Adolescents: concern about being disliked hair loss 3 year old buy finast overnight delivery, rejected hair loss in men 2016 purchase generic finast on line, or criticised by their peers? Not easy to recognise as young people often know that their fears are groundless and feel ashamed of what they think is a flaw in their character? Anxiety disorders: Separation anxiety disorder hair loss in men over 30 purchase finast 5mg amex, social phobia hair loss 3 months after pregnancy finast 5mg on-line, generalised anxiety disorder hair loss in men 39 s wearhouse locations buy discount finast 5mg, obsessive compulsive disorder hair loss treatment vitamins order finast 5mg with amex, post-traumatic stress disorder Separation Anxiety Disorder? Parents may have some insight but usually underestimate the severity of the maternal-child dependence and are very defensive? Diagnosis: irrational fear of harm to parents or that they will be abandoned by them? Quick return to school before problem becomes entrenched hair loss ketoconazole buy finast australia, even if only for a small portion of the day? Facing the fear is initially distressing but reduces the anxiety hair loss 8 months after birth buy finast discount, avoidance increases it? Problem is actual separation once settled into the day problem is likely to reduce? Standing up to a bully is pretty sophisticated behaviour in early teens not developmentally consistent with wanting to identify with the peer group? More likely to present with separation anxiety, phobias, somatic complaints and behaviour issues. More likely to talk of profound boredom and feeling unloved and lonely than appetite and sleep change? Consider differentials: Depression, drug abuse, eating disorder, psychosis (actual or prodrome), medical th th 662 4 and 5 Year Notes? Counselling: for milder depression, no remediable family factors, recent life events, if they want it? Developmental tasks of adolescence: Tasks Early: 10 13 years Mid: 14 16 years Late: 17 21 years Psychological tasks Independence Separates from parents: Separation creates Comfortable away questions, tests anxieties, ambivalence as form home, able to retreats to family return for counsel th th 664 4 and 5 Year Notes without shame Body image Adjust to dramatic Try on images to find real Satisfied with realistic changes in body self (incl. Sexual body image Constant comparisons identify), attempts to improve image Sexual drives Marked sexual Sexual experimentation, Beginnings of intimacy curiosity, masturbation narcissistic sexual and caring relationships Social Tasks Relationships Boys gangs? Crushes dating, try on other more important than on adults philosophies and beliefs group,? Set clear boundaries: It is appropriate to identify what is and is not acceptable behaviour (eg creating risk of harm to themselves or others). But also check they can get condoms, etc: if you ever were to , where would you go for information or contraceptives (tie them down to specifics)? How would you rate yourself over the last couple of weeks if 1 was foul and 10 was brilliant? Menarche relatively unchanged at 12 (ie earlier onset, but endpoint relatively unchanged). Getting earlier by 3-4 months per decade (but psycho-social development unchanged)? Clinical signs: Old bone age and growth spurt (in addition to eg breast development)? Bathing, shaving, teeth, dressing: how much assistance in needed, can they reach all body parts? Cognitive impairment: delirium, dementia, focal cognitive impairments (dysphasia, non-dominant hemisphere problems). Cultural and social differences between cohorts: eg response to health professionals, access to services, gender and spiritual issues? Diversity of physiology and function increases with age: stereotypes are unhelpful, need individual assessment? Multiple pathology: Not a single disease process presenting acutely, but a person presenting with disease(s) and/or disabilities. Need a model of care and assessment that considers individual disease processes, individual experience, the social context, and interactions between and within these dimensions? Atypical presentation: Strange or unusual presentations are more common compared with younger people, due to multiple diseases, reduced homeostatic capability, etc. Threshold effect: Change in functional status can occur in the absence of a clear precipitant due to build up of subclinical dysfunction and loss of physiologic reserve? Impairment: Loss or abnormality of psychological, anatomical or physiological function. Handicap: disadvantage for a particular individual resulting from impairment or disability that limits fulfilment of a role normal for someone of that age, culture, gender, etc. Will also include impact of environment (eg not being able to drive is not always a rd disability eg if you live in the 3 world)? Interventions should address all levels, and acknowledge the interaction between each level? For Osteoporosis and Osteoarthritis, see Metabolic Bone Disease, page 261 Health Care of the Elderly 673? Hospitalisation is dangerous to older people, especially leading to: drug toxicity, injury and mental deterioration? There is often a decline in functional status following discharge, unrelated to disease process? Bed rest (eg in hospital, especially if on drips, monitors etc) generally leads to? Volume depletion therapy (also results from bed rest) + age related vasomotor instability? Nutritional supplements: eg add milk powder to food, eat high-density foods, take supplements Falls? Information on body position: visual, vestibular, mechanoreceptors, proprioception, central processing? Sedative use, cognitive impairment, abnormalities of balance and gait, polypharmacy, history of stroke, hypotension? Treatment by extraction and implantation improves visual acuity in about 90% but a smaller proportion benefit in terms of activities of daily living? Senile arcus: ring of lipid and calcium salts in a ring at the junction of the cornea and sclera. Psychological: causing emotional anguish or fear, including intimidation, humiliation, harassment, threats, removal of decision making powers? Financial: improper use of funds or other resources Health Care of the Elderly 675? Passive neglect: refusal/failure of a carer to provide the basis necessities due to inadequate knowledge, infirmity, or dispute over the value of services? Prevalence: Significant under-reporting due to cognitive impairment, fear, life long pattern of abuse, access to someone to complain to , stigma associated with domestic violence. About 5% of elderly people subject to abuse, usually by a spouse, child or relative? Watch for injuries or health or emotional problems with vague or inconsistent explanations? Driving depends on cognitive function, motor function and sensori-perceptual function? Elderly are only 14% of those killed in crashes, but have a higher death to injury ratio? Older drivers more likely to be at fault in accidents involving intersections, merging and manoeuvring? Age associated changes affecting driving include: vision, psychomotor function, strength and dexterity, cognitive function (especially attention to multiple stimuli and finding ones way,? Medical assessment a legal requirement at 75, then 80 and every two years thereafter (including vision check). Cognitive screening should be included due to the profound effect on driving, the insidious nature of cognitive impairment, good social facades by patients, and frequent lack of insight. Goals should be agreed by negotiation with older person, the carer and the rehab team? Goals should include: who, will do what, under what circumstances, and to what degree of success? Depression: Unwell and disabled people have a high prevalence of usually treatable depression. Diagnosis can be complicated due to overlapping symptoms (eg fatigue, apathy, psychomotor retardation and sleep disturbance)? Low expectations and ageism: decline is not always as inevitable or severe as thought. Patients, carers and professionals can all have misconceptions and unrealistically low expectations? Right to dependency: some old people may not participate because they feel they should be looked after? Common rehabilitation interventions: physiotherapy (especially musculo-skeletal problems and mobility), occupational therapy (therapy to? Whether inpatient or outpatient setting is assessed on the basis of: level of dependency (especially night care), degree of complexity of disability, speed of response needed, housing and domestic circumstances, availability of in or outpatient services Rest Home and Hospital Care? Age adjusted mortality rate: adjusts with reference to a standard population to allow comparisons between populations with different age distributions? Premature mortality: death occurring before the average life expectancy within a given population? Changes over time have largely been due to social and economic changes (particularly public and personal hygiene). Impairment: reduction in physical or mental capacity usually due to an organ/system. Interviewer bias: systematic difference in soliciting, recording and interpreting of responses (? Matching does reduce the effect of confounding but there are other ways to deal with that when doing the number crunching? In a case-control study, the ratio between the cases and the controls is fixed by the study design, not the prevalence in the population. Deposit eggs in any container with water in or around homes (so can still get it if low rainfall or dry season)? Leads to all extremes of environmental health (death in combat, poor health, refugees, socio economic effects)? The presumptive identification of unrecognised/preclinical disease or defects by the application of tests, examinations or other processes that can be applied rapidly (and cheaply)? The downside is an increasing rate of false positives who have unnecessary further investigation? A highly specific test would maximise true negatives (ie minimise positives, so would not further test anyone unnecessarily), but at the cost of increasing false negatives who are the people you actually want to detect? Lead-time bias: interval from detection to point where diagnosis would have been made without screening. Depends on length of pre-clinical phase, frequency of testing, and the test sensitivity? Length bias: Cases with a disease with a longer natural history are more likely to be detected by a screening programme. Distribution: benefits accrue to a few and are large; harms fall on many and are minor. Students from poor households are more likely to underachieve, have lower participation rates in tertiary education. Due to development of manufacturing industries and centralisation of agricultural production (eg freezing works)? Part of history: tobacco given as gifts at Waitangi, Goldie images of smokers, etc? Needs whanau, local, national integration the Treaty of Waitangi (The Tiriti O Waitangi)? Kawanatanga (Governance) vs Sovereignty in English no Maori would have given this up? Implicit in treaty were concepts of equity, partnership, economic and cultural security? Concepts of health firmly based in Maori culture, which under the treaty are recognised and protected? Kawanatanga (Governance): Government has responsibilities to govern and should take reasonable steps to improve health. Right to establish and provide services (but its not just a right, it is also effective)? Maori have poorer health and poorer access, so neither equality of opportunity nor outcome? Maori discriminated against in social policy, entitlement to vote, treatment of returned servicemen, etc? Measures of Maori health: value of resources in Maori ownership, drop in crime rate, use of the reo? For family and friends, seeing the patient while alive is important, bring koha, say karakia? Everything is tapu those at the bedside are responsible for ensuring customs carried out? Avoid post-mortem: sanctity involved, impedes release of spirit (spirit lingers 3 8 days)? Conflict over where to bury the deceased: the tupapaku may be taken to a number of marae as a compromise? Pragmatic focus (ie get them to smoke outside rather than insisting on smoking cessation). Alcohol takes people from production and has greater secondary costs (on family, accidents, etc, and effects production from earlier in life)? Prevention Paradox: To get greatest gain from prevention need to target the mean, not the tail (although they drink the most), as most people, and therefore the biggest cost, relates to people around the mean. Market Failure Same as other goods and services Practice of Medicine A Science An art Economics Financial rewards reduce the Financial rewards generate high quality of caring quality care Policy Regulation needed to mitigate Reduce regulation, encourage economic forces. Encourage new medical technologies technologies Public Health 699 th th 700 4 and 5 Year Notes Evidence Based Medicine th? Clinical Practice Guideline: systematically developed statement to assist decision-making in specific clinical circumstances? Decision Analysis: application of explicit, quantitative methods to analyse decisions under conditions of uncertainty? Intention to treat analysis: analyses individuals according to the group to which they were randomised, even if they didn? Unless it is possible to adjust for the confounding variables, their effects cannot be distinguished from those of the factors being studied? Extent to which a variable or intervention measures or accomplishes what it is supposed to . Does it measure what it claims to measure described by specificity and sensitivity, etc Risks and Odds Outcome Exposure Yes No Yes A B No C D Evidence Based Medicine 703? If observed agreement = 78% of cases, and agreement on the basis of chance is 51%, then Kappa = (78 51)/(100 51) = 0. SnNout = when a test has a high sensitivity, a negative result rules out the diagnosis? Specificity: the proportion of people free of a disease who have a negative test. Sensitivity and specificity may vary between populations with significant disease and the general population? Avoidance of work-up bias: if there is bias in who is referred for the gold standard. All subjects given a test should receive either the gold standard test or be verified by follow-up? Are the likelihood ratios for the test results presented or data necessary for their calculation provided? An accurate test is very valuable if the target disorder is dangerous if undiagnosed, has acceptable risks and effective treatment exists Bayesian Theory? Combining information from history, exam and investigations to determine overall likelihood? Use as part of decision analysis to determine the level at which the probability of disease is sufficiently low to withhold treatment or further tests, or sufficiently high to start treatment. Balance between: severity of illness, efficiency, complications of test and treatment, and properties of the test Evaluation of Therapy Assessment of an article about Therapy? Neither prognostic or risk factors imply a cause and effect relationship Using an article about prognosis? Evidence Based Medicine 707 th th 708 4 and 5 Year Notes Professional Development Professional Boundaries. First aid after exposure (needle stick, splash, spill, bite): rinse affected area under running warm water for at least 3 minutes, squeeze a puncture wound gently, paint with povidone iodine or isopropyl alcohol? Need an additional form before cremation, which is then cleared by the Medical Referee? Certificate of Life Extinct: police form to say the person is dead eg if being referred to the Coroner. Acts asserts right to autonomy, to refuse treatment and to manage their own affairs? Exercising autonomy requires intellectual and emotional competence and the opportunity for action? Standpoints: law, religious belief, social conventions, morality all give standpoints from which can define right and wrong and they may disagree? Disclosure in the public interest: Health Information Privacy Code allows disclose to prevent a serious and imminent threat?
The tumour of of disease in cases with carcinoma head of the pancreas (80%) hair loss updates order finast canada, the head extends into the ampulla of Vater hair loss 1 year after birth generic finast 5mg amex, common bile and less often in cancer of the body and tail of the pancreas hair loss medicine order 5mg finast free shipping. Microscopically hair loss shampoo treatment purchase 5mg finast with amex, most pancreatic carcinomas arise from the prognosis of pancreatic cancer is dismal: median the ductal epithelium which normally comprises less than survival is 6 months from the time of diagnosis hair loss treatment cheap finast 5 mg without a prescription. Approxi 4% of total pancreatic cells hair loss cure killing discount finast on line, whereas carcinoma of the acini mately 10% patients survive 1 year and the 5-year survival is poor 1 to 2% hair loss in men kidney buy finast 5mg visa. The kidneys are bean-shaped paired organs fitoval shampoo anti-hair loss safe finast 5mg, each weighing about 150 gm in the adult male and about 135 gm in the adult female. The hilum of the kidney is situated at the midpoint on the medial aspect where the artery, vein, lymphatics and ureter are located. The kidney is surrounded by a thin fibrous capsule which is adherent at the hilum. Cut surface of the kidney shows 3 main structures: well demarcated peripheral cortex, inner medulla and the innermost renal pelvis (Fig. Remaining 15% nephrons consisting of collecting tubules, collecting ducts, loops of Figure 22. This latter part of the cortex forms faint striations called medullary rays, a of each renal pyramid for passage of urine collected from misnomer since theses structures are located in the cortex collecting ducts and goes down into minor calyces. Columns of renal cortical tissue the renal pelvis is the funnel-shaped collection area of that extend into the space between adjacent pyramids are the urine for drainage into the ureter. The minor calyces (8 called the renal column (septa) of Bertin; they contain the 18 in number in a normal kidney) collect urine from renal interlobar arteries. The base of a renal pyramid lies adjacent to the of approximately one million microstructures called outer cortex and forms the cortico-medullary junction, while nephrons. From point of view of diseases of the kidneys, 4 components of renal parenchyma require further elaboration: renal vasculature, glomeruli, tubules and interstitium. Each kidney is supplied with blood by a main renal artery which arises from the aorta at the level of the 2nd lumbar vertebra. It usually divides into anterior and posterior divisions at the hilum although occasionally these divisions may even arise directly from the aorta. The anterior and posterior divisions divide into segmental branches from which interlobar arteries arise which course between the lobes. Along their course, they give off the arcuate arteries which arch between the cortex and medulla. The arcuate arteries, in turn, give off interlobular arteries which lie in the cortex perpendicular to the capsular surface in the part overlying the pyramids and, therefore, are also called straight arteries Figure 22. Thus, occlusion of any of the branches results in infarction of the renal parenchyma supplied by it. The glomerulus consists of invagination of the blind end of the proximal tubule and contains a capillary tuft fed by the afferent arteriole and drained by efferent arteriole. The capillary tuft is covered by visceral epithelial cells (podocytes) which are continuous with those of the parietal epithelium at the vascular pole. The transition to proximal tubular cells occurs at the urinary pole of the glomerulus. Subdivisions of capillaries derived from the afferent arterioles result in the formation of lobules (up to 8 in number) within a glomerulus. Each lobule of a glomerular tuft consists of a centrilobular supporting stalk composed of mesangium containing mesangial cells and mesangial matrix. The mesangium is continuous at the hilum with the lacis cells of the juxtaglomerular apparatus. Besides their role as supportive cells, mesangial cells are involved in the production of mesangial matrix and glomerular basement membrane; they function in endocytosis of leaked macro molecules and also possibly in the control of glomerular Figure 22. The major function of glomerulus is complex filtration from the capillaries to the urinary space. Glomerular filtrate is quite similar in composition to plasma but lacks proteins arterioles take their origin, each one supplying a single and cells. Up to this stage, the arteries and arterioles are end of the following 3 components (Fig. The efferent arterioles leaving the glomerulus supply i) Fenestrated endothelial cells lining the capillary loops. It further consists of 3 layers?the the juxtamedullary glomeruli, however, give off a series central lamina densa, bounded by lamina rara interna on of parallel vessels called vasa recta which descend to the inner endothelial side of the capillary and lamina rara externa on medulla supplying the loop of Henle and collecting ducts visceral epithelial side of the capillary. Lymphatic drainage likewise occurs through following: lymphatics associated with the intrarenal vasculature leaving A normal lamina densa. The following important inferences can be drawn from A healthy covering of glomerular epithelial cells. The tubules of the kidney account for the ii) the macula densa is comprised by specialised region of greatest amount of the renal parenchyma. The structure of the distal tubule when it returns to the vascular pole of its renal tubular epithelium varies in different parts of the parent glomerulus. The tubular cells here are taller and nephron and is correlated with the functional capacity of that narrower than elsewhere with the nuclei lying close together. This is the first part between the macula densa and the arterioles and merge with arising from the glomerulus and is highly specialised part the glomerular mesangium. The descending segment of loop is lined by simple epithelium while the ascending limb is lined by columnar cells. The major function of loop of Henle is active reabsorption of sodium, potassium and chloride, and passive diffusion of water resulting in concentrated filtrate of urine. The system of collecting ducts is the final iii) Bacteriologic examination iv) Microscopy pathway by which urine reaches the tip of renal papilla. In health, the renal cortical interstitium is i) Urea scanty and consists of a small number of fibroblast-like cells. The simplest diagnostic tests for in the body: renal function is the physical, chemical, bacteriologic and 1. Excretion of waste products resulting from protein microscopic examination of the urine. Regulation of acid-base balance by excretion of H ions colour, specific gravity and osmolality. Regulation of salt-water balance by hormones secreted both 700-2500 ml (average 1200 ml) of urine is passed in 24 hours, intra and extra-renally. Formation of renin and erythropoietin and thereby playing the concentrating and diluting power of the kidneys. A number of been devised which give information regarding the following convenient dipstick tests are available for testing these parameters: chemical substances and pH. These consist of paper strips a) Renal blood flow impregnated with appropriate reagents and indicator dyes. Periodic acid-Schiff stain for highlighting glomerular consisting of only proteins indicating a non-inflammatory basement membrane. Immunofluorescence to localise the antigens, complements tration and dilution tests are designed to evaluate functional and immunoglobulins. Electron microscopy to see the ultrastructure of glomerular concentrate or dilute urine is dependent upon both functional changes. Failure to achieve maintain constant plasma concentration and accurately timed 653 adequate urinary concentration can be due to either defects urine samples are collected. However, determination of urinary fraction of this substance is secreted by the tubules. The specific gravity provides only a rough estimate of osmolarity clearance of creatinine is determined by collecting urine over of the urine. The tubular disease can be diagnosed in its early 24-hour period and a blood sample is withdrawn during the stage by water deprivation (concentration) or water excess day. However, if the tubular cells are concentration of urea is affected by a number of factors. Impairment of renal function tubules and its clearance is measured by determining its results in elevation of end-products of protein metabolism. Normally, renal this includes increased accumulation of certain substances blood flow is about 1200 ml per minute in an average adult. Traditionally, diseases of the kidneys are divided into 4 major High levels of creatinine are associated with high levels groups according to the predominant involvement of of? Glomerular diseases: these are most often immuno to glomerular disease or due to increased production by the logically-mediated and may be acute or chronic. The rate of this filtration can be measured toxic or infectious agents and quite often involve interstitium by determining the excretion rate of a substance which is as well as tubules (tubulo-interstitial diseases). Vascular diseases: these include changes in the nephron reabsorbed nor secreted by the tubules. The glomerular as a consequence of increased intra-glomerular pressure such filtration rate (normal 120 ml/minute in an average adult) is as in hypertension or impaired blood flow. C = where the major morphologic involvements of the kidneys in P the initial stage is confined to one component (glomeruli, C is the clearance of the substance in ml/ minute; tubules, interstitium or blood vessels), but eventually all U is the concentration of the substance in the urine; components are affected leading to end-stage kidneys. V is the volume of urine passed per minute; and Regardless of cause, renal disease usually results in the P is the concentration of the substance in the plasma. The decline in formation of the the pathophysiological aspects of acute and chronic renal urine leads to accumulation of waste products of protein failure are briefly discussed below. This is believed to occur creatinine) in the blood with consequent development of due to drawing of water and sodium by preceding high levels uraemia. Since tubular cells have not regained normal as pre-renal, intra-renal and post-renal in nature. The process of healing may take up to cardiac output and hypovolaemia or vascular disease causing one year with restoration of normal tubular function. Intra-renal disease is characterised by disorders in which neither the glomerulus nor the tubules disease of renal tissue itself. Typically, this of the arteries and arterioles within the kidney, diseases of pattern is seen in marginal ischaemia caused by renal arterial glomeruli, acute tubular necrosis due to ischaemia, or the obstruction, hypovolaemia, hypotension or cardiac effect of a nephrotoxin, acute tubulointerstitial nephritis and insufficiency. Since the tubular cells are functioning normally, the caused by obstruction to the flow of urine anywhere along nephron retains its ability to concentrate the glomerular the renal tract distal to the opening of the collecting ducts. This may be caused by a mass within the lumen or from wall of the tract, or from external compression anywhere along the lower urinary tract?ureter, bladder neck or urethra. Primary erythematosus, serum sickness nephritis and diabetic symptoms of uraemia develop when there is slow and nephropathy. Damage imbalances cause the following manifestations: to tubulointerstitial tissues results in alterations in 1. As a result of renal dysfunction, acid reabsorption and secretion of important constituents leading base balance is progressively lost. Tubulointer occurs, while bicarbonate level declines in the blood, resulting stitial diseases can be categorised according to initiating in metabolic acidosis. The clinical symptoms of metabolic etiology into 4 groups: vascular, infectious, toxic and acidosis include: compensatory Kussmaul breathing, obstructive. Hyperkalaemia is Nephrosclerosis causes progressive renal vascular occlusion further worsened by metabolic acidosis. The most common juxtaglomerular apparatus further aggravates sodium and example is intake of high doses of analgesics such as water retention. The main symptoms referable to sodium and phenacetin, aspirin and acetaminophen (chronic analgesic water retention are: hypervolaemia and circulatory overload nephritis). Uric acid crystals may leads to progressive damage to the nephron due to fluid back be deposited in joints and soft tissues resulting in gout. The waste-products of protein metabolism stones, blood clots, tumours, strictures and enlarged prostate. At this stage, damage to renal manifestations of uraemia are related to toxic effects of these parenchyma is marginal and the kidneys remain functional. A are normal and the patients are usually asymptomatic except number of extra-renal systemic manifestations develop at times of stress. At this stage, about 90% of functional renal as urochrome in the skin causes sallow-yellow colour. As a evaporation of the perspiration, urea remains on the facial result, the regulation of sodium and water is lost resulting skin as powdery uraemic frost. Radiologically, uraemic pneumonitis shows characteristic central, butterfly-pattern of oedema and congestion in the chest radiograph. Azotaemia directly induces mucosal ulcerations in the lining of the stomach and intestines. The skeletal manifestations of renal failure are referred to as renal osteodystrophy (Chapter 28). Two major types of skeletal disorders may occur: i) Osteomalacia occurs from deficiency of a form of vitamin D which is normally activated by the kidney (page 248). Since vitamin D is essential for absorption of calcium, its deficiency results in inadequate deposits of calcium in bone tissue. Decreased calcium level triggers the secretion of parathormone which mobilises calcium from bone and increases renal tubular reabsorption of calcium thereby conserving it. However, if the process of resorption of calcium phosphate from bone continues for sufficient time, hypercalcaemia may be induced with deposits of excess calcium salts in joints and soft tissues and weakening of bones (renal osteodystrophy). Approximately 10% of all persons are born with potentially significant malformations of the urinary system. These range in severity from minor anomalies which may not produce to accompanied pulmonary hypoplasia), haemorrhage, and clinical manifestations to major anomalies which are neoplastic transformation. A simple classification including either elsewhere in the urinary tract or in other organs. Medullary cystic disease under the heading of cystic diseases of the kidney? described 1. Multifocal cystic change in Wilms? tumour (page 696) include: abdominal mass, infection, respiratory distress (due neoplastic cystic lesions of the kidney are described later 657 (page 694). Renal dysplasia is the most common form of cystic renal disease in the newborn and infants. The condition may occur sporadically or maybe familial and part of a syndrome of other anomalies. There are cysts lined by flattened kidney or its affected part is replaced by disorderly mass epithelium while the intervening parenchyma consists of primitive of multiple cysts resembling a bunch of grapes. The true adult in the mass represent dilated tubules lined by flattened polycystic renal disease is always bilateral and diffuse. Glomeruli and tubules are retained, and symptoms appear in adult life, mostly between scanty, primitive or absent. Unilateral renal dysplasia is frequently discovered in newborn or infants as a flank mass. The cut surface shows cysts throughout the renal the prognosis of unilateral renal dysplasia following parenchyma varying in size from tiny cysts to 4-5 cm in removal of the abnormal kidney is excellent while bilateral diameter (Fig. The contents of the cysts vary from renal dysplasia results in death in infancy unless renal clear straw-yellow fluid to reddish-brown material. An adult type inherited as an autosomal dominant disease; Histologically, the cysts arise from all parts of nephron. It is transmitted as an autosomal recessive trait and the family history of similar disease is usually not present. The age at presentation may be perinatal, neonatal, infantile or juvenile, but frequently serious manifestations are present at birth and result in death from renal failure in early childhood. Grossly, the kidneys are bilaterally enlarged with smooth external surface and Figure 22. Cut surface reveals small, of comparison of gross appearance of the two main forms. The condition may become sectioned surface of the kidney sponge-like appearance clinically apparent at any age but most commonly manifests (Fig. The clinical manifestations depend are cysts in the pancreas, spleen, lungs and other organs. In severe form, the gross bilateral cystic Approximately 15% of patients have one or more intracranial renal enlargement may interfere with delivery. Almost all cases of infantile polycystic kidney disease have associated multiple epithelium-lined cysts in the liver or proliferation of portal bile ductules. In older children, associated hepatic changes evelop into what is termed congenital hepatic fibrosis which may lead to portal hypertension and splenomegaly. The contrasting features of the two main forms of the polycystic kidney disease are presented in Table 22. Medullary Cystic Disease Cystic disease of the renal medulla has two main types: A. Nephronophthiasis-medullary cystic disease complex, a common cause of chronic renal failure in juvenile age group. The condition occurs in loss of demarcation between cortex and medulla and replacement of the adults and may be recognised as an incidental radiographic entire renal parenchyma by cyst s varying in diameter from a few millimeters to 4-5 cm. These cysts are not communicating with the pelvi finding in asymptomatic cases, or the patients may complain calyceal system. The renal pelvis and calyces are distorted due to cystic of colicky flank pain, dysuria, haematuria and passage of change. G/A Symmetric bilateral enlargement Micro and macrocysts radiating from medulla to outer cortex 7. M/E Macrocysts Enlarged, sometimes asymmetric, sponge-like Cysts derived from all parts of nephron Cysts from dilated collecting ducts (glomeruli, tubules) 8. Simple Renal Cysts with secondary complications of infection and calculus Simple renal cysts are a very common postmortem finding. Since these cysts are rare in infants and children, they be enlarged, normal or shrunken in size depending upon appear to be acquired rather than congenital lesions. The association between simple cysts and ducts, which may contain spherical calculi.
Several studies demonstrated that there are significant variations in the expression profile of subtype peptide receptors also between the primary tumor and its metastases or even within the same tumor (Reubi hair loss clinic purchase 5mg finast amex, 2002; Reubi hair loss on arms discount finast 5mg visa, 2003) and so revalid hair loss 90 capsules cheap finast 5mg, an increase of receptor subtypes selectivity might be counterproductive in the development of imaging molecules hair loss cure 365 purchase finast american express. On the other hand hair loss with menopause cheap finast 5 mg on line, subtype-selective ligands are useful tools for functional imaging purposes as well as to study the changes in receptor expression and response to therapeutic interventions hair loss cure 9000 finast 5mg discount. Until recently the use of receptor-antagonists has not been considered for in vivo targeting of tumors overexpressing G-protein coupled receptors and this due to the low capability of antagonist to internalize into tumor cells hair loss cure how long buy 5mg finast fast delivery. Indeed hair loss in men 70s style buy finast 5mg mastercard, the cell internalization of imaging probes has been regarded for a long time as a fundamental prerequisite of labeled peptides, providing high contrast imaging. The benefit of the use of antagonist peptide ligands has a considerable impact on those systems, in which the binding of agonist-ligand either stimulates tumor growth or exerts unwanted pharmacological action. Many authors have demonstrated that different peptide receptors are co-expressed on tumors in a heterogeneous manner. These suggest that targeting more than one receptor class simultaneously would greatly enhance the sensitivity of tumor detection. These aspects (co-expression on tumors and low internalization capacity) stimulate the development of multivalent and/or multireceptor ligands able to bind either to multiple homo (multivalent) or to hetero (multireceptor) receptors present on the surface of the tumor cell. The presence of more ligands induces a number of peculiar biological characteristics to the targeting molecules that are not present in the monovalent ligand. Polyvalent interactions are generally much stronger than the corresponding monovalent and offer the basis for mechanisms of agonizing or antagonizing biological activities that are fundamentally different from those available in monovalent system. Multivalent interactions may become particularly attractive and biologically relevant when the ligand receptor binding is weak or the receptor density is low. Linkers and/or scaffolds structure is important because it must present ligands simultaneously to their cognate receptors with minimal entropic penalty. The development Peptides and Peptidomimetics in Medicinal Chemistry 309 of suitable linkers and/or scaffold structures, permitting the correct simultaneous presentation of ligands to their receptors, as well as the choice of opportune ligands for multivalency and/or multireceptor approaches may provide both new targets and strategies for designing new imaging agents. The first sheet is formed by strands A, E and the first half of B, while the second is formed by? D strand, the polypeptide chain adopts a 310 helix containing the PxxY motif that connects? These residues are aligned to form a surface patch, quite hydrophobic, in which the aromatic side chains are stacked against each other (Figure 8). High resolution crystal structures of this domain bound to proline-rich peptides containing either lysine or arginine residue shown that while the lysine side-chain is in a extended configuration and the? The aromatic surface patch is depicted in red, while the anionic side chain of the Asp and Glu residues involved in the interaction with the Lys residue in cyan. The motion of this residue is closely related to the presence of specific residues located in a key position;. Conclusion the focus of medicinal chemistry is on the design of molecules that can manipulate disease related biological targets for beneficial effects with low toxicity. As we have seen, peptides show great potential as both active drugs and diagnostics. The discovery and development of peptide-based drugs have both rational and empirical aspects. Random screening procedures can be used to identify ligands for known functional domains of target proteins, which can be followed by successive structural and computational analysis. The principal medicinal chemistry challenges for a peptide chemist are to design molecules characterized by a sufficient duration of action, sufficient receptor specificity, and a both stable and appropriate formulation. Recently, studies of self-organizing peptides (amyloids) yielded important information for the development of long-acting peptides. Peptide constraint has been used both to prevent proteolysis and to bias binding toward particular receptor subtypes. The latter activity appears still to be evolving into a rational design approach but still requires attention to an appropriate strategy for successful commercial development. Many of these issues are reminiscent of the rocky road? which other biotecnology drugs. However, the development of peptides into tools for diagnostic purposes and drugs, based on their specificity of target recognition and their versatility of mechanisms, offers enormous promise. While peptides as drugs is a concept that still involves considerable challenge, encouragement may be gleaned from the words of Arthur C. In: Advances in Enzymology and Related Areas of Molecular Biology, John Wiley & Sons, Inc. Introduction this chapter concerns influences of inhibitors and activators on carbonic anhydrase isoenzymes of various living systems. The sixteen isozymes differ in their subcellular localization, catalytic activity and susceptibility to different classes of inhibitors. Carbonic anhydrase inhibitors As will be discussed shortly, many of these isozymes are important targets for the design of inhibitors with clinical applications. Among the active structures found by Krebs were also the azodyes 2 (prontosil red) and 3, derived from sulfanilamide (Maren, 1976; Krebs, 1948; Supuran et al. Thus, in this review we will concentrate on the recent developments in this field that led to important advances in the design of topically acting antiglaucoma sulfonamides, isozyme specific inhibitors, inhibitors with modified sulfonamide moieties, antitumor sulfonamides, as well as diagnostic tools and biosensors based on this class of pharmacological agents (Supuran et al. All these binding modes have been demonstrated by means of X-ray crystallography of enzyme-inhibitor adducts (Nair et al. It should be noted that passing from sulfonamides and their bioisosteres (sulfamates, sulfamides, etc. Many of these compounds were initially developed years ago during the search for diuretics, among which the thiazides, compounds, as well as derivative 14 are stil widely clinically used (Supuran, 2008a). However, some of these enzyme inhibitors could also be used for the systemic treatment of glaucoma Carbonic Anhydrase Inhibitors and Activators: Small Organic Molecules as Drugs and Prodrugs 321 (see below), and more recently, newer derivatives have been discovered that have the potential as topical antiglaucoma agents, as well as antitumour, anti-obesity or anti-infective drugs (Supuran, 2008a,b,c). L-Adrenaline (22), one of the neurotransmitter catecholamines released by the sympathetic nervous system and adrenal medulla in response to a range of stresses in order to regulate the host physiological functions, is involved in regulation of blood pressure, vasoconstriction, cardiac stimulation, relaxation of the smooth muscles (such as the bronchial ones) as well as in several metabolic processes (Hoffman, and Lefkowitz, 1996). As a consequence, 4 has a variety of clinical uses, such as among others for relieving respiratory distress in asthma, in treating hypersensitivity reactions due to various allergens, cardiac arrest, or as a topical hemostatic agent, etc. His64 is shown only in the in? conformation, the only one making a hydrogen bond with the activator molecule. The methylamino group of 4 does not participate in any polar interaction, being rather close to the phenyl ring of Phe131 (bold line) (Temperini et al. Thus, in contrast to other activators investigated earlier, L-adrenaline (22) plugs the entrance of the active site cavity, obstructing it almost completely. In this conformation, it is unable to facilitate the shuttling of protons between the active site and the environment, also because the pKas of its protonatable moieties are in the range of 8. Proceedings of the National Academy of Sciences of the United States of America, 106, 16233-16238. In vitro inhibitory effects of some heavy metals on human erythrocyte carbonic anhydrases. The transcorneal permeability of sulphonamide carbonic anhydrase innhibitors and their effect on aqueous humor secretion. Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. A new method for the purification of carbonic anhydrase isozymes by affinity chromatography. Roles of the different isozymes and salivary factors in the maintenance of optimal conditions in the gastrointestinal canal. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. Carbonic Anhydrase Inhibitors and Activators: Small Organic Molecules as Drugs and Prodrugs 327 Scozzafava, A. In vitro inhibition of human erythrocyte glutathione reductase by some new organic nitrates. Pharmacological enhancement of synaptic efficacy, spatial learning and memory through carbonic anhydrase activation in rats. In carbonic anhydrase and modulation of physiologic and pathologic processes in the organism; Puscas, I. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Diuretics: From Classical Carbonic Anhydrase Inhibitors to Novel Applications of the Sulfonamides. Carbonic anhydrase and modulation of physiologic and pathologic processes in the organism. The Coumarin-binding site in carbonic anhydrase accommodates structurally diverse? Carbonic anhydrase: its properties, distribution and significance for carbon dioxide transport. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney. Introduction Modern computational science is converging on complex problems in the general field of systems biology. There is now a credible possibility of modeling drug delivery vesicles (liposomes) and their properties with qualitative and quantitative insight coming from atomistic calculations. Understanding the formation of vesicles from phospholipids bilayers and their fluidity and permeability properties is the basis of a large number of applications in the domain of drug delivery, in particular release of the active species according to the pH or ionic concentration changes. Prediction of structural changes (phase transition in particular) of membranes by modification of one or several constituents or addition of external molecular species may have potential therapeutic applications. Understanding the basic principles of biomembranes (lipid bilayers) governing and mediating various biologically relevant processes on the microscopic level is one of the great challenges in biology (Singh 2011). The total energy can be obtained from following: E= E[Low, real] + E[Med, int] + E[High, inner] E[Low,int]-E[Med, inner] = E6+E5+E4-E3-E2 High -E4 Medium -E2 -E5 Low -E3 +E6 System Size inner intermediate real where real denotes the entire system, which is treated at low level, while int denotes the part of the system partitioned to be the intermediate layers for which the energy is calculated at both medium and high levels. Here inner denotes the inner layer of the system partitioning, whose energy is calculated at both high and medium levels. Degree of penetration into the membrane interior obtained from computer simulations may also be useful in estimating the extent to which a drug or prodrug that is unstable in a given solution or biological fluid might be protected when bound to a lipid bilayer membrane (Fig. Multi-scale modeling and simulation revealed that the interactions between the drug and membrane are both electrostatic and hydrophobic. Increasing the chain length and lipophilicity may strengthen the binding interactions and overcome the problem of drug resistance. Membrane permeability, lipid metabolism and multi-drug resistance in Leishmania major Membrane impermeability is the major contributing factor to multidrug resistance in clinical isolates of Leishmania major (Perez Victoria et al. Reductionism which dominated biological research for over a century has provided a wealth of information about individual cellular components and their functions. Understanding the structure and the dynamics of the complex intercellular web of interactions that contribute to the structure and function of a living cell is a key challenge for biology in the 21st century. Lipid concentration changes in biological systems reflect regulation at multiple spatial and dynamic scales. Excluding the transport reactions, the percentage of intracellular reactions participating in lipid metabolism in L. In order to address the intricacies of lipid regulation, it is quite obligatory to analyze the lipid metabolic mechanisms (Fig. Lipids play an active role in a variety of dynamic processes involving the membranes that compartmentalize the cell. To achieve this, cell must regulate the mechanical properties of the membrane and it can do so partly by controlling its lipid composition. The underlying biophysical question is to understand the variability and chemical diversity of membrane lipid composition, the mechanical properties of the membrane and the associated protein functions. Lipid metabolism is essential to the development, multiplication, virulence and differentiation of Leishmania species in the host, thus making the pathways for synthesis of parasite lipids good targets for development of new anti-leishmanial drugs [Zufferey and Mamoun, 2005; Zhang K. Thereby, the diversity between Leishmania and mammals in lipid composition could be exploited towards selective chemotherapy. Lipids being a crucial entity of the pathogen cell surface are given Stochastic Simulation for Biochemical Reaction Networks in Infectious Disease 333 extensive importance and moreover due to the liposomal drug delivery system, targeting the lipids organized in the membrane of the pathogen would be an added advantage for the smooth release of the encapsulated drug. In different Leishmania species the phosphoglycan repeat units contain additional substitutions that mediate key roles in stage-specific adhesion. Henceforth, it is evident that lipids are essential cell constituents and therefore must be constantly synthesized to allow multiplication of the parasite. This suggests that the pathways leading to their synthesis are essential for parasite proliferation and pathogenesis and thus offers a reasonable target for rational design of novel antileishmanial drugs. Galf plays an important role in host specific cell recognition, parasitic growth and pathogenesis. Since Galf is not present in humans, the Galf biosynthetic pathway is an attractive target for the development of novel anti-parasitic drugs. Metabolic network reconstruction has become an indispensable tool for studying the systems biology of metabolism. The focus is laid onto reviewing the mathematical foundations for analyzing chemical reactions, and describing how these systems of coupled chemical reactions can provide insight into the behavior of complex regulatory mechanisms. This is accomplished using the simulation mechanisms based on the certain defined kinetic laws such as Convenience Kinetics, Generalized Mass Action Kinetics and the Hill-Hinze equation. A saturable rate law Convenience Kinetics? a generalised form of Michaelis-Menten kinetics, covers all possible stoichiometries, describes enzyme regulation by activators and inhibitors, and can be derived from a rapid-equilibrium random-order enzyme mechanism. Convenience kinetics is used to translate a biochemical network manually into a dynamical model with rational biological properties. Their mathematical forms make it especially suitable for parameter assessment and optimisation. To ensure thermodynamic correctness, it is written in terms of thermodynamically independent parameters [Liebermeister and Klipp, 2006]. Thus, they can be used to address specific questions about the properties of a model system, often more easily than experiments on the actual system. These techniques are carried out upon treating a biological process as a system of equations, represented by their rate constants and other parameters and simulating their interactions through numerical techniques. The numerical simulations capture the effects of genes and their expression level through the time-course of evolution at molecular concentration. Thus, it is a biochemical characterization of the enzymatic network using the systems biology approach by interconnecting mathematical, biological, and physical sciences with the aim to capture the behavioural sciences of the enzymes, in the temporal and spatial scales, eventually leading to the discrete stochastic kinetic simulation. The integration of genomic and physiological information is now increasingly important with the emergence of systems biology? This permits an iterative process of model development, hypothesis generation and testing, and further model development and refinement [Reed et al. Using this approach, a base is formulated for the appropriate selection of an inhibitor, taking into account the dynamics of the enzyme kinetics. Stochastic Simulation for Biochemical Reaction Networks in Infectious Disease 335 Fig. Defining a system by the dynamic state of its metabolome relies on the effective integration of omics data because the metabolic state of the system is largely derived from the global expression of its genome and proteome [Davidov et al. Recent advances enable the production of metabolic network models reconstructed from genome sequences, as well as experimental measurements of much of the metabolome [Douglas B. These techniques can also be used to identify potential novel therapeutic targets based on the characterisation of vulnerable or highly influential network components [Azuaje et al. Recently developed computational tools enable rational and graphical composition of genetic circuits for standard parts, and subsequent simulation for testing the predicted functions in silico [Marchisio and Stelling, 2009]. Model construction typically involves the translation of prior knowledge into a list of reactants and reactions [Aldridge et al. These models require information about the kinetics of each of the reactions participating in the network, such as the kinetic laws describing the dynamics of the reactions with their respective parameters. Thereafter, kinetic equations are mapped to the reaction model through either stochastic or deterministic approaches, and at times a hybrid model may be adopted. Several modelling approaches are derived from assuming different simplistic kinetic mechanisms: Convenience rate law, mass-action, Michaelis-Menten, power-law, LinLog [Sergio Grimbs, 2009]. There are several modes of modeling these metabolic networks: Structural modeling, Flux balance Analysis and Metabolic control Analysis. Thus, using the concept of mathematical modeling and applying the science of systems biology, the simulation of metabolic pathway is carried out based on certain kinetic laws and their parameters. Once a target is identified, whole cell screening assays can be designed, using synthetic biology strategies [Weber and Fusseneger, 2009]. Temporal information from computer simulations are validated by those done on simplified versions of yeast cell cycle and have shown to be in good agreement with experiment [Tyson et al. The conversion of a reconstruction into a mathematical format facilitates a myriad of computational biological 336 Medicinal Chemistry and Drug Design studies, including evaluation of network content, hypothesis testing and generation, analysis of phenotypic characteristics and metabolic engineering [Thiele and Bernhard, 2010]. Stochastic Simulation for Biochemical Reaction Networks in Infectious Disease 337 Thus, of the overall 20 metabolic pathways involved in Lipid and Fatty Acid Metabolism, there are 13 such pathways which are exclusively restricted to L. From the Table 1 it is found that the maximum number of the genes and the resultant gene products (enzymes), distinctive to the L. Network model architectures can be distinguished by the type of model: stochastic or deterministic, static or dynamic and the type of relationships between the variables (directed or undirected; linear or non-linear function or relation table). Although many undirected network representations exist, the focus of this chapter is on directed networks. Gene Regulatory Network constructed using Cytoscape for visualizing the inter connection of the Lipid Metabolic Pathways restricted to L. But, the pathways Ergosterol Biosynthesis and Ether Phospholipid Biosynthesis are the only ones that are not related with any of the other Metabolic Reactions, and are self-contained. Hence, the gene regulatory network gives an entire overview about the reacting species in the same dimension. The reactions and pathways that are inter-connected and have common enzymes and compounds taking part in the same reactions can further be investigated. Also, it gives an outline and a general idea related to the cluster of genes taking part in the reactions.
Thrombosed or sclerotic arteries may cross the ulcer which on erosion may result in haemorrhage hair loss cure news 2015 cheap finast generic. Gross and microscopic changes in gastric and duodenal ulcers are similar and quite characteristic hair loss in men at 50 best order finast. Gastric ulcers are found predominantly along the lesser curvature in the region of pyloric antrum hair loss 48083 buy finast 5mg without prescription, more commonly on the posterior than the anterior wall hair loss quick fix purchase finast 5 mg online. Most duodenal ulcers are found in the first part of the duodenum hair loss in men-0-pause buy finast 5mg fast delivery, usually immediate post-pyloric bio herbal anti-hair loss cost of finast, more commonly on the anterior than the posterior wall hair loss ulcerative colitis order finast with a mastercard. The ulcers may vary in depth from being superficial (confined to mucosa) to deep ulcers (penetrating into the muscular Figure 20 hair loss cure 4 hunger buy 5mg finast. In about 10-20% of cases, gastric and specimen showing a punched out round to oval ulcer on the mucosa, about 1 cm in diameter (arrow) and penetrating into muscularis layer. The dictum cancers ulcerate but ulcers rarely cancerate? holds true for most peptic ulcers. Peptic ulcers are remitting and healing of chronic, larger and deeper ulcers may result in relapsing lesions. These are as follows: summed up the saying: once a peptic ulcer patient, always a peptic ulcer patient. Development of fibrous scar at or near the ulcers show variations in clinical features which are as pylorus results in pyloric stenosis. The peak incidence of duodenal ulcer is in 5th deformity due to fibrosis and contraction. Duodenal ulcer occurs more commonly vessels in the base of an ulcer occurs in all the ulcers and can in people faced with more stress and strain of life. Chronic executives, leaders), while gastric ulcer is seen more often in blood loss may result in iron deficiency anaemia. The attacks in gastric ulcers last from 2-6 penetrating chronic ulcer may erode a major artery. The attacks gastric, gastroduodenal or splenic artery) and cause a massive of duodenal ulcer, are classically worsened by work, worry and severe hematemesis and sometimes death. Perforation occurs more commonly in or within 2 hours after food and never occurs at night. The photomicrograph on right shows necrotic debris, ulceration and inflammation on the mucosal surface. Hyperplastic (inflammatory) polyps (retrosternal pain) and water brash? (burning fluid into the 2. Epithelial melaena occur in gastric ulcers in the ratio of 60: 40, while in Adenomas (adenomatous or neoplastic polyps) duodenal ulcers in the ratio of 40: 60. Epithelial (90%) appetite but are afraid to eat, while duodenal ulcer patients (i) Adenocarcinoma (ii) Others have very good appetite. Patients of gastric ulcer commonly get used to a (i) Leiomyosarcoma bland diet consisting of milk, eggs etc and avoid taking fried (ii) Leiomyoblastoma foods, curries and heavily spiced foods. Loss of weight is a common finding in gastric ulcer patients while patients of duodenal ulcer tend to gain weight due to frequent ingestion of milk to avoid pain. Deep tenderness is demonstrable in hyperplastic glands, which may show cystic change. In the case of gastric ulcer it is in lining epithelium is mostly superficial gastric type but the midline of the epigastrium, while in the duodenal ulcer antral glands, chief cells and parietal cells may be present. They are of various types such as gastric origin (causes of haematemesis of oesophageal origin are polyps of the Peutz-Jeghers syndrome (page 582), juvenile already given on page 539). Morphologically, adenomatous polyps of the the various types of tumour-like lesions (polyps) and benign stomach resemble their counterparts in the large bowel and and malignant tumours of the stomach are given in are described on page 583. They are usually firm, circumscribed nodules, They may be single or multiple and are more often located less than 4 cm in size and appear as submucosal nodules. They resemble in gross and microscopic appearance with their counterparts in other parts of the body. Grossly, the lesions may be sessile or pedunculated, 1 cm Currently, the term gastrointestinal stromal tumours or larger in size, smooth and soft. Their behaviour is generally benign but may be recurrent, aggressive or even metastasis may occur. Carcinoma of the stomach comprises more than 90% of all gastric malignancies and is the leading cause of cancer-related deaths in countries where its incidence is high. The highest incidence is between 4th to 6th decades of life and is twice more common in men than in women. A number of etiologic factors have been implicated in causation of gastric cancer. The serial numbers in the figure indicate an important risk factor for the development of gastric cancer. It may be mutation in E-cadherin gene inherited as a autosomal mentioned here that similar association of H. Epidemiological studies suggest that die tary factors are most significant in the etiology of gastric 6. The evidences in support of this are multifold: some conditions of gastric mucosa which have increased risk i) Occurrence of gastric cancer in the region of gastric canal to development of gastric cancer. There are geographic variations Pathogenetically, a sequential evolution of all gastric in the incidence of gastric cancer. Within the country, different ethnic groups gross subtypes: may have variations in incidence of gastric cancer. Genetic influences have some role in the v) Ulcer-cancer etiology of gastric cancer. Not more than 4% of patients of In addition to the above classification, gastric gastric cancer have a family history of this disease. A, Conventional classification, showing correlation of the macroscopic subtypes with the main histological patterns. Infiltrating (formerly diffuse type) carcinomas have certain related terms as under: poorly-defined invasive border. The tumour cells are loose Epithelial dysplasia is cellular atypia seen in intestinal and invade singly or in small group. The diagnosis of this carcinoma crosses the basement membrane into the condition has been made possible by extensive work on muscularis propria or beyond, it is referred to as advanced histogenesis of gastric cancer by Japanese pathologists by gastric carcinoma. It is seen more commonly in the region of Type I : Polypoid type gastric canal (Fig. Direct spread by local extension is the most well-differentiated adenocarcinomas, commonly papillary common feature of gastric carcinoma. The involvement may more commonly, referred to as Krukenberg tumours (Chapter be localised to pyloric antrum, or diffuse affecting whole 24). Submucosal spread occurs more often upwards into the of the stomach from the cardia to pylorus. The lumen of oesophagus due to continuity of the layers of stomach with the stomach is reduced. There are no ulcers but rugae are those of oesophagus, while the spread downwards into the prominent (Fig. The tumour ring cell carcinoma, extensively infiltrating the stomach may directly involve other neighbouring structures and wall, but due to marked desmoplasia cancer cells may be organs like lesser and greater omentum, pancreas, liver, difficult to find (Fig. The groups like masses having gelatinous appearance due to secretion of lymph nodes involved are along the lesser and greater of large quantities of mucus. Blood spread of gastric chronic gastric ulcer is a rare occurrence (less than 1%). Location Commonly lesser curvature of pylorus and antrum Commonly greater curvature of pylorus and antrum 5. Gross features a) Size Small Large b) Shape Regular Irregular c) Mucosal folds Radiating Interrupted d) Ulcer bed Haemorrhagic Necrotic 6. Therapy Responds well to medical therapy Usually does not respond to medical therapy 558 Figure 20. Therefore, the prognosis is generally iv) Loss of appetite (anorexia) poor; 5-year survival rate being 5-15% from the time of v) Anaemia, weakness, malaise. However, 5-year the most common complication of gastric cancer is survival rate for early gastric carcinoma is far higher haemorrhage (in the form of haematemesis and/or melaena); (93-99%) and hence the need for early diagnosis of the others are obstruction, perforation and jaundice. Gastric carcinoma, gross appearance of subtypes and their corresponding dominant histological patterns. Other Carcinomas Carcinoid Tumour Besides the various morphologic patterns of adenocarcinoma Carcinoid tumours are rare in the stomach and are usually just described, other carcinomas that occur rarely in the non-argentaffin type but argentaffinomas also occur. Their stomach are: adenosquamous carcinoma, squamous cell behaviour is usually malignant; they are described on carcinoma and undifferentiated carcinoma, all of which are page 579. Lymphomas of Gut Leiomyosarcoma Primary gastrointestinal lymphomas are defined as lymphomas arising in the gut without any evidence of Leiomyosarcoma, though rare, is the commonest soft tissue systemic involvement at the time of presentation. Grossly, the tumour may be of variable size but is usually Gastric lymphomas constitute over 50% of all bowel quite large, pedunculated and lobulated mass into the lymphomas; other sites being small and large bowel in lumen. Prognosis of primary gastric Microscopically, leiomyosarcoma is characterised by high lymphoma is better than for intestinal lymphomas. Tumour is lymphoma of stomach is the most common malignant gastric usually well-differentiated. Clinical manifestations of gastric lymphomas may be Leiomyoblastoma (Epithelioid Leiomyoma) similar to gastric carcinoma. Age incidence for lymphomas of the gastrointestinal tract is usually lower than that for this is a rare tumour, the behaviour of which is intermediate carcinoma (30-40 years as compared to 40-60 years in gastric between clearly benign and malignant tumour. Microscopically, it is characterised by round to polygonal Grossly, gastric lymphomas have 2 types of appearances: cells with clear perinuclear halos. Diffusely infiltrating type, producing thickening of the determines the biological behaviour of the tumour. The luminal surface of the stomach in the region of pyloric canal shows an elevated irregular growth with ulcerated surface and raised margins. B, Malignant cells forming irregular glands with stratification are seen invading the layers of the stomach wall. The wall of the stomach in the region of pyloric canal is markedly thickened and fibrotic while the mucosal folds are lost. D, Microscopy shows characteristic signet ring tumour cells having abundant mucinous cytoplasm positive for mucicarmine (inbox). Histologically, the small bowel is identified by recognition Low-grade small lymphocytic well-differentiated B-cell of villi. The serosa is the outer covering of the small bowel which frequency (arising from Mucosa Associated Lymphoid is complete except over a part of the duodenum. The muscularis propria is composed of 2 layers of smooth the blood supply of the whole of small intestine, except 561 muscle tissue?outer thinner longitudinal and inner thicker the first part of the duodenum, is by the superior mesenteric circular layer. These muscles are functionally important for artery which supplies blood by mesenteric arterial arcades peristalsis. The main functions of the small intestine are digestion and absorption so that ultimately nutrients passing into the 3. The submucosa is composed of loose fibrous tissue with bloodstream are utilised by the cells in metabolism. It is Intestinal atresia is congenital absence of lumen, most supported externally by thin layer of smooth muscle fibres, commonly affecting the ileum or duodenum. The mucous membrane is thrown into segment has a blind end which is separated from distal folds or plicae which are more in the jejunum and less in the segment freely, or the two segments are joined by a fibrous ileum, thus increasing the absorptive surface enormously. The condition must be recognised early and treated the absorptive surface is further increased by the intestinal surgically, as otherwise it is incompatible with life. Villi are finger-like or leaf-like projections which contain 3 types of cells: Intestinal stenosis is congenital narrowing of the lumen i) Simple columnar cells. Intestinal segment due to the presence of brush border consisting of large above the level of obstruction is dilated and that below it is number of microvilli. It is almost always lined by small cells, on the other hand, require the addition of exogenous intestinal type of epithelium; rarely it may contain islands of reducing substance for staining). These are commonly multiple (diverticulosis), frequently located on the hypothalamus, pituitary and sympathetic ganglia. The deeper layer of the mucosa of the small flexure and the middle of transverse colon). Due to failure of intestine elsewhere contains intestinal glands or crypts of normal rotation of midgut, the following consequences can Lieberkuhn. They are lined by columnar cells, goblet cells, occur: endocrine cells and Paneth cells. B, Resected segment of the small intestine shows an outpouching which on section is seen communicating with the intestinal lumen. The causes of intestinal obstruction can be fibrous adhesions and bands may be without any preceding classified under the following 3 broad groups: peritoneal inflammation and are of congenital origin. It can occur as a result of the complete intestinal obstruction by outside pressure on the following causes: bowel wall. Meconium in mucoviscidosis External hernia is the protrusion of the bowel through a Roundworms defect or weakness in the peritoneum. Gallstones, faecoliths, foreign bodies Internal hernia is the term applied for herniation that Ulceration induced by potassium chloride tablets does not present on the external surface. Two major factors involved in the formation of a hernia ii) External compression: are as under: Peritoneal adhesions and bands i) Local weakness which may be congenital. Volvulus ii) Increased intra-abdominal pressure that is produced by Intra-abdominal tumour. Obstruction of the superior mesen Direct when hernia passes medial to the inferior teric artery or its branches may result in infarction causing epigastric artery and it appears through the external paralysis. Thrombosis Indirect when it follows the inguinal canal lateral to the Embolism inferior epigastric artery. When the contents of hernia such as loop of intestine can Out of the various causes listed above, conditions be returned to the abdominal cavity, it is called reducible. Some or due to adhesions in the hernial sac, it is referred to as of these are described below. In either case, the cause of 563 ischaemia is compromised mesenteric circulation, while ischaemic effect is less likely to occur in the stomach, duodenum and rectum due to abundant collateral blood supply. Depending upon the extent and severity of ischaemia, 3 patterns of pathologic lesions can occur (Fig. The ischaemic effect in mural infarction is limited to mucosa, submucosa and superficial muscularis, while mucosal infarction is confined to mucosal layers superficial to muscularis mucosae. Ischaemic colitis, due to chronic colonic ischaemia causing fibrotic narrowing of the affected bowel. When the blood flow in the hernial sac is obstructed, it these pathologic patterns are described below: results in strangulated hernia. Obstruction to the venous drainage and arterial supply may result in infarction or Transmural Infarction gangrene of the affected loop of intestine. The gross and Ischaemic necrosis of the full-thickness of the bowel wall is microscopic appearance of strangulated intestine is the same more common in the small intestine than the large intestine. The common causes of transmural Intussusception infarction of small bowel are as under: i) Mesenteric arterial thrombosis such as due to the following: Intussusception is the telescoping of a segment of intestine Atherosclerosis (most common) into the segment below due to peristalsis. The telescoped Aortic aneurysm segment is called the intussusceptum and lower receiving segment is called the intussuscipiens. The condition occurs Vasospasm more commonly in infants and young children, more often Fibromuscular hyperplasia in the ileocaecal region when the portion of ileum invaginates Invasion by the tumour into the ascending colon without affecting the position of Use of oral contraceptives the ileocaecal valve (Fig. Less common forms are ileo Arteritis of various types ileal and colo-colic intussusception. In the case of adults, the usual Endocarditis (infective and nonbacterial thrombotic) causes are foreign bodies and tumours. Atherosclerotic plaques the main complications of intussusception are intestinal Atrial myxoma obstruction, infarction, gangrene, perforation and peritonitis. The causes are as under: Volvulus is the twisting of loop of intestine upon itself through 180? or more. This leads to obstruction of the intestine as well as cutting off of the blood supply to the affected loop. The usual causes are bands and adhesions (congenital or acquired) and long mesenteric attachment. The condition is also referred to as haemorrhagic gastroenteropathy, and in the case of colon as Torsion membranous colitis. Grossly, irrespective of results from conditions causing non-occlusive hypoperfusion the underlying etiology, infarction of the bowel is (compared from transmural infarction which occurs from haemorrhagic (red) type (page 126). In the case of colonic Shock infarction, the distribution area of superior and inferior Cardiac failure mesenteric arteries. The affected areas become dark purple and Intake of drugs causing vasoconstriction. The affected segment of the of demarcation between the infarcted bowel and the bowel is red or purple but without haemorrhage and normal intestine, whereas in venous occlusion the exudation on the serosal surface. The mucosa is infarcted area merges imperceptibly into the normal bowel oedematous at places, sloughed and ulcerated at other (Fig. Microscopically, there is coagulative necrosis and ulcera Microscopically, there is patchy ischaemic necrosis of tion of the mucosa and there are extensive submucosal mucosa, vascular congestion, haemorrhages and haemorrhages. Subsequently, inflammatory cell infiltration superficial muscularis but deeper layer of muscularis and and secondary infection occur, leading to gangrene of the serosa are spared. The condition is clinically characterised by abdominal angina? in which the patient has acute abdominal pain, Clinically, as in transmural infarction, the features of nausea, vomiting, and sometimes diarrhoea. The disease is abdominal pain, nausea, vomiting and diarrhoea are present, rapidly fatal, with 50-70% mortality rate. With adequate therapy, normal morphology is completely restored in In healed cases, stricture formation, malabsorption and 565 superficial lesions, while deeper lesions may heal by fibrosis short bowel syndrome are the usual complications. Ischaemic having many similarities but the conditions usually have colitis is characterised by chronic segmental colonic distinctive morphological appearance. Ischaemic colitis passes through 3 commonly the segment of terminal ileum and/or colon, stages: infarct, transient ischaemia and ischaemic stricture.
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