Deowall Chattar-Cora, MD

• Department of Orthopedic Surgery
• Division of Plastic and Reconstructive Surgery
• University of Texas Health Science Center at San Antonio
• San Antonio, Texas
• Plastic and Reconstructive Surgery of Puerto Rico
• San Juan, Puerto Rico

Other categories of tumour arthritis in lower back after surgery buy generic arcoxia 120mg line, such as sarcomas arthritis in dogs heat or cold order arcoxia 60 mg without prescription, tend to have a grade assigned to the different types by definition arthritis pain tablets order arcoxia canada. For example severe arthritis in neck and back purchase arcoxia on line amex, dermatofibrosarcoma protuberans is considered to be a low-grade sarcoma arthritis knee foot pain purchase arcoxia 120mg mastercard, while synovial sarcoma is a high-grade sarcoma can you have arthritis in your neck order arcoxia pills in toronto. Answer 5 Grade has consistently been shown to be a prognostic factor across many types of malignant neoplasm. The higher the grade (and the more poorly differentiated the tumour), the worse the prognosis. Question 6 the patient undergoes some other investigations, including imaging studies. The oncologist explains to the patient that these are part of the process of staging the carcinoma. For example, a colorectal carcinoma that invades beyond the muscularis propria, but does not breach the serosa and has metastases in two local lymph nodes but no distant metastases, would be staged at T3 N1 M0. Answer 6 the stage of a malignant tumour is a measure of how far the tumour has spread. For carcinomas, this spread is Answer 7 Staging is almost always the single most important prognostic factor for any given malignancy. Spread of Case 4: Difficulty in swallowing 15 the tumour beyond its place of origin is the principal mechanism by which a malignant tumour causes morbidity and mortality. In addition, the suitability of surgery as a treatment option is dependent on stage. Low-stage tumours can be very amenable to surgery as resection removes all of the disease. As tumours attain a higher stage, the required surgery becomes more radical and there is a greater danger that the patient already harbours occult distant metastases that are too small to detect with current imaging technology. These distant metastases will not be cleared by the surgery and will continue to grow. For these higher-stage tumours, radiotherapy and/or chemotherapy may afford a better prognosis. Conversely, accurate staging is also essential to ensure that a patient receives therapy that is appropriately aggressive in order to maximize the chances of cure if such a possibility exists. Staging guides treatment to optimize it such that it is neither too mild nor too aggressive. This function is intrinsically linked to the close relationship between stage and prognosis. Question 9 What other prognostic parameters can be assessed on the resected specimen If the tumour has gained access to the lymphovascular system, it has a route of distant spread away from the primary site. Thus, the presence of lymphovascular invasion frequently indicates a worse prognosis. Perineural invasion is similar to lymphovascular invasion, but in this case the tumour invades inside the sheath of a nerve and uses the nerve fibre as a highway out of the primary site. Perineural invasion often fails to achieve significance as an independent prognostic indicator for many tumours. With the growing use of hormonal and other molecular targeted therapies, the expression of specific molecules by the tumour can be of prognostic value. The most frequent example is breast carcinoma in which the expression by the carcinoma of oestrogen receptors is associated with a better prognosis and provides an additional avenue of treatment. There has not been any haemoptysis, haematemesis, melaena or the passage of fresh blood per rectum. Question 1 What are the basic elements involved in initiating clotting of the blood Turbulent flow will develop at the site of an injury if the wall of the blood vessel is breached and blood can escape. However, turbulent flow can also arise in blood vessels that are severely narrowed by a pathological process such as atherosclerosis, or in the eddies that may develop in an aneurysm, in both of which cases the resulting clot can be harmful rather than protective. Answer 1b While the response to turbulent blood flow can be contributory, additional systems are necessary to ensure that the clotting process is initiated when it is required and the endothelium is central to this. Under normal circumstances, the endothelium provides a smooth lining to the blood vessels and provides a surface that does not encourage clotting. However, if the endothelium is damaged, the underlying tissue is exposed allowing tissue factor, which is a potent trigger for the initiation of clotting, to come into contact with the blood. The inflammatory response that accompanies tissue damage also involves mediators that promote clotting. Damaged endothelium upregulates procoagulant proteins and also releases vasoconstricting factors. Local vasoconstriction is a protective response which reduces the blood flow into the breach and therefore decreases blood loss. Answer 1c the ability of the endothelium and disturbances of blood flow to trigger clotting is effective only if the blood possesses the capacity to clot. The coagulation cascade consists of a series of proteins, each of which can exist in an inactive and active state. Case 5: Easy bruising 17 cascade being to drive the conversion of fibrinogen to fibrin. Fibrin forms a cross-linked network of fibres which spans the breach in the blood vessel and entangles erythrocytes and platelets within it. The biological relevance of the traditional division into the intrinsic and extrinsic pathways is currently under scrutiny, although it retains some usefulness when considering the meaning of certain tests of blood clotting. Cascades occur in various physiological processes and, while their details can be frustrating to learn, it is important to remember certain basic features that a cascade system confers. Using a cascade to bring about a final process allows for amplification of a small initial stimulus into a very powerful ultimate response. For example, if a cascade has five steps and one molecule at each stage can activate ten molecules in the next stage, one activated molecule at the top of the cascade could yield up to 10 000 activated end products. In the formation of the blood clot, this amplification is desirable because the breach to the circulation needs to be sealed quickly and effectively. Different substances outside the cascade can modulate the function of different parts of the cascade. This can afford a greater degree of control and regulation than if the pathway consisted of only a couple of components. Even a fully formed fibrin scaffold is insufficient to seal a breached blood vessel in the absence of patches to cover it. Although platelets contain various enzyme systems and granules, possess assorted surface membrane receptors and have microtubule arrays that let them change shape, they lack a nucleus, are much smaller than normal cells and are not classified as cells as such. Instead, they are the fragments of much larger progenitor cells called megakaryocytes which develop in the bone marrow then split into multiple pieces to generate platelets. Platelets become entrapped in the fibrin matrix and are instrumental in forming the blood clot, but their role in the process is not simply that of a passive patch. Platelets are active agents, able to secrete both procoagulant and anticoagulant factors, as well as having adhesive properties that allow them to bind to damaged endothelium and each other, in addition to being able to change shape. Indeed, small breaches in a blood vessel can be sealed by a mass of aggregated platelets without the need to invoke the coagulation cascade. The thrombin time has a more limited range and concentrates on thrombin and fibrinogen. Question 3 the patient has a normal clotting profile but her full blood count reveals a platelet count of 39; her haemoglobin and white cell count are normal. Question 4 A diagnosis is suspected and a bone marrow biopsy is undertaken to confirm it. The bone marrow trephine has normal erythropoiesis and myelopoiesis but demonstrates a significant increase in the number of megakaryocytes. Other than the increase in number, the megakaryocytes do not exhibit abnormal features. How can hyperplasia of the megakaryocyte population be related to a decrease in the number of platelets in the peripheral blood Answer 2 the simplest evaluation of clotting would include a full blood count and the basic clotting profile. The platelet count alone does not give any indication of the functional capacity of the platelets, but disorders of platelet function, as opposed to platelet numbers, are rare. This process of exclusion is typical of the diagnostic approach in many idiopathic diseases. Answer 6 Idiopathic thrombocytopenic purpura is an autoimmune condition in which the patient produces antibodies that are directed against his or her own platelets. Occasionally, the antibodies may operate at the megakaryocyte level and the typical megakaryocyte hyperplasia is not seen in the bone marrow. There is a mild reduction in expansion in the right lower zone, the percussion note is a little dull and the breath sounds are quiet relative to elsewhere. Answer 1 In a patient of this age who is a smoker or ex-smoker and presents with haemoptysis, bronchial carcinoma is a definite possibility, particularly in the absence of infection as an alternative cause. Examination reveals decreased expansion on the Answer 2 the majority of bronchial carcinomas develop as masses in the proximal bronchi, near to the hila of the lungs. As with other tubular structures and organs in the body, if a tumour develops, either from the mucosal lining of the tube or from the deeper tissues of the wall, the tube may become partially or completely obstructed by the neoplasm. Narrowing of a bronchus impedes air flow in and out of the part of the lung distal to that airway. In extreme cases, the obstruction is complete and causes collapse of the affected part of the lung. If a region of the lung is obstructed, the drainage of mucus and other airway secretions from that lung is impaired. Stagnant fluid is an advantageous environment for bacteria and they can colonize the fluid. Patients present with severe headache and congestion of veins in the face and upper body. In addition to its ability to obstruct the lung, a bronchial carcinoma can also ulcerate the bronchial mucosa and will invade deeper structures. When this happens, part of the tumour becomes necrotic and may undergo cavitation. Question 3 In addition to obstructing the bronchus, or infiltrating the underlying lung, where else may a bronchial carcinoma invade and what clinical features can result Answer 3 Centrally placed tumours have access to the mediastinum and the assorted structures therein. Damage to the left recurrent laryngeal nerve will lead to a unilateral vocal cord palsy, which will present as hoarseness or an altered voice. Damage to the phrenic nerve will produce a unilateral diaphragmatic paralysis and a raised hemidiaphragm. Rarely, this may be the first presentation, via a chest X-ray, of a bronchial neoplasm. A tumour that is situated in the apex of the lung can extend upwards into the lower aspects of the brachial plexus. This is the Pancoast tumour and produces its initial neurological symptoms in the distribution of the C8 and T1 nerve roots, including their sympathetic component. This results in weakness of the small muscles of the hand, paraesthesia in the C8 and T1 dermatomes, and an ipsilateral Horner syndrome. Peripherally situated carcinomas can invade into the pleura and cause a pleural effusion. Question 4 Returning to the patient, she attends the local thoracic medicine clinic at which a chest X-ray reveals a right hilar mass. When the patient attends for the bronchoscopy, she reports a new symptom of weakness in her lower limbs that is making it difficult to walk and particularly awkward to rise from a chair. The bronchoscopy confirms the presence of an obstructing, ulcerating tumour in the right lower lobe main bronchus. Given that the patient does not appear to have any cerebral or spinal metastases that would explain her neurological symptoms, how could they nevertheless be related to the tumour A paraneoplastic syndrome is one that is caused by the production of a humoral agent by, or as a direct consequence of, the tumour, but is not due to the simple mass effect of the tumour. Small cell carcinomas are especially associated with paraneoplastic phenomena and this reflects their origin from neuroendocrine cells which can normally release active agents. Dermatomyositis is also an autoimmune condition which has a strong association with the presence of an underlying neoplasm. The autoimmune response is directed against the skin and skeletal muscles, particularly those of the limb girdles. The cutaneous manifestations include the characteristic periorbital heliotrope rash. He is able to talk in sentences and is not using his accessory muscles of respiration. Expansion is decreased on the right side and the patient reports a sharp pain in his chest when asked to breathe in deeply. Question 2 How does the acute inflammatory response explain the clinical and radiological changes in the lungs The pathological process is that of acute inflammation in response to bacterial infection, most commonly Streptococcus pneumoniae.

These results were not commensurate arthritis from back surgery discount arcoxia 90 mg line, however arthritis unspecified icd 10 120mg arcoxia fast delivery, with a subsequent study by Zein et al how does arthritis in neck feel generic arcoxia 90 mg line. A limitation of this study was that few patients were diabetic arthritis in neck and shoulder treatment buy 60mg arcoxia amex, precluding statistical assessment of the effects of pentoxifylline on diabetics arthritis knee repair arcoxia 60mg. In addition arthritis flare up medication purchase genuine arcoxia online, the discrepancy between histologic improvement in the two studies may be related to the lack of cirrhotic patients in the study by Zein et al. Although improvements in aminotransferases and histologic activity scores were found in some studies, these findings were not found to differ from placebo in other studies. The data with vitamin E has been the most encouraging, but the results have been mixed. Importantly, vitamin E may not be completely benign as the available literature has suggested that its use may be associated with significant side effects. One metaanalysis implicated vitamin E as a risk factor for hemorrhagic stroke [36]. Patients given vitamin E should still be encouraged to lose weight as part of their treatment. An analysis of the adult trial of vitamin E demonstrated that those who took vitamin E and lost weight as well had the greatest histological benefit [38]. The complexities of the vitamin E response were further characterized in another analysis of the adult and pediatric trials that demonstrated no relationship between tocopherol levels before or during treatment and histological response [39]. In addition, of the 25 patients who completed therapy, improved insulin sensitivity and aminotransferases were noted. Of note, 67% of patients within the study experienced weight gain, and, within six months of cessation of therapy, aminotransferase levels increased to pretreatment levels [43]. In this study, nearly threequarters of the patients studied had aminotransferase normalization. In addition, there was a statistically significant reduction in hepatic steatosis and fibrosis on biopsy. Similar to previous studies, weight gain was appreciated (an average of 4%) in addition to an increase in total body adiposity [44]. Compared to placebo, those patients receiving rosiglitazone had a statistically significant improvement in aminotransferases and steatosis but no improvement in fibrosis. In addition, although there was a statistically significant improvement in aminotransferases, no improvement in fibrosis was observed. Animal studies with vitamin D receptor knockout mice have shown spontaneous development of hepatic steatosis [51]. Although many of the available agents show promise, their efficacy and scope of implementation are limited to carefully selected patients. In particular, vitamin E appears to be the most effective therapy based on currently available studies in nondiabetic subjects with insulin sensitizers being a suitable option for diabetic patients with careful consideration of side effects. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middleaged population utilizing ultrasound and liver biopsy: a prospective study. Systematic review: the epidemiology and natural history of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Coffee and non alcoholic fatty liver disease: brewing evidence for hepatoprotection High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Proteomic analysis of the eukaryotic parasite Encephalito zoon cuniculi (microsporidia): a reference map for proteins expressed in late sporogonial stages. Association of coffee and caffeine Should physicians be prescribing or patients self-medicating 187 15. Effects of coffee on inflammatory cytokine gene expression in mice fed highfat diets. Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Separate effects of the coffee diterpenes cafestol and kahweol on serum lipids and liver aminotransferases. A pilot study of orlistat treatment in obese, nonalcoholic steatohepatitis patients. A doubleblind randomized placebocontrolled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Pentoxifylline improves shortterm survival in severe acute alcoholic hepatitis: a doubleblind, placebocontrolled trial. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebocontrolled trial. Effects of vitamin E on stroke subtypes: metaanalysis of randomised controlled trials. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Systematic review with metaanalysis: nonalcoholic steatohepatitis-a case for personalised treatment based on pathogenic targets. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hypovitaminosis D is independently associated with metabolic syndrome in obese patients. Relationship of vitamin D with insulin resistance and disease severity in nonalcoholic steatohepatitis. Each component of the MetS is either a cause or a consequence of insulin resist ance. The liver, once fatty, also over produces many other markers of cardiovascular risk such as Creactive protein, fibrinogen, and coagulation factors [1]. For example, merely a 48h lowcarbohydrate (<50 g/day) energydeficit diet decreases liver fat content by 30% [7]. In the same study, liver fat content decreased by 9% by a highcarbohydrate, lowfat, energydeficit diet. Fasting plasma glucose and insulin and free fatty acids decreased significantly more with the low than the highcarbohydrate diet [7]. However, as discussed in the following, the magnitude of changes in features of the MetS is very modest even with 10% of weight loss. Liver fat content was measured with proton magnetic resonance spectroscopy in 96 sub jects with type 2 diabetes. Liver fat content decreased signifi cantly by 51% in the intensive lifestyle intervention group [8]. Glycemic control improved significantly more in the intervention than the control group. No significant differ ences were observed in the changes in serum lipids between groups. Metaanalysis of effects of weight reduction on lipids has also supported the view that such effects are very modest despite substantial weight loss [9]. Weight loss also lowers blood pressure, but this effect is unlikely to be mediated via changes in liver fat content. Weight loss averaged 20 kg more in the surgically than conventionally treated group. These data support the view that the more weight loss, the greater the longterm benefit both with respect to the incidence of type 2 diabe tes and frequency of abnormal liver chemistries. In an open trial, seven months of insulin therapy decreased liver fat content by 20% and increased hepatic insulin sensitivity as measured using the euglycemic insulin clamp technique combined with a glucose tracer [23]. Serum adiponectin did not change, but free fatty acids, which are quantitatively the most important sources of intrahepatocellular triglycerides [24], decreased significantly. In another open study, 3 months of insulin therapy decreased liver fat content by 45% [25]. All these drugs are currently approved for the treat ment of type 2 diabetes and liraglutide also for the treatment of obesity. As an example of effects on body weight, exenatide compared to insulin in the face of similar improvement in glycemic control induced a ~8 kg decrease in body weight over 3 years of treatment in type 2 diabetic patients [26]. Pioglitazone compared to placebo was shown to decrease liver fat by 50% and enhance hepatic insulin sensitivity within 16 weeks compared to placebo in patients with type 2 diabetes [15]. The concentration of plasma adi ponectin increases remarkably by two to threefold during glitazone but not metformin treatment and is likely to be one of the key mediators of the beneficial effects of glita zones on insulin sensitivity. Randomized controlled trials and a metaanalysis have shown that pioglitazone decreases not only steatosis but also hepatocellular ballooning, lobular inflammation, and possibly fibrosis in patients with and without type 2 dia betes [17]. The histologic benefits have been attributed at least in part to changes in circulating adiponectin concentrations [22]. Metformin Metformin enhances hepatic insulin sensitivity but does not change liver fat content [14] or liver histology [11]. Orlistat improves insulin sensitivity and decreases liver fat content in proportion to weight loss. Rimonabant decreased liver fat content and features of the MetS in proportion to weight loss [29]. Lipidlowering therapies Fibrates Recent evidence from a metaanalysis suggested that fibrate therapy on a background of statin treatment provides clinical benefits with respect to cardiovascular events in subgroups 192 Value of Treatment Measures of patients with the dyslipidemia characterizing the MetS, that is, high triglycerides (1. The mechanism of such benefit does not seem to involve a decrease in liver fat content or insulin sensitivity [31]. The incidence of type 2 diabetes increased and glycemic control deteriorated in this trial [33]. Nicotinic acid does not change liver fat content and may cause a deterioration in insulin sensitivity [31]. Liver fat content decreased marginally significantly by 29% in the omega3 compared to the placebo group. Statins and ezetimibe Only two placebocontrolled randomized clinical trials have examined the effects of statins on liver function tests or liver histology. A larger study with 204 subjects found no differences in liver function tests between pravastatin and placebotreated patients [37]. However, a recent Mendelian randomization analysis showed that statin use is associated with increased obesity and risk of type 2 diabetes [39]. The plan was to enroll 80 patients, but the trial was stopped early because ezetimibe treatment signifi cantly increased glycosylated hemoglobin concentrations. The fibrosis stage and ballooning score were, however, significantly improved with ezetimibe [40]. Pentoxifylline Pentoxifylline is an methyl xanthine derivative that inhibits production of proinflammatory cytokine such as tumor necrosis factor alpha. Liver fibrosis, hepatocellular ballooning, steatosis, and lobular inflamma tion improved significantly in obeticholic acid as compared to placebotreated patients. Body weight decreased slightly more in the obeticholic acid than the placebo group. Insulin therapy lowers liver fat content and enhances insulin sensitivity, but there are no randomized controlled trials or data on its effects on liver histology. Nonalcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Effect of a 12month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. In a phase 1B placebocontrolled trial with 82 patients treated for 12 weeks, a decrease in local cortisol production via inhibition of the enzyme 11hydroxysteroid dehydro genase type 1 slightly decreased body weight and liver fat content (-15%) [49]. Weight loss combined with exercise is effective in decreasing liver fat content as well as all aspects of the MetS, although the mag nitude of weight loss necessary to observe metabolic bene fits is substantial, at least around 10%. American Association for the Study of Liver Diseases, and American College of Gastroenterology. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resist ance, insulin clearance, and gene expression in adipose this sue in patients with type 2 diabetes. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone treated type 2 diabetic patients. Meta analysis: pioglitazone improves liver histology and fibrosis in patients with nonalcoholic steatohepatitis. A placebocontrolled trial of pioglitazone in subjects with nonalcoholic steato hepatitis. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Effect of insulin versus triple oral therapy on the progression of hepatic steatosis in type 2 diabetes. Effects of exenatide on measures of betacell function after 3 years in metformin treated patients with type 2 diabetes. Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women. Triglyceride rich lipoproteins and highdensity lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very lowdensity lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. A pilot study using simvastatin in the treatment of nonalco holic steatohepatitis: A randomized placebocontrolled trial.

Two major types of oncogenes have been identified: dominant oncogenes and tumour-suppressor genes (anti-oncogenes) arthritis pain relief gloves reviews order arcoxia 120 mg overnight delivery. Some oncogenes involved in carcinogenesis are mutated versions of normal cellular genes (called proto-oncogenes arthritis in knee ice or heat buy generic arcoxia 120 mg online, p-onc) enteropathic arthritis definition discount arcoxia 60 mg visa. Evidence for the existence of such genes has been largely circumstantial and was based on classic genetics symptoms of arthritis in feet and legs 90mg arcoxia sale, cytogenetics and molecular genetics arthritis in upper neck and back buy 120mg arcoxia visa. Programmed cell death (apoptosis) is an important component of cell regulation; and mutations in genes involved in the regulation of this pathway arthritis pain on fingers order arcoxia paypal. These categories of genes can act as dominant oncogenes or tumour-suppressor genes, depending on their actions within the pathways and whether loss of one or both alleles is needed to confer the effect. The exogenous sources include viral oncogenes (v-onc), which may be introduced into cells by tumour viruses. Endogenous genes are called cellular oncogenes (c-onc), and these are genes that are normally present in the cell but have been altered to produce the oncogene. As mentioned above, the normal gene from which the oncogene is derived is called the proto-oncogene. The viral or exogenous oncogenes can be divided into two types: those that show similarity to normal cellular genes and those that are completely different. A virus infects a cell and incorporates some of the cellular genes into its own genome. When the virus infects another cell, it can introduce the viral oncogene (a process called transduction), which leads to altered growth of the infected cell. There are a number of ways in which the function of oncogenes can be altered and this includes (1) point mutations, (2) amplification, (3) gene rearrangement/translocation, (4) deletion of part or whole of chromosome and (5) altered expression. As most Key facts Main differences between dominant oncogenes and tumour-suppressor genes Dominant oncogenes Number of alleles in normal cells Number of alleles mutated to exert effect Effect of mutation on the function of the protein product Germline (inherited) mutations identified, i. Inactivating, loss of function, recessive Chapter 13: Molecular genetics of cancer 336 Molecular genetics of cancer of the mechanisms described apply to both types of oncogenes, they are considered here together; however, there are differences in the pattern of alterations between dominant oncogenes and tumour-suppressor genes. In contrast to dominant oncogenes, which are mutated in a consistent manner by point mutation. N-myc), mutations in tumour-suppressor genes tend to be diverse in both type and position within the gene. The effect of the point mutation depends on its position and includes alteration of the protein structure by change in the amino acid composition and insertion of a stop codon with premature termination of the protein. Depending on the site where the mutation has occurred, patients will present with a combination of all or some of the above lesions. Only some of these amplifications have been demonstrated to have pathological significance. The small intragenic deletions have similar effects (abnormal protein, stop codons) to point mutations. It has recently become apparent that some putative tumour-suppressor genes do not exhibit these common phenomena in certain tumours. Instead changes in the methylation patterns of the promoter region of the gene, or even alterations in the chromatin pattern regulated by Normal cell growth is believed to be influenced by growth factors binding to receptors on the surface of the cell. This occurs without any mutational event in the gene; hence if the gene were sequenced, no changes would be detected. It is worth bearing in mind that, in tumorigenesis, methylation and acetylation play roles in the downregulation of the expression of tumour-suppressor genes. Several classes of growth factors have been classified according to sequence homology and biological activity. When the genes coding for these receptors are abnormal, there is persistent activity without receptor Receptor linked to G-protein Receptor linked to tyrosine kinase and G-protein. The growth factor receptors can be activated in this way by a number of mechanisms, including gene amplification, rearrangement and over-expression. Some tyrosine kinases are not attached to a receptor but are anchored to the plasma membrane and participate in signalling. The c-src oncogene alters the activity of one of these non-receptor tyrosine kinases. The ras genes usually acquire transforming activity as a result of point mutation within their coding regions. These activating point mutations are restricted to certain sites, notably codons 12, 13 and 61. The p21 product of both ras proto-oncogene and transforming genes is located in the inner surface of the cell membrane. These biochemical properties resemble those of the G-proteins, which are associated with the cell membrane and implicated in the modulation of signal transduction. It is becoming clear that ras proteins function as critical relay switches that regulate signalling pathways between the cell surface receptors and the nucleus. Overall, point mutation in the ras gene is the most common dominant oncogene abnormality in human tumours. It appears to play a major role in colon, pancreatic and thyroid cancers as well as in myeloid leukaemia. Unfortunately, in many patients, resistance to the drug also develops with recurrence of disease. This was originally identified as the oncogene carried by several acutely transforming retroviruses. They have been isolated on the basis of homology to v-myc or one of the myc proto-oncogenes; c-myc is expressed in many tissues and correlates with cell proliferation. In B- and T-cell lymphomas, translocation to an immunoglobulin (Ig) or T-cell receptor locus is seen. The end-result of all the signalling pathways is the transition of the cell through the cell cycle. This phenomenon of tumour suppression suggested that the normal cell must replace a defective function in the cancer cell. Retinoblastoma, a tumour arising from the embryonal neural retina, has a worldwide incidence of 1:20 000. The successful identification of genes, the proteins of which are physiological inhibitors of growth, stemmed from two main types of studies: (1) somatic cell hybrids and (2) genetic studies of inherited cancer syndromes. Tumour-suppressor genes/recessive oncogenes 341 Chapter 13: Molecular genetics of cancer tend to present earlier and develop bilateral disease. Advancement in surgery and radiotherapy led to improved survival, and it became clear that 50% of the offspring of patients with bilateral tumours were themselves at risk of the disease. Evaluation of family pedigrees clearly shows the inherited form as mendelian dominant. He pointed out that, if cancer arises due to a series of somatic events, then it is possible that sometimes one of these changes is inherited in the germline and hence is present in every cell of the body. All the cells are therefore already one step along the pathway of carcinogenesis and this forms the basis for the dominantly inherited (mendelian) cancer susceptibility. In addition, a further mutation occurring somatically during life in the same gene would knock out the function of the gene. Hence, although the susceptibility is dominant, the action at the cell level is recessive. Knudson examined data relating to the age of first appearance of the tumour in both familial and sporadic cases, and showed that it followed the expected statistical model based on this hypothesis. Cytogenetic studies had revealed that a few of the familial tumours showed germline deletions of chromosome 13 and careful karyotyping revealed deletions of 13q14. With the cloning of the gene, it could be confirmed that familial retinoblastoma is indeed due to an inactivating mutation. Interestingly, mutations of the retinoblastoma gene and expression of the mutant protein product have also been seen in almost every tissue, despite the restricted oncogenic effects. Mutations are also found in other types of tumours such as breast carcinoma, although breast cancer does not form part of any syndrome in association with retinoblastoma. Mutations in the E-cadherin gene are also responsible for predisposition to inherited gastric cancer of diffuse type in a percentage of patients. This protein acts in the nucleus to increase the activity of growth-promoting genes. These molecules have an effect on nuclear transcription and regulation of the cell cycle. Briefly, when the cells are in the resting or quiescent stage, the retinoblastoma protein is hypophosphorylated. This process is balanced by signals that inhibit the process, with p16 playing an important role. The cell cycle arrest is necessary and important because it allows the cell time to repair the damage before completion of cell division. The resultant cells either re-enter the cycle, terminally differentiate and leave the cell cycle, or enter a resting phase, G0. It proliferates without restraint During proliferation, new mutations occur, some of which confer an increased growth advantage and an ability to spread through basement membrane Part 4: Cell growth and its disorders Further mutations occur. As some of the important genes involved in cancer are already being assigned to have a role in particular types of repair mechanisms, they are listed here but it is not the intention that you should be able to regurgitate the different mechanisms in detail. Microsatellites are repeat units generally found within the non-coding part of the genome. They are highly polymorphic (the two alleles differ in size) and hence they provide a useful tool for the investigation of mutations within the genome. The implication of finding microsatellite instability is that the mismatch repair genes must be inactivated, otherwise the mismatch repair gene proteins would have corrected the mutations identified in the microsatellites. Hence analysis of microsatellite instability provides indirect evidence for mismatch repair gene abnormality, and patients with high levels of instability can have direct genetic testing to look for the mutations in the mismatch repair genes. Occasionally, the damage is so severe that the cell is unable to do this and a set of signals is initiated that lead to programmed cell death. This is an important protective mechanism as a cell with severe genetic damage is no threat if it is dead! It is only when it manages to go through the cell division cycle with its damage and pass the alterations on to the daughter cells that problems are likely to occur. Apart from showing increased proliferation, cancer cells also fail to undergo apoptosis and hence have an increased life span compared with normal cells. The inability of cancer cells to commit suicide is an important contributory factor to tumour growth, both at the primary site and at the sites of metastatic spread. This gene is a member of a large family of genes, some of which are pro-apoptotic (bax, bad), whereas others are anti-apoptotic (bcl-2, bcl-xL). Two other genes that are also prominent in the apoptotic pathway are p53 (discussed above) and the c-myc oncogene. Once a cell has divided, any mutation will be perpetuated if the daughter cell is capable of further division. An enzyme called telomerase plays a role in maintenance of the telomeres by preventing the erosion of telomeres that occurs during replication. Its expression is tightly regulated during development and, after this period, in humans, it is expressed in quantities sufficient to prevent telomere erosion in male germ cells, lymphocytes and stem cell populations, including basal keratinocytes. It is becoming clear that, in order to create a cancer cell, two barriers must be overcome: cellular senescence and crisis, both of which limit replicative potential. This hypothesis seems to be valid for both benign and malignant tumours, at least in in vitro experiments. It is not difficult to postulate that cancer cells have learnt how to circumvent the erosion of telomeres. Several lines of evidence have supported the major role of telomerase in oncogenesis. The traditional view has been that a cell, capable of replication, undergoes a mutation in a gene that allows it to have a growth advantage. Subsequent mutations over a long time period lead to further clonal expansions, which then become the reservoir for further mutations and expansions. There has been an increasing interest in stem cell biology over the last two decades and a role for stem cells in the development of cancers has been proposed. Normal stems cells must, by definition, be able to undergo self-renewal (produce an identical copy of itself) and be able to produce daughter/progenitor cells. Progenitor cells retain some characteristics of stem cells initially, but lose these features as they differentiate into the different tissue types with subsequent cell divisions. One of the problems with the traditional model is the knowledge that cancers take a long time to initiate and progress, and this contrasts with the relatively short life span of mature, differentiated cells. It has been proposed that stem cells, which are long lived and hence predisposed to the slow accumulation of genetic changes, may be the tumour-initiating cells. Although a huge amount of effort is currently invested in studying normal and cancer-associated stem cells, it is unclear at present whether cancers do indeed arise from normal stem cells or whether some cancer cells develop the ability to have stem cell-like characteristics as a result of transformation. This is a field in transit and worth keeping an eye on because it will change the way we think about primary and metastatic disease and how we manage it in the future. Chapter 13: Molecular genetics of cancer with appearances intermediate between normal morphology and frank malignancy. This led to the suggestion that many of these lesions may be precursors of the invasive carcinoma. The results demonstrate that both activating and inactivating events are involved and it is the coordinated involvement of many of these types of alterations that are important in colon tumour formation. Furthermore, it is not just the timing of the events but also the sequential accumulation of genetic damage that is important in tumour formation. The idea of the multistep model has been extended to almost every tumour type and there is good evidence that cancers in general develop in this way. The screening programmes are identifying lesions at a very early stage in development, and the classification and natural history of many such lesions are at present unknown.

Adaptive immunity takes days to weeks to be fully established on first encountering an antigen (so it is no use as a first line of defence) arthritis in fingers piano purchase cheap arcoxia on line, but it results in continued antibody secretion and the generation of long-lived memory B and T cells arthritis pain relief night buy arcoxia 120 mg low price, which are capable of mounting a quick and effective response on re-exposure to an antigen arthritis in neck at young age purchase arcoxia 120mg overnight delivery. The recruitment of the cells of the adaptive immune response can lead to clinically manifest chronic inflammation arthritis neck pain forum buy arcoxia 90 mg without a prescription. The lymphatic vessels comprise a one-way circulatory system from the tissues back to the blood circulation arthritis treatment great danes purchase generic arcoxia line. Ultimately arthritis qualify for disability purchase cheap arcoxia on-line, the lymphatics drain into the thoracic duct, which returns lymph fluid to the venous system. We alluded to the lymphatics in Chapter 4, page 121, because they are essential for clearing excess fluid from the tissues. The spleen is well placed to trap and remove from the circulation marauding bacterial organisms that have broken into the bloodstream (bacteraemia or septicaemia). Doctors can palpate the superficial lymph node groups, which can enlarge due to inflammation or neoplastic change (this may be primary, as in malignant lymphoma, or secondary to metastatic disease from a primary site in the region drained by the lymph node group) (see Chapter 14, page 356). The superficial lymph nodes are accessible to fine-needle aspiration or needle core biopsy. The lymph node is organised into zones to optimise the immune response: B lymphocytes, which can develop into plasma cells that produce antibodies, are gathered into aggregates called follicles. Bacterial infections are characterised by the enlargement of the B-cell areas (follicular hyperplasia). If infection is due to a virus then the T-cell response would be more important than antibody production and there would be paracortical hyperplasia. With any luck, the defence systems activated in the lymph nodes will stop the infection from spreading to the rest of the body. Infection of the blood (septicaemia) can also occur if tissue organisms directly enter blood vessels instead of the lymphatics. Larger lymphatics are lined by continuous endothelium and have valves to prevent back ow. The ltered lymph passes on to the next node in the chain and through several other lymph node stations before it re-enters the bloodstream via the thoracic duct. It exists to trap organisms, debris and particulate matter, and to promote immune cell proliferation. Other important encapsulated bacteria include Neisseria meningitides, Escherichia coli and Klebsiella pneumoniae. The capsules are made from polysaccharide and macrophages can bind only protein, so the bacteria need to be opsonised by IgG or complement C3b in order that the splenic macrophages can remove them. Patients who undergo splenectomy are often immunised against encapsulated bacteria, but even so require lifelong antibiotic treatment, usually with co-trimoxazole for protection. Without the splenic macrophages, microbes that are coated with Ig and C3b are difficult to remove from the bloodstream and the purpose of immunisation is to prevent them reaching it. The thymus plays a huge role in T-cell development in fetal and neonatal life, and at that time is a relatively large organ compared with other intrathoracic structures such as the heart. By young adult life the thymus has atrophied to a streak of tissue supported by fat. Examination of his pharynx shows red, swollen tonsils with a purulent exudate on the surface. If, for the sake of illustration, one of the nodes were to be excised for microscopical examination, it would show a number of changes. The changes arise because lymph fluid, containing cellular and particulate matter such as bacteria, secreted bacterial antigens, dendritic cells, macrophages and complement fragment C3b, drains into the lymph nodes of the neck. Together with antigen presentation by dendritic cells, this initiates a specific adaptive immune response that causes proliferation and differentiation of T and B cells. Lymphocytes home to the tissues from which they have just come and the cycle is repeated. A reactive or inflamed node retains its kidney shape but becomes larger and demonstrates increased flow (red arrows) through the hilum. Lymphocytes move from blood into white pulp of spleen through fenestrated endothelium B of lymphoid cells is important, because it allows information about invading organisms in one part of the body to be shared with other areas of lymphoid cell production, and the entire repertoire of lymphoid cell surface receptors is available to most of the body (each B and T cell carries a unique receptor that recognises just one antigenic epitope). The repopulation of the normal tissue lymphoid population is a feature of normal healing and repair. Dendritic cells: dendritic apc and follicular dendritic cells 185 upregulation of endothelial adhesion molecules and the activation of lymphoid tissue in the lymph nodes draining an acutely inflamed site lead to their proliferation. Foreign antigens and particles can also enter the lymph, sometimes loose but often having been engulfed by specialised cells of the monocyte/macrophage lineage. The first group belongs to the macrophage/monocyte lineage and are termed dendritic cells. They can take up antigen in a variety of ways, including via immunoglobulin (Fc) or complement (C3b) receptors. The dendrites and surface folds are constantly moving, sampling the environment, and can insinuate themselves between adjacent cells and engulf particles and microbes. Those with tightly fitting receptors for the antigen are selected for further proliferation. For T-cell activation to take place, both antigen presentation and engagement of co-stimulatory molecules must occur. They are thought to derive from embryonal mesenchymal tissue, and are not of macrophage/monocyte lineage, but nevertheless express Fc and complement receptors. The opsonins are fixed to the surface of the organism itself or to any soluble antigenic fragments that it may have released. But if antibody production is a function of the adaptive immune response, which takes several days to happen, how can there be any immunoglobulin for the phagocyte to adhere to The adaptive response can be split into humoral immunity and cell-mediated immunity. Humoral Surprisingly, it is the antigen that chooses the B cell best equipped to fight it, rather than the other way round! Mother nature equips the body with an enormous number of B cells, each armed with a receptor for a unique antigen. Imagine the B cells, lined up around the wall of a dance hall, waiting for the right antigen to ask them to dance! At the same time the bone marrow generates millions of different B-cell clones, each capable of secreting an antibody likely to be of use in combating infection. A population of natural antibodies is thus present within human (and higher primate) tissues from an early age. Low-affinity antibodies can attach loosely to more than one type of antigenic epitope, whereas high-affinity antibodies produced in the lymph nodes after antigen presentation are highly specific, bind tightly and react not just with one antigen, but with one epitope on an antigen. The type of microbial agent that initiates an inflammatory reaction determines the most appropriate host immune response. There are several subsets of T cells, but the two most important are the T-suppressor/cytotoxic cells, capable of direct attack and lymphokine production, and the T-helper cells, which act to regulate the immune response and interact widely with other immune-reactive cells. This cell acts independently and is important in the innate immune response and in cancer surveillance and killing. Each cell has a unique receptor for antigen on its surface, generated after the B cells have undergone a series of rearrangements in their heavy chain genes while in the bone marrow. The T cells have similarly rearranged their T-cell receptor genes during their maturation process in the thymus. Several B cells may have receptors that can bind to different parts of the antigen (epitopes); only those that fit closely are used. The antigen-binding site is a threedimensional structure, with three key sites at which bonds are made. Through a process of hypermutation, low-affinity binding sites can mutate to show high affinity for antigen. A large population of daughter B cells is produced through cloning and these differentiate to form plasma cells; a population of circulating memory B cells is also generated. Initially, the antibody is of IgM type and later the B-cell clone switches to produce IgG. Finding IgG antibody is less useful, as it can indicate that the patient has been exposed to the antigen at almost any time in the past, from weeks to years. If the particular antigen is encountered again, the memory cells will quickly undergo clonal proliferation and swamp it with specific antibody. It is worth stating that a B-cell inflammatory reaction will lead to the generation of numerous different antibodies, all directed at different antigenic sites (epitopes). This is very different from what happens in multiple myeloma, a malignant disease of plasma cells. All malignancies originate from a single mutated cell, so it follows that all the antibodies secreted by a malignant proliferation of plasma cells will be identical. This is an important concept because certain cancers that affect the lymphoid system may be difficult to distinguish from a reactive inflammatory proliferation. Multiple myeloma is a tumour that infiltrates the bone marrow and is caused by a malignant proliferation of plasma cells. Certain malignant lymphomas, representing cells at earlier stages in the path from B cell to plasma cell, may secrete antibodies. The finding that all the antibodies are exactly the same is of diagnostic value, because this is virtually unheard of in an inflammatory response. We have come across IgM and IgG so far, and we have mentioned that IgD is encountered on the surface of some B cells. How can such a large number of diverse antibodies have been generated from cells with a common ancestor Each immunoglobulin molecule (monomer) is formed from two identical heavy chains and two identical light chains joined by interchain disulphide links. There are two types of light chain (and) and five types of heavy chain (G, A, M, D, E). IgG is the most prevalent antibody in the blood and exhibits the most basic immunoglobulin structure, referred to as a monomer. IgG3, for instance, is best at fixing complement, whereas IgG1 is the best at opsonising for phagocytosis, because phagocytes such as macrophages and neutrophils bear specific receptors for FcIgG1. Different subtypes of IgG exist, each with fascinating properties: the precise subtype produced is governed by the cytokine balance prevalent at the time, which is determined by the innate immune system. Between them these subclasses of IgG can neutralise toxin, opsonise microbes for macrophage and neutrophil ingestion (and destruction), and activate complement. IgM is the largest antibody molecule: five monomeric units are joined by a J-chain to make a massive pentamer. By clustering antigen together in one spot (10 antigen molecules can be bound by one IgM pentamer), it is good at mopping up large quantities of invading pathogens at the start of an infection. IgM Dictionary Transduction: the translation of a signal into an action, usually involving messengers that refer the signal to the nucleus. Here particular genes are switched on and translated into proteins with actions appropriate to the initial stimulus. In the blood, IgA exists in a monomeric form, but IgA is most important as a mucosal protector, in gut secretions, for example. Its constant (Fc) region ends are linked by a chain, which prevents mucosal enzymes from digesting and destroying the antibody. Also, the dumbbell-shaped dimer can bind antigen at either end, clumping bugs together and making it easier for them to be caught up in mucin and carried out of the body. This means that IgA is the most plentiful antibody in the body but most of it is on the mucosal surfaces, not in the blood. In a clever extension of mucosal immunity, intestinal B lymphocytes can be stimulated by antigens and then migrate via the lymphatics and blood to localise in other areas, such as breast or salivary glands, so that specific IgA also defends these sites. When IgE is made, its Fc end is bound by mast cells, which are long-lived cells in the tissues. Here the antibody is ideally placed to recognise pathogens such as worms or flukes that invade the tissues. Chapter 6: Chronic inflammation and the adaptive immune response 192 Chronic inflammation and the adaptive immune response Table 6. Most abundant immunoglobulin in blood and extravascular fluid Most important immunoglobulin for protecting mucosal surfaces. Combines with secretory component to avoid being digested Important in early response to infection because it is a powerful agglutinator IgA IgM IgD B Present on the surface of some lymphocytes and may control lymphocyte activation/suppression Involved in mast cell degranulation, thereby protecting body surfaces. Important in allergy and parasitic infections IgE Part 2: Defence against disease A curious feature of IgE is that, once secreted by a plasma cell, it becomes bound to the surface of a tissue mast cell. When two or more IgE molecules, which are bound to the same mast cell, recognise and bind to epitopes on a marauding parasite, the IgE molecules can cross-link. Cross-linkage of IgE molecules triggers the immediate release of toxic granules from the mast cell on to the parasite. This is clever, because most parasites are too large to be phagocytosed by the usual defenders, the neutrophils and macrophages. A common feature of allergens, such as peanut, pollen or bee sting, is that they bear repeated sequences of the same epitope.

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