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Alarm features also had limited Gastric cancer is the third commonest cause of cancer mortality utility in detecting any organic pathology (malignancy generic depakote 500mg without a prescription, pep- worldwide with nearly a million cases annually (22) and ofen tic ulcer disease buy genuine depakote on line, or esophagitis) (33) proven 500 mg depakote. Endoscopy can detect gastric cancer at such as weight loss, anemia, or dysphagia had sensitivities and an earlier stage (23) and therefore is advisable in patients at sig- specifcities of ~66% with a positive likelihood ratio of 2. It should be noted endoscopy to investigate dyspepsia should only be performed in that this guideline does not cover patients presenting with alarm patients aged 55 and over. We have raised this threshold further features such as progressive dysphagia and/or weight loss in the to >60 years of age as evidence that endoscopy was cost-efective absence of epigastric pain. Such patients do not meet defnitions at the 55-year-old threshold at that time was borderline in eco- for dyspepsia and are out of the scope of this guideline. Furthermore, in the 10 years since then the this guideline does not cover epigastric pain presentations which age-specifc incidence of gastric cancer has fallen further in the suggest a pancreatic or biliary source (e. Further, alarm features not discussed above We have given this statement a conditional recommendation, (e. Tere were four trials (43,4749) involving 1,608 dys- pancreas such as abdominal ultrasound. In patients <60 years pepsia patients that compared these strategies with 1-year follow up. A test probability of pancreatic cancer, even in those presenting with systematic review (50) found there was a trend towards a reduction dyspepsia, is likely to be very low in this population, and therefore in cost for H. The recommendation is conditional as the group or who continued to have symptoms despite eradication therapy. Current data have not tion of costs and endoscopy was very strong and there was little evaluated severe symptoms or combinations of features, so the clinically important heterogeneity among studies. The randomized need for endoscopy needs to be evaluated on a case-by-case basis trials that have evaluated H. T e evidence was graded as high as there were no concerns regarding heterogeneity, publication bias, imprecision, or risk of bias in the estimate of efect. The evidence is somewhat indi- rect as we are recommending this for dyspepsia patients who are H. All trials were high risk of bias and the efect was uncertain so the quality of the evidence was rated very low. Furthermore, the prokinetics that were evaluated in randomized trials (cisapride and mosapride) are not available in most countries worldwide. Given risks of potential side efects with prokinetics, they should be used at the lowest efective dose and consistent with country specifc safety recommendations (e. Although the impact on dyspepsia symptoms is Conditional recommendation low quality evidence modest, H. A systematic review (72) identifed 13 trials clearly outweigh the harms of antibiotic prescribing. Tese were all stopped if it is no longer providing beneft and patients should not excluded, as they did not meet a priori eligibility criteria. All other prokinetic data had signifcant unexplained Antidepressant therapies have been shown in randomized trials heterogeneity and there was evidence of publication bias, small to reduce symptoms in irritable bowel syndrome (124). Furthermore so it is plausible that antidepressants will also be efective for dys- some prokinetics have signifcant risk of adverse events (131) with pepsia symptoms. Tere was a statistically signifcant efect in reducing dys- serious arrhythmias in those with pre-existing cardiac conditions. A previous systematic review tion of patients might prefer not to take antidepressant medication. All trials reported a sta- tistically signifcant beneft of psychological therapies over con- trol, which was most commonly usual management. The studies were all high ever, this can be accurately identifed with only two specialized risk of bias as there was no blinding and this is important given motility studies (i. Tere was computed tomography), neither of which is readily available unexplained heterogeneity among studies and many used difer- (183). Tese interventions have (barostat and single-photon emission computed tomography) or been reviewed (131) and there are numerous proposed herbal expensive, invasive and uncomfortable (barostat), and because remedies as well as other approaches. Again the authors felt that the data were of very low of a spectrum of gastric sensorimotor disorders (182). Abnormal gastric accommodation has of severe nausea and vomiting who fail empiric therapy. Symptom overlap between post- conducting systematic reviews that support this guideline. Diagnosis and management of gastro- Gerson for providing leadership in the process that supported this esophageal refux disease. T e Toronto consensus for the treatment of Helicobacter pylori infection in adults. Rating quality of evidence and evidence for each statement and the writing of the article. Rating quality of evidence and Potential competing interests: Paul Moayyedi has accepted speaker strength of recommendations: going from evidence to recommendations. Andrews has honoraria from Allergan, impact of the two week wait scheme on diagnosis and outcome of upper gastrointestinal cancer. Deaths and mortality rate, by selected (eds) Ancient Letters: Classical and Late Antique Epistolography. Functional dyspepsia: the eco- of cancer in primary care cohort study using General Practice Research nomic impact to patients. Can J Gastroenterol of a "test and treat" policy versus endoscopy based management in young 2005;19:285303. Aliment Pharmacol Ter H2-blocker therapy or prompt endoscopy in management of dyspepsia. Cost-efectiveness of initial endo- Helicobacter pylori Positive Patients With Dyspepsia in General Practice, scopy for dyspepsia in patients over the age of 50 years: a randomised Is It Necessary? University of Wales College of MedicineFinal Study controlled trial in primary care. Tr e a t i n g Helicobac- controlled trial of four management strategies for dyspepsia: relationships ter pylori infection in primary care patients with uninvestigated dyspepsia: between symptom subgroups and strategy outcome. Br J General Pract the Canadian adult dyspepsia empiric treatmentHelicobacter pylori 2001;51:61924. Beneft of Helicobacter pylori eradication in the management strategies for dyspepsia. Int J Technol Assess Health Care treatment of ulcer-like dyspepsia in primary care.

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Fertile for 5 7 days before ovulation If post-menopausal discount depakote online master card, when did periods stop and are there any symptoms Past gynaecological problems or procedures ? To avoid embarrassment depakote 250 mg low price, just ask straight Cigarette generic depakote 500mg on-line, alcohol and recreational drug use Occupation ? Check experiences with past exams Ensure chaperon if male Have available: light, additional light source and mirror for the patient Check bladder is empty Clear instructions to patient on what clothes to remove and position. Use narrow speculum for nulliparous, wider speculum for multiparous, and paediatric for child or sometimes post menopausal. If its left in then risk of chorioamnioitis, miscarriage or pre-term labour Mirena carries levonorgestrel (a progesterone) risk of implantation and lighter periods (Good for menorrhagia). Adverse effects are dose related give lowest dose that gives good cycle control. Contraceptive cover immediate Breakthrough bleeding is very common especially in the first 3 months. Can add 20 g estradiol every 24 hours, 12 hours after the usual pill, for one week. Little evidence that its not safe to continue to menopause Progesterone Only Pill (PoP) = Mini-pill Cervical mucus hostile to sperm (G Type mucus) + prevent ovulation in some + tubal motility. Small risk of follicular cyst (one that doesnt pop) pain with full bladder or rectum Worst side effect: erratic bleeding. For post-partum contraception see Six Week Check, page 374 Contraindications: History of ectopic pregnancy, breast cancer, liver disease or enzyme inducing drugs Must be taken same time each day (+/- 3 hours). Safe again after 2 days of restarting the pill Depot progestogen: Safe, simple and effective (failure rate 0. Has been discussion of risk of prostate cancer best evidence says no association. Prophylactic cover if suspected Suspicion of Abuse or Interpersonal Violence It is common and victims are high users of health services Epidemiology: 20% of women report sexual abuse before 16, full intercourse reported by 4%. Ever had bruises or had to stay in bed Sexual: Did anything sexually frightening happen to you as a child or young adult, have you ever been made to participate in sexual activity that made you feel uncomfortable. If very recent then nil- by-mouth and collect all urine and toilet paper until forensic examination. Rarely Turners syndrome or testicular feminisation Secondary amenorrhoea: when periods stop for > 6 months, except for pregnancy: Hypothalamic-pituitary-ovarian causes common. If withdrawal bleed following, then there is enough oestrogen to produce an endometrium Ovarian causes are uncommon: Polycystic ovarian syndrome, tumours, premature menopause Hyperthyroidism oestrogen breakdown Investigation: Pregnancy Test -ive 5 day progesterone challenge: +ive withdrawal bleed? Diagnosis of Reproductive and Obstetrics 345 exclusion Oligomenorrhoea: infrequent periods: common in the young and the nearly menopausal. Most often on ovaries and uterosacral ligaments Chronic and progressive: inflammation and local haemorrhage fibrosis and scarring Incidence: 10 15% of reproductive age. Patients usually in mid 30s early 40s, nulliparous Common in infertility and chronic pelvic pain Aetiology theories: Retrograde menstruation homologous grafts Genetics: 7 fold risk if +ive family history. Usually earlier and more severe disease Symptoms: classic triad = pelvic pain, deep dyspareunia, dysmenorrhoea. Also irregular bleeding, infertility (scars fallopian tubes) On exam: tender, retroverted uterus Confirmation by laproscopy. Red brown nodules on surface of ovaries and pelvic structures, and other sites (appendix, peritoneal scars, etc). Can develop large cysts, lined by endometrial stroma and glands and containing changed blood (chocolate cysts). Fix either in 95% ethyl alcohol for 20 - 30 minutes or cytofix sprayed from 20 30 cms. Can stop if > 5 years with no sex (this bit not in the guideline) Screening should be yearly for 2 years from 20 (some advocate starting earlier if > 2 years since commencing regular sex but as cancer in this age group is very uncommon, its not good screening practice. If cysts have smooth internal epithelium likely to be benign Borderline (20%): mucinous tumour of borderline malignancy. No atypia, minimal risk of carcinoma Complex hyperplasia: More crowded gland with budding and infolding. With atypia, 5% progress to carcinoma th th 354 4 and 5 Year Notes Complex hyperplasia with atypia: crowded, folded gland in which the lining cells are pleomorphic with loss of polarity and increased nuclear cytoplasmic ratio. If 6 weekly cycle, add 2 weeks (ovulation set by end of cycle not beginning) Date it well. See History, page 338 Actively treat any infection Any chronic infections (eg Herpes) Polycystic ovaries, uterine abnormality or surgery risk Gynaecological cancer: pregnancy hormones may exacerbate the disease Contraceptive history talk about restarting after pregnancy Smear history: last smear date, any abnormal Past Medical and Surgical History (and maybe very brief systems review): History of hypertension (any signs of renal disease? Reassure, small meals and stress Headaches, palpitations and fainting due to peripheral dilation. Give fibre and lots of fluid Reflux oesophagitis rd Backache in 3 trimester Carpal tunnel syndrome (due to fluid retention) Itchy rashes Ankle oedema almost universal. At 20 weeks up to umbilicus Lie and presentation from 32 weeks Fetal heart: use Doppler (mum can hear it too). Is the baby transverse or longitudinal Measure fundal height Find poles to determine lie Where is the back: Feel laterally (brace hand other side), then walk hands across. Score of fetal heart rate, breathing movements, fetal movement, fetal tone and amniotic fluid volume. Serum levels, maternal age and gestational age are used to calculate the risk of neural tube defects and chromosomal abnormalities classification as high risk (eg 1:50 for Down) or low risk (1:2700 for Down). If mosaic, skin cells in fetus closer to the babies karyotype than placental cells Amniocentesis: from 14 weeks (10 13 weeks 5% miscarriage). Culture amniotic cells for 2 3 weeks detects chromosomal abnormalities and neural tube defects. Difficult if anterior placenta or oligohydramnios Cordocentesis (Percutaneous umbilical blood sampling): from 18 weeks. These people to be chosen by the Abortion supervisory committee, with a view to expeditious access by any woman seeking an abortion. Supervisory committee also appoints/approves counselling services Ethics: Why is killing wrong: Violates the moral integrity of the entity killed It has negative consequences Evidences moral flaws in the killer Reasons for killing: to end suffering, to protect the innocent, lesser of two evils, to express societal condemnation Different views of the moral status of the fetus: Fetus has the same moral status: absence of a dividing line between a baby and a fetus does not show lack of difference Fetus has no moral status: Is seeking an abortion for trivial reasons wrong? Associated with preterm delivery Incomplete abortion: cervix is dilating, more pain, heavier bleeding. Usually active management to remove fetus Causes: None found most common Chromosomal abnormalities Hormonal imbalance: eg failure of corpus luteum to produce enough progesterone Maternal illness, abnormalities of the uterus (eg cervical incompetence), immunological factors Recurrent miscarriage = loss of 3 or more consecutive pregnancies, occurs in < 1% Ectopic pregnancy = Any implantation outside the uterine cavity. Atypical some initially have a fetus proliferation proliferating trophoblast Little invasive potential 10% invasive, Most have metastasised at Choriocarcinoma 5% diagnosis.

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Many of the pathogens that cause nosocomial infec- Aetiology tions have a high level of antibiotic resistance cheap 500 mg depakote visa, which is See Table 1 buy depakote 500 mg mastercard. Cause % Examples Infection 3040 Bacterial infections bacterial endocarditis order depakote visa, abscess (e. Previous illnesses including operations and psychi- r transoesophageal echocardiography for infective atric illnesses. Blind treatment should be avoided unless the patient is A full systematic examination is required including the septicaemic or deteriorating. In such cases a best guess following: of the cause and hence the antibiotic cover has to be r Documentation of pattern and duration of fever. Hypotension re- r Septicaemia is used to describe organisms multiplying sults from widespread induction of nitric oxide causing in blood causing symptoms. The systemic inammatory response syndrome is de- r Septic shock refers to the presence of severe sepsis with ned as follows: r Temperature over 38C or less than 36C. Specic causes include Organ hypoperfusion may manifest as altered mental r direct introduction of bacteria into the blood stream state, lactic acidosis or oliguria. Airway patency and oxygenation must be maintained and may require Pathophysiology theuseofanoropharyngealairwayorendotrachealin- The normal mechanisms involved in overcoming in- tubation. Blood pressure support involves aggressive fection become detrimental when the infection is uid replacement via wide bore canulae with care- generalised. Septicaemia from the urinary tract should adrenaline, noradrenaline, dopamine or dobutamine be treated with a cephalosporin and gentamicin. Pseudomonas infection is suspected piperacillin or r Identication and management of underlying causes ciprooxacin are effective. Septicaemia originating in skin and soft tis- sue infections requires ucloxacillin and benzylpeni- Prognosis cillin. Chest pain can arise from the cardiovascular system, the r Angina that occurs at rest or is provoked more easily respiratory system, the oesophagus or the musculoskele- than usual for the patient is due to acute coronary syn- tal system. Some patients describe a feeling r Alleviating factors of impending doom (angor animi). It is a ret- r Exacerbating factors rosternal or epigastric pain that radiates to the neck, r Symptoms associated with the pain back or upper abdomen. The pain of pericarditis may last days or even 23 (particularly the left) and jaw. Its onset is abrupt and of greatest intensity at the and may hang their legs over the side of the bed or go time of onset. Chest pain associated with tenderness is suggestive of r CheyneStokes respiration is alternate cyclical hy- musculoskeletal pain. Oesophageal pain is a ret- failure, in some normal individuals (often elderly), in rosternal sensation often related to eating and may be patients with cerebrovascular disease and patients re- associated with dysphagia. It is thought that this pattern retrosternal burning pain, often exacerbated by bending of breathing results from depression of the respiratory forwards. Equally,painarisingfromstructures r Patients with severe acute left ventricular failure often in the chest may present as abdominal pain, e. Dyspnoea However, the major causes of frank haemoptysis are from the respiratory system. In general dyspnoea arises from either the respiratory or cardio- vascular system and it is often difcult to distinguish Palpitations between them. The patient may notice it on strenuous a missed beat, or their heart beating irregularly. In severe failure, patients are breath- rate and rhythm (ask the patient to tap out the beat with less at rest. Associated symptoms may include breath- pnoea an underlying cause should be sought, such as lessness, dizziness, syncope and/or chest pain. This symptom normally arises when a patients exer- r Palpitations lasting just a few seconds are often due cise tolerance is already reduced. The patient becomes aware of the mechanisms are responsible for this phenomenon: a pause that occurs in the normal rhythm after a prema- redistribution of uid through gravity in the lungs ture beat and may sense the following stronger beat. Some patients may know how to terminate propping themselves up on pillows at night, or, in se- their rapid palpitations with manoeuvres such as vere cases, sleeping in a chair. Orthopnoea is highly squatting, straining or splashing ice-cold water on the suggestive of a cardiac cause of dyspnoea, although it face. These features are very suggestive of a distinct may also occur in severe respiratory disease due to the tachyarrhythmia rather than general anxiety or pre- second mechanism. It is thought to occur by a simi- Syncope lar mechanism to orthopnoea coupled to a decreased sensory response whilst asleep. Patients awake breath- Syncope is dened as a transient loss of conscious- less and anxious, they often describe having to sit up ness due to inadequate cerebral blood ow. There may be no warning, or patients may describe feel- The distance a patient can usually walk on the at be- ing faint, cold and clammy prior to the onset. Asthenarrowing tend to be ushed and sweaty but not confused (unless ofthearteriesbecomesmoresignicant,theclaudication prolonged hypoxia leads to a tonic-clonic seizure). Eventually rest pain may occur, this r Vasovagal syncope is very common and occurs in the often precedes ischaemia and gangrene of the affected absence of cardiac pathology. The heart contracts force- fully, which may lead to a reex bradycardia via vagal Oedema stimulation and hence a loss of consciousness. A number of mechanisms tion, hypovolaemia or due to certain drugs especially arethoughttobeinvolvedinthedevelopmentofoedema. Normally tissue uid is formed by a balance of hydro- r Cardiac arrhythmias may result in syncope if there is a static and osmotic pressure. This may oc- Hydrostatic pressure is the pressure within the blood cur in bradycardias or tachycardias (inadequate ven- vessel (high in arteries, low in veins). The loss of consciousness occurs produced by the large molecules within the blood (albu- irrespective of the patients posture. A StokesAdams min, haemoglobin) and draws water osmotically back attack is a loss of consciousness related to a sudden into the vessel. The hydrostatic pressure is high at the loss of ventricular contraction particularly seen dur- arterial end of a capillary bed hence uid is forced out of ing the progression from second to third degree heart the vasculature (see Fig. The colloid osmotic pressure then draws uid back in r Carotid sinus syncope is a rare condition mainly seen at the venous end of the capillary bed as the hydrostatic in the elderly. As a result of hypersensitivity of the carotid sinus, light pressure, such as that exerted by atight collar, causes a severe reex bradycardia and hence syncope. The syncope results from an inability of the heart to increase cardiac output in response to in- Hydrostatic Oncotic 0ncotic Hydrostatic creased demand.

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Thus buy genuine depakote, Roche is currently the worlds second biggest sup- plier of biotechnological products and purchase 500 mg depakote with visa, with more than 50 new drug projects under way at present cheap 500 mg depakote visa, has the worlds strongest early development pipeline in this area. Aventis and Glaxo- SmithKline, each with 45 drug candidates, share second place in this ranking. Amgen, currently the worlds largest biotech com- pany, had about 40 drug candidates in the pipeline in 2004. At the same time, worldwide growth in the biotechnology market shows no sign of slackening. Thus, at present 40% of the 22 sales of Roches ten best-selling pharmaceutical products are ac- counted for by biopharmaceuticals, and this figure is rising. The many young biotech companies with drug candidates now ap- proaching regulatory approval are also banking on this growth. Sales of these will support their development pipelines and thereby also intensify com- petition in this field. A comparison of the de- velopment pipelines of the big companies with those of the gen- erally smaller companies that are devoted exclusively to bio- technology suggests that this concentration is likely to become even greater in the coming years, though given the spectacular growth rate of this sector, the possibility of surprises cannot be ruled out. What is clear is that biotechnology has had a decisive influence on the pharmaceutical market and that the upheaval is not yet at an end. Spektrum Akademischer Verlag, Heidelberg, 4th edition 2003 Die Arzneimittelindustrie in Deutschland Statistics 2004. For example, complex biomolecules such as proteins can only be produced by living cells in complex fermentation plants, yet they have the potential to open up entirely new directions in medicine. Biopharmaceuticals Though you might not think so at first glance, transform medicine modern biotechnology and traditional drug de- velopment have much in common. The aim of both, for example, is to develop substances able to cure or pre- vent disease. For most patients it is a matter of indiffer- ence whether a drug is obtained by biotechnological or chemi- cal means. However, beneath the surface there are striking differences between the two kinds of drug product. On the other hand, therapeutic proteins, the largest group of biopharmaceuticals, are quite a different kettle of fish. They are made up of dozens, Terms sometimes hundreds, of amino acids, each of which Biopharmaceuticals drugs manufactured using biotech- nological methods. To take an example, the ac- Enzymes biocatalysts; proteins able to facilitate and accel- erate chemical reactions. Fermentation a chemical reaction in which biological sub- ic compound made up of 62 stances are acted upon by enzymes. Rituxan (rituximab), is nearly 350 times heavier, weighing in at a hefty 150,000 daltons. No wonder this large molecule poses entirely different challenges for research, devel- opment and production. Each of the amino acid residues in the protein erythropoietin is comparable to an aspirin molecule in size. Drugs from the fermenter 27 Proven methods The most important consequence of the size dif- for small molecules ference between traditional and biotechnological drugs relates to their structure. The three-dimen- sional shape of simple organic molecules, known in chemical parlance as small molecules, is essentially determined by fixed bonds between the individual atoms. As a result, traditional drugs are usually highly stable compounds that retain their three-dimensional shape in a wide range of ambient conditions. Traditional drugs are usual- ly easy to handle and can be administered to patients conve- niently in various forms such as tablets, juices or suppositories. It is true that many traditional drugs were originally derived from natural products. For example, healers used an extract of the leaves or bark of certain willow species to treat rheumatism, fever and pain hundreds of years before the Bayer chemist Felix Hoffmann reacted the salicylate in the extract with acetic acid in 1897 to form acetylsalicylic acid, a compound that is gentler on the stomach. The methods have been tried and tested for decades, and the drugs can be manufactured anywhere to the same standard and in any desired amount. Ster- ile conditions, which pose a considerable technical challenge, are rarely necessary. On the other hand, preventing the organic solvents used in many traditional production processes from damaging the environment remains a daunting task. Unstable structure Biopharmaceuticals require a far more elaborate of proteins production process. Most drugs manufactured by biotechnological methods are proteins, and pro- teins are highly sensitive to changes in their milieu. Their struc- ture depends on diverse, often weak, interactions between their amino-acid building blocks. These interactions are optimally coordinated only within a very narrow range of ambient condi- tions that correspond precisely to those in which the organism from which the protein is derived best thrives. Because of this, even relatively small changes in the temperature, salt content or pH of the ambient solution can damage the structure. This, in turn, can neutralise the function of the protein, since this de- pends on the precise natural shape of the molecule. Most of these mole- cules act as vital chemical Detecting signals: interferon gamma and its receptor messengers in the body. The target cells that receive and translate the signals bear special receptors on their surface into which the cor- responding chemical mes- senger precisely fits. If the three-dimensional shape of The signal protein interferon gamma (blue) is recognised by a the chemical messenger is specific receptor (left and right) located on the surface of its even slightly altered, the target cells. Interferon gamma as a biopharmaceutical is used to treat certain forms of immunodeficiency. The situation is similar for another group of therapeutic proteins, the antibodies. Their function is to recognise foreign structures, for which purpose they have a special recognition region whose shape pre- cisely matches that of the target molecule. Changing just one of the several hundred amino acids that make up the recognition region can render the antibody inactive.

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