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By Y. Marcus. School of the Art Institute of Chicago.

Authorship order 10 mg singulair asthma symptoms when running, titles buy singulair 5mg amex asthma phenotypes defined, and dates (content created or published discount 4mg singulair overnight delivery asthma treatment clinic, revised buy 5mg singulair with visa asthma definition nih, and cited if on the Internet) are still crucial but what else is essential? In addition, is it possible to apply the same order and punctuation to all references? Print materials are still used and need consideration; however, electronic resources prevail and citing these materials needs to be simplified. Backus / Joyce Backus Associate Director for Library Operations National Library of Medicine Foreword xv Foreword The Internet has fundamentally changed the publishing model that authors, editors and publishers have followed for centuries. Information that took months or years to publish, edit and distribute in print is now produced and available to the public worldwide on an accelerated schedule. Despite changes brought by technology, the need to accurately cite the source of information for scholarly publication remains. And, while the need to cite remains, the challenges of collecting and reporting accurate, lasting citation information have increased tremendously. Electronic publishing creates new issues of impermanence that paper did not present. With this publication, Citing Medicine, the National Library of Medicine strives to provide those charged with capturing an accurate scholarly citation with a guide to do so in this new era of electronic information, both permanent and ephemeral. These same rules and examples can be used for magazines and other types of periodicals. Journal Articles Sample Citation and Introduction Citation Rules with Examples Examples B. Parts of Journal Articles Sample Citation and Introduction Citation Rules with Examples Examples C. Sample Citation and Introduction to Citing Journal Articles The general format for a reference to a journal article, including punctuation: Examples of Citations to Journal Articles 4 Citing Medicine By tradition, the rules for formatting references to journal articles permit greater abbreviation compared to books: Journal references omit information on place of publication and publisher, whereas book references carry these details. This brevity in citing journal articles stems from the need to conserve space in printed bibliographies and the early databases. Following are some important points concerning citing journal articles: Cite the journal name that was used at the time of publication. Too many variations in type styles may actually make the reference harder to read. Running headers or footers may not carry the official title of a journal and date and issue information may be missing from these locations. Citation Rules with Examples for Journal Articles Components/elements are listed in the order they should appear in a reference. An R after the component name means that it is required in the citation; an O after the name means it is optional. Author (R) | Author Affiliation (O) | Article Title (R) | Article Type (O) | Journal Title (R) | Edition (R) | Type of Medium (R) | Date of Publication (R) | Supplement/Part/Special Number to a Date (R) | Volume Number (R) | Supplement/Part/Special Number to a Volume (R) | Issue Number (R) | Supplement/Part/Special Number to an Issue (R) | Location (Pagination) (R) | Physical Description (O) | Language (R) | Notes (O) Author for Journal Articles (required) General Rules for Author List names in the order they appear in the text Enter surname (family or last name) first for each author Journals 5 Capitalize surnames and enter spaces within surnames as they appear in the document cited on the assumption that the author approved the form used. This rule ignores some conventions used in non-English languages to simplify rules for English-language publications. International Union of Pure and Applied Chemistry, Organic and Biomolecular Chemistry Division. American College of Surgeons, Committee on Trauma, Ad Hoc Subcommittee on Outcomes, Working Group. American Academy of Pediatrics, Committee on Pediatric Emergency Medicine; American College of Emergency Physicians, Pediatric Committee. When possible follow a non-English name with a translation, placed in square brackets. Follow the same rules used for author names, but end the list of names with a comma and the specific role, that is, editor or translator. New accreditation product approved for systems under the ambulatory and home care programs. Separate the surname from the given name or initials by a comma; follow initials with a period; separate successive names by a semicolon. Pharmacological treatment of congestive heart failure in Canada: a description of care in five provinces. Journal article with organization as author, with subsidiary part of the organization included 6. Journal article with multiple organizations as author, with subsidiary part of the organization included 8. Journal article with a personal author and more than one organization as author 11. Journal article authors with compound last names (give as found in the article) 14. Journal article author names with particles, prepostitions, prefixes (give as found in the article) 15. If you abbreviate a word in one reference, abbreviate the same word in all references. Journals 13 Place the affiliation in parentheses Box 13 Names for cities and countries not in English Use the English form for names of cities and countries when possible. Moskva becomes Moscow Wien becomes Vienna Italia becomes Italy Espana becomes Spain Examples for Author Affiliation 17. Box 16 Translated article titles ending in punctuation other than a period Most article titles end in a period. When a translation of an article title is provided, place it in square brackets, with a closing period outside the right bracket. Metodo para el estudio de la funcion pulmonar en los laringectomizados [Method for the study of pulmonary function in laryngectomized patients]. Place the title in square brackets, with a closing period outside the right bracket. Influence of seed extract of Syzygium Cumini (Jamun) on mice exposed to different doses of -radiation. Influence of seed extract of Syzygium Cumini (Jamun) on mice exposed to different doses of gamma-radiation. Box 18 Article titles with headers Journal articles sometimes contain a header (such as news, case report, or clinical study) at the top of the page to indicate a section of the issue. Do not include a header as part of the article title unless the table of contents for the journal issue indicates that it is. Box 19 No article title can be found Occasionally an article does not appear to have any title; the article simply begins with the text. In this circumstance, create a title from the first few words of the text and place it in square brackets. Journal article in a language other than English with optional original language title included Journals 17 20. Journal article title with special characters Article Type for Journal Articles (optional) General Rules for Article Type An article type alerts the user that the reference is to an abstract of an article or a letter to the editor, not a full article. Increased cardiac Connexin45 results in uncoupling and spontaneous ventricular arrhythmias in mice [abstract]. Box 21 Article titles not in English Most journal article titles end in a period. When a translation of a journal article title is used as the title, place it in square brackets. Place (letter) or (abstract) within the square brackets and end title information with a period.

Amiodarone buy singulair 4mg free shipping asthma definition to word, an important therapeutic agent in the treatment of many life-threatening arrhythmias order singulair 10mg online asthma definition british thoracic society, has produced an adverse pulmonary reaction in about 6% of patients 5mg singulair otc asthma treatment cannabis, with 5% to 10% of these reactions being fatal ( 166) singulair 4mg with mastercard asthma definition 2015. Symptoms rarely develop in a patient receiving less than 400 mg/day for less than 2 months. The clinical presentation is usually subacute with initial symptoms of nonproductive cough, dyspnea, and occasionally low-grade fever. Pulmonary function studies demonstrate a restrictive pattern with a diffusion defect. Histologic findings include the intraalveolar accumulation of foamy macrophages, alveolar septal thickening, and occasional diffuse alveolar damage (167). It is unclear whether these changes cause interstitial pneumonitis, as these findings are seen in most patients receiving this drug without any adverse pulmonary reactions. Although an immunologic mechanism has been suggested, the role of hypersensitivity in amiodarone-induced pneumonitis remains speculative ( 168). Most patients recover completely after cessation of therapy, although the addition of corticosteroids may be required. Further, when the drug is absolutely required to control a potentially fatal cardiac arrhythmia, patients may be able to continue treatment at the lowest dose possible when corticosteroids are given concomitantly (169). Gold-induced pneumonitis is subacute in onset, occurring after a mean duration of therapy of 15 weeks and a mean cumulative dose of 582 mg ( 170). Exertional dyspnea is the predominant symptom, although a nonproductive cough and fever may be present. Radiographic findings include interstitial or alveolar infiltrates, whereas pulmonary function testing reveals findings compatible with a restrictive lung disorder. The condition is usually reversible after discontinuation of the gold injections, but corticosteroids may be required to reverse the process. Although this pulmonary reaction is rare, it must not be confused with rheumatoid lung disease. Drug-induced chronic fibrotic reactions are probably nonimmunologic in nature, but their exact mechanism is unknown. It is essential to recognize this complication because such reactions may be fatal and could mimic other diseases, such as opportunistic infections. The chest radiograph reveals an interstitial or intraalveolar pattern, especially at the lung bases. A decline in carbon monoxide diffusing capacity may even precede chest radiograph changes. Mononuclear cell infiltration of the interstitium may be seen early, followed by interstitial and alveolar fibrosis, which may progress to honeycombing. Even those who respond to treatment may be left with clinically significant pulmonary function abnormalities. Although an immunologic mechanism has been suspected in some cases ( 172), it is now generally believed that these drugs induce the formation of toxic oxygen radicals that produce lung injury. Noncardiogenic Pulmonary Edema Another acute pulmonary reaction without eosinophilia is drug-induced noncardiogenic pulmonary edema. Salicylate-induced noncardiogenic pulmonary edema may occur when the blood salicylate level is over 40 mg/dL ( 176). Hematologic Manifestations Many instances of drug-induced thrombocytopenia and hemolytic anemia have been unequivocally shown by in vitro methods to be mediated by immunologic mechanisms. The onset is usually abrupt, and recovery is expected within 1 to 2 weeks after drug withdrawal. Eosinophilia Eosinophilia may be present as the sole manifestation of drug hypersensitivity ( 179). Its recognition is useful because it may give early warning of hypersensitivity reactions that could produce permanent tissue damage or even death. However, most would agree that eosinophilia alone is not sufficient reason to discontinue treatment. There does not appear to be a common chemical or pharmacologic feature of these agents to account for the development of eosinophilia. Drug-induced eosinophilia does not appear to progress to a chronic eosinophilia or hypereosinophilic syndrome. However, in the face of a rising eosinophil count, discontinuing the drug may prevent further problems. Thrombocytopenia Thrombocytopenia is a well-recognized complication of drug therapy. The usual clinical manifestations are widespread petechiae and ecchymoses and occasionally gastrointestinal bleeding, hemoptysis, hematuria, and vaginal bleeding. Bone marrow examination shows normal or increased numbers of normal-appearing megakaryocytes. With the exception of gold-induced immune thrombocytopenia, which may continue for months because of the persistence of the antigen in the reticuloendothelial system, prompt recovery within 2 weeks is expected upon withdrawal of the drug (181). Readministration of the drug, even in minute doses, may produce an abrupt recrudescence of severe thrombocytopenia, often within a few hours. The mechanism of drug-induced immune thrombocytopenia is thought to be the innocent bystander type. Shulman suggested the formation of an immunogenic drug plasma protein complex to which antibodies are formed; this antibody drug complex then reacts with the platelet (the innocent bystander), thereby initiating complement activation with subsequent platelet destruction ( 182). Some studies indicate that quinidine antibodies react with a platelet membrane glycoprotein in association with the drug (183). Because heparin has had more widespread clinical use, the incidence of heparin-induced thrombocytopenia is about 5% ( 184). A heparin-dependent IgG antibody has been demonstrated in the serum of these patients. A low-molecular-weight heparinoid can be substituted for heparin in patients who previously developed heparin-induced thrombocytopenia ( 185). The diagnosis is often presumptive because the platelet count usually returns to normal within 2 weeks (longer if the drug is slowly excreted) after the drug is discontinued. Many in vitro tests are available at some centers to demonstrate drug-related platelet antibodies. A test dose of the offending drug is probably the most reliable means of diagnosis, but this involves significant risk and is seldom justified. Treatment involves stopping the suspected drug and observing the patient carefully over the next few weeks. Corticosteroids do not shorten the duration of thrombocytopenia but may hasten recovery because of their capillary protective effect. Platelet transfusions should not be given because transfused platelets are destroyed rapidly and may produce additional symptoms. Hemolytic Anemia Drug-induced immune hemolytic anemia may develop through three mechanisms: (a) immune complex type; (b) hapten or drug adsorption type; and (c) autoimmune induction (84). Another mechanism involves nonimmunologic adsorption of protein to the red blood cell membrane, which results in a positive Coombs test but seldom causes a hemolytic anemia. Hemolytic anemia after drug administration accounts for about 16% to 18% of acquired hemolytic anemias. The immune complex mechanism accounts for most cases of drug-induced immune hemolysis. Of note is that many of these drugs have also been associated with immune complex-mediated thrombocytopenia. The serum antidrug antibody is often IgM, and the direct Coombs test is usually positive. Penicillin is the prototype of a drug that induces a hemolytic anemia by the hapten or drug absorption mechanism (187). Penicillin normally binds to proteins on the red blood cell membrane, and among patients who develop antibodies to the drug hapten on the red blood cell, a hemolytic anemia may occur.

Years of basic research diseases arise at the level of cells buy 10mg singulair visa asthma vs allergies, then guring out investigating circuits of cellular communication led ways to treat them cheap singulair 10 mg free shipping asthma treatment ultra. Scores of drugs purchase singulair 5 mg on line asthma bronchitis in babies, some to treat scientists to tailor-make a new kind of cancer medicine cheap 4mg singulair with mastercard asthma treatment emedicine. The Food and Drug Administration described Gleevec s approval as a testament to the groundbreaking scientic research taking place Doctors use the drug in labs throughout America. Each of these methods Finding new medicines and cost-effective ways to bypasses the intestinal tract and can increase the manufacture them is only half the battle. An enor amount of drug getting to the desired site of mous challenge for pharmacologists is guring out action in the body. Slow, steady drug delivery how to get drugs to the right place, a task known directly to the bloodstream without stopping as drug delivery. Unfortunately, this rarely happens with the typical Hormones such as testosterone, progesterone, methods of delivering drugs: swallowing and and estrogen are available as skin patches. When swallowed, many medicines made forms of medicines enter the blood via a mesh of protein are never absorbed into the blood work of small arteries, veins, and capillaries in the stream because they are quickly chewed up by skin. Researchers also have developed skin patches enzymes as they pass through the digestive system. Some of these If the drug does get to the blood from the intes include Duragesic (a prescription-only pain tines, it falls prey to liver enzymes. For doctors medicine), Transderm Scop (a motion-sickness prescribing such drugs, this rst-pass effect (see drug), and Transderm Nitro (a blood vessel- page 7) means that several doses of an oral drug widening drug used to treat chest pain associated are needed before enough makes it to the blood. Despite their advantages, Drug injections also cause problems, because they however, skin patches have a signicant drawback. Both methods of administration also result in Inhaling drugs through the nose or mouth is uctuating levels of the drug in the blood, which another way to rapidly deliver drugs and bypass is inefcient and can be dangerous. Pharmacologists can work around therapy for years, and doctors prescribe nasal the rst-pass effect by delivering medicines via the steroid drugs for allergy and sinus problems. If can be inhaled by people with diabetes who rely clinical trials with inhaled insulin prove that it is on insulin to control their blood sugar daily. This safe and effective, then this therapy could make still-experimental technology stems from novel life much easier for people with diabetes. Less than a decade ago, scientists identied tiny molecular labels called phosphate groups. Cobb of the University of Texas the proteins a code, instructing the cell to do some Southwestern Medical Center at Dallas are studying thing, such as divide or grow. Medicines By Design I Molecules to Medicines 43 by learning how to hijack molecular transporters to shuttle drugs into cells. Gordon Amidon, a pharmaceutical chemist at the University of Michigan-Ann Arbor, has been studying one particular transporter in mucosal membranes lining the digestive tract. The challenge is a chemistry wants to extend this list by synthesizing hundreds problem most drugs are water-soluble, but of different molecules and testing them for their membranes are oily. Membranes are genomics, and bioinformatics have sped the search usually constructed to permit the entry of only for molecules that Amidon and other researchers small nutrients and hormones, often through can test. Many pharmacologists are working hard to devise ways to work not against, but with nature, 44 National Institute of General Medical Sciences Scientists are also trying to slip molecules Act Like a Membrane through membranes by cloaking them in disguise. Researchers know that high concentrations of Steven Regen of Lehigh University in Bethlehem, chemotherapy drugs will kill every single cancer Pennsylvania, has manufactured miniature cell growing in a lab dish, but getting enough of chemical umbrellas that close around and shield these powerful drugs to a tumor in the body with a molecule when it encounters a fatty membrane out killing too many healthy cells along the way and then spread open in the watery environment has been exceedingly difcult. So far, Regen has only used test mole drugs can do more harm than good by severely cules, not actual drugs, but he has succeeded in sickening a patient during treatment. The ability to do this particles called liposomes to package and deliver in humans could be a crucial step in successfully drugs to tumors. Liposomes are oily, microscopic delivering therapeutic molecules to cells via capsules that can be lled with biological cargo, gene therapy. They are very, very small only Anesthesia Dissected Scientists who study anesthetic medicines little physical resemblance to each other can all have a daunting task for the most part, produce anesthesia. This makes it difcult to track they are shooting in the dark when down causes and effects. Researchers do Sloan-Kettering Institute for Cancer Research in New know that anesthetics share one common York City claried how certain types of these mys ingredient: Nearly all of them somehow terious medicines work. Veselis and his coworkers target membranes, the oily wrappings measured electrical activity in the brains of healthy surrounding cells. However, despite the volunteers receiving anesthetics while they listened fact that anesthesia is a routine part of to different sounds. To determine how sedated the surgery, exactly how anesthetic medicines people were, the researchers measured reaction work in the body has remained a mystery for more time to the sounds the people heard. It s an important problem, since memory effects, they quizzed the volunteers at the anesthetics have multiple effects on key body func end of the study about word lists they had heard tions, including critical processes such as breathing. Veselis experiments Scientists dene anesthesia as a state in which show that the anesthetics they studied affect sepa no movement occurs in response to what should rate brain areas to produce the two different effects be painful. The ndings may help loses a pain response, the anesthesiologist can t doctors give anesthetic medicines more effectively tell what is happening inside the person s organs and safely and prevent reactions with other drugs and cells. Researchers have known about liposomes for many years, but getting them to the right place in the body hasn t been easy. Once in the blood stream, these foreign particles are immediately shipped to the liver and spleen, where they are destroyed. Materials engineer David Needham of Duke University in Durham, North Carolina, is investi gating the physics and chemistry of liposomes to better understand how the liposomes and their cancer-ghting cargo can travel through the body. David Needham designed liposomes resembling tiny molecular soccer Needham worked for 10 years to create a special balls made from two different oils that wrap around a drug. The end result is a tiny dogs revealed that, when heated, the drug-laden molecular soccer ball made from two different capsules ooded tumors with a chemotherapy oils that wrap around a drug. Researchers ture, the liposomes are solid and they stay solid at hope to soon begin the rst stage of human studies body temperature, so they can be injected into the testing the heat-triggered liposome treatment in bloodstream. The results their drug cargo into a tumor when heat is applied of these and later clinical trials will determine to the cancerous tissue. Heat is known to perturb whether liposome therapy can be a useful weapon tumors, making the blood vessels surrounding for treating breast and prostate cancer and other cancer cells extra-leaky. Needham and Duke oncologist Mark Dewhirst teamed up to do animal studies with the heat- activated liposomes. Experiments in mice and 46 National Institute of General Medical Sciences The G Switch (a) (b) (c) Hormone Plasma Membrane Active Cell Enzyme Receptor Inactive Cell Enzyme Inactive G Protein Active G Protein Cell Response G proteins act like relay batons to pass Imagine yourself sitting on a cell, looking messages from circulating hormones outward to the bloodstream rushing by. You don t realize it, but your own (c) The G protein passes the hormone s message to the cell by switching on body sent this substance a hormone called a cell enzyme (purple) that triggers epinephrine to protect you, telling you to a response. Your body reacts, whipping up the familiar, spine-tingling, ght-or-ight response that gears you to respond quickly to potentially threatening situations such as this one. Getting into a cell is a challenge, a strictly guarded process kept in control by a protective gate called the plasma membrane. Figuring out how molecular triggers like epinephrine communicate important messages to the inner parts of cells earned two scientists the Nobel Prize in physiology or medicine in 1994. Getting a cellular message across the membrane is called signal transduction, and it the world have focused on these signaling occurs in three steps. Research on G proteins and on all epinephrine) encounters the outside of a cell aspects of cell signaling has prospered, and as Got It? In the fall of 2000, Gilman embarked on transducer, or switch molecule, passes the a groundbreaking effort to begin to untangle What is a liposome? The group has a big dream: to understand One of the Nobel Prize winners, pharma everything there is to know about signaling cologist Alfred G. According to Gilman, Alliance Describe how Texas Southwestern Medical Center at Dallas, researchers focus lots of attention on G G proteins work. As with any switch, G proteins must be revolution in biomedical turned on only when needed, then shut off.

Are you concerned about failing (remember there are no failures quality 4mg singulair asthma symptoms no wheezing, only smokers who have not yet quit) or are you experiencing cessation anxiety? Did you quit or significantly reduce your tobacco consumption for a period of time during those attempts? Depending on your results singulair 5 mg low cost asthma kid, it may make sense to re-challenge your tobacco addiction with the same medication (assuming of course it did not cause any significant problems) or to add an additional rescue medication cheap singulair 5 mg otc asthma treatment usmle. If you reduced your cigarette consumption significantly (for example from 20 or 25 cigarettes per day down to 15 or less) or even if you were totally abstinent but you experienced craving and tobacco withdrawal symptoms buy singulair 10mg without a prescription asthma treatment 1960s, it may be helpful to consider multiple tobacco treatment medications that combine continuous medications with rescue medications. When considering multiple medications, it is important to add only one medication at a time. While it is always recommend that every smoker consult with his or her physician, healthcare provider and a tobacco treatment specialist, we realize that this is not always possible. The simplest treatment plan for many smokers may to rely only on over-the-counter medications. Self-Help for Tobacco Dependent Fire Fighters and other First-Responders either gum or lozenge; four milligram nicotine polacrilex gum or lozenges can address further reductions in cigarettes per day toward total cessation as well as breakthrough cravings. This is often helpful with smokers who enjoy (or would miss) the hand- to-mouth ritual of smoking or benefit from the oral stimulation or the cigarette handling aspects of smoking. Collaborating with a licensed health care provider is required because the nicotine inhaler is a prescription medicine. Forming a partnership with a concerned healthcare provider, knowledgeable in the stressful demands regularly placed on fire fighters and other first responders can have many other beneficial effects both in designing an effective cessation program, preventing or treating any adverse effects that may have occurred from prior tobacco use and ultimately in improving cardiopulmonary fitness. A number of well-designed research studies have shown that high-dose multiple nicotine patches can increase quit rates. For those with intermittent rather than constant cravings, rescue medications are a better option. For less urgent cravings, we recommend the inhaler, gum or lozenge depending on patient preferences. While multiple patches are safe and almost universally produce no difficulties or side effects (other than occasional and mild skin irritation), these combination treatment plans are complicated and require the assistance of trained healthcare professionals. Federal and State Programs The National Network of Tobacco Cessation Quitlines is a state/federal partnership that provides tobacco users in every state with access to the tools and resources they need to quit smoking; ensuring the highest level of assistance to tobacco users who want to quit. This program provides information on the health risks of smoking and the benefits of quitting as well as tips on how friends and family can help a smoker quit. Self-Help for Tobacco Dependent Fire Fighters and other First-Responders 345 cessation. If you are a first responder who has been on the job for more than a few years, you have probably tried to force an entry or knock down a fire that was difficult and didn t go as planned. That said, nothing should be more important to you, your family, and your friends than eliminating tobacco from your life. Information on the GlaxoSmithKline Consumer Healthcare program can be forund at: www. Information regarding the Nicoderm nicotine transdermal patches can be found at: www. Information regarding the Nicotine Inhaler and Nicotine Nasal Spray can be found at: www. Information regarding the Association for Treatment of Tobacco Use and Dependence Programs can be found at: www. Respiratory failure occurs when the respiratory system cannot adequately maintain gas exchange, most commonly because of a failure to provide and maintain adequate ventilation (the movement of air into and out of the lungs). The respiratory muscles, depending on their strength and endurance, enlarge (and sometimes contract) the volume of the chest (the chest bellows ). Normally, the load faced by the chest bellows is so low that ventilation occurs effortlessly. Stiff lungs or increase airway resistance results in an increased workload and depending on the magnitude of the load and other factors, the chest bellows may fail resulting in respiratory failure. Normally room air is 21% oxygen and the partial pressure of oxygen in arterial blood (PaO2) at sea level is ~90mmHg. For practical purposes, hypoxemic respiratory failure is considered to be present if PaO2 cannot be corrected to >50mmHg on a nontoxic level of supplemental oxygen (<50%). Hypercapnic respiratory failure is characterized by elevated levels of carbon dioxide in arterial blood. It is often accompanied by hypoxemia, though typically not as severely as is the case in hypoxemic respiratory failure. Types of Respiratory Failure Hypoxemic Hypercapnic Characterized by Hypoxemia (arbitrarily Characterized by Hypercapnia (>46mmHg) and <50mmHg) hypoxemia (usually) Typical Causes. The two types of respiratory failure also differ as to the conditions or diseases that typically produce them. Hypercapnic Respiratory Failure The common causes of hypercapnic failure are diseases of any of the components of the respiratory system leading up to the lungs: the brainstem, the respiratory muscles, the chest wall, or the airways (see Table 4-5. In hypercapnic respiratory failure, relatively mild hypoxemia occurs, primarily for the same reason that hypercapnia occurs: the level of ventilation is not adequate to refresh the oxygen within the lungs, just as it is not adequate to eliminate a normal amount of carbon dioxide. Hypercapnic respiratory failure results when the ventilatory pump is inadequate to meet the metabolic and ventilatory demands because of reduced central drive (brain), impaired respiratory muscle function (nerves or muscles), excessive respiratory workload, or some combination of these three factors2 (Table 4-5. Of the three potential causes of hypercapnic respiratory failure, the least common is impaired central drive. Unfortunately, symptoms correlate poorly with the severity of respiratory failure. Cyanosis of the mucous membranes and nail beds is an unreliable sign of hypoxemia. They allow for precise assessment of the adequacy of oxygenation, along with determination of acid/base status and of the adequacy of ventilation. Drawbacks are the painful nature of the necessary arterial puncture, the small risk of arterial injury, and the fact that they provide only a snapshot look at the status of respiratory function. Thus, although bicarbonate measurements without blood gases do not rule in or rule out respiratory failure, a normal venous bicarbonate can be reassuring, especially when the pulse oximeter reading is normal and the patient s mental status is well preserved. Pulse oximetry is a noninvasive technique to allow measurement and monitoring of blood oxygen (SpO2). A patient s fingertip is transilluminated by two wavelengths of light, typically 660nm (red) and approximately 900 nm (infrared), in rapid alternation. Changes in absorbance of each of the two wavelengths, caused by pulsing arterial blood is measured, and the ratio of the two is used to calculate percent oxygen saturation. It can quickly rule in or rule out most cases of hypoxic respiratory failure and those cases of hypercapnic respiratory failure where the oxygen level is also low. Pulmonary function testing is usually valuable in the evaluation of the underlying pulmonary condition(s) that cause or contribute to respiratory failure. Severe reductions suggest pulmonary parenchymal disease (pneumonia, pulmonary fibrosis, etc. Thus, central drive impairment due to drug overdose can often by treated by specific antidotes (e. Adjunctive treatments, especially the administration of supplemental oxygen, can be beneficial, while awaiting improvement in the underlying disease or in the situations in which the underlying disease cannot be corrected. The FiO2 actually delivered by nasal cannulae is quite variable and not reliably predictable by the liter per minute flow rate, in part because of variable amounts of mouthbreathing, but more importantly because inspiratory flow rates and consequent entrainment of room air are tremendously variable. The Venti-mask uses a jet of oxygen at high flow rate (5-15 liters per minute) through a delivery device shaped to entrain predictable amounts of room air (using the Venturi principle), so that FiO2 can be adjusted relatively precisely. The Venti-mask results in more predictable FiO2 than does nasal cannula, but it still suffers from entrainment of variable amounts of room air around the edges of the mask and through the holes that are built into the mask to allow egress of excess flow.

Another issue that must be solved is forms a glassy material with much better thermal the optimal chemical form of a radionuclide result- resistance than elemental 124The used for production ing from its separation from the target matrix: it of 124I; enriched 76SeO is also more suitable for pro- 2 must be compatible with further production of a duction of 76Br than elemental 76Se and Cu As for 3 radiopharmaceutical best 10mg singulair asthma history. Finally generic singulair 4mg amex asthmatic bronchitis jokes, presence of chemi- the production of the same 76Br via 3He activation cal impurities in the target matrix and chemicals of monoisotopic arsenic) singulair 4 mg online asthma definition value. A higher validated and each batch of target material tested beam energy loss requires a thicker target layer buy 5mg singulair mastercard asthma definition yeah, i. Due to the routine more material, ofen expensive, and more efcient character of radionuclide production for nuclear cooling due to higher heat dissipation in the tar- medicine, economic aspects play an important role get layer. Finally use of a wider energy range may in the choice for a complex solution of a target sys- increase the production of radionuclidic impurities. The time of bombardment (irradiation time) For a given radionuclide and given production is also strongly related to production costs, since route there are four parameters available to increase cyclotron operation is rather expensive. Example of a multipurpose internal slanted solid target with extremely low angle suitable for production of e. For radionuclides with a half-life signifcantly longer than the irradiation time, the produced activity is almost directly proportional to the irradiation time. Maximisation of the fnal variable, the beam current, is limited by the accelerator performance and by the targetry. The most widespread are: are directly cooled from the back during process- According to their location with respect to the ing, only the activated layer is etched and used for cyclotron (external or internal). Linear accelera- separation of a radionuclide, and the target can then tors always use external targets. Recently, an interesting varia- examples of internal slanted targets are production tion on liquid targets have attracted the attention systems for 67Ga, 111In, 201Tl or 211At. Tese were success- Modern compact cyclotrons accelerate protons fully used for the pilot production of e. The shape of the target modify the beam parameters), or located at the end body is very ofen conic in order to compensate for of a beam line whose elements allow for shaping the the gradual increase of the beam diameter due to beam. The external location enables installation of beam straggling in the gas flling, while minimis- all kinds of target systems, i. The phase of the target matrix strongly infu- Operation and processing of both liquid and gas ences the target s characteristics. Solid targets are targets can be easily automated, including recycling preferably metallic layers with the best possible of enriched flling. Disassembled external gas target system flled with highly enriched 82Kr for production of 81Rb (top) and its position on an external beam line of the cyclotron U-120M (bottom); a similar target flled with 124Xe is used for production of 123I (Nuclear Physics impurities are opened. This cooling efciency and the necessary amount of tar- allows the system to range further from the valley get matrix. Slanted targets (also called tangential of beta-stability thereby forming more exotic radi- or grazing angle targets) are a good choice for solid onuclides. Small angles and higher product yield is accompanied by a reduc- project the beam diameter on a larger target sur- tion in selectivity. In the extreme case of very high face, thereby reducing the heat power per unit of projectile energy (GeV protons) very thick targets area and the target thickness required for optimal (tens of g/cm2) can be irradiated and via fragmen- beam energy loss. Both factors improve cooling tation, spallation and fssion reactions virtually all and increase the maximum applicable beam cur- isotopes from hydrogen up to the target element are rent, especially for target matrices of low thermal produced simultaneously. Cyclotron production of 99mTc wou ld to combine mass separation with chemical separa- require external slanted, high-current targetry that tion to be able to extract single radionuclides. This means that only a few reaction channels that potentially contribute to formation of signifcant radionuclidic 3. The clinical restrictions requiring longer hospitalisation and isola- value and cost-efectiveness of myocardial perfusion tion afer 131I treatment. Deaths from Side efects are mild and reversible and quality-of-life prostate cancer are ofen due to bone disease and of the patients is improved [Kha11]. The defnition of symptomatic Lymphoma is a blood cancer afecting the white skeletal event covers very serious events such as blood cells. Tese patients with advanced follicular lymphoma that were events are decisive for the quality of life of a cancer either treated by an induction treatment (chemother- patient. The time to the a comprehensive comparison provided some caution frst symptomatic skeletal event was 15. It is expected that these sumption may difer signifcantly before, during and modifcations could further improve the outcome. Making an assessment of since data from the previous Dose Datamed 1 project possible future trends in radionuclide needs requires (1998-2002) show that Belgium had similar or higher frst of all a comprehensive view of the past and pre- per capita use of nuclear medicine procedures than sent use. Technetium-99m itself issue: if more generators become available more 82Rb is used in more than 80% of diagnostic nuclear will be used (see section 3. Tese applications represent Terapy procedures are still largely dominated approximately 30 million examinations worldwide by 131I for thyroid treatment. Terefore, a weekly 99Mo production of temporal evolution of the use of therapy isotope, about 10. Zevalin hours) and its daughter 99mTc (6 hours), a continu- (90Y-ibritumomab) and 177Lu-rituximab are used for ous supply of 99Mo/99mTc generators to hospitals or treatment of lymphomas. Worldwide radiopharmaceuticals they can be applied in more 99Mo production is presently being converted from hospitals and more countries. Teir priority is to achieve optimal coordi- reactor vs accelerator nation of their operating periods to ensure a secure supply of 99Mo worldwide. However, the current Today the worldwide supply of 99Mo relies on a limited number of research reactors and processing * It has to be stressed that it is indeed a pure policy issue and not a real proliferation risk since one 99Mo production target contains facilities. Its production is essential for provid- just 4 grams of 235U while many thousands of such targets would ing nuclear medicine with 99mTc in the form of be needed to make a nuclear bomb. The pathway of the produced 99Mo/99mTc from the irradiation facilities to the users. Argentina, Brazil and the Republic of Korea have Since 2008 several severe shortages have been also projects for the construction of new reactors experienced in the supply of 99Mo and 99mTc and new 99Mo processing facilities which would be [Pon10]. Europe is planning to develop replacement irra- Production of 99Mo in the 100Mo(n,2n) reaction. Non-fssion routes have the advantage of radioactive Tese have to be kept critical for a couple of days, waste reduction since mainly or only 99Mo is pro- then the produced high specifc activity 99Mo is duced but no fssion products. Tus a change the end of irradiation (proton energy 24 MeV, beam of generator technology or a switch to direct 99mTc current 500 A, irradiation time 6 h). Assuming production is easier to implement since it afects another 6 hours for target processing, packing, qual- only the radiopharmacies but not directly the end ity control and transport, one could provide up to users. To tics: one or more daily shipments of 99mTc instead cover domestic needs the Canadian Government of a once weekly delivery of a generator. Hence, in has funded eforts to establish the feasibility of particular for remotely located users with fewer accelerator production of 99Mo and 99mTc respec- patients per day, there is a risk that transport costs tively. Light Source, is working on the photonuclear reac- 99mTc is in the middle of the chart of nuclides, tion 100Mo(,n)99Mo driven by 40 kW electron surrounded by stable isotopes. However, and new cyclotrons plus the related target and Tc only a small fraction of these reactions can be seri- extraction technology for direct 99mTc production via the 100Mo(p,2n)99mTc reaction. To ensure truly 30 MeV) for 99mTc production is still under debate irreversible disarmament 20,000 warheads, each [Leb12]. The 99mTc yield increases with energy but containing on average 25 kg of highly enriched the specifc activity of 99mTc decreases and might uranium, were dismantled and the nuclear con- become too low for the labelling of certain kits tents mixed with natural uranium to produce [Qai14]. As for cyclotron production, the 99mTc 99 used for Mo production targets and several will be extracted from this low specifc activity 99Mo hundred kilograms for fuel elements of high with automated two-column selectivity inversion fux reactors producing medical isotopes. A longer-term project aims at also using disarmament helps medical isotope production the photonuclear reaction 100Mo(,n) 99Mo. Before a new method can contribute to industrial radionu- clide production it has to be demonstrated that its product satisfes the established quality criteria and ofen the new method has to be included in the drug master fles of the respective radiopharmaceuticals.

The ultimate goal of studying the human microbiome is to better understand the impact of microbial variation across individuals and populations and to use this information to target the human microbiome with antibiotics discount 5 mg singulair amex asthma symptoms list, probiotics singulair 5 mg line asthmatic bronchitis inhalers, and prebiotics as therapies for specific disorders 10mg singulair asthma symptoms gerd. While this field is in its infancy buy discount singulair 5 mg line asthma treatment nih, growing knowledge of the human microbiome and its function will enable disease classification and medicine to encompass both humans and their resident microbes. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 22 individuals. Lifestyle interventions alone are ineffective in these individuals at reducing the likelihood of early-onset cardiovascular disease (Huijgen et al. Consequently, the ability to identify the patients that carry the non-functional receptor makes it possible to proceed directly to the use of statin drugs at an early age, rather than first attempting to control cholesterol with diet and exercise. There is strong evidence that the early use of statin drugs in these individuals can provide a therapeutic benefit. These mutations predispose to cancer, particularly breast and ovarian cancer (King et al. Women who carry these mutations can reduce their risk of death from cancer through increased cancer screening or through prophylactic surgeries to remove their breasts or ovaries (Roukos and Briasoulis 2007); until these mutations were identified it was not possible to determine who carried the mutations or to take proactive steps to manage risk. In addition, epidemiological studies and other data have raised the possibility that H. The human genome and microbiome projects are only two examples of emerging biological information that has the potential to inform health care. It is similarly likely that other molecular data (such as epigenetic or metabolomic data), information on the patient s history of exposure to environmental agents, and psychosocial or behavioral information will all need to be incorporated into a Knowledge Network and New Taxonomy that would enhance the diagnosis and treatment of disease. Traditionally, lung cancers have been divided into two main types based on the tumors histological appearance: small- cell lung cancer and non-small-cell lung cancer. Drivers are mutations in genes that contribute to inappropriate cellular proliferation. If the inappropriate function of the mutant protein is shut down, dramatic anti-tumor effects can ensue. These receptors were known to send signals that promote cellular proliferation and survival, and increased signaling was thought to contribute to some cancers. However, the dramatic tumor shrinkage in some patients was enough for Food and Drug Administration approval in 2003, even though the molecular basis for the response was then unknown. Without the ability to recognize the responding patients as a biologically distinct subset, these agents were tried unsuccessfully on a broad range of lung-cancer patients, doing nothing for most patients other than increasing costs and side effects. In retrospect, some clinical trials with these agents probably failed because the actual responders represented too small a proportion of the patients in the trials (Pao and Miller 2005). This made it possible to predict which patients would respond to the therapy and to administer the therapy only to this subset of patients. This led to the design of much more effective clinical trials as well as reduced treatment costs and increased treatment effectiveness. Since then, many studies have further divided lung cancers into subsets that can be defined by driver mutations. Not all of these driver mutations can currently be targeted with drugs and cancer cells are quick to develop resistance to targeted drugs even when they are available. Nonetheless, this new information makes it possible to develop new targeted therapies that can extend and improve the quality of life for cancer patients. The traditional characterization of lung cancers based on histology has been replaced over the past 20 years by classifications based on driver mutations. However, the sophistication of this system for molecular classification has improved with the advent of more genetic information and the identification of many more driver mutations. Similar approaches could improve the diagnosis, classification, and treatment of many other diseases. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 25 The Urgent Need to Better Understand Phenotype-Genotype Correlations While dramatic progress in understanding the relationship between molecular features and phenotype is being made, there is an urgent need to understand these links better and to develop strategies to deal with their implications for athe individual patient. Of these, 1,167 were judged by the database s curators as likely to be clinically significant, while most of the rest were categorized as of unknown clinical significance. Among the mutations that are believed to be clinically significant, some are thought to confer a higher risk of cancer than others (Gayther et al. To what extent does their mutation increase their risks of breast and ovarian cancer and how do these risks change with age? All of these real-life decisions carry heavy personal consequences as well as implications for health care costs. These treatment decisions do not need to be made based on such fragmentary information. It would be possible to assess the extent to which prophylactic surgeries reduced risk. It would be possible to assess the effectiveness of increased cancer screening, the best ways to screen these patients, and the complications that arise from the inevitable false-positive results that come from increased screening. Efforts along these lines have so far been based on modest numbers of patients or cohorts that are not fully representative of the larger population because it has not been practical to integrate genetic information, treatment decisions, and outcomes data for large numbers of unselected patients. However, recent advances in genomic and information technologies now make it possible to systematically address these issues by integrating large data sets that already exist. Even if only a subset of this variation has significant implications for disease risk or treatment response we have the potential to improve the detection, diagnosis, and treatment of disease dramatically by large-scale efforts to assess phenotype-genotype correlations. By integrating patient genotype with health information and outcomes data a New Taxonomy could identify many new genetic variants with significant implications for health care. There is every reason to expect that the genetic influences on most common diseases will be complex. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 26 advances in our ability to understand epigenetic, environmental, microbial, and social contributions to disease risk and progression. Under these circumstances, there is an obvious need to categorize diseases with finer granularity, greater reference to the underlying biology, and in the context of a dynamic Knowledge Network that has the capacity to integrate the new information on many levels. Unraveling these diverse influences on human diseases will be a major scientific challenge of the 21st century. Prospective studies are particularly valuable because the occurrence or treatment of disease may alter the levels of the biochemical factors so that inference based on levels measured in a series of already diagnosed cases may be biased. These biomarkers can be combined with information on lifestyle risk factors such as smoking and body mass index, and measurements that may also change after diagnosis such as blood pressure, to create a risk score such as the Framingham Risk Score, that is widely used to predict the 10-year risk of heart attack (Anderson et al. Larger prospective cohort studies such as the Nurses Health Study (Missmer et al. For less common diseases, Consortia are again needed as no single study will have enough cases. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 27 consent mechanisms could generate similar large longitudinal sample sets and data through the provision of regular medical care, rather than considering these as research studies external to the health systems. Patients in these groups could then be recruited to provide samples or have their discarded clinical samples analyzed for research. In either case, the result would be a rich clinical characterization of patients at low cost and with linkages to corresponding biological samples that can be used for molecular studies. Research questions could be addressed faster and at lower cost as compared to the current standard practice of designing large, labor-intensive prospective studies. Such a scan may show that the original association is either an epiphenomenon of another pathology or part of a broader pathotype (Loscalzo et al. This approach provides an opportunity to explore this broader range of pathological mechanisms across a variety of disease types, which is not possible in single phenotype studies. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 28 relationships between genotype and disease is limited by the granularity and precision of the current taxonomic system for disease.

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