An example is the emergence of rifampin-resistant Mycobacterium tuberculosis when rifampin is used as a single antibiotic anti fungal diet butenafine 15 gm generic. Resistance properties are usually encoded in extrachromosomal R factors (resistance plasmids) antifungal and hydrocortisone cream 15 gm butenafine sale. Plasmids may enter cells by processes such as transduction (phage mediated) antifungal antibacterial dog shampoo buy butenafine 15 gm with mastercard, transformation antifungal probiotic butenafine 15 gm low cost, or bacterial conjugation fungal zygomycosis order 15 gm butenafine otc. Altered expression of proteins in drug-resistant organisms Drug resistance may be mediated by a variety of mechanisms fungus on grass buy butenafine 15gm online, such as a lack of or an alteration in an antibiotic target site, lowered penetrability of the drug due to decreased permeability, increased efflux of the drug, or presence of antibiotic-inactivating enzymes (see Figure 30. Decreased accumulation: Decreased uptake or increased efflux of an antibiotic can confer resistance, because the drug is unable to attain access to the site of its action in sufficient concentrations to injure or kill the organism. For example, gram-negative organisms can limit the penetration of certain agents, including ОІ-lactam antibiotics, tetracyclines, and chloramphenicol, as a result of an alteration in the number and structure of porins (channels) in the outer membrane. Enzymic inactivation: the ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms. Examples of antibiotic-inactivating enzymes include 1) ОІ-lactamases (вoepenicillinasesв) that hydrolytically inactivate the ОІ-lactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides. Prophylactic Antibiotics Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections (Figure 30. Because the indiscriminate use of antimicrobial agents can result in bacterial resistance and superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential risks. Complications of Antibiotic Therapy Because the mechanism of action of a particular antibiotic is selectively toxic to an invading organism does not insure the host against adverse effects. Hypersensitivity Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. Direct toxicity High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of Corti. Superinfections Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. Sites of Antimicrobial Actions Antimicrobial drugs can be classified in a number of ways. These include 1) by their chemical structure (for example, ОІ-lactams or aminoglycosides), 2) by their mechanism of action (for example, cell wall synthesis inhibitors), or 3) by their activity against particular types of organisms (for example, bacteria, fungi, or viruses). Chapters 31 through 33 are organized by the mechanisms of action of the drug, and Chapters 34 through 38 are organized according to the type of organisms affected by the drug (Figure 30. Prevention of meningitis among individuals in close contact with infected patients. Overview Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wallв"a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. The most important members of this group of drugs are the ОІ-lactam antibiotics (named after the ОІ-lactam ring that is essential to their activity) and vancomycin. Penicillins the penicillins are among the most widely effective antibiotics and also the least toxic drugs known, but increased resistance has limited their use. Members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue (Figure 31. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (ОІ-lactamases). Mechanism of action the penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage 1), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. Penicillin-binding proteins: Penicillins inactivate numerous proteins on the bacterial cell membrane. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. Alterations in some of these target molecules provide the organism with resistance to the penicillins. Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity. Production of autolysins: Many bacteria, particularly the gram-positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins and, therefore, in the absence of resistance are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide membrane (envelope) surrounding the cell wall that presents a barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry. Natural penicillins: these penicillins, which include those classified as antistaphylococcal, are obtained from fermentations of the mold Penicillium chrysogenum. Other penicillins, such as ampicillin, are called semisynthetic, because the different R groups are attached chemically to the 6-aminopenicillanic acid nucleus obtained from fermentation broths of the mold. Penicillin V has a spectrum similar to that of penicillin G, but it is not used for treatment of bacteremia because of its higher minimum bactericidal concentration (the minimum amount of the drug needed to eliminate the infection; see p. It is often employed orally in the treatment of infections, where it is effective against some anaerobic organisms. Their use is restricted to the treatment of infections caused by penicillinase-producing staphylococci. Ampicillin is the drug of choice for the gram-positive bacillus Listeria monocytogenes. These agents are also widely used in the treatment of respiratory infections, and amoxicillin is employed prophylactically by dentists for patients with abnormal heart valves who are to undergo extensive oral surgery. Resistance to these antibiotics is now a major clinical problem because of inactivation by plasmid-mediated penicillinase. They are effective against many gram-negative bacilli, but not against klebsiella, because of its constitutive penicillinase. Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms. Penicillins and aminoglycosides: the antibacterial effects of all the ОІ-lactam antibiotics are synergistic with the aminoglycosides. Because cell wall synthesis inhibitors alter the permeability of bacterial cells, these drugs can facilitate the entry of other antibiotics (such as aminoglycosides) that might not ordinarily gain access to intracellular target sites. Resistance Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall (for example, mycoplasma) or have cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by plasmid transfer has become a significant clinical problem, because an organism may become resistant to several antibiotics at the same P. Multiplication of such an organism will lead to increased dissemination of the resistance genes. By obtaining a resistance plasmid, bacteria may acquire one or more of the following properties, thus allowing it to withstand ОІ-lactam antibiotics. ОІ-Lactamase activity: this family of enzymes hydrolyzes the cyclic amide bond of the ОІ-lactam ring, which results in loss of bactericidal activity (see Figure 31. They are the major cause of resistance to the penicillins and are an increasing problem. ОІ-Lactamases are either constitutive or, more commonly, are acquired by the transfer of plasmids. Some of the ОІ-lactam antibiotics are poor substrates for ОІ-lactamases and resist cleavage, thus retaining their activity against ОІ-lactamase producing organisms. Administration: the route of administration of a ОІ-lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. Penicillin V, amoxicillin, amoxicillin combined with clavulanic acid, and the indanyl ester of carbenicillin (for treatment of urinary tract infections) are available only as oral preparations. They are slowly absorbed into the circulation and persist at low levels over a long time period. Absorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. Consequently, it is not appropriate therapy for the treatment of shigella- or salmonelladerived enteritis, because therapeutically effective levels do not P. Absorption of all the penicillinase-resistant penicillins is decreased by food in the stomach, because gastric emptying time is lengthened, and the drugs are destroyed in the acidic environment. Therefore, they must be administered 30 to 60 minutes before meals or 2 to 3 hours postprandially. All the penicillins cross the placental barrier, but none has been shown to be teratogenic. As the infection abates, inflammation subsides, and permeability barriers are reestablished. Metabolism: Host metabolism of the ОІ-lactam antibiotics is usually insignificant, but some metabolism of penicillin G has been shown to occur in patients with impaired renal function. Excretion: the primary route of excretion is through the organic acid (tubular) secretory system of the kidney as well as by glomerular filtration. Thus, the half-life of penicillin G can increase from a normal of between 30 minutes and 1 hour, to 10 hours in individuals with renal failure. Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter and, thus, can increase blood levels. Adverse reactions Penicillins are among the safest drugs, and blood levels are not monitored. The major antigenic determinant of penicillin hypersensitivity is its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. Approximately five percent of patients have some kind of reaction, ranging from maculopapular rash (the most common rash seen with ampicillin hypersensitivity) to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis. Among patients with mononucleosis who are treated with ampicillin, the incidence of maculopapular rash approaches 100 percent. Diarrhea: this effect, which is caused by a disruption of the normal balance of intestinal microorganisms, is a common problem. Nephritis: All penicillins, but particularly methicillin, have the potential to cause acute interstitial nephritis. Neurotoxicity: the penicillins are irritating to neuronal tissue, and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Hematologic toxicities: Decreased coagulation may be observed with the antipseudomonal penicillins (carbenicillin and ticarcillin) and, to some extent, with penicillin G. It is generally a concern when treating patients who are predisposed to hemorrhage (for example, uremics) or those receiving anticoagulants. Cation toxicity: Penicillins are generally administered as the sodium or potassium salt. Toxicities may be caused by the large quantities of sodium or potassium that accompany the penicillin. This can be avoided by using the most potent antibiotic, which permits lower doses of drug and accompanying cations. Cephalosporins the cephalosporins are ОІ-lactam antibiotics that are closely related both structurally and functionally to the penicillins. Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid. Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain ОІ-lactamases. Antibacterial spectrum Cephalosporins have been classified as first, second, third, or fourth generation, based largely on their bacterial susceptibility patterns and resistance to ОІ-lactamases (Figure 31. First generation: the first-generation cephalosporins act as penicillin G substitutes. They are resistant to the staphylococcal penicillinase and also have activity against Proteus mirabilis, E. Second generation: the second-generation cephalosporins display greater activity against three additional gram-negative organisms: H. Third generation: these cephalosporins have assumed an important role in the treatment of infectious disease. Although inferior to first-generation cephalosporins in regard to their activity against gram-positive cocci, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, including those mentioned above, as well as most other enteric organisms plus Serratia marcescens. Cefepime has a wide antibacterial spectrum, being active against streptococci and staphylococci (but only those that are methicillin-susceptible). Cefepime is also effective against aerobic gram-negative organisms, such as enterobacter, E. Resistance Mechanisms of bacterial resistance to the cephalosporins are essentially the same as those described for the penicillins. For example, ceftriaxone or cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by H. However, additional intraoperative cefazolin doses may be required if the surgical procedure lasts longer than 3 hours. Cefazolin is effective for most surgical procedures, including orthopedic surgery because of its ability to penetrate bone. Fate: Biotransformation of cephalosporins by the host is not clinically important.
Syndromes
Anti-inflammatory medicines called corticosteroids to decrease throat swelling
Pain from the heart
You have a breast or armpit lump
Laxative
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A critically ill individual with a high mortality rate would be assigned a low triage priority because it would be unethical to use limited resources on those with a low chance of survival fungus gnats coffee grounds order butenafine 15 gm mastercard. Others who are seriously ill and have a greater chance of survival should be treated fungus head purchase butenafine 15gm visa. Some cultural considerations include language differences antifungal topical order butenafine 15gm line, a variety of religious preferences (hygiene antifungal medicine side effects generic butenafine 15 gm fast delivery, 5 antifungal medication list generic 15 gm butenafine. Some common behavioral responses are depression antifungal hand wash purchase butenafine 15gm without prescription, anxiety, somatization (fatigue, malaise), posttraumatic stress disorder, substance abuse, interpersonal conflicts, and impaired performance. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. The right of Linda J Dodds to be identified as the author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act, 1988. Pharmacists are independent prescribers in a wide range of clinical areas and working under patient group directions to supply and administer medicines without a prescription. In hospitals, consultant pharmacists have their own case load of patients and provide the highest levels of pharmaceutical care as well as contributing to research and development in their chosen specialty, whereas in the community, pharmacists with a special interest are being commissioned to provide high-level services that contribute to the overall care of patients in their specialty area. In hospitals most pharmacists spend a large part of their day working on the wards providing direct patient care, such as taking drug histories, advising on and monitoring therapy, and supporting discharge. This places new and exciting demands on individual pharmacists which need P re fac e ix to be supported by undergraduate and postgraduate education, and followed up by appropriate and now mandatory continuing professional development. Patients rarely have a single disease with a textbook presentation, and many factors can influence the choice of therapy, such as comorbidities and their treatments, previous medical and drug history, changes in clinical opinion on drug use etc. Without an appreciation of all of these factors it can be difficult to understand the reason for a therapy decision that has already been taken, or to respond appropriately to questions regarding the choice of agent from a selection of similar products, or even to know when it is appropriate to offer drug-related information. If it is not clear why a particular product has been prescribed, it is also more difficult to monitor its usage appropriately and to counsel the patient. One way of acquiring the extra knowledge and skills needed to contribute effectively to the care of individual patients is to work with, and to learn from, experienced clinical pharmacists. Pharmacists with considerable experience of the clinical use of drugs have been asked to share their expertise by contributing a case study in an area of special interest to them. The topics chosen for inclusion in the book are ones which are either commonly encountered, associated with particular difficulties in dosage individualisation, or in which major advances in therapeutics have occurred in recent years. The chapters have been written by practitioners in primary and secondary care, and the cases cover patients who present and require pharmaceutical care in both sectors. Because patients move between care settings in the course x D r ugs i n U s e of their disease and treatment, it is vital that pharmacists who care for them at any point along their path have the knowledge and skills to ensure their medicines management is optimal wherever they receive care. I should like to take this opportunity to thank all the pharmacists who have contributed material for this fourth edition of Drugs in Use. Preparing case studies requires an enormous amount of time and effort, and everyone involved has given unstintingly of both. Once again the authors have had to adhere to a tight schedule to ensure the shortest possible time between the preparation of material and its publication. The reward for all this is largely the hope that the book will be of use to pharmacists who are committed to improving their clinical skills. Linda J Dodds May 2009 About the editor Linda Dodds is currently Joint Acting Director of Clinical Pharmacy for East and South East England Specialist Pharmacy Services. Linda is also a teacher practitioner at the Medway School of Pharmacy, where she has developed and delivers postgraduate programmes, including a Masters in Medicines Management, and the Diploma in General Pharmacy Practice for hospital and community pharmacists. Prior to these roles Linda was a pharmaceutical adviser, first to a Health Authority and latterly to primary care organisations, but for a large part of her career she worked in hospitals, most recently as a Clinical Services Manager and Clinical Trainer. She has contributed as an author and editor to a variety of clinical pharmacy publications, and worked part-time as a community pharmacist. Throughout her career Linda has undertaken and published pharmacy practice research on a variety of topics. It is a teaching aid and should not be regarded, or used, as a pharmacology textbook. The questions interspersing the case presentation aim to reflect those frequently asked by other healthcare professionals, plus those that should be considered by a pharmacist when the prescription is seen. In some cases questions have also been inserted to help ensure the reader appreciates the specialist techniques used to assess patients with the problems under discussion. In order to ensure that the overall pharmaceutical care of the patient is considered, as well as specific problems, at least one question for each patient relates to the construction of a pharmaceutical care plan. The observant reader will notice that the reference ranges for some laboratory indices vary between case studies. This reflects the normal practice of an individual laboratory setting its own reference ranges. The answer sections illustrate how the questions should be approached and what factors should be taken into consideration when resolving them. The answers are based on clinical opinion current at the time of writing, but to some degree they also represent the opinions of the authors themselves. It is thus highly likely that after studying the No t e s o n the us e o f thi s bo o k xvii literature and taking into account new drugs and new information that may have become available since the case studies were prepared, some readers will disagree with decisions arrived at by the authors. This is entirely appropriate in a book endeavouring to teach decision-making skills in complex areas where there is rarely an absolutely right or wrong answer. Indeed, it is hoped that the questions raised in the case studies will generate discussion and argument between pharmacists, as it is through such debate that communication skills are developed. The ability to put forward and defend drug therapy decisions to other healthcare professionals is almost as important a skill to the pharmacist wishing to develop his or her clinical involvement as the ability to make such decisions. Finally, as this book is intended for teaching purposes and not as a reference work, it has been indexed to disease states and approved drug names only. His haematology and biochemistry results were as follows: I I I I Sodium 140 mmol/L (135145) Potassium 4. Q15 What special considerations apply to the management of hypertension in the elderly? This level of risk determines the threshold for initiation of drug treatment for hypertension, and consideration of the use of aspirin and/or a statin. He is otherwise in good health, has several modifiable risk factors, and is only marginally over one of the two values normally considered as thresholds for drug treatment (160/100 mmHg in most guidelines). If only the diastolic or the systolic pressure is raised, treatment should still be initiated. Blood pressure is constantly changing, and any individual reading is influenced by a number of factors, such as posture, the time of the day, emotions and exercise. To overcome this and to ensure the patient is as relaxed as possible, several readings need to be taken over a period of time before a diagnosis of hypertension is made. The recommended period of time and the number of readings vary according to the severity of the raised blood pressure. The average of the recorded blood pressure values should be used in the risk assessment. The use of non-drug approaches may avoid the necessity for drug therapy, or reduce the number of therapies and their doses required to control his blood pressure. There is an association between overweight and hypertension for patients of all ages, although it is reduced in elderly patients. A reduction in weight usually brings about a corresponding albeit small reduction in blood pressure. However, compliance with weight-reducing diets is a problem and not easily maintained. The usual aim is to change specific areas of food intake, particularly the amount of fat consumed. It is also important that alcohol consumption, to the recommended value, is spread evenly across the week. This is recommended for all patients regardless of whether or not they are receiving active pharmacological treatment. There is some evidence that sodium restriction will result in a small reduction in systolic blood pressure. Although a very significant reduction is difficult, a high sodium intake can negate the effectiveness of antihypertensives and diuretics. Take regular physical exercise, especially dynamic rather than isometric exercise. Walking or swimming (for 3045 minutes three or four times a week) can bring about a modest reduction in blood pressure. It is important that the exercise is regularly maintained, as any benefit is lost 14 days after the exercise ceases. Drug therapy for smoking cessation should be checked to ensure there are no cautions or contraindications to the use of particular products. Avoid excessive consumption of coffee (>5 cups) and other caffeinerich products as these can raise blood pressure. This class of drug can cause fluid retention and a subsequent increase in blood pressure, and should thus be avoided. Combinations of the above lifestyle modifications may achieve significant reductions in blood pressure. Approximately 25% of patients undertaking multiple lifestyle modifications achieve an estimated 10 mmHg or more reduction in their blood pressure values in the first year. Patients need to be highly motivated, and require regular follow-up and considerable support over a long period of time. Given the situation in which the prescriber has a choice of first-line treatments, the actual choice should be made in conjunction with the 8 D r ugs i n U s e patient and take account of clinical judgement, risk of adverse effects and patient preferences. Counselling should cover the reasons why his blood pressure is being controlled and what lifestyle issues should be addressed, as well as specific information about ramipril. They promote sodium excretion, both by reducing aldosterone levels and by causing renal vasodilation. They can also be helpful for patients with claudication because of their vasodilatory effects. Renal artery stenosis, or narrowing, leads to reduced glomerular filtration pressure. Any advice Hy p e rte ns io n 9 given should be supported with leaflets and a selection of suitable website addresses, as appropriate. As an additional source of information, he should be directed to the patient information leaflets provided with his prescribed antihypertensive medications. In addition, as with any initiation of an antihypertensive treatment, he needs to appreciate that: (a) He should adhere to the prescribed dose to ensure that he maximises the reduction in blood pressure values for the minimum level of drug therapy. It may take several changes of dose and drug before his ideal blood pressure is achieved. He should discuss or report any possible adverse events to his prescriber or pharmacist. The lifestyle modifications described earlier need to be implemented as they are an adjuvant to reducing blood pressure. Hypertension is symptomless and he will not feel better in himself (he may feel worse); failure to understand this leads to poor adherence. The presence of protein or blood (proteinuria) in the urine can help to identify patients with kidney damage but cannot distinguish those who have renal disease and secondary hypertension from those whose kidneys have been damaged by the raised blood pressure. Sodium and potassium levels should be checked to exclude hypertension resulting from adrenal disease. Similarly, serum urea and creatinine levels reflect kidney function and are used to exclude kidney disease as a cause of secondary hypertension. Of course, some patients never achieve these targets even if motivated and with good professional support, because adverse effects limit what is practicable. For people with hypertension any reduction in blood pressure values is beneficial. Decisions regarding the intensity of treatment and treatment goals should be reached in discussion with the patient. A9 Blood pressure should be monitored routinely until stable and at the desired level. Patient adherence to therapy is crucial, so it is essential that they reach an agreement with the prescriber as to the need for treatment. Some guidelines suggest assessing blood pressure after 4 weeks of unchanged therapy before considering the effect of a particular drug dose. Renal dysfunction may occur, so monitoring of renal function (urea and creatinine) is required. Potassium levels may increase because of the inhibition of aldosterone, and should be monitored. A dry, irritating cough occurs in up to 15% of patients and should be actively enquired about. However, the risk of non-cerebral bleeding does increase, and this would have to be balanced against the benefits of reducing the risk of coronary heart disease for individual patients. If the latter was raised, statin therapy might well be indicated for dyslipidaemia. As a pharmacist, you need to identify any problems that pharmaceutical intervention could ameliorate. As with any patient with an increasingly complex drug regimen, tactful enquiries should be made as to how well he manages to take his treatment as prescribed. Counselling about drug treatment should be ongoing: a single session is unlikely to have a lasting impact. Despite the benefits of antihypertensive medication, population studies have demonstrated that hypertensive patients continue to have a substantially higher risk of coronary heart disease and stroke than nonhypertensive individuals, even after several years of treatment. A12 A stepped approach to antihypertensive treatment is recommended to achieve target blood pressure values, with the addition of other drugs as necessary. If this fails to control blood pressure, fourth-line agents may Hy p e rte ns io n 13 be required. Using this stepwise approach helps achieve one of the aims of hypertension therapy, which is to obtain maximum control of the blood pressure with minimal therapy, thereby reducing possible sideeffects and increasing the chance of adherence. They act at different sites to slow calcium influx into vascular smooth muscle cells, causing vasodilation and hence reduced blood pressure.
Treatment is wide local excision jalapeno antifungal cheap butenafine 15 gm line, but it is frequently multifocal xenopus fungus generic 15gm butenafine visa, and local recurrences are common Stewart-Treves Syndrome 1 fungus amongus band buy butenafine 15gm amex. Hemangiomas are vascular tumors characterized by increased cellular proliferation antifungal griseofulvin buy cheap butenafine 15gm line. Approximately 80% of hemangiomas are noted in the first month of life fungus hives order butenafine 15 gm on line, and 60% occur in the head and neck region antifungal prescription medications purchase butenafine 15 gm. May be present at birth (30-50%) but usually appear in the first two weeks of life, with 80% appearing in the first month of life 46 a. Proliferating phase 0-9 months (with most of the growth achieved by 3 months) b. Larger problematic lesions can be treated with medical therapy (oral prednisolone or oral propanolol) c. Lesions (of any stage) that are compromising function or destroying vital structures B. Arise in the fetus, are fully grown at birth, and do not have post-natal growth 2. Red-violaceous with coarse telangiectasias, central pallor, and a peripheral pale halo 3. More common in the extremities, have an equal sex distribution, and are solitary with an average diameter of 5 cm 4. Resection can be considered if the scar will be less noticeable than the lesion C. Presents as a large (>5cm), superficial, and diffuse lesion, with the overlying skin deep red-purple, tense, painful, and shiny 2. Typically involves the trunk and extremities, 50% present at birth (but can appear in childhood) 3. Kasabach-Merritt phenomenon (thrombocytopenia <25,000, bruising, and bleeding) is common 4. Regression seen after age 2, although long-term chronic pain and stiffness can persist 5. Slow-flowing vascular malformation characterized by ectatic vessels located at various levels within the dermis 2. Present at birth, slowly increase in size as the child grows, change size with position, and are prone to thrombosis (phlebolith formation) 3. Most commonly occur in the cervicofacial region, axilla/chest, mediastinum, retroperitoneum, buttock, and perineum 3. Treatment is reserved for symptomatic lesions that cause pain, significant deformity, or threaten vital structures a. High-flow vascular malformations characterized by warmth, pain, bony destruction, discoloration and sometimes ulceration of the overlying skin 2. A working knowledge of the anatomy of the head and neck is crucial in the diagnosis and surgical treatment of these diseases. Control active bleeding by pressure, may need direct ligation in operating room or embolization in interventional radiology suite 2. Palpate facial skeleton for underlying bone pain and instability; rule out injury to facial nerve, parotid duct, etc. Wounds closed preferably less than 8 hours post-injury, but primary closure may be delayed up to 24 hours b. Physical examination for asymmetry, bone mobility, diplopia, extraocular muscle entrapment, sensory loss, malocclusion, local pain c. Once occlusion is aligned, work systematically, either "outside-in" (Gruss) or "inside-out" (Manson), establishing facial height, width, and projection by aligning key facial buttresses (open reduction) and plating of fractures (internal fixation) 2. Nasal bone fracture most common facial fracture (a) Septal hematoma can cause septal necrosis; must be drained immediately (b) May be corrected by closed reduction/manipulation and placement of external splint and Doyle splints (internal) ii. Le Fort fractures (Figure 3) 51 (a) Disrupts vertical maxillary buttresses: major areas of structural stability (i) Zygomaticomaxillary (ii) Nasomaxillary (iii) Pterygomaxillary (b) Treatment involves open reduction and internal fixation with miniplates to reestablish facial proportions and occlusion Figure 3. Usually more conservative with operative repair in this patient population, due to growing facial skeleton and developing dentition. The head and neck are relatively resistant to infection due to their robust vascularity B. Scalp and orbital infections may spread intracranially via the dural sinuses and ophthalmic veins C. Facial cellulitis: mostly due to staphylococcus or streptococcus - may use a cephalosporin 2. Use extended spectrum penicillin or other anaerobic coverage (Augmentin/Unasyn) 3. Primarily managed by Otolaryngologists but provide major reconstructive challenges for Plastic Surgeons (see next section) E. Minor salivary glands: least common, with highest incidence of malignancy (about 75%) 2. Any mass in the pre-auricular region or at the angle of the jaw is a parotid tumor until proven otherwise b. Surgical removal of entire gland with sparing of nerve branches that are clearly not involved ii. Anatomical: malignancies behave differently according to anatomic site and prognosis worsens from anterior to posterior b. Examination - including indirect laryngoscopy and nasopharyngeal endoscopy when indicated b. Malignant (a) Wide local excision with tumor-free margins with/without lymph node dissection (b) Palliative resection may be indicated for comfort and hygiene (c) Immediate reconstruction with vascularized flaps when indicated by size and location of defect (see next section) b. Preoperative (a) To increase chance for cure, especially with large lesions (b) May make an inoperable lesion operable by shrinking it and reducing involvement with unresectable structures ii. Postoperative (a) If tumor-free margin is questionable (b) For recurrence (c) Prophylactic - controversial c. Primary closure often possible, can be assisted with galeal relaxation incisions (scoring) 3. Tissue expansion is an excellent option (can allow up to 50% reconstruction without obvious alopecia) C. Main goal: tension-free coverage of the globe to prevent exposure keratopathy and ectropion (chronic eyelid irritation) 2. Cutler-Beard flap: pass tissue from below the lower lid under it and tack it into the upper lid defect iii. Main goal: Create aesthetic piriform aperture coverage and maintain airway patency and nasal lining 2. Divided into 9 subunits: single dorsum, tip, columella, and paired sidewalls, soft triangles, and alar lobules (Figure 5) 3. Nasolabial flap: tissue from along the cheek-nose junction swung into defect on the nasal ala or sidewall c. Forehead flap: workhorse two-staged technique where tissue from the central forehead is swung down to reconstruct part or all of the nose Figure 5. Many distinct components with specific reconstruction options for each, mostly involving local rotational flaps when primary closure is not an option 3. Total reconstruction: tissue expansion of nearby skin, and then advancement overlying a cartilage graft construct based on the contralateral ear 5. Main goal: Recreate oral competence and speech with a sensate aesthetic construct 2. Abbй Lip Switch flap: two-stage, section of lip swung to fill defect in opposite lip 57 ii. Fibula osteocutaneous flap: workhorse, can be shaped into an entire mandible and can also provide skin and soft tissue for floor of mouth or tongue reconstruction ii. Metal reconstruction plates are an option for patients who cannot tolerate a free flap operation but extrusion through the tissue is a common problem H. Main goals: prevent salivary contact with neck structures, restore swallowing and speech 2. Normal occlusion: "mesiobuccal cusp of the maxillary first molar aligns with the buccal groove of the mandibular first molar" b. X-rays, including a cephalogram (lateral x-ray at a fixed distance) to measure relationships of skull, maxilla and mandible iii. Dental casts are made (usually by an orthodontist) and "model" or mock surgery is performed on the casts to determine degree of advancement/setback of bone. Use of osteotomies with repositioning of bone segments, bone grafts as needed, with or without orthodontic corrective measures as needed iii. Very significant asymmetry, deformity of the face, drooling, exposure of the cornea 59 b. Protect cornea by taping lids, lid adhesions: ophthalmology consultation is critical c. Re-establishment of nerve function by primary nerve repair or nerve graft (sural nerve common donor nerve) i. Can be done cross-facially by rerouting motor axons from unaffected side but takes months to see improvement and denervated muscles may become unsalvageable d. Other measures, such as muscle transfers, static suspension, skin resections, free tissue transfers of muscle, etc. Structural pillars of the facial skeleton: An approach to the management of Le Fort fractures. Subunit principles in midline fractures: the importance of sagittal buttresses, soft-tissue reductions, and sequencing treatment of segmental fractures. Management of the medial canthal tendon in nasoethmoid orbital fractures: the importance of the central fragment in classification and treatment. Conditions, treatment principles, and concerns for certain complications are different and must be considered. The most common pediatric plastic surgery problems comprise congenital craniofacial anomalies, acquired craniofacial problems (such as facial fractures), brachial plexus injuries, hand anomalies, congenital nevi, and vascular malformations. Paired maxillary and mandibular prominences both arise from neural crest cells migrating from 1st branchial arch d. Frontonasal prominence, which divides into: (a) Medial nasal process: nasal tip, columella, philtrum and premaxilla (b) Lateral nasal process: nasal alae ii. Maxillary prominences: upper jaw, upper lip (lateral to philtrum), orbital floor, inferior portion of lateral nasal wall iii. Between 5-6 weeks nasal processes enlarge, migrate and coalesce in midline to unite with maxillary process and form upper lip. Viscerocranium: structures that surround oral cavity, pharynx, upper respiratory system and face b. Cranial base (occipital, sphenoid and temporal bones): endochondral ossification ii. Appositional growth: bone resorption of the inner surface and bone deposition on the outer surface B. Head deformity is similar, but there is a parallelogram configuration of the head (if seen from above) with anterior displacement of the ipsilateral ear and occipital flattening. Longstanding debate as to whether non-syndromic patients have increased incidence of developmental delay. New evidence shows some degree of executive dysfunction in up to 50% of these children. Usually performed within first year of life to take advantage of molding capacity of skull iii. Minimally invasive procedures: extended strip suturectomy (<6 months) +/- springs, +/- postoperative helmet therapy. In general, craniofacial distraction leads to greater advancement, less relapse than conventional procedures. Lack of fusion of facial processes that results in abnormal separation of skeletal and soft tissue structures of the face and cranium (alternative theory of lack of mesodermal penetration) 2. Tessier Classification system relates soft tissue to skeletal landmarks (Figure 3) 5. Defined by the bilateral presence of three Tessier Clefts #6, 7, 8, which result in all the phenotypic manifestations. Hypoplasia/aplasia of the zygomatic arch (a) Lateral orbit deficiency (b) Midface retrusion (c) Lateral canthus hypoplasia/downward slanting palpebral fissures ii. Mandibular hypoplasia with microretrognathia (a) Airway compromise due to narrow pharyngeal diameter (b) Require tracheostomy and distraction of mandible 66 vi. Skeletal and soft tissue augmentation of deficient areas with autologous bone grafts (calvaria, rib, iliac crest) and autologous fat/tissue transfer, respectively. Spectrum of morphogenetic abnormalities affecting the cranial skeleton, soft tissues and neuromuscular structures derived from the 1st and 2nd branchial arches b. Third-most common congenital malformation (following club foot and cleft lip and palate) d. Hypoplasia of mandibular ramus (uni or bilateral) (a) +/- hypoplasia of the maxilla, zygoma and temporal bone (b) Deviated chin (c) Tilted occlusal plane malocclusion ii. Augment deficient areas (a) Skeletal: autologous bone (calvarium, rib, iliac crest) (b) Soft tissue: free flap and/or fat grafting ii. Distraction may be necessary to achieve correction of malocclusion versus conventional orthognathic procedures to correct jaw discrepancies in adolescence. Intrinsic/extrinsic disturbance of mandible development (leads to micrognathia) b. Tongue remains pressed against posterior pharynx = airway obstruction and feeding issues 4. Immediate treatment goals in the neonate are establishing a patent airway and improving feeding. Tongue-lip adhesion: old technique; temporary suturing of tongue to lower lip to address glossoptosis.
In contrast to single-molecule drugs fungus dogs cheap butenafine 15 gm overnight delivery, many complex devices involve a number of components that antifungal and antibacterial cream best butenafine 15gm, together antifungal treatment for toenails discount butenafine 15gm with visa, form a system anti fungal anti bacterial shampoo quality 15 gm butenafine. Table 7-1 summarizes several differences as they relate fungus gnats vegetable garden butenafine 15gm without a prescription, in particular fungus gnats outdoor potted plants butenafine 15gm with amex, to implants and other complex medical devices. The device consists of four major subsystems-a pump, an external controller, a clinical data acquisition system, and a patient home support system-plus accessories, including batteries, a battery charger, and a kit to protect the device during showering (H030003). Further, the pump subsystem involves multiple elements, including a housing that surrounded three additional components-an inflow tube, an outflow element, and a probe to measure blood flow-and a cable connecting the implanted pump to the external battery and controls. In addition to the cost-related differences noted in the table, companies that develop medical devices also have to consider other costs that may be only minor considerations for most pharmaceutical companies. One category of such costs involves the support and servicing of complex devices once they are released into the market. Depending on the device, highly skilled company personnel may provide training to physicians, clinical staff, and patients (and their families) on the proper use of the device. Service technicians often must be available promptly in case device-related problems arise. Companies must also consider potential obligations to patients if a decision is made at some point to discontinue the device. Some companies are large and have diverse product lines and substantial resources to devote to product development and interactions with government regulators. Compared to the drug industry, a larger proportion of device firms are small, focused on single products and narrow market segments, and limited in their resources (see Gelijns et al. Entrepreneurs at small start-up companies develop many innovative medical devices, including devices that address needs of small patient populations. In some cases, those involved may see the approach as a focused way to address an unmet need and contribute to society without having to navigate the decision making processes of a large, complex company. In some cases, the projected business opportunity is too small or too risky to be worth attention from an existing company but is still attractive enough to attract venture capitalists or a small group of entrepreneurs. In exchange for partial ownership of the start-up company, angel investors and venture capitalists often provide the financing needed to bring nascent innovations to the market. In addition to infusions of capital, 2 For example, implanted devices usually have a finite service life due to battery exhaustion (if electronic or electromechanical) or simply wear and tear, so patients will need replacements. If no alternative device is available and particularly if the patient depends on the device for survival, then the continued availability of a replacement device is crucial. As discussed further below, the processes of device development and refinement also differ in significant ways from the processes that characterize the development of drugs and biologics (see generally Linehan et al. Because medical device companies are often engaged in a continuous process of product refinement and innovation, patents and similar protections may be less important as a source of competitive advantage for device companies than they are for drug companies. In contrast, several device companies may compete simultaneously in the marketplace with devices for the same indication that differ in only limited respects. Even in instances when patents could provide an element of protection from market competition, the patent holder may elect to license its patents to one or more competitors in exchange for royalties or to cross-license patents in order to acquire access to patents held by a competitor. Nevertheless, medical device companies are aggressive in defending their intellectual property from infringements by competitors (Budd and Liebman, 2009). In the 1970s, following widely publicized problems with the Dalkon Shield (an intrauterine contraceptive device) (Hubacher, 2002), Congress turned to the regulation of medical devices with the Medical Device Amendments of 1976 (P. Device Classification and Regulation A fundamental element of the 1976 law was a risk-related device classification scheme that forms the basis for risk-related regulatory requirements. For example, such a reclassification was requested for the first device available to screen newborn infants for inherited abnormalities of amino acids and deficiencies in certain enzymes (Lloyd, 2004). Thus, the regulatory framework created by Congress covers all classes of devices and extends, in some cases, to requirements for sponsors to conduct postmarket studies to collect data about safety and effectiveness after a device is approved for marketing. The 510(k) notification typically does not require clinical data unless the technology for a new device differs from that of the predicate device and clinical data are necessary to evaluate the potential impact of this difference on safe and effective performance. Clinical data are included in approximately 10 percent of 510(k) notifications (Tillman and Gardner, 2004; Rosecrans, 2010). The cost will vary depending on the complexity of the device and the kinds of nonclinical and clinical data that the sponsor must submit to demonstrate safety and efficacy. This report focuses on complex devices intended specifically to treat complex rare conditions. It must also provide a description of the proposed research and analysis strategy. Diagnostic devices include such diverse items as blood pressure cuffs, vision evaluation instruments, cardiac monitors, and sophisticated imaging equipment. Based on their complexity, diagnostic devices are generally assigned to one of the three classes discussed above and regulated accordingly. In vitro diagnostic devices include genetic and other tests that are important in diagnosing many rare diseases. Such a device may not be used for human clinical diagnostic or prognostic use and the labeling must state: "For research use only. Analyte-specific reagents (which include polyclonal and monoclonal antibodies, specific receptor proteins, nucleic acid sequences, and similar reagents) are the building blocks that clinical laboratories use to develop in-house assays. If a manufacturer combines analytespecific reagents into a kit, or otherwise offers them for sale together, then the product must be approved as a medical device. Although the agency has indicated that it plans to regulate some of these tests as medical devices, the specifics and priorities have yet to be decided. Another area of regulatory complexity is co-development of a drug and a companion diagnostic. An example is a diagnostic test kit to assess whether a breast cancer patient has a gene mutation that is targeted by the drug trastuzumab (Herceptin). Combination Products Some medical products combine a medical device and a drug or biologic. Examples include the drug-eluting coronary stent (which adds a drug coating to a metal tests" and "frequently have a high risk intended use" (p. For a product such as the drug-eluting stent, the device and drug components are truly combined into a single entity, but two items that are physically distinct but packaged together qualify as a combination product. The category can also cover a product such as a drug that is packaged separately but is labeled as being for use only with a specific device or type of device (such as a specific diagnostic test). Alternate Approval Route for Medical Devices for Small Populations As is true for companies that manufacture drugs and biologics, device companies naturally seek business opportunities in markets of sufficient size and profitability to warrant the investment risk. The Safe Medical Devices Act of 1990 authorized the Humanitarian Device Exemption to encourage the development and introduction of complex device technologies to meet the needs of small patient populations. Although neither the text nor the title of the 1990 law uses the term "rare disease" or "orphan product," the purpose is broadly similar to the purpose of the Orphan Drug Act. The specifics vary in part because the details of device regulation differ and in part because the incentives (particularly market exclusivity) that were viewed as important for drug manufacturers were viewed as less meaningful for device manufacturers. As a general rule, that assignment is based on the primary mode of action of a combination product. For some combinations, the lead might go to the Center for Biologics Evaluation and Research. It is made from mixture of a genetically engineered human protein powder, bovine collagen, saline solution, and a thickening agent to form a putty-like material that is applied to each side of the spine section that is to be fused. The shipment limit means that substantially expanded use of a device either within the approved indication or off-label is controlled in a way that does not apply for orphan drugs. This difference reflects the process of ongoing device refinement described earlier and the less significant role of patent or patent-like protection in the medical device industry. Like developers of orphan drugs, developers of devices are also eligible for orphan products grants. They can recover certain costs, for example, those related to research and development, manufacturing, and distribution. He also is quoted as indicating that the price for the unit did not cover additional charges associated with training, associated technologies, and diagnostic and clinical support (Zacks, 2008). It would have been useful if the guidance had included a sample letter for such a deferral. If the testing of safety and effectiveness for an innovative drug required simultaneous use of the innovative device, that clinical testing should provide evidence to support both approval of the drug and clearance or approval of the device. An air leak present on postoperative day 7 is considered prolonged unless present only during forced exhalation or cough. An air leak present on day 5 should be considered for treatment if it is (1) continuous, (2) present during normal inhalation phase of inspiration, or (3) present upon normal expiration and accompanied by subcutaneous emphysema or respiratory compromise. Epicel (cultured epidermal autografts) is for use with patients who have deep dermal or fullthickness burns comprising a total body surface area of greater than or equal to 30 percent. It may be used in conjunction with split-thickness autografts or alone in patients for whom splitthickness autografts may not be an option due to the severity and extent of their burns. The device has regular premarket approval application for use with ventricular septal defects (P000049). Incentives for the Development of Pediatric Medical Devices Because children are generally a healthy population, companies often do not find it commercially feasible or attractive to develop devices specific to pediatric diseases or to develop smaller versions of adult devices for relatively small numbers of children who might benefit from them. As described in draft agency guidance, the Pediatric Medical Device Safety and Improvement Act of 2007, this number "is determined by estimating the number of individuals (pediatric and adult patients) affected by the disease or condition and likely to use the device each year multiplied by the number of devices reasonably necessary to treat each individual. The order includes no explanation of the number, but on its website, Medtronic, the device manufacturer, states that approximately 34,000 children are born each year with congenital heart disease, of which 20 percent are born with a malformation affecting blood flow between the heart and lungs (Medtronic, 2010). A subset of these infants will have a prosthetic conduit surgically implanted, and some of these devices will malfunction, which will require new surgery. The device is intended to extend the life of the malfunctioning conduit without open heart surgery. For instance, although it is possible to reduce on the "bench" the physical size of prosthetic mechanical heart valves routinely used with adults, fluid flow and pressure change once orifices are reduced below certain diameters. Connecting innovators and physicians to existing Federal and non-Federal Resources. A custom device is a one-of-a-kind device designed for an immediate need and for which the need is not likely to reoccur. In essence, a physician and a manufacturer collaborate to design a device for a specific circumstance. For such devices, it would be virtually impossible to conduct a clinical trial, and-assuming the device does meet all the criteria defining it as a custom device-the device would be exempt from premarket approval" (Henney, 2000). If the assessment of unmet needs recommended at the end of this chapter includes needs for custom devices, the assessment could help in determining whether allowing slightly broader approval of custom devices could benefit patients with very rare conditions. As described in Chapter 6, Medicare pays hospitals a bundled or per-case payment for institutional services provided in the course of treatment for a particular diagnosis with payment varying depending on the severity of the diagnosis and other factors. This has generally been interpreted to mean that a service or item must be safe and effective, medically necessary and appropriate, and not experimental in order to qualify for reimbursement. Another is the device for treatment of pulmonary air leaks mentioned in Box 7-1 (Spiration, 2009). Overall, of the seven applications for add-on payments approved between 2001 and 2008, six were for products classified as medical devices (Clyde et al. The committee did not examine the coverage and reimbursement policies of state Medicaid programs or private health plans, but it did find illustrative examples of variation in health plan policies. For example, Aetna will cover certain uses of total artificial heart devices and left ventricular assist devices, but it considers other uses experimental and investigational (Aetna, 2010). At least one health plan has posted a general policy on coverage that states Humanitarian Use Devices are subject to individual review and prior approval (Wellmark Blue Cross Blue Shield, 2009). For example, breakthrough implantable devices were made possible, in part, by scientific and engineering advances in areas outside biomedicine. Creative device ideas have often originated with physicians in the clinic who are trying to address specific problems they encounter or to help a specific patient with the tools at hand. The life cycle of devices includes iterative improvements over time, often involving collaborations between engineering and other disciplines. Emergence of Complex Medical Devices I cannot believe that six whole months have soared by since I was given a new lease on life. Sands, 2010 this man, who has lived for decades with muscular dystrophy, has been assisted by a variety of medical devices. As is the case with many devices used for patients with rare conditions, none were devised specifically for patients with muscular dystrophy but all have helped him survive. Its development and subsequent refinement were made possible by a number of scientific and engineering advances. Although medical devices have a long history in the form of basic surgical instruments, braces, medical thermometers, and similar relatively simple objects, the development of technologically sophisticated, complex devices advanced significantly in the 1950s and early 1960s, based in part on technological innovations in other arenas. Notably, the transistor, invented in 1947 at Bell Labs, provided the foundation for solidstate electronics, which in turn made possible the miniaturization of electronic devices and improved capabilities. Other innovation within and outside the medical device industry-led to the availability of durable and biologically compatible materials for use in orthopedic, neurological, cardiac, and other implants. Advances in mechanical valve materials and designs and newly available heart-lung machines made replacement heart valves feasible in the 1960s. Innovation Process for Complex Medical Devices Although moving from idea to marketing typically takes many years for both drugs and complex medical devices, the nature of medical device innovation and product development and the underlying technical expertise differ in some significant ways for devices. In simple terms, the innovation pathway for drugs is a laboratory-based discovery process that is led by biomedical scientists, chemists, and pharmacologists. Clinicians assume a primary role toward the end of the process, that is, when drugs undergo clinical testing in humans, which regulations require for all drugs. In contrast, device innovation and development has been primarily an engineering process that combines technical expertise from multiple disciplines. Clinicians may be involved from the outset and may continue to be involved in ongoing refinement once a device is authorized for marketing. As is true for engineered products generally, the process of device development is iterative and circular.
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References
Bornstein PN, JP, Bernanke D. Adrenocortical hyperfunction in association with anaplastic carcinoma of the respiratory tract. N Engl J Med 1961;264:363-71.
Aydin S, Ercan M, Caskurlu T, et al. Acupuncture and hypnotic suggestions in the treatment of non-organic male sexual dysfunction. Scand J Urol Nephrol. 1997;31(3):271-274.
Guerra-Junior G, Andrade KC, Barcelos IHK, et al: Imaging techniques in the diagnostic journey of disorders of sex development, Sex Dev 12(1- 3):95-99, 2018.
Ghali JK, Liao Y, Simmons B, et al: The prognostic role of left ventricular hypertrophy in patients with or without coronary artery disease, Ann Intern Med 117:831-836, 1992.
Neumann G, Hunter D, Nevitt M, et al. Location specific radiographic joint space width for osteoarthritis progression. Osteoarthritis Cartilage 2009; 17:761-5.
Bell W. Correction of mandibular prognathism by mandibular setback and advancement genioplasty. Int J Oral Surg 1981;10:221-229.
Heidenreich A, Sesterhenn IA, Mostofi FK, et al: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis, Cancer 83:1002n1011, 1998.
