The bone disorders

The bone disorders Introduction There are many different types of bone disorders and these can have vast implications on a patient suffering from any particular one of these bone disorder. There 7 main categories of bone disorders listed below, each of which will be discussed in detail. Genetic (inherited) disorders, i.e. Achondroplasia, Osteogenesis imperfecta. Nutritional disorders, i.e. Rickets, Osteomalacia. Autoimmune disorders, i.e. Rheumotid Arthritis Degenerative disorders, i.e. Osteoarthritis. Bone tumours, i.e. Primary Bone Cancer, Secondary Bone Cancer. Hormonal disorders, i.e. Osteoporosis. Pagets disease. Genetic (inherited) disorders. Achondroplasia. Achondroplasia is genetic disorder and is the main type of short-limbed dwarfism that takes place in humans, occurring amongst 1 in 15,000 and 40,000 live births. It has been estimated that about 90% of cases of achondroplasia are sporadic, and on average, there is a rise of paternal age at the moment of conception of affected individuals (Vajo et al., 2000). The literal meaning of achondroplasia is without the formation of cartilage, and sufferers have difficulty with bone growth. Achondroplasia affects mainly long bones e.g. legs and arms. It is an Autosomal Dominant Gene Defect (ADGI), and leads to the conversion of cartilage into bone. It occurs when one of the 22 non-sex genes is mutated, and this mutated gene has now been identified to be located on chromosome 4, which is known to be the Fibroblast Growth Factor Receptor 3 (FGFR3). Symptoms; Achondroplasia is typically distinguished by the formation of a long, narrow trunk and short limbs. Some other usual symptoms of achondroplasia include hyperextensibilty of joints in particular at the knees and hands, however the rotation of the elbow is limited as well being unable to fully extend. Sufferers of Achondroplasia normally have a large head, short broad hands, and suffer from hypertonia (poor muscle tone). Spinal cord compression at the cervicalmedullary junction is another typical feature of achondroplasia patients (Horton et al., 2007). The location of the mutated gene associated with achondroplasia was mapped to chromosome 4p16.3 in 1994, and this was followed soon after by the identification of the heterozygous mutations of FGFR3 (Rousseau et al., 1994). It has been further discovered that children that have FGFR3 mutations, they parents generally do not have the FGFR3 mutation, and there has also been a strong association between advanced paternal age, in particular over 35 years of age. Diagnosis; Because the symptoms of achondroplasia are very distinguishable, the diagnosis at birth should not be a problem. However, it has been estimated that about 20% of individuals are not diagnosed with achondroplasia at birth (Trotter et al., 2005). A common method that has been employed and widely used for the diagnosis of achondroplasia is prenatal ultrasound. This method detects effected foetuses in the third trimester of pregnancy. The diagnosis of Achondroplasia can be carried out via CVS (Chronic Villus Sampling), followed by molecular gene tests. CVS is a test that is carried out before birth, in which cells are inspected. Molecular genetic testing is carried out in order to identify possible mutations. Treatment; There is no clear treatment for achondroplasia, and there are many tests that are ongoing in order to do find one. The use of human growth hormone has been proposed as a possible method of treatment. Tests have shown that there was an initial increase in growth rate of subjects with achondroplasia, nevertheless, the long-term benefits of such treatment have not been made clear, and many experts do not recommend it (Horton et al., 1992). In order to increase the stature of achondroplasia patients, surgical limb lengthening is another proposed method to help achondroplasia patients. The typical method compromises of different bones being broken, i.e. femur, tibiae, and humeri, after which orthopaedic appliances are used in order to carry out slow stretching during the healing process. Although this method increases the standing height of the patient, this method is also not recommended due to the many complications arising from it. These complications include, the need of repeated surgeries, wound infections and problems arising from the stretching of skeletal tissue such as blood vessels. Osteogenesis Imperfecta. Osteogenesis imperfecta is a bone disorder causing imperfect bone formation. It effects roughly 1/5,000 to 1/10,000 individuals (Sillence et al., 1979). It occurs as a result of a poor quality of collagen or a lack of collagen production, and can lead to fragile bones that are easily broken and have a low bone mass. Another distinguishable characteristic of osteogenesis imperfecta patients is an s-shaped spine that can eventually break. Osteogenesis imperfecta occurs as a result of mutations in the genes that encode the chains of type I collagen. Type I collagen is the main protein found in bone. Genetically inherited cases of osteogenesis imperfecta normally show very mild symptoms. However, spontaneous cases are often more severe. Symptoms; The symptoms of osteogenesis Imperfecta range in severity, from intrauterine fractures and perinatal lethality, to very mild fractures. Diagnosis; The diagnosis of osteogenesis imperfecta in individuals with a family history of the disease is rather simple, but more difficult in those that do not have a family history. Generally osteogenesis imperfecta is diagnosed clinically, and based on the physical symptoms associated with the disease Osteogenesis imperfecta can be diagnosed via a collagen biopsy test, which is a new method. This test is known to identify 90% of osteogenesis imperfecta cases. Ultrasound is another method that can be used for diagnosis, and can detect more severe types of Osteogenesis imperfecta, even at the foetus phase and also 16 weeks into pregnancy. Test such as those that include culturing cells, and observing the collagen produced can also be carried out, as well as using blood samples to examine mutations of the collagen manufacturing genes. Although these types of tests can be useful in the diagnosis of osteogenesis imperfecta to some extent, they are generally no more than 85% accurate. Treatment; Currently there is no known cure for osteogenesis imperfecta. However particular emphasis has been placed on prevention on injury and maintaining healthy bones particularly in younger children. Supplements of calcium and phosphorus help increase bone density. Also Biophosphates are used, and these are drugs that help decrease the rate of bone resorption. Biophosphates have been clearly shown to prevent bone fractures from occurring and also increasing the bone strength and density. Growth hormones has been previously proposed as a possible treatment for osteogenesis imperfecta (Kruse and Kuhlencordt, 1975). However this has been later dismissed, and although the use of growth hormone in combination with Biophosphates may be a useful treatment, this has not yet been tested. Metal bone plates are also used for patients with more severe fractures, and helps to strengthen and reduce fractures of the affected bones, mainly long bones e.g. arms and legs. Nutritional disorders. Rickets and Osteomalacia. Rickets is a nutritional bone disorder which is found in children. It is known to affect about 1 in 1000 children in the UK alone. A very similar disorder takes place amongst adults and this is known as osteomalacia. Both these disorders occur as a result of abnormal mineralisation (calcification) of bone and cartilage. The body transfers calcium and vitamins from the bone into the blood due to vitamin deficiency i.e. deficiency in Vitamin D and calcium. This demineralisation subsequently leads to bone deformity, and thus the bones become soft and very vulnerable to fractures. There are many reasons that cause vitamin deficiency that subsequently leads to rickets and osteomalacia. Some of which include nutritional deficiency (poor diet), poor lifestyle (lack of exercise), insufficient sunlight exposure (remaining indoors for long periods of time) and abnormal metabolism (liver and kidney disease, chronic renal failure etc) (de Menezes Filho et al., 2006). Another main cause of rickets in children is due to the baby receiving a lack of vitamin D in the womb from the mother who may also be deficient in vitamin D. Symptoms; Symptoms of rickets and osteomalacia include; Growth retardation. Deformities in the upper and lower limbs. Insufficient weight gain in children. High vulnerability to bone fractures. Bone pain. Muscle weakness. Pelvic flattening. Bowing legs. Defects in structure of teeth. Diagnosis; A physical examination will firstly help to identify bone deformities and multiple fractures. A medical history check can also help to identify a possible genetic link. The levels of parathyroid hormone and alkaline phosphate will increase in the blood as a result of deficiency in vitamin D and calcium. These hormones are responsible for the transfer of minerals and vitamins from the blood to the bone. This rise in the bloodstream is a major sign of rickets and osteomalacia, and blood tests carried out to see this elevated rise of these hormones is a good method for diagnosis. X-rays can also show the demineralisation of the bone and reveal any abnormal bone structures. Treatment; Replacing vitamin D, calcium, and other necessary minerals in patients with rickets and osteomalacia is very important, and is the main method of treatment. Babies that received a lack of vitamin D whilst in the womb of their mother, or a shortage from their mothers milk should be given vitamin drops, e.g. Abidec, to help increase their levels of vitamin D. Food rich in Vitamin D and calcium are highly advised, and offer a replacement for their deficiency. These types of food include oily fish (tuna, salmon herrings, mackerels), dairy products (milk, yoghurt), liver, Vitamin supplements can also be prescribed from a doctor. An injection of vitamin D (calciferol) is also available and can last up to a year before another injection is needed. Adequate exposure to sunlight is also highly recommended. Autoimmune disorders. Rheumatoid arthritis (RA). It has been estimated that at least 1 in 100 people suffer from RA, and that in the UK alone there are about 400,000- 500,000 sufferers. It is a chronic inflammatory disease mainly affecting synovial membrane, cartilage and bone. This then can lead to joint destruction, which is typically distinguished by gradual bone erosion, and is the main cause of disability in RA. RA causes the immune system to start producing antibodies, which attack the lining of joints (synovium), and tissues (tendons), and so thus resulting in inflammation and swelling. In response to this, the body releases a special synovium thickening chemical which causes the joint to wear away and loose its shape, and eventually the joint is completely destroyed. RA is also systemic and can spread to other tissues and other parts of the body causing more problems mainly in the hands, feet and spine. In very severe cases the disease can spread to organs and this can be very critical. RA does not occur at a particular age group, and the disorder can develop at any age in sufferers lifetime. However, more commonly RA occurs in patients that are between the ages of 30 to 60 years old. The causes of RA are still relatively unknown, however that have been several theories involving possible genes that can cause RA (Barton and Worthington, 2009). RA may also occur as a result of pollution (bacteria, fungi, viruses). Symptoms; Symptoms of RA include; Swelling of joints. Stiffness, particularly early in the morning. Inflammation. Formation of rheumatoid nodules, which appear on hands, feet and elbows. Flu like symptoms such as fever. Weight loss. Diagnosis; The diagnosis of RA is rather difficult, due to the fact that the main symptoms of RA inflammation and joint stiffness/swelling, and these symptoms can be commonly associated with other diseases/disorders. A full family history is looked at first in order to establish any hereditary traits of RA in the patient. Imaging techniques such as X-rays, CT scans and ultrasound can used to look at rheumatic erosion (the disappearance of bones/joints). However, it can be difficult to diagnose RA in the early stages of the disorder, as there may not be any physical changes during these stages. The cytokines TNF (tumour necrosis factor) and IL-1 (Interlukin-1) are responsible for further inflammation which occurs in people that suffer from RA. Both of these cytokines are present in the joint of people with RA, and checking for the presence of these cytokines at joints is a method used to diagnose RA. ESR (erythrocyte sedimentation rate) is also another blood test that can be used to diagnose RA. It is a measure of the rate in which red blood precipitate in a period of 1 hour, and is a non specific measure of inflammation. The CRP test (C-reactive protein test) is the second most popular diagnosis test for RA. In response to inflammation of tendon/ligaments, the liver produces C-reactive proteins, and this test is used to detect the presence of these proteins in the blood. The antibody RF (Rheumatoid factor) is present in the blood of sufferers of RA. Therefore blood tests to identify the presence of this antibody in the blood, 8 out of 10 times will diagnose a person that is suffering from RA. Treatment; Currently there is no clear treatment for RA, however there a few drugs available that either help relieve some of the symptoms, or to help modify the disorder. Pain killers such as paracetamol and ibuprofen can help relieve some of the symptoms of RA. NSAIDs (non-steroidal anti-inflammatory drugs) are also a set of pain killers e.g. diclofenac, ibuprofen and naproxen, and help to control joint pain and stiffness. Although these drugs help with the symptoms of RA they do not directly impede the development of RA. Furthermore, there are many common side effects associated with NSAIDs including diarrhoea, nausea, increased risk of myocardial infarction etc. Disease modifying anti-arthritic/antirhumatic drugs (DMARDS) are drugs that function by blocking the affect of certain chemicals i.e. TNF following the damage of bone, joints, tendons and ligaments. These drugs not only ease the pain and stiffness related to RA, but also slow the progression of the condition. Maintaining a healthy lifestyle for an individual suffering from RA is also vital as it reduces the chances of further complications arising from the disease. There are also many therapies e.g. acupuncture, hydrotherapy, and also arthroplasty which can significantly help with the pain and joint stiffness linked to the disorder. Degenerative disorders. Osteoarthritis (OA). Osteoarthritis is an age-related disease that ultimately has an effect on each individual, who live onto they senior years (Wong and Carter, 2003). The pain associated with osteoarthritis typically emerges from the degeneration of the cartilage between the joints, as a result of primary osteoarthritis, or from trauma bringing about the loss of cartilage (Temenoff and Mikos, 2000). Given that cartilage demonstrates a poor ability to self-repair, these injuries are sustained for years and can ultimately bring about further degeneration (secondary osteoarthritis) (ODriscoll, 1998). The degeneration of cartilage causes bone ends to become exposed, and the deposition of new osseous tissue on the bone ends. This also reduces the space in the joint cavity and limits movement (Gerard J. Tortora, 2007). The underlying bone also forms osteophytes (spikes) which grow outwards due to the bone compensating for the loss of cartilage, and this hinders joint movement and causes pain. It has been estimated that roughly 36 million Americans are diagnosed with this form of arthritis (Temenoff and Mikos, 2000). Osteoarthritis is also the main reaso n as to why many individuals undergo hip and knee replacement surgery (Wilson et al., 2005), and is also the main cause of mobility impairment in elder individuals (Buckwalter, 1997). Symptoms; Acute pain causing stiffness and lack of joint movement is the main symptom of OA. The capsule surrounding joints become bigger due to inflammation and this reduces mobility, and thus muscles at the joint become weaker. Other symptoms include spasm and contractions in the tendons; accumulation of fluid at joints, muscle weakness, and hardy bone enlargements in small joints i.e. fingers and toes. Diagnosis; There is no single test used to diagnose OA. A physical examination can show a lack of mobility, joint weakness and swelling. X-rays can show the loss of joint space and in extreme cases the presence of osteophytes. Treatment; There is advanced research going into ways to engineer cartilage to help patients suffering from OA, although a major breakthrough has yet been developed. Instead a healthy lifestyle i.e. loss of weight and exercise is highly advised Sufferers are advised to exercise the affected area as this will enable better support for affected joints and strengthen the muscles surrounding the joint. This also helps in increasing the mobility of the joints, balance and posture. Drugs such as NSAIDs (non-steroidal anti-inflammatory drugs) i.e. ibuprofen can help in relieving pain and reducing inflammation. However the long term use of these types of drugs can cause many adverse reactions. Bone tumours. A Bone tumour is the neoplastic growth of tissue in bone i.e. cells in tissue continually dividing resulting in the formation of the tumour, and can be benign or malignant. This tumour can further spread throughout the body via the lymph system. The lymph system contains lymphocytes and phagocytes, and a further function of the lymph system is to remove worn out red blood cells. There are two main categories of bone tumours, primary bone tumours and secondary bone tumours. Primary bone tumours can be localised or can spread (malignant), and these bone tumours derive from within the tissue. Primary tumours can be further divided into benign tumours and cancer. Secondary bone tumours derive from other tumours from a different part of the body and spread to the tissue via the blood. The mutation of the P53 gene which suppresses bone tumour is thought to responsible for the formation of bone tumours; however the exact cause is still not fully known. There are many different types of bone tumours, of which the most common are listed below, including symptoms, diagnosis and treatments. Osteosarcoma- This is the most common type of bone tumour, and as well as Ewings syndrome (see below), is the most aggressive type of bone tumour. It affects people at an early age (5-25years), and is rare in people of above the age of 30. Osteosarcoma is a malignant tumour and eventually will spread throughout the body. It is also known to start in the cavities within the bone, and is it affects long bones mainly the knee. Osteosarcoma is diagnosed via examination and imaging techniques such as MRI or CT scan. Osteosarcoma if usually treated by surgery and chemotherapy before and after the surgery. Ewings Sarcoma- Just like Osteosarcoma, Ewings sarcoma affects people at a young age (5-15 years), and also the survival rate up to 3 years is a 60% chance. Ewings sarcoma in mainly found in the lower extremity, than the upper extremity (Eggli et al., 1993) Some of the symptoms of Ewings disorder include pain and swelling, warmth of the local area, and the appearance of onion skin. Ewings disorder can be diagnosed via MRI and CT scans. Treatments of Ewings disorder include surgery, radiation and multi-drug chemotherapy (Eggli et al., 1993). Chondrosarcoma- This bone tumour affects the chondrocytes of cartilage tissue and subsequently, the tissue eventually becomes cancerous. Chondrosarcoma can occur at any age, and this tumour grows slowly and normally without any pain. Lymphoma- Lymphoma is cancer of lymphatic cells, and usually begins in the lymph node, but can also form in the bones. Multiple Myeloma- This bone tumour occurs as a result of bone marrow cells becoming cancerous and can cause osteolytic bone damage. It usually occurs in people above the age of fifty five, and men are twice more likely to get it than women. The main symptom of multiple myeloma is pain, as well as normochromic anemia, spinal cord compression and renal insufficiency. Multiple myeloma can be diagnosed via MRI and CT scans. Chemotherapy, bone marrow transplant as well as Bisphosphonate drugs are some of the main treatments for multiple myeloma. Osteroid Osteoma- This tumour occurs as a result of the matrix of bone becoming cancerous. It normally occurs twice as often in males than females. It more commonly takes place in the proximal femur, then mainly in the tibia, followed by posterior elements of the spine and the humerus (Bloem and Kroon, 1993). Common symptoms include dull pain which gets worse during the night, an increase in skin temperature, increased sweating and abnormal growth. Radiological scans and CT scans are common methods for diagnosis. Non-steroidal anti-inflammatory drugs are given as part of the treatment for osteroid osteoma as well surgical removal. Osteoblastoma- Osteoblastoma is a benign tumour in bone tissue and occurs when osteoblast cells become cancerous. It is mainly common in children and young adults. Pain and bone mass reduction are the main symptoms of osteoblastoma. Method of diagnosis for osteoblastoma includes x-rays, microscopic examination of osteoblast cells and a biopsy. Surgical removal of the tumour is a common treat for this bone tumour as well as cryosurgery, radiation and chemotherapy. Hormonal disorders. Osteoporosis. Osteoporosis results in bones becoming porous and these pores become bigger (2 times bigger) in cancellous cortical bone. It occurs as a result of a reduction in bone mineral density (bone mineralisation). It is a direct disease of the bone as compared to some of the other bone disorders mentioned above. During osteoporosis the rate of bone renewal is slower than bone breakdown and it commonly affects the hip, wrists and spine. It is estimated that over 3 million people in the UK alone suffer from osteoporosis. There are two main types of osteoporosis (Type I and Type II). Type I osteoporosis occurs mainly in females following menopause. Following menopause there is a deficiency in oestrogen and testosterone and this disorder is known as postmenopausal osteoporosis. Type II is mainly caused by a poor lifestyle i.e. excess smoking and drinking. This leads to a deficiency of calcium and vitamin D as a result of disorders of the intestine. The deficiency may also arise from kidney disorders caused by a poor diet (too much fast foods and fizzy drinks) and excess alcohol consumption. Also people continuously taking drugs mainly corticosteroid drugs will have a loss of bone density. Symptoms; Osteoporosis does not have any specific symptoms; however its main outcome is an increased risk of bone fractures and breaks, and also an increased risk of falling due to fractures of the wrist, spine and hip. Diagnosis Bone mineral density (BMD) test to measure bone mineral density was the first test used to diagnose osteoporosis. There are many different types of BMD tests, the most common being quantitative ultrasound. This is a very good method for diagnosis and is also a much safer approach than x-rays and radiography, which can also be used to diagnose osteoporosis. Blood tests to identify deficiencies in calcium and vitamin D are a further method for diagnosis. Treatments; HRT (Hormone Replacement Therapy) was initially used to treat postmenopausal osteoporosis, however its used was later stopped due to its many side effects e.g. breast cancer, blood clotting, stroke etc. Bisphosphonates can be used to treat osteoporosis and it functions by slowing down the breakdown of bone, in order for the body to cope with bone renewal. Bisphosphonate intolerancy was then later discovered in 20 % of people. Calcitonin drugs are another type of drug used to treat osteoporosis. Calcitonin is produced naturally in the thyroid gland, and calcitonin drugs work by directly inhibiting osteoclast activity. Calcitonin is also found naturally in salmon. Strontium Renelate is another drug that can be used and helps to promote bone renewal. Calcium and vitamin D supplements also help to slow down osteoporosis. Exercise is also highly advised for osteoporosis sufferers and has been shown to maintain or increase bone mineral density especially in postmenopausal women. Pagets disease. Pagets disease is a bone disorder associated with a disorder in bone remodelling, and affects 10% of elderly people (Barker et al., 1980). Furthermore it is more prominent in males than females. In Pagets disease there is an increase in bone remodelling which is also disorganised, and this caused by a primary abnormality of osteoclast cells (Hosking et al., 1996). The bone turnover is increased by 40%, and in addition, bone is grown in areas where bone is not needed and removed from areas where bone is required. Pagets disease is now referred to as osteoclast pagetic disease. In the disorder, the osteoclasts which are bone cells responsible for the removal of bone are targeted. Over a period of time osteoblast activity subsequently increases in response to osteoclast activity, and helps in forming new bone. However, the new bone that is formed is a lot larger and thicker because of the very fast remodelling process, but critically the interior parts of the bone are porous, and a lot more fragile and tender. This therefore makes the bone more venerable to fractures and breaks. Below is an illustration of a particular deformity associated with Pagets disease sufferers (see Figure 2.) Symptoms/complications; Joint pain and bone paint are common symptoms associated with Pagets disease. As the disease progresses the swelling and expansion of the bone leads to the expanding bone becoming weaker. Also the initial symptoms of Pagets disease are not clear but do become clearer over time as the disorder develops. Fractures of long bones e.g. tibia, femur, pelvis, spine, skull are common symptoms of Pagets disease as well as skeletal deformity. Arthritis is a common complication which arises from Pagets disease and occurs mainly in the proximal ends of long bones. A further complication of Pagets disease is Gout. Gout arises from the excessive production of uric acid and salts leading to gouting arthritis, which is a disease of uric acid metabolism. The build up of uric acid and salts in the bloodstream leads to accumulation at the bone joints/cartilage which then causes kidney stones. Bone tumours, and in particular cancellous bone tumour can arise as a result of gout. The dysregulation of bone can also cause an increase in blood circulation and can consequently bring about heart failure. Compression of nerves is also seen in sufferers of Pagets disease and is caused by bone expansion and this brings about complications in movement. Also nerve compression in the skull brings about a loss of hearing and vision. Diagnosis; X-rays is a very clear method to help detect bone expansion, bone loss and bone deformity. Alkaline phosphate which is a by-product of any type of bone disease/disorder is present in the bloodstream, and so blood test can help to identify the presence of these. Treatment; Bisphosphonates and calcitonin are common drugs used to treat Pagets disease. These drugs bind to osteoclast cells and increase their activity, thus reducing their breakdown, and reabsorption of bone into the bloodstream. Pain killers can also be taken to help ease bone pain and neuralgic pain. It is also advised that Pagets disease sufferers should receive adequate sunshine, adequate amounts of vitamin D, and maintain a healthy lifestyle i.e. healthy diet and regular exercise. References Barker, D.J., Chamberlain, A.T., Guyer, P.B., and Gardner, M.J. (1980). Pagets disease of bone: the Lancashire focus. Br Med J 280, 1105-1107. Barton, A., and Worthington, J. (2009). Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Rheum 61, 1441-1446. Bloem, J.L., and Kroon, H.M. (1993). Osseous lesions. Radiol Clin North Am 31, 261-278. Buckwalter, J.A.a.H.J.M. (1997). Articular Cartilage. Part II: Degeneration and Osteoarthrosis, Repair, Regeneration, and Transplantation. Journal of Bone and Joint Surgery, 612-632. de Menezes Filho, H., de Castro, L.C., and Damiani, D. (2006). Hypophosphatemic rickets and osteomalacia. Arq Bras Endocrinol Metabol 50, 802-813. Eggli, K.D., Quiogue, T., and Moser, R.P., Jr. (1993). Ewings sarcoma. Radiol Clin North Am 31, 325-337. Gerard J. Tortora, B.D. (2007). Principles of Anatomy Physiology 11th Edition Binder Ready Version, 11 edn (John Wiley Sons, 2007). Horton, W.A., Hall, J.G., and Hecht, J.T. (2007). Achondroplasia. Lancet 370, 162-172. Horton, W.A., Hecht, J.T., Hood, O.J., Marshall, R.N., Moore, W.V., and Hollowell, J.G. (1992). Growth hormone therapy in achondroplasia. Am J Med Genet 42, 667-670. Hosking, D., Meunier, P.J., Ringe, J.D., Reginster, J.Y., and Gennari, C. (1996). Pagets disease of bone: diagnosis and management. BMJ 312, 491-494. Kruse, H.P., and Kuhlencordt, F. (1975). On an attempt to treat primary and secondary osteoporosis with human growth hormone. Horm Metab Res 7, 488-491. ODriscoll, S.W. (1998). The healing and regeneration of articular cartilage. J Bone Joint Surg Am 80, 1795-1812. Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J.M., Maroteaux, P., Le Merrer, M., and Munnich, A. (1994). Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252-254. Sillence, D.O., Senn, A., and Danks, D.M. (1979). Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16, 101-116. Temenoff, J.S., and Mikos, A.G. (2000). Review: tissue engineering for regeneration of articular cartilage. Biomaterials 21, 431-440. Trotter, T.L., Hall, J.G., and American Academy of Pediatrics Committee on, G. (2005). Health supervision for children with achondroplasia. Pediatrics 116, 771-783.

Importance of Critical Thinking

It was Francis Bacon who said â€Å"knowledge is power† and indeed it is. We all want to know, to gain knowledge. That’s why we go to school for a large portion of our lives, why we read, watch and listen to all we can when we are awake and sometimes even when we are asleep. But what exactly is knowledge? While there isn’t a single standard definition, the oldest accepted definition was given by famous philosopher Plato; â€Å"Justified true belief. † The pursuit of knowledge I define as research. So how does one reach the goal of attaining this justified true belief?I suggest the use of critical thinking skills as a means to that end. Linda Elder defines critical thinking as follows; â€Å"Critical thinking is self-guided, self-disciplined thinking which attempts to reason at the highest level of quality in a fair-minded way. † That is, a method of thinking developed by a person that would allow this person to reason at the apex of his/her intellig ence, objectively. Critical thinking is an important apparatus in seeking knowledge as it addresses issues like uniformity, bias and partiality.As human beings we are naturally selfish. The phrase â€Å"looking out for number one† comes to mind. The point is that we want for ourselves. Similarly in seeking knowledge on a particular subject matter, we tend to take into consideration only the evidence that suits our opinion, which supports our stance on the issue. Critical thinking requires that we move past our biases and examine every bit of evidence with sound logic, in order to after an objective analysis, arrive at a fair conclusion. Also, when we do research, our findings are often partial or incomplete.With the application of critical thinking skills we would overcome that obstacle as thinking critically requires us to bring together and evaluate all the necessary information. So we would not only assess the pros as it relates to something, but also the cons. Nor would w e analyze one party’s view and ignore the opposition. Everything relevant would be appraised, making our pursuit complete. Lastly, the idea of uniformity. Format and order are very important in conducting research. We must be able to see a continuum or sequence in our methodology.Critical thinking is a process, therefore there are stages involved such as evaluation and inference. Our thoughts would not be jumbled nor would our ideas seem scattered and random as might be the case when we don’t dig deeper beneath the surface of a concept and reason on a higher plain. The application of critical thinking skills would undoubtedly result in coherence. To conclude, the importance of critical thinking as a tool in the pursuit of knowledge cannot be denied as our usual mode of reasoning is damaged and it is just the tool for the fix. â€Å"Those who know how to think need no teachers. †- Mahatma Gandhi.

Classical Humanism and Architecture Essay

INTRODUCTION Classical humanism in architecture is a direct reflection of a human quest of self-realization through ages. As for the recorded evidences one can go back to the periods of Plato, Zeno, Epicurus or Aristotle – the period reigned by Greco-Roman philosophers – when this quest of ‘know thyself’ flourished and established itself as a philosophy to woo the future generations. Thus this essay takes a quick look to expressions of classical humanism through the wonderful architectural remains of Acropolis that contains the signs of evolution in architecture too – before coming into its own conclusion. Classical Division of Greco-Roman Architecture The period in discussion contains three distinctive division of architecture, viz. , Doric, Ionic and Corinthian order. Doric could be termed as the mainstream architecture of Greece, which later gave way to Ionic and Corinthian order, where each of them can be identified through their different finishes at the sections like cornice, frieze, architrave, capital, shaft and base. Out of them two styles still co habit in Acropolis – Parthenon and Erechtheum, while the third, belonging to Roman era, has two of its bright examples in the ‘Temple of the Sybil’ in Rome or in the Charlotte City Hall (Shulman). Classical Humanism It can be identified as the improvised state of early Greek Humanism (1200-750 B. C. ), when the Greeks had evolved with the concept of arete (human excellence), where the guiding elements were â€Å"courage, loyalty, generosity, mercy, dignity, decency, honor, stoicism and strength† (Sunami, 2004). Gradually the depiction of these elements as virtues took shape in architectural details besides other modes of expressions like drama, painting or writing, where a realistic approach dominated the proceedings. It is because of that the human-centered sculptures done by them or the details in their architecture attempts to create near-perfect depiction of figures. Parthenon In spite of its present dilapidated state, Parthenon (447-432 B. C.), the home of Greek goddess Athena Perthenos (the ‘Virgin Athena’) is easily the best example of both Doric architecture and Humanism, where its simple columns and the detailed human figures would reflect a ‘plain living and high thinking’ philosophy. In fact, the Doric architecture relied much on the solidity rather than frills, which is evident in its many expressions, like the shafts of its overall 46 columns or their capitals and friezes besides cornices. As for humanism, it contained many figures, and especially the ‘metops’ (relief-works), which were altogether 92 in number, spread all around to depict the series of mythological events or the successful war ventures of the people of Athens. The near-accurate depiction of various muscuto-skeletal states of humans speaks of the deep thoughts applied by their creators. Erectheum Thereafter, the fascination with mathematics and geometry of the Greeks belonging to the period 500 B. C. – 30 B. C. , led to their advancement in architecture (Sunami, 2004) while maintaining their idea of humanism. A great example of such an evolution could be seen in Erectheum (421-405 B. C. ), which had replaced Doric architecture by Ionic order, a style developed in Ionia region of Greece. The six Ionic columns of its facade beholding six sculpted figures of maidens with large ‘bead and reel’ and ‘egg and dart’ moldings (Osborne), corroborates the fact. Corinthian Order Further departure from Doric is observed in Corinthian order of architectural style, where the capitals of its pillars started having â€Å"flowers and leaves below a small scroll† (Shulman), besides tweaking its shafts and cornices to establish a flattened look, altogether indicating evolution in both architecture and philosophy of humanism, where the later emphasized on nature more than before. CONCLUSION The philosophy of humanism or the trends in architecture are both never-ending subjects, but the wonderful episode of their togetherness in the early era sill serves as food for thoughts like ‘simplicity is the hallmark of elegance’ or ‘every instance of human existence is embedded with history, philosophy and nature’. Ends Works Cited Shulman, B. R. â€Å"Classical Orders. † Retrieved 20 December 2007, from http://www. cmhpf. org/kids/dictionary/ClassicalOrders. html Sunami, C. 2004. â€Å"History of Humanism. † Retrieved 20 December 2007, from http://kitoba. com/pedia/History+of+Humanism. html Osborne, R. â€Å"The Erechtheum†. Retrieved 20 December 2007, from http://www. jact. org/publications/sample_erechtheum. htm.

How Did Wwii End The Great Depression And Restore Prosperity

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