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Because each line continues between two adjacent data points buy cialis american express impotence grounds for divorce states, we communicate that our measurements continue between the two scores on the X axis and therefore that this is a continuous variable order cialis pills in toronto erectile dysfunction tools. Later we will create graphs in other contexts that also involve connecting data points with straight lines purchase generic cialis online erectile dysfunction treatment los angeles. This same rule always applies: Connect adjacent data points with straight lines whenever the X variable is continuous. In this way, we create a complete geometric figure—a polygon—with the X axis as its base. Often in statistics you must a read a polygon to determine a score’s frequency, so be sure you can do this: Locate the score on the X axis and then move upward until you reach the line forming the polygon. To show the number of freshmen, sophomores, and a histogram with a few interval/ratio scores, and a juniors who are members of a fraternity, plot a. To show the number of people preferring chocolate versus females (a nominal variable), create a bar or vanilla ice cream in a sample, plot a. Call it a normal curve or a normal distribution or say that the scores are normally distributed. Because it represents an ideal population, a normal curve is different from the choppy polygon we saw previously. First, the curve is smooth because a population produces so many different scores that the individual data points are too close to- gether for straight lines to connect them. Second, because the curve reflects an infinite number of scores, we can- not label the Y axis with specific frequencies. Simply remember that the higher the curve is above a score, the higher is the score’s frequency. Finally, regardless of how high or low an X score might be, theoretically it might sometimes occur. Therefore, as we read to the left or to the right on the X axis, the frequencies approach—but never reach—a frequency of zero, so the curve approaches but never actually touches the axis. The score with the highest frequency is the middle score between the highest and lowest scores. As we proceed away from the middle score either toward the higher or lower scores, the frequencies at first decrease slightly. Farther from the middle score, however, the frequencies decrease more drastically, with the highest and lowest scores having relatively low frequency. In statistics the scores that are relatively far above and below the middle score of the dis- tribution are called the “extreme” scores. Then, the far left and right portions of a normal curve containing the low-frequency, extreme scores are called the tails of the distribution. The reason the normal curve is important is because it is a very common distribution in psychology and other behavioral sciences: For most of the variables that we study, the scores naturally form a curve similar to this, with most of the scores around the middle score, and with progressively fewer higher or lower scores. Because of this, the normal curve is also very common in our upcoming statistical procedures. Do you see that a score of 15 has a rela- tively low frequency and a score of 45 has the same low frequency? Do you see that there are relatively few scores in the tail above 50 or in the tail below 10? On a normal distribution, the farther a score is from the central score of the distribution, the less frequently the score occurs. A distribution may not match the previous curve exactly, but it can still meet the mathe- matical definition of a normal distribution. Curve A is skinny relative to the ideal because only a few scores around the middle score have a relatively high fre- quency. On the other hand, Curve C is fat relative to the ideal because more scores farther below and above the middle have a high frequency. Because these curves generally have that bell shape, however, for statistical purposes their differences are not critical. Other Common Frequency Polygons Not all data form a normal distribution and then the distribution is called nonnormal. A negatively skewed distribution contains extreme low scores that have a low fre- quency but does not contain low-frequency, extreme high scores. This pattern might be found, for example, by measuring the running speed of professional football players. Most would tend to run at higher speeds, but a relatively few linemen lumber in at the slower speeds. This pattern might be found, for example, if we measured participants’ “reaction time” for recogniz- ing words. Usually, scores will tend to be rather low, but every once in a while a person will “fall asleep at the switch,” requiring a large amount of time and thus producing a high score. Another type of nonnormal distribution is a bimodal distribution, shown in the left- hand side of Figure 3. A bimodal distribution is a symmetrical distribution contain- ing two distinct humps, each reflecting relatively high-frequency scores. High scores scores of each hump is one score that occurs more frequently than the surrounding scores, and technically the center scores have the same frequency. Such a distribution would occur with test scores, for example, if most students scored at 60 or 80, with fewer students failing or scoring in the 70s or 90s. Finally, a third type of distribution is a rectangular distribution, as shown in the right-hand side of Figure 3. There are no discernible tails be- cause the frequencies of all scores are the same. Labeling Frequency Distributions You need to know the names of the previous distributions because descriptive statistics describe the characteristics of data, and one very important characteristic is the shape of the distribution that the data form. Thus, although I might have data containing many different scores, if, for example, I tell you they form a normal distribution, you can mentally envision the distribution and quickly and easily understand what the scores are like: Few scores are very low or very high, with the most common, frequent scores in the middle. Therefore, the first step when examining any data is to identify the shape of the simple frequency distribution that they form. Recognize, however, that data in the real world will never form the perfect shapes that we’ve discussed. Instead, the scores will form a bumpy, rough approximation to the ideal distribution. For example, data never form a perfect normal curve and, at best, only come close to that shape. However, rather than drawing a different, approximately normal curve every time, we simplify the task by envisioning the ideal normal curve as our one “model” of any distribution that generally has this shape. Likewise, we envi- sion the ideal shape when discussing the other common curves that we’ve seen. Thus, we apply the names of our ideal distributions to actual data as a way of sum- marizing and communicating their general shape. Arrange the scores below from most frequent to distributions, bimodal distributions, and rectangu- least frequent.
With the exception of epididymitis in the elderly purchase 10mg cialis visa muse erectile dysfunction medication reviews, community- acquired urosepsis does not require P generic cialis 5 mg with visa erectile dysfunction with new partner. Table 6 Community-Acquired Urosepsis: Therapeutic Approach Urosepsis- associated syndrome Microorganisms Urine Gram stain Empiric coverage order 20 mg cialis with amex impotence propecia. Urosepsis in Critical Care 293 Table 7 Nosocomial Urosepsis: Therapeutic Approach Urosepsis- associated syndrome Usual uropathogens Urine Gram stain Empiric coverage. The importance of pre-existing urinary tract disease and compromised host defenses. Role of fluoroquinolones in the treatment of serious bacterial urinary tract infections. Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. Pseudomonas aeruginosa susceptible only to colistin in intensive care unit patients. Once daily tigecycline therapy of multidrug-resistant and non-multidrug resistant gram- negative bacteremias. Polymyxin B and doxycycline use in patients with multidrug-resistant Acinetobacter baumannii infections in the intensive care unit. In vitro activity of tigecycline and comparators against carbapenem-susceptible and resistant Acinetobacter baumannii clinical isolates in Italy. Treatment with tigecycline of recurrent urosepsis caused by extended-spectrum-beta-lactamase-producing Escherichia coli. Considerations in control and treatment of nosocomial infections due to multidrug-resistant Acinetobacter baumannii. Severe Skin and Soft Tissue Infections 17 in Critical Care Mamta Sharma and Louis D. John Hospital and Medical Center, and Wayne State University School of Medicine, Detroit, Michigan, U. Most of these infections are superficial and treated with regimens of local care and antimicrobial therapy. However, others like necrotizing infections are life-threatening and require a combined medical and surgical intervention. Prompt recognization and treatment is paramount in limiting the morbidity and mortality associated with these infections, and thus a thorough understanding of the various etiologies and presentation is essential in the critical care setting. It is also important to discriminate between infectious and noninfectious causes of skin and soft tissue inflammation. A detailed history and examination are necessary to narrow the possible etiologies of infection. In many instances, surface cultures are unreliable and misleading because surface-colonizing organisms can be mistaken for pathogens. In instances in which the diagnosis is in doubt, aspiration, biopsy, or surgical exploration of the skin can be considered. Typically, soft tissue infections result from disruption of the skin by exogenous factor, extension from subjacent infection, or hematogenous spread from a distant site of infection. Physiological factors that control the bacterial skin flora include humidity, water content, skin lipids, temperature, and rate of desquamation. Besides containing secretory immunoglobulin (IgA), sweat also possesses sufficient salt to create a high osmotic pressure, which may be responsible for inhibiting many microbial species. In spite of these barriers to colonization, the skin provides an excellent venue of various microenvironments. Differences in cutaneous microflora may relate to variability in skin surface temperature and moisture content as well as the presence of different concentrations of skin surface lipids that may be inhibitory to various microorganisms. Colonization with organisms sensitive to desiccation, such as gram-negative bacilli, is not favored. The predominant bacterial flora of the skin is the various species of coagulase-negative staphylococci (Staphylococcus epidermidis, S. Colonization of the anterior nares, perineum, or skin, particularly if the cutaneous barrier has been disrupted or damaged, may occur shortly after birth and may recur anytime thereafter (1–4). Approximately 20% of individuals always carry one type of strain and are called persistent carriers. Carriage rates are higher than in the general population for injection drug users, persons with insulin-dependent diabetes, patients with dermatological conditions, patients with long-term indwelling intravascular catheters, and those with human immunodeficiency virus infection. Other gram-negative bacilli are found more rarely on the skin, and these include Proteus and Pseudomonas in the toe webs and Enterobacter and Klebsiella on the hands. Antibiotics disturb the balance within commensal flora and leave the surface vulnerable to colonization by exogenous gram-negative bacilli and fungi. The principal fungal flora is lipophilic yeasts of the genus Malassezia, and nonlipophilic yeasts such as Candida spp. Primary skin infections occur in otherwise normal skin and are usually caused by group A streptococci or S. A deficiency in the expression of antimicrobial peptides may account for the susceptibility of patients with atopic dermatitis to skin infection with S. Other factors predisposing to skin infections include vascular insufficiency, disrupted venous or lymphatic drainage, sensory neuropathies, diabetes mellitus, previous cellulitis, foreign bodies, accidental or surgical trauma, burns, poor hygiene, obesity, and immunodeficiencies. Extension into the superficial dermis with involvement of lymphatic is typical of erysipelas, whereas cellulitis is an extension into the subcutaneous tissue. A clinically useful distinction with important management implications subdivides soft tissue infections into nonnecrotizing and necrotizing processes (9). The Center for Drug Evaluation and Research for development of antimicrobial drugs has classified skin and soft tissue infection as uncomplicated or complicated. The uncomplicated category included simple abscesses, impetiginous lesions, furuncles, and cellulitis. Compli- cated category included infection involving the deeper layer or requiring significant surgical intervention. Superficial infection in an anatomical site with a risk of gram-negative pathogen or anaerobes such as the rectal area was also considered to be complicated (10). DiNubile and Lipsky classified skin and soft tissue infections to assist clinician in recognizing uncomplicated and complicated infections (11). Classification can also be based according to the severity of local and systemic signs and symptoms of infection, and the presence and stability of any comorbidities. Class 1 patients have no signs or symptoms of systemic toxicity without any comorbidities and can be managed in an outpatient setting. Class 3 patients have toxic appearance, one unstable comorbidity, or a limb-threatening infection, whereas class 4 patients have sepsis syndrome or serious Table 1 Classification of Skin and Soft Tissue Infection Based on Uncomplicated and Complicated Infections and Systemic Syndromes Uncomplicated Complicated Systemic syndromes Superficial: impetigo, ecthyma Secondary infection of diseased skin Scalded-skin syndrome Deeper: erysipelas, cellulitis Acute wound infections: Traumatic Toxic shock syndrome Hair follicle associated: Bite related Purpura fulminans folliculitis, furunculosis Post operative Abscess: carbuncle, Chronic wound infections: Diabetic foot infections cutaneous abscess Venous stasis ulcer Pressure ulcers Perianal infections Necrotizing fasciitis (type 1 and type 2) Myonecrosis (crepitant and noncrepitant) Source: Adapted in part from Ref. Guidelines developed by the Infectious Disease Society of America are written in references to specific disease entities, mechanism of injury, or host factors (13). Classification of skin and soft tissue infections based on uncomplicated and complicated infections, and systemic syndromes is depicted in Table 1.
Although reported as “resistant discount 20mg cialis with mastercard erectile dysfunction wellbutrin xl,” such an isolate may in fact be susceptible in body sites that concentrate the antibiotic to greater than serum levels cheap 20 mg cialis amex impotence vs infertile, i generic cialis 2.5mg on line erectile dysfunction drugs cialis. Pseudomonas is not an infrequent colonizer of the urine in patients with indwelling urinary catheters, i. These strains should be identified as such and their spread limited by effective infection-control containment measures. The reason for this is that colonizing strains exist in sites where the concentration of antibiotics may be subtherapeutic. All other things being equal, subtherapeutic concentrations of antibiotics are more likely to predispose to resistance than our supra therapeutic concentrations. It is important to differentiate colonization from infection to avoid needless antibiotic use (3–6). The incorrect clinical assumption is that the isolate in the respiratory secretions is reflective of the pathological process in the parenchyma of the lung. Respiratory secretions and parenchyma of the lung are rarely related and nearly always represent colonization rather than infection. In ventilated patients with fever and leukocytosis with a shift to the left and pulmonary infiltrates, it is well known that the cause of such patients’ pulmonary infiltrates is more commonly noninfectious than infectious. The necrotic/invasive nature of this fulminating/necrotic pneumonia is manifested by demonstrating elastin fibers using an elastin stain in respiratory secretions. Aminoglycosides concentrate the high concentration in the urine and are ideal agents to use in P. There are relatively few anti-pseudomonal antibiotics that are effective and reach therapeutic concentrations in the lung. Aminoglyco- sides have modest anti-Klebsiella activity but cephalosporins are highly active against K. Traditionally, double-drug antibiotic therapy was used to treat serious systemic K. Because *33% of tigecycline is excreted into the urine, therapeutic urinary concentrations may not be achievable with the usual tigecycline dosing, i. Acinetobacter colonization of aqueous solutions in respiratory support equipment is usually responsible for A. In excluding outbreaks, nearly always Acinetobacter isolates recover from respiratory secretions, represent colonization rather than infection indicative of A. This 518 Cunha can be achieved most simply by avoiding the unnecessary treatment of colonized respiratory secretions or urine (6,7,10). Pseudomonas aeruginosa susceptible only to colistin in intensive care unit patients. Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Intravenous polymyxin B for the treatment of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. Extended spectrum beta-lactamase-producing Klebsiella pneumoniae chronic ambulatory peritoneal dialysis peritonitis treated successfully with Polymyxyin B. Surveillance cultures and duration of carriage of multidrug-resistant Acinetobacter baumannii. Emergence of resistant Acinetobacter baumannii in critically ill patients within an acute care teaching hospital and long-term acute care hospital. Clinical and economic impact of multidrug resistance in nosocomial Acinetobacter baumannii bacteremia. Polymyxin B and doxycycline use in patient with multidrug-resistance Acinetobacter baumannii infections in the intensive care unit. Post-neurosurgical meningitis due to multi-drug resistant Acinetobacter baumanii treated with intrathecal colistin: case report and review of the literature. Antimicrobial effects of varied combinations of meropenem, sulbactam, and colistin on a multidrug-resistant Acinetobacter baumannii isolate that caused meningitis and bacteremia. Antibiotic Kinetics in the Febrile 29 Multiple-System Trauma Patient in Critical Care Donald E. Fry Northwestern University Feinberg School of Medicine, Chicago, Illinois and Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico, U. Judicious and appropriate antibiotics are important for preventive indications when the traumatized patient requires a surgical procedure. Specific antibiotic therapy is necessary when infectious complications occur at the site of injury. Nosocomial infections occur at numerous locations during the critical care management and during the prolonged convalescence of these patients, antimicrobial chemotherapy for treatment. In the patient with an injury severity score > 30, antibiotics are employed frequently during the hospitalization and the emergence of resistant and unusual pathogens make the appropriate management of the infectious complications of these patients a formidable challenge. The principals in the utilization of antibiotics for different indications in the trauma patient have become established over the last several decades. For preventive indications, the antibiotic should be given immediately prior (<60 minutes) to the skin incision for invasive interventions. The antibiotic should have activity against the likely pathogens to be encountered in the procedure. Prolonged preventive antibiotics after the procedure do not benefit the patient and should be stopped within 24 hours of the procedure. Infections that occur at the site of traumatic injury require antibiotic therapy against the clinically suspected and the culture-documented pathogens, in conjunction with aggressive surgical drainage and debridement of the primary focus. Because of the impact of the critical care unit, hospital microflora, and antecedent antibiotic treatment, nosocomial infections will notoriously be secondary to resistant organisms and must have susceptibility evidence to guide choices of treatment. Although the above principals in the use of antibiotics are generally accepted, infection continues to be the major cause of death for injured patients without severe head injury who survive the initial 48 hours following the insult. The reasons for infectious deaths in the face of optimum antibiotic utilization are (i) the magnitude of contamination exceeds the capacity of the host and therapy to control, (ii) profound immunosuppression attends the injury, and (iii) antimicrobial resistance produces an array of pathogens that become very elusive to treat. An important consideration that should be contemplated is whether the pathophysiologic changes of the severely injured patient create a clinical scenario where otherwise conventional antibiotic strategies may fail. This chapter will detail the systemic changes that are the result of the systemic activation of the human inflammatory cascade, and why these changes require a reassessment of antibiotic dosing strategies in febrile multiple-trauma patients. Finally, new strategies for the utilization of antibiotics in these patients will be proposed. The biological processes that comprise pharmacokinetics include absorption, volume of distribution, biotransformation, and drug excretion. For antibiotics, the quantitative evaluation of each of these components is used to design the dose and the treatment interval that will be employed for clinical trials and 522 Fry subsequent use of the drug. The clear objective of pharmacokinetic assessment is to provide antibiotic concentrations, which will ensure activity against the likely pathogens that are consistent with quantitative susceptibility information. A second objective is to maintain antibiotic concentrations within the nontoxic concentrations.
Others think of d as the amount of impact the independent variable has buy 10mg cialis with mastercard erectile dysfunction test yourself, which can- not be negative buy cialis 5 mg with visa statistics on erectile dysfunction. Effect Size Using Proportion of Variance Accounted For This approach measures effect size cheap cialis 20 mg line erectile dysfunction pills gnc, not in terms of the size of the changes in scores but in terms of how consistently the scores change. Here, a variable has a greater impact, the more it “causes” everyone to behave in the same way, producing virtually the same score for everyone in a particular condition. This then is an important variable, because by itself, it pretty much controls the score (and behavior) that everyone exhibits. Thus, in an experiment, the proportion of variance accounted for is the pro- portional improvement achieved when we use the mean of a condition as the predicted score of participants tested in that condition compared to when we do not use this approach. Put simply it is the extent to which individual scores in each con- dition are close to the mean of the condition, so if we predict the mean for someone, we are close to his or her actual score. When the independent variable has more con- trol of a behavior, everyone in a condition will score more consistently. Then scores will be closer to the mean, so we will have a greater improvement in accurately pre- dicting the scores, producing a larger proportion of variance accounted for. On the other hand, when the variable produces very different, inconsistent scores in each condition, our ability to predict them is not improved by much, and so little of the variance will be accounted for. In Chapter 8, we saw that the computations for the proportion of variance accounted for are performed by computing the squared correlation coefficient. For the two-sample experiment, we compute a new correlation coefficient and then square it. The squared point-biserial correlation coefficient indicates the propor- tion of variance accounted for in a two-sample experiment. This pb can produce a proportion as a low as 0 (when the variable has no effect) to as high as 1. In real research, however, a variable typically accounts for between about 10% and 30% of the variance, with more than 30% being a very substantial amount. Statistics in Published Research: The Two-Sample Experiment 283 The formula for computing r2 is pb 1t 22 2 obt rpb 5 2 1tobt2 1 df This formula is used with either the independent-samples or related-samples t-test. Then, for independent samples, df 5 1n1 2 12 1 1n2 2 12 For related samples, df 5 N 2 1. Hypnosis is not of major importance here, because scores are not consis- tently very close to the mean in each condition. Therefore, hypnosis is only one of a number of variables that play a role here, and, thus, it is only somewhat important in determining recall. Further, fewer other variables need to be considered in order to completely predict scores, so this is an important relationship for understanding phobias and the therapy. We also use the proportion of variance accounted for to compare the relationships from different studies. Thus, the role of therapy in determining fear scores (at 67%) is about three times larger than the role of hypnosis in determining recall scores (which was only 22%). Thus, a published report of our independent-samples hypnosis study might say, “The hypnosis group (M 5 23. Obviously, you perform the independent-samples t-test if you’ve cre- ated two independent samples and the related-samples t-test if you’ve created two related samples. In both procedures, if tobt is not significant, consider whether you have sufficient power. If tobt is significant, then focus on the means from each condition so that you summarize the typical score—and typical behavior—found in each condition. Use effect size to gauge how big a role the independent variable plays in determining the behaviors. Finally, interpret the relationship in terms of the underlying behaviors and causes that it reflects. For either, the program indicates the at which tobt is significant, but for a two-tailed test only. It also computes the descriptive statistics for each condition and automatically computes the confidence interval for either 1 2 2 or D. Two samples are independent when participants are randomly selected for each, without regard to who else has been selected, and each participant is in only one condition. The independent-samples t-test requires (a) two independent samples, (b) normally distributed interval or ratio scores, and (c) homogeneous variance. Homogeneity of variance means that the variances in the populations being represented are equal. The confidence interval for the difference between two ms contains a range of differences between two s, one of which is likely to be represented by the difference between our two sample means. Two samples are related either when we match each participant in one condition to a participant in the other condition, or when we use repeated measures of one group of participants tested under both conditions. The confidence interval for mD contains a range of values of D, any one of which is likely to be represented by the sample’s D. The power of a two-sample t-test increases with (a) larger differences in scores between the conditions, (b) smaller variability of scores within each condition, and (c) larger ns The related-samples t-test is more powerful than the independent-samples t-test. Effect size indicates the amount of influence that changing the conditions of the independent variable had on the dependent scores. Cohen’s d measures effect size as the magnitude of the difference between the conditions. The proportion of variance accounted for (computed as r2 ) measures effect pb size as the consistency of scores produced within each condition. The larger the proportion, the more accurately the mean of a condition predicts individual scores in that condition. All other things being equal, should you create a related-samples or an independent-samples design? We study the relationship between hot or cold baths and the amount of relaxation they produce. The relaxation scores from two independent samples are Sample 1 (hot): X 5 43, s2 5 22. We investigate if a period of time feels longer or shorter when people are bored compared to when they are not bored. Using independent samples, we obtain these estimates of the time period (in minutes): Sample 1 (bored): X 5 14. A researcher asks if people score higher or lower on a questionnaire measuring their well-being when they are exposed to much sunshine compared to when they’re exposed to little sunshine. A sample of 8 people is measured under both levels of sunshine and produces these well-being scores: Low: 14 13 17 15 18 17 14 16 High: 18 12 20 19 22 19 19 16 (a) Subtracting low from high, what are H0 and Ha? A researcher investigates whether classical music is more or less soothing to air- traffic controllers than modern music. She gives each person an irritability question- naire and obtains the following: Sample A (classical): n 5 6, X 5 14.
Testic- ular dysgenesis results from the absence of müllerian inhibiting substance during embryonic development and may be caused by multiple genetic mutations and may be associated with the absence of müllerian-inhibiting substance and reduced testosterone production buy cialis 5mg valium causes erectile dysfunction. Feminization may also occur through androgen insensitivity and mutations in the androgen receptor 20 mg cialis for sale erectile dysfunction medications over the counter. Most cases are diag- nosed perinatally on the basis of reduced fetal growth or lymphedema at birth with nu- chal folds buy cialis 2.5mg lowest price erectile dysfunction medication, a low posterior hairline, or left-sided cardiac defects. Some girls may not be diagnosed in childhood and come to attention much later in life because of delayed growth and lack of sexual maturation. Limited pubertal development occurs in up to 30% of girls with Turner syndrome, with approximately 2% reaching menarche. Owing to the frequency of congenital heart and genitourinary defects, a thorough workup should be done after the diagnosis, including an echocardiogram and renal imaging. Long-term management includes growth hormone replacement during childhood and estrogen replacement to maintain bone mineralization and feminization. The presentation is not consistent with the bony deformities or blue sclera seen in patients with osteogenesis imperfecta, and he is tall with long extremities, which makes chondroplasia very unlikely. However, his hypermobility and lens disorders suggest Marfan syndrome or, less com- monly, Ehlers-Danlos syndrome. Given the high risk of aortic root disease in Marfan syn- drome, echocardiography is indicated in this patient. The other screening tests are not speciﬁc to Marfan syndrome and are not appropriate in a 30-year-old male. These patients often have skin cancers as a result of the mutagenic effects of ultraviolet light. Ataxia-telangiectasia is characterized by large telangi- ectatic lesions on the face, cerebellar ataxia, immunologic defects, and hypersensitivity to 38 I. Fanconi’s anemia is caused by mutations in multiple complementation groups that are characterized by various congenital anomalies and a marked predisposition to aplastic anemia and acute myeloid leukemia. It is characterized by X- linked inheritance and typical large ears, macroorchidism, and mental retardation. Areas of high dependence on oxidative phosphorylation include skeletal and cardiac muscle and the brain. During repli- cation, the number of mitochondria can drift among various cells and tissues, resulting in heterogeneity, or heteroplasmy. Acquired mutations in the mitochondrial genome are thought to play a signiﬁcant role in age-related degenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Uniparental disomy is the inheritance of dual copies of either maternal or paternal chromosomes. The Prader-Willi and Angelman’s syndromes may result from uniparental disomy involving inheritance of defective maternal or paternal chromosomes, respectively. Similarly, hydatidiform moles may contain normal numbers of diplid chromosomes, all of which are of paternal origin. Lyonization is epigenetic inactivation of one of the two X chromosomes in every cell of the female. Somatic mosaicism is the presence of two or more genetically dis- tinct cell lines in the tissue of an individual. The term anticipation is often used to refer to diseases caused by trinucleotide repeats that are often characterized by worsening of clin- ical phenotypes in successive generations. These diseases, such as Huntington’s disease and fragile X syndrome, are characterized by expansion of these repeats in subsequent generations of individuals, resulting in earlier and often more severe clinical phenotypes. Disorders of any of these macromolecules may result in a disorder of connective tissue. Clinically, it is characterized by decreased bone mass, brittle bones, blue sclerae, dental abnormalities, joint laxity, and progressive hearing loss. The phenotype may range from severe disease with in utero death to milder forms with lesser severity and survival into adulthood. Ehlers-Danlos syndrome is a heterogenous set of disorders characterized by joint laxity, hyperelasticity of the skin, and other defects in collagen synthesis. A variety of defects have been identiﬁed in differ- ent types of collagen as well as enzymes that facilitate collagen cross-linking. Marfan syn- drome is characterized by a triad of features: long, thin extremities (with arachnodactyly and loose joints), reduced vision as a result of ectopia lentis, and aortic aneurysms. McArdle’s disease is a defect in glycogenolysis that results from myophosphorylase deﬁciency. Lysosomal storage diseases result from mutations in various genes for these hydrolyases. In the infantile form, these patients have macrocephaly, loss of motor skills, an increased startle reaction, and a macular cherry red spot. The juvenile-onset form presents with ataxia and progressive dementia that result in death by age 15. The adult-onset form is characterized by clumsiness in childhood, progressive motor weakness in adoles- cence, and neurocognitive decline. The disease is seen most commonly in Ashkenazi Jews, with a carrier frequency of about 1 in 30. Clinical features result from an accumulation of lipid-laden macrophages, termed Gaucher cells, throughout the body. Bone marrow involvement is common, with subsequent infarction, ischemia, and necrosis. Although the liver and spleen may become massive, severe liver dysfunction is very rare. Enzyme therapy is currently the treatment of choice in signiﬁcantly affected patients. Other therapies include symptomatic management of the blood cytopenias and joint replacement surgery for bone injury. Type 3 dis- ease is nearly identical to type 1 disease except that the course is more rapidly progressive. The example provided is typical of patients with hemophilia A or Duchenne’s muscular dystrophy. X-linked recessive inheritance is marked by the fact that the incidence of the trait is much higher in males than in females. The genetic trait is passed from an affected male through all his daughters to, on average, half their sons. The trait may be transmitted through a series of carrier females; if that oc- curs, the affected males are related to each other through the female, as in this case. It is likely that the expression of these disor- ders depends on a family of genes that can impart a certain degree of risk and then be modi- ﬁed by subsequent environmental factors. The risk of the development of disease in a relative of an affected person varies with the degree of relationship; ﬁrst-degree relatives (parents, siblings, and offspring) have the highest risk, which in itself varies with the speciﬁc disease. This genotype also imparts an increased risk for chronic active hepatitis, myasthenia gravis, and Addison’s disease. By contrast, Wilson’s disease and cystic ﬁbrosis are inher- ited in an autosomal recessive fashion, and adult polycystic kidney disease and neuroﬁbro- matosis are among the disorders inherited in an autosomal dominant manner.
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