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• Director of Pharmacy, Jefferson Medical Center, Ranson, WV
• Adjunct Clinical Associate Professor, Department of Clinical Pharmacy, West Virginia University School of Pharmacy, Morgantown, West Virginia

Organs rich in phagocytic cells such as the spleen & liver are frequently enlarged in several forms of lysosomal storage diseases women's health gov publications our fact sheet birth control methods generic 2.5 mg femara amex. This is because cells of the mononuclear phagocytic system are rich in lysosomes & are involved in the degradation of a variety of substrates women's health diary 2014 order generic femara online. From among the various types of lysosomal storage diseases listed above women's health clinic harbor ucla cheap femara online amex, only Gaucher disease is discussed here to illustrate the basic principles of lysosomal storage diseases women's health center nyu buy discount femara 2.5 mg online. Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of old red blood cells & white blood cells women's health issues and physical therapy buy femara 2.5 mg mastercard. Type I (Chronic non-neuronopathic form) (Adult Gaucher disease): accounts for 99% of the cases womens health lynchburg purchase 2.5mg femara fast delivery. In the mating of a heterozygous carrier female parent & a normal male parent (the most frequent setting), the sons are hemizygous affected 50% of the time. Affected daughters are produced by matings of heterozygous females with affected males. This is because a male contributes his Y chromosome to his son & does not contribute an X-chromosome to his son. On the other hand, since a male contributes his sole X-chromosome to each daughter, all daughters of a male with an X-linked disorder will inherit the mutant allele. This figure shows an extended pedigree of an X-linked recessive disorder in which the male parents (in both generations) are normal & the female parents carriers. Pathogenesis of X-linked recessive disorders the genes responsible for X-linked disorders are located on the X-chromosome, & the clinical risks are different for the 2 sexes. Since a female has 2 X chromosomes, she may be either homozygous or heterozygous for a mutant gene, & the mutant allele may demonstrate either dominant or recessive expression. Therefore, in heterozygous females carrying X-linked recessive mutations, some cells have one active normal X chromosome & other cells have an active abnormal X chromosome containing the mutant allele. Therefore, the heterozygous female expresses the disorder partially & with less severity than hemizygous men. Very rarely, the mutant allele may be activated in most cells & this results in full expression of a heterozygous X-linked recessive condition in the female. The male is, therefore, said to be hemizygous (& not heterozygous) for the X-linked mutant genes. Males have only oner X-chromosome, so they will clinically show the full phenotype of X-linked recessive diseases, regardless of whether the mutation produces a recessive or dominant allele in the female. Thus, the terms X-linked dominant or X-linked recessive refer only to the expression of the mutations in women. Mitochondrial inheritance is mediated by maternally transmitted mitochondrial genes, which are inherited exclusively by maternal transmission. Chromosomal disorders (Cytogenetic disorders) are caused by chromosome & genome mutations (i. They are found in 50% of early spontaneous abortuses, in 5% of stillbirths, & in 0. The normal karyotype Chromosome classification & nomenclature: Karyotype is the chromosome constitution of an individual. The term is also used for a photomicrograph of the chromosomes of an individual arranged in the standard classification. Karyotyping uses many types of techniques of which G-banding is the most common procedure. G-banding has the following steps: Arrest dividing cells in metaphase by using colchicine. About 400 800 dark & light bands can be seen in a haploid set of chromosomes using G banding. And the first nd chromosome in such an arrangement is called chromosome 1, the 2 chromosome is called chromosome 2, etc. Metaphase chromosomes are divided longitudinally into 2 sister chromatids held together at the centromere, which delineates the chromosome into a short arm (p) & a long arm (q). In a banded karyotype, each arm of the chromosome is divided into 2 or more regions. Each region is further subdivided into bands & sub bands which are also similarly numbered. Nomenclature of a chromosome showing the division of the long arm (q) of the chromosome into regions 1 & 2. Even though not shown in this figure, the other bands of this q arm & the p arm are similarly divided & numbered. The following order is used to describe karyotypes: First the total number of chromosomes is given. Types of chromosomal anomalies Chromosomal anomalies may be numerical or structural. Structural anomalies are rearrangements of genetic material within or between chromosomes. In balanced structural anomalies, there is no change in the amount of essential genetic material whereas in the unbalanced ones there is a gain or loss of essential chromosome segments. Trisomy is the presence of 3 copies of a particular chromosome instead of the normal 2 copies. Monosomy is the presence of only one copy of a particular chromosome instead of the normal pair. Anaphase lag During meiosis or mitosis, one chromosome lags behind & is left out of the cell nucleus. Nondisjunction is the failure of chromosomes to separate during meiosis or mitosis. As shown in this figure both (B) & (C) produce gametes that are disomic or nullisomic for a specific chromosome. It is responsible for disorders such as trisomy 21, the most common form of Down syndrome. Nondisjunction can also occur in a mitotic division of somatic cells after the formation of the zygote. If mitotic nondisjunction occurs at an early stage of embryonic development, then clinically significant mosaicism may result. The mitotic nondisjunction occurred in one of cells & resulted in a trisomic cell. Also note that most of the cells undergo normal mitosis resulting in normal cells. And the clinical appearance of such an individual depends on the proportion of trisomic cells. Anyway, the clinical feature is less severe than that of an individual in whom all the cells are trisomic. In general, monosomies & trisomies of the sex chromosomes are compatible with life & usually cause phenotypic abnormalities. And trisomies of all autosomal chromosomes except chromosomes 13, 18, & 21 cause abortion or early death. However, trisomies of the autosomal chromosomes, 13, 18, & 21 permit survival with phenotypic abnormalities. Polyploidy is a chromosome number that is a multiple greater than 2 of the haploid number. Structural anomalies result from breakage of chromosomes followed by loss or rearrangement of genetic material are of the following types (See. Interstitial deletions arise from 2 breaks, loss of the interstitial acentric segment & fusion at the break sites. Ring chromosomes arise from breaks on either side of the centromere & fusion at the breakpoints on the centric segment. Segments distal to the breaks are lost so that individuals with chromosome rings have deletions from both the long arm & short arm of the chromosome involved. Isochromosome formation results when one arm of a chromosome is lost & the remaining arm is duplicated, resulting in a chromosome consisting of 2 short arms only or 2 long arms only. Inversion is reunion of a chromosome broken at 2 points, in which the internal segment is reinserted in an inverted position. Reciprocal (balanced translocation) is a break in 2 chromosomes leading to an exchange of chromosomal material between the two chromosomes. Since no genetic material is lost, balanced translocation is often clinically silent. But it can also cause disease as in the t(9, 22) which causes chronic myelogenous leukaemia. Robertsonian translocation is a variant in which the long arms of 2 acrocentric chromosomes are joined with a common centromere, & the short arms are lost. Before going into the discussion of some of the chromosomal disorders, it is good to remember what mosaicism is. Mosaicism is the presence of 2 or more cell lines with different karyotypes in a single individual. In a mosaic individual, a normal diploid cell commonly coexists with an abnormal cell line. A specific cell line may be represented in all tissues or may be confined to single or multiple tissues. The expression of the phenotype depends on the proportion & distribution of the abnormal cell line. Cytogenetic disorders involving autosomes include: o Down syndrome o Edward syndrome o Patau syndrome o Chromosome 22q11 deletion syndrome Down syndrome is the most frequent chromosomal disorder. Trisomy 21 accounts for 95% of cases & its incidence increases with maternal age. The fertilized ovum will have 3 chromosomes bearing the chromosome 21 material, the functional equivalent of trisomy 21. Down syndrome has the following clinical features: o Severe mental retardation o Broad (flat) nasal bridge & oblique palpebral fissure. Cytogenetic disorders involving sex chromosomes the following subtopics will be discussed below: 1. General features Sex chromosomal disorders have the following general features: a. They generally induce subtle, chronic problems relating to sexual development & fertility. They are often difficult to diagnose at birth & many are first recognized at the time of puberty. The higher the number of the X chromosomes (both males & females), the higher the likelihood of mental retardation. But there are some essential genes on the Y chromosome such as the genes which determine the testes, spermatogenesis, etc. Regardless of the number of the X chromosomes, the presence of a single Y chromosome leads to the male sex. The lyonization of the X chromosomes (X chromosome inactivation) In normal female somatic cells, there are 2 X chromosomes, but most of the genes on one of the X chromosomes are inactive. The X chromosome with most of the genes turned off is called the inactive X chromosome. If a somatic cell contains more than one X chromosome, all but one are inactivated. X inactivation occurs early in embryogenesis among all cells of the bastocyst at about the th 16 day of embryonic life. Either the X chromosome inherited from the mother (called Xm) or the X chromosome inherited from the father (called Xp) may be inactivated with equal likelihood. Once X inactivation occurs in an embryonic cell, the same X chromosome remains inactivated in all of the progeny of that cell. On average, half of the cells in a female have an inactive Xm & the other half of the cells have an inactive Xp. However, some tissues (& some women) may have substantially more cells with one or the other X chromosome active by chance. Some essential genes must be expressed in 2 copies from both X chromosomes for normal growth & development. So if one of these essential genes is absent (as occurs in Turner syndrome), it results in abnormal growth & development. Likewise, the presence of an extra X chromosome (as occurs in Klinefelter syndrome) leads to abnormal phenotype. The inactive X-chromosome may be visible in an interphase cell as a condensed mass of chromatin called the Barr body (X chromatin). The maximum number of Barr bodies seen in a cell is equal to the number of inactivated X chromosomes. Counting the number of Barr bodies in somatic cells (usually in smears of buccal mucosa) is the basis of the sex chromatin test for sex chromatin aneuplody. This test is no longer used in the Western countries because karyotyping is much more accurate. And most of the genes on the X chromosome do not have homologues on the Y chromosome.

Emmanuel Kant viewed human agency and free will as essential aspects of human dignity women's health clinic mandurah buy cheap femara on line. The term also can signal a special regard for humans as opposed to other species womens health weight loss proven femara 2.5mg, an appreciation of the intellectual capacities of humans women's health clinic dr gray's elgin femara 2.5 mg visa, and a commitment to promoting autonomy and human flourishing womens health alliance mesquite tx buy femara. Even if limited to preventing serious disease or disability womens health twitter discount 2.5mg femara fast delivery, the prospect of using heritable germline genome editing triggers concern that purely voluntary breast cancer awareness generic femara 2.5mg otc, individual decisions can collectively change social norms regarding the acceptance of less serious disabilities (Sandel, 2004). The disability rights community is not monolithic, and its attitudes toward genetic technologies such as prenatal screening can vary from supportive to skeptical (Chen and Schiffman, 2000; Saxton, 2000). There has been a long and ongoing debate between different parts of the disability community with regard to use of screening technologies. Still, disability activists have been among the most visible critics of using technology to screen for or determine the genetic qualities of children. The same observation has been made concerning the differing perceptions of disabled persons and medical professionals about the degree of distress caused by a particular condition (Longmore, 1995). One can argue that these concerns reflect a false dichotomy, and that unconditional love for a disabled child once born and respect for all people who are born with or who develop disabilities are not incompatible with intervening to avert disease and disability prior to birth or conception. And the decades that saw the explosion of prenatal diagnosis (accompanied by selective abortion of affected fetuses) and preimplantation diagnostics (accompanied by selective implantation of nonaffected embryos) are the same as those in which public attitudes toward disability became far more accepting (Hernandez et al. The disability community is characterized by a long and ongoing tension with regard to use of screening technologies. The literature appears to support openly acknowledging that this tension is real, continuing, and unlikely to be resolved entirely, and that any step toward the use of genome editing to eliminate disabilities must be carried out with care and open discussion, and the committee supports this call for continued public deliberation (Kitcher, 1997) (see Chapter 7). Public policy has shifted toward eliminating discrimination in employment or public services, and public investment in changing the social, physical, and employment environment to achieve this goal has increased, with measures ranging from accessible buildings to sign language presentations to aural signals for street crossings. The range of measures remains insufficient, however, and one cannot know whether this shift in attitude would have been even more dramatic if genetic screening and abortion laws had not made it easier to reduce the prevalence of birth defects. Nonetheless, this progress does to some extent address the concern that reducing the prevalence of disabilities will necessarily decrease empathy, acceptance, or integration of those who have them. One counterargument is that the research phase may include those less well-off, or that even if treatments for rare but compelling diseases often start with the wealthy, they eventually become more affordable and available for the poor. Moreover, the research that will make germline genome editing possible will likely provide insights that will lead to health care interventions for other disorders as well. While such a phenomenon already exists in the form of durable effects of better nutrition and use of vaccines among the advantaged populations of the world, some critics are concerned about adding yet another, more durable form of superior access to better health (Center for Genetics and Society, 2015). These concerns apply to a range of health advances, and are not limited to genome editing. The Slippery Slope Many scholars who support (or at least are not opposed to) germline modifications align the possible uses of genome editing along a continuum of acceptability. This continuum almost always starts with converting single-gene disorders to a common, nondeleterious sequence at the most-acceptable end, and moves toward enhancements that are unrelated to disease on the least acceptable end. The slippery slope claim is that taking the first step with single-gene disorders is likely to lead, in some number of years, to the conduct of nondisease enhancements that many would rather see prohibited. The slippery slope arguments of most critics do not claim inevitability but are instead probabilistic. They are based on what could be described as predictive sociology about how societies actually function and rejection of the notion that placing barriers and speed bumps on the slippery slope will be a sufficient deterrent to less desirable uses (Volokh, 2003). An opponent of editing the germline would not necessarily oppose on principle replacing a disease gene variant with a corresponding, common, non-disease gene, as such a change would give offspring no social advantage and is the type of instrumental action directed at future children that is currently part of modern medicine. Many opponents, however, do not believe genome editing would stop there and observe that a number of social processes make the slope more slippery. Parts of the medical profession might become invested in providing the service, or patient groups in seeking the service, creating powerful interest groups favoring its maintenance or even expansion. On the other hand, slippery slope arguments have their critics, who point to their inherent uncertainty and the fact that many such claims do not come to pass. Those who reject slippery slope arguments often are less concerned than proponents about situations which might be viewed as the bottom of the slope. Many of the attempts to introduce speed bumps or friction on the slippery slope in the evolution of genetic modification of humans have focused on the easily grasped linguistic/cognitive difference between a body/individual and offspring/society, thereby establishing the distinction between editing of somatic and germline cells. Critics would claim that the current debate about crossing the cognitive barrier. Overall, slippery slope arguments do not depend on universal condemnation of the initial, most compelling applications of heritable genome editing. But while many think that regulation could establish effective speed bumps, proponents of slippery slope arguments raise the question of whether and how society can develop regulations that are sufficiently robust to quell the fear of a progressive move toward less compelling and more controversial applications. Indeed, they would say that regulations would do little to stop the progression down a slippery slope because regulations are based on cultural views, and it is the underlying change in cultural views that is precisely the slippery slope. The legality of research, and perhaps even clinical application, would vary from state to state as a result of differing laws on fetal and embryo research. Federal funding for the research would likely be unavailable because of current legislative restrictions on funding research involving human embryos. Should heritable germline genome editing move into clinical investigations, the U. If germline genome editing succeeded in research trials and was approved for marketing, there would also be mechanisms for oversight in the postapproval context. Following the publication of the National Academies report on mitochondrial replacement techniques, which can result in heritable changes in small amounts of mitochondrial. Beyond that date, the prohibition may be extended or deleted, depending upon the details of the next budget exercise. More recently, as discussed in Chapter 1, the organizers of the December 2015 International Summit convened by the science and medicine academies of the United States, the United Kingdom, and China called for a pause of some undefined duration in any attempt at heritable germline editing. Their statement read: It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. In 2015, a self-organized group of multinational experts called the Hinxton group published a statement exploring the possibility that heritable germline genome editing might be acceptable, albeit with many caveats (Hinxton Group, 2015). They all note, however, that the science is continuing to progress rapidly, and they avoid calling for permanent prohibitions. Yet while relief from inherited diseases could accrue from its use, there is significant public discomfort about germline genome editing, particularly for less serious conditions and for situations in which alternatives exist. These concerns range from a view that it is inappropriate for humans to intervene in their own evolution to anxiety about unintended consequences for the individuals affected and for society as a whole. More research is needed before any germline intervention could meet the risk/benefit standard for authorizing clinical trials. But as the technical hurdles facing genome editing of progenitors of eggs and sperm are overcome, editing to prevent transmission of genetically inherited diseases may become a realistic possibility. If the technical challenges are overcome and potential benefits are reasonable in light of the risks, clinical trials could be initiated, if limited to only the most compelling circumstances, subject to a comprehensive oversight framework that would protect the research subjects and their descendants; and have sufficient safeguards to protect against inappropriate expansion to uses that are less compelling or less well understood. For some, it is about respecting parental desires for genetically related children. For others, it is primarily about allowing children to be born as healthy as possible. But as noted earlier in this chapter, some do not view heritable germline genome editing as a benefit to the resulting child, who otherwise might never have been conceived at all. And for others, the desire of parents who carry genetic disease to have a genetically related child through this technology, instead of having a genetically unrelated child, is not sufficient to outweigh the social concerns that have been raised. The committee calls for continued public engagement and input (see Chapter 7) while the basic science evolves and regulatory safeguards are developed to satisfy the criteria set forth here. Heritable germline genome editing raises concerns about premature or unproven uses of the technology, and it is possible that the criteria outlined here for responsible oversight would be achievable in some but not all jurisdictions. The phenomenon of medical tourism, which encompasses the search for faster and cheaper therapeutic options, as well as newer or less regulated interventions, will be impossible to control completely if the technical capabilities exist in more permissive jurisdictions (Cohen, 2015; Lyon, 2017). Human Genome Editing: Science, Ethics, and Governance 6 Enhancement Somatic gene and cell therapies are widely seen as morally acceptable. Beyond issues of safety, efficacy, and informed consent, there has been no concern about the legitimacy of somatic cell and gene therapies among those who generally endorse modern medicine. Genome editing is playing an increasing part in somatic gene therapy to treat and prevent disease (see Chapter 4). Recent advances, however, have increased the possibility that genome editing could also be used for purposes that go beyond the kinds of gene therapy and other medical interventions discussed above, and therefore have raised anew the question of whether enhancement should be regulated or prohibited, and whether there are important differences depending upon whether the enhancements are somatic or heritable. Enhancements may range from the mundane, such as cosmetic changes in hair color; to the more physically interventionist, such as elective cosmetic surgery; to the more dangerous and problematic, such as the use of some steroids and other drugs among athletes in competitive settings. Given the wide range of capabilities exhibited by humans for any particular trait, there is little basis for deeming any one condition normal or any meaningful value in determining an average. Nonetheless, there have been some attempts to describe the range of conditions that, given the right environment, are consistent with an ability to appreciate life and participate in the world. This chapter begins by reviewing several key issues in genome editing for enhancement. It then addresses in turn somatic (nonheritable) and germline (heritable) genome editing for enhancement purposes. In the present context, genetic variants that exist in nature may either support health or cause disease, and the human population contains multiple variants of most genes (see Chapter 4). The most widespread variant encodes a fully functional protein, whereas the sickle-cell variant can cause the protein to aggregate and distort the red cells into a sickle shape if both copies of the gene are this variant (the homozygous state), which in turn causes the symptoms of sickle-cell disease. As noted in Chapter 5, however, being heterozygous for this variant confers some resistance to malaria, and for this reason, the sickle-cell variant has been maintained by natural selection in populations from malaria-prone areas. So, in this case, which natural variant is advantageous depends on the environment. They can require significant personal effort, as in taking piano lessons, or they can be largely independent of personal effort, as in wearing teeth straightening braces.

Coal dust mainly contains carbon but has a variety of trace metals inorganic mineral and crystalline silica menstrual like cramps at 33 weeks buy genuine femara online. Anthracite (hard) coal contains significantly more quartz than bituminous (soft) coal breast cancer 2014 statistics purchase femara 2.5mg with amex. Anthracite (hard) coal is more frequently associated with lesions in the lungs; hence the name pulmonary anthracosis is coined for coal induced pulmonary lesions women's health center kissimmee fl generic femara 2.5mg online. Anthracosis: Where pigments are accumulated without cellular reaction and symptoms ii womens health events femara 2.5 mg without prescription. Simple coal workers pneumoconiosis With minimal cellular reaction and little or no pulmonary dysfunction iii pregnancy cravings order discount femara online. These macrophages are also seen along the lymphatics including pleural lymphatics or lymphoid tissue along bronchi and lung hilus menstrual blood art best buy for femara. Coal macules constitutes of carbon-laden macrophages aggregated, coal nodule is when the macule additionally contains collagen fibers. It is characterized by coal nodules intermingled with collagen fibers with central necrosis, size ranging from 2cm to 10cm. When it progress to progressive massive fibrosis in minority of cases it results in pulmonary hypertension and corpulmonale. Asbestos Related Disease Asbestos is a generic name that embraces the silicate minerals that occur as long, thin fibers. Asbestosis refers to the pneumoconiosis that results from the inhalation of asbestos fibers Pathogenesis Asbestos fibers are thin and long so that they can reach the bifurcations of bronchioles and alveoli. There, they are engulfed by macrophages to induce the cascade of inflammatory process, which finally result in interstitial pulmonary fibrosis. The asbestos body is the most diagnostic structure seen under the microscope, consisting of asbestos fiber beaded with aggregates of iron along its length. They are 2 to 3 mm thick, and microscopically they are densely collagenous and hyalinized and sometimes calcified. Tobacco Smoking Considering the globe, the adverse effects of tobacco smoking out number all the effects of other pollutants. It is considered as one of the most important preventable causes of death in the United States. In our society also even though its health impacts are not so pronounced it still has series health damage. Tobacco smoking affects not only those who are actively smoking but it also has an adverse consequence on the health of those who are by the vicinity of the smoker. Active Smoking and disease the cigarette smoke that is taken through the mouth into the lung has several types of chemicals that have diverse & serious effects on our health. The composition depends on the type of tobacco, length of the cigarette, and presence and effectiveness of filter tips. Usually present are (1) Carcinogens whose effects have been verified in lower animals. And the less common effects are peptic ulcer, Cancer that can originate from larynx, esophagus, pancreas, bladder & kidneys. Systemic arteriosclerosis and other forms of cancer are also diseases caused by cigarette smoking, which collectively contribute to many deaths. In general smoking is the single most important cause of cancer mortality in the United States. Several studies have shown that maternal smoking could cause low birth weight, prematurity, still birth and infant mortality. Moreover other complications of pregnancy like abruptio placentae, placenta previa, and premature rupture of membranes have been found to be caused by maternal smoking. Coronary heart disease causes most of the deaths 238 when it comes to effects of cigarette smoking. Involuntary smoke exposure (Passive Smoking) the effect of passive smoking has been identified during the last few decades. Its effect comes when non-smoking people inspire the ambient air, which is polluted by cigarette smoke. The health impact depends on the volume of the air in the room, number of active smokers, rate of air exchange and duration of exposure. Children & infants of smoking mothers will have an obvious intense exposure and hence retardation of physical and intellectual growth is likely to occur. Benefits of cessation or reducing exposure to cigarette smoke When a person stops smoking the risks of diseases and subsequent death start to decline the risk to reach to that of non-smoking people may take 20 years of smoke-free period. The amount of cigarettes smoked daily, and duration of smoking determines the rate of decrease of risks. The relative risk of lung cancer and laryngeal cancer start to decline after 1 to 2 smoke free years. However considering lung cancer former smokers will have slightly higher risk than non-smokers even after 30 years of smoke-free years. When it comes to coronary diseases the decline of risk is rapid and it can level with those of non-smokers after 5 to 20 years. Chemical & Drug injury Injuries due to chemicals can be from therapeutic agents and nontherapeutic agents. Adverse drug reactions Injuries due to therapeutic agents are known as adverse drug reactions. Adverse drug reactions are any response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. Exaggeration of the intended pharmacologic effect which are largely predictable effects 2. For example use of large dose daunorubicin or doxorubicin to treat some forms of cancer may cause cardiotoxicity. The reactions is called idiosyncrasy and is due to an abnormal immunologic response to the drug or un predictable cytotoxicity caused by the drug. Possible examples will be extensive hepatic necrosis, which develops after intake of therapeutic dose of acetaminophen, or anaphylaxis, which develop after therapeutic dose of penicillin. Non-therapeutic agents Ethyl alcohol A large percentage of our population is a social drinker and still a significant number of individuals are alcoholic or alcohol dependent. Alcohol has an obvious acute effect but has also an effect of a long-standing use of alcohol on organs and tissues. Alcohol Metabolism: About 2 to 10% of the ethanol consumed is excreted directly through the breath, urine or sweat. The amount exhaled is directly proportional to the blood level and hence is used by legal enforcement agencies. After ingestion, a small amount of ethanol is directly metabolized by gastric mucosa alcohol dehydrogenase. The rest is rapidly absorbed from stomach & intestines, once in the liver alcohol is metabolized by three pathways in the liver st cells. The 1 involves hepatic alcohol dehydrogenase, yielding acetaldehyde, which is then converted to acetate by aldehydedehydrogenase. It depresses the inhibitory control centers thereby releasing excitatory pathways that accounts for the wide spread belief that alcohol is a stimulant. The cortex affected first, the limbic system, cerebellum and finally brainstem are affected as the blood level increases. Not with a clearly understood mechanism, acute alcoholism has also "black out" effects that are episodes of forgetting what has happened during drinking. These are discussed in adequate detail in the chapter that deals with liver diseases. Cells are distended with fat accumulation, which can be mobilized when the exposure to alcohol is discontinued. Alcoholic hepatitis can occur with episodes of heavy drinking and may or may not be preceded by fat accumulation and may or may not be followed by cirrhosis which is the end stage of fatty changes that occur in chronic alcoholism. The chronic alcoholic subsists with an inadequate dietary intake and alcohol itself impairs intestinal absorption of thiamine. This condition may occur in non-chronic alcoholics who become thiamine deficient for various reasons. Clinically it is characterized by ataxia, global confusion, ophtalmoplegia and often nystagmus. The underlying morphology includes foci of symmetric discoloration and sometimes softening with congestion, & punctate hemorrhage in the paraventricular region of the thalamus & Hypothalamus, in the mammillary bodies about the aqueduct in the midbrain, in the floor of the fourth ventricle and in the anterior cerebellum. The neurons may be relatively spared in the early stages but eventually reveal degenerative changes and eventually cell death. These are supposed to be due to thiamine deficiency as well, rather than ethanol direct toxicity. Peripheral Nerves the peripheral nerves suffer a demylinating polyneuropathy, occasionally mononeuropathy that is fairly common in chronic alcoholics who are malnourished. On the other hand a direct ethanol injury to myocardium will result in cardiomyopathy, which is discussed in the chapter that deals with heart diseases. Miscellaneous changes: Chronic alcohol intake has a tendency to produce hypertension even though in low doses alcohol (ethanol) tends to reduce blood pressure. Chronic alcoholics suffer higher incidence of acute & chronic pancreatitis and regressive changes in skeletal muscle referred as alcoholic myopathy. During pregnancy a condition known as fetal alcohol syndrome may 243 take place in infants whose mothers have been taking alcohol even as low as two to three drinks per day. The fetues can have microcephally, mental retardation, facial mal formation & cardiac defects at times. Increased risks of cancer of pharynx, larynx, esophagus, stomach, & possibly rectum & lung have also been encountered in chronic alcoholics. Physical injuries these are mainly classified in to four groups: injuries due to mechanical forces, changes in temperature, changes in atmospheric presence, and electromagnetic energy. A-Injuries due to mechanical forces Injuries due to mechanical forces are (1) soft tissue injuries, (2) bone injuries, (3) head injuries. Here we deal with soft tissue injuries, which are divided accordingly to their depth. Abrasion: this type of injury represents the most superficial type of skin injury, which involves the epidermal layer. It occurs when superficial epidermal cells are turnoff by friction or a glancing blow. There is no perforation of the skin & hence regeneration occurs with out scarring. Laceration versus incision Laceration is an injury over the skin which is an irregular tear produced by overstretching. The margins of a laceration are frequently hemorrhagic & traumatized and there will be bridging stands of tissues like blood vessels or fibrous tissues at the base. The margins are relatively clean and there are no bridging fibrous strands or tissues. An incision, in contrast to laceration, will be approximated by sutures to heal leaving no or little scar. Contusion this is an injury that is cause by a blunt force that injurs small blood vessels & causes intestinal bleeding usually with out a breach on the superficial tissue the bleeding will be evident if the contusion is on a superficial tissue but if it is in deeper structures like skeletal 244 muscles the bleeding will be evident after several hours or may remain obscured excepts the swelling & pain that is felt at the area over the contusion. Gunshot wounds Looking at the gunshot wounds give a very detailed story as to whether the shot is from a distance or, near by, or from a rifle or a handgun. It also tells the direction from which the bullets came & other important information for a forensic pathologist. The character of a gunshot wound at entry & exit and the extent of injury depend on the type of gun used, caliber of bullet, the type of ammunition, the distance of the firearm from the body, etc. There are also peripheral stippling of discrete, larger particles formed by the unburned powder, When the shot distance increases a beat only the stippling are present and at greater distances no gray black discoloration or stippling are present rather a wound smaller in size from the bullet and with narrow enclosing rim of abrasion is present. Cutaneous exit wounds are generally more irregular than the entry wounds due to the wobbling or trajectory motion of the bullet. In high velocity riffle bullets the exit wounds are larger and there are no stippling or dark discolorations. Large caliber, light velocity bullets cause extensive injury around the traversing wound due to the mass, velocity and motion of the bullet. Small caliber low velocity bullets cause a limited amount of injury to surrounding tissue. In general, it suffices to say that gun shot wounds tell a story to the experienced individual. B-Injuries related to changes in temperature Human beings are homoeothermic and their internal temperature must be maintained 0 0 between 30 C and 43 C. Abnormally high and low temperatures are injurious to the body and their damage are different and have to be discussed separately. Injuries due to abnormally high temprature these can be brought by flame, boiled water or steam, electricity and etc. Epidermis can be fully or partially devitalized and it continues to provide a cover to the burned area. Such burns are characterized by blistering, protinacious fluid exudation from dilated and injured small blood vessels.

Syndromes

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• Pegvisomant (Somavert) directly blocks the effects of growth hormone, and has been shown to improve symptoms of acromegaly.
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Treatment of neuin the treatment of adrenocortical cancer patients: long-term surroendocrine carcinomas with combined etoposide and cisplatin. The extrahepatic bile duct tumors are further plasia, carcinoma in situ, and eventually invasive carcisubclassified into perihilar (proximal) and distal groups. Laboratory Stage Definition tests revealed a total and direct bilirubin level of 7. Alkaline phosphatase was eleI Tumor confined to bile duct histologically vated at 273 U/L. The relationship of the tumor to the surrounding structures, including the vasculature, is extremely important when assessing resectability. Bacterial cholangitis or liver subjected to local treatment unless symptomatic relief is failure is a potentially fatal complication. In such cases, local radiation may help relieve are expected to live longer and who wish to avoid repeated biliary obstruction. Capecitabine is fairly well tolerated and with suspected biliary tumors, although neither is specific may be substituted if needed. He is followed every 3 months with a history from 9% to 24%, and the specificity varied from 61% to and physical examination, liver function tests, and serum 100% (3). The 3 most common scenarios for locally that should also focus on supportive care. A retrospective analysis of 28 patients with localized, ing history of gallstones who presented with 1 month of nonmetastatic extrahepatic bile duct cancer showed a abdominal pain and 1 week of jaundice, decreased appesignificantly increased median survival in patients who tite, and 15-pound weight loss. In the last few days, she compared with those patients who underwent surgical also noticed itching of her skin. Laboratory tests sion compared with surgical decompression alone (16 revealed a total and direct bilirubin of 10. Abdominal ultrasound showed a suspicious mass in the gallbladder, with small gallstones, but no evidence of Evidence-Based Case Discussion cholecystitis. The presence of metastases to the lymph alized in the left lobe of the liver, measuring 4. When combined with other some difficulty, as long as the patient can tolerate treatagents such as oxaliplatin and cisplatin, the response ment. Chemotherapy is generally continued until there rate increased between 25% and 55%, with a median is evidence of disease progression. A role of targeted therapies, such as erlotinib, cetuximab, or recent meta-analysis of 104 trials, including 2810 patients bevacizumab. Doublet chemotherapy demweeks after the initiation of treatment showed no evidence onstrated superior response rates (28% vs. Labs revealed a platelet count of 105, 000/L, tion (80% of all cases) and other causes of cirrhosis such albumin of 3 g/dL, prothrombin time prolonged 4 s beyond as alcoholism, adult fatty liver disease, hemochromatosis, normal, and a bilirubin of 1. Both lesions showed arterial enhancement and malignant transformation without cirrhosis. Antineoplastic Stage Definition agents can include doxorubicin, mitomycin, and cisplatin. This approach helps minimize the patients with large, infiltrating, or multifocal disease. The microspheres are deposited into the because the disease burden falls outside the Milan criteria hepatic vasculature. He also ingly recognized due to efficient screening guidelines and noted decreased appetite and fatigue. He denied any histreated with surgical resection and demonstrates a 5-year tory of encephalopathy, varices, or ascites. Hepatic resection is a potentially examination revealed mild tenderness to palpation in the curative option in patients with adequate liver function, right upper quadrant. No jaundice or ascites was apprecithose with a solitary mass, no evidence of major vascular ated. A complete blood count and liver chemIn some centers, hepatic vein catheterization is performed istry were also within normal limits. Multiple retroperitocurrently no role for preor post-resection therapy; howneal lymph nodes were enlarged, suggesting metastatic ever, in clinical practice, neoadjuvant local techniques are disease. The Child-Pugh gery, but did not meet the primary end point of improving score was class A with a good performance status. Liver transplant is indicated for patients with underlyIn this case, tissue biopsy is not required to diagnose ing portal hypertension and cirrhosis. Child-Pugh Class C, and data on the use of sorafenib in the most appropriate treatment for F. The landmark study that sig800-mg sorafenib dose, but median duration of therapy nificantly impacted clinical practice was the Study of Heart was shorter in patients with Child-Pugh B cirrhosis. Overall median survival was significantly longer study investigated the use of second-line brivanib comin the sorafenib group than the placebo group (10. A 58-year-old man with primary biliary cirrhosis and ment for advanced disease (extrahepatic spread or portal Child-Pugh class A cirrhosis was referred for evaluainvasion) not amenable to other modalities in patients with tion. A 52-year-old Japanese man with a past medical history arterial phase enhancement of the mass, with washof hepatitis B infection and Child-Pugh class A cirrhosis out in the portal and venous phases but no portal vein presented for his 6-month surveillance for hepatocelluthrombosis or other evidence of extrahepatic disease. Ultrasonography showed a new the patient was living independently and working full sol it a r y 2 cm lesion i n t he lef t lobe of t he l iver. There was no portal vein thrombosis (C) Comfort care or other evidence of extrahepatic disease. On physical examina(E) Orthotropic liver transplantation tion, he was found to be alert and fully oriented, with no evidence of ascites. Which of required 3 large volume paracentesis during the past 2 the following is the most appropriate next step He was capable of only limited self care and was confined to the bed >50% of the day. On physical (A) Liver transplantation examination, he was malnourished and in a wheelchair. A 45-year-old obese white man with fatty liver disease alpha-fetoprotein was 15 ng/mL. On physical examination, he was (B) Surgical resection fully oriented, in no acute distress. Which the emergency department with 3 days of abdominal of the following is the most appropriate next step She had (A) Liver transplantation been otherwise healthy and active prior to this illness. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization dilatation, a 4. Arterial embolisation from the pancreatic head and second portion of the or chemoembolisation versus symptomatic treatment in patients duodenum, and multiple subcentimeter mesenteric with unresectable hepatocellular carcinoma: a randomized control trial. Chemoembolization grade cholangiopancreatography revealed a beading of hepatocellular carcinoma: results of a metaanalysis. Survival after Yttrium-90 (D) Systemic chemotherapy with gemcitabine resin microsphere radioembolization of hepatocellular carcinoma (E) Supportive care across Barcelona clinic liver cancer stages: a European evaluation. Management of hepatocellular carcinoma: abine versus gemcitabine for biliary tract cancer. Gallbladder cancer: lessons from a rare the treatment of small hepatocellular carcinomas in patients with tumour. Chemotherapy in advanced biliary tract treatment with sorafeNib): second interim analysis. The management of zumab for the treatment of advanced hepatocellular carcinoma: hepatocellular carcinoma. Diagnosis and to sorafenib or for whom sorafenib failed: results from the rantreatment of hepatocellular carcinoma. Colonoscopy showed a nonobstructing, circumAlthough large or perforated colonic tumors may spread ferential sigmoid mass, and pathology revealed poorly locally to involve adjacent organs or peritoneum, colon differentiated adenocarcinoma. Aside from having well-controlled diatal venous system, the liver is the most common site of betes and hypertension, L. Symptoms related obstructed; so urgent surgical intervention was not to the primary colorectal tumor include obstruction, perrequired. The origiof treatment, 89% did not experience any primary tumor nal regimen, devised at the Mayo Clinic, consists of bolus complication requiring intervention. The erenced guidelines, such as the National Comprehensive newest regimen, devised by de Gramont et al. Oncologists should warn their als have examined whether administering oxalate chelapatients about the high likelihood of cold sensitivity and tors, namely calcium and magnesium, can reduce the advise them to wear gloves in cold weather, to avoid holdincidence and intensity of oxaliplatin-related neurotoxing cold objects, and to drink room temperature bevericity. Many experts and official guidelines therefore advooxaliplatin based on diabetes alone. Patients who suffer from preexisting neuropathy, who underestimation of survival with this strategy. As opposed to the combination of irinotecan/Cmab yielded a signifiPmab, which is fully humanized, Cmab is chimeric and cantly higher response rate (23% vs. Cmab and Pmab appear to be equally accurately predict which patients should receive Cmab or effective and should therefore be regarded as interchangePmab. However, a review of and/or oral antibiotics, sunscreen, and moisturizers) and subsequent data, including an extensive molecular analdose reduction rather than drug discontinuation. These findings could not easily be attributed to fatigue, diarrhea, hypertension, and rash. Because no foroptimal place in the treatment algorithm has not been mula exists to dictate which regimen best suits an indiwell defined. Regorafenib is after considering goals of care, underlying age and comoran option for those who have progressed on other therabidity, side-effect profiles, matters of convenience, and pies, but its survival benefit is modest and its toxicity can patient preference. Both Colonoscopy with biopsy showed a circumferential, partrials closed prematurely due to slow accrual, so neither had tially obstructing adenocarcinoma, but the scope was sucpower to demonstrate differences in disease-free survival cessfully advanced to the cecum. However, a pooled analysis demonstrated 2 masses in the right hepatic lobe measuring 1. The patient recovered quickly from surgery and was However, the rates of potentially curative resection were referred to medical oncology to discuss prognosis and nearly identical (83% vs. Postoperative morbidity was slightly higher in the chemotherapy arm, but postoperative Evidence-Based Case Discussion mortality was 1% in both groups. The most (65%) presented with metachronous liver metastases treatment approach for A. First, an experienced surgical oncologist must and the cohort of patients eligible for aggressive therapy determine whether the patient is an appropriate candidate expanded. On the other hand, it became clear that intenfor aggressive resection, based on the predicted volume of sifying local therapy of known metastases without simulhealthy remnant liver following surgery, the ability to pretaneously eradicating micrometastatic disease would not serve vascular and biliary structures, and the overall health further improve treatment outcomes. Chemotherapy before liver resection should be limited toc 3 months if possible to minimize risk of postoperative complications; total duration of chemotherapy should be up to 6 months. He recovered well from surgery select out those patients who are not medically fit enough to and completed 3 more months of chemotherapy. Due to the complex decision-making process performed, and pathological evaluation revealed a moderand meticulous coordination of care that such an aggressive ately differentiated adenocarcinoma with metastasis to 6 approach demands, cases of newly diagnosed oligometaof 20 resected lymph nodes. Despite a complicated postoperative course, was associated with more grade 3 or 4 hematological she has recovered completely and maintains an excellent and gastrointestinal toxicity (34). In the intention-to-treat is both present and sensitive to cytotoxic chemotherapy. Therefore, patients who have presimilarly designed trial in Europe also showed no benefit existing neuropathy or who are not deemed fit enough to of Cmab in the adjuvant setting. Targeted agents currently randomized data to define an optimal schedule for surveilhave no role in the adjuvant setting outside of a clinical lance, large retrospective studies have demonstrated the protocol.

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