A common treatment regimen consists of tumor debulking cheap glucophage sr online mastercard, followed by administration of plati- num and taxane-based chemotherapy buy glucophage sr 500 mg with visa. Due to presentation of disease at advanced stages and development of resistance to therapy cheap glucophage sr 500 mg, the 5-year survival rate is <40 %. Gene expression proﬁles have been established that are associated with overall survival and response to platinum therapy. Despite those encouraging devel- opments, no biomarkers for prediction of response to therapy are yet in clinical use. New approaches for early diagnosis as well as treatment are, therefore, required to improve outcome in this disease. A woman’s risk of cancer is measured by using a 0–10 scale versus predeter- mined cut-off points. Women who are pre-menopausal have a cut off score of 5 whereas postmenopausal women have a 4. A prospective, multi-institutional trial enrolled female patients scheduled to undergo surgery for an adnexal mass (Bristow et al. Multivariate index assay was superior in predict- ing the absence of an ovarian malignancy, with a negative predictive value of 98. Determining Response to Chemotherapy in Ovarian Cancer Gene expression proﬁles can predict response of ovarian cancer patients to chemo- therapy. The method may enable clinicians to identify patients who are candidates for additional and/or novel chemotherapy drugs, and effectively choose appropriate cancer treatment. Similarly, the researchers then revamped the subtype gene expression signature by narrowing the initial list of 800 genes down to 100 genes. The worst outcome group, accounting for 23 % of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63 %, versus a median sur- vival of 46 months and platinum resistance rate of 23 % in other cases. An improved understanding of ovarian carcinoma development may ultimately lead to more effective treatments. In patients with recurrent ovarian cancer, it is often difﬁcult to select an effective treatment because the tumor develops resistance to many drugs. Currently, physicians select a drug and must wait about six months to see whether it is effective on a particular patient. Yale apoptosis assay is based on a biological principle that when a drug is effective, it will induce apoptosis in the cancer cell. Used together, both assays will distinguish drugs that can stop the growth of the tumor and/or kill the tumor. The technology will be studied with various cancers, starting with ovarian cancer. Each assay will be evaluated independently and then in combination in a multicenter clinical trial. A study in 2009 at Duke University showed that >50 % of physi- cians followed results of ChemoFx® in management of ovarian cancer and the results changed physician behavior. Use of ChemoFx® results in cost savings of $2,900–$8,100 per patient per round for primary or recurrent ovarian cancer cases over a six-cycle treatment period. The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology of ovarian cancer. Breast cancer-resistance protein 1-expressing verapamil- sensitive side population cells were identiﬁed in human ovarian cancer cell lines and primary ascites cells from patients with ovarian cancer. In the future, individualized therapy must incorporate analysis of the stem cell-like subpopulation of ovarian cancer cells when designing therapeutic strategies for ovarian cancer patients. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian can- cer, contributing to the development of resistance mechanisms. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. In the paired primary and relapse cohort, they observed a greater degree of genomic change in tumors from patients that were initially sensi- tive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Mapping the mechanisms that confer resistance may enable prediction of whether some women are likely to respond to a certain drug or not, and ﬁnd ways of reversing resistance. Pathway Targeted Therapies for Ovarian Cancer Mouse ovarian epithelial tumor cell lines that contain various combinations of genetic alterations in the p53, c-myc, K-ras and Akt genes have been used as model for the molecular characterization of pathway-targeted therapy. Response to a par- ticular anticancer drug can be related to the signaling pathway involved. Rapamycin effectively inhibits the growth of tumors that rely on Akt signaling for proliferation, whereas tumors in which Akt signaling is not the driving force in proliferation are resistant to rapamycin. The introduction of activated Akt to the rapamycin-resistant cells does not render the cells susceptible to rapamycin if they can use alternative pathways for survival and proliferation. Therefore, the rapamycin-sensitive tumors develop resistance to rapamycin when presented with alternative survival pathways, such as the mitogen-activated extracellular kinase signaling pathway. These ﬁndings indicate that mammalian target of rapamycin inhibitors may be effective in a subset of tumors that depend on Akt activity for survival but not effective in all tumors that exhibit Akt activation. Tumors with alternative survival pathways may require the inactiva- tion of multiple individual pathways for successful treatment. These results have signiﬁcant implications for the use of pathway-targeted therapy in advanced human ovarian cancers, which typically display numerous genetic alterations that are likely to require impairment of multiple molecular pathways for successful treatment. Universal Free E-Book Store Personalized Management of Cancers of Various Organs 323 Interruption of multiple speciﬁc biochemical pathways may be a promising therapeutic strategy in ovarian carcinomas that exhibit resistance to an individual targeted therapy. This strategy may be useful for developing personalized therapies for ovarian cancer. Resistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. These ﬁndings indicate that targeting the Notch pathway signiﬁcantly increases tumor sensitivity to platinum therapy. Both platinum-resistant and platinum-sensitive relapses may beneﬁt from such an approach as clinical data suggest that all relapses after platinum therapy are increas- ingly platinum resistant. A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. Overall, these discoveries set the stage for approaches to the treatment of high-grade serous ovarian cancer in which aberrant genes or networks are detected and targeted with therapies selected to be effective against these speciﬁc aberrations. Targeting Hematogenous Metastasis of Ovarian Cancer Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread were not well under- stood. These results highlight hematogenous spread as an important mode of ovarian cancer metastases and use of this knowledge to design better strategies for prevention and treatment. An estimated 80 % of platinum-resistant ovarian cancer patients have been found to have folate receptor-positive disease, and ~40 % express the receptor, as detected by etarfola- tide, in all of their target tumor lesions. Compared to patients who do not express folate receptors on their tumors, folate receptor-positive patients have been shown to have a poorer overall prognosis. Vintafolide is a conjugate of folic acid (vitamin B9) linked to an anticancer agent, the potent vinca alkaloid desacetylvinblastine hydrazide. Since cancer cells Universal Free E-Book Store Personalized Management of Cancers of Various Organs 325 generally consume higher levels of folate than normal cells to fuel their growth, some cancer cell types, including ovarian, have high concentrations of the folate receptor on their surface. Vintafolide is designed to selectively target the folate receptor to deliver the anti-cancer agent to the cancerous tissue. Tumors that have high concentrations of the folate receptor are identiﬁed by etarfolatide, a non- invasive imaging diagnostic agent.
Backscatter Peak When g-ray photons discount generic glucophage sr canada, before striking the detector buy glucophage sr 500mg fast delivery, are scattered at 180° by Compton scattering in lead shielding and housing buy glucophage sr online pills, and the scattered photons are absorbed in the detector, then a peak, called the backscatter peak, appears in the g-ray spectrum (see Fig. This peak can be mostly eliminated by increasing the distance between the shield and the detector. Iodine Escape Peak Photoelectric interaction of g-ray photons with iodine atoms of the NaI(Tl) detector usually results in the emission of characteristic K x-rays. These x- ray photons may escape the detector, resulting in a peak equivalent to photon energy minus 28keV (binding energy of the K-shell electron of iodine). This is called the iodine escape peak, which appears about 28keV below the photopeak (Fig. This peak becomes prominent when the energy of the photon is less than about 200keV, because, at energies above Fig. A spectrum of 111In with 171- and 245-keV photons showing a coincidence (sum) peak at 416keV. The b+- particles are annihilated to produce two 511-keV photons, which appear as photopeaks in the g-ray spectrum. If, however, one of the 511-keV photons escapes from the detector, then a peak, called the single-escape peak, cor- responding to the primary photon energy minus 511keV, will appear in the spectrum. If both annihilation photons escape, then a double-escape peak results, corresponding to the primary photon energy minus 1. Coincidence Peak A coincidence or sum peak results when more than one photon is absorbed simultaneously in the detector to be considered as a single event. Such situations occur with radionuclides that have short-lived isomeric states and thus emit g-rays in cascade. For example, 111In emits 171- and 245-keV photons, which can result in a sum peak of 416keV (Fig. Sum peaks are also caused by counting high-activity samples in which two photons may strike the detec- tor at the same time. These peaks can be reduced by counting the samples at larger distances between the source and the detector or by using smaller Liquid Scintillation Counters 93 detectors so that the likelihood of two photons striking the detector at the same time is reduced. In the case of high-activity samples, the level of activ- ity has to be reduced either by dilution or allowing to decay, in order to reduce the sum peak. Liquid Scintillation Counters − Low-energy b -particles are normally absorbed within the source and in the window and walls of the detectors, and therefore b−-emitters are difﬁcult to − detect in gas or solid detectors. For this reason, b -emitting radionuclides are counted using the liquid scintillation technique in which the radioactive sample is mixed with a scintillating material. Such coincidence counting reduces the background counts due to noise, including terrestrial and cosmic radiations, radioactive patients, etc. The liquid scintillation solution is prepared by dissolving a primary scin- tillating solute or ﬂuor and often a secondary ﬂuor in a solvent. The radioac- tive sample is added to and thoroughly mixed with the scintillating solution Fig. Light photons emitted from the sample strike the two photomultiplier tubes to produce pulses. Toluene, xylene, and dioxane are the most common solvents that easily dissolve the primary ﬂuor and often the radioactive sample, which is a requirement for a good solvent. These solvents, however, are poorly misci- ble in water, and therefore their disposal in the sewer system is restricted. For this reason, biodegradable solvents such as linear alkylbenzene and phenylxylylethane are widely used. Counting vials are usually glass or plastic, but the latter is not used when toluene or xylene is used as a solvent because the solvent tends to dissolve plastic. When radiations pass through the solvent, electrons are released from the solvent molecules after absorption of radiation energies. This mis- match is rectiﬁed by adding a secondary ﬂuor or solute, called the wave- length shifter, to the scintillating solution. An attempt is always made to keep the radioactive sample in solution in the liquid scintillator. Solubilizing agents are added to improve dissolution of speciﬁc samples, and the common example is the hydroxide of Hyamine 10-X used in counting tissue samples. In liquid scintillation counting, quenching is a problem caused by inter- ference with the production and transmission of light, which ultimately reduces the detection efﬁciency of the system. Chemical type, resulting from interference in energy transfer by sub- stances such as samples or extraneous materials (e. Dilution type, resulting from relatively large dilution of the scintillation mixture, in which case many light photons may be absorbed by the diluted sample. Optical type, resulting from absorption of light by a dirty vial containing frost or ﬁngerprints. Quenching must be corrected to obtain accurate counting of samples, and three methods have been adopted for this purpose, namely, internal standard method, channel ratio method, and external standard method. Characteristics of Counting Systems 95 The readers are referred to reference physics books for details of these methods. Background noise also arises from the interaction of light with scintillation solution. The liquid scintillation counting systems are provided with automatic sample changers for counting as many as 500 samples. The b−-emitters, 3H, 14C, 32P, and 35S, are commonly detected by liquid scintillation counting. Characteristics of Counting Systems Detection of radiation and therefore counting of radioactive samples is affected by different characteristics of the detector and the associated elec- tronics. A similar situation exists for semi- conductor detectors where the number of ionizations may vary from one g -ray to another of the same energy, leading to the broadening of the peak. Detection Efﬁciency The detection efﬁciency of a counter is given by the observed count rate divided by the disintegration rate of a radioactive sample. The count rate of a sample differs from the disintegration rate because of several factors. Radiations from a source are emitted isotropically around 4p steridians, but only a fraction of all photons emitted strikes the detector, depending on the solid angle subtended by the detector on the source. Only a fraction of all photons striking the detector may interact in the detector and produce pulses. Further- more, the count rate is affected by the abundance of a particular radiation Characteristics of Counting Systems 97 from a radionuclide. Considering these factors, the overall counting efﬁ- ciency of a counter for a radiation is given by the following expression: Efﬁciency = fi × fp × fg × Ni (8. Intrinsic Efﬁciency The fraction of all radiations of a given type and energy impinging on the detector that interacts with it to produce pulses is called the intrinsic efﬁ- ciency, fi, of the detector: No. Intrinsic efﬁciency depends on the type and energy of the radiation and the linear attenuation coefﬁcient (m) and thickness of the detector.
The center also will conduct large scale genome sequencing to discover genes that are involved in dis- eases purchase glucophage sr discount, and will start a program to teach researchers and physicians how to incorpo- rate genomic information into their studies or clinical practices 500 mg glucophage sr fast delivery, and to train graduate students 500mg glucophage sr with visa. A new Division of Personalized Medicine will be created within the School of Medicine. University of Colorado-afﬁliated institutions include the Colorado Health Medical Group; the Medical Center of the Rockies; Memorial Hospital Central; Memorial Hospital North; Poudre Valley Hospital; and the University of Colorado Hospital. These services will include tests to predict disease risk, to assess cancer patients’ responses to treatment, and to iden- tify the correct drugs and dosages for patients. The Colorado Molecular Correlates laboratory at the campus will handle the samples and testing, and is expanding to scale up for the increased number of submissions. Some personalized medicine and genetic counseling services are already being offered, and the center will expand upon these. Leadership in these key areas of research is fostered by the creation of contiguous ofﬁce and laboratory space that bolsters collaborations and the development of comprehensive research investigations and treatment tools. The program will initially focus on Jordan, Mexico, India, China, Brazil, Ghana, and South Africa, and the university eventu- ally plans to expand to more than 100 countries. Wisconsin Genomics Initiative In 2008, four Wisconsin-based research institutions started collaboration to form the Wisconsin Genomics Initiative with a focus on personalized healthcare research. The collaborators include the Marshﬁeld Clinic, the Medical College of Wisconsin, Department of Public Health, and the University of Wisconsin-Milwaukee. The institutions will combine resources to conduct research on predicting individual susceptibility to disease, targeting personalized treatments, determining how Universal Free E-Book Store 628 20 Development of Personalized Medicine patients respond to speciﬁc treatments, and disease prevention. Role of Healthcare Organizations Initially, Healthcare organizations did not show much interest in implementation of personalized medicine. Major health insurance companies such as Blue Cross and Blue Shield are now interested in this topic. Other healthcare organizations are collabo- rating with universities in developing personalized medicine. In November 2014, Hospital for Sick Children (SickKids), University Health Network, and University of Toronto announced the creation of the Ted Rogers Centre for Heart Research, funded by a private donation of $115 million. Among the methods that the new center will use are genomic technologies to decode the genetic underpinnings of cardiac disease. The center will integrate research in genomic medicine, stem cells, and bioengineering, to develop personalized disease management. Research will cover the entire human life span, from childhood to adulthood, with each partner focusing on improving a particular aspect of cardiac health. SickKids will perform cardiogenomic studies to improve prediction of car- diac disease before clinical manifestations and to provide personalized medicine to both children and adults. In 2012 it partnered with Life Technologies (now part of Thermo Fisher Scientiﬁc) to establish the Centre for Genetic Medicine, with a goal of sequencing 10,000 pediatric genomes per year. University Health Network will use bioinformatics to translate discoveries into advances in healthcare delivery and development of personalized medicine. University of Toronto’s Institute for Biomaterials and Biomedical Engineering will apply stem cell technology and novel approaches in cellular and tissue engineering to the cutting-edge science of regenerating heart muscle, coronary vessels, and heart valves. Research at the University of Toronto will also focus on how genetic, cellular, and molecular signal- ing networks function as the heart develops. The research center will bring together more than 30 expert scientists and clinicians from the three institutions, as well as up to 80 graduate students, postdocs, and clinical fellows. Role of the Medical Profession Substantial advances are being made in genomics and the results are beginning to play an important role in the practice of general clinical medicine. It is important for physicians involved in clinical practice to become more aware of emerging genomic Universal Free E-Book Store Role of the Medical Profession 629 data and participate in integrating medical genomic information into clinical practice. Medical Education As knowledge in molecular genetics and cell biology accelerates, the biomedical community is ﬁnding it increasingly hard to harness the explosion of new informa- tion and translate it into medical practice. Biomedical scientists should be trained to apply new biological knowledge to human health. A better understanding of medi- cine also can guide scientists in research directions that are most likely to beneﬁt the diagnosis and treatment of human disease. There is a growing need to incorporate the increasing body of knowledge of pharmacogenetics and pharmacogenomics in the standard curriculum of medical schools, so that the next generation of clinicians and researchers will be familiar with the latest developments in these areas, and will be capable of providing patients with the expected beneﬁts of personalized medicine. As a ﬁrst step, and in recogni- tion of such emergent needs, the graduate school of the Sackler Faculty of Medicine at the Tel-Aviv University in Israel introduced a course in 2002 titled ‘Introduction to Pharmacogenomics: Towards Personalized Medicine’ for graduate and under- graduate students with a basic background in pharmacology and human genetics. As personalized medicine is being developed by the pharmaceutical industry, there should be a parallel education of the public and physicians on these issues. The present generation of physicians does not have any formal education in molecular medicine and this can be remedied by continuing education. For the busy physi- cian who is unable to attend such conferences, the Internet educational programs offer an alternative. Extra courses need to be incorporated in the medical curricula and the pharmaceutical industry may invest in endowing chairs and supporting courses on clinical pharmacology that include pharmacogenetics, pharmacogenomics and personalized medicine. The ethical objection to involvement of pharmaceutical Universal Free E-Book Store 630 20 Development of Personalized Medicine companies that occurs while conducting symposia for pharmaceutical products does not apply to industrial sponsorship of education in techniques on the frontiers of mod- ern medicine. Apart from the education of the physicians, active steps are needed to encourage the incorporation of personalized medicine into clinical practice. The mere availability of new tests, new knowledge, and individually tailored medicines is no guarantee that these will be incorporated in clinical practice. The ability and willingness of physicians to adopt personalized medicine into practice is an important factor in realizing its potential beneﬁts. However, studies in the ﬁeld of innovation adoption as well as physician clinical reasoning processes indicate that all physicians do not incorporate new techniques into their practices at the same rate and some fail do so. The concern that personalized medicine will not be readily or proﬁciently integrated into practice is suggested by evidence that primary care physicians have not signiﬁcantly increased referrals for genetic services, nor have they increased identiﬁcation of candidates who are appropriate for genetic testing. An understanding of the physicians’ clinical reasoning processes or habits of diagnostic decision making may help to identify and remove the barriers to assimi- lating genetics related innovations into clinical practice. Focused training and edu- cational materials need to be developed to address not only the substance of new information but also the assumptions and diagnostic strategies that drive the prac- tice of medicine. Off-Label Prescribing and Personalized Medicine The term “off-label” is used when a drug or medical device is used to treat a disease or condition not listed on its label, or used in such a way that’s not outlined in the label, it is said to be used off-label. This off-label use is also sometimes referred to as extra-label use, nonapproved use or unapproved use. Off-label prescription is a common practice because new indications for approved drugs may not be tested in clinical trials due to heavy cost involved or may be in the long process of approval. In the future, personalization of care could mean much more off-label use of new medicines, guided by the latest literature, at least until the regu- latory approaches are able to fully adapt to a different paradigm where treatment is highly speciﬁc to individual patients. Role of Patients Educated patients with an interest in healthcare have easy access to information on conventional medicine and new trends based on scientiﬁc advances.
Effects of intravenous injection of Clostridium perfringens type D epsilon toxin in calves purchase glucophage sr paypal. Acute pulmonary inflammation induced by exposure of the airways to staphylococcal enterotoxin type B in rats purchase cheap glucophage sr on-line. Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir trusted 500mg glucophage sr. Efficacy of selected hand hygiene agents used to remove Bacillus atrophaeus (a surrogate for Bacillus anthracis) from contaminated hands. Botulism: cause, effects, diagnosis, clinical and laboratory identification, and treatment modalities. Evaluation of a Chlamydophila psittaci infection diagnostic platform for zoonotic risk assessment. Measurement of staphylococcal enterotoxin B in serum and culture supernatant with a capture enzyme-linked immunosorbent assay. Quantitative detection of norovirus excretion in pediatric patients with cancer and prolonged gastroenteritis and shedding of norovirus. In vitro post-antibiotic effect of fluoroquinolones, macrolides, beta-lactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, quinupristin/dalfopristin and rifampicin on Bacillus anthracis. Clinical presentation of inhalational anthrax following bioterrorism exposure: report of 2 surviving patients. Bichat guidelines for the clinical management of botulism and bioterrorism-related botulism. Bichat guidelines for the clinical management of brucellosis and bioterrorism-related brucellosis. Antibiotic susceptibility of 65 isolates of Burkholderia pseudomallei and Burkholderia mallei to 35 antimicrobial agents. Bichat guidelines for the clinical management of glanders and melioidosis and bioterrorism-related glanders and melioidosis. Managing Q fever during pregnancy: the benefits of long- term cotrimoxazole therapy. Q fever pneumonia: are clarithromycin and moxifloxacin alternative treatments only? Oropharyngeal aspiration of ricin as a lung challenge model for evaluation of the therapeutic index of antibodies against ricin A-chain for post-exposure treatment. RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol. Inhalation toxicology of ricin preparations: animal models, prophylactic and therapeutic approaches to protection. Neutralization of staphylococcal enterotoxin B by soluble, high-affinity receptor antagonists. Evaluation of intravenous zanamivir against experimental influenza A (H5N1) virus infection in the cynomolgus macaques. Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells. Role of law enforcement response and microbial forensics in investigation of bioterrorism. Bioterrorism and its aftermath: dealing individually and organizationally with the emotional reactions to an anthrax attack. Clinical features, pathogenesis and immunobiology of severe acute respiratory syndrome. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Seasonality of infectious diseases and severe acute respiratory syndrome—what we don’t know can hurt us. The laboratory diagnosis of severe acute respiratory syndrome: emerging laboratory tests for an emerging pathogen. A case of catastrophic antiphospholipid syndrome presenting with acute respiratory distress syndrome as the initial manifestation. Acute respiratory distress syndrome in persons with tickborne relapsing fever—three states, 2004–2005. Selection of Antibiotics in Critical Care 26 Divya Ahuja Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina, U. A portion of these patients present with life-threatening community-acquired infections, but all of them are susceptible to hospital-acquired infections on account of such necessary interventions as multiple vascular access lines, hemodynamic monitoring devices, mechanical ventilation, urethral catheter- ization, surgery, and trauma management. The familiar downsides include adverse drug reactions, colonization, and super- infection by opportunistic pathogens, cost, and—of global importance—emergence of increasingly difficult-to-treat drug-resistant strains. The purpose of this chapter is to review some principles pertaining to antibiotic selection. Such teams enhance the likelihood that the major principles for setting guidelines for antimicrobial use, which have been recognized for several decades, will indeed be honored in practice (2). Independent of institution setting, endorsement from hospital administration is essential to ensure sufficient authority, define program outcomes, and obtain necessary infrastructure, but the overarching desideratum is to achieve “buy-in” among all prescribing physicians. Such methods include computer-based surveillance, formulary restriction and preauthorization, prospective audit with intervention and feedback, and continuing medical education (3,5). Numerous studies over the past two decades demonstrate that inadequate antimicrobial therapy leads to increased mortality, prolonged lengths of stay, and poorer outcomes (6–9). Results of a study involving more than 600 patients indicated that the survival rate decreased by 7. Prior to the year 2000, investigations of the effect of initial “appropriate” antimicrobial therapy [usually defined by the use of agents to which the eventual pathogen(s) were determined to be susceptible] focused mainly on bloodstream infections, which allow easy retrospective analysis based on “clean” bacteriologic specimens. Such studies amply confirmed lower mortality rates for patients who received appropriate initial antimicrobial therapy (10,11). Overall mortality rate was 34%; the breakdown was 33% and 43% for patients who got adequate and inadequate antibiotics, respectively (12). Another Sepsis trial from Spain found excess in-hospital mortality of 39% with inadequate initial treatment. Factors to consider when prescribing initial empiric antimicrobial therapy include the following (Table 1): 1. The duration of hospitalization and recent antimicrobial exposure: Patients who have been hospitalized for less than 48 hours and who have not had recent exposure to antibiotics are more likely to have typical “community-acquired” pathogens. Common examples include Streptococcus pneumoniae and Haemophilus influenzae in pneumonia, E. Critically ill patients are also at risk for yeast infections, with reported rates of 1% to 2% of invasive candidiasis, although it still remains unclear whether to prescribe empiric antifungal drugs in the nonneutropenic patient (14). The clinical syndrome: Pneumonia in patients who have been hospitalized for more than 48 hours is most often due to gram-negative bacilli including P. Urosepsis in patients with prolonged hospitalization is commonly due to gram-negative bacilli.
Because it focuses only on genes that cause diseases in newborns buy glucophage sr with american express, it avoids the ethical problem of ﬁnd- ings that are unrelated to the problem at hand cheap glucophage sr express. As such generic glucophage sr 500mg fast delivery, a newborn’s sequence should ideally be obtained as early as possible to reduce potential health and developmental risks. However, personal genomic information will be useful only to the extent that the associations between the genetic sequence and diagnosis or prognosis of a disease can be accurately made in large numbers of people. Most of these association studies have yet to be carried out, but one can foresee that improved diagnostic and prognostic methods would lead to superior health economics and patient outcomes, despite the likelihood of ﬁnding a “healthy” genome in the majority of newborns. Alternatively, ignoring the genetic indicators of potential disease risk would almost certainly result in much higher costs, not only for patients but also for governments or insurance companies as compared to the cost of sequencing and analyzing a genome. With a positive healthcare economics rationale, governments or insurance companies will choose to pay for genomic sequencing as health-screening. A conventional ﬁne-mapping effort starts by sequencing dozens of randomly selected samples at susceptibility loci to discover candidate variants, which are then placed on custom arrays and algorithms are used to ﬁnd the causal variants. This reﬁned technique may identify individuals more likely to have mutations in causal genes. This approach will facilitate personalized medicine, in which treatment will be tailored to an individual’s genetic proﬁle. Identifying causal variants in disease genes provides an opportunity to develop drugs to rectify the biological consequences of these mutated genes. Common variants at these loci together explain <10 % of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritabil- ity of lipid traits. Resequencing of these genes revealed a signiﬁcant burden of rare missense or nonsense variants in Universal Free E-Book Store Personalized Cell and Gene Therapies of Genetic Disorders 543 individuals with hypertriglyceridemia, compared to variants in controls, corre- sponding to a carrier frequency of 28. Consideration of rare variants in these genes incrementally increased the proportion of genetic variation contributing to hypertriglyceridemia. Exome sequencing of a small number of unrelated affected individuals is a powerful, efﬁcient strategy for identifying the genes underlying rare mendelian disorders and will likely trans- form the genetic analysis of monogenic traits. The unique value of complete genome sequencing in families was demonstrated by results of another study to identify mutations underlying Miller syndrome and ciliary dyskinesia, an inherited lung dis- order in two affected siblings and their parents (Roach et al. It is now possible to see all the genetic variations, including rare ones, and to construct the inheritance of every piece of the chromosomes, which is critical for understanding the traits that are important in health as well as disease. Thus the analysis of a family’s genome can aid in the diagnosis and treatment of individual family members. It is possible that family’s genome sequence may become a part of an individual’s medical records in the future. Personalized Cell and Gene Therapies of Genetic Disorders Personalized biological therapies were described in Chap. This chapter will include brief description of applications of personalized cell and gene therapies in some genetic disorders. Children with this rare metabolic disease usually die by the age of six because they are missing an important enzyme, alpha-L-iduronidase, which leads to progres- sive damage in the brain, heart, bones, cartilage, liver and corneas. Patients with a milder form of the disease, with no brain involvement, can receive enzyme replace- ment therapy alone. However, because enzymes do not cross the blood-brain barrier, they cannot repair the brain damage that occurs in more severe forms of the disease. Treatment is limited to glucocorticoids that have the beneﬁt of prolonging ambulation by ~2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efﬁcacy with a minimal side effect proﬁle. Universal Free E-Book Store Personalized Cell and Gene Therapies of Genetic Disorders 545 Table 16. However, there are still unanswered questions regarding a variety of stem cells with myogenic potential, numerous cytokines and growth fac- tors acting solo or in an orchestrated manner. Most attractive are molecular-based therapies that can express the missing dys- trophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Duchenne muscular dystrophy gene that forms the basis of future gene therapy of this disorder, was identiﬁed in 1987 (Hoffman et al. Endogenous gene expression of dystrophin should be restored to >20 % of normal levels for improvement of muscular dystrophy symptoms. It is possible to block expression of both chromosomal copies of the defective native gene by an antisense approach. Normal protein can be expressed by a normal gene construct that is introduced and contains divergent codons to prevent blocking by the antisense compound. The goal of treatment should be to ﬁnd a product at least as effective as glucocorticoids with a lower side effect proﬁle or with a signiﬁcant glucocorticoid sparing effect (Malik et al. The transduced muscles rescue dystrophin expression and display a signiﬁcant recovery of function toward the normal values at single muscle ﬁber level. Development of antisense oligonucleotides with higher stability and lower toxic- ity, such as morpholinos, has made it possible to restore dystrophin efﬁciently in dystrophic mice in vivo with no obvious side effects. Weekly or biweekly systemic intravenous injections with a three-morpholino cocktail over the course of 5–22 weeks induced therapeutic levels of dystrophin expression throughout the body, with an average of about 26 % normal levels. Successful systemic treatment with morpholinos requires large doses of the antisense molecules and the technology is costly and difﬁcult to obtain. Exon skipping is not inextricable bound up with splicing regulatory sequences as the binding of an antisense oligoribonucleotide to sequences within the exon is suf- ﬁcient to induce exon skipping. This implies that probably most exons in the genome are skippable and that exon skipping could be applicable to the majority of muta- tions, including deletions, duplications, or nonsense mutations in in-frame exons. Their speciﬁc physicochemical characteristics each have their advantages and disadvan- tages with regard to safety and pharmacokinetics. Several candidates designed to skip other exons and address additional mutation groups are currently in preclinical development. However, given the increasingly lower prevalence of mutations, a nonstandard, orphan drug-tailored design of clinical studies is required. This is supported by the encouraging data obtained to date with drisapersen and eteplirsen, and may be based on extrapolation between patient populations, placebo groups and compounds (within a chemical class). Many of these therapies are individualized according to the needs of the patients, which vary considerably. Bioinformatic tools are used to analyze the data and identify genes that reveal drug efﬁcacy. Pharmacogenomic approach may eventually provide the opportunity to create drugs in a patient in a mutation-speciﬁc manner. Novel personalized therapy for cystic ﬁbrosis: treating the basic defect in all patients. Identiﬁcation of novel biomarkers for Niemann-Pick dis- ease using gene expression analysis of acid sphingomyelinase knockout mice. Excess of rare variants in genes identiﬁed by genome- wide association study of hypertriglyceridemia. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome).
There are a number of factors that might affect the hypertrophic response order 500mg glucophage sr mastercard, including nutritional support and genetic variation purchase generic glucophage sr from india, and a few individual genetic polymorphisms have been identiﬁed that may explain a small degree of variability in the resistance training-induced hypertrophic or strength gain phenotype purchase discount glucophage sr online. Personalized Surgery Surgery has been traditionally more personalized than drug therapy. Decision to use surgery and choice of procedure are often tailored to individual patients. Surgery for some conditions, genotype studies may inﬂuence the decision for surgery. Universal Free E-Book Store 586 19 Personalized Non-pharmacological Therapies An example is weight loss surgery. Even in standard textbook procedures, the surgeon often modiﬁes the approach according to the ﬁndings and other anatomical variables that may be encountered. Algorithms for patient management may contain medical and surgical alterna- tives, combination of both, or surgery as the only choice after failure of medical treatment. Improved understanding of the molecular basis of disease and reﬁne- ments in molecular diagnostics have contributed considerably to the decision mak- ing process as well as prediction of outcome of surgery. Role of surgery, wherever applicable, is described in the personalized management of various diseases in other chapters. Surgery is most frequently integrated with medical management and diag- nostics in case of cancer and neurological disorders. Response to other non-pharmacological methods may be used to make decision about surgery. Some of these methods can also be personalized and may be com- bined with surgery. Examples are personalized radiotherapy in management of can- cer and personalized hyperbaric oxygen. Increasing emphasis on personalized medicine with integration of diagnostics and surgery will likely reduce the need for surgery as well as failed surgical proce- dures and complications of surgery. Surgery of the future is also being reﬁned with integration of new technologies such as robotics and minimization of the invasive and traumatic process inherent in surgery. Genomic and metabolomic patterns segregate with responses to calcium and vitamin D supplementation. Standardized versus individualized acupuncture for chronic low back pain: a randomized controlled trial. Genetic and epigenetic contributions to human nutrition and health: man- aging genome-diet interactions. Using molecular classiﬁcation to predict gains in maximal aerobic capacity following endurance exercise training in humans. Deﬁning an adequate dose of acupuncture using a neuro- physiological approach – a narrative review of the literature. Universal Free E-Book Store Chapter 20 Development of Personalized Medicine Introduction In conventional medical practice, the physicians rely on their personal experience in treating patients. In spite of advances in basic medical sciences and introduction of new technologies, the physicians continue to rely on their judgment and sometimes intuition because practice of medicine is an art as well as a science. With advances in molecular biology and its impact on medicine, tremendous amount of new basic information has been generated particularly in genomics and gene expres- sion. The problem now is a ﬂood of information, which requires strategies to sort out the relevant from the irrelevant. Information on large number of studies with stratiﬁcation of large num- ber of patients will have to be analyzed to make decisions about treatment of an individual. The massive amount of publications need to be sorted out and analyzed for their relevance to individualized treatment. Players in the Development of Personalized Medicine Development of personalized medicine is a multidisciplinary undertaking and will need teamwork by many players. Pharmaceutical and biotechnology companies have taken a leading role in this venture in keeping with their future as healthcare enterprises rather than mere developers of technologies and manufacturers of medi- cines. The practicing physicians will play a vital role in implementing personalized medicine. Various players in the development of personalized medicine are listed in Table 20. It provides a structure for achieving consensus positions on crucial public policy issues and serves as a forum for debate and education. Its functions are: • To provide forums for public policy discussions – Personalized medicine: science, policy, and economics – Public attitudes toward genetics – Personalized medicine and cancer Universal Free E-Book Store Role of Pharmaceutical Industry 591 Table 20. This interest parallels the applications of knowledge gained from sequencing the genome in drug development and molecular diagnostics. Use of pharmacogenetics and pharmacogenomics in clinical trials sponsored by the phar- maceutical industry is increasing as described in earlier chapters of this report. Universal Free E-Book Store 592 20 Development of Personalized Medicine In recent history, the pharmaceutical industry has played the major role in devel- oping most of the innovations in therapy. Eventually for clinical applications, the collaborations involve academic healthcare centers that have the patients. The major incentive for the phar- maceutical industry to participate in the development of personalized medicine is the increasing interest and technologies available for developing such medicines. In future, we will see more competition among the companies in this area as those who do not remain on the forefront will be at a considerable disadvantage in the future healthcare market. Companies such as Hoffmann-La Roche are in a good position to develop such innovative healthcare systems as they have the largest molecular diagnostic facility and already have products where diagnostics and therapeutics are packaged together. Individual technologies and data for the development of person- alized medicine stem mostly from biotechnology companies. Principles of personal- ized medicine play an important role at all stages of the drug development process. Personalized Drug Discovery To start with use of established drugs is being personalized. Assays of drug action typically evaluate biochemical activity; however, accurately matching therapeutic efﬁcacy with biochemical activ- ity is a challenge. High-content cellular assays seek to bridge this gap by capturing broad information about the cellular physiology of drug action. The detailed infor- mation contained in genomic expression data is sufﬁcient to match the physiologi- cal effect of a novel drug at the cellular level with its clinical relevance. This capacity to identify therapeutic efﬁcacy on the basis of gene expression signatures in vitro has potential utility in drug discovery and drug target validation relevant to personalized medicine. Personalized Approach to Clinical Trials It is well recognized that average treatment effects estimated by systematic reviews of clinical trials do not really apply to an individual patient, and might differ in patient subgroups. This can lead to treatment of patients for whom the treatment is not effective, and may be harmful. Positive clinical trial results may mask a lack of meaningful beneﬁt for those at lower risks of illness, e. The authors emphasized that the problem of trials masking the “heterogeneity of Universal Free E-Book Store Role of Pharmaceutical Industry 593 treatment effects” can result in guidelines that promote overtreatment as well as undertreatment, and recommended estimation of treatment effects after stratifying trial participants according to baseline risk.