT transcription factors are implicated in the process of cell motility at the basis of metastasis formation of breast cancer. It’s known NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma, whilst NFAT3 (NFATc4) is an inhibitor of cell motility. NFAT1 regulates the expression of TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion. On the other hand, NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
— Metastases are shown to display in epigenetic histone modifications such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumours. This allows the proliferation and survival of disseminated tumour cells in distant organs.
— A recent study has shown that PKC-iota promotes Melanoma cell division by activating Vimentin during EMT (Epithelial-Mesenchymal Transition). When PKC-iota was inhibited or knocked down, it resulted in increased levels of E-Cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggest that PKC-ι is involved in the signalling pathways which up regulate EMT in melanoma thereby directly stimulates metastasis.
(a) Transcoelomic
Malignant cells can spread into body cavities via penetrating the surface of the peritoneal, pleural, pericardial or subarachnoid spaces
e.g. Ovarian tumours can spread transperitoneally to the surface of the liver.
(b) Lymphatic
Tumour cells are transported to regional lymph nodes near the primary tumour and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. “Positive Node” is a term used by medical specialists to describe regional lymph nodes that test positive for malignancy. It’s common for medical practitioners to test for malignancies by biopsy at least 1 lymph node near a tumour site when carrying out a surgical procedure to examine or remove a tumour. This lymph node is called a “sentinel lymph node”. Lymphatic spread is the most common route of initial metastasis for carcinomas. The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins, and therefore these metastatic cells eventually spread through the hematogenous route.
(c) Hematogenous
Sarcomas typically metastasis via this route, however it’s also the favoured route for certain types of carcinoma such as Renal Cell Carcinoma originating in the kidney. Because veins have thinner walls, they are more frequently invaded by metastatic tumour cells than are arteries, hence metastasis tends to follow the pattern of venous blood flow.
e.g. Colorectal cancer spreads primarily through the portal vein to the liver.
(d) Canalicular
Some tumours, especially carcinomas metastasise along anatomical canalicular spaces. These spaces include the bile ducts, the urinary system, the airways and the subarachnoid system.
Once cancer cells metastasises to your key organs like your heart, intestines, lungs, brain and kidneys, it will interfere with its bodily functions that are important to keep you alive. According to Doctor Gary Larson, you will begin to experience significant weight loss via the production of Cachectin-like substances, which informs the brain to stop feeling hungry. This will interfere with fat storage and utilisation, forcing the metabolic system to feed on normal tissue in order to satisfy its energy requirements. Muscle wasting and temporal wasting are common symptoms and they are difficult to reverse. During the chronic and progressive stages of cancer, you will feel unremitting pain as deposits of tumour cells erode through your bones (causing arthritis), nerves and visceral organs. Any of your vital organs may fail due to infiltration by cancer cells, but starvation usually happens before that does. When infiltration of tumour cells causes obstruction of your ureters, renal failure would ensure, hence you would slip into a coma, sometimes referred to as a painless cancer death according to the accounts of women afflicted with cervical cancer. Men with prostate cancer will experience extreme pain in their bones and their joints and eventually die of renal failure.
The direct effect of impingement by collections of cancer cells on vital organs would impair blood flow to them, causing tissue death. This is due to the back pressure on microcirculation rather than obstruction of larger arteries, which seldom become obstructed by cancer. This outcome is likely due to the high blood pressure in them. Nevertheless, because your veins are low pressure passageways for blood, they would be obstructed due to extrinsic compression. Other mass effects include obstruction of hollow organs such as:
- Bronchi (Lungs): This causes pneumonia by blocking the expulsion of secreted molecules from segments or lobes of your lungs. Stagnant collections of fluids that exposed to the infectious agents from the external environment will always become infected themselves causing pneumonia. In some patients suffering from lung cancer, this is the final nail in the coffin. Furthermore bronchial obstruction will cause shortness of breath by impairing airflow into the lung. When both of your lungs becomes blocked, you will die from asphyxiation.
- Bowel: In patients suffering from colon or rectal cancers, the expulsion of their faeces will be blocked, which leads to perforation and peritonitis. This outcome becomes fatal in a few hours if not surgically corrected.
- Bile Ducts: This will cause jaundice and ultimately liver failure. When Bilirubin can’t be excreted, it remains in your blood and is deposited into normal tissues. This may cause severe, intractable itching.
- Pancreatic Ducts: This causes your pancreas to digest itself. You will experience pancreatitis and/or infiltration of the visceral nerves in and around pancreas which causes severe pain. This is often the first symptom of pancreatic cancer.
When cancer cells reach your brain (specifically your motor cortex), this will lead to paralysis of your arm, leg and facial muscles. Furthermore you won’t be unable to speak (communicate), swallow and experience visual blindness. If your spinal cord becomes affected by cancer cells, this will cause paraplegia or quadriplegia meaning you won’t be able to consciously contract and move your muscles from the neck downwards. Your intracranial pressure will increase causing you to feel severe headaches. From this stage any neurological syndrome would occur.
Some cancers secrete a variety of substances into your bloodstream posing (1) endocrine problems and (2) immune mediated problems.
(1) e.g. In Cushing’s syndrome, cancer cells secretes excess cortisol in your blood due to excessive stimulation of your adrenal glands.
(2) e.g. In Myasthenia Gravis, there is diffuse muscle paralysis due to an autoimmune attack on the neuromuscular junctions.
If any cancer causes any multitude of problems remote from the tumour itself, then we refer to this phenomenon as “paraneoplastic syndromes”.
http://www.dailymail.co.uk/femail/article-3437192/People-believe-ve-experienced-death-explain-REALLY-feels-like.html
I know everyone understandably doesn’t want to discuss this topic but I’m curious as to how people experience death knowing they’re gradually fading away and about to die peacefully with your family and friends by your bedside. Is it when:
— You take your last breath of Oxygen?
— You close your eyes for the last time?
— You lose all your senses like touch, hearing, taste, sight and smell?
— Your heart stops beating completely indicated by a flat line on your heart rate monitor i.e. Cardiac arrest?
— Your brain’s neurons stops firing action potentials?
— You lose consciousness?
Out of the people who have been miraculously brought back to life within 30 mins of unconsciousness, they recount experiencing a range of emotions from blissful, serene, peaceful, exciting and relaxing to profound disappointment at not accomplishing their personal goals to terrifying emptiness. Some describe it as a painless, dreamless sleep with nothing but a dark void like a “heavy and invisible blanket of death”. Their visual perspective is perceived as peculiar, surrounded with a plasma of colours and your calls for help fall on deaf ears. Those colours may be "liquid clouds”, “galaxies”, “melting in each other, neither far, nor near and all around and through them” in a pan-vision. But neither of them have seen a religious being called God or Jesus nor seen a paradise above the clouds called paradise. Does this mean there is no life after death? There’s no such thing as a soul nor a God? There’s no such thing as paradise or hell? Hence there’s no such thing as ghosts? You would be just a motionless and unconscious collection of cells laying dormant and silent ready to be mummified, buried or cremated. Does this mean religion has been lying to us all this time? Are these fake beliefs an evil act of manipulation by exploiting our gullibility and weakness to question authority because of our desire for a normal lifestyle? It’s intriguing that people can vaguely remember their near-death experiences. They commonly recount it as a painful, dark, vulnerable, fragile nothingness and infinite sadness. So far researchers have a long way to go in explaining the scientific occurrences of near-death experiences because it’s different for each and every one of us. What we do know is that death can be progression toward a scientifically irreversible outcome. There’s a window of opportunity to restart a silent heart using a defibrillator or CPR, which is about a few minutes after loss of consciousness. But you can’t restart a dead brain even with electrical shocks. Some people come back to life but with a partial brain, hence a different personality with amnesia and severe memory impairment that they forget their own name, the language they speak, their family and friends’ names and faces. Some people are revived with moderate organ damage that is functional to some degree. These are the risks your doctors take into account when discussing bringing somebody back from a coma and live life like they used to. To the 6,316 people that die every day, you have my condolences and wish you rest in peace (RIP). I’ll discuss the physical, social and mechanical aspects of risk in another post.
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