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He melanocytes trusted cytotec 200 mcg, which is technically a ruefully commented that he wished he had returned for regular examinations after melanocarcinoma discount cytotec 200mcg without prescription, but is usually referred to his first round of surgery for benign intestinal polyps proven cytotec 200mcg. Mel Anoma returned to his physician after observing a brownish-black Moles (also called nevi) are tumors of the skin cytotec 100mcg free shipping. They are formed by irregular mole on his forearm (see Chapter 13) quality cytotec 200mcg. His physician thought the melanocytes that have been trans- mole looked suspiciously like a malignant melanoma, and performed an formed from highly dendritic single cells excision biopsy (surgical removal for the purposes of biopsy). CAUSES OF CANCER ment melanin that protects against sunlight Cancer is the term applied to a group of diseases in which cells no longer respond by absorbing UV light. Normal cells in the body respond to signals, such as may transform the mole into a malignant contact inhibition, that direct them to stop proliferating. They are also resistant to apoptosis, the programmed death process whereby unwanted or The study of cells in culture was a great impetus to the study of cancer, because the development of a tumor in animals could take months. Once cells could be removed from an animal and propagated in a tissue culture dish, the onset of transformation (the normal cell becoming a cancer cell) could be seen in days. What are the criteria that distinguish transformed cells from normal cells in culture? The first is the requirement for serum in the cell culture medium to stimulate growth. Transformed cells have a reduced requirement for serum, approximately 10% that required for nor- mal cells to grow. The second is the ability to grow without attachment to a supporting matrix (anchorage dependence). Normal cells (such as fibroblasts, smooth muscle cells) require adherence to a substratum (in this case, the bottom of the plastic dish) and will not grow if suspended in a soft agar mixture (the consistency of loose jello). Transformed cells, however, have lost this anchorage dependence for growth. An additional criterion used to demonstrate that cells are truly transformed is that they form tumors when injected into mice lack- ing an immune system. CHAPTER 18 / THE MOLECULER BIOLOGY OF CANCER 319 irreparably damaged cells self-destruct. Michael Bishop and Harold and do not become senescent (i. Furthermore, they can Varmus demonstrated that cancer grow independently of structural support, such as the extracellular matrix (loss of is not caused by unusual and novel genes, but rather by mutation within exist- anchorage dependence). A that causes cancer (an oncogene) there was tumor can be benign and harmless; the common wart is a benign tumor formed from a corresponding cellular gene, called the a slowly expanding mass of cells. In contrast, a malignant neoplasm (malignant proto-oncogene. Although this concept tumor) is a proliferation of rapidly growing cells that progressively infiltrate, seems straightforward today, it was a signif- invade, and destroy surrounding tissue. Tumors develop angiogenic potential, which icant finding when it was first announced is the capacity to form new blood vessels and capillaries. Bishop and Varmus were ate their own blood supply to bring in oxygen and nutrients. Cancer cells also can awarded the Nobel Prize in Medicine. The DNA sequence of the ras or replication errors (see Chapter 13). Mutations result from the damaged DNA if it oncogene cloned from these cells differed is not repaired properly or if it is not repaired before replication occurs. Sim- that can lead to transformation also may be inherited. When a cell with one muta- ilar mutations were subsequently found in tion proliferates, this clonal expansion (proliferation of cells arising from a single the ras gene of lung and colon tumors. Colin cell) results in a substantial population of cells containing this one mutation, from Tuma’s malignant polyp had a mutation in which one cell may acquire a second mutation relevant to control of cell growth or the ras proto-oncogene. With each clonal expansion, the probability of another transforming mutation increases.

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A significant decrease in the pain should be expected in 48 to 72 hours after steroid injection 100 mcg cytotec for sale. The hip joint injection of the steroids and bupivacaine hydrochloride can be performed in the outpatient clinic if physicians are confident that they can palpate the anatomy of the hip joint and are able to enter the hip joint order 100 mcg cytotec fast delivery. How- ever purchase cytotec 200 mcg without prescription, in older children or in children with less-clear landmarks cytotec 200mcg discount, it is better to perform the injection in the radiography suite under fluoroscopic control buy cytotec 100 mcg line. Steroids can be injected every 4 weeks for up to three injections if the pain has not made substantial improvement. At the same time, if the children are also having trouble sleeping and are eating poorly, an antidepressant, typi- cally amitriptyline hydrochloride (Elavil) twice a day, should be started. The antidepressant will improve pain control, sleep, and general attitude. The outcome of treatment in this scenario has a very high success rate, with complete resolution of the hip pain in 3 to 6 months. Substantial re- modeling of the hip joint with recreation of hip joint space often occurs as new cartilage seems to heal in the hip joint. However, this remodeling really only works in children who have open growth plates, and we would be very hesitant to expect this kind of outcome in adults. We have had no experience using this regimen except in children with open growth plates. At 1 year af- ter reconstruction, in spite of these problems, there is usually good recreation or maintenance of hip joint space on radiographs. Sudden Pain in Therapy Following hip surgery, children who are doing very well with improved range of motion and a decrease in postoperative pain may suddenly develop in- creased pain in physical therapy. When this sudden increased pain occurs, it is very important to do a careful physical examination to ensure that an acute fracture has not occurred. The most common site of an acute fracture fol- lowing hip reconstruction is in the distal metaphysis of the femur or the prox- imal metaphysis of the tibia (Figure 10. These fractures are frequently missed by emergency room doctors and primary care physicians because families and therapists believe the pain is focused on the hip, where it has been throughout this rehabilitation phase. These fractures are especially com- mon in children who have been in spica casts. The fractures themselves are not hard to diagnose if a careful clinical examination is performed, as there is usually obvious swelling and tenderness present in the area surrounding Figure 10. It is very important to do a careful examination of the child, as evidenced by this girl who had prolonged hip pain for 6 months requiring steroid injection. Then, 8 months postoperatively when she had been comfortable for several months, she again presented in severe pain. The parents felt the pain was due to recurrent hip pain. The local doctor obtained hip radiographs that ap- peared unchanged; however, when the severe pain continued for 1 week, she returned for an orthopaedic evaluation. Because of the long experience of hip pain, the resident ordered another hip radiograph that again was unchanged. A physical examination of the child was then performed and a clearly swollen and erythematous knee was noted. A radiograph demonstrated the typical in- sufficiency fracture. However, if radiographs and physical examination do not look at the knee joint, these fractures will not be found. Occasionally, there may also be a fracture surrounding the plate, so doing a good physical ex- amination and making a radiograph of the proximal femoral osteotomy site are also important. Another consideration, especially in the period from 4 to 9 months postoperatively, should be the possibility of a fracture of a thin piece of heterotopic ossification in the sheath of the iliopsoas. These frac- tures usually become painful and then resolve relatively quickly. Evulsion fractures of the lesser trochanter may also occur. Continued or increased pain in the hip following hip reconstruction in children who are noncommunicative can be a real challenge.

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The balance between need and availability is referred to as metabolic homeostasis (Fig buy 200 mcg cytotec amex. The intertissue integration required for metabolic homeostasis is achieved in three principal ways: • The concentration of nutrients or metabolites in the blood affects the rate at which they are used and stored in different tissues order cytotec 100mcg with amex; CHAPTER 26 / BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM BY INSULIN 100mcg cytotec visa, GLUCAGON generic cytotec 100mcg on-line, AND OTHER HORMONES 479 • Hormones carry messages to individual tissues about the physiologic state of the Fatty acids provide an example of body and nutrient supply or demand generic cytotec 200mcg free shipping; the influence that the level of a • The central nervous system uses neural signals to control tissue metabolism, compound in the blood has on its own rate of metabolism. The concentration directly or through the release of hormones. It use fatty acids or glucose as a fuel (see promotes the storage of fuels and the utilization of fuels for growth. In contrast, hormones are (by major hormone of fuel mobilization. Other hormones, such as epinephrine, are definition) carriers of messages between tis- sues. Insulin and glucagon, for example, are released as a response of the central nervous system to hypoglycemia, exercise, or two hormonal messengers that participate other types of physiologic stress. Epinephrine and other stress hormones also in the regulation of fuel metabolism by car- increase the availability of fuels (Fig. Its level is regu- basis to meet their rapid rate of ATP utilization. In the adult, a minimum of 190 g lated principally through the activation of glucose is required per day; approximately 150 g for the brain and 40 g for other the sympathetic nervous system. Significant decreases of blood glucose below 60 mg/dL limit glucose metabolism in the brain and elicit hypoglycemic symptoms (as experienced by Bea Fuel Tissue Selmass), presumably because the overall process of glucose flux through the availability needs blood-brain barrier, into the interstitial fluid, and subsequently into the neuronal cells, is slow at low blood glucose levels because of the Km values of the glucose transporters required for this to occur (see Chapter 27) The continuous movement of fuels into and out of storage depots is necessitated • Blood level of nutrient by the high amounts of fuel required each day to meet the need for ATP. Disastrous • Hormone level results would occur if even a day’s supply of glucose, amino acids, and fatty acids • Nerve impulse were left circulating in the blood. Glucose and amino acids would be at such high concentrations that the hyperosmolar effect would cause progressively severe neu- Fig 26. The concentration of glucose and amino acids between fuel availability and the needs of tis- sues for different fuels is achieved by three would be above the renal tubular threshold for these substances (the maximal con- types of messages: the level of the fuel or centration in the blood at which the kidney can completely resorb metabolites), and nutrients in the blood, the level of one of the some of these compounds would be wasted as they spilled over into the urine. Fuel + Insulin stores Blood + Glucagon fuel Growth + Stress hormones Dietary Fuels: • Carbohydrate NeuronalNeuronal Blood • Fat signalssignals fuel • Protein Blood fuel Fuel utilization ATP Cell function Fig 26. The major stress hormones are epinephrine and cortisol. Triacylglycerols circulate in cholesterol-containing lipoproteins, and the lev- stellation of symptoms such as els of these lipoproteins would be chronically elevated, increasing the likelihood of polyuria and subsequent polydip- atherosclerotic vascular disease. Consequently, glucose and other fuels are continu- sia (increased thirst). The inability to move ously moved in and out of storage depots as needed. As a result adipose stores are used, and the patient with II. MAJOR HORMONES OF METABOLIC HOMEOSTASIS poorly controlled diabetes mellitus loses weight in spite of a good appetite. Extremely The hormones that contribute to metabolic homeostasis respond to changes in the high levels of serum glucose can cause non- circulating levels of fuels that, in part, are determined by the timing and composi- ketotic hyperosmolar coma in patients with tion of our diet. Insulin and glucagon are considered the major hormones of meta- type 2 diabetes mellitus. Such patients usu- bolic homeostasis because they continuously fluctuate in response to our daily eat- ally have sufficient insulin responsiveness to ing pattern. They provide good examples of the basic concepts of hormonal block fatty acid release and ketone body for- regulation. Certain features of the release and action of other insulin counterregula- mation, but they are unable to significantly tory hormones, such as epinephrine, norepinephrine, and cortisol, will be described stimulate glucose entry into peripheral tis- and compared with insulin and glucagon. The severely elevated levels of glucose Insulin is the major anabolic hormone that promotes the storage of nutrients: glu- in the blood compared with inside the cell leads to an osmotic effect that causes water cose storage as glycogen in liver and muscle, conversion of glucose to triacylglyc- to leave the cells and enter the blood. It also increases the synthesis of albumin hyperglycemia, the kidney produces more and other blood proteins by the liver. Insulin promotes the utilization of glucose as urine, leading to dehydration, which in turn a fuel by stimulating its transport into muscle and adipose tissue. At the same time, may lead to even higher levels of blood glu- insulin acts to inhibit fuel mobilization. If dehydration becomes severe, further Glucagon acts to maintain fuel availability in the absence of dietary glucose by cerebral dysfunction occurs and the patient stimulating the release of glucose from liver glycogen (see Chapter 28), by stimulat- may become comatose. Chronic hyper- ing gluconeogenesis from lactate, glycerol, and amino acids (see Chapter 31), and, glycemia also produces pathologic effects in conjunction with decreased insulin, by mobilizing fatty acids from adipose tria- through the nonenzymatic glycosylation of a cylglycerols to provide an alternate source of fuel (see Chapter 23 and Fig.

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