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Her blood B12 order 800 mg zovirax overnight delivery, since the part of her stomach responsible sample is run in the analyzer generic zovirax 200 mg visa, and her platelet for production of intrinsic factor has been count is reported to be at a dangerously low removed generic 200 mg zovirax. A 55-year-old woman undergoes an open (E) Neurologic deficits are not seen with this cholecystectomy. She is admitted for postopera- kind of anemia tive observation and started on subcutaneous heparin treatment to prevent formation of deep 9. A 31-year-old pregnant woman presents to venous thrombosis, a major risk factor for pul- her obstetrician for a routine visit. Which of the following is eral questions for her doctor, one of which has true regarding the mechanism of action of to do with the supplements that she was advised heparin? She stated she (A) Heparin increases activity of antithrombin leads a very busy lifestyle and sometimes forgets (B) Serine proteases of the clotting cascade are to take all the pills she is supposed to take. She deactivated wants to know the purpose of folic acid supple- (C) Heparin catalyzes clotting in vitro mentation in pregnancy. A 63-year-old man has a history of atrial fi- (C) It aids in bone growth of the maturing fetus brillation. To reduce his risk of a stroke, his phy- (D) It stimulates myelopoiesis of erythroid pro- sician had given him an anticoagulant genitor cells medication. This agent, while being of tremen- (E) It reduces blood viscosity during pregnancy dous benefit to this patient, comes with its asso- ciated risks, such as spontaneous hemorrhage. A 29-year-old African-American man To monitor the appropriateness of the current presents to the emergency department with a dosage of the medication, the patient comes in chief complaint of severe pain in his arms and frequently to have the laboratory check his pro- legs. Which medication must this knows that what he is experiencing is a sickle patient be taking? You are very excited, (D) Coumarin because you, in fact, had just reviewed your (E) Protamine pharmacology. A 75-year-old man is brought to the emer- (B) Coumarin gency department after being found on the floor (C) Clopidogrel of his room. His wife tells you that his medical (D) Alteplase history includes two prior strokes, for which he (E) Dextran is now taking a ‘‘small pill that works on plate- lets. After 6–7 days of parenteral feeding, vitamin K stores are depleted and clotting factor biosynthesis is impaired. Ticlopidine is an anticoagulant, and urokinase is a thrombolytic; both would be contraindicated in this circumstance. Digoxin is a cardiac glycoside that can improve contractility in impaired myocardium but would not be used in this circumstance. Prophylactic antiplatelet therapy should be instituted while the diagnosis is confirmed. While increased bleeding tendency, dietary deficiency, and malabsorption are all true causes of iron deficiency anemia, they are not the culprits during pregnancy. Iron storage is regulated at the level of absorption, and very little of it is lost from the body. Participation in the mitochondrial reaction that produces succinyl-CoA refers to the mechanism of action of one of the natural cobalamins, deoxyadenosylcobalamin. Sideroblastic anemia may develop in alcoholics and patients undergoing anti- tuberculin therapy. Vitamin B12 and folic acid are used for megaloblastic anemias caused by depletion of the vitamin. Loss of vitamin B12 is a very slow process, with hepatic stores being sufficient for up to 5 years. Folic acid supplementation has been shown to decrease the incidence of neu- ral tube defects. Increasing the oxygen-carrying capacity of the blood refers to a possible role of iron supplements. Stimulating myelopoiesis of ery- throid progenitor cells refers to the mechanism of action of erythropoietin. Finally, reduction of blood viscosity during pregnancy refers to pentoxifylline; however, this medication is not recom- mended during pregnancy. Hydroxyurea increases the production of fetal hemoglobin and has been shown to be effective in reducing painful episodes of sickle crisis. Acetaminophen is unlikely to be helpful in this patient’s situation, as this agent is useful for mild-to-moderate pain. Oprelvekin has been shown to reduce the need for platelet transfusions follow- ing myelosuppressive chemotherapy. Leucovorin is used in patients undergoing treatment with methotrexate, to prevent some of its side effects. Heparin releases lipoprotein lipase from vascular beds, which accelerates clearing of lipoproteins from plasma. The clotting factor is inactivated, which releases heparin and allows it to be recycled. Coumarin is commonly used in patients with atrial fibrillation for prevention of thromboembolic events, such as stroke. Prothrombin times should be frequently monitored in patients taking coumarin, as bleeding is a common adverse effect.

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These molecular markers give valuable additional information for tumor diagnosis/prognosis and will be important for the development of person- alized therapy of cancer generic zovirax 800 mg line. An example of the application of microarrays for gene expression is bladder cancer purchase zovirax 200mg, a common malignant disease characterized by frequent recurrences order zovirax 800 mg visa. The stage of disease at diagnosis and the presence of surrounding carcinoma in situ are important in determining the disease course of an affected individual. Clinically relevant subclasses of bladder carcinoma have been identified using expression microarray analysis of well-characterized bladder tumors. Gene biomarker panels provide new predictive information on disease progression in tumors compared with conventional staging. Furthermore, gene expression profiles characterizing each stage and subtype identify their biological properties, producing new potential targets for therapy. Global gene expression analysis using microarrays has been used to characterize the molecular profile of breast tumors. Universal Free E-Book Store Impact of Molecular Diagnostics on the Management of Cancer 205 These results suggest that gene expression profiling of breast biopsies may become a valuable method for adequately characterizing and choosing treatment modality for patients with breast cancer. Gene expression microarray technology is helpful in all phases of the discovery, development and subsequent use of new cancer therapeutics, e. It can be used to identify molecular biomarkers for proof of concept studies, pharmacodynamic endpoints and prog- nostic markers for predicting outcome and patient selection. Catalog of Cancer Genes for Personalized Therapy Personalized medicine for cancer will eventually require a comprehensive catalog of cancer genes to enable physicians to select the best combination therapy for each patient based on the cellular pathways disrupted in their tumor and the specific nature of the disruptions. Such a catalog will also guide therapeutic development by identifying druggable targets. Although a few cancer genes are mutated in a high proportion of tumors of a given type (>20 %), most are mutated at intermediate frequencies (2–20 %). Using the MutSig tool, which weighs mutational burden as compared to the background mutation rate, mutational clustering, and enrichment of mutations in conserved regions, the researchers searched for candidate cancer genes. By combining the 22 MutSig lists, the researchers developed Cancer5000 set of 254 genes. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. Many new candidate cancer genes remain to be discovered beyond those in the current Cancer5000 set. Researchers estimate that near-saturation may be achieved with 600–5,000 samples per tumor type, depending on background mutation frequency. A comprehensive cancer catalog, would not only guide personalized cancer treatment, but also improve our under- standing of the mechanisms at play in cancer as well as spur the development of new therapies. IsoFlux System (Fluxion Biosciences) utilizes a unique microfluidic design to provide auto- mated cell introduction, trapping, sealing, whole-cell formation and recording pro- tocols. The focus is on breast and lung cancers with the goal of subtyping different forms of the disease and developing treatments personalized to each individual patient. Detection of Loss of Heterozygosity Many cancers are characterized by chromosomal aberrations that may be predictive of disease outcome. Rather than covering the entire genome, the microarray focuses on suspect regions of chromosomes for signs of deleted genetic material known to play a role in the cancer. Identifying the correct risk level allows doctors to treat aggressive cancers appropriately, while not subjecting children with low-risk cancer to overtreatment. It is a non-invasive, highly- sensitive, real-time “liquid biopsy” for screening, prognosis, prediction, and moni- toring of cancer. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcino- matosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumors successfully managed by locoregional treatment with surgery and/or irradia- tion are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squa- mous cell carcinoma of cervical nodes, or any other single metastatic site. Diagnostics for Detection of Minimal Residual Disease In the pre-molecular diagnostic era, hematologists used the microscope to identify a complete remission of leukemia after treatment with chemotherapy. In a hemato- logic complete remission, it is known that a large portion of the leukemic cells remain out of sight. There is a progressive reduction of the leukemic mass that exists below Universal Free E-Book Store 208 10 Personalized Therapy of Cancer the level of cytogenetic visibility, a decrease that is still ongoing in many patients 15 months after attainment of a complete cytogenetic remission with imatinib treat- ment. Moreover, patients who attained such a molecularly defined minimal tumor burden had a higher rate of progression-free survival than those who did not. There is evidence that drugs that inhibit one of these pathways in such tumors could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumor cells and have fewer side effects (Helleday et al.

Display and Storage In a typical nuclear medicine study buy 400mg zovirax mastercard, data are collected normally for preset counts (e buy cheap zovirax 400mg online. Until the mid- 90s discount zovirax 200 mg online, image data were captured on x-ray film or Polaroid film or stored on magnetic tapes, laser disks, and the like. Digital Cameras It is seen from the above description that the X- and Y-pulses are obtained in analog form and are projected on different display and recording systems. Such analog processing inherently includes instability in pulse formation and results in image nonlinearity and nonuniformity. To correct for these effects and also for the manipulation of data at a later time, analog data are digitized to be stored in a matrix map in a computer. The digitized data are later retrieved for further processing to display on video monitors. Each signal is then normalized by dividing it with the sum of all digital signals arising from the same scintillation event. To determine the loca- tion of each signal Zi, a weighting factor is calculated from the inverse of the uncertainties of X and Y positions, i. The location (X, Y) of the scintillation event is then cal- culated by using the appropriate values of locations and weighting factors in the reference tables in the memory. The digitized Zi(X, Y) is stored in the X, Y location of the image matrix, if the pulse discrimination does not reject the signal. Gamma Cameras cameras provide excellent intrinsic linearity and hence superior spatial resolution in image formation. Solid-State Digital Cameras The Digirad Corporation has made commercially available several gamma cameras using solid-state detectors. The detectors are fabricated in modules made of 128 3-mm × 3-mm detector elements. Each head is comprised of 32 modules consisting of a total of 4096 elements, resulting in a detector area of 8in. No X-, Y-positioning circuit is used, because each CsI(Tl)/silicon diode element functions as an individual detection system, independent of other elements, and each event of photon interaction in the crystal is posi- tioned on the image matrix corresponding to the location of the element (Early, 2005). This provides an excellent spatial resolution and quality of the images in the energy range of 60–300keV. Appropriate collimators are required for imaging different organs and for photons of different energies. These para- meters include spatial resolution, sensitivity, uniformity, and contrast, and they are described here in detail. A brief description of the quality control tests for gamma cameras is also included. Spatial Resolution The spatial resolution of a gamma camera is a measure of the ability of the device to faithfully reproduce the image of an object, thus clearly depicting the variations in the distribution of radioactivity in the object (Erickson, 1984). The spatial resolution of a gamma camera is empirically defined as the minimum distance between two points in an image that can be detected by the system. The overall spatial resolution (Ro) of a gamma camera com- prises three components, namely, intrinsic resolution (Ri) of the detection system, collimator resolution (Rg), and scatter resolution (Rs), and is given by R R R R (10. Intrinsic Resolution Intrinsic resolution, Ri, is the component of spatial resolution contributed by the detector and associated electronics, and is a measure of how well an imaging device can localize an event on the image. Intrinsic resolution arises primarily from the statistical fluctuations in pulse formation that have been discussed in the section entitled Gamma Ray Spectrometry in Chapter 8. Intrinsic resolution improves with higher g-ray energy and deteriorates with lower energy because greater statistical fluctuations occur in the production of light photons by lower energy photons and vice versa. For 99m example, the 140-keV photons of Tc produce almost twice as many light 201 photons in the detector as the 69- to 80-keV photons of Tl and thus result in better intrinsic resolution. However, there is little improvement in intrin- sic resolution with photon energy above 250keV because of multiple scat- tering of photons within the detector that can result in photoelectric absorption (see below). Multiple Compton scattering of a g-ray photon followed by absorption of all scattered photons in the detector causes uncertainty in the X, Y loca- tion of the original g-ray interaction and makes the intrinsic resolution, and hence spatial resolution, worse. This effect is worse with thicker detectors and high-energy photons (>250keV) because of the increased chances of multiple scattering. Collimator Resolution Collimator resolution, also termed the geometric resolution (Rg), constitutes the major part of the overall spatial resolution and primarily arises from the collimator design. As already mentioned in Chapter 9, there are four major col- limators: parallel-hole, pinhole, converging, and diverging. The different parameters of a typical parallel-hole collimator are shown in Figure 10. The spatial resolution for this collimator is given by the geo- metric radius of acceptance, Rg: dte b c Rg = (10. The te is empirically given by t = t − 2m−1, where m is the linear attenuation coefficient of the photons in e 120 10. A parallel-hole collimator with thickness t, hole diameter d, septal thick- ness a, and source-to-collimator distance b. The collimator is attached to a detector whose midplane is at a distance c from the back surface of the collimator.

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Although it is an encouraging step buy zovirax 800 mg with visa, it remains to be seen if it will facilitate the introduction of person- alized medicine and add to the advances already made in the industrial sector cheap zovirax 400mg on-line. Compared to previous personalized bills purchase 200 mg zovirax overnight delivery, including that introduced by Barack Obama in 2006, this bill was more emphatic with an aim to stimulate and accelerate the research and development of products used in personalized medicine and to move these diagnostic and treatment modalities from the laboratory into clinical practice. The legislation also addresses several issues that have arisen with the increased prevalence of genetic testing, including coverage and reimburse- ment of personalized medicine products, and oversight of genetic tests (including direct-to-consumer marketing). The full 300-page report, Personalized Health Care: Pioneers, Partnerships, Progress is available on line at: http://www. In a prologue to the report, meant as a note for the next government, it is explained that personaliz- ing healthcare “is not a niche concern. With cost-cutting in the current financial crisis, it is not certain if any expensive innovations will be covered under Medicaid. There is a need for answers to the questions: • What is the best pain management regimen for disabling arthritis in an elderly African-American woman with heart disease? Unfortunately, the answer to these types of comparative, patient-centered questions in health care is often, “We don’t really know. Physicians and other clinicians see patients every day with common ailments, and they sometimes are unsure of the best treatment because limited or no evidence com- paring treatment options for the condition exists. As a result, patients seen by differ- ent clinicians may get different treatments and unknowingly be receiving less effective care. Patients and their caregivers search in vain on the Internet or elsewhere for evidence to help guide their decisions. They often fail to find this information either because it does not exist or because it has never been collected and synthesized to inform patients and/or their caregivers in patient-friendly language. When they do find information, it may be informed by marketing objectives, not the best evidence. Agency for Healthcare Research and Quality The American Recovery and Reinvestment Act of 2009 provided $1. The projects entailed a range of approaches, including prospective studies that explore the outcomes of pharmacogenetic testing in guiding selection of therapeutic interventions, evaluation of new imaging technologies to diagnose or monitor treat- ments, and prospective and longitudinal cohort studies of effectiveness and com- parative effectiveness of diagnostics, devices, and drugs. These reports are used for informing and developing coverage decisions, quality measures, educational mate- rials and tools, guidelines, and research agendas. Comparative Effectiveness Research Due to numerous advances in biomedical science, clinicians and patients often have a plethora of choices when making decisions about diagnosis, treatment, and pre- vention, but it is frequently unclear which therapeutic choice works best for whom, when, and in what circumstances. The purpose of this research is to improve health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circum- stances. Defined interventions compared may include medications, proce- dures, medical and assistive devices and technologies, diagnostic testing, behavioral change, and delivery system strategies. This research necessitates the development, expansion, and use of a variety of data sources and methods to assess comparative effectiveness and actively disseminate the results. It also can inform the health choices of those Americans who cannot or choose not to access the health care system. Clinicians and patients need to know not only that a treatment works on average but also which interventions work best for specific types of patients (e. Policy makers and public health professionals need to know what approaches work to address the prevention needs of those Americans who do not access health care. This information is essential to translating new discoveries into better health outcomes for Americans, accelerating the application of beneficial innovations, and delivering the right treatment to the right patient at the right time. Patients increasingly and appropriately want to take responsibility for their care. Therefore healthcare providers have a responsibility to provide comparative infor- mation to enable informed decision-making. This patient-centered, pragmatic, “real world” research is a fundamental requirement for improving care for all Americans. Comparative effectiveness differs from efficacy research because it is ultimately applicable to real-world needs and decisions faced by patients, clinicians, and other decision makers. The results of such studies are therefore not necessarily gener- alizable to any given patient or situation. But what patients and clinicians often need to know in practice is which treatment is the best choice for a particular patient. Comparative effectiveness has even been called patient-centered health research or patient- centered outcomes research to illustrate its focus on patient needs. The project aims to evaluate genetic tests and other genomic applications currently in transition from research to clinical use. Of the three recommendations, the one investigating gene expression profiling in breast cancer is the furthest along. There is limited evidence of analytic validity, limited evidence of clinical validity but no direct evidence, i. In spite of these concerns, there is a positive balance with potential benefits versus potential harms. Although there was no evidence to sug- gest that genomic tests for ovarian cancer have adverse effects beyond those com- mon to other ovarian cancer tests, i. This work will help accelerate the achievement of the 2010 predictions of routine genetic testing, personalized medicine and improved quality of patient care.