Anna Locasciulli, M.D.

• Associated Professor
• Pediatric Hematology
• University of Medicine
• Director
• Pediatric Hematology
• San Camillo Hospital
• Rome, Italy

However symptoms nausea buy 6mg exelon amex, of great interest are gene interactions involving complex diseases in humans treatment tracker purchase exelon 4.5mg without prescription. Most cancer-causing mutations occur in somatic cells; only about 5 to 10 percent of cancers have a hereditary component medications 3 times a day cheap exelon 6mg with visa. Cancer cells in primary and secondary tumors are clonal symptoms thyroid generic 4.5 mg exelon with visa, arising from one stem cell that accumulated several cancer-causing mutations medicine 027 exelon 3 mg free shipping. The development of cancer is a multistep process requiring multiple mutations and clonal expansions symptoms ms women buy exelon 4.5mg without prescription. Cancer cells show high levels of genomic instability, leading to the accumulation of multiple mutations, some in cancer-related genes. Mutations in proto-oncogenes and tumor-suppressor genes contribute to the development of cancers. Genetic changes that lead to cancer can be triggered by virus infections as well as numerous natural and humanmade carcinogens. It strikes people of all ages, and one out of three C people will experience a cancer diagnosis sometime in his or her lifetime. Each year, more than 14 million cases of cancer are diagnosed worldwide and more than 8 million people will die from the disease. Over the last 40 years, scientists have discovered that cancer is a genetic disease at the somatic cell level, characterized by the presence of gene products derived from mutated or abnormally expressed genes. The combined effects of numerous abnormal gene products lead to the uncontrolled growth and spread of cancer cells. Although some mutated cancer genes may be inherited, most are created within somatic cells that then divide and form tumors. This new understanding of cancer genetics is also leading to new genespecific treatments, some of which are now entering clinical trials. Some scientists predict that gene-targeted therapies will replace chemotherapies within the next 25 years. The goal of this chapter is to highlight our current understanding of the nature and causes of cancer. As we will see, cancer is a genetic disease that arises from the accumulation of mutations in genes controlling many basic aspects of cellular function. Please note that some of the topics discussed in this chapter are explored in greater depth elsewhere in the text (see Chapter 19 and Special Topic 3-Genomics and Precision Medicine). However, unlike other genetic diseases, cancer is caused by mutations that arise predominantly in somatic cells. Clinically, cancer defines a large number of complex diseases that behave differently depending on the cell types from which they originate and the types of genetic alterations that occur within each cancer type. Cancers vary in their ages of onset, growth rates, invasiveness, prognoses, and responsiveness to treatments. However, at the molecular level, all cancers exhibit common characteristics that unite them as a family. All cancer cells share two fundamental properties: (1) abnormal cell growth and division (proliferation), and (2) defects in the normal restraints that keep cells from spreading and colonizing other parts of the body (metastasis). In normal cells, these functions are tightly controlled by genes that are expressed appropriately in time and place. It is this combination of uncontrolled cell proliferation and metastatic spread that makes cancer cells dangerous. When a cell simply loses genetic control over cell growth, it may grow into a multicellular mass, a benign tumor. However, if cells in the tumor also have the ability to break loose, enter the bloodstream, invade other tissues, and form secondary tumors (metastases), they become malignant. As we will see later in the chapter, there are multiple steps and genetic mutations that convert a benign tumor into a dangerous malignant tumor. Although malignant tumors may contain billions of cells, and may invade and grow in numerous parts of the body, all cancer cells in the primary and secondary tumors are clonal, meaning that they originated from a common ancestral cell that accumulated specific cancer-causing mutations. This is an important concept in understanding the molecular causes of cancer and has implications for its diagnosis. For example, reciprocal chromosomal translocations are characteristic of many cancers, including leukemias and lymphomas (two cancers involving white blood cells). This demonstrates that cells in a tumor arise from a single cell, and this cell passes on its genetic aberrations to its progeny. Although all cancer cells within a tumor are clonal, containing the same core set of cancer-causing genes that arose in the ancestral tumor cell, not all cells in a tumor are genetically identical throughout their entire genomes. Next-generation sequencing studies reveal that tumors are composed of subpopulations, or subclones, each of which contains its own sets of distinctive mutations. We will discuss the origins and implications of cancer subclones later in the chapter. The Cancer Stem Cell Hypothesis A concept that is related to the clonal origin of cancer cells is that of the cancer stem cell. Many scientists now believe that most of the cells within tumors do not proliferate. Those that do proliferate and give rise to all the cells within the tumor or within a tumor subclone are known as cancer stem cells. Stem cells are undifferentiated cells that have the capacity for self-renewal-a process in which the stem cell divides unevenly, creating one daughter cell that goes on to differentiate into a mature cell type and one that remains a stem cell. Stem cells are also discussed elsewhere in the text (see the Genetics, Ethics, and Society essay in Chapter 23). The cancer stem cell hypothesis is in contrast to the random or stochastic model that predicts that every cell within a tumor has the potential to form a new tumor. Cancer stem cells have been identified in leukemias as well as in solid tumors of the brain, breast, colon, ovary, pancreas, and prostate. It is still not clear what fraction of any tumor is composed of cancer stem cells. For example, human acute myeloid leukemias contain less than 1 cancer stem cell in 10,000. In contrast, some solid tumors may contain as many as 40 percent cancer stem cells. It is possible that cancer stem cells may arise from normal adult stem cells within a tissue, or they may be created from more differentiated somatic cells that acquire properties similar to stem cells after accumulating numerous mutations and changes to chromatin structure. Data from these studies are revealing that tens of thousands of somatic mutations can be present in cancer cells. Researchers believe that only a handful of mutations in each tumor-called driver mutations-give a growth advantage to a tumor cell. The total number of driver mutations that occur in any particular cancer is small-between 2 and 8. These studies confirm that there is a great deal of genetic variation between individual cells and subclones within tumors. Most of these variations are due to the accumulation of different types of passenger mutations, with the few key driver mutations remaining constant between subclones. Although most of these passenger mutations may not initially confer a selective advantage on the cells that contain them, if environmental conditions change-such as during chemotherapy or radiotherapy-a passenger mutation may confer a new phenotype such as drug resistance which will be selected for, leading to clonal expansion of that cell and the appearance of a new subclone within the tumor. As we will discover in subsequent sections of this chapter, the genes that acquire driver mutations that lead to cancer (called oncogenes and tumor-suppressor genes) are those that control a large number of essential cellular Cancer as a Multistep Process, Requiring Multiple Mutations and Clonal Expansions Although we know that cancer is a genetic disease initiated by driver mutations that lead to uncontrolled cell proliferation and metastasis, a single mutation is not sufficient to transform a normal cell into a tumor-forming (tumorigenic) malignant cell. Because there are approximately 10 16 cell divisions in a human body during a lifetime, a person might suffer up to 10 10 mutations per gene somewhere in the body, during his or her lifetime. The phenomenon of age-related cancer is another indication that cancer develops from the accumulation of several mutagenic events in a single cell. Another indication that cancer is a multistep process is the delay that occurs between exposure to carcinogens (cancer-causing agents) and the appearance of the cancer. For example, there was an incubation period of five to eight years between the time people were exposed to radiation from the atomic explosions at Hiroshima and Nagasaki and the onset of leukemias. Each step in tumorigenesis (the development of a malignant tumor) appears to be the result of two or more genetic alterations that release a cancer stem cell from the controls that normally operate on proliferation and malignancy. Each step confers a selective advantage to the growth and survival of the cell and is propagated through successive clonal expansions leading to a fully malignant tumor. The stepwise clonal evolution of tumors is illustrated by the development of colorectal cancer. The first step is the conversion of a normal epithelial cell into a small cluster of cells known as an adenoma or polyp. The second step in the development of colorectal cancer is the acquisition of a second genetic alteration in one of the cells within the small adenoma. This is usually a mutation in the Kras gene, a gene whose product is normally involved with regulating cell growth. The mutations in Kras that contribute to colorectal cancer cause the Kras protein to become constitutively active, resulting in unregulated cell division. The products of these genes control several important aspects of normal cell growth and division, such as apoptosis, growth signaling, and cell-cycle regulation-all of which we will discuss in more detail later in the chapter. The resulting carcinoma is able to further grow and invade the underlying tissues of the colon. A few cells within the carcinoma may break free of the tumor, migrate to other parts of the body, and form metastases. The resulting loss of genomic integrity leads to a general increase in the mutation rate for every gene in the genome, including cancer-causing driver mutations. The high level of genomic instability seen in cancer cells is known as the mutator phenotype. Some of the genes that acquire driver mutations and cause the progressive development of colorectal cancer are shown above the photographs. These driver mutations accumulate over time and can take 40 years or more to result in the formation of a malignant tumor. Cancer cells that are grown in cultures in the lab also show a great deal of genomic instability- duplicating, losing, and translocating chromosomes or parts of chromosomes. Often cancer cells show specific chromosomal defects that are used to diagnose the type and stage of the cancer. Epigenetic effects can be inherited from one cell to its progeny cells and may be present in either somatic or germ-line cells. The genomic patterns and locations of these modifications can affect gene expression. The effects of chromatin modifications and epigenetic factors on gene expression and cancer are discussed in more detail earlier in the text (see Chapters 17 and 19). At the same time, the promoters of some genes are hypermethylated in cancer cells. Genes that encode histone acetylases, deacetylases, methyltransferases, and demethylases are often mutated or aberrantly expressed in cancer cells. The large numbers of epigenetic abnormalities in tumors have prompted some scientists to speculate that there may be more epigenetic defects in cancer cells than there are gene mutations. In addition, because epigenetic modifications are reversible, it may be possible to treat cancers using epigenetic-based therapies. Cell proliferation is the process of cell growth and division that is essential for all development and tissue repair in multicellular organisms. Differentiated cells are those that are specialized for specific functions, such as photoreceptor cells of the retina or muscle cells of the heart. The most extreme examples of nonproliferating cells are nerve cells, which divide little, if at all, even to replace damaged tissue. In contrast, many differentiated cells, such as those in the liver and kidney, are able to grow and divide when stimulated by extracellular signals and growth factors. However, the growth and differentiation of cells must be strictly regulated; otherwise, the integrity of organs and tissues would be compromised by the presence of inappropriate types and quantities of cells. Normal regulation over cell proliferation involves a large number of gene products that control steps in the cell cycle. In this section, we will review steps in the cell cycle, some of the genes that control the cell cycle, and how these genes, when mutated, lead to cancer. During M phase, the duplicated chromosomes condense, sister chromosomes separate to opposite poles, and the cell divides in two. These phases of the cell cycle are also discussed in more detail earlier in the text (see Chapter 2). In early to mid-G1, the cell makes a decision either to enter the next cell cycle or to withdraw from the cell cycle into quiescence. Continuously dividing cells do not exit the cell cycle but proceed through G1, S, G2, and M phases; however, if the cell receives signals to stop growing, it enters the G0 phase of the cell cycle. Most differentiated cells in multicellular organisms can remain in this G0 phase indefinitely. In contrast, cancer cells are unable to enter G0, and instead, they continuously cycle. Their rate of proliferation is not necessarily any greater than that of normal proliferating cells; however, they are not able to become quiescent at the appropriate time or place. Cells in G0 can often be stimulated to reenter the cell cycle by external growth signals. These signals are delivered to the cell by molecules such as growth factors and hormones that bind to cell-surface receptors, which then relay the signal from the plasma membrane to the cytoplasm. The process of transmitting growth signals from the external environment to the cell nucleus is known as signal transduction. Ultimately, signal transduction initiates a proD2 A B gram of gene expression that propels the cell out of G0 back into the cell cycle. Sometimes, abnormal signal transduction molE ecules send continuous growth signals to the nucleus even in the absence of external growth signals. An example of abnormal signal transducG1 S G2 M tion due to mutations in the ras gene is described in Section 24. Cyclin D1 accumulates early in G1 and is expressed at proliferation within a mature tissue. Cyclin E accumulates in Cell-Cycle Control and Checkpoints In normal cells, progress through the cell cycle is tightly regulated, and each step must be completed before the next step can begin.

Gene regulatory special feature: Transcriptional network underlying Caenorhabditis elegans vulval development medicine 3 times a day order exelon. Unraveling the tangled skein: the evolution of transcriptional networks in development medicine of the prophet purchase exelon in india. Developmental patterning genes and their conserved functions: From model organisms to humans medications side effects prescription drugs buy 6 mg exelon otc. Natural alleles at a tomato fruit size quantitative trait locus differ by heterochronic regulatory mutations medications elderly should not take buy exelon uk. Fine mapping of quantitative traits loci using selected overlapping recombinant chromosomes in an interspecific cross of tomato treatment 2 lung cancer order exelon with visa. The genetic medicine chest cheap exelon 6mg otc, developmental and molecular bases of fruit size and shape variation in tomato. Birth weight and gestation time in relation to maternal age, parity and infant survival. Experimental studies of the distribution of gene frequencies in very small populations of Drosophila melanogaster. Why does cystic fibrosis display the prevalence and distribution observed in human populations The interaction of sexually and naturally selected traits in the adaptive radiations of cichlid fishes. The combined landscape of Denisovan and Neaderthal ancestry in present-day humans. The genotype of an organism is defined as the specific allelic or genetic constitution of an organism, or, often, the allelic composition of one or a limited number of genes under investigation. There can be many such variants in a population, but for a diploid organism, only two such alleles can exist in any given individual. They consist of linear sequences of nucleotides and usually exert their influence by producing proteins through the processes of transcription and translation. Chromosomes are long strands of nucleotides that contain linear assemblies of genes. Chromosomes (and by extension, genes) are duplicated by a variety of enzymes so that daughter cells inherit copies of the parental hereditary information. The processes of transcription and translation are integral to understanding these relationships. When a vector is cleaved with the same enzyme, complementary ends are created such that ends, regardless of their origin, can be combined and ligated to form intact double-stranded structures. Such recombinant forms are often useful for industrial, research, and/or pharmaceutical efforts. Supporters of organismic patenting argue that it is needed to encourage innovation and allow the costs of discovery to be recovered. Capital investors assume that there is a likely chance that their investments will yield positive returns. Others argue that natural substances should not be privately owned and that once they are owned by a small number of companies, free enterprise will be stifled. Model organisms are not only useful, but also necessary for understanding genes that influence human diseases. Given that many genetic/molecular systems are highly conserved across broad phylogenetic lines, what is learned in one organism is usually applied to all organisms. In addition, most model organisms have peculiarities, such as ease of growth, genetic understanding, or abundant offspring, that make their use straightforward and especially informative in genetic studies. For approximately 60 years discoveries in genetics have guided our understanding of living systems, aided rational drug design, and dominated many social discussions. Genetics provides the framework for universal biological processes and helps explain species stability and diversity. Mitosis maintains chromosomal constancy, so there is no change in chromosome number or kind in the two daughter cells. By contrast, meiosis provides for a reduction in chromosome number and an opportunity for exchange of genetic material between homologous chromosomes. During oogenesis, only one of the four meiotic products is functional; however, four of the four meiotic products of spermatogenesis are potentially functional. Errors during either mitosis or meiosis (such as nondisjunction events) can lead to cells with too many or too few chromosomes. Chromosomes that are homologous share many properties including overall length, position of the centromere (metacentric, submetacentric, acrocentric, telocentric), banding patterns, type and location of genes, and autoradiographic pattern. Haploidy refers to the presence of a single copy of each homologous chromosome (n). In plants, a cell plate that was laid down during telophase becomes the middle lamella where primary and secondary layers of the cell wall are deposited. In animals, constriction of a cell membrane produces a cell furrow of daughter cells. In other words, there are two chromosomes (and four chromatids) that make up a bivalent. It is a method of providing genetic variation through the breaking and rejoining of chromatids. Sister chromatids are genetically identical (except where mutations have occurred) and are originally attached to the same centromere. This is achieved by synapsis of homologous chromosomes and their subsequent separation. It would seem to be more mechanically difficult for genetically identical daughters to form from mitosis if homologous chromosomes paired. By having chromosomes unpaired at metaphase of mitosis, only centromere division is required for daughter cells to eventually receive identical chromosomal complements. First, through independent assortment of chromosomes at anaphase I of meiosis, daughter cells (secondary spermatocytes and secondary oocytes) may contain different sets of maternally and paternally derived chromosomes. Second, crossing over, which happens at a much higher frequency in meiotic cells as compared with mitotic cells, allows maternally and paternally derived chromosomes to exchange segments, thereby increasing the likelihood that daughter cells (that is, secondary spermatocytes and secondary oocytes) are genetically unique. By contrast, daughter cells resulting from mitosis are usually genetically identical. In angiosperms, meiosis results in the formation of microspores (male) and megaspores (female), which give rise to the haploid male and female gametophyte stage. The folded-fiber model is based on each chromatid consisting of a single fiber wound like a skein of yarn. A coiling process occurs during the transition of interphase chromatin into more condensed chromosomes during prophase of mitosis or meiosis. At the end of prophase I, maternal and paternal copies of each homologous chromosome (Am and Ap, Bm and Bp, Cm and Cp) will be synapsed. At the completion of anaphase I, eight possible combinations of products (Am or Ap, Bm or Bp, Cm or Cp) will occur. Fertilization of the gametes described in Problem 29 will give the following zygotes: Zygote 1: two copies of chromosome A two copies of chromosome B three copies of chromosome C two copies of chromosome A two copies of chromosome B one copy of chromosome C Zygote 2: None of the zygotes will be diploid. The resulting zygote would have one copy of chromosome 21 (from the father) and two copies of all the other chromosomes. For the phenotypic frequencies, set up the problem in the following manner: 3/4 B 3/4 A -1/4 bb 1/4aa-3/4 B 1/4 bb 3/4 C = 27/64 A B C 1/4 cc = 9/64 A B cc 3/4 C 1/4 cc 3/4 C 1/4 cc 3/4 C 1/4 cc etc. To deal with parts (b) and (c) it is easier to see the observed values for the monohybrid ratios if the phenotypes are listed: smooth, yellow smooth, green wrinkled, yellow wrinkled, green 315 108 101 32 4. It is naturally self- For the smooth: wrinkled monohybrid component, the smooth types total 423 (315 + 108), while the wrinkled types total 133 (101 + 32). Expected ratio 3/4 1/4 Observed (o) 423 133 Expected (e) 417 139 fertilizing, but it can be crossbred. First, two alternatives (black and white) of one characteristic (coat color) are being described; therefore, a monohybrid condition exists. Note that all the offspring are black; therefore, black can be considered dominant. The second sentence of the problem verifies that a monohybrid cross is involved because of the 3/4 black and 1/4 white distribution in the offspring. We fail to reject the null hypothesis and are confident that the observed values do not differ significantly from the expected values. When homologous chromosomes separate from each other at anaphase I, alleles will go to opposite poles of the meiotic apparatus. Different gene pairs on the same homologous pair of chromosomes (if far apart) or on nonhomologous chromosomes will separate independently from each other during meiosis. In Cross 2, a typical 3:1 Mendelian ratio is observed, which indicates that two heterozygotes were crossed: Ww * Ww 14. We would therefore say that there is a "good fit" between the observed and expected values. The only difference is that the recessive genes are coming from both parents, rather than from one parent only as in part (a). When you have genes on the autosomes (not X-linked), independent assortment, complete dominance, and no gene interaction (see later) in a cross involving double heterozygotes, the offspring ratio will be 9:3:3:1. Even though this cross involves two gene pairs, it will give a "monohybrid" type of ratio because one of the gene pairs is homozygous (body color) and one gene pair is heterozygous (wing length). As the critical p value is increased, it takes a smaller x2 value to cause rejection of the null hypothesis. It would take less difference between the expected and observed values to reject the null hypothesis; therefore, the stringency of failing to reject the null hypothesis is increased. Under that circumstance, there is a 25 percent chance that each of their children would be affected. The probability that two children of heterozygous parents would be affected would be 0. In the first cross, notice that a 3: 1 ratio exists for the spiny to smooth phenotypes, leading to the hypothesis that the spiny allele is dominant to smooth. Apply the same reasoning to the second cross, where there is a 3: 1 ratio of purple to white. The purple, spiny F1 would support the hypothesis that purple is dominant to white and spiny is dominant to smooth. In the F2, a 9: 3: 3: 1 ratio would not only support the above hypothesis, but also indicate the independent inheritance and expression of the two traits. Also, there are only three possibilities: both are heterozygous, neither is heterozygous, and at least one is heterozygous. You have already calculated the first two probabilities; the last is simply 1 - (1/12 + 6/12) = 5/12. One would reject the null hypothesis and assume a significant difference between the observed and expected values. In fact, most statisticians recommend that the expected values in each class should not be less than 10. Crosses: ckck ckck ckcd ckcd ckca ckca * * * * * * cdcd cdca cdcd cdca cdcd cdca all sepia all sepia 1/2 sepia; 1/2 cream 1/2 sepia; 1/2 cream 1/2 sepia; 1/2 cream 1/2 sepia; 1/4 cream; 1/4 albino (d) Parents: sepia * cream Because the sepia parent had a full color parent and an albino parent (Cck * caca), it must be ckca. The cream parent had two full color parents that could be Ccd or Cca; therefore, it could be cdcd or cdca. Crosses: ckca * cdcd ckca * cdca b = red 1/2 sepia; 1/2 cream 1/2 sepia; 1/4 cream; 1/4 albino 4. C chC ch = chestnut C cC c = cremello C chC c = palomino (b) the F1 resulting from matings between cremello and chestnut horses would be expected to be all palomino. The F2 would be expected to fall in a 1: 2: 1 ratio as in the third cross in part (a). F2 offspring would have the following "simplified" genotypes with the corresponding phenotypes: A C = 9/16 (agouti) A cc = 3/16 (colorless because cc is epistatic to A) aaC = 3/16 (black) aacc = 1/16 (colorless because cc is epistatic to aa) the two colorless classes are phenotypically indistinguishable; therefore, the final ratio is 9: 3: 4. Half of the pigmented offspring are black and half are agouti; therefore, the female must have been Aa. Your essay should include a description of alleles that do not function independently of each other or that reduce the viability of a class of offspring. With multiple alleles, there are more than two alternatives of a given gene at a given locus. The P allele behaves as a recessive in terms of lethality (seen only in the homozygote) but as a dominant in terms of coat color (seen in the homozygote). Because many individuals in a population could have genotypes with the i allele, one could not prove that a particular male was the father by this method. Three independently assorting characteristics are being dealt with: (1) flower color (incomplete dominance), (2) flower shape (dominant/recessive), and (3) plant height (dominant/recessive). Phenotypes: gray * gray (c) Notice that 16/64 or 1/4 of the offspring are albino; therefore, the parents are both heterozygous at the C locus. Second, notice that without considering the C locus, there is a 27: 9: 9: 3 ratio that reduces to a 9: 3: 3: 1 ratio. F2: Phenotypes: 3/16 normal females 3/16 normal males 1/16 ebony females 1/16 ebony males 3/16 scalloped females 3/16 scalloped males 1/16 scalloped, ebony females 1/16 scalloped, ebony males Forked-line method: P1: F1: F2: Wings 1/4 1/4 1/4 1/4 females, normal females, scalloped males, normal males, scalloped Color 3/4 normal 1/4 ebony 3/4 normal 1/4 ebony 3/4 normal 1/4 ebony 3/4 normal 1/4 ebony 3/16 1/16 3/16 1/16 3/16 1/16 3/16 1/16 X sd X sd; e +/e + * X +/Y; e/e 1/2 X +X sd; e +/e (female, normal) 1/2 X sd/Y; e +/e (male, scalloped) 20. Notice that the X symbol may remain to remind us that the sd gene is on the X chromosome. It is extremely important that one account for both the mutant genes and each of their wild-type alleles. Phenotypic expression is dependent on the genome of the organism; the immediate molecular and cellular environment of the genome; and numerous interactions between a genome, the organism, and the environment. The dominant genes are on one homolog, while the recessive alleles are on the other homolog. Given the degree of outcrossing, that the gene is probably quite rare and therefore heterozygotes are uncommon, and that the frequency of transmission is high, it is likely that this form of male precocious puberty is caused by an autosomal dominant, sex-limited gene. Your essay should include methods of detection through crosses with appropriate, distinguishable markers and that, in most cases, the frequency of crossing over is directly related to the distance between genes.

Cardioembolic strokes are often larger symptoms 6 days past ovulation order exelon 1.5mg with visa, involve superficial and deep structures of the brain treatment of strep throat order exelon toronto, and may involve multiple vascular territories at the same time treatment 32 for bad breath order exelon paypal. Rare Causes and General Considerations Unusual presentations of stroke medications for ibs 4.5mg exelon amex, such as young age or other systemic disease treatment xdr tb exelon 4.5mg for sale, may point to a less common etiology symptoms 9 days after embryo transfer buy exelon overnight delivery, such as infection, vasculitis, or genetic disorders, which have a tendency for progression or worsening course. Optimization of medical care also impacts the progression of cerebral ischemia, irreversible cellular injury, and neurological decline. While there is preclinical and clinical evidence of the beneficial effects of hypothermia as a neuroprotectant in neurological injury, spontaneous hypothermia at presentation has been linked to early neurological worsening in ischemic patients (28). Hyperglycemia is seen in up to 40% of patients and is also associated with worsening outcomes. The following steps are essential for optimum stroke outcomes: rapid diagnosis, appropriate provision of acute revascularization therapy, close monitoring, supportive care, recognition of etiology, and timely initiation of secondary prevention strategies. Rapid Diagnosis Failure to recognize a stroke, either because of transient or ambiguous symptoms, or lack of sufficient expertise, puts the patient at risk of recurrent stroke. Acute Revascularization Therapy the timely revascularization of occluded vessels can significantly reduce stroke symptoms and disability. The decision to perform endovascular thrombectomy in these cases is controversial, and studies are ongoing. Thorough assessment of the stability of their collaterals may assist in the decision making and include perfusion imaging or a bedside orthostatic challenge test. Prehospital and emergency department protocols for hyperacute clinical and radiological assessment of stroke should be instated to facilitate the rapid recognition and determination of patient eligibility for time-sensitive treatments. Patient Monitoring Stroke patients should be monitored in units with sufficiently trained nursing staff and appropriate monitoring equipment. The admission of patients to dedicated stroke units has been shown to improve outcomes when compared to patients admitted to nonstroke units (42). While frequent neurological assessment is important for all stroke patients, monitoring should be vigilant in the high-risk populations, including patients who have undergone revascularization treatments (systemic thrombolysis or mechanical thrombectomy), have impending flow failure. Supportive Care Certified stroke centers have evidence-based protocols aimed to reduce common complications and optimize outcomes. Routine methods for prevention of common sequelae of stroke, such as aspiration pneumonia and deep venous thrombosis, have been established and include screening protocols and order sets. While flat bed rest was found to have no specific benefit for stroke patients in general (43), patients with impending flow failure may benefit from flow augmentation measures that include flat bed rest, supplementation with intravenous fluids, or pharmacological pressure support. Strict control of temperature and prevention of hyperthermia is of clinical benefit. While the prospects of hypothermia as a neuroprotectant are promising, there is no evidence for its routine implementation in clinical care currently. Similarly, management of hyperglycemia is advisable, although the value of aggressive glycemic control is still the subject of investigation. Recognition of Etiology Occasionally, the etiology of stroke becomes apparent during the hyperacute triage phase. However, when the etiology is not immediately identified, further workup should be initiated based on presentation. For example, in a febrile patient with an embolic pattern of infarction, endocarditis is of greater concern and evaluation should include transthoracic echo and blood cultures. Though invasive, catheter-based angiography can provide valuable information regarding stroke etiology when the etiology is not clear with less invasive testing. Patients with impaired cerebrovascular reserve are at higher risk of flow failure related recurrence. Secondary Prevention Strategies Measures of secondary prevention include the timely initiation of antithrombotic therapy. This regimen of maximum medical therapy for 3 months duration has been found to result in lower risk of recurrent stroke compared to endovascular intracranial stenting (53). Angioplasty, with or without intracranial stenting, remains a treatment option for patients who have recurrent stroke in spite of maximum medical therapy. Depending on the size of infarct, anticoagulation may be initially held to decrease the chance of hemorrhagic conversion with systemic anticoagulation. With small strokes anticoagulation can at times be started 24 hours after the infarct, whereas large strokes can require up to 2 weeks without anticoagulation (54). Given the high recurrence rate of stroke in these patients, revascularization should occur as early as safely possible. The benefit of revascularization declines rapidly over time, as does the risk of recurrence. Patients with 50% to 69% stenosis, for example, mostly benefit if revascularization is performed within 2 weeks from the index event (62). The number needed to treat after 4 weeks is three times that of patients treated in the first 2 weeks. For patients with large hemispheric strokes, however, delayed carotid revascularization may be reasonable. For patients with less common etiologies of stroke, secondary prevention should be tailored to the underlying condition. Discovery of an infectious vegetation, for instance, requires intravenous antibiotics, while discovery of an atrial myxoma might necessitate surgery. Patients with emboli from prosthetic valve or left ventricular assist device typically warrant earlier anticoagulation despite a risk for hemorrhagic conversion given the high risk for further emboli. Aortic plaques are treated with antiplatelet or anticoagulant agents, depending on size, morphology, and response. However, in those patients with larger, mobile atheroma, or who fail antiplatelet agents, anticoagulation is more commonly used. In patients diagnosed with vasculitis, evaluation for immunosuppression therapy should be quickly initiated. Risk varies based on underlying stroke mechanism, with specific clinical scenarios carrying significantly higher risk of worsening. Strategies aimed at early diagnosis and identification of stroke etiology can help identify high-risk patients. Appropriate rapid revascularization, supportive care in monitored stroke units, and treatment of the underlying disease with implementation of secondary prevention vastly improve stroke outcomes. Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments. Leukoaraiosis correlates with the, neurologic deterioration after small subcortical infarction. Neurological deterioration in acute lacunar infarctions: the role of excitatory and inhibitory neurotransmitters. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. Infarct patterns, collaterals and likely causative mechanisms of stroke in symptomatic intracranial atherosclerosis. Incidence and outcome of cerebrovascular events related to cervical artery dissection: the Dijon Stroke Registry. The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Endovascular treatment and the outcomes of atherosclerotic intracranial stenosis in patients with hyperacute stroke. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Telemedicine quality and outcomes in stroke: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. Aortic plaque in patients with brain ischemia: diagnosis by transesophageal echocardiography. Noninvasive cardiac event, monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. Sex difference in the effect of time from symptoms to surgery on benefit from carotid endarterectomy for transient ischemic attack and nondisabling stroke. Clopidogrel plus aspirin ver, sus warfarin in patients with stroke and aortic arch plaques. This nontraumatic rupture of cerebral blood vessels is the second most common form of stroke and accounts for approximately 10% to 30% of first ever stroke presentations (2). Intracerebral hemorrhage has a 1-month mortality ranging from 30% to 55%, and approximately 75% of survivors continue to suffer severe disability long term (2,3). In contrast to ischemic stroke, intracerebral hemorrhage has not significantly changed in the past 40 years (4). Intracerebral hemorrhage is increasingly seen with age and may relate to the increased use of anticoagulation in older adults and the higher prevalence of amyloid angiopathy and hypertension (1). Earlier studies have previously suggested an increased rate of hemorrhage in men; however, more recent work by Gokhale et al. The only exception to this is in Japanese men, where there is a significantly higher occurrence of intracerebral hemorrhage (4). Certain ethnicities are also associated with higher rates of intracerebral hemorrhage, including East and Southeast Asians, Latin Americans, Blacks, and Native Americans (1,4). Within ethnic groups, geographical differences in intracerebral hemorrhage incidence have also been noted. There is a higher rate of hemorrhage in those living in Asia versus Asian migrants living in North America (4). Black New Yorkers have a higher rate of hemorrhage occurrence compared to those living outside of the United States (4). Environmental factors, such as cardiovascular risk control, socioeconomic status, and appropriate healthcare access are clearly influential in the incidence of intracerebral hemorrhage. Due to limited treatment options and our aging population, hospital admissions for intracerebral hemorrhage increased by 18% from 1990 to 2000 (1) and are projected to increase further. Care of patients with intracerebral hemorrhage is further complicated by the dynamic nature of the disease. Patients are often subject to rapid changes in their clinical status within the first few hours to days of symptom onset (7). These changes are often associated with complications that can lead to clinical deterioration and include fever, seizure, intraventricular extension, and hematoma expansion (8,9). Hematoma expansion after arrival stands as one of the most critical and frequent contributors to poor outcome. It occurs early in the presentation and is the proposed therapeutic target of treatment trials, both past and present. An improved understanding of this process can ultimately lead to treatments that are successful at preventing it. This article focuses specifically on our current understandings of hematoma expansion: how we define it, how it occurs, what best predicts it, and how we may treat it in the future. Yet, the amount of expansion required to be deemed significant has been a subject of continued debate. Moreover, the frequency and occurrence of hematoma expansion vary depending on the definition used (3). Hematoma expansion has been an area of active investigation over the past 30 years as brain imaging has become more accessible. Early expansion definitions first used in the late 1980s were varied, largely arbitrary, and without statistical basis. The first attempt to derive a statistically based definition of hematoma expansion was conducted in the mid-1990s by Kazui et al. First, a change in hematoma volume of at least 33% relative to the baseline correlates with a 10% change in the diameter of a hematoma. Second, it was deemed that a change of 33% or greater would represent true growth and not variability secondary to imaging technique. Since its introduction in 1997, this definition has been adopted widely and used for a number of subsequent studies (14). Another definition of 6 mL was loosely based on expansion definitions used in neurotrauma and neurosurgical circles to evaluate traumatic intraparenchymal hemorrhages and has also been used by several subsequent studies (14,15).

Because of its substantial impact on stroke-related morbidity and mortality symptoms 3 weeks into pregnancy buy exelon 3mg low cost, infection is considered a major source of complication after acute stroke medications not to mix cheap exelon 3 mg with visa. The latter explains why acute stroke patients are particularly susceptible to developing early infections symptoms 10 days before period purchase cheap exelon, irrespective of merely stroke-related disability medications erectile dysfunction order 4.5 mg exelon otc. Immobility medicine ads buy generic exelon 6mg on-line, mechanical ventilation symptoms pneumonia purchase exelon visa, and indwelling tubes and intravenous/intra-arterial lines all can increase the risk for infection. Decreased level of alertness, dysphagia, and impaired cough can lead to aspiration, a common cause of pneumonia in stroke patients. The plurality of evidence suggests that poststroke pneumonia is often due to aspiration (4). Aspiration pneumonia is the most important acute complication of poststroke dysphagia (found in nearly 50% of acute stroke patients), affecting up to one-third of dysphagic patients (5). Aspiration pneumonia often occurs after aspiration of colonized oropharyngeal material. In addition, similar to nonstroke hospitalized patients, acute stroke patients are at risk for nosocomial pneumonia. Urinary incontinence and retention are common after stroke, occurring in 29% to 58% of patients (9). Other potential causes of infection in acute stroke patients are central venous catheters and arterial lines. The frequency of line infections in acute stroke patients is similar to any other hospitalized patient who undergoes these procedures. It is primarily placed in patients with intraventricular hemorrhage at risk for developing hydrocephalus, or in those with cerebellar infarcts or hematomas obliterating the fourth ventricle. The theory behind "poststroke immunodepression" is complex and involves several proposed mechanisms, including poststroke systemic inflammation, giving rise to a "protective" immunosuppressive state (2). Experimental and clinical evidence suggests peripheral lymphocytopenia, decreased monocyte count and function, and interferon-gamma deficiency, which begins a few hours after ischemia and lasts for several weeks (12). Neuroendocrine pathways involving acetylcholine and norepinephrine immediately activated after acute stroke may alter the production and function of inflammatory and anti-inflammatory cytokines, creating a state of immunologic disarray (1). This state, in turn, creates a suitable environment for pathogens causing hospital-acquired infections. As the infectious process progresses, upregulation of the systemic inflammatory response from infection leads to excessive inflammation of the brain, causing edema, elevated intracranial pressure, and possibly stroke expansion (2). Specifically, those with moderate-to-severe dysphagia or severe oropharyngeal dysfunction as a result of stroke may be at an increased risk of developing aspiration pneumonia. Aspiration pneumonia can be prevented by early involvement of the dysphagia team or the speech pathologist. Objective measures of voluntary cough can identify stroke patients who are at risk for aspiration (14). The head of the bed should be placed in a position allowing adequate draining of oropharyngeal secretions. Frequent patient repositioning, maintaining adequate oral hygiene, diet modifications and postural compensation, prescription of appropriate fluid and solid food consistency, and expiratory muscle strengthening are some of the strategies for prevention of aspiration in acute stroke patients. In patients with feeding tubes, the position of the tube and gastric residual volume should be monitored and assessed regularly. Last, sedation should be minimized (unless the patient requires mechanical ventilation). The use of gastrointestinal stress ulcer prophylaxis should be balanced against the potential for elevation of stomach pH, which promotes colonization with potentially pathogenic organisms (16). Inappropriate use of indwelling bladder catheters, for example in stroke patients who are mobile or are able to void on volition, should be avoided. If a Foley catheter is instituted in a patient, an objective plan should be formulated to promptly discontinue the device. In men without urinary retention, condom catheters represent a noninvasive alternative. Other measures to prevent infection in acute stroke patients include avoiding unnecessary invasive procedures and lines, and early mobilization. The concept of antibiotic prophylaxis in stroke patients has been studied in several clinical trials. Between 40% and 61% of patients who experience stroke develop fever, and those patients with fever are far more likely to die within the first 10 days after a stroke than those with lower temperatures (20,21). An infectious etiology is responsible for 40% to 80% of fever in poststroke patients (22). Other clinical signs and symptoms of infection are cough, hypoxia, dyspnea, tachypnea, dysuria, altered mental status, abdominal pain, and diarrhea. Acute onset of any of these features should prompt investigation for an infectious process. A chest x-ray should be obtained in patients with fever, clinical signs and symptoms of pneumonia, or aspiration. It should be considered in patients with a high clinical index of suspicion for pneumonia without clear infiltrates on chest x-ray. A bronchopneumonia pattern is most commonly observed, with a distribution that is characteristically gravity dependent. Chest x-ray frequently shows an infiltrate in the dependent lung segments (the superior or posterior basal segments of a lower lobe or the posterior segment of an upper lobe). Sputum Gram stain and culture are more useful in the diagnosis of nosocomial and therefore, it is rarely done for evaluation of aspiration pneumonia. In aspiration pneumonia, Gram stain and microscopy may reveal a multitude of bacteria types, which are characteristically anaerobic. However, anaerobic bacteria are difficult to culture and identification of these pathogens is time-consuming, expensive, and tedious. Urine specimens are obtained from adult patients via the clean-catch midstream technique or via the aseptic method to remove urine from the catheter tubing with a needleless syringe. A positive leukocyte esterase merely depicts inflammation and not necessarily infection. Although it is associated with low specificity and positive predictive value, its absence virtually eliminates infection as a cause. A positive nitrite test is highly specific for the presence of a nitrite-reducing organism, most commonly Escherichia coli. With a positive urinalysis, cultures can be performed to identify the culprit organism and determine its antimicrobial sensitivities. Infections associated with vascular access devices can be diagnosed via blood cultures. Therefore, an absolute cutoff for the diagnosis of infection cannot be established. Observation trends and comparison of values over time is the appropriate way of utilizing this index. The choice of antibiotics has to be guided by local pathogen epidemiology and clinical features. Treatment strategies are different for the two conditions and consist of supportive management itself for aspiration pneumonitis and antimicrobial therapy for aspiration pneumonia (26). However, it is common practice to use antibiotics with the potential for aspiration pneumonia in mind. Common pathogens in aspiration pneumonia are bacteria that normally reside in the upper airways or stomach, primarily oral anaerobes and streptococci (27). Broad-spectrum antibiotics are usually initiated with a plan to de-escalate the regimen based on definitive and quantitative culture in the following 72 hours. For patients allergic to beta-lactam, intravenous aztreonam or ciprofloxacin is used. This is for organism identification and performing antibiotic susceptibility testing that steers antibiotic therapy. Intrathecal vancomycin or gentamicin is sometimes used in situations in which conventional intravenous therapy has failed. Patient characteristics and disability scores are useful in identifying patients who are at high risk for poststroke infections. Once infection is suspected, appropriate antimicrobial agents should be initiated with a solid plan to de-escalate the regimen based on microbiology. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Placing nasogastric tubes in stroke patients with dysphagia: efficiency and tolerability of the reflex placement. Ventilator-associated pneumonia in critically ill stroke patients: frequency, risk factors, and outcomes. Urinary tract infections complicating stroke: mechanisms, consequences, and possible solutions. Urinary tract infection and bacteriurua in stroke patients: frequencies, pathogen microorganisms, and risk factors. Predicting aspiration in patients with ischemic stroke: comparison of clinical signs and aerodynamic measures of voluntary cough. The Intensive Care Society rec, ommended bundle of interventions for the prevention of ventilator-associated pneumonia. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. Nosocomial infections after aneurysmal subarachnoid hemorrhage: time course and causative pathogens. Epidemiology and outcomes of fever burden among patients with acute ischemic stroke. Criteria for the diagnosis of urinary tract infection and for the assessment of therapeutic effectiveness. Cell index-a new parameter for the early diagnosis of ventriculostomy (external ventricular drainage)-related ventriculitis in patients with intraventricular hemorrhage How important are anaerobic bacteria in aspiration pneumonia: when should they be treated and what is optimal therapy. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Diagnosis, prevention, and, treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Managing uncomplicated urinary tract infection-making sense out of resistance data. Effective anticoagulation education involves face-to-face interaction with a trained professional who ensures that the patient understands the risks involved, the precautions that should be taken, and the need for regular monitoring. The teaching should be tailored to each patient, accompanied with written resources and utilize the teach-back method. It can be incorporated in a variety of pharmacy practice settings, including in ambulatory care clinics, hospitals, and community pharmacies. Keywords: pharmacy; anticoagulation; patient education; counseling; communication 1. Introduction Anticoagulants, which are considered "high alert medications," can often lead to adverse drug events in the inpatient and outpatient healthcare setting if not managed appropriately. High alert medications refer to drugs that have an increased risk of causing significant harm when used in error [1]. Many of anticoagulation-associated adverse effects result from medication errors, suggesting they are preventable [2]. Therefore, national patient safety goals for the Joint Commission emphasize decreasing the possibility of patient harm due to anticoagulants (including apixaban, dabigatran, edoxaban, rivaxoraban, and warfarin) and recommend accurate and accessible patient education [3]. Even less comprehensive methods, such as a single patient counseling session at discharge, have noted positive outcomes. Patients had inadequate understanding of warfarin-diet and warfarin-drug interactions. The most common concerns regarding taking warfarin were related to warfarin-drug interactions (36. Pharmacist-managed warfarin services, which includes patient education, have shown positive outcomes with respect to safety, efficacy, and cost savings. Prior exposure and management in anticoagulation clinics increases patient understanding of anticoagulation and the potential consequences of noncompliance. According to the Joint Commission, education should be provided regarding anticoagulant therapy to prescribers, staff, patients, and families. Effective anticoagulation patient education involves face-to-face interaction with a trained professional who ensures that the patient understands the risks involved, the precautions that should be taken, and the need for regular monitoring [5]. Anticoagulation education is often provided as a standard of care and emphasized across healthcare settings [5,30]. Although the majority of research is associated with counseling in the ambulatory care clinic or hospital setting, patient education can be implemented in any setting, including at the community pharmacy [13,14]. Patient Counseling Effective medication counseling can empower patients to be active partners in their care and enhance treatment compliance. Studies demonstrate that patients who are engaged in their health have enhanced care experiences, better outcomes and reduced overall healthcare costs [33,34]. Establishing a therapeutic relationship built on trust can be critical to promoting understanding and empowering self-management.

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