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Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin chronic active gastritis definition purchase 10 mg aciphex fast delivery. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management gastritis with duodenitis buy aciphex with a mastercard. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy gastritis symptoms difficulty swallowing generic 20mg aciphex fast delivery. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin gastritis symptoms and home remedies purchase 10mg aciphex overnight delivery. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in U. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment,. Suspend Avastin administration for 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. All but one of these events were Grade 1 in severity and resolved without medical intervention. The overall incidence of Grade 3 4 venous thromboembolic events in Study 1 was 15. Neutropenia and Infection the incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was U. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria In Studies 1, 2 and 4, the incidence of Grade 3 and 4 proteinuria, characterized as >3. The highest incidence of proteinuria was observed in a dose-ranging, placebo-controlled, randomized study of Avastin in patients with metastatic renal cell carcinoma, an indication for which Avastin is not approved. Among patients for whom 24-hour urine collections were obtained (approximately half of the enrolled patients), four of 19 (21%) patients receiving Avastin at 10 mg/kg every two weeks, two of 14 (14%) patients receiving Avastin at 3 mg/kg every two weeks, and none of the 15 placebo patients experienced Grade 3 proteinuria ( > 3. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. All Grade 3 4 adverse events and selected Grade 1 2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Grade 3 4 adverse events occurring at a higher incidence ( 2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. Sensory neuropathy, hypertension, and fatigue were reported at a 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2. The data below are presented to provide information on the overall safety profile U. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1 4 events which occurred at a higher incidence ( 5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3. Capecitabine Alone) Capecitabine Capecitabine + Avastin (n = 215) (n = 229) Body as a Whole Asthenia 102 (47%) 131 (57%) Headache 28 (13%) 76 (33%) Pain 53 (25%) 71 (31%) Cardiovascular Hypertension 5 (2%) 54 (24%) Digestive Stomatitis 41 (19%) 58 (25%) Metabolic/Nutrition Weight loss 9 (4%) 21 (9%) Musculoskeletal Myalgia 17 (8%) 32 (14%) Respiratory Dyspnea 39 (18%) 61 (27%) Epistaxis 3 (1%) 36 (16%) Skin/Appendages Exfoliative 162 (75%) 193 (84%) dermatitis Urogenital Albuminuria 16 (7%) 51 (22%) Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%. Of these, the incidence of Grade 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%. Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In Study 4, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11 50 days]) and the importance of the drug to the mother. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0. The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 4, patients aged 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged 65 years (8. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6. Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11 50 days.
Syndromes
- Abdominal MRI
- High blood pressure and high cholesterol
- The skin may become leathery and brownish in the problem area.
- Disorders associated with excessive daytime sleepiness
- New symptoms develop
- Headaches
- Diarrhea that persists
- Stressful life events, such as the loss of a parent to death or divorce
Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither o ers of coverage nor medical advice gastritis diet karbohidrat purchase aciphex 20 mg free shipping. This Clinical Policy Bulletin contains only a partial gastritis diet queen 10mg aciphex with visa, general description of plan or program benefits and does not constitute a contract gastritis symptoms in spanish discount aciphex 10 mg overnight delivery. Aetna does not provide health care services and gastritis diet en espanol cheap aciphex 20 mg with visa, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its a liates. Treating providers are solely responsible for medical advice and treatment of members. Several of these syndromes require immediate diagnosis and decisions on treatment, some of them life-saving. Critical decisions must often be made quickly by professionals with different backgrounds and levels of expertise with limited resources. Against this background, the AccA clinical decision-Making toolkit was created as a comprehensive resource encompassing all aspects of acute cardiovascular care but structured as an easy-to-use instrument in environments where initial acute cardiovascular care is typically initiated. However, it does not replace textbooks and other sources of information that need to be consulted to reach an optimal management of these patients. University Medical Center Groningen, Groningen, the Netherlands Pascal vranckx Department of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, Hasselt, Belgium christiaan vrints Department of Cardiology, Antwerp University Hospital, Edegem, Belgium doron Zahger Department of Cardiology, Soroka Univ, Medical Center, Beer Sheva, Israel uwe Zeymer Department of Cardiology, Herzzentrum Klinikum Ludwigshafen, Ludwigshafen, Germany 1 p. Acute respiratory failure in the elderly: etiology, emergency diagnosis and prognosis. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. If the answers to these questions are positive, the episode has a high likelihood of being syncope. Situational syncope is diagnosed if syncope occurs during or immediately after specifc triggers. Orthostatic syncope is diagnosed when it occurs after standing up and there is documentation of orthostatic hypotension. Cardiovascular syncope is diagnosed when syncope presents in patients with prolapsing atrial myxoma, severe aortic stenosis, pulmonary hypertension, pulmonary embolus or acute aortic dissection. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month post-discharge death in an international registry. Dual b O C or A therapy O C or A c dual therapy with oral anticoagulation and one antiplatelet agent (aspirin or clopidogrel) beyond one year may be O C or A considered in patients at very high risk of coronary events. Pre-hospital management of patients with chest pain and/or dyspnoea of cardiac origin. Hemodynamic criteria to defne cardiogenic shock Systolic blood pressure <80 to 90 mmHg or mean arterial pressure 30 mmHg lower than baseline Severe reduction in cardiac index: <1. The available devices differ in terms of the insertion procedure, mechanical properties, and mode of action. This fow is the sum of the mechanical circulatory support output and the remaining function of the heart. Adenosine Electrical or pharmacological If no cardioversion is considered: using oral or i. Atrioventricular impulse from the sinus node and has a rate of under 60 beats transmission is delayed, resulting in a Pr interval per minute longer than 200 msec Sinoatrial exit block. If a laboratory test for a cardiac biomarker has already been performed during initial diagnostic work-up (e. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index. Pharmacological treatment: For more information on individual drug doses and indications, See chapter 8: Use of drugs in Acute Cardiovascular Care. Myocardiocytolysis markers: Elevated TnT/TnI the clinical suspicion of myocarditis Fever 38. Adjust infusion: Phosphodiesterase inhibitor shock continuous CrCl 50ml/min: start 0. Reduces pulmonary and systemic vr, PcP cardiogenic dopaminergic effect:, a, dopaminergic agonist shock 2-5 g/Kg/min i. The guidance suggested in the Toolkit does not override the individual responsibility of the healthcare professional to make appropriate decisions according to each patients circumstances and profle, as well as local regulations and licenses. Acknowledgements We are indebted to all the authors for their commitment and for the strong effort to synthesise their wide scientifc knowledge and clinical experience into simple algorithms and schemes using the aim to help clinicians in everyday clinical practice in the easiest possible manner as the main driver of their work. We appreciate the generous unrestricted educational grants and the independence to develop the Toolkit with no infuence whatsoever in the selection of faculty, topics, clinical or scientifc content. Acute cardiovascular care Association clinical decision-Making toolKit european society of cardiology Acute cardiovascular care Association (AccA) toolKit online 2035 Route des Colles version les templiers cs 80179 Biot 06903 sophia Antipolis France Tel. Even the most seasoned clinician, standing at the bedside of the patient in extremis, can be unclear about the cause of shock and the optimal initial therapeutic approach. Traditional physical examination techniques can be misleading given the complex physiology of shock. Therefore, diagnosis and initial care must be accurate and prompt to optimize patient outcomes. Ultrasound technology has been rapidly integrated into Emergency Department care in the last decade. Studies have demonstrated that initial integration of bedside ultrasound into the evaluation of the patient with shock results in a more accu rate initial diagnosis with an improved patient care plan. Thus, bedside ultrasound has become an essential component in the evaluation of the hypotensive patient. The classic example of this class of shock is sepsis, in which the vascular system is vasodilated to the point that the core vascular blood volume is insufficient to maintain end organ perfusion. Other examples of distributive shock include neurogenic shock, caused by a spinal cord injury, and anaphylactic shock, a severe form of allergic response. The third major form of shock is cardiogenic shock, resulting from pump failure and the inability of the heart to propel the needed oxygenated blood forward to vital organs. Cardiogenic shock can be seen in patients with advanced cardiomy opathy, myocardial infarction, or acute valvular failure. This type is most commonly caused by cardiac tamponade, tension pneumothorax, or large pulmonary embolus. Many patients with obstructive shock will need an acute intervention such as pericardiocentesis, tube thoracostomy or anticoagulation, or thrombolysis. At the bedside of a critical patient, it is often difficult to assess clinically which clas sification of shock best fits the patients current clinical status. For example, patients with tamponade, cardiogenic shock and sepsis (when myocardial depression compounds this form of distributive shock) may all present with distended neck veins and respiratory distress. Because of this diagnostic challenge, practitioners used to perform Swan-Ganz catheterization in hypotensive patients, providing immediate intravascular hemodynamic data. Although the data obtained from these catheters was detailed and often helpful at the bedside, large studies demonstrated no improvement in mortality in the patients who received such prolonged invasive monitoring. The first, and most crucial, step in evaluation of the patient in shock is determination of cardiac status, termed for simplicity the pump (Table 1. First, the pericardial sac can be visualized to determine if the patient has a pericardial effusion that may be compressing the heart, leading to a mechanical cause of obstructive shock. Determination of the size and contractility status of the left ventricle will allow for those patients with a cardiogenic cause of shock to be rapidly identified. A heart that has an increased size of the right ventricle relative to the left ventricle may be a sign of acute right ventricular strain from a massive pulmonary embolus in the hypotensive patient. Integration of lung ultrasound techniques can quickly allow the clinician to identify a pneumothorax, which in the hypotensive patient may represent a tension pneumothorax requiring immediate decompression. Tension pneumothorax presum ably limits venous return into the heart due to increased pressure within the chest cavity. Next the clinician should turn to evaluation of the venous side of the vascular system. The femoral and popliteal veins can be exam ined with a high frequency linear array transducer for compressibility. A smaller foot print phased-array transducer is ideal for this examination as it permits the intercostal scanning required of the heart. The tradi tional views of the heart for bedside echocardiography are the parasternal long and short-axis views, the subxiphoid view, and the apical 4-chamber view (Fig. The par asternal views are taken with the probe positioned just left of the sternum at intercostal space 3 or 4.
Topical treatment: Topical drugs First line management of adult mild-to-moderate adult plaque psoriasis is with topical treatment gastritis diet 66 generic aciphex 20mg with amex, including vitamin D analogues and topical corticosteroids gastritis diet of worms discount aciphex 10 mg with amex. Calcipotriol is a vitamin D analogue that regulates epidermal cell proliferation and differentiation gastritis diet vi order cheapest aciphex and aciphex, as well as production and release of pro-inflammatory cytokines gastritis diet natural remedies order aciphex discount. Topical corticosteroids are available in different potencies and formulations but despite more than 40 years of experience, their use remains mostly based on individual experience. Published guidelines often specify the place of topical steroids within psoriasis treatment strategies [113] [114] [115] but not the efficacy and practical modalities of use. It should be noted that the majority of adverse events seen with topical therapies are cutaneous rather than systemic in nature and that the riskbenefit ratio for these patients is better with topical therapies than with biological [116]. In our days phototherapy is a valuable option in the treatment of many psoriatic and nonpsoriatic conditions, including atopic dermatitis, sclerosing skin conditions such as morphea, sclero derma, vitiligo, and mycosis fungoides [118]. Excimer laser: this form of light therapy, used for mild to moderate psoriasis, treats only the involved skin. Pulsed dye laser: Similar to the excimer laser, the pulsed dye laser uses a different form of light to destroy the tiny blood vessels that contribute to psoriasis plaques. Systemic treatment: Oral or injected medications Patients with moderate to severe disease generally require systemic agents (e. The severity of psoriasis traditionally has been evaluated by objective measurement of the extent of the body surface affected and consideration of the subtype of psoriasis, degree of disability, and feasibility of topical therapy [124]. Retinoids: Several systemic retinoids (derivatives of vitamin A) have been developed for the treatment of psoriasis. Systemic retinoids are known to have immunosuppressive and anti-inflammatory activity and to modulate epidermal proliferation and differentiation [125]. Taken orally, methotrexate helps psoriasis by decreasing the production of skin cells and suppressing inflammation. Cyclosporine: It was first used (inadvertently) for the treatment of psoriasis in 1979 [130]. Cyclosporine suppresses the immune system and is similar to methotrexate in effectiveness. Dime thylfumarate, and its metabolite monomethylfumarate, appear to be the principal active components of Fumaderm. Treatment with dimethylfumarate and/or monomethylfumarate produces a beneficial shift towards Th2-like cytokine secretion associated with a reduction in peripheral lymphocytes (primarily T cells) [131] and inhibits the proliferation of epidermal keratinocytes in patients with psoriasis. During these treatments, cutaneous adverse effects may occur like eczema, lupus, alopecia areata or psoriasis, which represents a paradoxical adverse effect. They are considered a class effect of these drugs, and their incidence ranges from 1 to 5%, with paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis and their combinations) being most frequently reported [135]. These subtypes differ with re spect to their regulatory behaviour and tissue expression patterns. In summary: Managing psoriasis Currently, there is no universal standard of care for patients with moderate to severe psoriasis, and the benefits and risks of systemic therapy must be weighed carefully for each patient to ensure optimal management of psoriasis symptoms and minimization of acute and cumulative toxicities [143]. Whether the symptoms are mild, moderate, or se vere, the optimal treatment plan is the one the patient is most likely to follow. Phototherapy is generally the first-line treatment for patients with extensive psoriasis or disabling symptoms. When phototherapy is not feasible or is ineffective, systemic treatments with conventional oral agents or biologics are indicated [144]. Psoriasis is a common skin disorder that needs Psoriasis Types, Causes and Medication 27 dx. Epidemiology of the rheumatic dis eases, Oxford University Press, New York (1993), pp. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. Investiga tions of the active edge of plaque psoriasis: vascular proliferation precedes changes in epidermal keratin. Study de sign and preliminary results from the pilot phase of the PraKtis study: self-reported 28 Psoriasis Types, Causes and Medication diagnoses of selected skin diseases in a representative sample of the Italian popula tion. The Koebner (isomorphic) response in psoriasis: associations with early age of onset and multiple previous therapies. Family history of psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute gut tate psoriasis: results of a case-control study. Loh Correspondence): Acute Guttate Psoriasis in a 15 Year-Old Girl With Epstein-Barr Virus infection. Incidence and clinical predictors of psoriatic arthritis in patients with psoriasis: a population based study. A prospective, clinical and radiologi cal study of early psoriatic arthritis: an early synovitis clinic experience. Stress, corticotropin-releasing hor mone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects. Number of cell layers of the stratum corneum in normal skinrelationship to the anatomical location on the body, age, sex and physi cal parameters. Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquama tion. Stratum corneum tryptic enzyme in normal epi dermis: a missing link in the desquamation process Reddish, scaly, and itchy: how proteases and their inhibitors con tribute to inflammatory skin diseases. Calcium regu lation of growth and differentiation of mouse epidermal cells in culture. Increased in vitro expression of beta 2-adrenoceptors in differentiating lesional keratinocytes of vitiligo patients. Influence of the beta-1 selective blocker, metoprolol, on the development of pulmonary edema in tocolytic therapy. Inhibitory effects of beta-adre nergic stimulants on increased vascular permeability caused by passive cutaneous anaphylaxis, allergic mediators, and mediator releasers in rats. Cutaneous permeability responses to bradykinin and histamine in the guinea-pig: possible dif ferences in their mechanism of action. Attenua tion of histamine-induced endothelial permeability responses after pacing-induced heart failure: role for endogenous catecholamines. Review of mechanisms involved in the apparent differential desensiti zation of beta1 and beta2-adrenoceptor-mediated functional responses. Characterization of the beta adrenergic receptors of cultured human epidermal keratinocytes. Beta-adrenergic stimulation in duces intracellular Ca++ increase in human epidermal keratinocytes. Psoriasis and altered calcium metabolism: downregulated ca pacitative calcium influx and defective calcium-mediated cell signaling in cultured psoriatic keratinocytes. Cutaneous barrier per turbation stimulates cytokine production in the epidermis of mice. Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. The interleukin-6 cytokine system regulates epidermal permeability barrier homeo stasis. Imiquimod-in duced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis. Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis. Stress-induced endocrine and immuno logical changes in psoriasis patients and healthy controls. An immunohistochemical study on catecholamine synthesizing enzymes and neuropeptides of the skin. Beta-adrenergic blocking drugs and psoriasis: the role of an immu nologic mechanism. Genetics of Psoriasis: Evidence for Epistatic Interaction between Skin Barrier Abnormalities and Immune Deviation.
The dashed line shows the line of best fit through the elastic region chronic gastritis of the stomach generic 10 mg aciphex amex, from which the elastic modulus is calculated gastritis diet generic aciphex 10 mg with mastercard, and the Dash-dotted line shows the line parallel to the elastic line of best fit chronic gastritis meaning buy generic aciphex 20mg online, offset by 0 gastritis diet buy discount aciphex 20mg line. The error bars are standard errors of mean (n=5); there were no significant differences between any of the groups. The porcine femoral head is significantly larger than the ovine femoral head with a more densely packed trabecular structure than ovine tissue, in particular near the femoral head surface. A visible growth plate is seen in the centre of the porcine femoral head, however this is only seen in the femoral neck of the ovine sample. The error bars are standard errors of mean and the red asterisk represents a significant difference with other groups (P<0. Bovine specimens had significantly different offset yield stress when compared with other groups. A regression line is fitted to each data set and all the samples combined, and R2 values are shown next to each line. Cavity created in the inferior position of the head during removal of the femoral head in surgery is marked by dashed circle. The locations where bone plugs were removed from the femoral head with respect to anterior and posterior directions and ligamentum teres. All bone plugs were taken as 9mm cylindrical specimens, and for demonstration purposes, they are shown as xxiii elliptical shapes due to perspective and depending on location of sample. The locations from which the bone plugs were removed are demonstrated (a) laterally and (b) medially. The X-ray source applies X-rays towards the detector, and the object that is placed between the source and detector rotates, producing cross-sectional images of the object. The spring was placed on the rod protruding from the base and removed prior to testing when the loading part was placed on the specimen, as shown in this image. Smaller lesions as well as thinned trabeculae, and fractured articular surface are also seen. The error bars represent standard error of mean, and specimen numbers are shown above each column. Most of the samples in this study had lesions that filled 50-70% of the femoral heads. Significant differences were not found between the means of groups (Students t-test)(n=3. The lesions within the femoral head are shown as black, and regions of femoral head where normally dispersed trabeculae xxviii exist are shown in white, allowing for measurement of the volume of the lesions rather than the volume of trabeculae. The * and ** indicate that 7 and 14-day treated samples respectively had significantly greater percent digested collagen when compared to control samples. A polynomial xxx trend-line is fitted, demonstrating a positive trend in publications related to avascular necrosis. It may be referred to with other terms, such as osteonecrosis, ischaemic necrosis and osseous ischemia (Jones, 2001. It commonly occurs in the femoral head of the hip, but can occur in other skeletal sites such as the knee, shoulder, and ankle (Assouline-Dayan et al. In the femoral head, it commonly results in the collapse of the femoral head following a series of pathological events. Following this point, the articular surface becomes arthritic and the patients commonly undergo total hip replacement surgery (Tofferi and Diamond, 2012. The average age of patients in the Chinese population who have undergone total hip replacement due to avascular necrosis has been reported as 50 years old (Lai et al. Avascular necrosis may have a variety of causes associated with it, but the endpoint of the disease always results in necrosis of the bone and collapse of the femoral head. Some of the most common causes of avascular necrosis include trauma, steroid or alcohol abuse as well as some diseases such as sickle cell disease (Lavernia et al. At this stage, a dense band of sclerotic bone, interrupted by focal resorption, forms around the periphery of the lesion at this stage, trying to resorb the Chapter 1 | Page 1 lesion. The necrotic and sclerotic bone is weaker than healthy bone, has a lower modulus and may collapse under the high loads applied in the hip. The articular cartilage would collapse also, leading to arthritis and destruction of the joint, at which point the patient requires total hip replacement surgery (Brown et al. Two factors affect the rate of the collapse of the femoral head: size and position of the lesion as well as the material properties of the dead and remodelling bone. If these factors are to be studied, a laboratory mechanical model of the disease must be developed. The developed model will be advantageous both in a clinical and industrial aspect. It may also help to improve identification of mechanical risk-factors that could help to choose the most effective treatment for a patient. The findings of the study were used to develop an in vitro simulation model of the disease using an animal femoral head. From Chapter 1 | Page 2 an industrial perspective, such a model is beneficial as allows optimisation and validation of new orthopaedic implants aimed at treating the disease. It is a synovial joint: it has a joint cavity, in which joint surfaces are covered with articular cartilage; it is surrounded by a ligamentous capsule and it has a synovial membrane which produces synovial fluid (Byrne et al. It consists of two bony structures, the femoral head which is the proximal part of the femur, and the acetabulum which is part of the pelvis. Figure 2-1 Lateral view of the hip joint with the joint opened showing the main femoral head, acetabulum and the ligaments within the joint. Image from Tank and Gest, (2008, p141)(Reproduced with limited permission from Lippincott Williams & Wilkins) the acetabulum receives its blood supply from three main arteries: the obturator, the superior gluteal and inferior gluteal. The femoral head and neck are mainly supplied by the medial and lateral circumflex femoral arteries. A Chapter 2 | Page 5 small proportion of the blood supply is provided through the foveal artery which enters the femoral head through fossa of the ligamentum teres (Figure 2-2)(Hughes et al. Figure 2-2 Diagram showing cross section through the femur and acetabulum to show the blood supply into the hip joint. In the macro-scale, the femur is composed of a hollow shaft (diaphysis) which transitions through an increasingly dense metaphysis into the dense epiphysis. The metaphysis and epiphysis are a mixture of trabecular and cortical bone: a reflection of the need for these regions to withstand loads in multiple orientations (Figure 2-3)(Clarke, 2008. Chapter 2 | Page 6 Figure 2-3 Image showing cortical bone and cancellous bone in the cross section of the femoral head Image from Martens et al. Trabecular bone is made up of a very porous, honeycomb-like structure of trabeculae, the diameter of the trabecular struts typically ranges from 100 300 m with spaces of 300-1500 m between them (Figure 2-4) (Athanasiou et al. This difference in density alongside the dissimilarity in microstructures of these two bones leads to different mechanical properties (Rho et al. The more dense area on bottom right of the image is cortical bone, and less dense region on top left of the image is trabecular bone. In the micro scale, the primary organic component of the bone consists of crystals, collagens and non-collagenous organic proteins. The bone matrix is collagen type I, which self-assembles into parallel fibrils (Rho et al. The plate shaped Dahllite (or hydroxyapatite) crystals, are the only mineral type present in mature bone (Weiner and Wagner, 1998) and they occur within the discrete spaces in the collagen fibrils in a specific crystalline orientation (Rho et al. In adult human bone, the collagen fibres formed by the assembly of many collagen fibrils are interwoven to form lamellae of 3-7 m thickness (Marotti, 1993; Rho et al. These lamellae stack together to form lamellar bone, which arrange in different formats to form cortical or cancellous bones (Keaveny et al. Chapter 2 | Page 8 In cortical bone, around 3-15 lamellae are arranged in concentric cylinders around a Haversian canal, which is a vascular channel of about 50 m in diameter, containing blood vessel capillaries, nerves and bone cells (Figure 2-5. This then forms the Haversian system or osteon, which is a cylinder of roughly 200-250 m diameter and 1-3mm length, running parallel to the long axis of the bone. In addition to Haversian canals, Volkmanns canals run perpendicular to the long axis of the bone, and provide a radial path for blood flow within the bone (Rho et al. Osteocytes (bone cells) are surrounded by lacunae, which are thin layers of extracellular fluid arranged along the interfaces between lamellae. The osteocytes are connected to each other using processes that extend from them, called canaliculi (Keaveny et al. Figure 2-5 Diagram of a sector of the shaft of a long bone, presenting the types of bones and channels found in bone. The trabeculae are irregular lattices of small rods and plates, in the following basic cellular structures: rod-rod, rod-plate, or plate-plate, varying within species, with the age of the species and the location of the bone in the body (Figure 2-6) (Rho et al. Within each trabeculae, three cell types are found: Osteocytes that maintain the bone matrix, osteoclasts that Chapter 2 | Page 9 degrade regions of existing structure, and osteoblasts that actively build new sections of bone (Seal and Otero, 2001.
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