Last post of the semester! This one shouldn't be too long because we didn't really have a lot of time to cover this topic.
Describe the characteristics of Muscular Dystrophy. Identify the differences between the Duchenne and Myotonic forms of the disease. What is Gower's manoeuvre?
Muscular dystrophy is a genetic muscular disorder in which dystrophin is defective. This can lead to muscle weakness and even breakdown of muscle tissue to be replaced by fat and connective tissue. (I've posted some pictures of mouse tissue with this disease here.)
One of the more severe types of muscular dystrophy is Duchenne's muscular dystrophy. It is an X-linked recessive disorder, so it is more common in males. It has an early onset and rapidly progresses, so that patients are often wheelchair-bound in their teens and eventually die of respiratory failure due to the breakdown of respiratory muscles.
Another type of muscular dystrophy is the myotonic variety, in which muscle relaxation is delayed. This is also genetic, but it is autosomal dominant. It progresses more slowly than the Duchenne variety.
Other general characteristics of muscular dystrophy include cardiomyopathy (disease affecting the heart muscle), increased creatine kinase (an enzyme common in muscle cells that is released when they die), vertebral deformities such as scoliosis, and Gower's manoeuvre. Gower's manoeuvre is a result of patients being too weak to stand easily, which often occurs as pelvic muscles are usually the first to be affected by this disease. Essentially, patients will use their hands to push themselves up, walking their hands up their legs as they do so.
What is the cause of Myasthenia Gravis? What are its symptoms? How is it diagnosed? (Note: This disorder is not on the exam, but I'm going to include it for completeness.)
I've already mentioned myasthenia gravis in a post for Immunology, but I'm going to flesh it out with some more details. Myasthenia gravis, which is more common in females, causes muscle weakness, initially in the face. This causes stuff such as diplopia, ptosis, facial droop and difficulty swallowing. Stress or alcohol may induce a myasthenia crisis, where breathing is affected.
Tests for myasthenia gravis include looking for antibodies against ACh, EMG (electromyography- recording the electrical activity produced by muscles) and looking for a response to AChE (acetylcholinesterase) inhibitors. Acetylcholinesterase is an enzyme that breaks down acetylcholine, and when it is inhibited, that leaves more acetylcholine to stimulate the relatively low number of ACh receptors in patients with the disease. Patients can experience dramatic improvements with these.
Treatment includes the aforementioned AChE inhibitors, thymectomy (thymus hyperplasia is often associated with this disease), immunosuppressants and plasmapheresis. Plasmapheresis is a technique in which plasma is removed, antibodies against ACh are removed from the plasma, and the plasma is returned to the patient.
And that's my last post for the semester! Good luck for finals!
Sunday, December 4, 2016
Joint and Bone Disorders
Second last post! These last two will probably be relatively short.
What are the characteristics of osteoarthritis? Explain the difference between Heberden's and Bouchard's nodes.
Osteoarthritis is essentially a disease of "wear and tear." Repeated stress at the articular cartilage, from overuse of the joint or whatever, can wear away the cartilage, exposing the bone underneath. This can cause local inflammation inside the joint (as opposed to the systemic inflammation of rheumatoid arthritis), leading to narrowing of the joint. Another characteristic of osteoarthritis is the formation of osteophytes, or "bone spurs," inside the joint.
Signs and symptoms of osteoarthritis include pain, limited mobility and crepitus. Pain and limited mobility can lead to disuse of the joint, which can in turn lead to muscle atrophy. Another sign of osteoarthritis is the formation of hardened lumps, or nodes. Nodes in the distal phalanx (of the finger) are known as Heberden's nodes, whereas nodes in the proximal phalanx are known as Bouchard's nodes.
Treatments for osteoarthritis include rest (so as not to put more stress on the joint), glucocorticoids (to reduce inflammation), analgesics (to alleviate pain) and, if severe, joint replacement.
Why do rickets and osteomalacia occur? What is the difference between these two conditions?
Rickets and osteomalacia are conditions in which there is insufficient bone mineralisation. This is often due to a vitamin D deficiency (remember, vitamin D helps out with absorption of calcium and phosphate), which in turn may be due to malabsorption of these nutrients or renal disease (as vitamin D is activated by the kidneys). The difference between the two is the age at which they occur. Rickets occurs in children, and may lead to bowed (curved) legs that may stay that way for life if the condition is untreated. Osteomalacia occurs in adults whose bones have already formed, so bowed legs are generally not seen here.
Describe the characteristics of osteoporosis. What are some of the treatments that are commonly used?
Osteoporosis is a condition where there is not only insufficient mineralisation, but also insufficient matrix formation. This results in a decrease in bone matrix and bone density, especially in cancellous bone. People with osteoporosis are more at risk of compression fractures between vertebrae, at the femoral neck and so on, as well as spinal abnormalities such as kyphosis ("hunchback").
Primary osteoporosis, which is osteoporosis that isn't caused by another condition, is often seen in older adults, especially women. I have explained why this is so here. Secondary osteoporosis is osteoporosis due to another condition, such as Cushing's disease (the excess cortisol eats up the matrix), malabsorption and hyperparathyroidism. Other risk factors include decreased mobility, poor diet, smoking, caffeine and some drugs such as glucocorticoids, antacids (particularly those containing aluminium) and chemotherapy.
One of the main treatments for osteoporosis is supplementation of calcium and vitamin D. Exercise is also important in maintaining bone density. Bisphosphonates, which are molecules that resemble a double phosphate, may be used as they are less easily broken down by osteoclasts. Other drugs that may be used include oestrogen receptor modulators (SERMs), which increase oestrogen activity in bone but not in the reproductive tract (so as not to increase the risk of reproductive tract cancers); calcitonin, which opposes parathyroid hormone; and strontium ranelate, which acts as a calcium analogue that can increase the activity of OPG.
One more post to go!
What are the characteristics of osteoarthritis? Explain the difference between Heberden's and Bouchard's nodes.
Osteoarthritis is essentially a disease of "wear and tear." Repeated stress at the articular cartilage, from overuse of the joint or whatever, can wear away the cartilage, exposing the bone underneath. This can cause local inflammation inside the joint (as opposed to the systemic inflammation of rheumatoid arthritis), leading to narrowing of the joint. Another characteristic of osteoarthritis is the formation of osteophytes, or "bone spurs," inside the joint.
Signs and symptoms of osteoarthritis include pain, limited mobility and crepitus. Pain and limited mobility can lead to disuse of the joint, which can in turn lead to muscle atrophy. Another sign of osteoarthritis is the formation of hardened lumps, or nodes. Nodes in the distal phalanx (of the finger) are known as Heberden's nodes, whereas nodes in the proximal phalanx are known as Bouchard's nodes.
Treatments for osteoarthritis include rest (so as not to put more stress on the joint), glucocorticoids (to reduce inflammation), analgesics (to alleviate pain) and, if severe, joint replacement.
Why do rickets and osteomalacia occur? What is the difference between these two conditions?
Rickets and osteomalacia are conditions in which there is insufficient bone mineralisation. This is often due to a vitamin D deficiency (remember, vitamin D helps out with absorption of calcium and phosphate), which in turn may be due to malabsorption of these nutrients or renal disease (as vitamin D is activated by the kidneys). The difference between the two is the age at which they occur. Rickets occurs in children, and may lead to bowed (curved) legs that may stay that way for life if the condition is untreated. Osteomalacia occurs in adults whose bones have already formed, so bowed legs are generally not seen here.
Describe the characteristics of osteoporosis. What are some of the treatments that are commonly used?
Osteoporosis is a condition where there is not only insufficient mineralisation, but also insufficient matrix formation. This results in a decrease in bone matrix and bone density, especially in cancellous bone. People with osteoporosis are more at risk of compression fractures between vertebrae, at the femoral neck and so on, as well as spinal abnormalities such as kyphosis ("hunchback").
Primary osteoporosis, which is osteoporosis that isn't caused by another condition, is often seen in older adults, especially women. I have explained why this is so here. Secondary osteoporosis is osteoporosis due to another condition, such as Cushing's disease (the excess cortisol eats up the matrix), malabsorption and hyperparathyroidism. Other risk factors include decreased mobility, poor diet, smoking, caffeine and some drugs such as glucocorticoids, antacids (particularly those containing aluminium) and chemotherapy.
One of the main treatments for osteoporosis is supplementation of calcium and vitamin D. Exercise is also important in maintaining bone density. Bisphosphonates, which are molecules that resemble a double phosphate, may be used as they are less easily broken down by osteoclasts. Other drugs that may be used include oestrogen receptor modulators (SERMs), which increase oestrogen activity in bone but not in the reproductive tract (so as not to increase the risk of reproductive tract cancers); calcitonin, which opposes parathyroid hormone; and strontium ranelate, which acts as a calcium analogue that can increase the activity of OPG.
One more post to go!
Joints
What are synarthroses? Amphiarthroses? Diarthroses?
Synarthroses, amphiarthroses and diarthroses essentially refer to how moveable a joint is. This is a different classification to that used on my earlier post about the articular system.
Synarthroses are immovable joints. These include the suture joints referenced on that earlier post. Amphiarthroses are slightly moveable joints, and include synchondroses (cartilaginous) and syndesmoses (fibrous). Diarthroses are freely moveable joints, and include synovial joints.
Describe the components of a synovial joint.
See this post for more details.
What is the difference between a tendon and a ligament? A sprain and a strain?
Tendons are connective tissue that join muscle and bone, whereas ligaments join bone and bone. Tears in tendons are known as strains, whereas tears in ligaments are known as sprains. Both tendons and ligaments have poor blood supply, which results in poor healing if they do get damaged.
What is a subluxation? An avulsion?
A subluxation is a partial dislocation of a joint. An avulsion is a complete dislocation that may involve separation of a ligament or tendon from the bone.
What is Repetitive Strain Injury?
Repetitive strain injury occurs as a result of, well, repetitive strain (doing the same thing over and over). An example of this is carpal tunnel syndrome, enemy of typists and clarinettists worldwide. The transverse carpal ligament, which goes across the wrist, can press down on the nerves and blood vessels beneath, causing pain. If this is really severe, surgery may be required (my high school clarinet teacher can attest to that).
Describe the characteristics of the following spinal abnormalities and their possible causes: kyphosis, lordosis, scoliosis
Kyphosis and lordosis can refer to the normal curvature of the spine, but they can also refer to an exaggerated curvature. Kyphosis is when the spine is curved backwards, resulting in a "hunchback." This can result due to weakening of the bones due to osteoporosis or tuberculosis, or bones growing faster than muscles during adolescence. Lordosis is when the spine is curved forwards, resulting in a "swayback." This can occur due to obesity or pregnancy.
In scoliosis, the spine is not curved forwards or backwards, but rather to the sides. This can be due to uneven muscle weaknesses as in muscular dystrophy or cerebral palsy, some kind of trauma, a congenital problem, or maybe simply idiopathic (i.e. we simply don't know why it occurs in some cases).
What are the characteristics of Rheumatoid Arthritis?
I've already spoken about rheumatoid arthritis in one of my earlier posts on Immunology, but now we're going to learn a few more details. Rheumatoid arthritis usually affects smaller joints first, causing pain and swelling, resulting in contracture (shortening) of muscles around the joint. This contracture can result in other deformities, such as swan neck and Boutonniere deformities (deformed positions of fingers and toes). The pain and contracture can lead to disuse of the joint, which in turn can result in atrophy of the muscles.
Aside from pain and swelling, rheumatoid arthritis can also cause some more systemic symptoms, such as fatigue, malaise, anorexia (loss of appetite) and formation of nodules. These nodules, located close to joints, are granulomas (that is, tissue surrounding an area of necrosis).
Unfortunately, we're not 100% sure what causes rheumatoid arthritis, but some people may have genetic susceptibilities to this disease.
What is pannus? Ankylosis?
Since inflammation occurs within joints (synovitis) in rheumatoid arthritis, granulation tissue may also form. When granulation tissue forms inside the joint, this is called pannus. Fibrous tissue may also form, resulting in ankylosis, or joint fixation.
How does Juvenile Rheumatoid Arthritis differ from the adult form?
In contrast to adult rheumatoid arthritis, juvenile rheumatoid arthritis is acute with a remission rate of over 50% (rather than chronic, like in the adult form), and tends to affect large joints first, rather than small ones. Additionally, rheumatoid factor, which is present in 80% of adult patients, is not present in children. Instead, ANA (anti-nuclear antibodies) may be found. Systemic effects of juvenile rheumatoid arthritis include Still disease, which has symptoms such as rash, fever, enlarged spleen and uveitis (iris inflammation).
What is gout? What treatments are currently used for this disease? What are tophi?
Gout is a build-up of uric acid crystals in the synovial cavities, especially in the big toe. This results in the formation of tophi, which consist of tissue forming around a uric acid crystal. Uric acid may build up due to excess purine (adenine and guanine) breakdown or due to poor excretion of purines. Risk factors for gout include gender (males are more likely to have it), age (>40yr), obesity and alcohol use.
Treatments for gout include a low-protein diet (so as to avoid build-up of uric acid), allopurinol (to stop the breakdown of purines into uric acid), Colchicine (prevents gout attacks and relieves pain), uricosurics (drugs that increase the excretion of uric acid, such as probenecid), increasing fluid and increasing urine pH (increases the solubility of uric acid to aid in excretion).
Synarthroses, amphiarthroses and diarthroses essentially refer to how moveable a joint is. This is a different classification to that used on my earlier post about the articular system.
Synarthroses are immovable joints. These include the suture joints referenced on that earlier post. Amphiarthroses are slightly moveable joints, and include synchondroses (cartilaginous) and syndesmoses (fibrous). Diarthroses are freely moveable joints, and include synovial joints.
Describe the components of a synovial joint.
See this post for more details.
What is the difference between a tendon and a ligament? A sprain and a strain?
Tendons are connective tissue that join muscle and bone, whereas ligaments join bone and bone. Tears in tendons are known as strains, whereas tears in ligaments are known as sprains. Both tendons and ligaments have poor blood supply, which results in poor healing if they do get damaged.
What is a subluxation? An avulsion?
A subluxation is a partial dislocation of a joint. An avulsion is a complete dislocation that may involve separation of a ligament or tendon from the bone.
What is Repetitive Strain Injury?
Repetitive strain injury occurs as a result of, well, repetitive strain (doing the same thing over and over). An example of this is carpal tunnel syndrome, enemy of typists and clarinettists worldwide. The transverse carpal ligament, which goes across the wrist, can press down on the nerves and blood vessels beneath, causing pain. If this is really severe, surgery may be required (my high school clarinet teacher can attest to that).
Describe the characteristics of the following spinal abnormalities and their possible causes: kyphosis, lordosis, scoliosis
Kyphosis and lordosis can refer to the normal curvature of the spine, but they can also refer to an exaggerated curvature. Kyphosis is when the spine is curved backwards, resulting in a "hunchback." This can result due to weakening of the bones due to osteoporosis or tuberculosis, or bones growing faster than muscles during adolescence. Lordosis is when the spine is curved forwards, resulting in a "swayback." This can occur due to obesity or pregnancy.
In scoliosis, the spine is not curved forwards or backwards, but rather to the sides. This can be due to uneven muscle weaknesses as in muscular dystrophy or cerebral palsy, some kind of trauma, a congenital problem, or maybe simply idiopathic (i.e. we simply don't know why it occurs in some cases).
What are the characteristics of Rheumatoid Arthritis?
I've already spoken about rheumatoid arthritis in one of my earlier posts on Immunology, but now we're going to learn a few more details. Rheumatoid arthritis usually affects smaller joints first, causing pain and swelling, resulting in contracture (shortening) of muscles around the joint. This contracture can result in other deformities, such as swan neck and Boutonniere deformities (deformed positions of fingers and toes). The pain and contracture can lead to disuse of the joint, which in turn can result in atrophy of the muscles.
Aside from pain and swelling, rheumatoid arthritis can also cause some more systemic symptoms, such as fatigue, malaise, anorexia (loss of appetite) and formation of nodules. These nodules, located close to joints, are granulomas (that is, tissue surrounding an area of necrosis).
Unfortunately, we're not 100% sure what causes rheumatoid arthritis, but some people may have genetic susceptibilities to this disease.
What is pannus? Ankylosis?
Since inflammation occurs within joints (synovitis) in rheumatoid arthritis, granulation tissue may also form. When granulation tissue forms inside the joint, this is called pannus. Fibrous tissue may also form, resulting in ankylosis, or joint fixation.
How does Juvenile Rheumatoid Arthritis differ from the adult form?
In contrast to adult rheumatoid arthritis, juvenile rheumatoid arthritis is acute with a remission rate of over 50% (rather than chronic, like in the adult form), and tends to affect large joints first, rather than small ones. Additionally, rheumatoid factor, which is present in 80% of adult patients, is not present in children. Instead, ANA (anti-nuclear antibodies) may be found. Systemic effects of juvenile rheumatoid arthritis include Still disease, which has symptoms such as rash, fever, enlarged spleen and uveitis (iris inflammation).
What is gout? What treatments are currently used for this disease? What are tophi?
Gout is a build-up of uric acid crystals in the synovial cavities, especially in the big toe. This results in the formation of tophi, which consist of tissue forming around a uric acid crystal. Uric acid may build up due to excess purine (adenine and guanine) breakdown or due to poor excretion of purines. Risk factors for gout include gender (males are more likely to have it), age (>40yr), obesity and alcohol use.
Treatments for gout include a low-protein diet (so as to avoid build-up of uric acid), allopurinol (to stop the breakdown of purines into uric acid), Colchicine (prevents gout attacks and relieves pain), uricosurics (drugs that increase the excretion of uric acid, such as probenecid), increasing fluid and increasing urine pH (increases the solubility of uric acid to aid in excretion).
Bones and Trauma
Now we're onto our final topic for PHGY350! The end is nigh!
In a bone, what are the epiphysis, metaphysis and diaphysis?
Firstly, let's start off by talking about the structure of long bones (like the ones in your arms and legs). They are made up of a shaft (diaphysis) and two ends (epiphyses, singular epiphysis). Sometimes the junction between the shaft and the end is called the metaphysis. Within the diaphysis is the medullary cavity, which contains the bone marrow. As you may recall if you have been reading my Immunology posts, haematopoiesis (development of blood cells) occurs in the bone marrow. As you get older, fewer bones take part in this process.
In a bone, what are lamellae? Lacunae? Haversian canals (a.k.a. "osteons")?
What is the difference between spongy and compact bone? What other terms are used for these structures?
Bones can be further divided down into spongy and compact bone. I've already written about these types and their components here.
Describe the role that osteoblasts and osteoclasts play in the deposition and resorption of bone.
The matrix of bones is mainly made up of collagen. Calcium compounds such as hydroxyapatite (which consists of calcium, phosphate and hydroxide) are also essential in keeping bones hard and strong. Bone composition is maintained by an equilibrium between osteoblasts, which are cells that build up bone, and osteoclasts, which are cells that break down bone. Osteoblasts have an enzyme called alkaline phosphatase which can take phosphates off other molecules to be incorporated into hydroxyapatite. Osteoblasts can also deposit calcium.
Osteoclasts, on the other hand, assist in the resorption of calcium from bone, thus breaking down the bone. They do this by releasing small amounts of acid via the action of H+ ATPases. This acid also provides the optimum pH for enzymes such as cathepsins to break down the matrix of the bone.
Describe how RANK, RANK ligand, osteoprotegrin and oestrogen regulate bone remodelling. What roles do PTH (parathyroid hormone) and Vitamin D3 play?
Osteoblasts make RANK ligand, as well as osteoprotegrin (OPG). RANK ligand can bind to RANK receptors on osteoclasts, stimulating their breakdown activity. Osteoprotegrin is the opposite- it can bind to RANK ligand, reducing the amount that can bind to RANK receptors, causing inhibition of osteoclasts. Hence, osteoprotegrin is required for making sure that bones don't break down. Oestrogen increases osteoprotegrin levels, which is why postmenopausal women (who no longer have high levels of oestrogen) are at a higher risk of osteoporosis. (As for men- they still have plenty of testosterone, which can be converted to oestrogen via aromatases in the bone.)
PTH (parathyroid hormone) is especially important for increasing serum calcium levels. (This is important because nerves go crazy if they don't have enough calcium.) PTH increases renal calcium reabsorption while simultaneously decreasing phosphate reabsorption. Since hydroxyapatite requires both calcium and phosphate, having only calcium increases serum calcium since it won't become incorporated into the bone.
Vitamin D3, also known as calcitriol, is activated by the kidneys. It increases GI absorption of calcium and phosphate, while also increasing calcium reabsorption by the kidneys. Because it increases both calcium and phosphate, vitamin D3 can help with bone mineralisation. Interestingly enough, vitamin D3 can also promote resorption of bone in some places so that it can be built up in others.
Growth hormone also plays a role in bone growth through stimulating osteoblasts.
Another important hormone is cortisol, which breaks down the matrix. Remember, cortisol stimulates gluconeogenesis (making sugar from other stuff, like proteins), and the matrix is made up of protein (collagen) that can be broken down.
Describe the process and location of bone formation in long bones.
Before a person is fully grown, their long bones have epiphyseal plates ("growth plates"). These are made up of cartilage. In the process of bone growth, chondrocytes (cartilage cells) produce cartilage, before osteoblasts invade and add calcium to build a strong, hard bone.
Describe the characteristics of the following types of fractures: oblique, comminuted, open, segmented, spiral, transverse, greenstick, Colle's, Pott's
Fractures can be characterised in several ways.
Firstly, they can be classified as complete (the bone is completely broken) or incomplete (the bone is only partially broken). Incomplete fractures are sometimes known as Greenstick fractures, and are especially common in children whose bones have a greater proportion of matrix, which helps to hold the bone together.
Secondly, they can be classified as open or closed, depending on whether or not they pierce the skin. Open fractures can be dangerous as they are at risk of infection.
Thirdly, they can be classified by the number of fracture lines. A simple fracture only has one break, a segmented fracture has several breaks close to each other, and a comminuted fracture has many breaks close to each other, so you end up with lots of really little pieces that are hard to put back together.
Fractures can also be classified by the direction. A transverse fracture goes straight across, an oblique fracture goes on a diagonal and a spiral fracture goes on, well, a spiral. The latter is often due to the bone turning as it breaks.
There are several other types of fractures that don't always fit neatly into the above categories. Impacted fractures occur when one bone is shoved into the other, and may occur between the head of the femur and the pelvis. Pathological fractures occur due to disease. Compression fractures occur when one bone compresses another, as may happen between vertebrae.
Two special types of fractures that you need to know about are Colles' fracture and Pott's fracture. Colles' fracture occurs between the wrist and distal radius. (I remember this one by thinking that carpal and Colles' are in the same area, and both begin with C.) Pott's fracture is between the ankle and distal radius.
What are the symptoms of a bone fracture?
A fracture often starts with numbness which progresses into pain. At the same time there may be swelling and loss of function. Another symptom is crepitus, which is the sound of bones grinding against each other.
What are the steps involved in healing a fracture? What factors affect the healing process?
Fracture healing occurs in five main steps:
In a bone, what are the epiphysis, metaphysis and diaphysis?
Firstly, let's start off by talking about the structure of long bones (like the ones in your arms and legs). They are made up of a shaft (diaphysis) and two ends (epiphyses, singular epiphysis). Sometimes the junction between the shaft and the end is called the metaphysis. Within the diaphysis is the medullary cavity, which contains the bone marrow. As you may recall if you have been reading my Immunology posts, haematopoiesis (development of blood cells) occurs in the bone marrow. As you get older, fewer bones take part in this process.
In a bone, what are lamellae? Lacunae? Haversian canals (a.k.a. "osteons")?
What is the difference between spongy and compact bone? What other terms are used for these structures?
Bones can be further divided down into spongy and compact bone. I've already written about these types and their components here.
Describe the role that osteoblasts and osteoclasts play in the deposition and resorption of bone.
The matrix of bones is mainly made up of collagen. Calcium compounds such as hydroxyapatite (which consists of calcium, phosphate and hydroxide) are also essential in keeping bones hard and strong. Bone composition is maintained by an equilibrium between osteoblasts, which are cells that build up bone, and osteoclasts, which are cells that break down bone. Osteoblasts have an enzyme called alkaline phosphatase which can take phosphates off other molecules to be incorporated into hydroxyapatite. Osteoblasts can also deposit calcium.
Osteoclasts, on the other hand, assist in the resorption of calcium from bone, thus breaking down the bone. They do this by releasing small amounts of acid via the action of H+ ATPases. This acid also provides the optimum pH for enzymes such as cathepsins to break down the matrix of the bone.
Describe how RANK, RANK ligand, osteoprotegrin and oestrogen regulate bone remodelling. What roles do PTH (parathyroid hormone) and Vitamin D3 play?
Osteoblasts make RANK ligand, as well as osteoprotegrin (OPG). RANK ligand can bind to RANK receptors on osteoclasts, stimulating their breakdown activity. Osteoprotegrin is the opposite- it can bind to RANK ligand, reducing the amount that can bind to RANK receptors, causing inhibition of osteoclasts. Hence, osteoprotegrin is required for making sure that bones don't break down. Oestrogen increases osteoprotegrin levels, which is why postmenopausal women (who no longer have high levels of oestrogen) are at a higher risk of osteoporosis. (As for men- they still have plenty of testosterone, which can be converted to oestrogen via aromatases in the bone.)
PTH (parathyroid hormone) is especially important for increasing serum calcium levels. (This is important because nerves go crazy if they don't have enough calcium.) PTH increases renal calcium reabsorption while simultaneously decreasing phosphate reabsorption. Since hydroxyapatite requires both calcium and phosphate, having only calcium increases serum calcium since it won't become incorporated into the bone.
Vitamin D3, also known as calcitriol, is activated by the kidneys. It increases GI absorption of calcium and phosphate, while also increasing calcium reabsorption by the kidneys. Because it increases both calcium and phosphate, vitamin D3 can help with bone mineralisation. Interestingly enough, vitamin D3 can also promote resorption of bone in some places so that it can be built up in others.
Growth hormone also plays a role in bone growth through stimulating osteoblasts.
Another important hormone is cortisol, which breaks down the matrix. Remember, cortisol stimulates gluconeogenesis (making sugar from other stuff, like proteins), and the matrix is made up of protein (collagen) that can be broken down.
Describe the process and location of bone formation in long bones.
Before a person is fully grown, their long bones have epiphyseal plates ("growth plates"). These are made up of cartilage. In the process of bone growth, chondrocytes (cartilage cells) produce cartilage, before osteoblasts invade and add calcium to build a strong, hard bone.
Describe the characteristics of the following types of fractures: oblique, comminuted, open, segmented, spiral, transverse, greenstick, Colle's, Pott's
Fractures can be characterised in several ways.
Firstly, they can be classified as complete (the bone is completely broken) or incomplete (the bone is only partially broken). Incomplete fractures are sometimes known as Greenstick fractures, and are especially common in children whose bones have a greater proportion of matrix, which helps to hold the bone together.
Secondly, they can be classified as open or closed, depending on whether or not they pierce the skin. Open fractures can be dangerous as they are at risk of infection.
Thirdly, they can be classified by the number of fracture lines. A simple fracture only has one break, a segmented fracture has several breaks close to each other, and a comminuted fracture has many breaks close to each other, so you end up with lots of really little pieces that are hard to put back together.
Fractures can also be classified by the direction. A transverse fracture goes straight across, an oblique fracture goes on a diagonal and a spiral fracture goes on, well, a spiral. The latter is often due to the bone turning as it breaks.
There are several other types of fractures that don't always fit neatly into the above categories. Impacted fractures occur when one bone is shoved into the other, and may occur between the head of the femur and the pelvis. Pathological fractures occur due to disease. Compression fractures occur when one bone compresses another, as may happen between vertebrae.
Two special types of fractures that you need to know about are Colles' fracture and Pott's fracture. Colles' fracture occurs between the wrist and distal radius. (I remember this one by thinking that carpal and Colles' are in the same area, and both begin with C.) Pott's fracture is between the ankle and distal radius.
What are the symptoms of a bone fracture?
A fracture often starts with numbness which progresses into pain. At the same time there may be swelling and loss of function. Another symptom is crepitus, which is the sound of bones grinding against each other.
What are the steps involved in healing a fracture? What factors affect the healing process?
Fracture healing occurs in five main steps:
- Bleeding/haematoma beneath the periosteum. (The periosteum, which is basically a connective tissue covering for bone, helps to hold the blood in place).
- Formation of granulation tissue.
- Formation of a "procallus." Essentially, chondrocytes are providing "glue" to stick the bone back together.
- Bony callus formation. Bone is deposited into the procallus.
- Remodelling. Over time, osteoblasts and osteoclasts will fine-tune things to get the bone back in shape. This process can take 3-4 months.
There are many factors that can affect healing:
- Degree of damage- the more damage there is, the longer it takes to heal.
- Approximation- broken ends need to be kept close together. One complication is that muscles may contract and move the bones out of position. This can be reduced via a process called reduction, which pulls the bones out a little bit.
- Muscle spasm- bones need to be kept immobile in order to heal, but they might spasm due to the pain
- Foreign material- the removal of this is known as debridement.
- Diabetes
- Glucocorticoids- break down the protein matrix, as described earlier
- Nutrition- you need a good supply of Vitamin D, calcium, protein etc.
- Infection
- Ischaemia- you need a good blood supply as tissue that is healing has a higher metabolic demand.
- Compartment syndrome- if surrounding muscles etc. swell, they can compress nerves and blood vessels, leading to ischaemia.
- Fat emboli- fat from the bone can plug up blood vessels, again leading to ischaemia.
Complications of healing can lead to non-union (i.e. the bones not coming back together, or healing in a misaligned fashion).
Thursday, December 1, 2016
Immune Responses to Transplants
Last lecture for Immunology!
Transplants can be very useful in extending the lives of seriously ill patients for a few more years. Some common transplants are kidney transplants, as donors can survive with one less kidney, and bone marrow, which can help treat immunocompromised patients (as outlined here).
The issue with transplants is that the immune system may see the transplanted tissue as a foreign entity and attack it. The likelihood of this happening increases with the degree of "foreignness," which is a concept I touched on a while ago when talking about immunogenicity. An autograft, which is the least likely to be rejected, is derived from your own tissue (e.g. from stem cells collected at birth). Isografts come from identical twins, allografts come from unrelated members of the same species, and xenografts come from different species.
Rejection of grafts is mediated through several different pathways, such as T-cells and antibodies, as I'll explain in a bit. Memory cells can also be formed, so while transplant number 1 might take around 10 days to be rejected, transplant number 2 from the same donor will be rejected in only a few days. Because all of this requires a working immune system, nude mice (which lack a thymus) will happily accept grafts without any issue.
MHC molecules are some of the major antigens involved in rejection. Direct allorecognition is when the recipient's T-cells recognise "foreign" MHC molecules on the APCs from the donor. Aside from MHCs, there are also minor histocompatibility antigens (as opposed to the major ones), which are other proteins that differ from person to person. For example, males have H-Y antigen whereas females do not, so in a transplant from a male to a female, the female's immune system cells may react against it.
Thankfully, we don't just have to rely on trial and error to see if a donor and recipient match well or not. MHC testing can be carried out through several different methods. In one method, PCR is used to figure out which MHC molecules a person has (i.e. which haplotype). The other method is called Mixed Lymphocyte Reaction, or MLR, and involves mixing together T-helper cells from the recipient with APCs from the donor. These cells are also mixed with 3H-thymidine, a radioactive molecule that can be inserted into the DNA of proliferating cells. If the T-helper cells recognise the foreign class II MHC in the APCs, they will become activated and proliferate, taking up 3H-thymidine in the process. Uptake can be measured, giving an indication of whether or not the recipient will react against the donor cells or not.
As mentioned earlier, antibodies and T-cells can play a role in rejection. If the person already has antibodies against donor antigens (such as in the case of blood donation), then the rejection reaction happens very quickly, and is classified as "hyper-acute." Antibodies binding to donor tissue result in activation of complement, formation of immune complexes, formation of the MAC complex and so on, ultimately resulting in inflammation and other undesirable effects such as obstruction of blood vessels.
T-cells can also fight off a graft in pretty much the same way they fight off everything else, after first recognising foreign MLC and/or foreign peptides. That is, helper T-cells produce cytokines, cytotoxic T-cells kill stuff, and so on. These responses can be suppressed with several medications. Rapamycin blocks lymphocyte proliferation, whereas corticosteroids jut have general anti-inflammatory effects. Unfortunately, this can leave the patient at greater risk of infection.
Rejection can be classified according to the length of time over which the process occurs. Hyper-acute reactions, which occur within 24 hours, are mediated by preformed antibodies. Acute rejection, which takes from 10 days to a few weeks, relies on general humoral and cell-mediated immunity processes. Chronic rejection, which is often just the acute rejection process drawn out over time by immunosuppressants, can take several months to years. This is sometimes also mediated by minor histocompatibility antigens.
One special case that I want to touch on is that of bone marrow transplants. Bone marrow transplants are usually given to patients with severe immunodeficiency in order to help them "grow a new immune system." Here, since the patients are immunocompromised, the issue of the host rejecting the graft isn't so much an issue. Instead, there's an issue in which the immune cells in the graft might reject the host, causing a "Graft vs. Host (G vs. H)" reaction. In order to prevent this from happening, anti-CD3 is added to remove donor T-cells from the graft before transplantation. The recipient is also gamma-irradiated in order to kill off any immune system cells that they might have so that the donor cells can completely replace theirs. If donor T-cells are not eliminated, symptoms of G vs. H reactions, such as skin rashes, fever, anaemia, weight loss and diarrhoea, may occur. In extreme cases, this can be fatal.
Perhaps not the nicest note to finish on, but that's it for Immunology!
Transplants can be very useful in extending the lives of seriously ill patients for a few more years. Some common transplants are kidney transplants, as donors can survive with one less kidney, and bone marrow, which can help treat immunocompromised patients (as outlined here).
The issue with transplants is that the immune system may see the transplanted tissue as a foreign entity and attack it. The likelihood of this happening increases with the degree of "foreignness," which is a concept I touched on a while ago when talking about immunogenicity. An autograft, which is the least likely to be rejected, is derived from your own tissue (e.g. from stem cells collected at birth). Isografts come from identical twins, allografts come from unrelated members of the same species, and xenografts come from different species.
Rejection of grafts is mediated through several different pathways, such as T-cells and antibodies, as I'll explain in a bit. Memory cells can also be formed, so while transplant number 1 might take around 10 days to be rejected, transplant number 2 from the same donor will be rejected in only a few days. Because all of this requires a working immune system, nude mice (which lack a thymus) will happily accept grafts without any issue.
MHC molecules are some of the major antigens involved in rejection. Direct allorecognition is when the recipient's T-cells recognise "foreign" MHC molecules on the APCs from the donor. Aside from MHCs, there are also minor histocompatibility antigens (as opposed to the major ones), which are other proteins that differ from person to person. For example, males have H-Y antigen whereas females do not, so in a transplant from a male to a female, the female's immune system cells may react against it.
Thankfully, we don't just have to rely on trial and error to see if a donor and recipient match well or not. MHC testing can be carried out through several different methods. In one method, PCR is used to figure out which MHC molecules a person has (i.e. which haplotype). The other method is called Mixed Lymphocyte Reaction, or MLR, and involves mixing together T-helper cells from the recipient with APCs from the donor. These cells are also mixed with 3H-thymidine, a radioactive molecule that can be inserted into the DNA of proliferating cells. If the T-helper cells recognise the foreign class II MHC in the APCs, they will become activated and proliferate, taking up 3H-thymidine in the process. Uptake can be measured, giving an indication of whether or not the recipient will react against the donor cells or not.
As mentioned earlier, antibodies and T-cells can play a role in rejection. If the person already has antibodies against donor antigens (such as in the case of blood donation), then the rejection reaction happens very quickly, and is classified as "hyper-acute." Antibodies binding to donor tissue result in activation of complement, formation of immune complexes, formation of the MAC complex and so on, ultimately resulting in inflammation and other undesirable effects such as obstruction of blood vessels.
T-cells can also fight off a graft in pretty much the same way they fight off everything else, after first recognising foreign MLC and/or foreign peptides. That is, helper T-cells produce cytokines, cytotoxic T-cells kill stuff, and so on. These responses can be suppressed with several medications. Rapamycin blocks lymphocyte proliferation, whereas corticosteroids jut have general anti-inflammatory effects. Unfortunately, this can leave the patient at greater risk of infection.
Rejection can be classified according to the length of time over which the process occurs. Hyper-acute reactions, which occur within 24 hours, are mediated by preformed antibodies. Acute rejection, which takes from 10 days to a few weeks, relies on general humoral and cell-mediated immunity processes. Chronic rejection, which is often just the acute rejection process drawn out over time by immunosuppressants, can take several months to years. This is sometimes also mediated by minor histocompatibility antigens.
One special case that I want to touch on is that of bone marrow transplants. Bone marrow transplants are usually given to patients with severe immunodeficiency in order to help them "grow a new immune system." Here, since the patients are immunocompromised, the issue of the host rejecting the graft isn't so much an issue. Instead, there's an issue in which the immune cells in the graft might reject the host, causing a "Graft vs. Host (G vs. H)" reaction. In order to prevent this from happening, anti-CD3 is added to remove donor T-cells from the graft before transplantation. The recipient is also gamma-irradiated in order to kill off any immune system cells that they might have so that the donor cells can completely replace theirs. If donor T-cells are not eliminated, symptoms of G vs. H reactions, such as skin rashes, fever, anaemia, weight loss and diarrhoea, may occur. In extreme cases, this can be fatal.
Perhaps not the nicest note to finish on, but that's it for Immunology!
Tuesday, November 29, 2016
Vaccines and Immunotherapy
I'm a bit hesitant to write about this topic because it's one that some people have very strong opinions about, and I really don't want to start a flame war on this blog. At least this lecture was short, so I guess I'll just say my piece quickly and get the hell out.
Immunisation
Most of the time, when we talk about immunisation, we are referring to active immunisation. The goal of active immunisation is to ultimately form a memory response so that the person can easily fight off the pathogen again. There is also passive immunisation, in which preformed products are given to patients to prevent illness following exposure (to tetanus, rabies etc.). These may also block toxins, as in the case of diphtheria antitoxin and snake antivenoms. Passive immunisation, however, is not long lasting and produces no memory response.
A vaccine, as I'm sure you know, basically contains a modified component of the pathogen that can elicit an immune response without actually making you catch the disease. The end result is that you can build up immunity to said diseases without experiencing some of the risks of the disease itself, like deafness (measles), infertility (mumps), paralysis (polio), and so on. Vaccination basically works on the principles of the primary and secondary response, which I've outlined here: when you are vaccinated you produce IgM, and during subsequent booster shots, or exposures to the antigen, you produce more antigen-specific IgG which can clear the infection much more rapidly.
One of the nice things about vaccination is that it doesn't just protect the individual. If an individual is immune to the disease, then they generally won't be able to pass it on. The more people that are immunised, the less potential "disease vectors" there are to spread the disease to people who can't be immunised (due to being immunocompromised, too young etc.) or people who, for whatever reason, didn't generate a memory response following vaccination.
Vaccination was also responsible for the eradication of smallpox. You've probably heard the story: Edward Jenner found that milkmaids who had experienced cowpox (a disease related to smallpox but much less severe) never caught smallpox. He then immunised many people with the cowpox virus so that they would not catch smallpox. This worked because cowpox and smallpox, being related viruses, share many surface antigens. Therefore, antibodies generated against cowpox could help to clear smallpox as well.
There are several different types of vaccines. Some vaccines, known as live attenuated vaccines, contain a weakened version of the virus or organism. If these mutate to become active again they can cause issues, but this is very rare. Live attenuated vaccines include the Sabin polio vaccine, the MMR vaccine and the BCG vaccine against tuberculosis (BCG is related to tuberculosis). Some vaccines, such as the Salk polio vaccine and the flu vaccine, contain an inactivated or killed organism. Other vaccines only contain subunits of the organism- for example, the tetanus and diptheria vaccines contain toxoids (toxins that have been made harmless), and the Hepatitis B and HPV vaccines contain recombinant proteins (immunogenic proteins which have been created artificially). Inactivated/killed vaccines and subunit vaccines cannot give you the diseases that they protect against; however, they may be slightly less effective, and may require an adjuvant (usually aluminium) to produce an immune response.
Immunotherapy
One type of immunotherapy is cytokine therapy, in which certain cytokines are given to treat a disease. An example of this is IFN-α, which can be given to treat certain types of cancers.
Another type of immunotherapy, anti-cytokine therapy, has the opposite effect: it blocks the actions of cytokines. For example, anti-TNF-α can be given to patients with rheumatoid arthritis to reduce inflammation.
Only one more lecture to go for this unit!!
Immunisation
Most of the time, when we talk about immunisation, we are referring to active immunisation. The goal of active immunisation is to ultimately form a memory response so that the person can easily fight off the pathogen again. There is also passive immunisation, in which preformed products are given to patients to prevent illness following exposure (to tetanus, rabies etc.). These may also block toxins, as in the case of diphtheria antitoxin and snake antivenoms. Passive immunisation, however, is not long lasting and produces no memory response.
A vaccine, as I'm sure you know, basically contains a modified component of the pathogen that can elicit an immune response without actually making you catch the disease. The end result is that you can build up immunity to said diseases without experiencing some of the risks of the disease itself, like deafness (measles), infertility (mumps), paralysis (polio), and so on. Vaccination basically works on the principles of the primary and secondary response, which I've outlined here: when you are vaccinated you produce IgM, and during subsequent booster shots, or exposures to the antigen, you produce more antigen-specific IgG which can clear the infection much more rapidly.
One of the nice things about vaccination is that it doesn't just protect the individual. If an individual is immune to the disease, then they generally won't be able to pass it on. The more people that are immunised, the less potential "disease vectors" there are to spread the disease to people who can't be immunised (due to being immunocompromised, too young etc.) or people who, for whatever reason, didn't generate a memory response following vaccination.
Vaccination was also responsible for the eradication of smallpox. You've probably heard the story: Edward Jenner found that milkmaids who had experienced cowpox (a disease related to smallpox but much less severe) never caught smallpox. He then immunised many people with the cowpox virus so that they would not catch smallpox. This worked because cowpox and smallpox, being related viruses, share many surface antigens. Therefore, antibodies generated against cowpox could help to clear smallpox as well.
There are several different types of vaccines. Some vaccines, known as live attenuated vaccines, contain a weakened version of the virus or organism. If these mutate to become active again they can cause issues, but this is very rare. Live attenuated vaccines include the Sabin polio vaccine, the MMR vaccine and the BCG vaccine against tuberculosis (BCG is related to tuberculosis). Some vaccines, such as the Salk polio vaccine and the flu vaccine, contain an inactivated or killed organism. Other vaccines only contain subunits of the organism- for example, the tetanus and diptheria vaccines contain toxoids (toxins that have been made harmless), and the Hepatitis B and HPV vaccines contain recombinant proteins (immunogenic proteins which have been created artificially). Inactivated/killed vaccines and subunit vaccines cannot give you the diseases that they protect against; however, they may be slightly less effective, and may require an adjuvant (usually aluminium) to produce an immune response.
Immunotherapy
One type of immunotherapy is cytokine therapy, in which certain cytokines are given to treat a disease. An example of this is IFN-α, which can be given to treat certain types of cancers.
Another type of immunotherapy, anti-cytokine therapy, has the opposite effect: it blocks the actions of cytokines. For example, anti-TNF-α can be given to patients with rheumatoid arthritis to reduce inflammation.
Only one more lecture to go for this unit!!
Saturday, November 26, 2016
Immunodeficiency
Immunodeficiency, as you can guess from the name, is a deficiency in one or more components of the immune system. There are two main categories: Primary deficiency, which is from a genetic or congenital issue, and secondary deficiency, which is much more common and is acquired through disease (e.g. HIV/AIDS), burns, chemotherapy, immunosuppressive drugs and so on. Blood counts and other tests to detect Ig levels and efficacy of immune response can be used to screen for immunodeficiency diseases.
Primary Innate Immunity Defects
Chronic Granulomatous Disease
I've already covered chronic granulomatous disease (CGD) in an earlier post. Essentially it's a defect in phagocyte oxidase, which means no production of reactive oxygen intermediates (ROIs), which means impaired killing of microbes.
Complement Immunodeficiency
Complement immunodeficiency is just what it says on the box: a deficiency of complement, which I've covered in greater detail in an earlier post. Without complement, functions involving complement such as immune complex clearance, inflammation, phagocytosis and lysis are all impaired.
Primary Adaptive Immunity Defects
DiGeorge's Syndrome
DiGeorge's Syndrome got a cameo appearance here, but now I'm going to cover it in more detail! DiGeorge's Syndrome is essentially where the thymus fails to develop. This can be partial or complete, leading to low or no T-cells. People with this condition are extremely susceptible to many infections. Even live vaccines can be life-threatening towards these patients.
Bruton's disease (X-linked agammaglobulinaemia)
In Bruton's disease, B-cells fail to mature. This is due to a defect in Bruton tyrosine kinase (BTK), which phosphorylates a lot of proteins important in B-cell development. Like DiGeorge syndrome, this can be partial or complete, leading to low or no B-cells. This, in turn, causes lymph nodes to be small and antibodies to be absent in the blood. Symptoms usually do not show up until around 3 months of age, as the child will have received IgG from their mother which protects them for the first few months of life.
Hyper-IgM Syndrome
In this syndrome, there is a mutation in the CD40 ligand molecule on T-cells, preventing T-cell dependent B-cell activation (a process which I've described in greater detail in an earlier post). This, in turn, leads to defects in other processes, such as class switching. As class switching is affected, most B-cells remain producing IgM. People with this condition may be susceptible to certain microbes, such as Pneumocystis carinii.
Common Variable Immunodeficiency (CVID)
In CVID, there are reduced levels of IgG and IgA, due to variable failures of B-cell maturation into plasma cells. This, in turn leads to reduced antibodies (hypogammaglobulinaemia- low levels of gamma globulins). This can be treated via intravenous immunoglobulins.
ADA (Adenosine Deaminase) Deficiency (ADA)
In ADA, there is a deficiency in the enzyme adenosine deaminase, which usually helps to break down deoxyadenosine. Deoxyadenosine is toxic to lymphocytes, so its accumulation leads to reduced numbers of B and T cells. ADA has been identified as an autosomal recessive disorder, so you need both copies of the gene to inherit it.
Severe Combined Immunodeficiency Diseases (SCID)
SCID, as I've mentioned before, is a disease involving mutations in the RAG1 and RAG2 genes responsible for formation of BCRs and TCRs. Hence, a hallmark of this disease is a failure of B- and T-cell maturation, leading to increased susceptibility of many infections past ~3 months (when the IgG from the mother has gone). Live vaccines also cannot be given to these patients. Fortunately, SCID can be treated with a bone marrow transplant with working RAG1 and RAG2 genes. Once these working genes have been reintroduced, RAG1 and RAG2 can be produced, allowing for production of both B- and T-cells. Transplanted bone marrow can stay around for life.
Secondary (Acquired) Immunodeficiency
We will only be learning about one example of secondary immunodeficiency, which is that caused by HIV (Human Immunodeficiency Virus). HIV is a nasty bug, as it infects the macrophages and T-helper cells of our immune system. During the "first wave," gp120, one of the glycoproteins of the HIV virus capsid, binds to CD4 and CCR5 on the macrophage cell surface. (CCR5 is a ligand for MIP chemokine, MIP being short for "macrophage inflammatory protein.") During the next wave, gp120 binds to CD4 and CXCR4, the latter being a chemokine receptor for CXCL12. Another important glycoprotein is gp41, which is required for virus fusion and internalisation.
In the early stages of HIV, the patient may or may not experience a "flu-like disease" as they begin to mount an adaptive immune response to the attack. This brings down levels of the virus in plasma, but unfortunately not forever. As I've mentioned in a post for PHAR2210, HIV can mutate very rapidly, leading to not only drug resistance, but resistance to antibodies and cytotoxic T-cells. The immune system is unable to keep up, especially since HIV is destroying it at the same time. After 2-12 years in a latent phase, where the patient shows no symptoms, the immune system eventually gets overwhelmed and the patient can become very ill. Eventually, T-helper cell levels drop to the point where the patient is considered to have AIDS.
Primary Innate Immunity Defects
Chronic Granulomatous Disease
I've already covered chronic granulomatous disease (CGD) in an earlier post. Essentially it's a defect in phagocyte oxidase, which means no production of reactive oxygen intermediates (ROIs), which means impaired killing of microbes.
Complement Immunodeficiency
Complement immunodeficiency is just what it says on the box: a deficiency of complement, which I've covered in greater detail in an earlier post. Without complement, functions involving complement such as immune complex clearance, inflammation, phagocytosis and lysis are all impaired.
Primary Adaptive Immunity Defects
DiGeorge's Syndrome
DiGeorge's Syndrome got a cameo appearance here, but now I'm going to cover it in more detail! DiGeorge's Syndrome is essentially where the thymus fails to develop. This can be partial or complete, leading to low or no T-cells. People with this condition are extremely susceptible to many infections. Even live vaccines can be life-threatening towards these patients.
Bruton's disease (X-linked agammaglobulinaemia)
In Bruton's disease, B-cells fail to mature. This is due to a defect in Bruton tyrosine kinase (BTK), which phosphorylates a lot of proteins important in B-cell development. Like DiGeorge syndrome, this can be partial or complete, leading to low or no B-cells. This, in turn, causes lymph nodes to be small and antibodies to be absent in the blood. Symptoms usually do not show up until around 3 months of age, as the child will have received IgG from their mother which protects them for the first few months of life.
Hyper-IgM Syndrome
In this syndrome, there is a mutation in the CD40 ligand molecule on T-cells, preventing T-cell dependent B-cell activation (a process which I've described in greater detail in an earlier post). This, in turn, leads to defects in other processes, such as class switching. As class switching is affected, most B-cells remain producing IgM. People with this condition may be susceptible to certain microbes, such as Pneumocystis carinii.
Common Variable Immunodeficiency (CVID)
In CVID, there are reduced levels of IgG and IgA, due to variable failures of B-cell maturation into plasma cells. This, in turn leads to reduced antibodies (hypogammaglobulinaemia- low levels of gamma globulins). This can be treated via intravenous immunoglobulins.
ADA (Adenosine Deaminase) Deficiency (ADA)
In ADA, there is a deficiency in the enzyme adenosine deaminase, which usually helps to break down deoxyadenosine. Deoxyadenosine is toxic to lymphocytes, so its accumulation leads to reduced numbers of B and T cells. ADA has been identified as an autosomal recessive disorder, so you need both copies of the gene to inherit it.
Severe Combined Immunodeficiency Diseases (SCID)
SCID, as I've mentioned before, is a disease involving mutations in the RAG1 and RAG2 genes responsible for formation of BCRs and TCRs. Hence, a hallmark of this disease is a failure of B- and T-cell maturation, leading to increased susceptibility of many infections past ~3 months (when the IgG from the mother has gone). Live vaccines also cannot be given to these patients. Fortunately, SCID can be treated with a bone marrow transplant with working RAG1 and RAG2 genes. Once these working genes have been reintroduced, RAG1 and RAG2 can be produced, allowing for production of both B- and T-cells. Transplanted bone marrow can stay around for life.
Secondary (Acquired) Immunodeficiency
We will only be learning about one example of secondary immunodeficiency, which is that caused by HIV (Human Immunodeficiency Virus). HIV is a nasty bug, as it infects the macrophages and T-helper cells of our immune system. During the "first wave," gp120, one of the glycoproteins of the HIV virus capsid, binds to CD4 and CCR5 on the macrophage cell surface. (CCR5 is a ligand for MIP chemokine, MIP being short for "macrophage inflammatory protein.") During the next wave, gp120 binds to CD4 and CXCR4, the latter being a chemokine receptor for CXCL12. Another important glycoprotein is gp41, which is required for virus fusion and internalisation.
In the early stages of HIV, the patient may or may not experience a "flu-like disease" as they begin to mount an adaptive immune response to the attack. This brings down levels of the virus in plasma, but unfortunately not forever. As I've mentioned in a post for PHAR2210, HIV can mutate very rapidly, leading to not only drug resistance, but resistance to antibodies and cytotoxic T-cells. The immune system is unable to keep up, especially since HIV is destroying it at the same time. After 2-12 years in a latent phase, where the patient shows no symptoms, the immune system eventually gets overwhelmed and the patient can become very ill. Eventually, T-helper cell levels drop to the point where the patient is considered to have AIDS.
Chronic Degenerative Disorders
In my last post, I wrote about chronic, but non-progressive brain disorders. In this post, I will write about degenerative disorders- that is, those that get worse over time.
Multiple Sclerosis
Multiple sclerosis is a disease in which there is demyelination of central neurons (that is, neurons in the brain and spinal cord). There is also inflammation that produces plaques, particularly in the brain stem, ventricles and optic nerve. Onset of multiple sclerosis usually happens at around 20-40 years of age. Unfortunately we don't know what causes it, but it seems to be more common in females, as well as in people living in temperate climates, so maybe vitamin D plays a role.
Symptoms of MS include bladder or bowel dysfunction, progressive muscle weakness, paresthaesias, fatigue, mood issues including depression and euphoria and vision issues including diplopia ("double vision") and scotoma (seeing a fuzzy patch somewhere in the field of vision). These symptoms can wax and wane, in exacerbations and remissions. Hence, an MRI or a spinal tap showing protein or lymphocytes in the CSF may be required for a more definitive diagnosis.
Unfortunately there is no cure for multiple sclerosis, but interferon, monoclonal antibodies and glucocorticoids to reduce inflammation may help, as well as avoiding exertion.
Parkinson's Disease
Parkinson's Disease affects the basal nuclei, especially the substantial nigra. The basal nuclei are usually involved in trunk and proximal movement, starting and stopping movement and slow and sustained movements. Hence, issues with this area cause symptoms such as a resting tremor (you're unable to stop movement, so you're still shaking a bit even when you don't want to), rigidity, bradykinesia (slow to start movements), difficulty swallowing and walking with a shuffling gait and stooped posture. In later stages, orthostatic hypotension (inability of the body to adjust blood pressure when you stand up) and dementia may also be a problem.
Dopamine appears to be deficient in Parkinson's, or at least not in balance with ACh, which may be too high. Hence, treatments for Parkinson's include L-dopa, which is a dopamine precursor able to cross the blood-brain barrier, and anticholinergics. Exercise may also help patients.
Huntington's Disease (a.k.a. "Huntington's Chorea")
Huntington's Disease also affects the basal nuclei, but it affects a slightly different area called the caudate nucleus, and there appears to be some brain atrophy with this disease. It also involves different neurotransmitters: GABA and ACh appear to be deficient here. This results in choreiform (jerky) movements (hence the nickname "Huntington's Chorea") as well as mood swings, poor judgement and memory lapses.
Unlike many other brain disorders, Huntington's Disease is one that we do know the cause for. It's a genetic disease which is autosomal dominant. Patients with the defective gene begin having troubles at around 35-50 years of age.
Amyotrophic Lateral Sclerosis (ALS) (a.k.a. Lou Gehrig's Disease)
ALS is a disease in which there is degeneration of motor neurons, such as those in the lateral corticospinal tracts. There is, however, no inflammation, and sensory and autonomic nerves are not affected. Interestingly enough, 20% of patients with this have a mutation in the gene coding for superoxide dismutase, which, as I said here, is one of the enzymes that helps us get rid of free radicals.
Onset of ALS usually happens at around 40-60 years, and is more common in males. If upper motor neurons are affected, spasticity is likely to result; if lower motor neurons are affected, paresis is more likely to result. ALS affects distal areas first, before moving inwards. Speech and swallowing can also be affected. Eventually, the disease can progress to respiratory failure.
Dementia
Dementia, which is loss of cortical function, is usually caused by Alzheimer's (which I'll cover soon) or vascular injury. Symptoms include language difficulty, innumeracy, loss of motor coordination, personality changes and memory problems. These memory problems can be distinguished from regular forgetfulness in two main ways. Firstly, people with dementia still struggle to remember things even after given clues to aid in recall. Secondly, they often struggle with computational (numeracy) tasks.
Alzheimer's Disease
Alzheimer's Disease, as I just alluded to, is the most common cause of dementia. There are several brain changes that occur in Alzheimer's, most of which can unfortunately only be detected during an autopsy. These include beta-amyloid plaques, which are clusters of degenerating nerve terminals around an amyloid core, and neurofibrillary "tangles," which are clumps of neurons caused by the Tau protein (these can, however, be seen even in those that are not experiencing cognitive decline). Changes that may be detectable during the patient's life include cortical atrophy, dilated ventricles and widened sulci. However, the sensory cortex is usually fine. Unfortunately, the cause of Alzheimer's is unknown, but it may be genetic as there is a high incidence in patients with Down Syndrome. (Chromosome 21 also happens to be the location of the amyloid gene.)
Alzheimer's Disease progresses in stages. In early stages, patients can get lost easily, lose their sense of humour and become withdrawn. As the disease progresses, they can become confused in familiar places, struggle with daily tasks and communication. In late stages, patients may have motor issues (including incontinence) and lose awareness of their surroundings.
There is no cure for Alzheimer's, but maintaining a daily routine with exercise can help, as can treating any anxiety issues that the patient may have. Low ACh has been associated with Alzheimer's, so inhibitors of cholinesterase (an enzyme that breaks down ACh) may be used, but these have so far only shown limited success. In later stages, patients may need help with tasks such as feeding, particularly if they are having trouble swallowing.
Schizophrenia
Now we move into the world of mental disorders- well, kind of. We're only going to cover schizophrenia in this course, because there simply isn't any time to cover more.
Schizophrenia is a mental illness in which patients lose touch with reality. Symptoms can be divided into "positive" (i.e. presence of abnormal symptoms) and "negative" (i.e. absence of normal traits). (Don't confuse "positive" with "good" here- all of the symptoms are shit.) Positive symptoms include delusions, bizarre behaviours, paranoia, incoherence and hallucinations, whereas negative symptoms include feeling "flat" and apathetic, anhedonia (loss of joy) and social withdrawal.
There are some brain changes implicated in schizophrenia, such as reduced grey matter in the temporal lobes and reduced blood flow to frontal lobes, as well as some possible changes with regards to neurotransmitters such as increased dopamine, reduced serotonin and possibly issues with glutamate receptor function. Dopamine can be decreased with dopamine antagonists, though these can have unpleasant side effects such as tardive dyskinesia (repetitive, involuntary movements). Serotonin can be increased with SSRIs (selective serotonin reuptake inhibitors), which inhibit the reuptake of serotonin into neurons, so that there's more bouncing around in the synapse stimulating the next neuron. Interestingly enough, LSD, a serotonin antagonist, and PCP ("angel dust"), a glutamate receptor blocker, can both mimic the symptoms of schizophrenia, such as hallucinations and paranoia.
Multiple Sclerosis
Multiple sclerosis is a disease in which there is demyelination of central neurons (that is, neurons in the brain and spinal cord). There is also inflammation that produces plaques, particularly in the brain stem, ventricles and optic nerve. Onset of multiple sclerosis usually happens at around 20-40 years of age. Unfortunately we don't know what causes it, but it seems to be more common in females, as well as in people living in temperate climates, so maybe vitamin D plays a role.
Symptoms of MS include bladder or bowel dysfunction, progressive muscle weakness, paresthaesias, fatigue, mood issues including depression and euphoria and vision issues including diplopia ("double vision") and scotoma (seeing a fuzzy patch somewhere in the field of vision). These symptoms can wax and wane, in exacerbations and remissions. Hence, an MRI or a spinal tap showing protein or lymphocytes in the CSF may be required for a more definitive diagnosis.
Unfortunately there is no cure for multiple sclerosis, but interferon, monoclonal antibodies and glucocorticoids to reduce inflammation may help, as well as avoiding exertion.
Parkinson's Disease
Parkinson's Disease affects the basal nuclei, especially the substantial nigra. The basal nuclei are usually involved in trunk and proximal movement, starting and stopping movement and slow and sustained movements. Hence, issues with this area cause symptoms such as a resting tremor (you're unable to stop movement, so you're still shaking a bit even when you don't want to), rigidity, bradykinesia (slow to start movements), difficulty swallowing and walking with a shuffling gait and stooped posture. In later stages, orthostatic hypotension (inability of the body to adjust blood pressure when you stand up) and dementia may also be a problem.
Dopamine appears to be deficient in Parkinson's, or at least not in balance with ACh, which may be too high. Hence, treatments for Parkinson's include L-dopa, which is a dopamine precursor able to cross the blood-brain barrier, and anticholinergics. Exercise may also help patients.
Huntington's Disease (a.k.a. "Huntington's Chorea")
Huntington's Disease also affects the basal nuclei, but it affects a slightly different area called the caudate nucleus, and there appears to be some brain atrophy with this disease. It also involves different neurotransmitters: GABA and ACh appear to be deficient here. This results in choreiform (jerky) movements (hence the nickname "Huntington's Chorea") as well as mood swings, poor judgement and memory lapses.
Unlike many other brain disorders, Huntington's Disease is one that we do know the cause for. It's a genetic disease which is autosomal dominant. Patients with the defective gene begin having troubles at around 35-50 years of age.
Amyotrophic Lateral Sclerosis (ALS) (a.k.a. Lou Gehrig's Disease)
ALS is a disease in which there is degeneration of motor neurons, such as those in the lateral corticospinal tracts. There is, however, no inflammation, and sensory and autonomic nerves are not affected. Interestingly enough, 20% of patients with this have a mutation in the gene coding for superoxide dismutase, which, as I said here, is one of the enzymes that helps us get rid of free radicals.
Onset of ALS usually happens at around 40-60 years, and is more common in males. If upper motor neurons are affected, spasticity is likely to result; if lower motor neurons are affected, paresis is more likely to result. ALS affects distal areas first, before moving inwards. Speech and swallowing can also be affected. Eventually, the disease can progress to respiratory failure.
Dementia
Dementia, which is loss of cortical function, is usually caused by Alzheimer's (which I'll cover soon) or vascular injury. Symptoms include language difficulty, innumeracy, loss of motor coordination, personality changes and memory problems. These memory problems can be distinguished from regular forgetfulness in two main ways. Firstly, people with dementia still struggle to remember things even after given clues to aid in recall. Secondly, they often struggle with computational (numeracy) tasks.
Alzheimer's Disease
Alzheimer's Disease, as I just alluded to, is the most common cause of dementia. There are several brain changes that occur in Alzheimer's, most of which can unfortunately only be detected during an autopsy. These include beta-amyloid plaques, which are clusters of degenerating nerve terminals around an amyloid core, and neurofibrillary "tangles," which are clumps of neurons caused by the Tau protein (these can, however, be seen even in those that are not experiencing cognitive decline). Changes that may be detectable during the patient's life include cortical atrophy, dilated ventricles and widened sulci. However, the sensory cortex is usually fine. Unfortunately, the cause of Alzheimer's is unknown, but it may be genetic as there is a high incidence in patients with Down Syndrome. (Chromosome 21 also happens to be the location of the amyloid gene.)
Alzheimer's Disease progresses in stages. In early stages, patients can get lost easily, lose their sense of humour and become withdrawn. As the disease progresses, they can become confused in familiar places, struggle with daily tasks and communication. In late stages, patients may have motor issues (including incontinence) and lose awareness of their surroundings.
There is no cure for Alzheimer's, but maintaining a daily routine with exercise can help, as can treating any anxiety issues that the patient may have. Low ACh has been associated with Alzheimer's, so inhibitors of cholinesterase (an enzyme that breaks down ACh) may be used, but these have so far only shown limited success. In later stages, patients may need help with tasks such as feeding, particularly if they are having trouble swallowing.
Schizophrenia
Now we move into the world of mental disorders- well, kind of. We're only going to cover schizophrenia in this course, because there simply isn't any time to cover more.
Schizophrenia is a mental illness in which patients lose touch with reality. Symptoms can be divided into "positive" (i.e. presence of abnormal symptoms) and "negative" (i.e. absence of normal traits). (Don't confuse "positive" with "good" here- all of the symptoms are shit.) Positive symptoms include delusions, bizarre behaviours, paranoia, incoherence and hallucinations, whereas negative symptoms include feeling "flat" and apathetic, anhedonia (loss of joy) and social withdrawal.
There are some brain changes implicated in schizophrenia, such as reduced grey matter in the temporal lobes and reduced blood flow to frontal lobes, as well as some possible changes with regards to neurotransmitters such as increased dopamine, reduced serotonin and possibly issues with glutamate receptor function. Dopamine can be decreased with dopamine antagonists, though these can have unpleasant side effects such as tardive dyskinesia (repetitive, involuntary movements). Serotonin can be increased with SSRIs (selective serotonin reuptake inhibitors), which inhibit the reuptake of serotonin into neurons, so that there's more bouncing around in the synapse stimulating the next neuron. Interestingly enough, LSD, a serotonin antagonist, and PCP ("angel dust"), a glutamate receptor blocker, can both mimic the symptoms of schizophrenia, such as hallucinations and paranoia.
Friday, November 25, 2016
Chronic Neurological Problems
Now we're moving from more acute neurological problems to the chronic ones! Specifically, we will be covering cerebral palsy and seizure disorders (a.k.a. epilepsy), both of which are of particular interest to me because one of my cousins is unfortunate enough to have both.
Cerebral Palsy
Cerebral palsy is a non-progressive disorder in which there are issues with motor skills and persistence of infant reflexes, such as the Moro reflex (where a baby that thinks it's falling will stretch out its arms and legs). Some other symptoms include dysarthria (a problem with verbal articulation due to motor issues), seizures and vision defects.
The cause of cerebral palsy is unfortunately unknown, but some factors that may contribute include genetic mutations, abnormal problems and infection or damage in the perinatal period (i.e. at the time of birth). For example, a difficult delivery may cause haemorrhages or hypoxia. Other potential factors include kernicterus (a lot of bilirubin crossing the blood-brain barrier), which can occur due to Rh factor incompatibility or prematurity (premature babies have more red blood cells containing foetal haemoglobin that they have to get rid of). Hypoglycaemia may also be a factor.
Cerebral palsy can be categorised in several ways. Firstly, it can be categorised according to the area affected. If all four limbs are affected, this is quadriplegia. If one side of the body is affected, this is hemiplegia (the most common form). If both arms or both legs are affected, this is diplegia. Secondly, cerebral palsy can be categorised according to the area of the brain that has been affected. In spastic CP, which is the most common, the pyramidal tract is affected, resulting in "scissors gait" (walking with crossed legs) and hyperreflexia. In dyskinetic CP, the basal nuclei and cranial nerves are affected, resulting in choreiform (jerky) involuntary movements and loss of gross motor movements. Finally, in ataxic CP, the cerebellum is affected, resulting in loss of balance and difficulty controlling gait.
Seizure Disorders (a.k.a. Epilepsy)
In seizure disorders, there is uncontrolled excessive neuron activity in the brain which spreads before ending spontaneously. Many seizures are idiopathic- that is, they have no known cause, but may have a genetic component. Some seizures are as a result of head injury. Individuals prone to seizures may have them in response to flashing lights, alkalosis, hypoglycaemia or fever. Seizures as a result of fever ("febrile seizures") are more common in babies and young children, who usually grow out of them.
Generalised Seizures
Generalised seizures are seizures affecting most parts of the brain. There are two main types: petit mal and grand mal.
Petit mal, or absence seizures, are the less severe of the two. These involve a brief loss of awareness, eyelid twitching and staring. Although they generally do not involve a loss of consciousness, patients will generally have no awareness of the event. These usually occur in children.
Grand mal, or tonic/clonic seizures, are quite severe and occur in stages. In the prodromal phase, where no clear signs appear on an ECG, a patient may experience symptoms like irritability or an aura (seeing or smelling strange things). Loss of consciousness may then occur. In the ictal phase, patients have tonic muscle contraction, which is essentially flexion of muscles followed by rigidity. This results in forced expiration, a clenched jaw and so on. Clonic contraction may also occur, in which there is jerky contraction and relaxation that occurs so quickly that it looks like a tremor. These contractions may result in incontinence and vomiting. Finally, in the post-ictal phase, which follows the main part of the seizure, the patient is limp and sleepy.
One complication of generalised seizures is status epilepticus, which occurs when there are many recurrent seizures with loss of consciousness. These seizures can be so frequent that they interfere with normal bodily functions, such as breathing. This can result in hypoxia, hypoglycaemia and acidosis.
Partial Seizures
Partial seizures affect only a small area of the brain. These cause symptoms such as repeated motor activity and/or unusual sensations such as tingling or ringing in the ears. There is no loss of consciousness in a partial seizure, though there may be reduced consciousness. One type of partial seizure is a Jacksonian seizure, in which there is a progressive spread of clonic contractions.
Seizure Treatment
Seizures can be treated with anti-convulsive drugs such as Dilantin, or even sedatives. Unfortunately they don't always have the nicest side effects- they can result in a low white blood cell count, or gingival hyperplasia, which is excessive growth of gum tissue. As with nearly everything in medicine, treating epilepsy requires evaluating the benefits and the risks.
Cerebral Palsy
Cerebral palsy is a non-progressive disorder in which there are issues with motor skills and persistence of infant reflexes, such as the Moro reflex (where a baby that thinks it's falling will stretch out its arms and legs). Some other symptoms include dysarthria (a problem with verbal articulation due to motor issues), seizures and vision defects.
The cause of cerebral palsy is unfortunately unknown, but some factors that may contribute include genetic mutations, abnormal problems and infection or damage in the perinatal period (i.e. at the time of birth). For example, a difficult delivery may cause haemorrhages or hypoxia. Other potential factors include kernicterus (a lot of bilirubin crossing the blood-brain barrier), which can occur due to Rh factor incompatibility or prematurity (premature babies have more red blood cells containing foetal haemoglobin that they have to get rid of). Hypoglycaemia may also be a factor.
Cerebral palsy can be categorised in several ways. Firstly, it can be categorised according to the area affected. If all four limbs are affected, this is quadriplegia. If one side of the body is affected, this is hemiplegia (the most common form). If both arms or both legs are affected, this is diplegia. Secondly, cerebral palsy can be categorised according to the area of the brain that has been affected. In spastic CP, which is the most common, the pyramidal tract is affected, resulting in "scissors gait" (walking with crossed legs) and hyperreflexia. In dyskinetic CP, the basal nuclei and cranial nerves are affected, resulting in choreiform (jerky) involuntary movements and loss of gross motor movements. Finally, in ataxic CP, the cerebellum is affected, resulting in loss of balance and difficulty controlling gait.
Seizure Disorders (a.k.a. Epilepsy)
In seizure disorders, there is uncontrolled excessive neuron activity in the brain which spreads before ending spontaneously. Many seizures are idiopathic- that is, they have no known cause, but may have a genetic component. Some seizures are as a result of head injury. Individuals prone to seizures may have them in response to flashing lights, alkalosis, hypoglycaemia or fever. Seizures as a result of fever ("febrile seizures") are more common in babies and young children, who usually grow out of them.
Generalised Seizures
Generalised seizures are seizures affecting most parts of the brain. There are two main types: petit mal and grand mal.
Petit mal, or absence seizures, are the less severe of the two. These involve a brief loss of awareness, eyelid twitching and staring. Although they generally do not involve a loss of consciousness, patients will generally have no awareness of the event. These usually occur in children.
Grand mal, or tonic/clonic seizures, are quite severe and occur in stages. In the prodromal phase, where no clear signs appear on an ECG, a patient may experience symptoms like irritability or an aura (seeing or smelling strange things). Loss of consciousness may then occur. In the ictal phase, patients have tonic muscle contraction, which is essentially flexion of muscles followed by rigidity. This results in forced expiration, a clenched jaw and so on. Clonic contraction may also occur, in which there is jerky contraction and relaxation that occurs so quickly that it looks like a tremor. These contractions may result in incontinence and vomiting. Finally, in the post-ictal phase, which follows the main part of the seizure, the patient is limp and sleepy.
One complication of generalised seizures is status epilepticus, which occurs when there are many recurrent seizures with loss of consciousness. These seizures can be so frequent that they interfere with normal bodily functions, such as breathing. This can result in hypoxia, hypoglycaemia and acidosis.
Partial Seizures
Partial seizures affect only a small area of the brain. These cause symptoms such as repeated motor activity and/or unusual sensations such as tingling or ringing in the ears. There is no loss of consciousness in a partial seizure, though there may be reduced consciousness. One type of partial seizure is a Jacksonian seizure, in which there is a progressive spread of clonic contractions.
Seizure Treatment
Seizures can be treated with anti-convulsive drugs such as Dilantin, or even sedatives. Unfortunately they don't always have the nicest side effects- they can result in a low white blood cell count, or gingival hyperplasia, which is excessive growth of gum tissue. As with nearly everything in medicine, treating epilepsy requires evaluating the benefits and the risks.
Thursday, November 24, 2016
Tumour Immunology
I'm sure you have a vague idea of what cancer is- it's when cells keep on replicating even when you don't want them to. One thing that you might not know, however, is that the immune system can play a role in the growth (or lack of growth) of a tumour. And no, this has nothing to do with vague "boost your immune system!" claims found on many products in health stores.
Another thing that you most likely know about cancer is that it is caused by the accumulation of many mutations in several significant genes. These genes include RAS (a "proto-oncogene" responsible for cell signalling and differentiation), tumour-suppressive genes (e.g. P53) and genes regulating apoptosis (e.g. BAD). Factors that can make cancer development more likely include certain chemicals, pesticides, radiation, and some viruses such as HPV (leading to cervical cancer), Hepatitis B (leading to liver cancer) and Epstein-Barr Virus (which can lead to Burkitt's lymphoma, which is a tumour of B-lymphocytes). Even the Herpes virus can lead to a cancer called Kaposi's sarcoma, which manifests in abnormal purple skin lesions. This is especially likely to occur in HIV-positive patients.
Inflammation can also play a role in the development of cancer. Chronic inflammation increases cellular stress signals, which increases mutation rates in cells. Some pro-inflammatory cytokines can also induce cell proliferation. Another side-effect of inflammation is that it is pro-angiogenic, or promotes the growth of new blood vessels. These blood vessels can also help nourish the cancerous cells, or make it easier for tumour cells to invade into surrounding tissues.
Tumour Antigens
Tumour cells may express unique antigens, which help in recognition by lymphocytes. Antigens that are exclusively expressed by tumours are called tumour-specific antigens (TSAs), and include HPV E6. There are also tumour-associated antigens (TAAs), which are antigens that are either overexpressed, or expressed at the wrong time (i.e. a gene normally expressed during foetal development is expressed in an adult). An example of the former is HER2, which is overexpressed in breast cancer tumours.
The Immune Response to Cancer
Thankfully, we have a few ways in which we can fight back against cancer!
Innate responses
Many tumours express lower levels of MHC in order to try and "hide" from cytotoxic T-cells, but this comes back to bite them in the butt. As I've mentioned earlier, NK cells kill cells that have a reduced expression of MHC molecules. If there are mutations that cause NK cells to become less active, certain cancers may be more likely. Another innate response involves macrophages, which can secrete TNF-α. TNF stands for "tumour necrosis factor," and, true to its name, acts strongly against tumours.
Adaptive responses
Lymphocytes that can infiltrate tumours are known as tumour-infiltrating lymphocytes, or TILs. Most of these are T-cells. B-cells can also generate antibodies against TSAs.
Cytokines
There are several different cytokines that can also be helpful in cancer. Types I and II interferon (IFN) can both enhance anti-tumour activities, particularly type I IFN, which can induce tumour cell death. TNF-α can also exhibit anti-cancer effects, as I said above. IL-12 doesn't attack cancer cells directly, but it does help activate TH1 and cytotoxic T-lymphocyte responses, which can help in the removal of a tumour.
All three systems work together, but they are not always perfect. In the best case scenario, there is an elimination phase in which the immune system can clear the cancerous cells before they become an issue (so basically the immune system wins). In the equilibrium phase, the immune system can get rid of some of the cells, but not all (so there's like a stalemate between the immune system and the cancer). In the escape phase, the cancer wins out, and cells that have managed to evade detection multiply and activate T-reg cells, suppressing further immune responses.
Immunosuppression by Tumours
The immune system might be able to fight against tumours, but the tumours can also fight back. They can do this by recruiting T-reg cells as well as myeloid-derived suppressor cells (MDSCs), the latter being related to macrophages (though have completely different functions). Soluble TGF-β and IL-10, which are anti-inflammatory cytokines, can also suppress the immune system.
As mentioned before, tumours may also express less MHC in order to evade detection.. The reduced amount of MHC may be due to mutations in genes for TAP and/or β2-microglobulin. Tumour cells may also provide poor co-stimulatory signals to T-cells, leading to anergy and immune tolerance.
Cancer Immunotherapy
Understanding of the role of the immune system in cancer has led to some new therapies. In some of these therapies, monoclonal antibodies are given against TSAs or TAAs. An example of this is Herceptin, which acts against the HER2 receptor (a TAA) in breast cancer. Immunotherapies may also work to block DNA synthesis and cell division, or induce or enhance the immune response against tumours.
One such immunotherapy that achieves the latter is called adoptive cellular therapy. In this therapy, tumour-specific T-cells are obtained from the tumours or peripheral blood from patients and are mixed with cytokines in order to activate and expand these cells. Following this, cells are then re-infused.
There are also therapies that involve removal and re-infusion of dendritic cells. In these therapies, dendritic cells are either cultured with tumour antigens, causing them to express tumour peptides on MHC molecules, or they are transfected with plasmids expressing the tumour antigen, again for the purpose of their presentation on MHC molecules. These are re-infused into the patient, causing activation of tumour-specific T-cells.
Another thing that you most likely know about cancer is that it is caused by the accumulation of many mutations in several significant genes. These genes include RAS (a "proto-oncogene" responsible for cell signalling and differentiation), tumour-suppressive genes (e.g. P53) and genes regulating apoptosis (e.g. BAD). Factors that can make cancer development more likely include certain chemicals, pesticides, radiation, and some viruses such as HPV (leading to cervical cancer), Hepatitis B (leading to liver cancer) and Epstein-Barr Virus (which can lead to Burkitt's lymphoma, which is a tumour of B-lymphocytes). Even the Herpes virus can lead to a cancer called Kaposi's sarcoma, which manifests in abnormal purple skin lesions. This is especially likely to occur in HIV-positive patients.
Inflammation can also play a role in the development of cancer. Chronic inflammation increases cellular stress signals, which increases mutation rates in cells. Some pro-inflammatory cytokines can also induce cell proliferation. Another side-effect of inflammation is that it is pro-angiogenic, or promotes the growth of new blood vessels. These blood vessels can also help nourish the cancerous cells, or make it easier for tumour cells to invade into surrounding tissues.
Tumour Antigens
Tumour cells may express unique antigens, which help in recognition by lymphocytes. Antigens that are exclusively expressed by tumours are called tumour-specific antigens (TSAs), and include HPV E6. There are also tumour-associated antigens (TAAs), which are antigens that are either overexpressed, or expressed at the wrong time (i.e. a gene normally expressed during foetal development is expressed in an adult). An example of the former is HER2, which is overexpressed in breast cancer tumours.
The Immune Response to Cancer
Thankfully, we have a few ways in which we can fight back against cancer!
Innate responses
Many tumours express lower levels of MHC in order to try and "hide" from cytotoxic T-cells, but this comes back to bite them in the butt. As I've mentioned earlier, NK cells kill cells that have a reduced expression of MHC molecules. If there are mutations that cause NK cells to become less active, certain cancers may be more likely. Another innate response involves macrophages, which can secrete TNF-α. TNF stands for "tumour necrosis factor," and, true to its name, acts strongly against tumours.
Adaptive responses
Lymphocytes that can infiltrate tumours are known as tumour-infiltrating lymphocytes, or TILs. Most of these are T-cells. B-cells can also generate antibodies against TSAs.
Cytokines
There are several different cytokines that can also be helpful in cancer. Types I and II interferon (IFN) can both enhance anti-tumour activities, particularly type I IFN, which can induce tumour cell death. TNF-α can also exhibit anti-cancer effects, as I said above. IL-12 doesn't attack cancer cells directly, but it does help activate TH1 and cytotoxic T-lymphocyte responses, which can help in the removal of a tumour.
All three systems work together, but they are not always perfect. In the best case scenario, there is an elimination phase in which the immune system can clear the cancerous cells before they become an issue (so basically the immune system wins). In the equilibrium phase, the immune system can get rid of some of the cells, but not all (so there's like a stalemate between the immune system and the cancer). In the escape phase, the cancer wins out, and cells that have managed to evade detection multiply and activate T-reg cells, suppressing further immune responses.
Immunosuppression by Tumours
The immune system might be able to fight against tumours, but the tumours can also fight back. They can do this by recruiting T-reg cells as well as myeloid-derived suppressor cells (MDSCs), the latter being related to macrophages (though have completely different functions). Soluble TGF-β and IL-10, which are anti-inflammatory cytokines, can also suppress the immune system.
As mentioned before, tumours may also express less MHC in order to evade detection.. The reduced amount of MHC may be due to mutations in genes for TAP and/or β2-microglobulin. Tumour cells may also provide poor co-stimulatory signals to T-cells, leading to anergy and immune tolerance.
Cancer Immunotherapy
Understanding of the role of the immune system in cancer has led to some new therapies. In some of these therapies, monoclonal antibodies are given against TSAs or TAAs. An example of this is Herceptin, which acts against the HER2 receptor (a TAA) in breast cancer. Immunotherapies may also work to block DNA synthesis and cell division, or induce or enhance the immune response against tumours.
One such immunotherapy that achieves the latter is called adoptive cellular therapy. In this therapy, tumour-specific T-cells are obtained from the tumours or peripheral blood from patients and are mixed with cytokines in order to activate and expand these cells. Following this, cells are then re-infused.
There are also therapies that involve removal and re-infusion of dendritic cells. In these therapies, dendritic cells are either cultured with tumour antigens, causing them to express tumour peptides on MHC molecules, or they are transfected with plasmids expressing the tumour antigen, again for the purpose of their presentation on MHC molecules. These are re-infused into the patient, causing activation of tumour-specific T-cells.
Tuesday, November 22, 2016
Autoimmune Diseases
Continuing on from my posts on hypersensitivity, where your immune system reacts inappropriately to an innocuous antigen, I'm now going to talk about autoimmune diseases, where your immune system reacts inappropriately to your own body! Such autoimmune diseases are rare, but the risk of developing one may be linked to your own personal brand of MHC molecules.
Development of Tolerance
Just as a reminder, both B-cells and T-cells undergo negative selection to reduce the possibility of self-reaction. This process is called central tolerance when it happens in the primary lymphoid organs (bone marrow and thymus), or peripheral tolerance when it happens somewhere else. A B-cell that is self-reactive will be stimulated to undergo apoptosis or receptor editing, as outlined here. T-cells that are self-reactive are stimulated to undergo apoptosis, as outlined here. If central tolerance fails to weed out all of the self-reactive cells, regulatory T-cells (which I've spoken about here) swoop in and play a role in peripheral tolerance.
Tolerance is defined as immunological unresponsiveness to self-antigens. Regulatory T-cells can bind to MHC-II displaying "self" peptides on B-cells, causing either anergy (i.e. making the cell unreactive), apoptosis and/or release of cytokines that inhibit surrounding autoreactive T-cells. (At least, that's my understanding of how it works.)
Breaking of Tolerance
There are several ways in which tolerance can be broken.
Infection with certain viruses
Certain viruses can cause activation of immune cells. For example, the Epstein-Barr virus (EBV), which is responsible for infectious mononucleosis (a.k.a. "the Kissing Disease") causes random activation of B-cells. Some of these B-cells might include anergic self-reactive B-cells. When activated, they are obviously no longer anergic- they're ready to kill and wreak havoc. Since many B-cells are activated at once, many non-specific antibodies are produced.
This method was discovered via experiments with mice. Transgenic mice were made that express a nucleoprotein from the LCMV virus in their pancreatic β cells. These mice built up tolerance to the nucleoprotein, but still had some anergic B-cells that were reactive against it. When these mice were infected with LCMV, these anergic B-cells became active and killed the pancreatic β cells that were also expressing the nucleoprotein. As a result, these rats became diabetic.
Release of sequestered antigen
There are several antigens around the body that usually "hide" from the immune system- for example, in the brain, eyes and testes. (I've mentioned how this affects the brain here.) When these organs are damaged, these normally "hidden" antigens may be released, causing activation of T-cells. The T-cells then go around and start attacking the source of the antigen.
Molecular mimicry
Some pathogens have antigens that are very similar to our own. For example, some of the antigens on the cell wall of streptococci are similar to those in our heart. Hence, antibodies against streptococcus can cause rheumatic fever and rheumatic heart disease. I've gone more into depth on rheumatic fever in an earlier post for PHGY350.
Other Autoimmune Diseases
The remaining autoimmune diseases that I'm going to cover will draw on many principles of types II, III and IV hypersensitivity, which I've covered in a previous post.
Graves' Disease
I've covered Graves' Disease before, but just a recap: autoreactive B-cells make antibodies against the TSH receptor, causing the thyroid to produce more thyroid hormones. This is one cause of primary hyperthyroidism. Graves' Disease can be considered to be similar to type II hypersensitivity in that IgG is reacting against cell-surface antigens.
Myasthenia Gravis
Myasthenia gravis is also similar to type II hypersensitivity, in which IgG is reacting against cell-surface antigens. In this case, IgG is reacting against acetylcholine receptors on muscle cells, causing them to be endocytosed and degraded. As these receptors are required for muscle contraction, myasthenia gravis manifests in abnormal muscular weakness, fatigue and ptosis (droopy eyelids).
Rheumatoid Arthritis
In contrast to the past couple of diseases, rheumatoid arthritis is more similar to type III hypersensitivity, in which IgG reacts against a soluble antigen and immune complexes are formed. These immune complexes are formed in joints, causing redness, pain and swelling (so basically just inflammation) in the lining of joints. 80% of people with rheumatoid arthritis are positive for rheumatoid factor (RF), which is essentially IgG or IgM binding to self-antigens on other antibodies (usually IgG).
Systemic Lupus Erythematosus (SLE)
SLE is also similar to type III hypersensitivity. In SLE, antibodies are created against self-DNA, resulting in immune complexes and inflammation in many areas of the body. Blood vessels, the heart, lungs, joints, kidneys and skin can all be affected, with some patients developing a characteristic "butterfly rash" on the face. Steroids may be prescribed to reduce inflammation.
Diseases similar to type IV hypersensitivity
Some diseases have characteristics in common with type IV hypersensitivity, which is mediated by T-cells, macrophages etc. These include diabetes and multiple sclerosis. Rheumatoid arthritis also involves some antigens which are attacked in a process similar to type IV hypersensitivity.
Development of Tolerance
Just as a reminder, both B-cells and T-cells undergo negative selection to reduce the possibility of self-reaction. This process is called central tolerance when it happens in the primary lymphoid organs (bone marrow and thymus), or peripheral tolerance when it happens somewhere else. A B-cell that is self-reactive will be stimulated to undergo apoptosis or receptor editing, as outlined here. T-cells that are self-reactive are stimulated to undergo apoptosis, as outlined here. If central tolerance fails to weed out all of the self-reactive cells, regulatory T-cells (which I've spoken about here) swoop in and play a role in peripheral tolerance.
Tolerance is defined as immunological unresponsiveness to self-antigens. Regulatory T-cells can bind to MHC-II displaying "self" peptides on B-cells, causing either anergy (i.e. making the cell unreactive), apoptosis and/or release of cytokines that inhibit surrounding autoreactive T-cells. (At least, that's my understanding of how it works.)
Breaking of Tolerance
There are several ways in which tolerance can be broken.
Infection with certain viruses
Certain viruses can cause activation of immune cells. For example, the Epstein-Barr virus (EBV), which is responsible for infectious mononucleosis (a.k.a. "the Kissing Disease") causes random activation of B-cells. Some of these B-cells might include anergic self-reactive B-cells. When activated, they are obviously no longer anergic- they're ready to kill and wreak havoc. Since many B-cells are activated at once, many non-specific antibodies are produced.
This method was discovered via experiments with mice. Transgenic mice were made that express a nucleoprotein from the LCMV virus in their pancreatic β cells. These mice built up tolerance to the nucleoprotein, but still had some anergic B-cells that were reactive against it. When these mice were infected with LCMV, these anergic B-cells became active and killed the pancreatic β cells that were also expressing the nucleoprotein. As a result, these rats became diabetic.
Release of sequestered antigen
There are several antigens around the body that usually "hide" from the immune system- for example, in the brain, eyes and testes. (I've mentioned how this affects the brain here.) When these organs are damaged, these normally "hidden" antigens may be released, causing activation of T-cells. The T-cells then go around and start attacking the source of the antigen.
Molecular mimicry
Some pathogens have antigens that are very similar to our own. For example, some of the antigens on the cell wall of streptococci are similar to those in our heart. Hence, antibodies against streptococcus can cause rheumatic fever and rheumatic heart disease. I've gone more into depth on rheumatic fever in an earlier post for PHGY350.
Other Autoimmune Diseases
The remaining autoimmune diseases that I'm going to cover will draw on many principles of types II, III and IV hypersensitivity, which I've covered in a previous post.
Graves' Disease
I've covered Graves' Disease before, but just a recap: autoreactive B-cells make antibodies against the TSH receptor, causing the thyroid to produce more thyroid hormones. This is one cause of primary hyperthyroidism. Graves' Disease can be considered to be similar to type II hypersensitivity in that IgG is reacting against cell-surface antigens.
Myasthenia Gravis
Myasthenia gravis is also similar to type II hypersensitivity, in which IgG is reacting against cell-surface antigens. In this case, IgG is reacting against acetylcholine receptors on muscle cells, causing them to be endocytosed and degraded. As these receptors are required for muscle contraction, myasthenia gravis manifests in abnormal muscular weakness, fatigue and ptosis (droopy eyelids).
Rheumatoid Arthritis
In contrast to the past couple of diseases, rheumatoid arthritis is more similar to type III hypersensitivity, in which IgG reacts against a soluble antigen and immune complexes are formed. These immune complexes are formed in joints, causing redness, pain and swelling (so basically just inflammation) in the lining of joints. 80% of people with rheumatoid arthritis are positive for rheumatoid factor (RF), which is essentially IgG or IgM binding to self-antigens on other antibodies (usually IgG).
Systemic Lupus Erythematosus (SLE)
SLE is also similar to type III hypersensitivity. In SLE, antibodies are created against self-DNA, resulting in immune complexes and inflammation in many areas of the body. Blood vessels, the heart, lungs, joints, kidneys and skin can all be affected, with some patients developing a characteristic "butterfly rash" on the face. Steroids may be prescribed to reduce inflammation.
Diseases similar to type IV hypersensitivity
Some diseases have characteristics in common with type IV hypersensitivity, which is mediated by T-cells, macrophages etc. These include diabetes and multiple sclerosis. Rheumatoid arthritis also involves some antigens which are attacked in a process similar to type IV hypersensitivity.
Acute Neurological Conditions
Second post on brain pathophysiology!
Vascular Disorders
The first set of conditions that we are going to look at involve problems with blood flow. There are two main categories: haemorrhagic and ischaemic. Haemorrhagic ("bleeding") disorders cause an increase in intracranial pressure, and as such can cause some of the generalised symptoms outlined in my last post. Blood in the interstitial fluid may cause vasospasm (vasoconstriction), which is essentially a reflex to protect the brain from further injury, but may lead to ischaemic disorders. In ischaemic disorders, not enough nutrients get to the brain, so ATP-dependent pumps stop working, as outlined in one of my earliest posts for this course. This causes more Na+ to accumulate in cells, which leads to water entering the cells and cerebral oedema. Ischaemic disorders may be caused by problems such as shock or cardiac arrest.
Transient Ischaemic Attacks (TIAs)
One example of an ischaemic disorder is TIAs. TIAs are caused by temporary, localised small occlusions in one of the blood vessels supplying the brain. This can be caused by narrowing due to atherosclerosis, or an embolus (a clot from somewhere else breaking off and travelling around the blood). Symptoms include paresis (muscle weakness), paraesthesia (altered sensation), visual disturbance or transient confusion, which resolve. Despite the patient retaining consciousness and feeling "fine" after some time, care should be taken as TIAs are potential warning signs for stroke.
Cerebrovascular Accidents (CVAs) (a.k.a. Strokes)
CVAs are essentially the extreme version of TIAs. In a CVA, there is complete occlusion of a blood vessel, which causes liquefactive necrosis of the brain tissue that is no longer receiving blood. Risk factors for CVAs include diabetes, hypertension, heart disease, atherosclerosis, contraceptives and smoking. Sometimes the damage can be reduced by anastomoses, such as the Circle of Willis.
There are three main categories of CVAs: occlusion, embolus and haemorrhagic. CVAs caused by gradual occlusion of the arteries, such as by atherosclerosis, tend to be quite gradual, whereas those caused by emboli are more sudden. Haemorrhagic CVAs can be quite damaging due to the resultant increase in intracranial pressure.
Signs and symptoms of stroke include contralateral paresis and paraesthesia, temporary loss of speech, confusion, dizziness, sudden vision loss and sudden headache. Sometimes stroke is not immediately obvious because it happens in "silent" areas of the brain, or areas that don't control really obvious things. Other effects include flaccid paralysis which develops into spastic paralysis, or inflammation that leads to cerebral oedema.
Stroke caused by occlusion and embolus can be treated by "clot-busting" drugs such as tPA, which converts plasminogen to plasmin, which stops formation of a clot (see here for more information on coagulation pathways). Long-term anticoagulants can help prevent further strokes. However, these can be very damaging in haemorrhagic stroke, as they increase the amount of bleeding.
Other drugs that can be helpful are glucocorticoids, which reduce the amount of inflammation, and antihypertensives, especially when hypertension was one of the potential causes of the stroke. Aside from drugs, therapy can also help stroke patients recover. Therapy makes use of brain plasticity, which is basically the ability of the brain to form new connections and adapt.
Aneurysms
Aneurysms are basically parts of the vascular wall that become weak and bulge out. In the brain, these are more likely to happen at bifurcation points (i.e. ares where an artery branches out) around the Circle of Willis, as blood "hits" these points before separating into two directions. These aneurysms are known as "berry" aneurysms because of their shape, and as they enlarge they can put pressure on the optic nerve or other cranial nerves.
One of the major dangers with aneurysms is that they can rupture and spill out their blood, which is intensely irritating to the nerves. A ruptured aneurysm has a poor prognosis, with a mortality rate of over 50%. Rupture can cause vasospasm as a protective reflex (as stated above), which in turn causes increased intracranial pressure. Irritation to nerves can cause photophobia (extreme discomfort when looking at light), intense headache, confusion, slurred speech, nuchal rigidity (stiff neck due to irritation to nerves supplying neck muscles). Treatment involves surgical "clipping," or insertion of a metal ring to block of the bleeding area, but as you can probably guess by the mortality rate, this is far from perfect.
Concussions
A concussion is when there is excessive brain movement that can cause loss of consciousness or amnesia. Physical damage is usually not evident and a patient can appear to recover in 24 hours, but if multiple concussions are incurred, there is a risk of permanent brain damage. A contusion is a concussion in which there is rupture of small blood vessels, leading to bruising of brain tissue.
One risk with concussions is that sometimes the brain doesn't just endure one "knock"- in contrecoup, the brain rebounds off and hits the other side as well, leading to twice the amount of damage.
Haematomas
Haematomas are collections of blood outside of the blood vessels. They can occur anywhere in the body, but since this is a post about neurological conditions, I'm obviously going to focus on the brain. There are several different kinds of haematomas that can occur in the brain.
Vascular Disorders
The first set of conditions that we are going to look at involve problems with blood flow. There are two main categories: haemorrhagic and ischaemic. Haemorrhagic ("bleeding") disorders cause an increase in intracranial pressure, and as such can cause some of the generalised symptoms outlined in my last post. Blood in the interstitial fluid may cause vasospasm (vasoconstriction), which is essentially a reflex to protect the brain from further injury, but may lead to ischaemic disorders. In ischaemic disorders, not enough nutrients get to the brain, so ATP-dependent pumps stop working, as outlined in one of my earliest posts for this course. This causes more Na+ to accumulate in cells, which leads to water entering the cells and cerebral oedema. Ischaemic disorders may be caused by problems such as shock or cardiac arrest.
Transient Ischaemic Attacks (TIAs)
One example of an ischaemic disorder is TIAs. TIAs are caused by temporary, localised small occlusions in one of the blood vessels supplying the brain. This can be caused by narrowing due to atherosclerosis, or an embolus (a clot from somewhere else breaking off and travelling around the blood). Symptoms include paresis (muscle weakness), paraesthesia (altered sensation), visual disturbance or transient confusion, which resolve. Despite the patient retaining consciousness and feeling "fine" after some time, care should be taken as TIAs are potential warning signs for stroke.
Cerebrovascular Accidents (CVAs) (a.k.a. Strokes)
CVAs are essentially the extreme version of TIAs. In a CVA, there is complete occlusion of a blood vessel, which causes liquefactive necrosis of the brain tissue that is no longer receiving blood. Risk factors for CVAs include diabetes, hypertension, heart disease, atherosclerosis, contraceptives and smoking. Sometimes the damage can be reduced by anastomoses, such as the Circle of Willis.
There are three main categories of CVAs: occlusion, embolus and haemorrhagic. CVAs caused by gradual occlusion of the arteries, such as by atherosclerosis, tend to be quite gradual, whereas those caused by emboli are more sudden. Haemorrhagic CVAs can be quite damaging due to the resultant increase in intracranial pressure.
Signs and symptoms of stroke include contralateral paresis and paraesthesia, temporary loss of speech, confusion, dizziness, sudden vision loss and sudden headache. Sometimes stroke is not immediately obvious because it happens in "silent" areas of the brain, or areas that don't control really obvious things. Other effects include flaccid paralysis which develops into spastic paralysis, or inflammation that leads to cerebral oedema.
Stroke caused by occlusion and embolus can be treated by "clot-busting" drugs such as tPA, which converts plasminogen to plasmin, which stops formation of a clot (see here for more information on coagulation pathways). Long-term anticoagulants can help prevent further strokes. However, these can be very damaging in haemorrhagic stroke, as they increase the amount of bleeding.
Other drugs that can be helpful are glucocorticoids, which reduce the amount of inflammation, and antihypertensives, especially when hypertension was one of the potential causes of the stroke. Aside from drugs, therapy can also help stroke patients recover. Therapy makes use of brain plasticity, which is basically the ability of the brain to form new connections and adapt.
Aneurysms
Aneurysms are basically parts of the vascular wall that become weak and bulge out. In the brain, these are more likely to happen at bifurcation points (i.e. ares where an artery branches out) around the Circle of Willis, as blood "hits" these points before separating into two directions. These aneurysms are known as "berry" aneurysms because of their shape, and as they enlarge they can put pressure on the optic nerve or other cranial nerves.
One of the major dangers with aneurysms is that they can rupture and spill out their blood, which is intensely irritating to the nerves. A ruptured aneurysm has a poor prognosis, with a mortality rate of over 50%. Rupture can cause vasospasm as a protective reflex (as stated above), which in turn causes increased intracranial pressure. Irritation to nerves can cause photophobia (extreme discomfort when looking at light), intense headache, confusion, slurred speech, nuchal rigidity (stiff neck due to irritation to nerves supplying neck muscles). Treatment involves surgical "clipping," or insertion of a metal ring to block of the bleeding area, but as you can probably guess by the mortality rate, this is far from perfect.
Concussions
A concussion is when there is excessive brain movement that can cause loss of consciousness or amnesia. Physical damage is usually not evident and a patient can appear to recover in 24 hours, but if multiple concussions are incurred, there is a risk of permanent brain damage. A contusion is a concussion in which there is rupture of small blood vessels, leading to bruising of brain tissue.
One risk with concussions is that sometimes the brain doesn't just endure one "knock"- in contrecoup, the brain rebounds off and hits the other side as well, leading to twice the amount of damage.
Haematomas
Haematomas are collections of blood outside of the blood vessels. They can occur anywhere in the body, but since this is a post about neurological conditions, I'm obviously going to focus on the brain. There are several different kinds of haematomas that can occur in the brain.
- Epidural haematomas occur above the dura mater when the meningeal artery tears. Patients with these haematomas are initially fine, but in around an hour they may lose consciousness.
- Subdural haematomas result from tears in veins and can occur in hours (acute) or weeks (subacute). They take longer to appear in the elderly- due to atrophy of the brain, they have more space that they can "fill" before signs of increased intracranial pressure become evident.
- Subarachnoid haemorrhage isn't actually a haematoma, because blood doesn't pool outside of the blood vessels, but I'm going to include it here anyway. This usually occurs due to aneurysm of blood vessels at the base of the brain. Blood mixes with cerebrospinal fluid and is carried off with it, which is why a haematoma does not form.
- Intracerebral haemorrhage, which also isn't a haematoma, can occur due to shearing injuries or hypertension. It can take weeks to months before signs and symptoms become evident.
Traumatic Brain Injury
Many nasty signs and symptoms can occur as a result of traumatic injury:
- Increased intracranial pressure can result, as haemolysis (destruction of blood cells) increases osmotic pressure, which draws fluid into the brain.
- Seizures
- Headache
- Cranial nerves can become impaired, leading to issues with smell, vision, hearing, swallowing and accessory breathing muscles.
- Otorrhoea and rhinorrhoea (CSF coming out of the ear and nose, respectively) can result due to a disruption in the meninges.
- Otorrhagia (blood coming out of the ear) can also occur as a result of the above.
- Fever
Glucocorticoids can be used to keep inflammation down, and prophylactic antibodies can also be used to stop bacteria from crossing the blood-brain barrier, which is likely compromised. Surgery, in which part of the skull is removed until pressure decreases, may also be warranted.
Spinal Cord Injuries
The most vulnerable parts of the body to spinal cord injuries are the neck (whiplash) and lower spine (from falling on your arse). The good news is that while nerves can't regenerate, the axons can, but this might take a long time.
Spinal cord injuries can cause spinal shock, which is a loss of neurological activity below the point of injury. This starts off as flaccid paralysis and a loss of sensation, as well as loss of autonomic control. Cervical injury, which affects the phrenic nerve (which supplies important stuff like the heart and diaphragm), can cause low blood pressure, loss of sweating, poor temperature control and difficulty emptying the bladder and bowels.
If the spinal cord injury only affects half of the spinal cord, you may get ipsilateral paralysis (as lower motor neurons affect ipsilateral organs), contralateral loss of pain and temperature sensations (as the spinothalamic nerves take sensations from contralateral organs) and ipsilateral loss of fine touch (as the dorsal column nerves take sensations from ipsilateral organs).
As you recover from spinal shock, you get some return of reflex activity, but you may develop spastic paralysis. Complications can include decubitus ulcers (i.e. bed sores, due to many patients having to remain immobile), respiratory infections and something nasty called autonomic dysreflexia.
Autonomic dysreflexia is more likely to occur if the spinal cord injury occurred higher up in the spinal cord. It is essentially the triggering of a widespread sympathetic nervous system response to a relatively mild stimulus like pain, a full bladder, full bowels etc. This widespread activation causes vasoconstriction and increased blood pressure. The increased blood pressure may be sensed by baroreceptors, which ultimately cause bradycardia via the vagus nerve (which is usually unaffected).
Sunday, November 20, 2016
Hypersensitivity II
Second post on hypersensitivity! In this post, I will cover Types II, III and IV. (To learn about type I hypersensitivity, please see my first post on the topic.)
Type II Hypersensitivity
While Type I Hypersensitivity is IgE-mediated, type II hypersensitivity is IgG mediated. IgG reacts to the cell surface antigens of the target cell, attracting complement and NK cells, which result in inflammation and tissue injury. These reactions are a bit slower than Type I reactions, taking around 30-60 minutes.
A typical type II hypersensitivity reaction occurs when an incompatible blood group is given. I've already spoken about blood groups here.
Type III Hypersensitivity
Type III hypersensitivity, like type II hypersensitivity, is mediated by IgG. In this case, however, IgG binds to soluble antigens (not membrane-bound antigens), forming an "immune complex" made up of several antigens and antibodies. Usually, immune complexes can be cleared by macrophages, but in the case of type III hypersensitivity, the immune complexes are of an "awkward size," making it hard for macrophages to eat them up. This causes activation of complement and thus inflammation, or occlusion of blood vessels due to the size of the complexes. Type III hypersensitivity reactions are even slower than type II reactions, taking around 2-6 hours.
One example of type III hypersensitivity is the Arthus reaction, which is used to test for tetanus antibodies. A subcutaneous injection of antigen is given, and if antibodies are present, localised cutaneous vasculitis (inflammation of blood vessels) occurs.
Another example is "farmer's lung," which is caused by antigens from hay dust which deposit in the walls of the alveoli. This can be distinguished from bronchial asthma (a type I hypersensitivity reaction) by the type of antibodies: bronchial asthma is IgE-mediated, whereas "farmer's lung" is IgG-mediated.
A third example is "serum sickness," which occurs after being given antiserum and can persist for weeks. A common method of producing antiserum against a toxin (from a venomous snake, for example) is to inject a horse with it (since horses are strong and can survive), take its antibodies, and give it to a patient. After the horse antibodies get rid of the toxin, there might still be some horse antibodies left over, which the body sees as foreign. Hence, you produce antibodies against the horse antibodies, causing systemic cutaneous vasculitis that can persist for weeks.
Type IV Hypersensitivity
Finally, we have type IV hypersensitivity, also known as Delayed-Type Hypersensitivity (DTH), which I've mentioned here and here. Type IV hypersensitivity is not mediated by antibodies- instead, it is mediated by TH1 cells, cytokines and macrophages. Hypersensitivity reactions to poison ivy, as well as to metals like nickel and chromate, fall into this category. Another example is the tuberculin test. Type IV hypersensitivity reactions are the slowest of all, taking around two days to occur.
Type IV hypersensitivity reactions basically proceed the same way as other cell-mediated immunity pathways: an antigen is taken up by a professional antigen presenting cell and processed and presented on MHC-II to a TH1 cell, which then, in conjunction with the pAPC, sends out a shitload of cytokines to activate macrophages and so on.
And that's it for hypersensitivity reactions! Let's round this off with a table:
Type II Hypersensitivity
While Type I Hypersensitivity is IgE-mediated, type II hypersensitivity is IgG mediated. IgG reacts to the cell surface antigens of the target cell, attracting complement and NK cells, which result in inflammation and tissue injury. These reactions are a bit slower than Type I reactions, taking around 30-60 minutes.
A typical type II hypersensitivity reaction occurs when an incompatible blood group is given. I've already spoken about blood groups here.
Type III Hypersensitivity
Type III hypersensitivity, like type II hypersensitivity, is mediated by IgG. In this case, however, IgG binds to soluble antigens (not membrane-bound antigens), forming an "immune complex" made up of several antigens and antibodies. Usually, immune complexes can be cleared by macrophages, but in the case of type III hypersensitivity, the immune complexes are of an "awkward size," making it hard for macrophages to eat them up. This causes activation of complement and thus inflammation, or occlusion of blood vessels due to the size of the complexes. Type III hypersensitivity reactions are even slower than type II reactions, taking around 2-6 hours.
One example of type III hypersensitivity is the Arthus reaction, which is used to test for tetanus antibodies. A subcutaneous injection of antigen is given, and if antibodies are present, localised cutaneous vasculitis (inflammation of blood vessels) occurs.
Another example is "farmer's lung," which is caused by antigens from hay dust which deposit in the walls of the alveoli. This can be distinguished from bronchial asthma (a type I hypersensitivity reaction) by the type of antibodies: bronchial asthma is IgE-mediated, whereas "farmer's lung" is IgG-mediated.
A third example is "serum sickness," which occurs after being given antiserum and can persist for weeks. A common method of producing antiserum against a toxin (from a venomous snake, for example) is to inject a horse with it (since horses are strong and can survive), take its antibodies, and give it to a patient. After the horse antibodies get rid of the toxin, there might still be some horse antibodies left over, which the body sees as foreign. Hence, you produce antibodies against the horse antibodies, causing systemic cutaneous vasculitis that can persist for weeks.
Type IV Hypersensitivity
Finally, we have type IV hypersensitivity, also known as Delayed-Type Hypersensitivity (DTH), which I've mentioned here and here. Type IV hypersensitivity is not mediated by antibodies- instead, it is mediated by TH1 cells, cytokines and macrophages. Hypersensitivity reactions to poison ivy, as well as to metals like nickel and chromate, fall into this category. Another example is the tuberculin test. Type IV hypersensitivity reactions are the slowest of all, taking around two days to occur.
Type IV hypersensitivity reactions basically proceed the same way as other cell-mediated immunity pathways: an antigen is taken up by a professional antigen presenting cell and processed and presented on MHC-II to a TH1 cell, which then, in conjunction with the pAPC, sends out a shitload of cytokines to activate macrophages and so on.
And that's it for hypersensitivity reactions! Let's round this off with a table:
| Type | Mediated by | Length of time | Examples |
| Type I | IgE on mast cells | ~20min | Allergic rhinitis Bronchial asthma Food allergies Skin prick test |
| Type II | IgG | 30-60min | Blood transfusion reactions |
| Type III | IgG (Ab-Ag immune complexes) | 2-6hr | Serum sickness "Farmer's lung" Arthus reaction (test for tetanus Abs) |
| Type IV | TH1, macrophages, cytokines etc. | ~2 days | Tuberculin test Metal allergies Poison ivy hypersensitivity |
Brain- Protection and Injury
Now for a new topic- the brain! Unlike the other topics covered in this course so far, I haven't actually written very much on the brain (in fact pretty much all I've written is in one other post, and it doesn't say very much).
Cerebral Blood Supply
One of the few things that I did mention in my other post (albeit only briefly) is the cerebral blood supply. I've also touched on this in a Cardiovascular System post for PHYL2001. The brain is pretty dependent on good blood flow, as it requires oxygen and glucose for metabolism, accepting no other substitutes. Blood vessels supplying the brain do not have receptors for adrenaline or noradrenaline (as these would cause the blood vessels to constrict, which you never want happening to the brain), but instead respond to local cues such as autoregulation and local mediators (see here for more details). The base of the brain has a circular formation of arteries called the Circle of Willis. This circular formation provides anastomoses, which provide alternate pathways in the case of blockages.
Blood vessels supplying the brain have very tight endothelial junctions that prevent nasty stuff from getting through. Astrocytes help out with this too, forming a structure called the Blood Brain Barrier (BBB). While lipid-soluble molecules such as alcohol and some anaesthetics can cross easily, larger and/or charged molecules cannot.
The BBB is not fully formed at birth, which can cause some issues with regards to giving the right dosages of medications and so forth. Also, a condition called kernicterus can occur when bilirubin crosses the BBB. This is a problem shortly after birth when the baby gets rid of their old foetal haemoglobin in order to get new haemoglobin- red blood cells are destroyed, causing an increase in bilirubin that may cross the BBB.
The BBB can also be breached due to other causes, such as hypertension, infection and trauma. One significant effect of BBB damage is the entry of white blood cells. The brain normally has its own supply of immune cells, separate to immune cells of the rest of the body. Hence, immune cells from the rest of the body may be unable to recognise antigens in the brain, and essentially begin to wage war on the brain.
Cerebrospinal Fluid
Another important fluid in the brain is cerebrospinal fluid (CSF). It is formed in the choroid plexus, which is located in the third and fourth ventricles. CSF circulates through the ventricles and subarachnoid space. Arachnoid villi, which "poke into" venous sinuses, are the point at which CSF can enter the blood and essentially get washed out of the brain. CSF flow is always one-way: CSF flows into the blood, but not back. In contrast to blood, CSF contains hardly any protein- protein in the CSF is generally a marker of some kind of disease.
So what does CSF do? CSF helps to protect the brain. It also helps it to float around a bit so that it's not smashed up against the top of the spine. As I just alluded to, CSF gets washed out in the blood, so CSF is also a medium through which waste products can be removed. If CSF cannot be drained for whatever reason, hydrocephalus, or "water brain," can result. This causes increased intracranial pressure (ICP), which I'm going to talk about now.
Increased Intracranial Pressure (ICP)
Increased intracranial pressure, as the name suggests, is basically increased pressure within the skull. This can be caused by increased CSF (as mentioned earlier), tumours, trauma, haemorrhage, infection and so on. As there is only so much room within the skull, the pressure presses against the blood vessels, meaning that there is less blood flow. Build-up of CO2 causes vasodilation (for more information about this, see here), which increases volume, which increases pressure, and the vicious cycle continues. Signs of ICP include lethargy, headache, vomiting and papilledema (a "fuzzy" kind of area at the back of the eye as pressure pushes against the nerves).
ICP can affect eye movement, as the pressure can press on cranial nerve III (the oculomotor nerve). This causes ptosis, which is a half-closed eyelid, and an unresponsive, dilated pupil on the same side (ipsilateral) to the pressure. (Side note: "ipsilateral" = same side, "contralateral" = opposite side.) This latter effect is due to impairment of the parasympathetic nervous system, which generally constricts pupils when you want to rest.
Another effect of ICP is that parts of the brain can herniate, or push into one another. In cingulate hernias, one part of the brain pushes into the hemisphere at the level of the cingulate gyrus. Uncal hernias occur where the cerebrum meets the cerebellum, and cerebellar/tonsillar hernias occur in the cerebellum. Uncal and cerebellar hernias are particularly dangerous as they can compress the brainstem, which deals with a lot of vital functions such as respiration and heart rate.
Finally, ICP can also affect blood pressure. Cerebral ischaemia signals to vasomotor centres, in what is called "Cushing's reflex" (which has nothing to do with Cushing's syndrome, aside from that they were both discovered by the same guy). This causes systemic vasoconstriction, increasing the blood pressure. The increased blood pressure is picked up by baroreceptors, which slow the heart rate. At the same time, the increased blood pressure causes CO2 to reach the lungs faster, and when this is detected, respiration slows. Despite all of this, the increased blood pressure does help ischaemia to improve, to the point where signals to the vasomotor centres cease and the blood pressure drops again. This causes ischaemia to recur, causing the cycle to start all over again. The overall effect is a rise in blood pressure. This rise is greater in systolic than in diastolic blood pressure, so pulse pressure also increases.
Neurological Dysfunction
Aside from the more general problems that I've spoken about earlier, such as increased ICP, some types of neurological dysfunction have more local (focal) effects depending on the part that is damaged.
Lesion locations
This is going to be a bit all over the place, but bear with me.
The first little anatomy tidbit that I'm going to tell you about is the tentorium cerebelli. It's like an extension of the dura mater that separates the cerebrum and cerebellum. Lesions above the tentorium cerebelli are said to be supratentorial, and tend to cause a specific problem in a discrete area of the body. Infratentorial lesions (below the tentorium cerebelli), however, tend to cause more widespread impairment. Respiratory and circulatory function may be affected, as the brainstem lies in this area.
Next up, the hemisphere that is affected may cause different issues. I'm sure you've heard the whole "left brain" vs. "right brain" thing before, so I won't go into it any more (especially since the professor didn't say any more about it).
The area of the brain that gets affected may also affect whether consciousness is retained or not. If the cortex is affected, consciousness won't be lost unless an extensive area is affected. However, if the Reticular Activating System (RAS) in the medulla is affected, even if the lesion is small, you could get knocked out right away.
Motor dysfunction
More vague-ish anatomy lessons!
Upper motor neurons of the brain can be divided into two groups: pyramidal and extrapyramidal. Pyramidal tracts, such as lateral corticospinal neurons, cross to the other side of the body at the medulla, and are responsible for voluntary actions. Extrapyramidal tracts, such as ventral corticospinal neurons, cross to the other side of the body at the exit level from the spinal cord, and are generally responsible for postural reflexes. As both types of tracts cross from one side to the other, effects in these neurons cause contralateral (i.e. on the other side to the injury) spastic paralysis. (Spastic paralysis is basically when your muscles can't relax.)
Lower motor neurons are the last neurons in the "chain" that deliver a message to the muscle cell. Hence, not all of them are really "low down"- cranial nerves that communicate directly to muscle cells are also called lower motor neurons. These do not cross over, and thus they cause ipsilateral flaccid paralysis (flaccid paralysis being when your muscles can't contract).
Sensory deficits
Just like with upper motor neurons, sensory nerves also cross over. Spinothalamic nerves (that run from the spine to the thalamus) are responsible for crude touch, pain and temperature, and they cross over pretty much as soon as they enter the spinal cord. Hence, damage to the spinothalamic nerves tend to affect the side contralateral to the injury. Dorsal column nerves deal with fine touch, pressure and stretch and don't cross over until they get to the medulla, so damage to these nerves causes problems on the ipsilateral side.
Visual defects
Vision, which is mainly controlled by cranial nerve II, is kinda funky. Essentially, each eye has two nerves coming out of it. Nerves of the inner retinas, which deal with peripheral vision, cross over at the optic chiasm, so a lesion in the middle of the optic chiasm will get rid of your peripheral vision. Nerves of the outer retinas do not cross over. If there is a lesion past the optic chiasm, hemaniopia, or loss of vision of half of the visual field, will result. This is because you've essentially cut the nerve for the ipsilateral outer retina and the contralateral inner retina.
Aphasias
Aphasias are the inability to express or understand language. They come in three main types. Expressive (motor) aphasia is caused by a problem in Broca's area, receptive aphasia is caused by a problem in Wernicke's area, and global aphasia is caused by a problem in both Broca's and Wernicke's area, as well as the connecting fibres between them.
There are, of course, many other language problems that a person can develop. This isn't a speech pathology course, so I'm not going to go into all of them- in fact, I'm only really going to touch the very tip of the iceberg. Dysarthria is a problem with verbal articulation caused by motor injury (the person can't control the muscles required for speech). Agnosia is a loss of verbal recognition, where a patient can recognise an object but can't tell you what it is (i.e. they can't match the name with the object, just like how sometimes people have trouble matching names to faces).
Cerebral Blood Supply
One of the few things that I did mention in my other post (albeit only briefly) is the cerebral blood supply. I've also touched on this in a Cardiovascular System post for PHYL2001. The brain is pretty dependent on good blood flow, as it requires oxygen and glucose for metabolism, accepting no other substitutes. Blood vessels supplying the brain do not have receptors for adrenaline or noradrenaline (as these would cause the blood vessels to constrict, which you never want happening to the brain), but instead respond to local cues such as autoregulation and local mediators (see here for more details). The base of the brain has a circular formation of arteries called the Circle of Willis. This circular formation provides anastomoses, which provide alternate pathways in the case of blockages.
Blood vessels supplying the brain have very tight endothelial junctions that prevent nasty stuff from getting through. Astrocytes help out with this too, forming a structure called the Blood Brain Barrier (BBB). While lipid-soluble molecules such as alcohol and some anaesthetics can cross easily, larger and/or charged molecules cannot.
The BBB is not fully formed at birth, which can cause some issues with regards to giving the right dosages of medications and so forth. Also, a condition called kernicterus can occur when bilirubin crosses the BBB. This is a problem shortly after birth when the baby gets rid of their old foetal haemoglobin in order to get new haemoglobin- red blood cells are destroyed, causing an increase in bilirubin that may cross the BBB.
The BBB can also be breached due to other causes, such as hypertension, infection and trauma. One significant effect of BBB damage is the entry of white blood cells. The brain normally has its own supply of immune cells, separate to immune cells of the rest of the body. Hence, immune cells from the rest of the body may be unable to recognise antigens in the brain, and essentially begin to wage war on the brain.
Cerebrospinal Fluid
Another important fluid in the brain is cerebrospinal fluid (CSF). It is formed in the choroid plexus, which is located in the third and fourth ventricles. CSF circulates through the ventricles and subarachnoid space. Arachnoid villi, which "poke into" venous sinuses, are the point at which CSF can enter the blood and essentially get washed out of the brain. CSF flow is always one-way: CSF flows into the blood, but not back. In contrast to blood, CSF contains hardly any protein- protein in the CSF is generally a marker of some kind of disease.
So what does CSF do? CSF helps to protect the brain. It also helps it to float around a bit so that it's not smashed up against the top of the spine. As I just alluded to, CSF gets washed out in the blood, so CSF is also a medium through which waste products can be removed. If CSF cannot be drained for whatever reason, hydrocephalus, or "water brain," can result. This causes increased intracranial pressure (ICP), which I'm going to talk about now.
Increased Intracranial Pressure (ICP)
Increased intracranial pressure, as the name suggests, is basically increased pressure within the skull. This can be caused by increased CSF (as mentioned earlier), tumours, trauma, haemorrhage, infection and so on. As there is only so much room within the skull, the pressure presses against the blood vessels, meaning that there is less blood flow. Build-up of CO2 causes vasodilation (for more information about this, see here), which increases volume, which increases pressure, and the vicious cycle continues. Signs of ICP include lethargy, headache, vomiting and papilledema (a "fuzzy" kind of area at the back of the eye as pressure pushes against the nerves).
ICP can affect eye movement, as the pressure can press on cranial nerve III (the oculomotor nerve). This causes ptosis, which is a half-closed eyelid, and an unresponsive, dilated pupil on the same side (ipsilateral) to the pressure. (Side note: "ipsilateral" = same side, "contralateral" = opposite side.) This latter effect is due to impairment of the parasympathetic nervous system, which generally constricts pupils when you want to rest.
Another effect of ICP is that parts of the brain can herniate, or push into one another. In cingulate hernias, one part of the brain pushes into the hemisphere at the level of the cingulate gyrus. Uncal hernias occur where the cerebrum meets the cerebellum, and cerebellar/tonsillar hernias occur in the cerebellum. Uncal and cerebellar hernias are particularly dangerous as they can compress the brainstem, which deals with a lot of vital functions such as respiration and heart rate.
Finally, ICP can also affect blood pressure. Cerebral ischaemia signals to vasomotor centres, in what is called "Cushing's reflex" (which has nothing to do with Cushing's syndrome, aside from that they were both discovered by the same guy). This causes systemic vasoconstriction, increasing the blood pressure. The increased blood pressure is picked up by baroreceptors, which slow the heart rate. At the same time, the increased blood pressure causes CO2 to reach the lungs faster, and when this is detected, respiration slows. Despite all of this, the increased blood pressure does help ischaemia to improve, to the point where signals to the vasomotor centres cease and the blood pressure drops again. This causes ischaemia to recur, causing the cycle to start all over again. The overall effect is a rise in blood pressure. This rise is greater in systolic than in diastolic blood pressure, so pulse pressure also increases.
Neurological Dysfunction
Aside from the more general problems that I've spoken about earlier, such as increased ICP, some types of neurological dysfunction have more local (focal) effects depending on the part that is damaged.
Lesion locations
This is going to be a bit all over the place, but bear with me.
The first little anatomy tidbit that I'm going to tell you about is the tentorium cerebelli. It's like an extension of the dura mater that separates the cerebrum and cerebellum. Lesions above the tentorium cerebelli are said to be supratentorial, and tend to cause a specific problem in a discrete area of the body. Infratentorial lesions (below the tentorium cerebelli), however, tend to cause more widespread impairment. Respiratory and circulatory function may be affected, as the brainstem lies in this area.
Next up, the hemisphere that is affected may cause different issues. I'm sure you've heard the whole "left brain" vs. "right brain" thing before, so I won't go into it any more (especially since the professor didn't say any more about it).
The area of the brain that gets affected may also affect whether consciousness is retained or not. If the cortex is affected, consciousness won't be lost unless an extensive area is affected. However, if the Reticular Activating System (RAS) in the medulla is affected, even if the lesion is small, you could get knocked out right away.
Motor dysfunction
More vague-ish anatomy lessons!
Upper motor neurons of the brain can be divided into two groups: pyramidal and extrapyramidal. Pyramidal tracts, such as lateral corticospinal neurons, cross to the other side of the body at the medulla, and are responsible for voluntary actions. Extrapyramidal tracts, such as ventral corticospinal neurons, cross to the other side of the body at the exit level from the spinal cord, and are generally responsible for postural reflexes. As both types of tracts cross from one side to the other, effects in these neurons cause contralateral (i.e. on the other side to the injury) spastic paralysis. (Spastic paralysis is basically when your muscles can't relax.)
Lower motor neurons are the last neurons in the "chain" that deliver a message to the muscle cell. Hence, not all of them are really "low down"- cranial nerves that communicate directly to muscle cells are also called lower motor neurons. These do not cross over, and thus they cause ipsilateral flaccid paralysis (flaccid paralysis being when your muscles can't contract).
Sensory deficits
Just like with upper motor neurons, sensory nerves also cross over. Spinothalamic nerves (that run from the spine to the thalamus) are responsible for crude touch, pain and temperature, and they cross over pretty much as soon as they enter the spinal cord. Hence, damage to the spinothalamic nerves tend to affect the side contralateral to the injury. Dorsal column nerves deal with fine touch, pressure and stretch and don't cross over until they get to the medulla, so damage to these nerves causes problems on the ipsilateral side.
Visual defects
Vision, which is mainly controlled by cranial nerve II, is kinda funky. Essentially, each eye has two nerves coming out of it. Nerves of the inner retinas, which deal with peripheral vision, cross over at the optic chiasm, so a lesion in the middle of the optic chiasm will get rid of your peripheral vision. Nerves of the outer retinas do not cross over. If there is a lesion past the optic chiasm, hemaniopia, or loss of vision of half of the visual field, will result. This is because you've essentially cut the nerve for the ipsilateral outer retina and the contralateral inner retina.
Aphasias
Aphasias are the inability to express or understand language. They come in three main types. Expressive (motor) aphasia is caused by a problem in Broca's area, receptive aphasia is caused by a problem in Wernicke's area, and global aphasia is caused by a problem in both Broca's and Wernicke's area, as well as the connecting fibres between them.
There are, of course, many other language problems that a person can develop. This isn't a speech pathology course, so I'm not going to go into all of them- in fact, I'm only really going to touch the very tip of the iceberg. Dysarthria is a problem with verbal articulation caused by motor injury (the person can't control the muscles required for speech). Agnosia is a loss of verbal recognition, where a patient can recognise an object but can't tell you what it is (i.e. they can't match the name with the object, just like how sometimes people have trouble matching names to faces).
Thursday, November 17, 2016
Hypersensitivity I
This is a topic that I've spoken about before, notably here and here. But now we get to go over it again! Yay!
Hypersensitivity is basically when your immune system is oversensitive and freaks out at random shit that most would consider to be harmless. (Essentially me in a nutshell- my immune system is probably the only thing about me that generally isn't hypersensitive. At least, as far as I know, it isn't hypersensitive.)
In this post I'm going to talk about Type I hypersensitivity, which is analogous to type B immediate drug reactions. It is also known as IgE-mediated hypersensitivity, and you'll see why that is in a moment. Atopy is the tendency of an individual to develop this type of hypersensitivity.
Sensitisation and Activation
Believe it or not, people with allergies generally aren't born immediately allergic to stuff. They have to be sensitised first.
In the first exposure to an allergen, IgM is produced, just like in every other immune response. Over the course of the immune response, though, TH2 cells are activated and produce IL-4 and IL-13. These cytokines stimulate the class switching of B cells to produce IgE. IgE can then bind to FcεRI (Fc-epsilon-receptor I) on mast cells, where they sit there and wait for the next exposure to the allergen.
In subsequent exposures to the allergen, IgE bound to mast cells cross-links, causing the mast cell to degranulate, or release its granules. The first wave of stuff to be released are granules containing vasoactive amines such as histamine, which cause vasodilation and itchiness. Chemotactic factors that attract neutrophils and eosinophils are also released at this stage. The next wave consists of lipid mediators such as prostaglandins and leukotrienes, which add to the vasodilation. The third wave consists of cytokines, such as IL-3 and IL-5, which induce more eosinophil activation, and IL-4 and IL-13, which induce greater activation of TH2 cells. A chemokine called MIP-1α, which attracts neutrophils, is also released at this stage.
Fun fact of the day: some allergens (essentially antigens that cause allergic responses) are also enzymes. For example, phospholipase A2, which I've spoken about here and here, is found in bee venom. Cysteine protease, also known as the Der p 1 enzyme (herp derp!) is found in the faecal pellets of house dust mites. Der p 1/cysteine protease can cleave occludin, which is a protein found in tight junctions, allowing it to enter the mucosa. In the mucosa, it meets dendritic cells, which go off and do their whole antigen presenting thing, which ultimately leads to T-cell activation, B-cell activation and BOOM the poor person has now been sensitised to dust.
Allergic Rhinitis
Allergic rhinitis is an immune system disease in which the body responds to allergens in the upper respiratory tract. Some of the symptoms of this include excess mucus secretion, which leads to coughing, sneezing and difficulty breathing. There may also be some irritation due to histamine, which can be treated via antihistamines.
Bronchial Asthma
In contrast to allergic rhinitis, allergens in bronchial asthma tend to affect the lower respiratory tract. People with this condition essentially have chronic bronchial inflammation, causing repeated asthma attacks and possible tissue destruction in the alveoli further down the track. The culprits here are eosinophils, cytokines released by TH2 cells and LTC4. LTC4 is a leukotriene released from mast cells which causes bronchoconstriction.
There are several medications that can help people with asthma. Cromolyn is a medication that can stabilise mast cells, preventing release of vasoconstrictive leukotrienes. Corticosteroids can halt production of inflammatory cytokines. Epinephrine/adrenaline can prevent bronchoconstriction.
Food Allergies
Food allergies are, well, allergies caused by food. They can cause vomiting, diarrhoea, skin conditions and, in really bad cases, anaphylaxis. Skin conditions that can be caused by food allergies include urticaria (hives), which is an acute condition that can be treated with antihistamines, and atopic eczema, which is a chronic condition that requires more aggressive treatment with corticosteroids. Anaphylaxis, as I've mentioned before, is basically when the histamine and other inflammatory mediators go overboard, causing blood pressure to drop and airways to constrict, ultimately leading to death if medical attention isn't sought quickly. This can be treated via epinephrine, which is often given via an automatic injector like the EpiPen.
Skin Prick Test
If type I hypersensitivity is suspected, a skin prick test can be done to make a more definitive diagnosis. In this test, a low dose of an antigen is delivered subcutaneously. If the patient is allergic, then around 20 minutes later they will develop a "wheal and flare." The "wheal" is a small swelling, and a "flare" is erythema (redness) surrounding the wheal.
Hypersensitivity is basically when your immune system is oversensitive and freaks out at random shit that most would consider to be harmless. (Essentially me in a nutshell- my immune system is probably the only thing about me that generally isn't hypersensitive. At least, as far as I know, it isn't hypersensitive.)
In this post I'm going to talk about Type I hypersensitivity, which is analogous to type B immediate drug reactions. It is also known as IgE-mediated hypersensitivity, and you'll see why that is in a moment. Atopy is the tendency of an individual to develop this type of hypersensitivity.
Sensitisation and Activation
Believe it or not, people with allergies generally aren't born immediately allergic to stuff. They have to be sensitised first.
In the first exposure to an allergen, IgM is produced, just like in every other immune response. Over the course of the immune response, though, TH2 cells are activated and produce IL-4 and IL-13. These cytokines stimulate the class switching of B cells to produce IgE. IgE can then bind to FcεRI (Fc-epsilon-receptor I) on mast cells, where they sit there and wait for the next exposure to the allergen.
In subsequent exposures to the allergen, IgE bound to mast cells cross-links, causing the mast cell to degranulate, or release its granules. The first wave of stuff to be released are granules containing vasoactive amines such as histamine, which cause vasodilation and itchiness. Chemotactic factors that attract neutrophils and eosinophils are also released at this stage. The next wave consists of lipid mediators such as prostaglandins and leukotrienes, which add to the vasodilation. The third wave consists of cytokines, such as IL-3 and IL-5, which induce more eosinophil activation, and IL-4 and IL-13, which induce greater activation of TH2 cells. A chemokine called MIP-1α, which attracts neutrophils, is also released at this stage.
Fun fact of the day: some allergens (essentially antigens that cause allergic responses) are also enzymes. For example, phospholipase A2, which I've spoken about here and here, is found in bee venom. Cysteine protease, also known as the Der p 1 enzyme (herp derp!) is found in the faecal pellets of house dust mites. Der p 1/cysteine protease can cleave occludin, which is a protein found in tight junctions, allowing it to enter the mucosa. In the mucosa, it meets dendritic cells, which go off and do their whole antigen presenting thing, which ultimately leads to T-cell activation, B-cell activation and BOOM the poor person has now been sensitised to dust.
Allergic Rhinitis
Allergic rhinitis is an immune system disease in which the body responds to allergens in the upper respiratory tract. Some of the symptoms of this include excess mucus secretion, which leads to coughing, sneezing and difficulty breathing. There may also be some irritation due to histamine, which can be treated via antihistamines.
Bronchial Asthma
In contrast to allergic rhinitis, allergens in bronchial asthma tend to affect the lower respiratory tract. People with this condition essentially have chronic bronchial inflammation, causing repeated asthma attacks and possible tissue destruction in the alveoli further down the track. The culprits here are eosinophils, cytokines released by TH2 cells and LTC4. LTC4 is a leukotriene released from mast cells which causes bronchoconstriction.
There are several medications that can help people with asthma. Cromolyn is a medication that can stabilise mast cells, preventing release of vasoconstrictive leukotrienes. Corticosteroids can halt production of inflammatory cytokines. Epinephrine/adrenaline can prevent bronchoconstriction.
Food Allergies
Food allergies are, well, allergies caused by food. They can cause vomiting, diarrhoea, skin conditions and, in really bad cases, anaphylaxis. Skin conditions that can be caused by food allergies include urticaria (hives), which is an acute condition that can be treated with antihistamines, and atopic eczema, which is a chronic condition that requires more aggressive treatment with corticosteroids. Anaphylaxis, as I've mentioned before, is basically when the histamine and other inflammatory mediators go overboard, causing blood pressure to drop and airways to constrict, ultimately leading to death if medical attention isn't sought quickly. This can be treated via epinephrine, which is often given via an automatic injector like the EpiPen.
Skin Prick Test
If type I hypersensitivity is suspected, a skin prick test can be done to make a more definitive diagnosis. In this test, a low dose of an antigen is delivered subcutaneously. If the patient is allergic, then around 20 minutes later they will develop a "wheal and flare." The "wheal" is a small swelling, and a "flare" is erythema (redness) surrounding the wheal.
Tuesday, November 15, 2016
Renal Pathophysiology
Now that we're done talking about poo, let's talk about pee! There's not too much you need to know about this for this unit though, which is why this is going to be the only post about it for a while.
Just in case you don't remember anything about renal function:
Describe some of the factors that could promote a urinary tract infection (UTI)
Urinary tract infections are more common in women due to the proximity of the anus and urethra. Other risk factors for UTIs include uncontrolled diabetes, as high glucose levels "feed" the bacteria lurking down there, and anything that might obstruct the flow of urine (such as kidney stones).
Distinguish between cystitis and pyelonephritis. Describe their symptoms. What are cell casts?
Cystitis is infection of the bladder, whereas pyelonephritis is infection of the kidneys themselves. Pyelonephritis is a lot rarer, and usually arises from a pathogen ascending up the ureters, but sometimes the pathogen may be blood-borne. Cystitis and pyelonephritis are both types of UTIs and share many of the same symptoms, such as dysuria (painful urination), urgency, bacteriuria (bacteria in the urine), haematuria (blood in the urine) and other systemic signs such as fever and leukocytosis.
There are, however, a couple of symptoms that are unique to pyelonephritis. One of these is flank pain, or pain in the area of the kidney. Another symptom is cell casts. Cell casts occur when inflammation increases the leakiness of the blood vessels, causing protein to leak into the urine. Protein in the urine causes the formation of jelly-like "casts" which may also contain cells.
How does "strep throat" lead to glomerulonephritis?
Streptococci are pretty nasty. I've already mentioned before how untreated streptococcal infections can lead to rheumatic fever and rheumatic heart disease. Unfortunately, their ability to cause pain and suffering doesn't end there- they are also the most common cause of glomerulonephritis, or inflammation of the glomeruli! (Read here if you don't remember what glomeruli are.)
Just like with rheumatic fever, acute poststreptococcal glomerulonephritis (APSGN) develops around two weeks after a streptococcus infection, such as strep throat. It occurs due to antibody-streptococcus complexes lodging in the small glomerular capillaries. This activates complement, a key molecule in the immune system, as described several times before. This, in turn, leads to inflammation, increased permeability of the glomerular vessels, leakage of protein and red blood cells into the filtrate, and, if severe, a decrease in GFR as the kidneys overcompensate for the dilated blood vessels by inducing vasoconstriction.
Describe the symptoms of APSGN. How does altered renal function account for these symptoms?
Signs and symptoms include flank pain (like in pyelonephritis), the presence of protein, blood or red blood cell casts in the urine (leading to "smoky"-coloured urine) and facial oedema due to the reduction of plasma proteins which would normally assist in holding fluid in the blood. Just like with rheumatic fever, there may be an increase in antibodies against streptococcus infection, such as ASO (antistreptolysin O) and ASK.
In severe cases of APSGN, there may be vascular congestion, due to all of those antibody-strep complexes clogging up the blood vessels. This causes an increase in serum urea (which can be measured via BUN- blood urea nitrogen) and creatinine, which would normally be eliminated via the urine. On the other hand, there is a decrease in serum complement, as that's all down in the kidneys fighting the infection. Acidosis, due to reduced elimination of acidic compounds, and oliguria (reduced production of urine) also result due to congestion. At the same time, the reduced blood flow through the kidney is detected by nephrons in the juxtaglomerular apparatus, which produce renin and kick off the RAAS pathway, which ultimately results in an increase in blood pressure- not what you want when you have vascular congestion!
Treatment of APSGN, aside from trying to treat the strep infection early, is mainly symptomatic. Sodium, fluid and protein have to be restricted, as these are no longer being eliminated as efficiently as before. Glucocorticoids may be needed to keep inflammation down, and antihypertensives may be required to counteract the increased blood pressure from RAAS activation.
Describe the two most common types of renal stones, their source and their solubility in acids or bases.
Renal stones are also known as kidney stones, nephrolithiasis or urolithiasis. They form around tubular debris, which is basically debris from broken down luminal epithelial cells in the nephron. Their main causes are excessive amounts of insoluble salts and insufficient fluid intake.
The most common types of stones are calcium salts. One of these is calcium oxalate. Usually dietary calcium keeps oxalate in the stool, but in the case of diseases such as IBD, where fat absorption is impaired, calcium might bind to the fat instead, allowing oxalate to become taken up by the body. Another common calcium salt is phosphate, which is less soluble in alkaline (basic) urine, presumably because less phosphate will be ionised at basic pH.
Another common type of stone is derived from uric acid. Uric acid stones may result from gout, which is a problem with purine metabolism, or from cancer chemotherapy. In contrast to calcium phosphate stones, uric acid stones are less soluble in acidic environments, presumably because less uric acid will be ionised at acidic pH (uric acid will hold onto its protons more readily than the stuff in the environment around it).
Describe the signs and common treatments of renal stones.
As you probably know, kidney stones come with a lot of pain. Specifically, this pain is flank pain, and is colicky (comes and goes with the contractions of the ureters). Treatments generally involve getting rid of the stones by lithotripsy (using shockwaves to break up the stone) etc. Increasing the fluid intake can also help. Potassium citrate can also help treat kidney stones, as the citrate can more reaily bind to calcium, allowing the more soluble calcium citrate to be washed out of the kidney. Changing urine pH to make the stone more or less soluble (so acidifying the urine in the case of a calcium phosphate stone or alkalising it in the case of a uric acid stone) is another possible solution.
Give examples of potential causes of acute renal failure. What are the two most common conditions leading to chronic renal failure?
Renal failure is essentially when the kidneys stop working. Acute causes include glomerulonephritis, circulatory shock (not enough blood getting to the kidneys), burns (broken down red blood cells clog up the vessels) and nephrotoxins such as excessive amounts of NSAIDs (inhibit prostaglandins, which usually cause vasodilation). The most common chronic conditions that cause renal failure are diabetes and hypertension.
Describe the symptoms and principles of treatment of end stage renal failure.
To talk about end stage renal failure, I'm first going to talk about what the different stages are.
In the first stage, there is a decreased reserve. Normally, we have many more nephrons than we actually need. If some of these fail, the others can compensate, but that means that you still have an overall reduction in the number of working nephrons.
In the second stage, renal insufficiency, so many nephrons have stopped working that the kidney isn't quite keeping up with everything that it needs to do. This causes a decrease in GFR (glomerular filtration rate), which in turn leads to increased serum creatinine and urea. The increased urea (as measured by blood urea nitrogen, as mentioned earlier) can affect neurons, including those that control appetite, so anorexia (loss of appetite) is another symptom that may occur. The decrease in GFR also causes an increase in renin production, activating the RAAS pathway and causing an increase in blood pressure. Although many nephrons aren't working, the nephrons that are working have a limited ability to reabsorb fluids, so polyuria (excess urine production) is another symptom. Finally, erythropoietin (EPO) and vitamin D3, which are normally either produced or activated by the kidneys, cease to do their job, so anaemia and/or osteoporosis may result.
Finally, we reach the end stage of renal failure, where there's hardly any working nephrons. Symptoms include oliguria (reduced urine production), hyperkalemia (high potassium), hypocalcemia, acidosis and azotemia (increased levels of nitrogen-containing compounds, such as urea- high urea can be specifically referred to as uremia) due to the kidneys not being able to get rid of or reabsorb the stuff that it needs to.
Treatment for end stage renal failure is, unfortunately, not curative. The first step is to control the diet by making sure not to take in too much of the stuff that your body can no longer get rid of effectively, for example phosphate, protein and fluid. Medications can be taken to help with anaemia (such as injectable EPO) and hypertension. Transplants may also be considered, though this is no permanent solution: most transplanted kidneys only last around 10 years or so before the immune system destroys it.
Many patients may have to undergo dialysis, which is where the blood is removed, filtered through a machine and then returned to the body. There are two main types of dialysis. In haemodialysis, patients have to come to the hospital several times a week for hours at a time. Blood is removed from their arm, filtered through a machine and returned. Peritoneal dialysis, which can be done overnight at home, fills the peritoneal cavity with dialysate (fluid used for dialysis), which is drained by another tube. The dialysate in both cases contains several osmotically active particles so as not to cause too much fluid to move into the body via osmosis. The fluid always contains glucose so that the body can maintain its supply of glucose.
And that's all you need to know about kidneys. Yay!
Just in case you don't remember anything about renal function:
Describe some of the factors that could promote a urinary tract infection (UTI)
Urinary tract infections are more common in women due to the proximity of the anus and urethra. Other risk factors for UTIs include uncontrolled diabetes, as high glucose levels "feed" the bacteria lurking down there, and anything that might obstruct the flow of urine (such as kidney stones).
Distinguish between cystitis and pyelonephritis. Describe their symptoms. What are cell casts?
Cystitis is infection of the bladder, whereas pyelonephritis is infection of the kidneys themselves. Pyelonephritis is a lot rarer, and usually arises from a pathogen ascending up the ureters, but sometimes the pathogen may be blood-borne. Cystitis and pyelonephritis are both types of UTIs and share many of the same symptoms, such as dysuria (painful urination), urgency, bacteriuria (bacteria in the urine), haematuria (blood in the urine) and other systemic signs such as fever and leukocytosis.
There are, however, a couple of symptoms that are unique to pyelonephritis. One of these is flank pain, or pain in the area of the kidney. Another symptom is cell casts. Cell casts occur when inflammation increases the leakiness of the blood vessels, causing protein to leak into the urine. Protein in the urine causes the formation of jelly-like "casts" which may also contain cells.
How does "strep throat" lead to glomerulonephritis?
Streptococci are pretty nasty. I've already mentioned before how untreated streptococcal infections can lead to rheumatic fever and rheumatic heart disease. Unfortunately, their ability to cause pain and suffering doesn't end there- they are also the most common cause of glomerulonephritis, or inflammation of the glomeruli! (Read here if you don't remember what glomeruli are.)
Just like with rheumatic fever, acute poststreptococcal glomerulonephritis (APSGN) develops around two weeks after a streptococcus infection, such as strep throat. It occurs due to antibody-streptococcus complexes lodging in the small glomerular capillaries. This activates complement, a key molecule in the immune system, as described several times before. This, in turn, leads to inflammation, increased permeability of the glomerular vessels, leakage of protein and red blood cells into the filtrate, and, if severe, a decrease in GFR as the kidneys overcompensate for the dilated blood vessels by inducing vasoconstriction.
Describe the symptoms of APSGN. How does altered renal function account for these symptoms?
Signs and symptoms include flank pain (like in pyelonephritis), the presence of protein, blood or red blood cell casts in the urine (leading to "smoky"-coloured urine) and facial oedema due to the reduction of plasma proteins which would normally assist in holding fluid in the blood. Just like with rheumatic fever, there may be an increase in antibodies against streptococcus infection, such as ASO (antistreptolysin O) and ASK.
In severe cases of APSGN, there may be vascular congestion, due to all of those antibody-strep complexes clogging up the blood vessels. This causes an increase in serum urea (which can be measured via BUN- blood urea nitrogen) and creatinine, which would normally be eliminated via the urine. On the other hand, there is a decrease in serum complement, as that's all down in the kidneys fighting the infection. Acidosis, due to reduced elimination of acidic compounds, and oliguria (reduced production of urine) also result due to congestion. At the same time, the reduced blood flow through the kidney is detected by nephrons in the juxtaglomerular apparatus, which produce renin and kick off the RAAS pathway, which ultimately results in an increase in blood pressure- not what you want when you have vascular congestion!
Treatment of APSGN, aside from trying to treat the strep infection early, is mainly symptomatic. Sodium, fluid and protein have to be restricted, as these are no longer being eliminated as efficiently as before. Glucocorticoids may be needed to keep inflammation down, and antihypertensives may be required to counteract the increased blood pressure from RAAS activation.
Describe the two most common types of renal stones, their source and their solubility in acids or bases.
Renal stones are also known as kidney stones, nephrolithiasis or urolithiasis. They form around tubular debris, which is basically debris from broken down luminal epithelial cells in the nephron. Their main causes are excessive amounts of insoluble salts and insufficient fluid intake.
The most common types of stones are calcium salts. One of these is calcium oxalate. Usually dietary calcium keeps oxalate in the stool, but in the case of diseases such as IBD, where fat absorption is impaired, calcium might bind to the fat instead, allowing oxalate to become taken up by the body. Another common calcium salt is phosphate, which is less soluble in alkaline (basic) urine, presumably because less phosphate will be ionised at basic pH.
Another common type of stone is derived from uric acid. Uric acid stones may result from gout, which is a problem with purine metabolism, or from cancer chemotherapy. In contrast to calcium phosphate stones, uric acid stones are less soluble in acidic environments, presumably because less uric acid will be ionised at acidic pH (uric acid will hold onto its protons more readily than the stuff in the environment around it).
Describe the signs and common treatments of renal stones.
As you probably know, kidney stones come with a lot of pain. Specifically, this pain is flank pain, and is colicky (comes and goes with the contractions of the ureters). Treatments generally involve getting rid of the stones by lithotripsy (using shockwaves to break up the stone) etc. Increasing the fluid intake can also help. Potassium citrate can also help treat kidney stones, as the citrate can more reaily bind to calcium, allowing the more soluble calcium citrate to be washed out of the kidney. Changing urine pH to make the stone more or less soluble (so acidifying the urine in the case of a calcium phosphate stone or alkalising it in the case of a uric acid stone) is another possible solution.
Give examples of potential causes of acute renal failure. What are the two most common conditions leading to chronic renal failure?
Renal failure is essentially when the kidneys stop working. Acute causes include glomerulonephritis, circulatory shock (not enough blood getting to the kidneys), burns (broken down red blood cells clog up the vessels) and nephrotoxins such as excessive amounts of NSAIDs (inhibit prostaglandins, which usually cause vasodilation). The most common chronic conditions that cause renal failure are diabetes and hypertension.
Describe the symptoms and principles of treatment of end stage renal failure.
To talk about end stage renal failure, I'm first going to talk about what the different stages are.
In the first stage, there is a decreased reserve. Normally, we have many more nephrons than we actually need. If some of these fail, the others can compensate, but that means that you still have an overall reduction in the number of working nephrons.
In the second stage, renal insufficiency, so many nephrons have stopped working that the kidney isn't quite keeping up with everything that it needs to do. This causes a decrease in GFR (glomerular filtration rate), which in turn leads to increased serum creatinine and urea. The increased urea (as measured by blood urea nitrogen, as mentioned earlier) can affect neurons, including those that control appetite, so anorexia (loss of appetite) is another symptom that may occur. The decrease in GFR also causes an increase in renin production, activating the RAAS pathway and causing an increase in blood pressure. Although many nephrons aren't working, the nephrons that are working have a limited ability to reabsorb fluids, so polyuria (excess urine production) is another symptom. Finally, erythropoietin (EPO) and vitamin D3, which are normally either produced or activated by the kidneys, cease to do their job, so anaemia and/or osteoporosis may result.
Finally, we reach the end stage of renal failure, where there's hardly any working nephrons. Symptoms include oliguria (reduced urine production), hyperkalemia (high potassium), hypocalcemia, acidosis and azotemia (increased levels of nitrogen-containing compounds, such as urea- high urea can be specifically referred to as uremia) due to the kidneys not being able to get rid of or reabsorb the stuff that it needs to.
Treatment for end stage renal failure is, unfortunately, not curative. The first step is to control the diet by making sure not to take in too much of the stuff that your body can no longer get rid of effectively, for example phosphate, protein and fluid. Medications can be taken to help with anaemia (such as injectable EPO) and hypertension. Transplants may also be considered, though this is no permanent solution: most transplanted kidneys only last around 10 years or so before the immune system destroys it.
Many patients may have to undergo dialysis, which is where the blood is removed, filtered through a machine and then returned to the body. There are two main types of dialysis. In haemodialysis, patients have to come to the hospital several times a week for hours at a time. Blood is removed from their arm, filtered through a machine and returned. Peritoneal dialysis, which can be done overnight at home, fills the peritoneal cavity with dialysate (fluid used for dialysis), which is drained by another tube. The dialysate in both cases contains several osmotically active particles so as not to cause too much fluid to move into the body via osmosis. The fluid always contains glucose so that the body can maintain its supply of glucose.
And that's all you need to know about kidneys. Yay!
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