What is rheumatoid arthritis (RA)?
Rheumatoid arthritis is a chronic inflammatory disease that is mainly characterised by peripheral small joint arthritis. It is not just a local infection- it is systemic, and affects many areas of the body. It is fairly common and has a heterogeneous presentation, so it has been hypothesised that what we think of as "rheumatoid arthritis" is actually a number of different diseases lumped together.
Aetiology
The aetiology of rheumatoid arthritis is not fully understood, but is thought to be multifactorial. A whole range of factors may lead to an autoimmune condition in which there is a loss of tolerance of self that cannot be recovered.
Genetics
There is strong evidence for a genetic basis for RA. A positive family history increases RA risk by 3-5 times. The heritability of seropositive (i.e. can detect rheumatoid factor (RF) and/or autoantibodies against citrullinated peptides (ACPAs)) is around 40-65%, whereas the heritability of seronegative disease is only around 20%.
There are over 100 loci associated with RA risk, but possibly the most well-studied loci have been MHC/HLA loci. In particular, HLA DRB1 molecules are more common in people with RA. Some of these molecules have a "shared epitope" sequence, which seems to determine which antigens bind. The actual role of this "shared epitope" is unknown, but it is associated with the presence of serological markers such as RF and ACPAs. RF is an antibody directed against the Fc component of IgG, whereas ACPA are antibodies against citrullinated peptides. (RF and ACPAs are present in around 50-70% of patients, and are associated with a poorer prognosis.) Other loci associated with RA risk are likely to be involved with co-stimulatory pathways, such as cytokine signalling and lymphocyte receptor activation.
Environmental
The main environmental factors implicated in RA are gender, low socioeconomic status, smoking, antigens and infections. Females are 3x as likely to get RA than males, especially in the three months after giving birth. Smoking is very strongly linked to RA- it increases the risk 5x in individuals with only one copy of shared epitope or ACPA, and increases the risk 25x in those with two copies of shared epitope or ACPA. Smoking induces citrullination, forming citrullinated peptides that ACPAs act against. Infections that might increase risk of RA include mycoplasma, periodontal disease, EBV, parvovirus and herpes (though some of these links are ill-defined). The microbiome may also play a role- gastrointestinal dysbiosis is implicated in rheumatoid arthritis. Antigens that may play a role in RA include heat-shock proteins and type II collagen.
Pathogenesis
The pathogenesis of RA is still poorly understood, but it is thought that it begins with the formation of immune complexes between ACPAs and antigens. RF then binds, leading to complement activation. Over time, the concentration and epitope diversity of ACPAs increases, as does the concentration of serum cytokines.
ACPAs, which are produced by B-cells, are present for up to 10 years before diagnosis. They have an altered glycosylation status that enhances their Fc-receptor and citrullinated antigen binding. ACPAs may activate macrophages and/or osteoclasts.
Epidemiology
RA affects around 1% of the global adult population. As mentioned earlier, it affects more women than men. The peak age of onset is between the ages of 45 and 65 years.
Clinical presentation and course
As mentioned earlier, RA is fairly heterogeneous, so different patients will present differently. It is mostly progressive, but early diagnosis and treatment can reduce the damage. The main symptoms are swelling of small peripheral joints with morning stiffness and diffuse aching. Joints have inflammatory infiltrate, synovial hyperplasia, increased vascularity and formation of pannus (abnormal granulation tissue). Sometimes deformities, such as "swan necking" and Boutonniere deformities, may result. These symptoms may be preceded by fatigue, malaise and depression.
As also mentioned earlier, RA is systemic and therefore doesn't only affect the joints. It can also cause cardiovascular problems such as pericarditis, pulmonary problems such as pulmonary nodules and pleuritis, eye problems such as conjunctivitis, and haematologic problems such as granulocytopenia (decrease in white blood cells).
Brief management
The main aims of treatment are to deal with pain and prevent joint destruction. The main drugs used are simple analgesics, anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs (DMARDs) such as methotrexate, leflunomide and sulfasalazine, and biologics and small molecules such as antibodies. Biologics are relatively expensive, so they are generally used in more treatment- resistant cases. The aim is to have a DAS (disease activity score) less than 2.4.
Friday, October 6, 2017
Determinants of Hormone Control
In my last post for PHYL3004, I spoke about one class of hormones (the steroids). In this post, I will be covering eicosanoid and protein hormones.
Eicosanoids
Eicosanoid hormones are derived from arachidonic acid, which is a constituent of cell plasma membranes. Eicosanoids include leukotrienes, thromboxanes, prostacyclin and prostaglandins. I have covered all of these hormones here. The most important eicosanoids for the reproductive system are prostaglandins, which are involved in ovulation and uterine contractions.
Proteins
Proteins are chains of amino acids. I've written far more detail than you need to know for this unit about protein structure here, and about protein synthesis here. Proteins are hydrophilic and generally don't need binding proteins to transport them around the blood. They cannot, however, readily diffuse into cells, so they usually bind to an external membrane-bound receptor, which then activates some second messengers. These second messengers usually increase calcium levels or act as transcription factors in order to carry out their effects.
Gonadotrophins
The main gonadotrophins that you need to know are luteinising hormone (LH), released from the anterior pituitary, follicle-stimulating hormone (FSH), also from the anterior pituitary, and human chorionic gonadotrophin (hCG), from the syncytiotrophoblast (a structure formed during implantation of the blastocyst into the endometrium). All of these hormones have two chains (an alpha- and a beta-chain), and the alpha-chain is the same for all of the hormones. I've written more about LH and FSH here. hCG acts on luteal cells in the ovary to maintain progesterone, and on Leydig cells in the fetal testis in order to increase androgen production and testis development.
Somatomammotrophins
Somatomammotrophins are involved in tissue growth and function. The main somatomammotrophin is prolactin, released from the anterior pituitary. It is involved in lactation. If prolactin levels are high, fertility is suppressed.
Cytokines
Cytokines are often thought of as the main signalling molecules for the immune system, but they can do more than that. Inhibin is a cytokine that is involved in the reproductive system. It is released from granulosa cells (in females) or Sertoli cells (in males), and is involved in guiding gamete development and in gonad-pituitary interactions.
Oligopeptides
Oligopeptides are small peptides that are usually derived from cleaving a larger polypeptide precursor. Examples include GnRH, a highly-conserved 10 amino acid peptide that controls gonadotrophin secretion, and oxytocin, a posterior pituitary hormone involved in parturition, milk letdown and bonding.
Determinants of Hormone Action
The main determinants of hormone action are transport, blood concentration, secretion patterns and receptor expression, so let's get started!
Transport
As mentioned before, steroid hormones generally need a carrier protein to move around the blood, whereas proteins can normally move around by themselves. Only unbound hormones are biologically active.
Blood concentration
The blood concentration of hormone = production rate / clearance rate. Clearance may be due to hormone metabolism, which mainly occurs in the liver, but a small amount of metabolism can occur in the lung during respiration.
Secretion patterns
Most reproductive hormones are secreted in a pulsatile (on/off) manner. Some may follow a kind of circadian (~24hr) rhythm. Testosterone has a somewhat circadian pattern in younger males, but not so much in older males. However, the significance of this is still unknown. Pulsatile release is very important for some hormones, such as GnRH. If GnRH was secreted continuously, receptors would be down-regulated, and LH (a hormone "downstream" of GnRH in the signalling pathway) would decrease.
As you hopefully know by now, female fertility is episodic, with a monthly cycle in ovarian activity. Meanwhile, males pretty much have repeated pulsatile release of hormones from puberty onwards.
Receptor expression
Hormones can only have an effect if they bind to their target. Therefore, the number of targets (receptors) present is related to the strength of the effect. As I just mentioned, continuous release of GnRH can result in downregulation of GnRH receptors and therefore a decrease in the effectiveness of this hormone. Progesterone has the opposite effect: it can upregulate progesterone receptors on the endometrium.
Control of the Endocrine System
The main control systems are simple control, negative feedback, positive feedback and inhibitory control.
Simple control
In simple control, one hormone stimulates another. For example, GnRH stimulates LH.
Negative feedback
See previous post: Control Systems 1
Both males and female reproductive systems use negative feedback.
Positive feedback
See previous post: Control Systems 1
The female reproductive system can use positive feedback in ovulation and in childbirth.
Inhibitory control
In inhibitory control, an inhibitory factor prevents the release of a hormone. For example, dopamine acts as an inhibitory factor preventing the release of prolactin. Therefore, dopamine agonists such as bromocriptine may be considered in the treatment of hyperprolactinaemia (see here).
Eicosanoids
Eicosanoid hormones are derived from arachidonic acid, which is a constituent of cell plasma membranes. Eicosanoids include leukotrienes, thromboxanes, prostacyclin and prostaglandins. I have covered all of these hormones here. The most important eicosanoids for the reproductive system are prostaglandins, which are involved in ovulation and uterine contractions.
Proteins
Proteins are chains of amino acids. I've written far more detail than you need to know for this unit about protein structure here, and about protein synthesis here. Proteins are hydrophilic and generally don't need binding proteins to transport them around the blood. They cannot, however, readily diffuse into cells, so they usually bind to an external membrane-bound receptor, which then activates some second messengers. These second messengers usually increase calcium levels or act as transcription factors in order to carry out their effects.
Gonadotrophins
The main gonadotrophins that you need to know are luteinising hormone (LH), released from the anterior pituitary, follicle-stimulating hormone (FSH), also from the anterior pituitary, and human chorionic gonadotrophin (hCG), from the syncytiotrophoblast (a structure formed during implantation of the blastocyst into the endometrium). All of these hormones have two chains (an alpha- and a beta-chain), and the alpha-chain is the same for all of the hormones. I've written more about LH and FSH here. hCG acts on luteal cells in the ovary to maintain progesterone, and on Leydig cells in the fetal testis in order to increase androgen production and testis development.
Somatomammotrophins
Somatomammotrophins are involved in tissue growth and function. The main somatomammotrophin is prolactin, released from the anterior pituitary. It is involved in lactation. If prolactin levels are high, fertility is suppressed.
Cytokines
Cytokines are often thought of as the main signalling molecules for the immune system, but they can do more than that. Inhibin is a cytokine that is involved in the reproductive system. It is released from granulosa cells (in females) or Sertoli cells (in males), and is involved in guiding gamete development and in gonad-pituitary interactions.
Oligopeptides
Oligopeptides are small peptides that are usually derived from cleaving a larger polypeptide precursor. Examples include GnRH, a highly-conserved 10 amino acid peptide that controls gonadotrophin secretion, and oxytocin, a posterior pituitary hormone involved in parturition, milk letdown and bonding.
Determinants of Hormone Action
The main determinants of hormone action are transport, blood concentration, secretion patterns and receptor expression, so let's get started!
Transport
As mentioned before, steroid hormones generally need a carrier protein to move around the blood, whereas proteins can normally move around by themselves. Only unbound hormones are biologically active.
Blood concentration
The blood concentration of hormone = production rate / clearance rate. Clearance may be due to hormone metabolism, which mainly occurs in the liver, but a small amount of metabolism can occur in the lung during respiration.
Secretion patterns
Most reproductive hormones are secreted in a pulsatile (on/off) manner. Some may follow a kind of circadian (~24hr) rhythm. Testosterone has a somewhat circadian pattern in younger males, but not so much in older males. However, the significance of this is still unknown. Pulsatile release is very important for some hormones, such as GnRH. If GnRH was secreted continuously, receptors would be down-regulated, and LH (a hormone "downstream" of GnRH in the signalling pathway) would decrease.
As you hopefully know by now, female fertility is episodic, with a monthly cycle in ovarian activity. Meanwhile, males pretty much have repeated pulsatile release of hormones from puberty onwards.
Receptor expression
Hormones can only have an effect if they bind to their target. Therefore, the number of targets (receptors) present is related to the strength of the effect. As I just mentioned, continuous release of GnRH can result in downregulation of GnRH receptors and therefore a decrease in the effectiveness of this hormone. Progesterone has the opposite effect: it can upregulate progesterone receptors on the endometrium.
Control of the Endocrine System
The main control systems are simple control, negative feedback, positive feedback and inhibitory control.
Simple control
In simple control, one hormone stimulates another. For example, GnRH stimulates LH.
Negative feedback
See previous post: Control Systems 1
Both males and female reproductive systems use negative feedback.
Positive feedback
See previous post: Control Systems 1
The female reproductive system can use positive feedback in ovulation and in childbirth.
Inhibitory control
In inhibitory control, an inhibitory factor prevents the release of a hormone. For example, dopamine acts as an inhibitory factor preventing the release of prolactin. Therefore, dopamine agonists such as bromocriptine may be considered in the treatment of hyperprolactinaemia (see here).
Tuesday, October 3, 2017
Introduction to Medically Important Helminths
Another infodumping lecture! Yay!
Classification
The two main phylums of helminths (worms) are nematodes (round worms) and platyhelminthes (flat worms). Platyhelminthes can be subdivided into two main classes: cestodes (which includes tapeworms) and trematodes (which includes flukes and Schistosoma).
Transmission
Helminths can be transmitted by direct transmission, ingestion or by vectors (e.g. mosquitoes). The most common helminths to be transmitted directly are gastrointestinal nematodes, while the most common to be transmitted by ingestion are tapeworms and some nematodes. Vector-borne helminths have a limited geographical range compared to the other two types of transmission.
Nematodes
Nematodes (round worms) come in all shapes and sizes, from under 1mm to over 1m in length. They are dioecious (have male and female forms). Nematodes can be roughly divided into gastrointestinal nematodes, or tissue/blood nematodes. Gastrointestinal nematodes are some of the commonest worm infections and are predicted to infect roughly 50% of the world's population. They can be ingested, or larvae can burrow into the skin.
Caenorhabditis elegans is one of the most important nematodes in medicine and medical research. It is known to survive space. It is also transparent and emits blue fluorescence upon death, which makes it useful for research. Other nematodes include Trichuris trichura ("whipworm"), Enterobius vermicularis ("pinworm"), Trichinella spiralis (a tissue/blood nematode that is the only intracellular helminth), Guinea Worm (a tissue/blood nematode that is predicted to be the next disease to be eradicated) and Toxocara canis (a tissue/blood nematode that often affects the eye).
In this post, we'll focus on a couple of gastrointestinal nematodes (Ascaris lumbricoides and hookworms) as well as a tissue worm (filarial worms). Let's get started!
Ascaris lumbricoides
Ascaris lumbricoides is a fairly large worm (15-50cm long) that can lay around 200 000 eggs per day. Infection by Ascaris is often asymptomatic, but can lead to abdominal pain, bowel obstruction, ulcers, bloody sputum and faeces, fever and cough. If the larvae migrate through the lungs, they can cause Loffler's syndrome, which is basically eosinophilia in the lungs. Children infected with Ascaris may also experience growth retardation.
Ascaris can be diagnosed by identifying the eggs in the faeces. In severe cases, adult worms can be seen protruding from the anus. The infection can be treated with anti-helminthic agents such as mebendazole, nitazoxanide and ivermectin.
Hookworms
The main species of hookworms are Ancylostoma duadenale and Necator americanus. Infection is usually asymptomatic, but since hookworms feed on blood, they can cause anaemia. Hookworms can also cause growth retardation in children, and if infection occurs during pregnancy, children may be born with a low birth weight. Diagnosis is by identification of eggs in faeces, and treatment is with mebendazole or albendazole.
Filarial Worms
Filarial worms can cause three types of filariasis, all of which are spread via vectors such as mosquitoes. In lymphatic filariasis, the worms live in the lymphatic system and cause chronic disease, which may lead to elephantiasis (swelling of the legs). Subcutaneous filariasis, where worms stay in the subcutaneous layer of the skin, may lead to "river blindness." Finally, serous cavity filariasis has relatively mild symptoms.
Filarial worms can enter our blood when mosquitoes bite us. Once in the human body, adults can produce sheathed microfilariae that can enter lymph and blood. At night, these microfilariae enter the peripheral blood, where they can be taken up by the next mosquito to bite us. Once in the mosquito, microfilariae shed their sheaths and move to the mosquito's thoracic cavity to form larvae, which grow and move back to the head. The worms can then enter the blood of the mosquito's next victim.
Lymphatic filariasis can be diagnosed by looking for microfilaria in a finger prick test. As microfilaria move towards the peripheral blood during the night, the timing of the test is important. Subcutaneous filariasis can be diagnosed via a skin snip. All kinds of filariasis can be diagnosed with antigen tests.
Treatment for filarial worms mainly targets microfilaria. Albendazole combined with ivermectin kills microfilaria, as does diethylcarbamazine. A new treatment for filariasis uses the antibiotic doxycycline to kill off Wolbachia, which is a bacteria that is needed for the worms to survive.
Platyhelminthes- Cestodes
Cestodes (tapeworms) are haemaphrodites (each worm has male and female reproductive organs). Their bodies are composed of segments and their heads have a structure called a scolex (suckers and hooks), which helps them to attach to the gut. They can cause intestinal infections (which are mainly asymptomatic, with some exceptions) or tissue infections (which tend to be pathological).
Intestinal tapeworms
Intestinal tapeworms, which include Taenia solium and Taenia saginata, can be acquired by eating undercooked meat. Cattle and pigs acquire intestinal tapeworms by ingesting contaminated vegetation and then form cysts in their muscles. Humans can then acquire the infection by eating undercooked meat of infected animals. Once inside humans, these worms can attach to the gut via the scolex and grow up to around 3m long. If humans directly ingest the eggs of Taenia solium (not Taenia saginata), they can develop cysticercosis (cysts). These cysts usually form in subcutaneous tissue, muscle or brain.
Intestinal tapeworms can be diagnosed by identifying eggs in stool sample. The eggs are identical between T. solium and T. saginata, so proglottids (one of the segments or joints) need to be visualised with India ink, or adult worms need to be found, in order to differentiate the species. PCR of ribosomal genes can also be done. Cysticercosis can also be diagnosed with X-rays, CT or biopsy.
Treatment of intestinal tapeworms can be done with praziquantel, niclosamide or albendazole. Some care needs to be taken as dying larvae can elicit a major immune response. Corticosteroids may be given at the same time as anti-helminthic therapy in order to prevent this major immune response.
Tissue tapeworms
Tissue tapeworms include Echinococcus species, such as Echinococcus granulosus and Echinococcus multilocularis. They are acquired by ingesting ova in contaminated food or by direct contact with certain animals, such as dogs. In contrast to intestinal tapeworms, these worms tend to be quite small (~2-7mm). They can form "bladder-like" cysts in Hydatid disease, or they can form new "daughter cysts." The "daughter cysts" of E. granulosus are membrane-bound and are a bit more like a benign tumour, whereas the daughter cysts of E. multilocularis tend to spread more like a metastatic tumour.
Cysts caused by tissue tapeworms can be detected via X-ray or MRI, and diagnosis can be confirmed with biopsy or PCR. Treatment begins with surgery to remove the cysts (if possible), followed by long-term (>2 years) benzimidazoles (class of drugs including albendazole and mebendazole). In non-responsive cases, intravenous amphotericin B may also be used.
Platyhelminthes- Trematodes
The trematodes include tissue flukes and schistosomes. Tissue flukes are haemaphrodites, whereas schistosomes are dioecious. They are obligate parasites (i.e. need to live in a host cell in order to reproduce) and can live for a long time.
Schistosomes
Schistosomes cause schistosomiasis, also known as Bilharzia. Adult schistosomes are asymptomatic, but eggs can cause tissue damage, which over time can lead to chronic organ damage and cancer. Schistosomes are spread by snails: miracidia (trematode larvae) can penetrate snail tissue. Once inside snails, schistosomes form sporocysts, and eventually are released into the water as cercariae (which I *think* is the larval form? Too many unexplained words). Cercariae can penetrate human skin. Once inside humans, they lose their tails and migrate to the liver, where they mature.
Diagnosis of schistosomes is done through identification of eggs, serology tests and biopsy. Treatment is done via praziquantel. As with intestinal tapeworms, dying worms can elicit an immune response, so steroids are also necessary.
Flukes
Flukes include Fasciola, Clonorchis and Opisthorchis, which live in the liver, and Paragonimus, which lives in the lung. The life cycle of flukes is similar to that of schistosomes, aside from the fact that they don't mate (they are haemaphrodites). Flukes are often acquired by eating seafood.
Diagnosis of flukes is done via identifying eggs in the faeces or bile. There is a risk of false positives, however, as no eggs are laid in the first few months. A serology test for antibodies (ELISA) can also be done, as can PCR on faecal material. Treatments include triclabendazole (a benzimidazole) and praziquantel.
Anti-Helminthic Drugs
I'm just going to cross my fingers and hope that we don't need to know everything on this slide. Anyway, apparently we will be getting a lecture on antiparasitic agents in two weeks' time, so stay tuned, I guess!
Classification
The two main phylums of helminths (worms) are nematodes (round worms) and platyhelminthes (flat worms). Platyhelminthes can be subdivided into two main classes: cestodes (which includes tapeworms) and trematodes (which includes flukes and Schistosoma).
Transmission
Helminths can be transmitted by direct transmission, ingestion or by vectors (e.g. mosquitoes). The most common helminths to be transmitted directly are gastrointestinal nematodes, while the most common to be transmitted by ingestion are tapeworms and some nematodes. Vector-borne helminths have a limited geographical range compared to the other two types of transmission.
Nematodes
Nematodes (round worms) come in all shapes and sizes, from under 1mm to over 1m in length. They are dioecious (have male and female forms). Nematodes can be roughly divided into gastrointestinal nematodes, or tissue/blood nematodes. Gastrointestinal nematodes are some of the commonest worm infections and are predicted to infect roughly 50% of the world's population. They can be ingested, or larvae can burrow into the skin.
Caenorhabditis elegans is one of the most important nematodes in medicine and medical research. It is known to survive space. It is also transparent and emits blue fluorescence upon death, which makes it useful for research. Other nematodes include Trichuris trichura ("whipworm"), Enterobius vermicularis ("pinworm"), Trichinella spiralis (a tissue/blood nematode that is the only intracellular helminth), Guinea Worm (a tissue/blood nematode that is predicted to be the next disease to be eradicated) and Toxocara canis (a tissue/blood nematode that often affects the eye).
In this post, we'll focus on a couple of gastrointestinal nematodes (Ascaris lumbricoides and hookworms) as well as a tissue worm (filarial worms). Let's get started!
Ascaris lumbricoides
Ascaris lumbricoides is a fairly large worm (15-50cm long) that can lay around 200 000 eggs per day. Infection by Ascaris is often asymptomatic, but can lead to abdominal pain, bowel obstruction, ulcers, bloody sputum and faeces, fever and cough. If the larvae migrate through the lungs, they can cause Loffler's syndrome, which is basically eosinophilia in the lungs. Children infected with Ascaris may also experience growth retardation.
Ascaris can be diagnosed by identifying the eggs in the faeces. In severe cases, adult worms can be seen protruding from the anus. The infection can be treated with anti-helminthic agents such as mebendazole, nitazoxanide and ivermectin.
Hookworms
The main species of hookworms are Ancylostoma duadenale and Necator americanus. Infection is usually asymptomatic, but since hookworms feed on blood, they can cause anaemia. Hookworms can also cause growth retardation in children, and if infection occurs during pregnancy, children may be born with a low birth weight. Diagnosis is by identification of eggs in faeces, and treatment is with mebendazole or albendazole.
Filarial Worms
Filarial worms can cause three types of filariasis, all of which are spread via vectors such as mosquitoes. In lymphatic filariasis, the worms live in the lymphatic system and cause chronic disease, which may lead to elephantiasis (swelling of the legs). Subcutaneous filariasis, where worms stay in the subcutaneous layer of the skin, may lead to "river blindness." Finally, serous cavity filariasis has relatively mild symptoms.
Filarial worms can enter our blood when mosquitoes bite us. Once in the human body, adults can produce sheathed microfilariae that can enter lymph and blood. At night, these microfilariae enter the peripheral blood, where they can be taken up by the next mosquito to bite us. Once in the mosquito, microfilariae shed their sheaths and move to the mosquito's thoracic cavity to form larvae, which grow and move back to the head. The worms can then enter the blood of the mosquito's next victim.
Lymphatic filariasis can be diagnosed by looking for microfilaria in a finger prick test. As microfilaria move towards the peripheral blood during the night, the timing of the test is important. Subcutaneous filariasis can be diagnosed via a skin snip. All kinds of filariasis can be diagnosed with antigen tests.
Treatment for filarial worms mainly targets microfilaria. Albendazole combined with ivermectin kills microfilaria, as does diethylcarbamazine. A new treatment for filariasis uses the antibiotic doxycycline to kill off Wolbachia, which is a bacteria that is needed for the worms to survive.
Platyhelminthes- Cestodes
Cestodes (tapeworms) are haemaphrodites (each worm has male and female reproductive organs). Their bodies are composed of segments and their heads have a structure called a scolex (suckers and hooks), which helps them to attach to the gut. They can cause intestinal infections (which are mainly asymptomatic, with some exceptions) or tissue infections (which tend to be pathological).
Intestinal tapeworms
Intestinal tapeworms, which include Taenia solium and Taenia saginata, can be acquired by eating undercooked meat. Cattle and pigs acquire intestinal tapeworms by ingesting contaminated vegetation and then form cysts in their muscles. Humans can then acquire the infection by eating undercooked meat of infected animals. Once inside humans, these worms can attach to the gut via the scolex and grow up to around 3m long. If humans directly ingest the eggs of Taenia solium (not Taenia saginata), they can develop cysticercosis (cysts). These cysts usually form in subcutaneous tissue, muscle or brain.
Intestinal tapeworms can be diagnosed by identifying eggs in stool sample. The eggs are identical between T. solium and T. saginata, so proglottids (one of the segments or joints) need to be visualised with India ink, or adult worms need to be found, in order to differentiate the species. PCR of ribosomal genes can also be done. Cysticercosis can also be diagnosed with X-rays, CT or biopsy.
Treatment of intestinal tapeworms can be done with praziquantel, niclosamide or albendazole. Some care needs to be taken as dying larvae can elicit a major immune response. Corticosteroids may be given at the same time as anti-helminthic therapy in order to prevent this major immune response.
Tissue tapeworms
Tissue tapeworms include Echinococcus species, such as Echinococcus granulosus and Echinococcus multilocularis. They are acquired by ingesting ova in contaminated food or by direct contact with certain animals, such as dogs. In contrast to intestinal tapeworms, these worms tend to be quite small (~2-7mm). They can form "bladder-like" cysts in Hydatid disease, or they can form new "daughter cysts." The "daughter cysts" of E. granulosus are membrane-bound and are a bit more like a benign tumour, whereas the daughter cysts of E. multilocularis tend to spread more like a metastatic tumour.
Cysts caused by tissue tapeworms can be detected via X-ray or MRI, and diagnosis can be confirmed with biopsy or PCR. Treatment begins with surgery to remove the cysts (if possible), followed by long-term (>2 years) benzimidazoles (class of drugs including albendazole and mebendazole). In non-responsive cases, intravenous amphotericin B may also be used.
Platyhelminthes- Trematodes
The trematodes include tissue flukes and schistosomes. Tissue flukes are haemaphrodites, whereas schistosomes are dioecious. They are obligate parasites (i.e. need to live in a host cell in order to reproduce) and can live for a long time.
Schistosomes
Schistosomes cause schistosomiasis, also known as Bilharzia. Adult schistosomes are asymptomatic, but eggs can cause tissue damage, which over time can lead to chronic organ damage and cancer. Schistosomes are spread by snails: miracidia (trematode larvae) can penetrate snail tissue. Once inside snails, schistosomes form sporocysts, and eventually are released into the water as cercariae (which I *think* is the larval form? Too many unexplained words). Cercariae can penetrate human skin. Once inside humans, they lose their tails and migrate to the liver, where they mature.
Diagnosis of schistosomes is done through identification of eggs, serology tests and biopsy. Treatment is done via praziquantel. As with intestinal tapeworms, dying worms can elicit an immune response, so steroids are also necessary.
Flukes
Flukes include Fasciola, Clonorchis and Opisthorchis, which live in the liver, and Paragonimus, which lives in the lung. The life cycle of flukes is similar to that of schistosomes, aside from the fact that they don't mate (they are haemaphrodites). Flukes are often acquired by eating seafood.
Diagnosis of flukes is done via identifying eggs in the faeces or bile. There is a risk of false positives, however, as no eggs are laid in the first few months. A serology test for antibodies (ELISA) can also be done, as can PCR on faecal material. Treatments include triclabendazole (a benzimidazole) and praziquantel.
Anti-Helminthic Drugs
I'm just going to cross my fingers and hope that we don't need to know everything on this slide. Anyway, apparently we will be getting a lecture on antiparasitic agents in two weeks' time, so stay tuned, I guess!
Fungal Infections
Just when I thought that we were done with infodumping lectures, we get another one! Maybe this is our "welcome back from study break" treat >_> Just like in the first few posts, anything in red can be found on Microbe Invader (http://microbeinvader.com/).
Descriptions of Fungal Infection
Location
Fungal infections can be described as superficial, cutaneous, subcutaneous or systemic. Superficial infections, such as dandruff and oral candidiasis, generally don't cause an immune response, but they are also very rarely fatal. Cutaneous infections, such as tinea, infect keratinised tissue. Subcutaneous infections, such as sporotrichosis, can lead to granuloma formation and cysts. Finally, systemic infections can cause severe illnesses that are often fatal, and are often caused by the more virulent fungi, including the primary pathogens Coccidioides, Histoplasma, Blastomyces and Paracoccidioides. Even opportunistic pathogens, such as Candida, may be able to cause systemic infections in the immunocompromised.
Endemic vs. Opportunistic
Fungi can also be classified as endemic or opportunistic. Endemic mycoses are caused by fungi which are not part of the normal human flora, but are acquired from environmental sources. They are often associated with outdoor activities and other specific exposures: for example, Histoplasma is associated with old buildings with bird or bat droppings, Coccidioides is associated with deserts, and Blastomyces is associated with wetlands and wooded areas. (All of those three are mainly found in North America.) Other risk factors for endemic mycoses include increasing age and decreasing cell-mediated immunity. Opportunistic mycoses, on the other hand, are caused by organisms that are often part of the normal flora, and mainly cause disease in the immunocompromised.
Morphology
Yeasts are fungi that are round and multiply by budding. Filamentous fungi grow as filaments and hyphae (chain of cells that line up nicely to form smooth "branches"), which can intertwine to form a network called a mycelium. Filamentous fungi often produce asexual spores called conidia, which are located on long chains on a conidiophore.
There are also dimorphic (or more accurately polyphenic) "yeast-like fungi" which can grow as yeasts or form chains. Some of these chains might be hyphae, and some might be pseudohyphae (kind of like hyphae, but with "constrictions" between the cells in the chain). The ability of dimorphic fungi to change shape can help with overcoming defences. Dimorphic fungi tend to be in the yeast form at body temperature, aiding in dissemination. Their filamentous form, which is more common at room temperature, helps with tissue damage and invasion.
Cell Walls
Just a quick note on cell walls: fungal cell walls are mainly made up of polysaccharides, particularly glucan, chitin and mannan. The cell wall composition changes between different species.
Virulence Factors
Just like bacteria, fungi have several virulence factors that help them to fight against their host.
Phenotypic Switching and Dimorphism
As I mentioned above, some fungi can change their morphology. Aside from dimorphic fungi, which can change between yeasts and hyphae, several different fungi can change their cell surface properties, colony appearance, and so on. For example, Candida albicans can switch from white cells to opaque cells for sexual mating.
Adhesion
Like bacteria, some fungi have adhesins, which help them to bind to host cells.
Secreted hydrolytic enzymes
Some fungi can secrete enzymes, such as proteases, lipases and phospholipases. These have a wide range of roles, from acquiring nutrition (e.g. pinching iron from RBCs), damaging tissue and overcoming the host immune system.
Biofilm
Fungi, like bacteria, can form biofilm or "slime" which provides a physical barrier from phagocytosis, lysozyme and antimicrobials.
Candida
Since Candida (especially Candida albicans) is a relatively common fungus, let's focus on it for a little while! Candida mainly exists in yeast form, and is thus oval or round and can reproduce by budding. It is, however, polyphenic, and can form pseudohyphae when exposed to certain physiological conditions. When Candida enters tissue, it can form true hyphae, which aid in invasion and infection.
Candida is found in a lot of places, including soil, food, animals and humans (yep, it is part of our commensal flora). There are over 150 species, but only a handful cause infection, and even then they mainly only cause infections in the immunocompromised. Conditions caused by Candida include intertrigo (skin fold infection), paronychia (nail bed infection), onychomycosis (nail infection), nappy rash, oral candidiasis, vaginitis and oesophagitis.
Candida can even enter the blood, causing Candidaemia. The usual causes of candidaemia are colonisation of intravenous cannulae and contaminated injections by drug users. Invasive candidiasis can cause some pretty nasty conditions, such as endophthalmitis (inflammation of the interior of the eye), meningitis, endocarditis, pyelonephritis and osteomyelitis.
Diagnosis of Candida can be done via microscopy and culture. On agar, Candida forms smoth, creamy white colonies. In serum, Candida albicans forms germ tubes (which are basically precursors of hyphae), which differentiates it from other Candida species.
Dermatophytes
Dermatophytes are fungi that usually cause milder skin diseases, such as tinea. The main genera are Microsporum, Epidermophyton and Trichophyton. They invade the epidermis and release proteinases and keratinases, causing inflammation of the skin and keratinised tissues. Dermatophyte infections include tinea pedis ("athlete's foot"), tinea corporis ("body ringworm"), tinea cruris (infection of warm, moist creases), tinea capitis (scalp infection) and tinea unguinum (thick, crumbly and discoloured nails).
For some reason, there was a slide on pityriasis versicolor here, even though it's caused by Malassezia, which is not a dermatophyte. (I've also covered it here.)
To diagnose a dermatophyte infection, skin scrapings or nail clippings are often used. Since the fungus is most active in the advancing margin of the lesion, skin scrapings are usually done in this area.
Aspergillus
The main type of Aspergillus is Aspergillus fumigatus, which is fairly ubiquitous. Most people will inhale many A. fumigatus conidia (spores) daily without any ill effect, though the immunocompromised are a different story.
There are three main manifestations of aspergillosis: allergic bronchopulmonary aspergillosis (ABPE), aspergilloma and invasive aspergillosis. ABPE is caused by an allergic or hypersensitivity response to Aspergillus spores, and causes breathlessness and fevers. Aspergilloma is a fungal ball which grows inside a pre-existing lung cavity. Invasive aspergillosis, which is an acute or subacute infection, mainly affects the lungs and causes fever, cough and haemoptysis (coughing up blood). Invasive aspergillosis occurs mainly in transplant patients. Mortality rates are fairly high, though they are not so bad if treatment is started within 10 days of symptom commencement.
Aspergillus can be diagnosed via culture, the galactomannan assay and/or the β-D-glucan assay, though these diagnostic techniques may also need to be backed up by histological proof (i.e. looking at the tissue). Culture of Aspergillus has a high likelihood of false positives, and has only around 30% sensitivity. The galactomannan assay, which is an ELISA for a particular cell wall component of Aspergillus, has some inter-lab variability, problems with false positives and negatives, and requires serial testing (i.e. test the same patient several times over several days). The β-D-glucan assay also looks for part of the cell wall of Aspergillus, but amoxicillin-clavulanate, piperacillin-tazobactam and Streptococcus pneumoniae (which also has some β-D-glucan) can all cause false positives.
Mucormycosis
Mucormycosis is an invasive lethal mycosis caused by moulds such as Rhizopus, Rhizomucor, Mucorales and Absidia. It is a severe infection of the facial sinuses that mainly affects diabetics and the immunocompromised.
Cryptococcus
I've spoken about Cryptococcus a bit here, so now I'll go into a bit more detail! Cryptococcus neoformans is mainly associated with soil and bird poo, whereas Cryptococcus gattii is mainly associated with eucalyptus trees. It mainly causes disease in the immunocompromised, but it may also cause disease in healthy people. Cryptococcus can be diagnosed via microscopy (particularly with the India ink test), testing for cryptococcal antigen in the serum or CSF, as well as by looking at the manifestations (symptoms include meningoencephalitis, pneumonia and skin lesions).
Descriptions of Fungal Infection
Location
Fungal infections can be described as superficial, cutaneous, subcutaneous or systemic. Superficial infections, such as dandruff and oral candidiasis, generally don't cause an immune response, but they are also very rarely fatal. Cutaneous infections, such as tinea, infect keratinised tissue. Subcutaneous infections, such as sporotrichosis, can lead to granuloma formation and cysts. Finally, systemic infections can cause severe illnesses that are often fatal, and are often caused by the more virulent fungi, including the primary pathogens Coccidioides, Histoplasma, Blastomyces and Paracoccidioides. Even opportunistic pathogens, such as Candida, may be able to cause systemic infections in the immunocompromised.
Endemic vs. Opportunistic
Fungi can also be classified as endemic or opportunistic. Endemic mycoses are caused by fungi which are not part of the normal human flora, but are acquired from environmental sources. They are often associated with outdoor activities and other specific exposures: for example, Histoplasma is associated with old buildings with bird or bat droppings, Coccidioides is associated with deserts, and Blastomyces is associated with wetlands and wooded areas. (All of those three are mainly found in North America.) Other risk factors for endemic mycoses include increasing age and decreasing cell-mediated immunity. Opportunistic mycoses, on the other hand, are caused by organisms that are often part of the normal flora, and mainly cause disease in the immunocompromised.
Morphology
Yeasts are fungi that are round and multiply by budding. Filamentous fungi grow as filaments and hyphae (chain of cells that line up nicely to form smooth "branches"), which can intertwine to form a network called a mycelium. Filamentous fungi often produce asexual spores called conidia, which are located on long chains on a conidiophore.
There are also dimorphic (or more accurately polyphenic) "yeast-like fungi" which can grow as yeasts or form chains. Some of these chains might be hyphae, and some might be pseudohyphae (kind of like hyphae, but with "constrictions" between the cells in the chain). The ability of dimorphic fungi to change shape can help with overcoming defences. Dimorphic fungi tend to be in the yeast form at body temperature, aiding in dissemination. Their filamentous form, which is more common at room temperature, helps with tissue damage and invasion.
Cell Walls
Just a quick note on cell walls: fungal cell walls are mainly made up of polysaccharides, particularly glucan, chitin and mannan. The cell wall composition changes between different species.
Virulence Factors
Just like bacteria, fungi have several virulence factors that help them to fight against their host.
Phenotypic Switching and Dimorphism
As I mentioned above, some fungi can change their morphology. Aside from dimorphic fungi, which can change between yeasts and hyphae, several different fungi can change their cell surface properties, colony appearance, and so on. For example, Candida albicans can switch from white cells to opaque cells for sexual mating.
Adhesion
Like bacteria, some fungi have adhesins, which help them to bind to host cells.
Secreted hydrolytic enzymes
Some fungi can secrete enzymes, such as proteases, lipases and phospholipases. These have a wide range of roles, from acquiring nutrition (e.g. pinching iron from RBCs), damaging tissue and overcoming the host immune system.
Biofilm
Fungi, like bacteria, can form biofilm or "slime" which provides a physical barrier from phagocytosis, lysozyme and antimicrobials.
Candida
Since Candida (especially Candida albicans) is a relatively common fungus, let's focus on it for a little while! Candida mainly exists in yeast form, and is thus oval or round and can reproduce by budding. It is, however, polyphenic, and can form pseudohyphae when exposed to certain physiological conditions. When Candida enters tissue, it can form true hyphae, which aid in invasion and infection.
Candida is found in a lot of places, including soil, food, animals and humans (yep, it is part of our commensal flora). There are over 150 species, but only a handful cause infection, and even then they mainly only cause infections in the immunocompromised. Conditions caused by Candida include intertrigo (skin fold infection), paronychia (nail bed infection), onychomycosis (nail infection), nappy rash, oral candidiasis, vaginitis and oesophagitis.
Candida can even enter the blood, causing Candidaemia. The usual causes of candidaemia are colonisation of intravenous cannulae and contaminated injections by drug users. Invasive candidiasis can cause some pretty nasty conditions, such as endophthalmitis (inflammation of the interior of the eye), meningitis, endocarditis, pyelonephritis and osteomyelitis.
Diagnosis of Candida can be done via microscopy and culture. On agar, Candida forms smoth, creamy white colonies. In serum, Candida albicans forms germ tubes (which are basically precursors of hyphae), which differentiates it from other Candida species.
Dermatophytes
Dermatophytes are fungi that usually cause milder skin diseases, such as tinea. The main genera are Microsporum, Epidermophyton and Trichophyton. They invade the epidermis and release proteinases and keratinases, causing inflammation of the skin and keratinised tissues. Dermatophyte infections include tinea pedis ("athlete's foot"), tinea corporis ("body ringworm"), tinea cruris (infection of warm, moist creases), tinea capitis (scalp infection) and tinea unguinum (thick, crumbly and discoloured nails).
For some reason, there was a slide on pityriasis versicolor here, even though it's caused by Malassezia, which is not a dermatophyte. (I've also covered it here.)
To diagnose a dermatophyte infection, skin scrapings or nail clippings are often used. Since the fungus is most active in the advancing margin of the lesion, skin scrapings are usually done in this area.
Aspergillus
The main type of Aspergillus is Aspergillus fumigatus, which is fairly ubiquitous. Most people will inhale many A. fumigatus conidia (spores) daily without any ill effect, though the immunocompromised are a different story.
There are three main manifestations of aspergillosis: allergic bronchopulmonary aspergillosis (ABPE), aspergilloma and invasive aspergillosis. ABPE is caused by an allergic or hypersensitivity response to Aspergillus spores, and causes breathlessness and fevers. Aspergilloma is a fungal ball which grows inside a pre-existing lung cavity. Invasive aspergillosis, which is an acute or subacute infection, mainly affects the lungs and causes fever, cough and haemoptysis (coughing up blood). Invasive aspergillosis occurs mainly in transplant patients. Mortality rates are fairly high, though they are not so bad if treatment is started within 10 days of symptom commencement.
Aspergillus can be diagnosed via culture, the galactomannan assay and/or the β-D-glucan assay, though these diagnostic techniques may also need to be backed up by histological proof (i.e. looking at the tissue). Culture of Aspergillus has a high likelihood of false positives, and has only around 30% sensitivity. The galactomannan assay, which is an ELISA for a particular cell wall component of Aspergillus, has some inter-lab variability, problems with false positives and negatives, and requires serial testing (i.e. test the same patient several times over several days). The β-D-glucan assay also looks for part of the cell wall of Aspergillus, but amoxicillin-clavulanate, piperacillin-tazobactam and Streptococcus pneumoniae (which also has some β-D-glucan) can all cause false positives.
Mucormycosis
Mucormycosis is an invasive lethal mycosis caused by moulds such as Rhizopus, Rhizomucor, Mucorales and Absidia. It is a severe infection of the facial sinuses that mainly affects diabetics and the immunocompromised.
Cryptococcus
I've spoken about Cryptococcus a bit here, so now I'll go into a bit more detail! Cryptococcus neoformans is mainly associated with soil and bird poo, whereas Cryptococcus gattii is mainly associated with eucalyptus trees. It mainly causes disease in the immunocompromised, but it may also cause disease in healthy people. Cryptococcus can be diagnosed via microscopy (particularly with the India ink test), testing for cryptococcal antigen in the serum or CSF, as well as by looking at the manifestations (symptoms include meningoencephalitis, pneumonia and skin lesions).
Reproductive Endocrinology
This lecture was mainly a refresher to get us stuck into the topic, so hopefully this post will be easy to write...! (Also- 500th post! 0_o)
Hormone Action
See previous post: Biochemical Messengers
Steroids
Steroids are lipid-soluble hormones that are derived from cholesterol. Some examples of steroid hormones include progesterone, aldosterone, cortisol, testosterone and oestradiol. As they do not dissolve well in water, roughly 95% of steroid hormone in the blood is bound to a carrier protein. The remaining 2-5% is free hormone that can diffuse into cells. Steroids usually bind to an intracellular receptor, which then diffuses into the nucleus and acts as a transcription factor. (For more details, see here.)
Progestagens
Progestagens are a type of steroid that includes progesterone. Progesterone is the most potent progestagen (i.e. has the highest affinity for its receptor). Other progestagens include 17α-hydroxyprogesterone (17α-OHP), which is around 40-70% as potent as progesterone, and 20α-hydroxyprogesterone (20α-OHP), which is only around 5% as potent as progesterone. Progestagens are particularly important in gestation, thickening of the endometrium in the second half of the menstrual cycle, and negative feedback on pituitary secretion of FSH and LH.
Androgens
Androgens include 5α-dihydrotestosterone (DHT), which is the most potent, testosterone, which is the most common but is only 50% as potent as DHT, androstenedione, which is 8% as potent as DHT, and dehydroepiandrosterone (DHEA), which is only around 4% as potent as DHT. Testosterone can be converted into DHT by 5α-reductase (see here for more information). Androgens are mainly important in the development of secondary sex characteristics, such as male genitalia, body hair, and so on. They are also anabolic and have negative feedback on pituitary secretion of FSH and LH.
Oestrogens
Oestrogens include oestradiol 17β, which is the most common and the most potent, oestriol, a common hormone in pregnancy which is only around 10% as potent as oestradiol, and oestrone, which is only around 1% as potent as oestradiol. Oestrogens are all formed from androgens via the action of an enzyme called aromatase. The functions of oestrogens include development of the endometrium during the first half of the menstrual cycle, increasing the water content of cervical mucus, and providing negative feedback to the pituitary.
Corticosteroids
Corticosteroids aren't normally associated with reproduction, but they may have some roles in the reproductive system. Corticosteroid levels increase during gestation and are important for fetal organ maturation. It has also been suggested that corticosteroids may be involved in the onset of parturition (labour), maternal behaviour, and suppression of the reproductive system, but further research is needed to confirm these.
Hormone Action
See previous post: Biochemical Messengers
Steroids
Steroids are lipid-soluble hormones that are derived from cholesterol. Some examples of steroid hormones include progesterone, aldosterone, cortisol, testosterone and oestradiol. As they do not dissolve well in water, roughly 95% of steroid hormone in the blood is bound to a carrier protein. The remaining 2-5% is free hormone that can diffuse into cells. Steroids usually bind to an intracellular receptor, which then diffuses into the nucleus and acts as a transcription factor. (For more details, see here.)
Progestagens
Progestagens are a type of steroid that includes progesterone. Progesterone is the most potent progestagen (i.e. has the highest affinity for its receptor). Other progestagens include 17α-hydroxyprogesterone (17α-OHP), which is around 40-70% as potent as progesterone, and 20α-hydroxyprogesterone (20α-OHP), which is only around 5% as potent as progesterone. Progestagens are particularly important in gestation, thickening of the endometrium in the second half of the menstrual cycle, and negative feedback on pituitary secretion of FSH and LH.
Androgens
Androgens include 5α-dihydrotestosterone (DHT), which is the most potent, testosterone, which is the most common but is only 50% as potent as DHT, androstenedione, which is 8% as potent as DHT, and dehydroepiandrosterone (DHEA), which is only around 4% as potent as DHT. Testosterone can be converted into DHT by 5α-reductase (see here for more information). Androgens are mainly important in the development of secondary sex characteristics, such as male genitalia, body hair, and so on. They are also anabolic and have negative feedback on pituitary secretion of FSH and LH.
Oestrogens
Oestrogens include oestradiol 17β, which is the most common and the most potent, oestriol, a common hormone in pregnancy which is only around 10% as potent as oestradiol, and oestrone, which is only around 1% as potent as oestradiol. Oestrogens are all formed from androgens via the action of an enzyme called aromatase. The functions of oestrogens include development of the endometrium during the first half of the menstrual cycle, increasing the water content of cervical mucus, and providing negative feedback to the pituitary.
Corticosteroids
Corticosteroids aren't normally associated with reproduction, but they may have some roles in the reproductive system. Corticosteroid levels increase during gestation and are important for fetal organ maturation. It has also been suggested that corticosteroids may be involved in the onset of parturition (labour), maternal behaviour, and suppression of the reproductive system, but further research is needed to confirm these.
Heart Disease and Nutrition
Define coronary heart disease (CHD)
Coronary heart disease (CHD), also known as coronary artery disease, is a disease in which the coronary arteries supplying the heart are unable to provide it with enough blood.
Discuss the importance of CBF & myocardial O2 demand
The heart is a very oxygen-hungry organ. Every minute, it consumes more oxygen than any other organ of the body. The heart is also extremely efficient at extracting oxygen from the blood (removes around 75% of oxygen from the blood passing through), so during times of increased oxygen demand, there isn't a lot of leeway for the heart to remove more oxygen from the blood. Instead, coronary blood flow (CBF) is most important for maintaining oxygen delivery during times of need, such as during exercise.
Coronary blood flow is greatest during diastole (relaxation of the heart), as during systole (contraction) the blood vessels are squeezed. In fact, at the end of isovolumetric contraction, there might even be some backflow from the coronary arteries to the aorta. Another factor affecting CBF is perfusion pressure: the greater the perfusion pressure, the greater the blood flow.
Explain the causes & risk factors for CHD
Causes
The main causes of CHD are vascular spasm, atherosclerosis, and other complications such as thromboses (clots).
Vascular spasm refers to transient vasoconstriction. Common triggers include cold, physical exertion and anxiety, and can occur in both healthy and CHD patients. Vascular spasm is reversible and rarely causes long-term damage. Vascular spasm can be caused by α-vasoconstrictors (e.g. noradrenaline), but in some cases it might be caused by a heightened vasoconstrictor response to acetylcholine, or by deficient basal release of nitric oxide.
Atherosclerosis refers to the formation of a plaque, which is made up of cholesterol, calcium and white blood cells. It is initiated by inflammatory processes. Macrophages can digest LDL, forming foam cells, which can eventually rupture to form fatty streaks. There are two main types of plaques: stable plaques, which consist of mainly smooth muscle and extracellular matrix, and unstable plaques, which consist of mainly macrophages and foam cells. Atherosclerosis can cause partial or complete blockages of the coronary arteries. The amount of damage caused depends on the size and location of the blood vessel.
When atherosclerotic plaques form, they may not be noticed immediately. That is because we have collateral vessels that can grow rapidly when there is a blockage. Symptoms may only occur once the collateral vessels are also blocked. Therefore, CHD is often known as a "silent killer."
Thromboses are caused by blood platelets sticking to collagen. This may be related to atherosclerosis: collagen may be exposed when plaque breaks through a weakened endothelial lining. Thromboses can also block arteries and cause damage.
Risk factors
Risk factors can be broken down into uncontrollable and controllable risk factors. Uncontrollable factors are things that you can't do much about, such as age (risk increases with age), sex (pre-menopausal females are less likely to get CHD as oestrogen has a protective effect) and heredity (certain conditions, such as familial hypercholesterolaemia, can increase your risk). Controllable factors are things that you can control to some extent, such as blood pressure, high blood cholesterol, smoking, obesity, physical activity, and so on.
There are several ways in which hypertension can lead to CHD. Hypertension induces endothelial dysfunction, exacerbating atherosclerosis. It may also lead to left ventricular hypertrophy, as the ventricles need to grow larger to pump against the greater pressure. The problem with this is that the larger muscle needs more blood. Hypertension is also associated with other metabolic disorders such as insulin resistance, which may contribute to CHD risk.
Hyperglycaemia, such as in diabetes, can raise CHD risk in several ways. Hyperglycaemia can lead to glycosylation of proteins in the arterial wall, which in turn can lead to atherosclerosis. Hyperglycemia can also increase the formation of reactive oxygen species, also leading to atherosclerosis.
Smoking is not only bad for your lungs, but is also bad for your heart. Smoking lowers HDL levels and increases circulating fibrinogen, increasing risk of atherosclerosis. Nicotine can cause vasoconstriction, and carbon monoxide reduces the oxygen carrying capacity of the blood.
Discuss prevention & treatment of CVD
The main preventative strategies for CVD are eating a healthy diet and exercising. Treatments involve lifestyle changes, medication (mainly nitroglycerin, a potent vasodilator) and, in more extreme cases, bypass surgery.
Describe the Mediterranean diet
The Mediterranean diet is often touted as a healthy diet for CHD prevention. It is characterised by lots of fruit, vegetables, grains, and so on, more fish, poultry and dairy than red meat, and olive oil as the main source of fat. Olive oil has very high levels of monounsaturated fats, particularly oleic acid, which may have a protective effect against CHD. Olive oil also contains phenols, which inhibit the production of reactive oxygen species.
Coronary heart disease (CHD), also known as coronary artery disease, is a disease in which the coronary arteries supplying the heart are unable to provide it with enough blood.
Discuss the importance of CBF & myocardial O2 demand
The heart is a very oxygen-hungry organ. Every minute, it consumes more oxygen than any other organ of the body. The heart is also extremely efficient at extracting oxygen from the blood (removes around 75% of oxygen from the blood passing through), so during times of increased oxygen demand, there isn't a lot of leeway for the heart to remove more oxygen from the blood. Instead, coronary blood flow (CBF) is most important for maintaining oxygen delivery during times of need, such as during exercise.
Coronary blood flow is greatest during diastole (relaxation of the heart), as during systole (contraction) the blood vessels are squeezed. In fact, at the end of isovolumetric contraction, there might even be some backflow from the coronary arteries to the aorta. Another factor affecting CBF is perfusion pressure: the greater the perfusion pressure, the greater the blood flow.
Explain the causes & risk factors for CHD
Causes
The main causes of CHD are vascular spasm, atherosclerosis, and other complications such as thromboses (clots).
Vascular spasm refers to transient vasoconstriction. Common triggers include cold, physical exertion and anxiety, and can occur in both healthy and CHD patients. Vascular spasm is reversible and rarely causes long-term damage. Vascular spasm can be caused by α-vasoconstrictors (e.g. noradrenaline), but in some cases it might be caused by a heightened vasoconstrictor response to acetylcholine, or by deficient basal release of nitric oxide.
Atherosclerosis refers to the formation of a plaque, which is made up of cholesterol, calcium and white blood cells. It is initiated by inflammatory processes. Macrophages can digest LDL, forming foam cells, which can eventually rupture to form fatty streaks. There are two main types of plaques: stable plaques, which consist of mainly smooth muscle and extracellular matrix, and unstable plaques, which consist of mainly macrophages and foam cells. Atherosclerosis can cause partial or complete blockages of the coronary arteries. The amount of damage caused depends on the size and location of the blood vessel.
When atherosclerotic plaques form, they may not be noticed immediately. That is because we have collateral vessels that can grow rapidly when there is a blockage. Symptoms may only occur once the collateral vessels are also blocked. Therefore, CHD is often known as a "silent killer."
Thromboses are caused by blood platelets sticking to collagen. This may be related to atherosclerosis: collagen may be exposed when plaque breaks through a weakened endothelial lining. Thromboses can also block arteries and cause damage.
Risk factors
Risk factors can be broken down into uncontrollable and controllable risk factors. Uncontrollable factors are things that you can't do much about, such as age (risk increases with age), sex (pre-menopausal females are less likely to get CHD as oestrogen has a protective effect) and heredity (certain conditions, such as familial hypercholesterolaemia, can increase your risk). Controllable factors are things that you can control to some extent, such as blood pressure, high blood cholesterol, smoking, obesity, physical activity, and so on.
There are several ways in which hypertension can lead to CHD. Hypertension induces endothelial dysfunction, exacerbating atherosclerosis. It may also lead to left ventricular hypertrophy, as the ventricles need to grow larger to pump against the greater pressure. The problem with this is that the larger muscle needs more blood. Hypertension is also associated with other metabolic disorders such as insulin resistance, which may contribute to CHD risk.
Hyperglycaemia, such as in diabetes, can raise CHD risk in several ways. Hyperglycaemia can lead to glycosylation of proteins in the arterial wall, which in turn can lead to atherosclerosis. Hyperglycemia can also increase the formation of reactive oxygen species, also leading to atherosclerosis.
Smoking is not only bad for your lungs, but is also bad for your heart. Smoking lowers HDL levels and increases circulating fibrinogen, increasing risk of atherosclerosis. Nicotine can cause vasoconstriction, and carbon monoxide reduces the oxygen carrying capacity of the blood.
Discuss prevention & treatment of CVD
The main preventative strategies for CVD are eating a healthy diet and exercising. Treatments involve lifestyle changes, medication (mainly nitroglycerin, a potent vasodilator) and, in more extreme cases, bypass surgery.
Describe the Mediterranean diet
The Mediterranean diet is often touted as a healthy diet for CHD prevention. It is characterised by lots of fruit, vegetables, grains, and so on, more fish, poultry and dairy than red meat, and olive oil as the main source of fat. Olive oil has very high levels of monounsaturated fats, particularly oleic acid, which may have a protective effect against CHD. Olive oil also contains phenols, which inhibit the production of reactive oxygen species.
Stress, Fasting and Starvation
Study break is over so it's back to classes. Woohoo...
Body energy stores
We have a small amount of free glucose in our blood, but this will only last us around half an hour. Thankfully, we can also store other nutrients so that we don't starve to death between meals. We have glycogen stores, which can last for around 18 hours, triacylglycerol (a.k.a. fats), which can last for around 55 days, and protein stores (basically all the tissues in our body can be broken down for fuel), which can last around 21 days.
Short term fasting
In short-term fasting (i.e. before glycogen stores have been depleted), plasma glucose decreases. Since glucose levels decrease, insulin decreases and glucagon increases. The actions of these two hormones promote glycogenolysis (breakdown of glycogen to form glucose) and inhibit glycogenesis (formation of glycogen from glucose), which helps to keep glucose levels high enough to sustain the various body tissues. I have described the functions of insulin in more detail here. Glucagon pretty much just does the opposite of insulin.
Long term starvation
As I mentioned above, glycogen stores only last for around 18 hours. Therefore, if you starve for a while, fats and protein become more important fuel sources.
Fats are our largest energy source and can keep us going for around 55 days. A large proportion of this fat is stored in adipose tissue. Unfortunately, not all tissues can derive energy from fats directly. These tissues include the brain, heart, erythrocytes and renal cortex. Therefore, some alternatives are necessary: energy derived from breaking down fat can be used to power gluconeogenesis (discussed here), or acetyl CoA can be converted into ketone bodies (discussed here). Gluconeogenesis depletes supplies of oxaloacetate (a component of the citric acid cycle), which prevents acetyl CoA from entering the citric acid cycle, resulting in production of ketone bodies instead. Ketone bodies are released into the blood (blood ketones reach around 6-8mmol/L) and enter other cells, where they are converted back to acetyl CoA and oxidised to produce ATP via the citric acid cycle.
During starvation, our metabolism also decreases. This is due to a decrease in leptin secretion, which in turn decreases TSH secretion, which in turn decreases thyroid hormone secretion.
Summary
When we stop eating, insulin decreases and glucagon increases. As glycogen stores are depleted, tissues that are capable of metabolising fatty acids start doing that (so as to save glucose for tissues that need it, like the brain). The liver also performs gluconeogenesis and ketone production in order to power tissues that can't oxidise fatty acids. Metabolism also decreases. During long-term starvation, there is a kind of steady state with gradual depletion of protein and fat stores. Blood ketones reach around 6-8mmol/L, of which around 2/3 is used by the brain. When fats are depleted, protein degradation increases dramatically, ultimately resulting in organ failure.
Body energy stores
We have a small amount of free glucose in our blood, but this will only last us around half an hour. Thankfully, we can also store other nutrients so that we don't starve to death between meals. We have glycogen stores, which can last for around 18 hours, triacylglycerol (a.k.a. fats), which can last for around 55 days, and protein stores (basically all the tissues in our body can be broken down for fuel), which can last around 21 days.
Short term fasting
In short-term fasting (i.e. before glycogen stores have been depleted), plasma glucose decreases. Since glucose levels decrease, insulin decreases and glucagon increases. The actions of these two hormones promote glycogenolysis (breakdown of glycogen to form glucose) and inhibit glycogenesis (formation of glycogen from glucose), which helps to keep glucose levels high enough to sustain the various body tissues. I have described the functions of insulin in more detail here. Glucagon pretty much just does the opposite of insulin.
Long term starvation
As I mentioned above, glycogen stores only last for around 18 hours. Therefore, if you starve for a while, fats and protein become more important fuel sources.
Fats are our largest energy source and can keep us going for around 55 days. A large proportion of this fat is stored in adipose tissue. Unfortunately, not all tissues can derive energy from fats directly. These tissues include the brain, heart, erythrocytes and renal cortex. Therefore, some alternatives are necessary: energy derived from breaking down fat can be used to power gluconeogenesis (discussed here), or acetyl CoA can be converted into ketone bodies (discussed here). Gluconeogenesis depletes supplies of oxaloacetate (a component of the citric acid cycle), which prevents acetyl CoA from entering the citric acid cycle, resulting in production of ketone bodies instead. Ketone bodies are released into the blood (blood ketones reach around 6-8mmol/L) and enter other cells, where they are converted back to acetyl CoA and oxidised to produce ATP via the citric acid cycle.
During starvation, our metabolism also decreases. This is due to a decrease in leptin secretion, which in turn decreases TSH secretion, which in turn decreases thyroid hormone secretion.
Summary
When we stop eating, insulin decreases and glucagon increases. As glycogen stores are depleted, tissues that are capable of metabolising fatty acids start doing that (so as to save glucose for tissues that need it, like the brain). The liver also performs gluconeogenesis and ketone production in order to power tissues that can't oxidise fatty acids. Metabolism also decreases. During long-term starvation, there is a kind of steady state with gradual depletion of protein and fat stores. Blood ketones reach around 6-8mmol/L, of which around 2/3 is used by the brain. When fats are depleted, protein degradation increases dramatically, ultimately resulting in organ failure.
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