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Immunisation Gene transfer Mouse with human Ig genes Human monoclonal antibodies Fully human therapeutic antibodies are obtained by infect- production of immunoglobulins (Ig) with the target for the ing a transgenic mouse that carries human genes for the antibodies that one wishes to produce discount sildalis 120 mg without prescription. As a result sildalis 120mg on-line, medical science now has at its disposal an arsenal of therapeutic antibodies that are structurally identical to their natural counterparts in the human body discount 120mg sildalis with mastercard. Example MabThera: A good example of a highly effective chimeric an- hope for patients with tibody is the Roche product MabThera/Rituxan lymphoma (rituximab). The target protein of this therapeutic antibody is a receptor located on the surface of B lymphocytes (white blood cells), which in lymphomas grow uncontrollably. The antibodies bind to the cancer cells, marking them out for destruction by the body’s immune system. At the same time rituximab makes the cells more susceptible to certain forms of chemotherapy, thus improving the survival chances of patients who previously had no further therapeutic options fol- lowing unsuccessful chemotherapy. A turbocharger for the Therapeutic antibodies such as rituximab help immune system the patient’s immune system to home in on dis- eased target cells. Main avenues of research 47 Enhanced immune response: modified therapeutic antibodies 120 Engineering of antibody 100 80 60 40 Wildtype antibody 20 Engineered negative 0 control antibody 0 10 20 30 40 50 Antibody concentration (ng/ml) Specifically modified therapeutic antibodies can induce a five to eight times stronger immune response (e. The next drug The next step was to link therapeutic antibodies generation: small with small molecules to form what are known as molecule conjugates small molecule conjugates. Antibodies have a disadvantage that they share with other thera- peutic proteins: they are too bulky to penetrate into the interior of cells. Potential targets are therefore limited to molecules lo- cated outside of or on the surface of the body’s cells. By contrast, many conventional, chemically synthesised small molecule drugs can readily pass through the cell membrane to targets within the cell or even the cell nucleus. Small molecule conjugates combine the specificity of therapeu- tic proteins – especially antibodies –with the broad target range of small molecules. To produce them, researchers have de- veloped complexes, or conjugates, consisting of therapeutic antibodies coupled to low-molecular-weight drugs. In such con- jugates the antibody’s role is to ferry the actual drug directly to its target in the body. Drugs commonly used to destroy cancer cells also attack healthy cells in the body. Once Co plexbinds this occurs, the entire conju- tocell gate is internalised in the cell. In cancer cells the anti- body is digested and releases the small molecule, which Cancercell then destroys the diseased cell. In this way cancer cells Cancercell orzelle can be specifically targeted and adverse effects on Co plexcarries drugintocell healthy cells can be minim- ised. If Entireco plexinsidecell the findings from tests are borne out, the latest gener- ation of these drugs could Cancercell signal a breakthrough not Drugkills cancercell only in cancer therapy but in many other therapeutic Conjugated antibodies combine the specificity of thera- areas where medical science peutic proteins with the broad target range of small mole- has hitherto had to contend cules. The antibodies target a specific structure on the with severe side effects surface of cancer cells. Once the antibody has located its target and bound to it, the conjugated small molecule drug caused by the unspecific is released, penetrates the cancer cell and kills it. Spektrum Akademischer Verlag, Heidelberg, 6th edition 2003 Presentations at a media conference: The Roche Group – one of the world’s leaders in bio- tech, Basel, November 2004 http://www. As well as the therapeutic possibilities it offers, modern biotechnology can lead to novel ways of combating diseases such as diabetes, cancer and rheumatic diseases. For example, early and specific diagnosis, and also tests that can monitor treatment and the course of an illness, can result in more effective treatment of patients. The more doctors know about the causes of diseases, the more ef- fectively they can deal with them. This realisation may sound simple, but translating it into practice remains difficult, be- cause the critical part of treatment is often finding the right diagnosis. It is precisely in this area that biotechnology has made tremendous strides in recent decades. Thus, for example, alleviating pain should not be the only goal when treating patients with chronic pain. It is only when the source of the pain has been identified that steps can be taken to counter it in the long term. Yet pain patients in particular often have to undergo veritable medical odysseys as a result of uncer- tain diagnoses, failed treatments and ever increasing pain. De- spite having similar symptoms, painful rheumatic diseases can be caused by very different disorders, each of which re- Terms quires a distinct treatment. Whether a treatment is suc- Biopharmaceuticals drugs manufactured using biotech- nological methods. The picture is similar with Genome the (largely unalterable) complement of all genes of cancer, where the sheer va- an organism. Genomics the science concerned with the form, function riety of causes requires a new and interaction of the genes of an organism. A tu- Genotype the variants of a given gene possessed by an mor can remain completely organism; as a rule a human can have no more than two variants of each gene – one from the father and the other from the mother. Proteomics the science that deals with the form, function origin and genetic pattern of and interactions of the proteins of a biological system. In this respect, biotechnology has devised new means for identifying the precise molecular causes of such disorders. For thousands of years experienced doctors have gathered crucial information about their patients’ health from visible wounds, bone structure, posture and the colour of the skin, eyes, blood and excrement. Other methods of conventional diagnostics include palpation, for example for muscular indurations or masses, and an in-depth exchange of information between the doctor and patient. Modern medical science has supplemented this range of methods with imaging techniques, e. These routine methods still form the basis of every successful therapy – even if they often prove inadequate for the diagnosis of many diseases. Diagnostics at the organ The next level of medical diagnostics concerns and tissue level the internal structure of the body and focuses specifically on the functions and interactions of organs and tissues. In this area as well, modern diagnostic tech- niques such as sonography, computed tomography, intestinal endoscopy and arthroscopy have added to the arsenal of con- ventional examination methods. Treatment begins with diagnosis 53 Take liver biopsy tests, for example, which involve the removal of liver cells through a long needle inserted into the abdominal wall. Examining these cells closely under a microscope is still the most reliable way to identify diseases of the liver. However, in most cases biopsy is the final link in a diagnostic chain that starts with laboratory tests. Such tests became possible only with the advent of enzymes pro- duced by biotechnological means. Thanks to such screening tests,which do not require surgical intervention and produce re- liable results quickly and easily, doctors are now able to recog- nise and treat many more functional disorders of organs and tis- sues. An added benefit is that if screening test findings are negative, patients are spared an unnecessary and relatively risky intervention. Diabetes: better quality of In the case of diabetes, the advantages of quick life, fewer complications tests go even further: such tests are actually an in- tegral part of diabetes therapy. Diabetes is due ei- ther to deficient insulin production by pancreatic cells or to an acquired insensitivity of certain body cells to insulin. In either case, the detection and treatment of the disease require regular monitoring of blood glucose levels with the help of enzymes produced by biotechnological methods. On the basis of these measurements, diabetics are able to determine when and how much insulin they should inject. Until just a few decades ago diabetics had to visit their doctor for such tests, making it all but impossible to adapt insulin doses in- dividually. Today, by contrast, modern diagnostic devices like Roche’s Accu-Chek allow diabetics to check their blood glucose levels themselves at any time and thus adapt their treatment to their individual needs. This advance has not only enhanced the quality of life of diabetics but has also led to a 54 marked reduction in complications due to inadequate diabetes therapy. The enzymesrequired for measuring such blood or urine param- eters were produced as early as 1954 by Boehringer Mannheim using conventional biotechnological methods. From the biomass thus produced enzymes such as glucose oxidase and cholesterol oxidase were obtained for measuring blood glucose and cholesterol levels, respectively.

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Non-inferiority trial A study that seeks to show that one of two treatments is not worse than the other purchase 120 mg sildalis with visa. Normal (1) A normal distribution or Gaussian distribution of variables order 120mg sildalis with visa, the bell-shaped curve buy cheap sildalis 120mg. Null hypothesis The assumption that there is no difference between groups or no association between predictor and outcome variables. Objective Information observed by the physician from the patient examination and diagnostic tests. Observational study Any study of therapy, prevention, or harm in which the exposure is not assigned to the individual subject by the investigator(s). A synonym is “non- experimental” and examples are case–control and cohort studies. Odds The number of times an event occurred divided by the number of times it didn’t. Odds ratio The ratio of the odds of an event in one group divided by the odds in another group. One-tailed statistical test Used when the alternative hypothesis is directional (i. P value The probability that the difference(s) observed between two or more groups in a study occurred by chance if there really was no difference between the groups. Pathognomonic The presence of signs or symptoms of disease which can lead to only one diagnosis (i. Patient satisfaction A rating scale which measures the degree to which patients are happy with the care they received or feel that the care was appropriate. Patient values A number, generally from 0 (usually death) to 1 (usually complete recovery), which denotes the degree to which a patient is desirous of a particular outcome. Pattern recognition Recognizing a disease diagnosis based on a pattern of signs and symptoms. Percentiles Cutoffs between positive and negative test result chosen within preset percentiles of the patients tested. Placebo An inert substance given to a study subject who has been assigned to the control group to make them think they are getting the treatment under study. Point On a decision tree, the outcome of possible decisions made by the patient and clinician. The confidence interval tells you the range within which the true value of the result is likely to lie with 95% confidence. Point of indifference The probability of an outcome of certain death at which a patient no longer can decide between that outcome and an uncertain outcome of partial disability. Population The group of people who meet the criteria for entry into a study (whether they actually participated in the study or not). Positive predictive value Probability of disease after the occurrence of a positive test result. Power The probability that an experimental study will correctly observe a statistically significant difference between the study groups when that difference actually exists. Measure of random variation or error, or a small standard deviation of the measurement across multiple measurements. Predictive values The probability that a patient with a particular outcome on a diagnostic test (positive or negative) has or does not have the disease. Predictor variable The variable that is going to predict the presence or absence of disease, or results of a test. Prevalence The proportion of people in a defined group who have a disease, condition, or injury. Prognosis The possible outcomes for a given disease and the length of time to those outcomes. Important in studies on therapy, prognosis, or harm, where retrospective studies make hidden biases more likely. Publication bias The possibility that studies with conflicting results (most often negative studies) are less likely to be published. Random selection or assignment Selection process of a sample of the population such that every subject in the population has an equal chance of being selected for each arm of the study. Randomization A technique that gives every patient an equal chance of winding up in any particular arm of a controlled clinical trial. Referral bias Patients entered into a study because they have been referred for a particular test or to a specialty provider. Relative risk The probability of outcome in the group with exposure divided by the probability of outcome in the group without the exposure. Reliability Loose synonym of precision, or the extent to which repeated measurements of the same phenomenon are consistent, reproducible, and dependable. Representativeness heuristic The ease with which a diagnosis is recalled depends on how closely the patient presentation fits the classical presentation of the disease. Research question (hypothesis) A question stating a general prediction of results which the researcher attempts to answer by conducting a study. Retrospective study Any study in which the outcomes have already occurred before the study and collection of data has begun. Risk Probability of an adverse event divided by all of the times one is exposed to that event. Risk factor Any aspect of an individual’s life, behavior, or inheritance that could affect (increase or decrease) the likelihood of an outcome (disease, condition, or injury. Rule out To effectively exclude a diagnosis by making the probability of that disease so low that it effectively is so unlikely to occur or would be considered non-existent. Sampling bias To select patients for study based on some criteria that could relate to the outcome. Sensitivity The ability of a test to identify patients who have disease when it is present. Sensitivity analysis An analytical procedure to determine how the results of a study would change if the input variables are changed. Setting The place in which the testing for a disease occurs, usually referring to level of care. Specificity The ability of a test to identify patients without the disease when it is negative. Spectrum In a diagnostic study, the range of clinical presentations and relevant disease advancement exhibited by the subjects included in the study. Spectrum bias The sensitivity of a test is higher in more severe or “well-developed” cases of a disease, and lower when patients present earlier in the course of disease, or when the disease is occult. Standard gamble A technique to determine patient values by which patients are given a choice between a known outcome and a hypothetical-probabilistic outcome. Stratified randomization A way of ensuring that the different groups in an experimental trial are balanced with respect to some important factors that could affect the outcome. Strategy of exhaustion Listing all possible diseases which a patient could have and running every diagnostic test available and necessary to exclude all diseases on that list until only one is left. Subjective Information from the patient, the history which the patient gives you and which they are experiencing. Surrogate marker An outcome variable that is associated with the outcome of interest, but changes in this marker are not necessarily a direct measure of changes in the clinical outcome of interest. Survival analysis A mathematical analysis of outcome after some kind of therapy in which patients are followed for given a period of time to determine what percentage are still alive or disease-free after that time. Systematic review A formal review of a focused clinical question based on a comprehensive search strategy and structured critical appraisal of all relevant studies. Testing threshold Probability of disease above which we should test before initiating treatment for that disease, and below which we should neither treat nor test. Threshold approach to decision making Determining values of pretest probability below which neither testing nor treatment should be done and above which treatment should be begun without further testing. Time trade-off A method of determining patient utility using a simple question of how much time in perfect health a patient would trade for a given amount of time in imperfect health. Treatment threshold Probability of disease above which we should initiate treatment without first doing the test for the disease. Triggering A thought process which is initiated by recognition of a set of signs and symptoms leading the clinician to think of a particular disease. Two-tailed statistical test Used when alternative hypothesis is non-directional and there is no specification of the direction of differences between the groups. Unadjusted life expectancy (life years) The number of years a person is expected to live based solely on their age at the time.

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Disorders of the The pituitary gland lies in the sella turcica buy 120 mg sildalis visa, which is a hypothalamus itself are very rare generic sildalis 120 mg on-line; however sildalis 120mg visa, disorders of tightly enclosed bony space at the base of the cranium, the pituitary are common. The optic chiasm lies just above the pituitary fossa and the cavernous sinuses Pituitary adenomas run lateral to it. It consists of two lobes: Definition r The posterior lobe is a physical and functional exten- Pituitary adenomas are benign slow growing tumours sion of the ventral hypothalamus. Gene though the anterior lobe is of separate origin to the hy- mutationshavebeencharacterisedinsomepituitaryade- pothalamus,itisunderitsclosecontrol. The hy- Pathophysiology pothalamussecretespolypeptidehormonesthatregulate Seventy per cent of pituitary adenomas are functioning, anterior pituitary hormone secretion, mostly by stim- i. Increasingly asymptomatic hormone (10%) pituitary adenomas are found at incidental imag- ing. Continuing growth disrupts other hormone secretion and can result in hypopituitarism. Definition Macroscopy Hypopituitarism is a clinical term referring to under- r Tumours less than 1 cm in diameter without enlarge- function of the pituitary gland. This may imply a defi- ment of, or extension outside the pituitary fossa are ciency of single or multiple hormones. The commonest causes are pituitary or hypothalamic r Tumours ≥1–2 cm may extend outside the fossa to- tumours, or secondary to pituitary surgery or cranial wards the hypothalamus and optic chiasm, laterally radiotherapy (see Table 11. Pathophysiology Hypopituitarism may be primary due to destruction of Investigations the anterior pituitary gland or secondary to a deficiency r A mass within the sella turcica (pituitary fossa) may of hypothalamic stimulation (or excess of inhibition). Microadenomas take up less Symptoms and signs are related to the deficiency of hor- contrast and macroadenomas take up more contrast. General symptoms of panhy- Ifapituitarymassisidentified,hormoneassaysshould popituitarism include dry, pale skin with sparse body beundertakentoidentifyfunctioningadenomas. On examination postural hypotension and brady- ing also helps identify any associated hypopituitarism, cardia may be found with decreased muscle power and with stimulation or suppression testing where appro- delayed deep tendonreflexes. Management Investigations r Forprolactinomas medical treatment with a All functions of the pituitary should be assessed using dopaminergic drug is the treatment of choice (see sec- basal levels, stimulation tests and suppression testing tion on Hyperprolactinaemia, page 424). Progestagen is used to induce bleeding and Type Causes prevent endometrial hyperplasia. In ado- Pituitary apoplexy (haemorrhagic infarction of lescent males testosterone induces epiphyseal closure, pituitary tumour) so replacement therapy should be delayed as long as Infiltration Sarcoidosis, haemochromatosis, histiocytosis X possible. Treatment of associated infertility requires Injury Head trauma complex hormone replacement to stimulate ovula- Immunologic Organ-specific autoimmune disease Iatrogenic Surgery, irradiation tion/spermatogenesis. Pituitary haemorrhage causing death of the r Gonadotrophin deficiency in women may be treated lactotrophs results in failure of lactation (Sheehan’s with cyclical oestrogen replacement to maintain syndrome). The zona deficiency glomerulosa and aldosterone secretion usually remains relatively intact, so Addisonian crisis is rare. Clinical features Hyperprolactinaemia In women hyperprolactinaemia causes primary or sec- ondary amenorrhoea, oligomenorrhoea with anovula- Definition tion or infertility. Hyperprolactinaemia is a raised serum prolactin level Oestrogen deficiency can cause vaginal dryness and causing galactorrhoea and gondadal dysfunction. In men galactor- Incidence rhoea occurs occasionally, but the most common early Most common endocrine abnormality of the hypothala- features are decreased libido and sexual dysfunction, mic–pituitary axis. Complications Acromegaly Headache, visual impairment and hypopituitarism due to local effects of the adenoma. Sex Management M = F Prolactinomasaretreatedwithdopaminergicdrugssuch as cabergoline. The minority of tumours that do not Aetiology respond to medical treatment and hyperprolactinaemia r 95% of cases result from growth-hormone-secreting due to stalk compression are treated surgically. Sleep, exercise, stress Hypoglycaemia Postprandial hyperglycaemia/ free fatty acids Clinical features Glucocorticoids (hence short The course of the disease is slowly progressive. Soft tissue stature in children on overgrowth is the characteristic early feature, causing long-term oral steroids) enlargement of hands and feet, coarse facial features. Acne, sebaceous r Accompanying hypopituitarism is treated as appro- cysts and skin tags are common. Acanthosis nigricans priate with corticosteroids, thyroxine and gonadal of the axillae and neck may occur. Acromegaly causes increased morbidity and r Organomegaly: Thyroid and salivary gland enlarge- mortality mainly due to diabetes and cardiovascular dis- ment, hepatomegaly. Thyroid axis Macroscopy/microscopy The tumour is solid and trabecular, often 1 cm in diame- terbythe time of diagnosis. Oestrogens conversely increase the sensitivity suppress growth hormone production. Large tumours re-absorption of colloid by the cells and the production may be resected by transfrontal craniotomy. The majority of T is converted from the less active 3 r Octreotide or lanreotide, a long-acting somatostatin T4 by peripheral tissues. Disorders of the thyroid axis are analogue, may be used prior to surgery, following in- shown in Table 11. Fur- Age ther classification is based on whether the patient is hy- Increases with age. Irregularmultinodularenlargementofthethyroidgland, which may be hyperthyroid (toxic) or is commonly eu- thyroid (nontoxic). Clinical features Patients may present for cosmetic reasons, with thyro- Incidence/prevalence toxic symptoms, or because of complications. Multin- 25% of cases of thyrotoxicosis are due to multinodular odular goitre can present with a particularly promi- goitre. Causes include the following: r Benign follicular adenoma: Single lesions with well- Macroscopy/microscopy developed fibrous capsules. Nodules may be cystic, haemorrhagic and fi- hormones, which may result in hyperthyroidism. Enlargement of the gland can cause tracheal compres- r Thyroid cyst (15–25%): These may be simple cysts sion leading to shortness of breath and choking. About more common with retrosternal goitre, when the nod- 15% are necrotic papillary tumours. Toxic multinodular goitre has a particularly high incidence of cardiac arrhythmias and other cardiac complications. Clinical features Patients may present with a palpable lump or may be diagnosed on incidental imaging. Ultrasound scanning of the thyroid may be useful r History of neck irradiation exposure. Cystsand r Malignancy is more common in children and patients nodules may be aspirated by fine needle aspiration for over 60 years. Investigations Management r Thyroid function tests are used to determine thyroid Subtotal thyroidectomy may be required for cosmetic status. Isotope scans may also be used to demon- reasons or due to compression symptoms or thyrotoxi- strate either a cold nodule, a hyperactive gland (toxic cosis. Patients must be medically treated and euthyroid multinodular goitre) or a ‘cold’ gland containing a before surgery. A solitary mass within the thyroid gland that may be r Fine needle aspiration for cytology is used to differen- solid or cystic. Incidence Management 5% of population have a palpable solitary thyroid nod- Benign lesions only require treatment if they cause hy- ule. Up to 50% of population have a solitary nodule at perthyroidism or for cosmetic reasons. Chapter 11: Thyroid axis 431 If suspicious cells are identified on cytology a thyroid r The autoantibody can cross the placenta, causing lobectomy should be performed. Clinical features Graves’ disease (primary thyrotoxicosis) Hyperthyroidism produces palpitations, nervousness, fatigue, diarrhoea, sweatiness, tremor and intolerance Definition of heat. Weight loss with increased or normal appetite Graves’ disease is an autoimmune thyroid disease. Proptosis (exophthalmos) with lid retraction, stare and Sex lid lag are prominent features, and in its most severe F > M form it may cause sight loss due to damage to the optic nerve. Thyroid dermopathy (also called pretibial myxoedema) r Fifteen per cent of patients have a close relative with is a thickening or ‘orange-peel appearance’ of the skin, Graves’, and 50% of relatives have circulating thyroid most often affecting the lower leg. Microscopy The thyroid epithelial cells are increased in number and size with large nuclei.

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