By O. Raid. Amberton University. 2018.
Following such an injury it is important to consider the possibility of an intraocular foreign body generic sustiva 200mg on line, espe- cially when there is a history of using a hammer and chisel discount 200 mg sustiva fast delivery. A small metallic foreign body lying on the The outcome of a perforating injury is retina generic sustiva 200mg with visa. If the cornea alone is damaged, excel- reous forceps under microscopic control or lent results can be obtained by careful suturing using a magnet. The exact surgical technique is under general anaesthesia using the operating planned beforehand once the foreign body has microscope. Airgun cataract surgery might be needed and deeper pellets cause particularly severe eye injuries and penetration can result in the need for retinal the eye is often lost because of the extensive dis- detachment surgery. Some intraoc- On admission or in the casualty department, ular foreign bodies, such as glass particles or the patient is given tetanus prophylaxis and some alloys, might be tolerated quite well and a both systemic and local antibiotics. If early decision could have to be made as to whether surgery under general anaesthesia is likely to be observation is preferable in the rst instance. When a foreign body is not to be clear that the injury is a serious one, it is better removed immediately, many ophthalmologists to warn the patient at an early stage about the would insert intravitreal antibiotics as a pro- possible risk of losing the sight of the eye or phylactic measure against endophthalmitis. When a foreign body is found lying deeply in the cornea, its removal can result in loss of aqueous and collapse of the anterior chamber. Intraocular Foreign Body It is prudent to arrange that removal should be Metallic foreign bodies tend to enter the eyes of done under full sterile conditions in the operat- those who operate high-speed grinders without ing theatre, where the corneal wound can be goggles or those using a hammer and chisel on sutured if necessary. These injuries might seem slight at rst and sometimes Sympathetic Ophthalmia patients do not attach much importance to them. Any such eye injury with this occupational This rare complication of perforation is more history warrants an X-ray of the eye. The injured eye remains ferrous metals remain in the eye they can cause markedly inamed and the wound might have immediate infection, or at a later date the depo- been cleaned inadequately or too late. Over a sition of ferrous salts, in a process known as period of two weeks to several months or even siderosis. This can eventually lead to blindness years a particular type of inammatory of the eye. Other metals also tend to give reac- response begins in the uvea and subsequently a tions,particularly copper and for this reason the similar reaction occurs in the other eye. The condition does, however, Ocular Trauma 133 respond well to steroid treatment and it is paid when the medial part of the eyelid has been extremely rare. They need to be examined carefully for theatre, the risk of a permanently watering eye signs of uveitis. Contusion of the eyelids, otherwise known as a black eye, is of course a common problem, Injuries to the Eyelids especially on Saturday nights in a general cas- ualty department. Usually, the presence of a Loss or destruction of eyelid tissue should black eye is an indication that the aficted was always be treated as a threat to vision. The upper smart enough to close his eye in time to avoid lid especially is important in this respect. It is unusual to nd damage immediate concern is to ensure that the cornea to the eyes after Saturday night st-ghts,unless is properly covered when the eyelids are closed. Broken beer glasses If more than one-third of the margin of the produce devastating injuries to the eyes as well upper lid is lost, this must be replaced by graft- as to the eyelids. When less than one-third is missing, the gaping wound can usually be closed directly. Up to one-third of the lower lid Injuries to the Orbit can also be closed by direct suturing. When more than this is lost or when it has been trans- Blows on the side of the cheek and across one ferred to the upper lid, a slide of tissue from the or other eye occur in ghts, industrial accidents lateral canthus can be effected, combined if nec- and road trafc accidents. Here the globe One of the most important features of the and contents of the orbit are forced backwards, repair of lid injuries is the method of suturing. An untidy repair can there is mechanical limitation of upward move- result in a permanently watering eye because of ment. This interferes with the the orbital oor, can also be injured, producing proper moistening of the cornea during blink- anaesthesia of the skin of the cheek. Special attention must be surrounding swelling has subsided, the post- erior displacement of the globe becomes obvious and the globe of the eye itself often shows evidence of contusion. A considerable improvement from the functional and cosmetic point of view can be obtained by positioning a plastic or Teon implant in the oor of the orbit after freeing the prolapsed tissue. Fractures of the skull that extend into the orbit can be accompanied by retro-orbital haemor- rhage and proptosis. Cranial nerve palsies affect- ing the ocular movements are also commonly seen in this type of injury and the vision can be affected by optic nerve damage. There is usually severe pain and photophobia so that The eyes might be exposed to a wide range of it might not be possible to open the eyes, electromagnetic radiation from the shorter hence the term snow blindness. The use of wavelength ultraviolet rays through the wave- locally applied steroid and antibiotic drops lengths of visible light to the longer infrared hastens recovery.
Environ- mental assessment is now also recognized as key to planning for the patient s physical and social well-being effective sustiva 200 mg. The pressing challenges of the future include development of better methods for rapidly screening and assessing dietary intakes and incorporating results routinely into computerized databases and other communications to optimize patient care cheap sustiva 200mg with visa. This chapter provides tools for selecting appropriate dietary and nutritional assessment methods for the purpose of evaluating and planning the diets of individuals with the arthritic and other rheumatic diseases discount 200mg sustiva mastercard. Disordered nutritional status is identified by assessing all of these components together. At the initial stage, careful probing of dietary intake and other aspects of nutritional status are helpful in discovering inadequate intake. When combined with anthropometric, biochemical tests, and clinical signs and symptoms, poor nutritional status may be detected earlier and appropriate interventions initiated. The most common anthropometric measurements used for nutritional assessment include height, weight, waist and arm circumferences, and skinfold thickness. Population-based reference standards are available for both healthy adults and children (3,4). Height/Stature Measurement of stature is critical because reported heights from patients are usually grossly overestimated (5). Infants, toddlers, and adults must be able to lay flat to measure recumbent length. When they are unable to do so, special measures must be used that provide an indirect estimate of height. Recumbent length is measured using a tape measure to estimate height for individuals who do not have any deformities or contractures (5). Knee height is measured using knee-height calipers, and tables are available for estimating stature from knee height. Standard equations for age, gender, and race are available to estimate height using this measurement (5,6). Weight and Body Mass Index Weight is another anthropometric measure that is essential in nutritional assessment. Weight must be measured directly because it is usually underestimated when it is self-reported (8). Some people may be misclassified, particularly those who are obese but not particularly large, or those who are heavy from bone and muscle but are not obese. In patients with arthritis, relative immobility and muscle wasting combined with edema may lead to failure to recognize excessive fatness or other changes in body composition that occur with the illness. An obese individual with a recent weight loss may still be overweight but may be at risk for malnutrition and should be monitored. Loss of weight may be caused by wasting, with losses of both fat and lean tissue, and gains in weight are usually caused by changes in fat tissue. However, rapid changes in weight also often occur with alterations in water balance (8). When weight changes are used in conjunction with clinical measures such as presence of edema or ascites and wasting, some estimates of true changes in fat stores can be made. Weight gain of both fat and fluid is also promoted by some medications such as steroids (prednisone) and other drugs (9 11). The weight history is another key component of anthropometric assessment in chronic disease. When weight loss or gain is evident, monitoring should intensify, and causes should be determined and corrected. It is important to determine whether the weight loss or gain was intentional or unintentional because unintentional changes are often due to the result of disease or drug use. Significant weight loss is a loss of 5% of usual weight over a 1 month period or 10% over a 6 month period; severe weight loss is a loss of more than 5% over a 1 month period or more than 10% over a 6 month period (5). Changes in functional status and health outcomes are often present among individuals with severe weight loss (8). These should be documented, as they are important in determining quality of life and care plans. Individuals at a current weight of 85 to 90% of their usual reported body weight are considered to have mild malnutrition (5). Additional measures may be needed for greater accuracy to measure fatness in research studies that require additional precision and accuracy. Changes in weight may reflect an accumulation or depletion of fat stores in the subcutaneous, visceral, and intramuscular body fat compartments, but especially in the subcutaneous fat deposits. Obese, elderly, and physically inactive individuals tend to have a higher proportion of central fat. Waist Circumferences Used To Assess Body Fat Distribution Circumference measurements are often used because they are simple and detect changes in fat distribution that are associated with disease risk. Waist circumference is used to measure excess abdominal adiposity, which is associated with risk for diabetes and metabolic syndrome (5).
Although following uterine prolapse and sporadic rupture of other extravascular erythrocyte destruction is more common major arteries are other causes of acute blood loss generic 200mg sustiva free shipping. Self- in most species sustiva 200 mg discount, cattle have several forms of hemolytic induced trauma or laceration of a prolapsed uterus with anemia caused by intravascular destruction of erythro- subsequent hemorrhage has been observed in dairy cattle sustiva 200mg with mastercard. A very common cause of intravascular hemolysis Manual removal of a corpus luteum through rectal palpa- in calves is water intoxication. Calves watered intermit- tion to induce heat has fortunately fallen out of favor with tently that are then given plentiful supplies of water may bovine practitioners. This procedure occasionally resulted overdrink to the point that severe vasodilation occurs in severe blood loss or exsanguination. Hemoglobinuria and history are Winter dysentery rarely causes severe blood loss from diagnostic. Fever, trembling, hair Chronic infections and neoplasms are most often associ- standing on end, and hemoglobinuria are the clinical ated with inadequate erythrocyte production or nonre- signs in the patient that identify the therapeutic error. Bacillary hemoglobinuria caused by monly associated with acute disease, thrombocytopenia, Clostridium novyi type D (Clostridium hemolyticum) is and blood loss. Hemoglobinuria gener- cause of diffuse neoplasia, nonregenerative anemia ally is observed in those with these diseases. Iron deciency anemia may rarely cause severe weak- Autoimmune hemolytic anemia, as described in other ness in milk-fed calves. Concurrent erythrolysis does not occur naturally in cattle, but the inammatory diseases may alter this typical stress leu- disorder has been observed when cattle were vaccinated kogram. Subsequent passive transfer of maternal an- a normal neutrophil count because of glucocorticoid- tibodies against specic blood types to calves from these induced neutrophilia counterbalancing the expected cattle results in some calves showing isoerythrolysis. Cattle and their leukograms are ex- although several other factors may be involved. A single Determination of when an anemic patient requires injection of 20 mg or more dexamethasone usually re- whole blood transfusion must be made primarily based sults in a stress leukogram characterized by neutrophilia, on the physical examination and secondarily based on lymphopenia, and eosinopenia within 24 hours. In ad- weakness, and other general signs that would indicate dition to altering numbers of neutrophils, corticosteroids the need for a transfusion. Neutrophil function may be impaired during greater than 100 beats/min, respiratory rates of greater the periparturient period and in cattle with retained fetal than 60 breaths/min, obvious mucous membrane pal- membranes. Heart rates that are greater than A degenerative left shift wherein neutropenia coex- 120 beats/min and pounding, respiratory rates over ists with the appearance of band neutrophils is typical of 60 breaths/min, and obvious pallor all dictate a need for cattle with severe acute inammation or endotoxemia. Although the degenerative left shift remains a Cattle are unique in regard to the leukogram and its negative prognostic indicator and a positive indicator of response to various diseases and stresses. Cattle that have a degenerative left shift will may be associated with normal or variable leukograms often have a return to normal neutrophil numbers within that shed little light on which disease the patient has. This time lapse may simply reect the time bovine patients in an academic referral hospital, we nd necessary for resolution of a severe infection. If the infec- that the majority of these leukograms, regardless of the tion requires more than 1 week for resolution, rebound cause of illness, have been within normal limits. Stress and glucocorticoids reliably alter the leukogram Certainly some cattle with chronic infections have neu- to create neutrophilia, lymphopenia, and eosinopenia. It is rare to see an adult cow with more than consistent with stress or exogenous corticosteroid ad- 18,000 to 20,000 neutrophils unless exogenous cortico- ministration. Although monocytosis is not a consis- potential for greater morbidity and mortality to be tent nding in the peripheral blood of ruminants associated with concurrent infectious diseases such as infected with Listeria monocytogenes, as in humans and Salmonellosis or Pasteurellosis should not be over- rodents so infected, some cattle with listeriosis do have looked diagnostically during a herd outbreak of enteric a classical monocytosis. Frequently it is difcult to know Bovine Leukocyte Adhesion Deciency whether the lymphopenia is associated directly with the (Bovine Granulocytopathy Syndrome) disease or simply represents stress associated with a dis- ease. Although eosinopenia should accompany lympho- Etiology penia when the cause is stress or corticosteroid adminis- A fatal syndrome consisting of poor growth, chronic or tration, eosinophil counts have limited value in this recurrent infections, and persistent extreme neutrophilia regard. Absolute lymphocytosis that is transient is rare in has been observed in Holstein calves since the late dairy cattle and when present usually is associated with 1970s. Affected calves had persistent neutrophil counts a neutrophilia in patients recovering from acute infec- exceeding 30,000/ l, and some had counts exceeding tion. Lymphocyte counts may range from 30,000 to humans brought about further suspicion of an inher- 100,000 in such cases, and immature lymphocytes and ited disorder in leukemoid calves. Recessive homozygotes are expected as a result of parasite loads and other con- affected, and heterozygote carriers have intermediate ditions. Denitive diagnosis alongside identication migration into tissue sites of inammation. Infections thought to be clinically minor re- Treatment spond poorly or not at all to appropriate therapy. Recur- Treatment is only palliative, and most affected calves die rence of signs and multiple problems are typical. To date those that survive to develop chronic disease associated most affected calves studied have had greater than with poor growth are suspected to have the disease. Al- cause variable expression of the glycoprotein deciency though myelogenous leukemia is a consideration, is possible in homozygote recessives and in heterozy- neutrophil function tests differentiate these diseases gotes, it also is possible that mild forms of disease and because neutrophils in myelogenous leukemic patients prolonged survival occur. Affected calves must recessives bleed excessively or repeatedly following inju- be differentiated from calves with chronic abscessation ries or routine surgical procedures such as castration or of the thorax or abdomen and calves persistently in- dehorning. Thrombocytopenia is the most common cause of abnormal coagulation in dairy cattle.
The challenge facing many healthcare providers and payment agencies today is to develop systems which will provide a framework that carries the trust of patients and families sustiva 200mg without a prescription, or which will enable fair decision making in healthcare and resource allo- cation now and sustainably into the future generic sustiva 200mg with visa. Patients and other key stake- holders are actively engaging to try and bring this about discount 200mg sustiva overnight delivery, but the shape of a sustainable healthcare future for rare disease patients is not yet clear anywhere across the globe. So, we have a potent mix of elements, all of which have come together to raise the prole of rare diseases and the patients of families aected by them. View Online x Foreword Rising to the challenge is a critical priority for all involved if patients are to see their expectations for eective therapies realised, scientists to generate the insights that will create clinical service improvements for doctors and the possibility of a return on investment for industry. This book is a timely contri- bution to the literature in this fast-changing eld. Council Recommendations on action in the eld of rare diseases, European Commission, Luxembourg, 2009. Preface As a term, rare diseases covers an enormous and hugely diverse range of diseases, disorders and conditions. In a similar way, the term orphan drug is also subject to some confusion and misconception within the drug discovery community. When we decided to undertake the editing of this book, we had a number of aims in mind. First and foremost, we wished to produce a broadly accessible book that would set out clearly what is meant by the terms rare diseases and orphan drugs. In so doing, we wanted to highlight the critical role that disease advocacy has played and continues to play in building drug discovery eorts in this area of biomedical science, and discuss some of the unique challenges that this eld presents. Secondly, we wished to present the range of innovative science taking place to create therapies directed at rare diseases through a combination of review and case studies, highlighting the breadth of drug modalities that research in the eld has produced. Research and clinical development in this area has oen been both path-nding and innovative, and in many cases this has been pioneered by small biotech- nology companies, or in some cases small parts of much larger companies. As such, undertaking to write a book chapter from within a small group is a signicant commitment, and we are most grateful to the chapter authors for contributing their time to the writing of this book. Finally, in what is an expanding and evolving area of drug discovery research, we wanted to provide some perspective on where the eld may evolve to in the near future. We found the planning and editing of this book hugely informative and enjoyable, and armed with the knowledge that this book provides, we hope the reader will also share our enthusiasm for this important area of drug discovery. David C Pryde and Michael J Palmer C ontents What are Rare Diseases and Orphan Drugs? Orphan designation is reserved for medicines that will treat diseases with prevalence below the threshold set for rare diseases, and may have additional factors such as the lack of availability of alternative treatments. It has been estimated that there are more than 7000 rare diseases known,7 but only around 5% of these have therapies available8,9 and the unmet medical need across the breadth of rare diseases remains high. Fiy percent of all rare diseases aect children and 85% are classied as serious or life-threatening. Some rare diseases may only aect literally a handful of individuals around the world, while others may aect hundreds of thousands of patients. In the developed world alone, rare diseases are thought to aect some 6% of the population, with estimates of more than 25 million North Americans and more than 30 million Europeans aected by a rare disease. Across the thousands of highly heterogeneous rare diseases that are known, there is no unifying classication that links them all, with the exception that they aect a relatively small number of people. Designing and conducting clinical trials is constrained, as there is usually little understanding or information about the natural progression of the disease to inform end point selection. These challenges increase the uncertainty that a research programme will lead to a new therapy, resulting in historically less investment into these therapies. An interesting example was raised by Tambuyzer,8 who highlighted that for Gaucher disease patients in Germany, only around 5% of all possible patients are being treated despite treatments being available for more than 15 years. This example also highlights the diculties of obtaining accurate prevalence data for rare diseases, and how variable dierent sources of these data are. Certain rare diseases are also known to have very dierent prevalence rates in View Online Denitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs 5 dierent populations and geographical regions, for example the glycogen storage disease Pompe disease, which can range in prevalence from 1 in 200 000 in Caucasians to as much as 1 in 14 000 in African Americans. While provisions vary from country to country, the key incentives created under various orphan drug regulations generally include marketing exclusivity, which prevents similars from competing with the original approved product during the exclusive period but is in no way intended to create a monopoly if clinical dierentiation can be demonstrated. For example, several small molecule treatments (imatinib, dasatinib and nilotinib) have been approved in parallel for chronic myeloid leukaemia. There is also support for sponsors taking their orphan drug through the regulatory approval process in the form of fee waivers, additional scientic advice and expedited review. These incentives have successfully increased drug development activities within the orphan drug space. Orphan drugs can oer faster development timelines, lower R&D costs, lower marketing costs and lower risk of generic competition. An analysis has suggested that orphan drug approval rates were greater than those of mainstream drugs, and the proportion of overall new drug approvals in recent years that are orphan drugs has steadily grown. The Orphan Drug Act sought to encourage development of drugs, diagnostics and vaccines intended to improve the treatment options for rare diseases by designating them as an orphan drug.