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!
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