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Microscopy is useful for cell biologists medicine in french 1gr secnidazole free shipping, owing to fortunate coincidences within the electromagnetic spectrum professional english medicine buy secnidazole 500 mg cheap. First treatment jellyfish sting purchase 1 gr secnidazole, the wavelength of visible light (390 to 700 nm) is suitable for imaging cells and their membrane bounded organelles (0 symptoms zinc deficiency adults 1gr secnidazole visa. Second medications like lyrica order generic secnidazole line, one can focus visible light with glass lenses and electrons with electromagnetic lenses medicine wheel order secnidazole 500mg visa. Resolution, the ability to discriminate two points, is directly related to the wavelength of the light. The limit of resolution with visible light and glass lenses is normally approximately 0. Fortunately, various superresolution methods described below allow much higher resolution imaging with visible light. Soft x-rays with a wavelength of approximately 3 nm have the potential to provide high resolution, but are not practical for routine imaging because the lenses are relatively crude. However, analysis of molecular crystals by diffraction of higher energy x-rays (wavelength ~0. The wavelength of electrons accelerated at 100 kiloelectron volt (keV) is small, and with new detectors and image averaging, researchers are now able to achieve resolutions of less than 1 nm, making them preferable to x-rays for visualizing large macromolecular assemblies. The first is to enlarge an image of the specimen so that it can be seen with the eye or a camera. Just as important, but less appreciated, microscopes must produce contrast so that details of the enlarged image stand out from each other. Light Microscopy Methods Six methods are used to produce contrast in light micrographs of biological specimens (Table 6. These are called wide-field methods, as a broad beam of illuminating light is focused on the specimen by a condenser lens. The classic light microscopic method is bright field, whereby the specimen is illuminated with white light. For this reason, specimens are fixed with crosslinking chemicals and permeabilized before staining with organic dyes that absorb light and create contrast. In either case, the cells are killed by fixation or sectioning prior to observation. Phase-contrast microscopy generates contrast by interference between light scattered by the specimen and a slightly delayed reference beam of light. Two nearby beams interfere with each other, producing contrast in proportion to the gradient of local differences in the refractive index across the specimen. Thus, an organelle with a high refractive index (slow speed of light) in cytoplasm will appear light on one side (where the refractive index is increasing with respect to the cytoplasm) and dark on the other (where the refractive index is decreasing). Computer processing can greatly enhance contrast and remove optical artifacts from images. Dark-field microscopy and polarization microscopy have specialized uses in biology. In dark-field microscopy, the specimen is illuminated at an oblique angle so that only light scattered by the specimen is collected by the objective lens. Recall how easy it is to detect tiny dust particles in a beam of light in a dark room. The contrast is so great that a single isolated microtubule stands out brightly from the dark background. Upright light microscope generic light path Observer or camera Ocular lens Eyepiece Ocular lens Processing optics Objective lenses Specimen Condenser lenses Diaphragm Processing optics Mirror Field diaphragm Lamp lens Lamp Lamp B. Inverted epifluorescence microscope Fluorescent specimen Objective lens Dichroic mirror D. Theobjectivelensactsas the condenser to focus the exciting, short-wavelength light (green, in this example) on the specimen. In polarization microscopy, the specimen is placed between two crossed polarizing filters so no light passes through the second polarizer unless the specimen modifies its polarization state. This happens if the polarized light passes more slowly through the specimen when vibrating in one plane than when vibrating in the perpendicular plane (much as a saw cuts wood faster with the grain than across it). Fluorescence Microscopy Remarkable sensitivity makes fluorescence microscopy a powerful tool. When a fluorescent molecule absorbs a photon, an electron is excited into a higher state. Nanoseconds later, the electron falls back to its ground state and most of the energy is converted into a longer-wavelength (lower-energy) photon. For example, the fluorescent dye rhodamine absorbs green light (shorter wavelength) and emits red light (longer wavelength). Fluorescent Probes Fluorescence microscopy requires a fluorescent molecule, either an organic dye or fluorescent protein in the specimen. The historic approach was to target molecules in fixed, permeabilized cells with a protein or nucleic acid labeled with a fluorescent dye. The application of fluorescence microscopy to live cells began with labeling a purified lipid, protein, or nucleic acid with a fluorescent dye. A critical but often neglected aspect of these studies is to demonstrate by genetic or biochemical experiments that the fusion protein functions normally. Filters and dichroic mirrors that reflect short wavelengths direct the exciting light through the objective to the specimen. Fluorescent molecules in the specimen emit longer-wavelength light in every direction, some of which is collected by the objective. The emitted light passes through the dichroic mirror and a camera records the image. This thin optical section eliminates the blur from fluorescence in other planes of focus. Superimposition and out-of-focus noise can be minimized either computationally or optically. An image processing method called deconvolution produces clear fluorescence images of thick specimens by using an iterative computer process to restore light that is blurred out of focus to its proper focal plane. This excites molecules only near the surface of the slide and avoids fluorescent molecules deeper in the specimen. These points of light are scanned across the specimen in a raster (parallel lines) pattern to excite fluorescent molecules. Light emitted at each consecutive point in the specimen passes through a pinhole in front of the camera to remove outof-focus light. Laser scanning confocal Specimen Excitation light Emission light Objective lens Laser Pinholes Dichroic mirror Photon detector B Tilting mirror scans the specimen C. Light sheet Digital camera F Shaped laser Acquired data Light sheet Illu m in at Im Specimen ag i ng ax is G. A series of confocal images taken at different planes of focus can be used for threedimensional reconstructions. A detection objective sits at right angles to the illumination objective to collect emitted fluorescence for the camera. The sample resides between the two objectives on a rotatable stage that allows light sheet illumination of successive planes. Acquisition of threedimensional images at high imaging speeds is possible, allowing all the cells in thick specimens, including intact embryos, to be imaged at high resolution. Superresolution Fluorescence Microscopy Three methods have extended the resolution of fluorescence microscopy well beyond the classic limit of 0. Scanning this focal spot across the sample allows formation of an image with ~70- to 90-nm resolution. It can image live cells faster and with much less light than that required by other superresolution approaches. Each fluorescent molecule is bleached and the process is repeated many times to assemble a high-resolution image. The resolution of approximately 3 nm was sufficient to bridge the gap between light microscopy and macromolecular structures. Between 1950 and 1970 electron micrographs of thin sections of cells and tissues revealed most of what is known about the organization of their organelles. Electron microscopy advanced with the introduction of new methods to prepare cells and molecules. This is called electron cryomicroscopy, because the stage holding the frozen specimen is cooled to the temperature of liquid nitrogen. Frozen specimens can be cut with a microtome or by ion beam etching into sections thin enough for direct viewing. Low contrast and superimposition of details limited electron cryomicroscopy until image-processing methods called tomography were developed to reconstruct three-dimensional volumes. The specimen is tilted inside the microscope, and micrographs taken from a wide range of angles. Although the image of each fluorescent molecule is blurred by the point spread function of the microscope, the center of each point of light can be determined precisely by fitting the distribution with a computer. An image is built up of these point localizations through thousands of cycles of photoactivation/conversion, imaging, and photobleaching. Initially this process took many minutes, but highspeed digital cameras can now collect hundreds of images per second, making the method useful for live cells. The initial reports used epifluorescence and total internal reflection for photoconversion and localization. Because single molecules are imaged, localization microscopy is also used to estimate the stoichiometry and spatial correlations of molecules within cells, and to track their motions. C, A cultured cell prepared by rapid freezing, fracturing, deep etching, and rotary shadowingwithplatinum. Theimage shows a mitochondrion (mi), microtubules (mt), and synaptic vesicles (sv) inside the plasma membrane. E, Scanning electron micrograph of developing flowers of the Western mountain aster. Frequently, the cleavage plane splits apart the two halves of lipid bilayers to reveal proteins embedded in the plane of the membrane. Electron microscopy is valuable to study macromolecules, macromolecular assemblies, polymers, and twodimensional crystals. A shell of dense stain encases particles on the surface of a thin film of carbon and can preserve structural details at a resolution of approximately 2 nm. Single particles are reconstructed by first classifying images of tens of thousands of randomly oriented particles into categories corresponding to different views. It is now possible to visualize amino acid side chains in many large macromolecular structures that were difficult or impossible to study by x-ray diffraction. These recent advances in electron microscopy have revolutionized studies of complex biological structures. Many cycles of etching and imaging can be used to reconstruct the entire specimen in three dimensions. These valuable experimental tools have attracted investigators to a growing number of "model" organisms (Table 6. Haploid organisms with one copy of each chromosome after mitotic division are particularly favorable for detecting the effects of changes in genes, called mutations (Box 6. It is useful for a haploid organism to have a diploid stage with two copies of each chromosome and a sexual phase, during which meiotic recombination occurs between the chromosomes from the two parents. In addition, diploids carrying a lethal mutation of a gene that is essential for life can be propagated, provided that the mutation is recessive. Budding yeast and fission yeast meet all these criteria, so they are widely used to study basic cellular functions. Moving between haploid and diploid stages greatly simplifies the process of creating and analyzing recessive mutations. Mutation giving an altered phenotype only under certain conditions, such as temperature, medium composition, and so on. Mutation giving an altered phenotype, even in the presence of a copy of the wild-type gene on another chromosome. A change in the chemical composition of a gene, including changes in nucleotide sequence, insertion, deletions, and so on. Physical exchange of regions of the genome between homologous chromosomes or between a plasmid and a chromosome. The naturally occurring allele of a gene; the phenotype of the naturally occurring organism. The mustard Arabidopsis thaliana is the most popular plant for genetics, because its genome is small, reproduction is relatively rapid, and methods for genetic analysis are well developed. The moss Physcomitrella patens has experimental advantages for studying basic plant biology. One challenge has been the lack of methods to replace genes by homologous recombination in plants (see later section). By focusing on a limited number of easy-to-use model organisms, biological research has raced forward beginning during the last quarter of the 20th century. Thousands of other solutions to survival exist in nature, and they tend to be ignored. At the cellular level, these liabilities are less severe, as most cellular adaptations are ancient and shared by most organisms. Multicellular organisms are required to study the development and function of tissues and organs. Flies, nematode worms, mice, and humans share many ancient, conserved genes that control their cellular and developmental systems, so flies and worms are popular for basic studies of animal development and tissue function. However, vertebrates evolved a substantial number of new gene families (roughly 7% of total genes) and a large number of new proteins by rearranging ancient domains in new ways. Therefore, mice are often used for experiments on specialized vertebrate functions, especially the nervous system. Although not an experimental organism, humans are included on this list, because much can be learned by analysis of human genetic variation and its relationship to disease.

Autoantibodies (IgG or IgA1) against this polymeric galactose-deficient IgA1 result in the formation of immune complexes that are deposited in glomeruli treatment 24 seven purchase secnidazole 1 gr fast delivery. Morphology: the commonest pattern of glomerular disease is a mesangial proliferative glomerulonephritis symptoms low blood sugar discount secnidazole 500mg overnight delivery, although a significant minority of cases show endocapillary or extracapillary proliferation treatment lymphoma buy discount secnidazole 500mg on-line. Whilst affected individuals usually have microscopic haematuria with preserved renal function medicine q10 cheap secnidazole 1 gr online, those with compound heterozygous or homozygous mutations may progress to chronic renal failure adhd medications 6 year old purchase secnidazole pills in toronto. Post-infectious glomerulonephritis An acute glomerulonephritis may develop following infections medicine 6 year in us purchase 1 gr secnidazole overnight delivery, most commonly group A streptococci. Other bacterial and viral infections, including pneumococci and staphylococci, may produce a similar picture. Clinical features: the typical history of post-streptococcal glomerulonephritis is the development of nephritic syndrome with macroscopic haematuria approximately 2 weeks following a streptococcal throat infection. A similar presentation may be seen in association with other bacterial infections including cellulitis, localised staphylococcal infections such as abscesses and osteomyelitis, and infective endocarditis. In the majority of cases with an acute presentation there is resolution with recovery of renal function. However, severe cases presenting as a rapidly progressive glomerulonephritis, and those with chronic renal damage evident at the time of diagnosis, may suffer chronic renal impairment. Pathogenesis: Glomerular inflammation results from deposition of immune complexes that contain microbial antigens, IgG and complement. These complexes may develop in the circulation or develop in situ, with antibody and complement binding to planted antigen within the glomerular capillary wall. This pattern is described as an acute proliferative glomerulonephritis (although there is typically little proliferation of endogenous glomerular cells). In glomerulonephritis associated with chronic infections there is evidence of sclerosis and frequently a membranoproliferative pattern of disease. Severity of proliferation and presence of segmental sclerosis correlate with rate of deterioration of renal function. In approximately 20% of cases there are also capillary wall deposits of IgA and/or glomerular IgG deposits that are associated with more active proliferative disease and aggressive clinical course. They may be divided clinically and morphologically into Alport syndrome and thin basement membrane disease but there is considerable genetic and clinical heterogeneity within each of these. Alport syndrome: this is characterised by (1) renal manifestations (haematuria, proteinuria), usually presenting in childhood and progressing to chronic renal failure in adulthood, (2) sensorineural deafness and (3) ocular abnormalities. The earliest morphological changes are detected on electron microscopy, which demonstrates marked thinning of the lamina densa of the glomerular basement membrane, with areas of multilayering, producing a basket-weave appearance. Thin membrane disease: this is a common inherited condition, defined by marked thinning of the lamina densa of the glomerular basement membrane. The condition is also Vasculitis Renal involvement is common in small vessel vasculitides, with a necrotising glomerulonephritis being the usual manifestation. Renal arteritis is less common, being present in only 20% of patients with a vasculitic glomerulonephritis. Clinical features: Small vessel vasculitis that is not associated with immune complex deposition increases in incidence with age, being most frequent in elderly adults. Systemic symptoms may be relatively non-specific, such as pyrexia and arthralgia, or reflect vasculitic involvement of other organs, such as a purpuric rash and pulmonary haemorrhage. There is serological evidence of inflammation with an elevated C-reactive protein. Most patients respond to immunosuppressive therapy with high-dose steroids and cyclophosphamide. Pathogenesis: Glomerular and other microvascular injury results from neutrophil activation and degranulation, releasing enzymes that cause cellular injury and matrix degradation. Glomerular necrosis is associated with rupture of capillaries and exudation of fibrin and cytokines. Morphology: There is a focal segmental necrotising glomerulonephritis without glomerular deposits of antibody or complement (pauci-immune). The necrotising lesions heal by forming scars; in later stages of disease glomerulosclerosis is a dominant feature. There is endocapillary hypercellularity with large numbers of intracapillary neutrophils [A]. This confusion in classification reflects our incomplete understanding of the pathogenesis of the vasculitides. In some patients, the antibodies also bind to alveolar capillary basement membranes, resulting in pulmonary haemorrhage with haemoptysis. The response to standard therapy (plasmapheresis, cyclophosphamide and methylprednisolone) depends to a large extent on residual renal function at presentation; there is little prospect for recovery if the patient is dialysis dependent. There may be scattered multinucleate giant cells or central necrosis with surrounding palisaded macrophages, but granulomas are not a feature. Pathogenesis: the mechanism of renal failure in acute tubular injury is multifactorial. Glomeruli show fibrin exudation and extracapillary proliferation (cellular crescent). Pathogenesis: Genetic and environmental factors contribute to the development of the autoantibody. The presence of clusters of cases suggests the possibility of an infectious trigger but the organism has not been identified. Morphology: Renal biopsy typically shows diffuse global glomerular necrosis with crescents. These include cytoplasmic vacuolation, mitochondrial swelling and resorption droplets of filtered proteins. This may be an autoimmune reaction but in most cases there is a T-cell-mediated response against exogenous antigens: for example, drugs that are excreted in the urine and which undergo tubular reabsorption. Clinical features: There is acute renal failure that is frequently polyuric, reflecting failure of tubular reabsorption of glomerular filtrate. Removal of the causative agent and steroid therapy will result in recovery unless there is substantial chronic renal damage at the time of diagnosis. Pathogenesis: Tubular epithelial injury is mediated by T cells; tubular deposits of antibodies are seen in only a minority of cases, notably in IgG4-mediated systemic disease in which there are IgG4-containing immune complexes along the tubular basement membranes. In severe cases, there is death of epithelial cells which are shed into the tubular lumen, termed acute tubular necrosis. Drug-induced tubulointerstitial nephritis with a mixed inflammatory cell infiltrate including large numbers of eosinophils [B]. Morphology: There is an interstitial infiltrate of mononuclear inflammatory cells (lymphocytes, plasma cells, macrophages) with infiltration of tubules by lymphocytes. If persistent, the tubular injury and inflammation results in tubular atrophy and interstitial fibrosis. Renal failure results from tubular obstruction, crystal-induced epithelial injury or interstitial inflammation and fibrosis. Presentation may be with acute or chronic renal failure, depending on the rate of crystal deposition. The prognosis depends on early diagnosis and treatment of the underlying disorder. Acute urate nephropathy results from massive cell destruction in tumour lysis syndrome or crush injury. There are intraluminal deposits of urate crystals with associated tubular obstruction and acute tubular injury. Chronic urate nephropathy is most commonly associated with chronic hyperuricaemia, gout and hypertension (gouty nephropathy). Uric acid calculi are frequent and may result in a chronic obstructive pyelonephritis (see below). Presentation is typically with chronic renal failure that frequently progresses to end-stage kidney disease. Nephrocalcinosis Nephrocalcinosis is the deposition of calcium phosphate within renal tubules and interstitium and is usually a consequence of chronic hypercalcaemia. Causes include: Uratenephropathy Uric acid is the product of purine metabolism and is generated by all cells in the body. Hyperuricaemia may result from increased production or reduced renal excretion, and in the majority of cases is idiopathic. Presenting features are of chronic renal failure with inability to concentrate the urine, resulting in polyuria and nocturia. There are frequently calculi within the collecting system that may be associated with secondary infection and obstruction. The formation of calcium oxalate stones may be associated with infection or symptoms of obstruction, such as renal colic. In primary oxalosis there may be oxalate deposition in many tissues, particularly after the development of chronic renal failure that exacerbates systemic oxalosis. B Light chain cast nephropathy (myeloma cast nephropathy) Excessive production of monoclonal light chains by a malignancy of plasma cells (multiple myeloma) may result in high levels of free light chains (also termed Bence Jones proteins) in the glomerular filtrate. Serum electrophoresis demonstrates a monoclonal protein (paraprotein) and free light chains are detectable in the urine. On histology, the tubular casts have a hard, fractured appearance with associated inflammation and tubular injury. Treatment is for the underlying plasma cell dyscrasia and renal replacement therapy when required. Oxalatenephropathy Oxalate nephropathy is the deposition of calcium oxalate crystals within renal tubules. As oxalate is excreted only in the urine, an increased level within the blood (hyperoxalaemia) results in an increase in the urine (hyperoxaluria), supersaturation of the urinary filtrate within tubules and the development of crystals. The term is used by pathologists to describe the histological appearances of microvascular endothelial injury, whilst nephrologists will use terms that describe the clinical and haematological features of these conditions. As described below, there is a link between mechanism of injury, clinical presentation and histological features. Increased intake: Ingestion of ethylene glycol (antifreeze) or large amounts of ascorbic acid (vitamin C) that are metabolised to oxalate. Enteric hyperoxaluria: Calcium within the intestinal lumen normally binds oxalate, limiting its absorption. Fragmentation and lysis of erythrocytes occurs as they pass through the damaged microvasculature. These fragmented erythrocytes may be seen in a blood smear and are termed schistocytes. There is a proliferative response to this injury, producing cellular intimal thickening and, finally, production of matrix, resulting in intimal fibrosis. Glomerular endothelial injury results in capillary thrombosis, endothelial swelling and expansion of the subendothelial space. Once detached from the original glomerular basement membrane, endothelial cells produce a new basement membrane, resulting in the appearance of double contours on silver stains. As hypertension is a result as well as a cause of chronic kidney disease, it is frequently difficult to ascertain which came first. The histological changes of hypertensive nephropathy resemble those of age-related nephrosclerosis, which are present in the kidneys of most elderly individuals. In susceptible populations, in particular those of black African descent, the hypertensive vascular changes are more severe and may result in end-stage renal failure. Other features such as haematuria or an active urinary sediment may indicate the presence of an underlying primary renal disease. Pathogenesis: the association of renal fibrosis with hypertension does not necessarily mean that it is the raised blood pressure per se that causes the pathological changes in the kidneys. There is growing experimental evidence that it is not the blood pressure but rather the direct fibrogenic activity of hormones and cytokines, such as angiotensin and aldosterone, which result in renal scarring. Morphology: There is arterial intimal thickening, mainly by reduplication of the internal elastic lamina, termed arterial fibroelastosis. There is focal segmental and global glomerulosclerosis, tubular atrophy and interstitial fibrosis. These changes initially involve nephrons immediately beneath the renal capsule, resulting in subcapsular fibrosis. Macroscopic examination of kidneys showing these changes reveals a finely granular surface and cortical thinning, or atrophy. There is an increase in pressure proximal to the obstruction that is transmitted back into the collecting ducts, resulting in loss of tubular function. Irreversible tubular atrophy develops if the obstruction is not recognised and corrected promptly. Stagnant urine proximal to the obstruction predisposes to bacterial infections and the development of magnesium ammonium phosphate stones. Clinical features: Signs and symptoms may relate to associated urinary infections or to the cause of the obstruction. For example, a ureteric stone may produce renal colic, and prostatic hypertrophy may produce lower urinary tract symptoms (see Ch. Bilateral partial obstruction may present with polyuria due to impaired tubular function, resulting in failure to concentrate urine. If obstruction is not corrected, there is progressive cortical atrophy, with tubular atrophy and interstitial fibrosis evident on histology. The renal pelvis and calyces are grossly dilated with atrophy of renal parenchyma, secondary to obstruction of the upper ureter by a stone. Calcium stones (70%), composed of calcium oxalate or calcium oxalate with calcium phosphate.

The disease usually begins distally 5 medications that affect heart rate quality 1gr secnidazole, involving the rectum (ulcerative proctitis) symptoms west nile virus cheap secnidazole 1gr line, and extends in a continuous fashion proximally to varying extent treatment 02 secnidazole 1 gr cheap. Morphology the disease is typically maximal in the rectum symptoms nerve damage purchase 500 mg secnidazole mastercard, extends proximally but does not involve the mucosa of the anal transitional zone or the anal canal medications known to cause miscarriage generic secnidazole 1 gr amex. However daughter medicine buy secnidazole without prescription, in severe cases, there is extension into the main muscle coats and perforation may occur. Polymorphs are seen in the lamina propria, in the crypt epithelium and as aggregates within distended crypts (crypt abscesses). The presence of numerous plasma cells at the base of the mucosa (basal plasmacytosis) is a key finding of ulcerative colitis. Crypts are often destroyed during the acute phase, and when regeneration occurs they are frequently distorted by branching or dilatation and may no longer reach to the muscularis mucosae. The architectural distortion of the crypts is a useful diagnostic pointer in quiescent cases, when the inflammatory features may have totally subsided. In long-standing ulcerative colitis, colorectal biopsy will reveal crypt atrophy and distortion, replacement fibrosis and metaplastic features such as the presence of Paneth cells. Local complications Acute local complications include haemorrhage, dehydration with serious electrolyte disturbances due to extensive blood and fluid loss from extensive ulceration and so-called toxic dilatation. Toxic dilatation of the colon (toxic megacolon) occurs when ulceration affects large areas of the muscle coats, impairing their viability and contractile strength. The resultant adynamic segment of the colon becomes progressively distended, and the consequent thinning of the wall predisposes to perforation. Perforation into the peritoneal cavity results in generalised faecal peritonitis and a fatal outcome is likely. Systemic complications Patients with ulcerative colitis are at risk of developing systemic problems (Table 15. These include different organs: Liver involvement Eye involvement Joint involvement Pathogenesis of inflammatory bowel disease the cause of inflammatory bowel disease is still unknown. Attempts to implicate certain infectious organisms with the disease onset have provided inconsistent results. The possibility that an abnormal immune response possibly related to cellmediated cytotoxicity or autoantibodies against colonic epithelial cells may be involved in this disease has been studied extensively in the past. However, findings so far have not been unique to patients with inflammatory bowel disease, nor were they invariably present. The clinical factors associated with a higher cancer risk are onset of the disease in childhood, clinically severe first attack, involvement of the whole colon and continuous rather than intermittent symptoms. If high-grade (severe) dysplasia is seen, the development of carcinoma is considered imminent and, depending on the extent of the dysplasia, endoscopic resection or total colectomy is recommended. Ischaemic injury to the intestine occurs either as a consequence of vascular occlusion or stenosis (occlusive ischaemia) or in circumstances where, despite patency of the vessels, the blood supply falls to a level at which the nutrition of mucosa cannot be maintained (non-occlusive ischaemia). Occlusive ischaemia can result from embolism originating from atrial or ventricular mural thrombosis, thrombosis on the basis of atherosclerosis, vascular compression due to adhesions or volvulus, vasculitis or radiation damage. Nonocclusive ischaemia is a consequence of heart failure, systemic hypotension (blood loss, dehydration), or vasospasm from medications/drugs such as digitalis and cocaine (in about 20%). In less than 5% of cases, acute intestinal ischaemia is due to mesenteric venous thrombosis, which, by preventing outflow of blood, causes infarction by intense congestion. Predisposing factors include hypercoagulability states, portal hypertension, intra-abdominal inflammation and previous surgery or abdominal trauma. Infarct Mucosal Outcome Regeneration: mucosal integrity restored Mural Repair and regeneration: fibrous stricture Transmural Acute ischaemia Acute mesenteric ischaemia is a life-threatening emergency with mortality rates between 60% and 100%. Mucosal infarction Mucosal infarction is usually considered transient or reversible because the lesion can be followed by complete regeneration. However, mucosal damage leads to release of chemokines that cause an influx of polymorphs, and their adhesion to vascular endothelium coupled with platelet aggregation further compromising the microcirculation. Mural infarction Mural infarction reaches into the submucosa or into, but not through, the muscularis propria. The mucosa is variably ulcerated and, where intact, is haemorrhagic and elevated by marked submucosal oedema. The deeper extent of necrosis with involvement of connective tissues necessitates healing by granulation tissue formation and a more prolonged process of repair. Transmural infarction Transmural infarction of the intestine is the most common consequence of acute ischaemia. The bowel becomes flaccid and dilates, and the serosal aspect is deeply congested and coated with a thin layer of fibrin. The infarct is usually widespread, affecting several loops of small intestine, but can be segmental, in particular in the colon. Segmental infarction results either from occlusion of distal mesenteric vessels, or by mechanical obstruction of the supply to a loop of intestine. This type of involvement is amenable to surgical treatment, but many patients already have peritonitis, endotoxaemia and severe circulatory problems at the time of diagnosis, so operative results remain poor. Massive infarction, most commonly seen in the small intestine following complete occlusion of the superior mesenteric artery, has a hopeless prognosis. Chronic mesenteric insufficiency is used to describe a condition in which there is insufficient blood flow to the small intestine to satisfy the demands of increased motility, secretion and absorption that develop after meals. The disease manifests as abdominal distension and bloody stools with respiratory and circulatory disturbances. No single bacterial pathogen has been consistently identified, but organisms frequently isolated include E. Prematurity is the only consistent risk factor; an immature mucosal barrier coupled with an impaired humoral (secretory IgA) and cellular immune response to bacteria are the suggested mechanisms. The disease can also (rarely) affect adults where it is caused by infection with Clostridium perfringens type C, which produces a powerful beta-toxin. Paralytic ileus develops and progresses to intestinal infarction, sepsis and shock. The appearances are typically those of gas gangrene, with either segmental or total involvement of the small and large intestines by coagulative necrosis and intramural gas bubble formation. Vascular anomalies Vascular anomalies in the gut are uncommon but enter into the differential diagnosis of gastrointestinal haemorrhage. The exact mechanism of the development of angiodysplasia is not known but chronic venous obstruction is thought to have a role. Histologically, there is abnormal dilatation of submucosal veins, which become prone to bleeding. Diverticular disease is found in 30% of adults in Western countries and in up to 60% of patients above the age of 70. In contrast, the prevalence in countries with a high-fibre diet, as in rural Africa, is less than 2%. These diverticulae form at sites of potential weakness, notably where lymphoid aggregates breach the muscularis mucosae and extend through the muscularis propria at the point of entry or exit of blood vessels bulging into the subserosa. Sigmoid motility is sensitive to the bulk of the colonic contents and when this is low, as with a low-fibre diet, abnormally high intraluminal pressures are generated which push the mucosa into and ultimately through the wall. The faecal contents can lead to abrasion of the herniated mucosa, or a microscopic perforation in the apex of a diverticulum can occur, resulting in the development of a suppurative diverticulitis. This, in turn, can cause a pericolic abscess and a fistula may form into the bladder, vagina or small intestine. More seriously, a peridiverticular abscess may perforate and produce a generalised faecal peritonitis. Intussusception An intussusception is an invagination of one segment of bowel into another, resulting in intestinal obstruction. There is usually a lesion in the wall of the bowel which disturbs normal peristaltic contractions, forcing the lesion and a segment of proximal bowel into a distal segment. Lymphoid hyperplasia close to the ileocaecal valve is the cause of ileocolic intussusception, the most common form of this disorder. As the contents of the intestine are pushed onwards, more and more intestine is dragged into the adjoining bowel, potentially resulting in venous congestion and infarction. The low incidence of carcinoma means that other neoplasms, such as neuroendocrine cell tumours and lymphomas, assume more importance in the small intestine where they are relatively more common than in the large bowel. These can be broadly divided into epithelial and mesenchymal polyps and into benign and malignant categories (Table 15. Epithelial polyps are rare in the small intestine and some, such as hyperplastic polyps, are confined to the large bowel. Benignepithelialpolyps Benign epithelial polyps fall into four categories: adenomas, and inflammatory, hamartomatous and hyperplastic polyps. Adenomas Adenomas are very common and there is an increasing incidence with age so that at the age of 60, they are found in about 20% of the population. There are two main histological types: tubular (75%) and villous (10%); the remaining 15% are intermediate in pattern and are designated tubulovillous. Tubular adenomas are generally small (usually less than 10 mm in diameter), and macroscopically resemble a raspberry. Microscopically, they consist of numerous elongated and branching crypts lined by mucussecreting epithelium showing varying degrees of dysplasia. They are often over 20 mm in diameter and some extend over a wide area as a thick, carpet-like growth. However, Volvulus and strangulation Intestinal obstruction can result from a twist in the bowel that occludes its lumen (volvulus) or when a segment of bowel becomes trapped in a defect in either the posterior peritoneum or mesentery (internal herniation), or herniates into an inguinal or paraumbilical peritoneal sac. The neck of the sac may then constrict the bowel and compromise its blood supply (strangulation). About two-thirds of cases affect the small intestine; most of the remaining one-third affect the sigmoid colon. Inflammatory polyps these usually arise in the context of inflammatory bowel disease and represent excessive reparative and regenerative tissue formed in the aftermath of mucosal ulceration. They are common lesions, being found with increasing age, and are most frequently situated in the rectum. Microscopically, they are sessile, have elongated crypts with a serrated appearance of the cells lining the upper crypt and at the surface. In contrast to adenomas, these polyps show no evidence of dysplasia and have little or no malignant potential. Although of low malignant potential, serrated adenomas exhibit a distinct pathway of genetic changes leading to adenocarcinoma different from the pathway of polypoid adenomas. Malignantmesenchymalpolyps Malignant varieties include the sarcomas equivalent to the benign tumours, and malignant lymphomatous polyps. Examination of adenomas showing early malignancy has demonstrated an association with increasing size, villous growth pattern and more severe dysplasia, although non-polypoid (flat) adenomas frequently show high-grade dysplasia in spite of their small size. Adenomas and carcinomas are frequently found together in a resected segment of bowel. Such patients have an increased risk of developing a second cancer in the remaining large intestine, compared with patients having carcinoma alone. Recent genome-wide scans have revealed a colorectal cancer susceptibility locus on chromosome 8q24 that is common to some sporadic adenomas, providing genetic evidence of the link and indicating that the locus is involved in tumour initiation rather than progression. A very small minority of polyps are neoplasms derived from neuroendocrine cells (see p. In recent years, it has also become clear that acquired epigenetic changes are of major importance in the process. Loss or mutations of tumour suppressor genes Tumour suppressor genes appear to be very important in colorectal carcinoma. Subsequent deletion of the accompanying normal allele results in the complete loss of the tumour suppressor function, leading to colorectal cancer. Just as with oncogene activation, mutations are not the only mechanism leading to loss of function of tumour suppressor genes. Hypermethylation of CpG dinucleotides has been linked to the transcriptional silencing of tumour suppressor genes. Interestingly, CpG island hypermethylation is found in about a third of hyperplastic polyps. Analysis of adenomas, small and large, and of invasive carcinomas and their metastases reveals a cascade of gene mutations, deletions and activations corresponding to the altered behaviour of the tumour cells. Aetiology Apart from the role played by inherited genetic factors, and the small number of cases developing in long-standing ulcerative colitis, the most important factor in the aetiology of colorectal cancer appears to be environmental. Diet affects the bacterial flora of the large bowel, the bowel transit time, and the amount of cellulose, amino acids and bile acids in the bowel contents. Thus, the type of diet that has been linked to colorectal cancer is a high fat, high protein, low fibre diet. High fat leads to an increase in bile salt production and higher load of faecal bile acids; high protein favours the transformation of amino acids by bacteria; low fibre reduces volatile fatty acids and prolongs intestinal transit so that there is more time for bacterial action on the contents and more prolonged contact between any carcinogen generated and the mucosa. These factors, more than anything else, account for the high incidence of colorectal cancer in developed countries. Clinicopathological features Approximately 50% of cancers occur in the rectum, where they are equally divided between the upper, middle and lower thirds; about 30% occur in the sigmoid colon and the rest are equally distributed in the caecum ascending, transverse and descending colon.

Particulateradiation As well as photons medicine 3 sixes discount secnidazole online master card, certain subatomic particles may also produce ionisation medicine 8 iron stylings order secnidazole once a day. These include alpha particles (helium nuclei) symptoms xanax abuse discount secnidazole 1gr line, beta particles (electrons) and neutrons symptoms 2 year molars purchase secnidazole cheap. The distinction between beta particles and electrons is the same as that between gamma rays and X-rays: beta particles are produced through the process of radioactive decay symptoms in spanish discount secnidazole 1 gr with amex, whereas electrons are a structural component of atoms that may be artificially projected as a beam medicine neurontin secnidazole 500 mg on-line. The tumours produced are basal cell and squamous cell carcinomas, and malignant melanomas. Melanin pigmentation, itself induced by ultraviolet light, is protective against these effects. In the European Union it is now mandatory that medical practitioners using radiation for investigating or treating patients know about radiation protection. This section deals with certain aspects of this, particularly in relation to: Units of dose Various units have been used for measuring radiation. However, different forms of radiation vary in the distribution of energy deposited in tissues, hence the biological effect. Tissues also differ in their sensitivity; gonads are the most sensitive to radiation, with breast and bone marrow about half as sensitive; thyroid and bone are considerably less sensitive. Another relevant unit is a measure of the rate of disintegration of unstable atoms; 1 becquerel (Bq) is one emission per second. Electromagneticradiation Only part of the electromagnetic spectrum produces ionising events. The production of ions requires a photon of high energy and thus of short wavelength, in practice shorter than that of ultraviolet light. Some draught-proofed homes in areas of high natural airborne radiation accumulate radon to concentrations exceeding acceptable industrial limits, thereby placing occupants at risk of lung disease from irradiation. Mode of action When radiation passes through tissue, any collisions within it will be randomly distributed amongst its components. However, it seems that direct damage as a result of ionisation of proteins or membranes does not make a major contribution to the biological end result. Water is the most prevalent molecule, and following ionisation several types of short-lived but highly reactive radicals are formed such as H. B Effective dose equivalent in sievert (Sv) Effects on tissues the immediate physicochemical events and consequent biomolecular damage are over in a few milliseconds; the varied outcomes are manifest in hours to years. The dose given will influence this outcome, as will the radiosensitivity of the cell. Tissue and organ changes will reflect the overall reactions in the component parts. Tissue consequences are usually divided into early tissue reactions or deterministic effects, which are predictable according to the dose received, and later stochastic effects, where only the probability is related to the dose. Thus, cataract and skin erythema (tissue reactions) will not occur below a certain threshold dose, while in contrast there is no dose threshold below which there is no probability of cancer (a stochastic effect). However, for any particular atom the latter is known, so the dose can be calculated. Background radiation Everyone is exposed to background radiation from their environment. Hierarchical cell organisations, such as the bone marrow or gut epithelium, which have a dividing stem cell population and daughter cells of brief finite life expectancy, will show the most pronounced effects. In essence, the supply of functioning differentiated cells is cut off or suspended. In addition, there is vascular endothelial damage, resulting in fluid and protein leakage rather like that of the inflammatory response (Ch. Over 90% of the artificial component is from medical usage, such as diagnostic X-rays and nuclear medicine. Vascular endothelial cell loss will result in exposure of the underlying collagen. This will prompt platelet adherence and thrombosis, which is subsequently incorporated into the vessel wall and is associated with the intimal proliferation of endarteritis obliterans. A possible result of this is long-term vascular insufficiency with consequent atrophy and fibrosis. However, the observed atrophy may simply be a function of continuing cell loss over a long period of time, reflecting an inherently slow rate of proliferation of cells in the tissue concerned. If this is the case, the vascular alterations are part of the late effects of radiation, but not the cause of the atrophy. The limits of tissue tolerance cannot be exceeded even if many years have elapsed. In addition to the effects mentioned above, radiation-induced mutation of the genome causes an increased risk of neoplastic transformation (see below). Damage to keratinocytes and melanocytes results in melanin deposition in the dermis where it is picked up by phagocytic cells; these tend to remain in the skin and result in local hyperpigmentation (post-inflammatory pigmentation). Some fibroblasts in the dermis will be killed, while others are at risk of an inability to divide, or to function correctly. As a consequence, the dermis is thinned, and histology shows bizarre, enlarged fibroblast nuclei. Small and thin-walled vessels will leak fluid and proteins, and mimic the inflammatory response; in the long term, they can be permanently dilated and tortuous (telangiectatic). Larger vessels develop intimal proliferation and may permanently impair blood flow. In summary, the skin is at first reddened with desquamation, and subsequently shows pigmentation. Later, it is thinned with telangiectasia; if damage is too severe, it will break down and ulcerate (radionecrosis). Bonemarrow Haemopoietic marrow is a hierarchical tissue that maintains the blood concentration of functional cells of limited lifespan by a constant high rate of mitotic activity. Subsequent blood counts will fall at a rate corresponding to the physiological survival of cells; granulocytes will diminish after a few days but erythrocytes survive much longer. The ultimate outcome will depend on the dose received, and will vary from complete recovery to death from marrow failure (unless a marrow transplant is successful). Localised heavy radiation will not alter the blood count, but it will result in local loss of haemopoiesis and fibrosis of the marrow cavity. Gonads Germ cells are very radiosensitive, and permanent sterility can follow relatively low doses. Also of great significance is the possibility of mutation in germ cells, which could result in passing on defects to the next generation; this is a teratogenic effect. However, although this has been demonstrated experimentally in mice, firm data quantifying the magnitude of the effect in human populations is lacking. A significant dose of radiation will therefore result in loss of protective and absorptive functions over a similar time-scale; diarrhoea and the risk of infection then follow. If a high dose is given to a localised region, the mucosa will regrow, although often with a less specialised cell type, and with the probability of mutations in the remaining cells. The muscle coat will also have been damaged, and there is the risk of granulation tissue causing a stricture later. Skin the changes in the skin reflect its composition from epithelium, connective tissue and blood vessels. Epidermis will suffer the consequences of cessation of mitosis, with desquamation and hair loss. Note the abrupt demarcation between the solid scarred lung (left) and the adjacent normally aerated lung (right); this is due to the sharp cut-off at the edge of the irradiated field, to minimise the extent of damage to adjacent structures. Renal irradiation results in gradual loss of parenchyma and impaired renal function, leading to the development of hypertension. Whole body irradiation Whole body irradiation can be the result of accidental or therapeutic exposure. At lower doses, the clinical picture is dominated in the first few days by gastrointestinal problems, and later by bone marrow suppression; either may prove fatal. Therapeutic usage is for ablation of the bone marrow prior to transplantation of marrow, using either stored marrow from the patient or marrow from another donor. Occupational exposure to radon gas in mines also shows a correlation with the risk of lung tumours. Common to all these observations is a time delay between exposure to radiation and development of the tumour. Studies of Japanese survivors of the atomic bombs show significant numbers of cases of leukaemia by about 6 years, with a mean delay of 12. Regarding low doses (less than 100 mSv), it is more difficult to be sure if the radiation is carcinogenic because the anticipated number of tumours would be so small compared with the overall number of tumours arising anyway in the exposed population. However, more recent studies of a cohort of 100 000 Japanese atomic bomb survivors exposed Table 5. This is now firmly established for relatively high doses, but with low-dose radiation some uncertainty remains. There is a roughly linear relationship between the dose received and the incidence of tumours. As the radiation dose increases, so a greater number of cells will be lethally irradiated, thus reducing the number surviving and at risk of neoplastic transformation. Thus, children who received radiation of the thyroid gland show an incidence of tumours corresponding to the dose received. However, estimates of the risk of cancer in this dose range may be two or three times too high or too low. Children may be at a greater risk than adults for any given dose, an effect compounded by their projected longer survival at risk. Incidence of tumours All other cancers Principles of radiation protection In view of the risk of harm from ionising radiation, it is important that it is used safely and only when there are no suitable alternatives. The dose equivalent to individuals shall not exceed the limits recommended for the appropriate circumstances by the Commission. It may be reasonable to reduce the frequency of investigations, or to use methods that do not involve radiation, such as ultrasound or magnetic resonance imaging. The impact of radiotherapy on cells and tissues can be harnessed for therapeutic benefit in the form of radiotherapy for cancer treatment. The most common effect required from radiation is the ability to kill cells; this is used in the treatment of tumours. Usually, the aim is to give as high a Commonly confused conditions and entities relating to cellular injury Commonly confused Apoptosis and necrosis Distinction and explanation Both are modes of cell death. Apoptosis is an active process involving single-cell death occurring in normal. Necrosis is a response to injury, almost always pathological and involving groups of cells; cell membrane integrity is lost and an inflammatory and repair response is common. In coagulative necrosis the cells are dead but the tissue architecture is often preserved in the early stages; the tissue then softens and eventually heals by fibrosis and scarring. Colliquative (or liquefactive) necrosis occurs characteristically in the brain; the tissue liquefies and heals by cyst formation. Granulation tissue is an important component of healing and comprises small blood vessels in a connective tissue matrix with myofibroblasts. Healing by first intention occurs when there has been no significant loss of tissue. Both have similar physical properties, but X-rays are produced by a machine and their production can be controlled by a switch, whereas gamma rays are produced by radioactive decay and protection from them can be achieved only by a barrier. Modern radiotherapy equipment and planning techniques allow a high degree of conformation of the radiated volume to the tumour itself, with less normal tissue included in the field. Irrespective of the part of the body treated, nausea and vomiting are very common side effects of radiotherapy. The mechanism is not understood, but it is more likely to occur when large volumes of tissue are treated. The skin will receive a proportion of any dose given to any internal target and skin reactions ranging from acute inflammatory phases to residual pigmentation are common. Fibrosis is a late manifestation in irradiated tissue and will also be restricted to the treated field. Most treatment techniques take care to avoid clinical consequences from such fibrosis, but occasionally an individual patient will show an excessive reaction, such as a stricture of the bowel. Side effects can be minimized if the total radiation dose administered is divided into a number of fractions and given on different days (fractionation). Each treatment fraction induces tissue damage, but normal cells included in the treated tissue volume are better able to repair effectively than are neoplastic cells. Consequently, there is a differential cell killing of more tumour cells than normal cells. Congenital metabolic disorders usually result from inherited enzyme deficiencies causing significant clinical consequences. However, in some conditions the intermediate metabolite accumulates within the cells in which it has been synthesised, causing them to enlarge and compromising their function or that of neighbouring cells; these conditions are referred to as storage disorders.

Darwinian medicine Darwinian medicine is based on belief that diseases not only have proximate causes and mechanisms medications 563 buy secnidazole 1gr without prescription. Darwinian medicine focuses on the latter aspect and treatment for sciatica order cheap secnidazole on-line, while it may not yield cures symptoms webmd safe 500 mg secnidazole, it can help us to understand current disease prevalence xanax medications for anxiety proven 1 gr secnidazole. Darwinian medicine is also rooted in the belief that natural selection favours reproductive success rather than health or life-span medications you cannot crush cheap 500 mg secnidazole visa. In Why we get sick: the new science of Darwinian medicine medicine 027 purchase cheap secnidazole line, Randolph Nesse, an evolutionary biologist, and George Williams, a psychiatrist, explain the application of evolutionary ideas to modern medicine with these examples: Limits of normality Normal is not a single discrete state, because there are differences between individuals and natural changes during fetal development, childhood, puberty, pregnancy, ageing, etc. Most quantifiable biological characteristics are normally distributed, in statistical terms, about an average value. No constant numbers can be used to define a normal height, weight, serum sodium concentration, etc. In contrast, atheroma in a teenager is so unusual that it would be regarded as abnormal and worthy of further investigation. Adaptation Adaptation of the individual to an adverse environment is well illustrated by the following examples. Microbes evolve more rapidly than humans, thus explaining the perpetual struggle against infection and its worsening by the inappropriate use of antibiotics to which resistance soon develops. Allergic reactions are due to an immune system that is biased towards hypersensitivity to innocent agents rather than insufficient reactivity to genuine threats. Disease predisposition as an adaptive advantage Paradoxically, a disease or disease predisposition can have beneficial effects. A few diseases or disease susceptibilities can, in addition to their deleterious effects, confer adaptive protection against specific environmental pathogens. This advantage may explain the high prevalence of a disease in areas where the specific pathogen for another disease is endemic. Environmental causes of diseases are called pathogens, although this term is used commonly only when referring to microbes: bacteria capable of causing disease are pathogenic; those that are harmless are non-pathogenic. They are due to a combination of causes, such as genetic factors and infective agents. Sometimes the aetiology of a disease is unknown, but the disease is observed to occur more commonly in people with certain constitutional traits, occupations, habits or habitats; these are regarded as risk factors. Other risk factors may simply have a permissive effect, facilitating the development of a disease in that individual; examples include malnutrition, which favours infections. For example, ionising radiation can cause rapid deterioration leading to death, scarring of tissues, or tumours. Heterozygosity for the most common mutation (deletion of phenylalanine at position 508) in the cystic fibrosis conductance regulator renders decreased susceptibility to Salmonella typhi infection. Most common diseases have entirely environmental causes, but genetic influences in disease susceptibility are being increasingly discovered, and many diseases with no previously known cause are being shown to be due to genetic abnormalities (Ch. This is the reward of applying the principles of clinical genetics and the techniques of molecular biology to the study of human disease. The extent to which a disease is due to genetic or environmental causes can often be deduced from some of its main features or its association with host factors. Features pointing to a significant genetic contribution include a high incidence in particular families or races, or an association with an inherited characteristic. Diseases associated with particular occupations or geographic regions tend to have an environmental basis; the most abundant environmental causes of disease are microbes (bacteria, viruses, fungi, etc. Some agents capable of causing disease, such as alcohol, Characteristic sets of disease features enable them to be better understood, categorised and diagnosed. For many diseases, however, our knowledge is still incomplete or subject to controversy. Host predisposition to disease Many diseases are the predictable consequence of exposure to the initiating cause; host factors make relatively little contribution. This is particularly true of physical injury: the immediate results of mechanical trauma or radiation injury are dose-related; the outcome can be predicted from the strength of the injurious agent. This is exemplified by infections with potentially harmful bacteria: the outcome can be influenced by various host factors such as nutritional status, genetic influences and pre-existing immunity. Some diseases occur more commonly in individuals with a congenital predisposition. Diseases associated with an increased risk of cancer are designated premalignant conditions; for example, hepatic cirrhosis predisposes to hepatocellular carcinoma, and ulcerative colitis predisposes to carcinoma of the large intestine. The histologically identifiable antecedent lesion from which the cancers directly develop is designated the premalignant lesion. This is exemplified by opportunistic infections in patients with impaired defence mechanisms resulting in infection by organisms not normally harmful. Causes and agents of disease Distinction should be made between the cause and the agent of a disease. There is, in fact, incontrovertible evidence that the decline in incidence of many serious infectious diseases is attributable substantially to improved hygiene, sanitation and general nutrition rather than to immunisation programmes or specific antimicrobial therapy. Such arguments are of relevance here only to emphasise that the socio-economic status of a country or individual may influence the prevalence of the environmental factor or the host susceptibility to it. Causal associations A causal association is a marker for the risk of developing a disease, but it is not necessarily the actual cause of the disease. The stronger the causal association, the more likely it is to be the aetiology of the disease. Many infectious diseases result only if sufficient numbers of the microorganism. The utility of these statements is illustrated by the association between lung cancer and cigarette smoking. Lung cancer is more common in smokers than in non-smokers; tobacco smoke contains carcinogenic chemicals; the risk of lung cancer is proportional to cigarette consumption; population groups that have reduced their cigarette consumption. For example, because some heavy cigarette smokers never develop lung cancer, smoking cannot alone be regarded as a sufficient cause; other factors are required. Conversely, because some non-smokers develop lung cancer, smoking cannot be regarded as a necessary cause; other causative factors must exist. For example, syphilis, a venereal disease, is always due to infection by the spirochaete Treponema pallidum; there is no other possible cause for syphilis; syphilis is the only disease caused by Treponema pallidum. The reason for discussing these time intervals here is that it is during these periods that the pathogenesis of the disease is being enacted, culminating in the development of symptomatic pathological and clinical manifestations that cause the patient to seek medical help. However, each postulate merits further comment because there are notable exceptions: Structural and functional manifestations the aetiological agent (cause) acts through a pathogenetic pathway (mechanism) to produce the manifestations of disease, giving rise to clinical signs and symptoms. The pathological manifestations may require biochemical methods for their detection and, therefore, should not be thought of as only those visible to the unaided eye or by microscopy. The biochemical changes in the tissues and the blood are, in some instances, more important than the structural changes, many of which may appear relatively late in the course of the disease. Although each separately named disease has its own distinctive and diagnostic features, some common structural and functional abnormalities, alone or combined, result in ill health. Cultivation of some organisms is remarkably difficult, yet their role in the aetiology of disease is undisputed. Ethics prohibit wilful transmission of a disease from one person to another, but animals have been used successfully as surrogates for human transmission. Immunosuppression may lessen the antibody response and also render the host extremely susceptible to the disease. In addition, if an antibody is detected it should be further classified to confirm that it is an IgM class antibody, denoting recent infection, rather than an IgG antibody, denoting long-lasting immunity due to previous exposure to the organism. Structuralabnormalities Common structural abnormalities causing ill health are: Pathogenesis the pathogenesis of a disease is the mechanism through which the aetiology (cause) operates to produce the pathological and clinical manifestations. Groups of aetiological agents often cause disease by acting through the same common pathway of events. Other structural abnormalities visible only by microscopy are very common and, even though they do not directly cause clinical signs or symptoms, they are nevertheless diagnostically useful and often specific manifestations of disease. For this reason, the morphological examination of diseased tissues is fruitful for clinical diagnosis and research. At an ultrastructural level (electron microscopy), one might see alien particles such as viruses in the affected tissue; there could be abnormalities in the number, shape, internal structure or size of tissue components such as intracellular organelles or extracellular material. By light microscopy, abnormalities in cellular morphology or tissue architecture can be discerned. With the unaided eye, changes in the size, shape or texture of whole organs can be discerned either by direct inspection or by indirect means such as radiology. Lesions A lesion is the structural or functional abnormality responsible for ill health. A lesion may be purely biochemical, such as a defect in haemoglobin synthesis in a patient with a haemoglobinopathy. Some diseases have no overtly visible lesions, despite profound consequences for the patient; for example, schizophrenia and depressive illness yield nothing visibly abnormal in the brain if examined using conventional methods. Pathognomonicabnormalities Pathognomonic features denote a single disease, or disease category, and without them the diagnosis is impossible or uncertain. Similarly, the presence of Mycobacterium tuberculosis, in the appropriate context, is pathognomonic of tuberculosis. Pathognomonic abnormalities are extremely useful clinically, because they are absolutely diagnostic. Unfortunately, some diseases are characterised only by a combination of abnormalities, none of which on its own is absolutely diagnostic; only the particular combination is diagnostic. Examples include the spread of an infective organism from the original site of infection, where it had provoked an inflammatory reaction, to another part of the body, where a similar reaction will occur. Similarly, malignant tumours arise initially in one organ as primary tumours, but tumour cells eventually permeate lymphatics and blood vessels and thereby spread to other organs to produce secondary tumours or metastases. Each of these common symptoms has a pathological basis and, in those conditions that remit spontaneously, treatment for symptomatic relief may be sufficient. In addition to the general symptoms of disease, there are other specific expressions of illness that help to focus attention, diagnostically and therapeutically, on a particular organ or body system. This is important to know because often nothing more than symptomatic treatment is required because either the disease will remit spontaneously. When we say that the 5-year survival prospects for carcinoma of the lung are about 5%, this is the prognosis for that condition. The prognosis for any disease may be influenced by medical or surgical intervention; indeed that is the objective. So one must distinguish between the prognosis for a disease that is allowed to follow its natural course and the prognosis for the same disease in a group of patients receiving appropriate therapy. In assessing the long-term prognosis for a chronic disease, it is important to compare the survival of a group of patients with actuarial data for comparable populations without the disease. The survival data for the group with the disease should be corrected to allow for deaths that are likely to occur from other diseases. Some are punctuated by periods of quiescence when the patient enjoys relatively good health. Some diseases may oscillate through several cycles of remission and relapse before the patient is cured of or succumbs to the disease. The tendency of some diseases to go through cycles of remission and relapse can make it difficult to be certain about prognosis in an individual case. For example, a non-fatal myocardial infarct (heart attack) leaves an area of scarring of the myocardium, impairing its contractility and predisposing to heart failure: this is the morbidity of the disease in that particular patient. Mortality is expressed usually as a percentage of all those patients presenting with the disease. For example, the mortality rate of myocardial infarction could be stated as 50% in defined circumstances. Until the 19th century, many diseases and causes of death were recorded in a narrative form, often based on symptoms. Primaryandsecondary the words primary and secondary are used in two different ways in the nomenclature of disease: 1. Primary in this context means that the disease is without evident antecedent cause. Other words with the same meaning are essential, idiopathic, spontaneous and cryptogenic. Thus, primary hypertension is defined as abnormally high blood pressure without apparent cause. Secondary means that the disease represents a complication or manifestation of some underlying lesion. Thus, secondary hypertension is defined as abnormally high blood pressure as a consequence of some other lesion. The words primary and secondary may be used to distinguish between the initial and subsequent stages of a disease, most commonly in cancer. The primary tumour is the initial tumour from which cancer cells disseminate to cause secondary tumours elsewhere in the body. Disabilityanddisease Many diseases result in only transient disability; for example, influenza or a bad cold may necessitate time off work for an employed person. Some diseases, however, are associated with a significant risk of permanent disability; in such cases, treatment is intended to minimise the risk of disability.

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