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The 1980s and 1990s have led to the widespread use of a host of new drugs erectile dysfunction treatment electrical discount levitra plus 400 mg overnight delivery, such as the taxanes (paclitaxel and docetaxel) erectile dysfunction pre diabetes generic levitra plus 400 mg on-line, ifosfamide generic erectile dysfunction drugs in canada cheap levitra plus 400 mg without a prescription, the topoisomerase inhibitors (topotecan and irinotecan) drugs for erectile dysfunction pills discount levitra plus uk, and nucleoside analogs (gemcitabine and capecitabine). The growing number of agents in the chemotherapeutic armamentarium has been accompanied by advances in alternative dosing regimens; differing formulations using liposomal or polymer-based encapsulation; and varying schedules, sequences, and routes of administration. A thorough knowledge of the cell cycle and growth kinetics is fundamental to understanding of the appropriate uses of chemotherapy. The physician can, with use of these drugs, ameliorate and sometimes even cure diseases that were usually fatal in the past. Until recently, in most cases chemotherapy has been reserved for relatively late stages of the disease, but its increasingly successful use, particularly in the treatment of hematologic malignancies, suggests that chemotherapy should be administered earlier. All physicians and surgeons must understand the nature and use of cancer chemotherapy so that they can make rational decisions about when it may be indicated. The clinical response to chemotherapy may be assessed utilizing standard Response Evaluation Criteria in Solid Tumors defined by the National Cancer Institute (Table 17-1). Control appears to be mediated by an unknown feedback mechanism, probably resulting from contact phenomena when cells are crowded together. Knowledge of growth patterns has aided in the derivation of chemotherapeutic principles. Strategies for therapy have evolved to take advantage of these differences in growth characteristics between normal and malignant tissues. Normal tissues fall into three predominant categories: static, expanding, and renewing. Static populations of cells are generally well differentiated and after a period of proliferation in fetal life rarely undergo division during adult life. Expanding tissue populations are also usually inactive in adult life, but unlike static populations they retain the ability to proliferate rapidly in response to stress or injury. Last, the renewing cell populations are those that are constantly undergoing division, such as bone marrow and gastrointestinal epithelium. Renewing tissues are most sensitive to injury by chemotherapeutic agents (Table 17-2). In the malignant growth, cells do not cease multiplying when they reach a critical mass. This unregulated growth appears to result from a combination of loss of normal cell cycle controls and a failure of normal apoptotic mechanisms. Despite uncontrolled growth, malignant cell division does not appear to be more rapid than normal cell division. In general, as tumors grow they display gompertzian growth characteristics (Figure 17-1): As the tumor mass increases in size, the time necessary to double its size also becomes progressively longer. Thus, in the early phases of growth, tumor cells appear to grow exponentially, but as tumor mass increases there is a progressive increase in the doubling time, although doubling times in humans may vary greatly. For example, embryonal tumors and some lymphomas have relatively short doubling times (20-40 days), whereas adenocarcinomas and squamous cell carcinomas have relatively long doubling times (50-150 days). A decrease in the growth fraction (cells participating in cell division in the tumor) 3. An increase in cell loss from tumor cells with insufficient nutrients and vascular supply the gompertzian model has several important implications for cancer progression. A 5-mm mass (a size that is first recognizable on a radiograph) may have undergone 27 doublings. It follows that a 1-cm mass will have undergone 30 doublings, and a clinician will be pleased to have detected such an "early" lesion. Using this rationale, clinical techniques that are currently available tend to recognize malignancies late in their growth, and metastatic disease may well have occurred long before there was obvious clinical manifestation of the primary lesion. Another implication from this kinetic information is that in late stages of tumor growth a few doublings in tumor mass make a dramatic impact on the size of the tumor and the status of the patient. Once a tumor becomes palpable (1 cm in diameter-30 doublings), only three more doublings will produce a very large tumor mass (8 cm in diameter). The gompertzian model also has clinical implications that have guided a good deal of clinical chemotherapy research. Although these sequential combinations have been theoretically attractive, none has shown clear superiority in clinical trials. The smaller the size of the metastatic focus, the greater is the differential sensitivity. Therefore the insensitivity of a primary tumor to a given drug regimen might not necessarily predict the response of metastasis to the same regimen. The rationale for the use of drugs in the treatment of cancer is to achieve the selective killing of tumor cells. Underlying this rationale are the basic principles of the "cell kill" hypothesis first described by Skipper and associates. The survival of an animal with cancer is inversely related to the number of cancer cells. For most drugs, a clear relationship exists between the dose of the drug and its ability to eradicate tumor cells. A given dose of a drug kills a constant fraction of cells, not a constant number, regardless of the cell numbers present. This fourth and most important principle implies that chemotherapeutic agents work by first-order kinetics- that is, they kill a constant fraction of cells rather than a constant number.
Tubular proteinuria Some proteins are so small that impotence lisinopril discount 400 mg levitra plus with visa, unlike albumin and other larger proteins vegetable causes erectile dysfunction purchase levitra plus 400 mg fast delivery, they pass through the glomerulus freely erectile dysfunction ear order cheap levitra plus on line. If these proteins are detected in excess in the urine erectile dysfunction medication wiki order 400mg levitra plus overnight delivery, this reflects tubular rather than glomerular dysfunction, i. However, tubular function is normally investigated in other ways, and the measurement of these proteins in urine is normally confined to the screening and detection of chronic asymptomatic tubular dysfunction, or a small number of specific clinical scenarios. Its significance lies in the fact that, unlike the other proteins mentioned above, it is not derived from the blood, but rather is produced and secreted into the filtrate by the thick ascending limb of the loop of Henle. It forms large aggregates that, when concentrated, can in turn form urinary casts (gel-like cylindrical structures that reflect the shape of the renal tubules and that get dislodged and pass into the urine). When Overflow proteinuria Overflow proteinuria occurs when the ability of the glomeruli to hold back Normal Overflow Glomerular Tubular Secreted. Dipstick urinalysis the procedure for dipstick urine testing is shown in Figure 16. Dipsticks are commercially available disposable strips, impregnated with coloured reagent blocks, which are immersed in urine. The reagents in each block react with a specific component of urine in such a way that the block changes colour if the component is present. Protein is just one of several components tested for; others include glucose, blood and bilirubin. It is convenient for both patient and clinician, and provides a near-instant result at the point of care. However, it gives only a rough indication of the presence or absence of pathological proteinuria, and cannot be used alone to diagnose or exclude proteinuria. An early morning sample is preferred (because it correlates best with 24-hour protein excretion) but random samples are acceptable. Urine protein excretion A 24-hour timed urine collection for protein excretion is still widely used as the reference method for comparing other ways of assessing urine. However, timed urine collections are inconvenient and not always completely accurate. However, these immunoassay methods are more expensive than those used to measure urine total protein. It is a benign condition in which proteinuria occurs only when the subjects are standing upright, and is a result of an increase in the hydrostatic pressure in the renal veins. Accuracy is further improved by measuring the urinary creatinine concentration as well and expressing the result as the protein/creatinine ratio; this corrects for Case history 12 A patient attending the hospital outpatient clinic is found to have proteinuria on dipstick testing. This leads to a relatively higher serum urea concentration than creatinine, which is not so readily reabsorbed. Metabolic acidosis: because of the inability of the kidney to excrete hydrogen ions. It usually presents as a sudden deterioration of renal function indicated by rapidly rising serum urea and creatinine concentrations. As acute renal failure is common in the severely ill, sequential monitoring of kidney function is important for early detection in this group of patients. Usually, urine output falls to less than 400 mL/24 hours, and the patient is said to be oliguric. Causes include: n n n n decreased plasma volume because of blood loss, burns, prolonged vomiting, or diarrhoea diminished cardiac output local factors, such as an occlusion of the renal artery. If these pre- or post-renal factors are not corrected, patients will develop intrinsic renal damage (acute tubular necrosis). Post-renal: the urinary drainage of the kidneys is impaired because of an obstruction. Biochemical findings in pre-renal uraemia include the following: n Acute tubular necrosis Acute tubular necrosis may develop in the absence of pre-existing pre-renal or post-renal failure. Urea is increased disproportionately more than n acute blood loss in severe trauma septic shock specific renal disease, such as glomerulonephritis nephrotoxins, such as the aminoglycosides, analgesics or herbal toxins. Classification: Pre-renal Post-renal Renal Patients in the early stages of acute tubular necrosis may have only modestly increased serum urea and creatinine that then rise rapidly over a period of days, in contrast to the slow increase over months and years seen in chronic renal failure. The biochemical features that distinguish pre-renal uraemia from intrinsic renal damage are shown in Table 18. Care should be taken that the patient does not become 18 Acute renal failure Table 18. Indications for dialysis include a rapidly rising serum potassium concentration, severe acidosis, and fluid overload. Urine volume (mL/24 h) 5000 4000 3000 2000 1000 0 1 Oliguria Diuresis Recovery Reference range 2 3 4 5 6 7 Days 8 9 10 11 12 Recovery There may be three distinct phases in the resolving clinical course of a patient with acute renal failure (Fig 18. An initial oliguric phase, where glomerular impairment predominates, is followed by a diuretic phase when urine output is high, as glomerular function slowly improves but tubular function remains impaired. The serum potassium usually rises very quickly in catabolic patients, with or without tissue damage, and falls quickly once the urine flow rate increases. Prompt identification of pre- or post-renal factors may allow correction of the problem before damage to nephrons occurs. Management of a patient with intrinsic renal damage will include sequential measurement of creatinine, sodium, potassium, phosphate and bicarbonate in serum, and urine sodium and potassium excretion and osmolality. Care should be taken to prevent fluid overload in the treatment of patients with renal disease. The rapidly increasing serum potassium is usually the indication to start the patient on dialysis. The end result of progressive renal damage is the same no matter what the cause of the disease may have been. The major effects of renal failure all occur because of the loss of functioning nephrons.
Vaginal examination There may be discharge or tenderness associated with pelvic inflammatory disease erectile dysfunction how can a woman help purchase levitra plus with american express. For the purpose of description of localised swellings erectile dysfunction caused by lack of sleep discount levitra plus 400 mg otc, the abdomen has been divided into seven areas erectile dysfunction zinc deficiency order on line levitra plus, i smoking erectile dysfunction statistics order levitra plus online. Hepatomegaly, splenomegaly and renal masses, although referred to in this section, are dealt with under the relevant heading in the appropriate section of the book. Recent weight loss may suggest carcinoma of the head of the pancreas or carcinoma of the gall bladder. Right colon Lassitude, weakness, lethargy suggesting anaemia from chronic blood loss. Central abdominal colicky pain, vomiting and constipation and change in bowel habit will suggest colonic carcinoma. It is large and smooth and moves with respiration, projecting from under the ninth costal cartilage at the lateral border of rectus abdominis. Empyema presents with an acutely tender gall bladder, which is difficult to define due to pain and tenderness. Carcinoma of the gall bladder may present as a hard, irregular mass in the right hypochondrium, but normally presents as obstructive jaundice due to secondary deposits in the nodes at the porta hepatis causing external compression of the hepatic ducts. Right colon Faeces are usually soft and putty-like and can be indented but may also feel like a mass of rocks. A diverticular mass is usually tender and ill-defined, unless there is a large paracolic abscess. With caecal volvulus, there is a tympanitic mass which may be tender with impending infarction. With intussusception, there will be a smooth, mobile tender sausage-shaped mass in the right hypochondrium. Colon Lower abdominal colicky pain and change in bowel habit may suggest carcinoma or diverticular disease. Pancreatic tumours may be impalpable or present as a fixed mass, which does not move with respiration. Although a full list of epigastric swellings is given below, only those not referred to in other sections will be discussed in the history and examination sections. They may become strangulated, in which case they are tender, and occasionally the skin is red. Occasionally a patient may indicate a firm bony lump in the upper epigastrium, which is in fact a normal xiphisternum. This may have become apparent due to either a deliberate attempt to lose weight or sudden weight loss as a result of underlying disease. Metastatic deposits may present as single or multiple fixed lumps in the skin or subcutaneous tissue. Retroperitoneum A history of backache may suggest an aortic aneurysm or the patient may complain of a pulsatile epigastric swelling. A fatty, occasionally tender, nonmobile swelling in the midline will suggest an epigastric hernia. The majority of epigastric hernias are composed of extraperitoneal fat, although there may be a sac with bowel contents. Hard, irregular, fixed lumps in the abdominal wall suggest metastatic deposits, especially if there is a history of carcinoma of the breast or bronchus. Retroperitoneal lymph node metastases from testicular cancer may present as a AbdominAl SwellingS 17 large retroperitoneal mass. Check all other sites for lymphadenopathy (especially the left supraclavicular node). Only those not referred to in those sections will be discussed in the history and examination sections. It is due to secondary deposits of carcinoma of the stomach, colon, ovary or breast. Hernia An umbilical hernia presents in infancy as an umbilical swelling which is reducible, and will usually have been noted at birth. It may present with incarceration or with a tender painful swelling, suggesting strangulation. Small bowel Small bowel masses are usually very mobile, may be sausage-shaped, and may be tender. A spigelian hernia occurs just lateral to the rectus muscle, halfway between the umbilicus and symphysis pubis. Large bowel A short history of central abdominal, colicky pain followed by a sharply localised pain in the right iliac fossa will suggest the diagnosis of acute appendicitis. After 48 hours, if there is not generalised peritonitis, an appendix mass will have formed and an abscess may subsequently form in the right iliac fossa. With carcinoma of the caecum, the patient will either have noticed a mass or will present with alteration in bowel habit and the symptoms of anaemia. Faeces will be indentable and hard, rock-like masses will be felt around the colon. Caecal volvulus will present with central abdominal colicky pain and abdominal distension. Sigmoid volvulus will present with lower abdominal colicky pain and a tense, palpable mass in the left abdomen, which is tympanitic on percussion.
These findings doctor's guide to erectile dysfunction buy generic levitra plus online, however impotence grounds for annulment philippines buy levitra plus 400mg overnight delivery, do not exclude the possibility of hepatic metastasis erectile dysfunction videos discount 400 mg levitra plus free shipping, giving rise to localized areas of intrahepatic obstruction impotence causes cheap levitra plus 400mg. A normal serum calcium does not exclude the possibility of bone metastasis, which is another source of the high alkaline phosphatase activity. A third possibility is that there may be a local recurrence with the tumour itself producing alkaline phosphatase, though this would be very unlikely. The diagnosis of diabetes mellitus is not confirmed until specimens collected on at least two separate occasions place the patient in the diabetic category. Case history 19 By far the most likely diagnosis based on the information given is the nephrotic syndrome. In the nephrotic syndrome you would expect the serum albumin to be low and the urinary albumin to be high. Although the glomerular basement membrane may be damaged, the glomerular filtration rate is usually normal in the early stages of the nephrotic syndrome. This patient is likely to be losing immunoglobulin and some of the components of the complement system in her urine and this could lead to a relative immune deficiency. Case history 26 By far the most likely diagnosis in this case is diabetic ketoacidosis. This may have caused anorexia and, thus, the patient may have omitted to take her insulin. The blood glucose can be checked at the bedside as can a specimen of urine for the presence of ketones. The laboratory tests that may be requested are urea and electrolytes to assess renal function, the presence or absence of hyperkalaemia and the serum sodium concentration. It is essential in cases such as this that samples of blood and urine and, if appropriate, sputum are sent to the microbiological laboratory to look for the presence of infection. Case history 23 In this case, the most likely diagnosis is carcinoma of the head of the pancreas obstructing the common bile duct. The other major differential would be enlarged lymph nodes at the porta hepatis obstructing the common bile duct, which would explain the clinical picture as well as pancreatic cancer. Other differentials include cholangiocarcinoma and gall stones, although these are unlikely. This is uncomplicated obstructive jaundice, which is characterized by an alkaline phosphatase activity that is more than three times the upper limit of the reference interval. The aspartate and alanine aminotransferase activities do not indicate severe hepatocellular damage. By far the most important further investigations to be performed on this patient would be to image the structures in the vicinity of the head of the pancreas and the common bile duct looking for the cause of the obstruction. He is one of the approximately 20% of patients with myeloma that do not have a paraprotein in the serum but have Bence Jones proteinuria. The diagnosis can be made by measuring her blood glucose while she is symptomatic. Indirect evidence of nocturnal hypoglycaemia may be obtained by measuring her urinary catecholamine excretion or urinary cortisol excretion overnight. In many such cases a diagnosis of nocturnal hypoglycaemia is inferred if the symptoms are relieved by changing the insulin regimen or getting the patient to eat more food before she retires at night. As magnesium salts cause diarrhoea they need to be given parenterally, especially in this case where there is established diarrhoea and malabsorption. It is likely that once the patient is magnesium replete, her original vitamin D and calcium supplements will be sufficient to maintain her in a normocalcaemic state. Thus, to maintain a normal level of the physiologically active free T4 the total serum T4 needs to be increased. By far the most important investigation for this woman is a fine-needle aspiration biopsy of the thyroid nodule. It is important, however, that adequate thyroid epithelium be obtained to enable the diagnosis of thyroid cancer to be excluded or confirmed. Case history 28 As renal failure is the most common cause of hypocalcaemia, her serum urea and electrolytes should be measured. An increased serum alkaline phosphatase would be compatible with vitamin D deficiency. It cannot, however, be used to demonstrate the involvement of a specific bone or deformity; this has to be done radiologically. If a patient is being given a bisphosphonate it is important to monitor the serum calcium, as hypocalcaemia is a well-recognized side effect of these drugs. Skeletal and cardiac muscles are affected in hypothyroidism, causing the release of creatine kinase into the circulation. This, combined with a decrease in the catabolic rate of creatine kinase, will be sufficient to cause the creatine kinase to increase to the levels observed in this case. High initial doses can precipitate myocardial ischaemia, and where the hypothyroidism is severe, as in this case, pericardial effusions and impaired ventricular function. Case history 29 the two most likely diagnoses in this case are primary hyperparathyroidism and hypercalaemia of malignancy.
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