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Case reports are often not well described and critical clinical information is frequently lacking [7] cheap 10 mg slimex otc. A recent study found that reports of drug-induced liver diseases often did not provide the data needed to determine the causes of suspected adverse effects [7] buy cheapest slimex and slimex. Although a case report has been published discount slimex uk, it does not prove that the drug is hepatotoxic order slimex 15 mg without prescription. In LiverTox® there is data on almost all medications marketed in the United States, both on those who have been reported to cause liver injury and those without reports of liver injury. Although in LiverTox® a thorough literature search has been undertaken and is provided, no attempt has been made to judge the quality of the published reports or the causality of the suspected liver injury reported. In a recently published paper, drugs in LiverTox® were classified into categories, using all reports in this website [9]. In this critical analysis, many of the published reports did not stand up to critical review and currently there is no convincing evidence for some drugs with reported hepatotoxicity to be hepatotoxic [9]. Although certain drugs have a distinct phenotype such as isoniazid, which generally leads to a hepatocellular pattern or chlorpromazine cholestatic liver damage, many drugs can lead to both hepatocellular and cholestatic injury. Listing all types of patterns that have been reported for all these drugs is unfortunately not possible in this paper. Categories of Hepatotoxicity In the creation of LiverTox, drugs were arbitrarily divided into four different categories of likelihood for causing liver injury based on reports in the published literature [8]. Category A with >50 published reports, B with >12 but less than 50, C with >4 but less than 12, and D with one to three cases. In the Hepatology paper, drugs were categorized based on these numbers and another category, T, was added for agents leading to hepatotoxicity mainly in higher-than-therapeutic doses [9]. The analysis was based mainly on published case reports, but case series were used if a formal causality assessment had been undertaken. In the analysis of the hepatotoxicity of drugs found in LiverTox, fewer drugs than expected had documented hepatotoxicity. Among 671 drugs available for analysis, 353 (53%) had published convincing case reports of hepatotoxicity. Thus, overall, 47% of the drugs listed in LiverTox did not have evidence of hepatotoxicity. This is at odds with product labeling which very frequently lists liver injury as adverse reaction to drugs [3]. It has to be taken into consideration that 116/863 (13%) of marketed agents had be excluded from the analysis. New drugs approved within the last five years were not included as most instances of hepatotoxicity appear in the post-marketing phase [11]. Metals (iron, nickel, arsenic), illegal substances (cocaine, opium, heroin), and infrequently used and/or not available (not marketed currently) drugs were also excluded [9]. Herbal and dietary supplements listed in LiverTox were not included in the category analysis. Among the 671 drugs available for analysis, the proportions of the drugs in the different categories were: A, 48 (14%); B, 76 (22%); C, 96 (27%); and D, 126 (36%). In general, drugs in categories A and B were more likely than those in C and D to have been marketed for a long time, and both were more likely to have at least one fatal case of liver injury and reported cases of positive rechallenge. However, in categories C and D with one to 12 cases reported, it is still not clear whether these agents are really hepatoxic drugs. Category A Although drugs in this category (n = 48) were supposed to have >50 case reports of liver injury associated with the use of these drugs, 81% of the drugs had >100 cases reported. In Table 1, the category A drugs are illustrated with the indication and/or class of drug. Treatment with these drugs should motivate physicians to guide patients about potential symptoms of liver injury when taking these drugs and about prompt discontinuation if these symptoms occur. All except one entity (estrogens-progestins) or 98% had at least one convincing case that was associated with fatal outcome. All of these drugs except telithromycin had been approved for marketing for more than 15 years and 63% for more than 35 years [9]. The most common types of drugs were antimicrobials among 33% of the drugs, followed by drugs acting on the central nervous system (12. Although antimicrobials were the most common agents among drugs, antimicrobials were also the most common agents in categories B (30%), C (19%) and D (27%). There is unfortunately not enough room to discuss many of these well-documented hepatotoxic agents. As mentioned in the abstract, azathioprine and infliximab have in one study been found to be associated with the highest risk of liver injury [9]. Both hepatocellular and cholestatic injury has been described due to azathioprine [8,9]. Despite the common problem of hepatotoxicity with azathioprine, there is a lack of studies with a significant number of well-characterized patients with this type of liver injury. Drugs that, according to analysis of data in LiverTox [8], have been associated with more than 100 cases of drug-induced liver injury. This seems particularly true for drugs with reports of documented rechallenge, which had been reported in at least one case in 38% of the drugs [9]. In comparison with category A drugs, which almost exclusively had been associated with fatality, approximately 50% of category B drugs had been associated with a fatal outcome. Thus, in drugs with less frequent reporting of liver injury in category B, only 38% had rechallenge reported vs. Drugs in category B (>12 and >40 cases) that, according to analysis of data in LiverTox [8], have been associated with >30 published case reports of drug induced liver injury. Categories C, D and E Overall, 222/353 (63%) of drugs in LiverTox® with hepatotoxicity fall into categories C and D. Compared with category D, with only one to three cases reported, category C (<12 and >4 case reports) drugs were more likely to have rechallenge reports, with 26% vs. A positive rechallenge is usually defined with biochemical criteria, showing recurrence of liver test abnormalities upon readministration of the drug, due to either intentional or inadvertent re-exposure [4,5]. This is generally considered to be the gold standard of the diagnosis of drug-induced liver injury. A documented positive rechallenge provides more evidence of the hepatotoxicity of a Int. Given the frequency of case reports with drugs in categories A and B, there seems little doubt that drugs in these categories can lead to hepatotoxicity and little need to do a strict causality assessment of reports with these drugs. However, in category C, consisting of 4–11 case reports, the hepatotoxicity of some drugs can be put into question. Thus, it can be concluded that these drugs do not have a well-documented hepatotoxicity, although liver injury with their use cannot be excluded. The poorly documented exclusion of competing causes, as well as the use of other concomitant drugs, made a causality assessment difficult. It is very important that observations of hepatotoxicity of new drugs should lead to well-documented case reports with detailed clinical and biochemical information. Table 3 illustrates the five most common drugs associated with liver injury in at least three prospective studies. In India, anti-tuberculous drugs (58%), anti-epileptics (11%), olanzapine (5%), and dapsone (5%) were the most common causes [16]. The 10 most frequently implicated drugs were: amoxicillin-clavulanate, flucloxacillin, erythromycin, diclofenac, sulfamethoxazole/Trimethoprim, isoniazid, disulfiram, Ibuprofen and flutamide [12–14,21]. Drugs with an intermediate risk were amoxicillin-clavulanic acid and cimetidine, with a risk of one per 10 per 100,000 users [24]. The limitations of this study were the retrospective design with a lack of complete data regarding diagnostic testing and a lack of data on over-the-counter drugs and herbal agents [24]. Amoxicillin-clavulanate-induced liver injury was found in one of 2350 outpatient users, which was higher among those who were hospitalized already, one of 729. This might be due to a detection bias, with more routine testing of the liver in the hospital, but it cannot be excluded that sicker patients are more susceptible to liver injury from this drug. The incidence rates were higher than previously reported, with the highest being one of 133 users for azathioprine and one of 148 for infliximab.

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The term “asthma” is now used to refer to a set of “signs and symptoms” including reversible airway narrowing (“wheezing”) order generic slimex, airway inflammation and remodeling order generic slimex on line, and airway hyper-reactivity generic slimex 15 mg with visa. These various “signs and symptoms” likely reflect distinct etiologies in different patients cheap slimex 10mg overnight delivery. Many subjects with asthma have an allergic component, while in other cases, no clear allergic contributor can be defined (Hill et al. In some patients, asthma attacks are precipitated by exercise or aspirin (Cheong et al. Some patients, particularly those with severe asthma, may be resistant to treatment with corticosteroids (Searing et al. This phenomenological approach to asthma diagnosis has led to a plethora of asthma sub-types such as “allergic asthma,” “exercise-induced asthma,” and “steroid-resistant asthma” that may be clinically useful but provide little insight into underlying etiologies. Over the years, linkage-analysis, candidate-gene, and genome-wide-association approaches have been applied to the study of the genetic underpinnings of asthma, leading to the identification of several associated genes and sub-phenotypes (Lee et al. However, these findings still leave most of the genetic influences of asthma unexplained (Li et al. Moreover, pediatric asthma research, in particular, has focused on a broad range of social and environmental, as well as genetic, contributors to the increased prevalence and severity of illness (Hill et al. Since the burden of asthma disproportionately affects children living in socioeconomically disadvantaged neighborhoods (D. A knowledge- network-derived-taxonomy based on the biology of disease may help to divide patients with asthma—as well as many other diseases— into subtypes in which the different etiologies of the disorder can be better understood, and for which appropriate, subtype-specific approaches to treatment and prevention can be devised and tested. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 39 The Proposed Knowledge Network of Disease Would Include Information about Pathogens and Other Microbes Particularly because of advances in genomics, the proposed Knowledge Network of Disease has unprecedented potential to incorporate information about disease-causing and disease-associated microbial agents. Thousands of microbial genomes have been sequenced, providing a wealth of data on pathogenic and non-pathogenic organisms, and there has been an associated renaissance in studies of the molecular mechanisms of host-pathogen interactions. In parallel with these advances in microbiology, the analysis of human-genome sequences is enhancing the understanding of host responses and variation in individual susceptibility to microbial pathogens and infectious diseases. Today, sequence data, combined with other biochemical and microbiological information, are being used to understand microbial contribution to health, improve detection of pathogens, diagnose infectious diseases, and identify potential new targets for novel drugs and vaccines. In addition, comparing the sequences of different strains, species, and clinical isolates is crucial for identifying genetic polymorphisms that correlate with phenotypes such as drug resistance, morbidity, and infectivity. Combining this information with the molecular signature of the host will provide a more complete picture of an individual’s diseases allowing custom-tailoring of therapeutic interventions. The Proposed Knowledge Network of Disease Would Go Beyond Description A Knowledge Network of Disease would aspire to go far beyond disease description. It would seek to provide a unifying framework within which basic biology, clinical research, and patient care could co-evolve. The scope of the Knowledge Network’s influence would encompass: Disease classification. The use of multiple molecular-based parameters to characterize disease may lead to more accurate and finer-grained classification of disease (see Box 3-2: Distinguishing Disease Types). Disease classification is not merely an academic exercise: more nuanced diagnostic accuracy and ability to recognize disease sub-types would undoubtedly have important therapeutic consequences, allowing treatment regimes to be customized based on the precise molecular features of a patient’s disease. Gene-expression profiling led to the discovery that B-cell lymphomas comprise two distinct subtypes of disease with different driver mutations and different prognoses (Alizadeh et al. One subtype bears a gene-expression profile similar to germinal center B-cells and has a good prognosis, while a second subtype bears a gene- expression profile similar to activated B-cells and has a poor prognosis. Recognition of these biological and clinical differences between subtypes of B-cell lymphomas makes it possible to predict patient prognosis more accurately and guide treatment decisions. Similarly, leukemias are also now categorized based on differences in driver mutations, revealing subtypes with different prognoses and responses to particular treatment approaches. These are two of many known examples in which molecular data have been used to distinguish subtypes of malignancies with different prognoses and that benefit from different treatments. The proposed Knowledge Network of Disease could be expected to lead to many more insights of this type. A Knowledge Network in which diseases are increasingly understood and defined in terms of molecular pathways has the potential to accelerate discovery of underlying disease mechanisms. In a molecularly based Knowledge Network, a researcher could readily compare the molecular fingerprint (such as one defined by the transcriptome or proteome) of a disease with an unknown pathogenic mechanism to the information available for better understood diseases. Similarities between the molecular profiles of diseases with known and unknown pathogenic mechanisms might point directly to shared disease mechanisms, or at least serve as a starting point for directed molecular interrogation of cellular pathways likely to be involved in the pathogenesis of both diseases. A Knowledge Network that integrates data from many different levels of disease determinants collected from individual subjects over time may reveal new opportunities for detection and early diagnosis. The availability of information on a multitude of diverse diseases should facilitate epidemiological research to identify novel diagnostic markers based on correlations among diverse datasets (including clinical, social, economic, environmental, and lifestyle factors) and disease incidence, treatment decisions, and outcomes. In some instances, these advances would follow from the new insights into pathogenic mechanisms discussed above. In other cases, however, molecular profiles may prove sufficiently predictive of a patient’s future health to have substantial clinical utility long before the mechanistic rationale of the correlation is understood. A Knowledge Network of Disease that links information from many levels of disease determinants, from genetic to environment and lifestyle, will improve our ability to predict and survey for diseases. Following outcomes in individual patients over time will allow the prognostic value of molecular-based classifications to be tested and, ideally, verified. Obviously, the clinical utility of identifying disease predispositions depends on the availability of interventions that would either prevent or delay onset of disease or perhaps ameliorate disease severity. The ultimate goal of most clinical research is to improve disease treatments and health outcomes. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 41 Knowledge Network of Disease and its derived taxonomy may be expected to impact disease treatment and to contribute to improved health outcomes for patients. As many of the examples already discussed illustrate, finer grained diagnoses often are the key to choosing optimal treatments. In some instances, a molecularly informed disease classification offers improved options for disease prevention or management even when different disease sub-types are treated identically (see Box 3. A Knowledge Network that integrates data from multiple levels of disease determinants will also facilitate the development of new therapies by identifying new therapeutic targets and may suggest off-label use of existing drugs. In other cases, the identification of links between environmental factors or lifestyle choices and disease incidence may make it possible to reduce disease incidence by lifestyle interventions. Importantly, as discussed below, the Committee believes the Knowledge Network and its underlying Information Commons would enable the discovery of improved treatments by providing a powerful new research resource that would bring together researchers with diverse skills and integrate knowledge about disease processes in an unprecedented way. Indeed, it is quite possible that the transition to a modernized “discovery model” in which disease data generated during the course of normal healthcare and analyzed by a diverse set of researchers would ultimately prove to be a Knowledge Network of Disease’s greatest legacy for biomedical research. Consequently, patients and physicians must currently make decisions about whether to undertake more intensive cancer surveillance (for example, by breast magnetic resonance imaging or vaginal ultrasound) without being able clearly to assess the risks and benefits of such increased screening and the anxiety and potential morbidity that arises from inevitable false positives. Furthermore, some patients elect to undergo prophylactic mastectomies or oophorectomies without definitive information about the extent to which these drastic procedures actually would reduce their cancer risk. Studies attempting to quantify these risks have largely focused on particular ethnic groups in which a limited set of mutations occur at high enough frequencies to allow reliable conclusions from analyses carried out on a practical scale. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 42 individual patients, health-care providers, and payers, by making it possible to avoid unnecessary screening and treatment while reducing cancer incidence and promoting early detection. Molecular similarities amongst seemingly unrelated diseases would also be of direct relevance to drug discovery as it would lead to targeted investigation of disease-relevant pathways that are shared between molecularly related diseases. In addition, ongoing access to molecular profiles and health histories of large numbers of patients taking already-approved drugs would undoubtedly lead to improved drug safety by allowing identification of individuals at higher-than-normal risk of adverse drug reactions. Indeed, our limited understanding of—and lack of a robust system for studying—rare adverse reactions is a major barrier to the introduction of new drugs in our increasingly risk-aversive and litigious society. Major disparities in the health profiles of different “racial”, ethnic, and socio-economic groups within our diverse society have proven discouragingly refractory to amelioration. As discussed above, it is quite likely that key contributors to these disparities can be most effectively addressed through public-health measures and other public policies that have little to do with the molecular basis of disease, at least as we presently understand it. However, the Committee regards the Information Commons and Knowledge Network of Disease, as potentially powerful tools for understanding and addressing health disparities because they would be informed by data on the environmental and social factors that influence the health of individual patients,. For the first time, these resources would bring together, in the same place, molecular profiles, health histories, and data on the many determinants of health and disease, thereby optimizing the ability to decipher the mechanisms through which exogenous factors give rise to endogenous, biological inputs, directly affecting health. Researchers and policy makers would then be better able to sort out the full diversity of possible reasons for observed individual and group differences in health and to devise effective strategies to prevent and combat them. A Hierarchy of Large Datasets Would Be the Foundation of the Knowledge Network of Disease and Its Practical Applications The establishment of a Knowledge Network, and its research and clinical applications, would depend on the availability of a hierarchy of large, well-integrated datasets describing what we know about human disease. These datasets would establish the foundation for the New Taxonomy and many other basic and applied activities throughout the health-care system.

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Objectives that only 14 per cent of the participants consumed the recom- This chapter will mended six to eight glasses of water per day slimex 15mg without prescription, and the majority • describe some of the barriers to adequate nutrition in the (60 per cent) snacked less than once a day (Winston 2008) order slimex canada. A workplace discount slimex master card, qualitative study in which physicians were interviewed about • discuss how inadequate nutrition can affect physicians their workplace nutrition habits reported that 19 of the 20 par- personally and professionally discount slimex 10 mg online, and ticipants expressed that they sometimes have diffculty eating • suggest ways in which individual physicians can infuence and drinking during work hours (Lemaire et al 2008). In particular the usual attention to healthy What is the impact of inadequate nutrition on physi- nutrition has been gradually eroded by long sessions in cians? Poor nutrition for physicians during the work day has the operating room and lengthy work days. The resident signifcant consequences, both for the individual physician and regards the nutrition choices at the hospital as unaccept- for the workplace. Physicians have previously described how able and fnds they are missing meals, losing weight and their inability to eat and drink properly during work hours is generally feeling awful on most days. When considering physicians’ nutrition in the For physicians: workplace, the solution should be simple—just make time to • Eat breakfast. However, the issue is not so straightforward, and • Carry healthy and convenient snacks with you. Nutrition in the health care workplace To improve nutrition in the workplace, physicians and health For health care organizations: care organizations must enhance their awareness and under- • Improve the quality and variety of foods available standing of the impact of inadequate nutrition and the barriers in the workplace. Without this knowledge, there will be little • Improve access to nutritious food (e. For example, one study provided a description of some eat, drink and store food from home. They also Case resolution felt that inadequate nutrition had a negative impact on both The resident is facing an issue common to most physi- their ability to complete their work and on their interactions cians—diffculty obtaining adequate nutrition during the with patients, colleagues and other health care professionals. The resident consumed adequate nutrition during a work day had better becomes more aware of the link between nutrition and cognitive function than those who neglected their nutritional well-being. Physicians have identifed several baked rice or whole grain crackers, juice boxes, yogurt practical barriers to healthy eating in the work environment. The resident identifes clean and secure These include lack of time to stop and eat, mostly as a result storage areas on the units where they work and also keeps of staff shortages and workload issues, lack of scheduled a few snacks in their lab coat pocket and locker. The breaks, lack of convenient access to food, poor food choices resident makes time for a healthy balanced breakfast daily. In addition to these practical barriers, physicians have room and ward work schedule. The resident encourages also described how certain attributes of medical professional- the other members of the team to do the same. The ism may in fact hinder their workday nutrition (Lemaire et al resident lobbies the health care organization to improve 2008). For example, doctors have expressed how their strong access to and quality of available nutrition, and to provide work ethic and sense of professionalism discourages them designated, convenient spaces for nutrition breaks. Changing the status quo Many physicians are aware of healthy nutritional choices and Winston J, Johnson C, Wilson S. To overcome these barriers, there needs to be advocacy for ad- equate nutrition in the workplace. Education and dialogue will guide physicians and health care organizations to an increased awareness of the doctors’ nutrition patterns, a facilitation of positive change, and an appreciation of the link between physician nutrition and work performance. As physicians and health care organizations promote the benefts of improved nutrition and workplace wellness, everyone will beneft, given the important link between physician wellness and quality of patient care. Summary Various personal and workplace factors can make it diffcult for physicians to ensure adequate nutrition during their work day. Physicians and health care organizations share a responsibility to improve workplace nutrition by raising awareness, changing nutrition practises and improving access to nutritious food in the workplace. It begins for The medical student most people with deciding sometime during the undergraduate Admission to medical school is a tremendous accomplish- years of university to pursue studies in medicine. There is the delight of achievement, the pride of family is the frst step toward a professional career that is rich in per- and friends, and the promise of a rewarding future. The memory of this joy will serve taken lightly, as the years of training are demanding and require successful candidates in good stead during their transition to self-discipline and dedication. This transition is not meant to be easy, but it preparation, followed by many years of practice, along with brings great potential for personal and academic growth. Medical school admission Medical school can present challenges to one’s personal life. Applicants are expected to have mitment required can challenge relationships: not everyone had a breadth of life experience, as demonstrated in volunteer will fnd it easy to accommodate the medical student’s new work, job experiences, extracurricular activities, a proven ability schedule and its demands. Added to these stresses is the fnan- to assume responsibility, an altruistic nature and good interper- cial burden of tuition, which may create or add to an existing sonal skills. This standardized examination has four sections focusing on physical sciences, This combination of challenges tests everyone at some point biological sciences, verbal reasoning and writing. Medical students are at risk of develop- these daunting requirements are the fnancial implications of ing unhealthy lifestyle habits. All of these factors—poor coping strategies that arise in re- sponse to stress and constraints of time—can quickly lead to further diffculties. It is important to be aware that medical schools have devel- oped a wide range of personal and professional resources to provide support for their students. These resources can be readily accessed through the institution’s undergraduate medi- cal education offce. Physicians who are graduated physicians lived within the hospital to further their satisfed with their career are not only disciplined, effective and clinical training and hone their skills. The term lives on, al- productive: they also take pleasure in the work—but not at though the times have changed. It therefore from two to six years in duration—are instrumental for the requires considerable commitment to proactively manage one’s development of expertise in a chosen specialty. The years of training are preparation for a way of the same issues that existed in medical school persist, new of being. It is important for residents to pursue medicine in challenges will come with increased responsibility for patient a fashion that is in keeping with who they are as individuals. The intrinsic aspects of a physician’s work are those of the resident: the challenge of diagnosis, the interaction with Key references patients and their families, collaborating with colleagues, and Danek J and M Danek. Toronto: John keep these satisfying aspects in the forefront of one’s mind, for Wiley and Sons. Signifcant pressures are associated with the Physician Health: The Essential Guide to Understanding the Health Care training, but developing strategies to ensure that respite is built Needs of Physicians. The Resilient Physician: Effective marriage and having one’s own family may be considered. They need to ensure that they take the vacation and educational leaves that are available to them. Frequent exposure to suffering and death, acute clini- residents, cal situations requiring rapid and complex decision-making, • describe how these elements can affect the learner both prolonged work hours often accompanied by signifcant sleep personally and academically, and deprivation, demanding and increasingly better-informed pa- • consider ways to improve the training environment to tients, information and technology overload, social isolation, enhance resident resilience. Organizational challenges such Case as bed shortages and pressures to move patients through the A fourth-year resident initially identifed as a great com- system quickly are stressful for all health care workers but can municator with a unique ability to make the preoperative be overwhelming for residents, who feel that many of these patient feel at ease going into surgery, has realized that they problems affect their ability to do their jobs but are beyond have started to dread conversations with patients. The resident has sought feedback from more senior to meet external standards of performance within this intense residents and staff who have suggested that it is easier to milieu, residents may feel perpetually under the microscope and focus on getting the information needed and move on. The trainee– has heard the surgeons lament that hospital politics will supervisor relationship is fraught with challenges ranging from once again mean cutbacks, reduced operating room time inconsistent evaluation standards, to intergenerational misun- and fewer nurses available after hours. In a survey of over ing that, although they seem to be getting home earlier, 1200 residents in the United States, 93 per cent of respondents the resident is losing the ability to remember details about had experienced maltreatment at some point in their residency; each patient, is less interested in their stories and, frankly, further, they believed this to have signifcantly affected their enjoys their days less. Perpetrators of resident abuse fnish residency and start practicing that they might have can be faculty but include other residents and health care pro- the inclination and infuence to do things differently. In a survey of stress experienced in residency training in Alberta, nurses were Introduction identifed as the greatest source of intimidation and harass- Healthy workplaces support their employees in achieving ment (Cohen and Patten 2005). Most trainees do not report healthy lifestyles, behaviours and adaptive coping skills. Ironically, health care settings can be among the least healthy Residents are not the only recipients of disruptive behaviours. Experiences of medical trainees, Some report witnessing what they feel are derogatory acts particularly in their clinical years, can have detrimental effects directed at other health care professionals, patients and their on their personal well-being, professional behaviours and aca- families.

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It is found that the mitochondrial content is directly proportional to the amount of energy one cell is required to generate and expend buy 10mg slimex amex. The mitochondrial content is most likely greatest in which of the following types of cells? A 45-year-old man without a history of bleeding or excessive bruising dies suddenly due to rupture of an aortic dissection generic slimex 10mg without a prescription. A 42-year-old woman comes to the physician for a follow-up examination after two separate Pap smears have shown dysplastic epithelial cells purchase cheap slimex line. The viral E6 protein binds to the cellular p53 tumor suppressor gene order 10 mg slimex, causing it to be degraded. Which of the following best describes the mechanism by which the E6 protein causes cervical cancer? Which of the following is the correct sequence of events in the initiation of contraction of a skeletal muscle fiber? Conformational Release of Ca2+ from Change in Acetylcholine Depolarization Troponin-Tropomyosin Sarcoplasmic Propagation into Binding to of Sarcolemma Complex Reticulum Transverse Tubules Receptors (A) 1 2 3 4 5 (B) 2 5 4 3 1 (C) 3 5 2 4 1 (D) 4 2 5 3 1 (E) 5 3 4 1 2 14. A 90-year-old woman is brought to the emergency department 30 minutes after she fell while climbing the steps into her house. Increased activity of which of the following cell types is the most likely cause of the decrease in bone mass in this patient? A 50-year-old man comes to the physician because of a cough productive of large quantities of mucus for 6 months. Which of the following cell types is the most likely cause of the increase in this patient’s secretion of mucus? A 65-year-old man with severe atherosclerotic coronary artery disease comes to the emergency department because of a 12-hour history of chest pain. During an experimental study, an investigator finds that the regulation of cell cycle and programmed cell death may be initiated by the mitochondrion. The interaction of the mitochondrion with the activation of the caspase family of proteases and subsequent apoptosis is most likely mediated by which of the following? He enrolls in a clinical study of a novel chemotherapeutic agent that, as a side effect, blocks kinesin, a component of the cellular microtubular transport system. An alteration in which of the following components of the neuromuscular junction is the most likely cause of the muscle weakness? A pathologist uses monoclonal antibodies against several intermediate filament proteins and finds that a tumor section stains positive for cytokeratin only. B - 30 - Microbiology Microbiology Module (125 items) Systems General Principles of Foundational Science 70%–75% Biology of tissue response to disease Pharmacodynamic and pharmacokinetic processes Microbial identification and classification Bacterial biology Antibacterial agents Viral biology Antiviral agents Fungal biology Antifungal agents Parasitic biology Antiparasitic agents Prions Immune System 1%–5% Blood & Lymphoreticular System 1%–5% Nervous System & Special Senses 1%–5% Skin & Subcutaneous Tissue 1%–5% Musculoskeletal System 1%–5% Cardiovascular System 1%–5% Respiratory System 1%–5% Gastrointestinal System 1%–5% Renal & Urinary System 1%–5% Pregnancy, Childbirth, & the Puerperium 1%–5% Female Reproductive & Breast 1%–5% Male Reproductive 1%–5% Multisystem Processes & Disorders 1%–5% Immunology Module (25 items) Systems Immune System 75%–80% Development of cells of the adaptive immune response Structure, production, and function Cellular basis of the immune response and immunologic mediators Basis of immunologic diagnostics Disorders associated with immunodeficiency Immunologically mediated disorders Adverse effects of drugs on the immune system Blood & Lymphoreticular System 5%–10% Nervous System & Special Senses 1%–5% Skin & Subcutaneous Tissue 1%–5% Respiratory System 1%–5% Pregnancy, Childbirth, & the Puerperium 1%–5% - 31 - 1. A 45-year-old woman comes to the physician because of progressive facial swelling and pain during the past week. Physical examination shows ecchymoses over the left orbital and periorbital regions with proptosis. Findings on microscopic examination of material from the lesion include broad, irregularly shaped, nonseptate hyphae with branches at right angles. A 21-year-old woman who is a college student is brought to the emergency department 2 hours after the onset of fever, chills, severe headache, and confusion. Physical examination shows numerous petechial lesions over the upper and lower extremities. Analysis of cerebrospinal fluid shows numerous leukocytes and gram-negative diplococci. Administration of which of the following vaccines is most likely to have prevented this patient’s condition? A sexually active 37-year-old woman comes to the physician because of a 2-day history of pain in the area of her genitals. Pelvic examination shows shallow, small, extremely tender ulcers with red bases in the vulvar and vaginal regions. Which of the following infectious agents is the most likely cause of these findings? During an experimental study, an investigator develops a new member of the class of non-nucleoside reverse transcriptase inhibitors. The organism agglutinates with antiserum directed against type B surface carbohydrate. The virulence of this organism is related to a bacterial constituent that interferes with which of the following host phagocyte functions? A 33-year-old woman contracts malaria while on a 3-month business trip to a Central American country. Which of the following species of Plasmodium is most likely to have caused the second febrile illness? Three weeks after traveling to California to study desert flowers, a 33-year-old man develops fever, chest pain, and muscle soreness. Two days later, red, tender nodules appear on the shins, and the right ankle is tender and painful. At a banquet, the menu includes fried chicken, home-fried potatoes, peas, chocolate eclairs, and coffee. Within 2 hours, most of the diners become violently ill, with nausea, vomiting, abdominal pain, and diarrhea. Analysis of the contaminated food is most likely to yield large numbers of which of the following organisms? A 35-year-old woman is admitted to the hospital because of fever and dry cough for 3 days. A 69-year-old woman comes to the emergency department because of a 2-day history of increasingly severe fever and back pain; she also has a burning sensation with urination, and there is an aromatic smell to the urine. She has had three urinary tract infections treated with ciprofloxacin during the past year. During an experiment, an investigator gently abrades the skin from the flank of a mouse, creating a 1 × 2-cm skin window. A glass coverslip is then placed over the area so that cells attracted to the site attach to the coverslip for assessment. Two hours later, an extravasation of cells from the vasculature is noted on the coverslip. Which of the following complement components is the direct cause of the enhanced vascular permeability and chemoattraction in the abraded skin area in this experiment? He has had persistent left upper quadrant abdominal pain for 3 weeks despite therapy with omeprazole. Which of the following mechanisms of action is most likely involved in this resistance? A 3-year-old girl is brought to the emergency department by her father because of a persistent cough for 2 weeks. An investigator injects an experimental animal with a newly discovered bacterial strain to evaluate T-lymphocyte activation. Which of the following cell-surface molecules on the macrophage is most directly involved in the presentation of the processed peptides? An investigator conducts an experiment on Clostridium perfringens and then sterilizes the culture dishes by autoclaving. This method of sterilization is most appropriate because it ensures that which of the following bacterial structures are inactivated? A 52-year-old woman living in Maryland comes to the physician because of a 1-week history of low-grade fever, fatigue, and a red rash over the skin behind her left knee. Physical examination shows an 8-cm, warm, nontender, erythematous lesion with partial central clearing over the skin of the left popliteal area. An 8-month-old girl is brought to the emergency department because of a 1-day history of rapid breathing. A 45-year-old man comes to the physician because of fever and night sweats for 8 days. D - 38 - Neuroscience Systems General Principles of Foundational Science 5%–10% Nervous System & Special Senses 90%–95% Embryonic development, fetal maturation, and perinatal changes Organ structure and function Brain stem Brain Sensory systems Motor systems Autonomic nervous system Peripheral nerves Cell/tissue structure and function Repair, regeneration, and changes associated with stage of life Infectious, immunologic, and inflammatory disorders Neoplasms (cerebral, spinal, and peripheral) Cerebrovascular disease Disorders relating to the spine, spinal cord, and spinal nerve roots Cranial and peripheral nerve disorders Neurologic pain syndromes Degenerative disorders/amnestic syndromes Global cerebral dysfunction Neuromuscular disorders Movement disorders Paroxysmal disorders Sleep disorders Traumatic and mechanical disorders and disorders of increased intracranial pressure Congenital disorders Endocrine System 1%–5% Multisystem Processes & Disorders 1%–5% - 39 - 1. This results in weakness of elevation and retraction of the shoulder on the ipsilateral side and difficulty turning the head up and toward the contralateral side.

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