Paul J. Kim, DPM

• Assistant Professor of Podiatric Medicine and Surgery
• Midwestern University
• Glendale, Arizona

Bladder (Vesical) Urolithiasis Formation of stones in the bladder is rare in the developed world though more common in developing countries depression disease definition purchase escitalopram discount, including in children depression definition pubmed cheap escitalopram 20mg buy on-line. Some patients are asymptomatic; those with symptoms may experience dysuria depression facts purchase discount escitalopram on-line, suprapubic pain depression years after break up order 5mg escitalopram amex, and urinary hesitancy anxiety xanax and dementia 10 mg escitalopram buy amex. A stone in the bladder may irritate the urothelium and result in hematuria; once the bladder neck or urethral oriice is reached, manifestations of obstruction may appear. Diagnostic tests are similar to those for calculi in other segments of the urinary tract. Stone expulsion is often spontaneous; stones causing obstruction pose a risk for postrenal acute kidney injury and require prompt intervention. Stone removal procedures include transurethral lithotripsy for stones smaller than 1 cm, percutaneous cystolithotomy for stones up to 5 cm, and open cystolithotomy for stones 5 cm. Stones in the lower urinary tract produce some manifestations that are similar to stones formed and lodged in the kidney. Lower Urinary Tract Urolithiasis Stones, or calculi, usually form in the kidneys (nephrolithiasis). Individuals with stones that approach the bladder may experience pain that is sharp in quality but intermittent in nature. Otherwise, the pain may increase and radiate in to the groin region, testicles, or labia. Obstructive signs and symptoms will present if stones obstruct the bladder neck or urethral oriice. If infection is present, it is treated with appropriate antimicrobials, based on culture and sensitivity tests. Intervention for stones that do not pass spontaneously is endoscopic (transurethral) lithotripsy. In adults, the most prevalent pathologic conditions are voiding dysfunction, malignancies, infections, and urinary stones. The prevalence of incontinence increases with age and is more common in women than men. However, incontinence is not a result of the normal aging process, and patients should be urged to seek evaluation and treatment. Behavioral, pharmacologic, and surgical approaches may be used to manage voiding dysfunction. Interstitial cystitis/painful bladder syndrome is a chronic condition consisting of bladder pain and a variety of other manifestations typically associated with other bladder pathologies. In the United States, bladder cancer is the fourth most common type of cancer in men and the ninth most common type in women. Vesicoureteral relux is the most prevalent congenital lower urinary tract disorder. Stones in the lower urinary tract usually arrive there after being formed in the kidney. Risk factors and treatment are much the same as those for nephrolithiasis; however, manifestations of urolithiasis in the ureters or bladder differ. Casey G: Incontinence and retention-how the bladder misfunctions, New Zealand Nurs J 17:26­31, 2011. Abrams P, et al: the standardization of terminology of lower urinary tract function, Neurourol Urodyn 21:167­178, 2002. Stothers L: Should hormone replacement therapy be used in postmenopausal women for voiding dysfunction Neveus T, et al: the standardization of terminology of lower urinary tract function in children and adolescents, J Urol 176:314­324, 2006. Shreeram S, et al: Prevalence of enuresis and its association with attention-deicit/hyperactivity disorder among U. Neveus T, et al: Evaluation of and treatment for monosymptomatic enuresis, J Urol 183:441­447, 2010. Bascom A, et al: High risk of sleep disordered breathing in the enuresis population, J Urol 186:1710­1714, 2011. Burgu B, et al: Lower urinary tract conditions in children with attention deicit hyperactivity disorder, J Urol 185:663­668, 2011. Ramakrishnan K: Evaluation and treatment of enuresis, Am Fam Physician 78:489­496, 2008. Hannula A: Vesicoureteral relux in children with suspected and proven urinary tract infection, Pediatr Nephrol 25:1463­1469, 2010. Demirbag S: Bladder dysfunction in infants with primary vesicoureteric relux, J Int Med Res 37:1877­1881, 2009. Karnak I, et al: Prenatally detected ureteropelvic junction obstruction: clinical features and associated urologic abnormalities, Pediatr Surg Int 24:395­402, 2008. Funahashi Y, et al: Radical prostatectomy for prostate carcinoma with ectopic ureters: a case report, Nippon Hinyokika Gakkai Zasshi 98:580­ 582, 2007. Spatafora S, Pierfrancesco B, Leoni S: Combined percutaneoustransurethral incision for treatment of ureterocele in adults, Urology 68(6):1333­1335, 2006. Nonmura K, Kakizaki H: Recent trends of genitourinary endoscopy in children, Int J Urol 12:607­614, 2005. Kajbafzadeh A, et al: Evolution of endoscopic management of ectopic ureterocele: a new approach, J Urol 177:1118­1123, 2007. Shaikh N, et al: Prevalence of urinary tract infection in childhood: a metaanalysis, Pediatr Infect Dis J 27(4):302­308, 2008. Hanno P, et al: Bladder Pain Syndrome Committee of the International Consultation on Incontinence, Neurourol Urodyn 29:191­198, 2010. Seitz C: Medical expulsive therapy of ureteral calculi and supportive therapy after extracorporeal shock wave lithotripsy, Eur Urol Suppl 9:807­813, 2010. Arrabal-Martin M, et al: Treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis, Urol Int 84:254­259, 2010. Which genitourinary structures develop embryologically from the wolfian ductal system in males How do the processes of capacitation and acrosome reaction affect the fertilization process The anatomy and embryology of the male genitourinary tract-those organs involved in the processes of sexual reproduction and elimination of nitrogenous wastes-will be presented irst. Because these organs are derived from common embryologic structures, the anatomy and embryology of the male genitalia and urinary system will be emphasized, and the differences in embryologic development between males and females will be considered when pertinent. The remainder of this chapter will deal with the physiologic processes of male reproduction. The kidneys receive their blood from the renal arteries, which arise directly from the aorta. The renal pelvis and upper part of the ureter receive blood from branches of the renal artery. The arterial blood supply of the bladder comes from the superior, middle, and inferior vesical arteries, which originate from the anterior division of the hypogastric artery. Venous drainage occurs by a rich plexus of veins that surround the bladder and ultimately drain in to the hypogastric veins. The bladder and urethra receive their nerve supply from both the sympathetic and the parasympathetic divisions of the autonomic Lower Genitourinary Tract Bladder the bladder is a hollow muscular organ that serves as a reservoir for urine. When empty, the bladder lies behind the pubic symphysis and is mainly a pelvic organ. With overdistention or chronic urine retention, the abdomen may bulge, allowing easy palpation of the bladder in the suprapubic region. The ureteral oriices are situated on a crescent-shaped ridge and are approximately 2. As will be discussed later in the chapter, the trigone has a different embryologic origin from the rest of the bladder body, or fundus. In males, the bladder lies anterior to the seminal vesicles, vasa deferentia, ureters, and rectum. The dome and part of the posterior bladder surfaces are covered by peritoneum and are thus in close proximity to the small bowel and the sigmoid colon. In males, the prostate lies between the bladder and the muscle layers of the pelvic loor that composes the urogenital diaphragm. The triangular area demarcated by the interureteric ridge and the bladder neck is the trigone. The sympathetic ibers, originating mainly from the lower thoracic and upper lumbar segments (T11-T12 and L1-L2), innervate the bladder and urethra as the hypogastric nerves. These sympathetic ibers are distributed more densely in the bladder base and proximal end of the urethra than in the bladder dome. The parasympathetic nerve supply originates from the sacral segments (S2-S4), which proceed to form a plexus surrounding the bladder. In the male, a separate segment will reach the prostate and form the prostatic plexus. Branches of the bladder plexus penetrate the muscular coat of the bladder and become distributed throughout the detrusor. Parasympathetic muscle receptors are cholinergic in nature, and parasympathetic stimulation induces a detrusor contraction that causes bladder emptying. Auxiliary Genital Glands the auxiliary genital glands of the male consist of the prostate, the seminal vesicles, and the bulbourethral glands. Prostate the prostate lies below the bladder and has both a muscular and a glandular component. The prostate consists of a thin ibrous capsule with internally circular smooth muscle ibers and collagenous tissue that surround the urethra. Deep in this layer of connective and elastic tissue lies the prostatic stroma, which contains the prostatic epithelial glands. These glands drain in to excretory ducts, which open chiely on the loor of the urethra between the verumontanum and the vesical neck. In conjunction with the seminal vesicles, the prostate produces the luid that supports the sperm. In Urethra the male urethra, which extends from the bladder to the external opening (urethral meatus) at the tip of the penis, functions as a conduit for both urinary and genital systems. The main blood supply of the prostate is derived from the inferior vesical artery, a branch of the hypogastric artery. Besides the prostate, this artery also supplies the distal portion of the ureter, the seminal vesicles, and part of the bladder. A complex plexus situated between the prostate and overlying tissue freely communicates with the inferior hypogastric veins and provides venous drainage to the prostate. Bulbourethral Glands the bulbourethral or Cowper glands are located on each side of the membranous urethra within the urogenital diaphragm. Each compartment contains a male gonad, or testis, with its associated epididymis and the lower portion of the vas deferens protected by the spermatic cord and its coverings. The scrotum not only supports the testes but also, by relaxation and contraction of its muscular layer, helps regulate temperature of the testes. The scrotal skin overlies the dartos muscle layer, whose smooth muscle ibers are embedded in loose connective tissue. The dartos muscle functions to contract the scrotal pouch when cold and expand it when warm. The external spermatic fascia is continuous with the external oblique aponeurosis of the abdominal wall. A few slips of skeletal muscle derived from the internal oblique muscle layer make up the cremasteric muscle, which adds to the upper part of the cord. The internal spermatic fascia is a continuation of the transverse fascia of the abdominal wall, with the transversus abdominis muscle not contributing to the cord layers. Finally, the peritoneum provides the tunica vaginalis layers, which are actually separated from the abdominal cavity by obliteration of the processus vaginalis. The scrotum receives its blood supply from the external pudendal artery, a branch of the femoral artery. In addition, the scrotum receives blood from portions of the internal pudendal artery (a branch of the hypogastric artery) and the cremasteric and testicular arteries that transverse the spermatic cord. Testes the testes are the male reproductive organs responsible for sperm production. The body and the tail of the epididymis form one continuous tube that serves as a conduit for maturing spermatozoa. As the convoluted tube of the tail leaves its testicular attachments, it increases in diameter to become a thick, muscular tube called the ductus deferens, also called the vas deferens. Leaving the spermatic cord, the vas deferens follows an extraperitoneal course and passes caudally and laterally along the pelvic wall. As it passes medial to the distal end of the ureter, it bends caudally to reach the midline and lies on the posterior wall of the bladder just medial to the seminal vesicles. It terminates in a dilated ampulla that courses underneath the base of the prostate. At this point the duct of the seminal vesicle joins with the duct of the ampulla, and the ejaculatory duct is formed. The ejaculatory ducts open in the prostatic urethra at the level of the verumontanum. This ibrous mediastinum sends ibrous septa in to each testis that separate it in to many different lobules. Each lobule contains one to four seminiferous tubules that if stretched to full length would measure approximately 60 cm. The seminiferous tubules have a basement membrane consisting of elastic and connective tissue that supports the seminiferous cells. The seminiferous cells are either Sertoli cells (supporting cells) or spermatogenic cells. The tubules, which are connected by the straight efferent ducts, drain in to the head of the epididymis. The testicular blood supply is derived from the internal spermatics, which arise directly from the aorta below the renal arteries. They course inferiorly through the spermatic cord and anastomose with the cremasteric arteries and the arteries of the vas; these vessels also contribute to the blood supply. The blood from the testis returns through a plexus of veins in the spermatic cord (the pampiniform plexus) that forms the spermatic veins.

In this case mood disorder famous people order cheap escitalopram on line, 95% of all people with ankylosing spondylitis have a positive B27 phenotype anxiety pregnancy buy 5mg escitalopram visa. However anxiety nausea buy escitalopram 10mg cheap, not everyone with a positive B27 phenotype develops ankylosing spondylitis bipolar depression pregnancy escitalopram 10mg mastercard, both because of differences in the way antigen is presented to the immune system and because of environmental factors mood disorder with psychotic features dsm generic escitalopram 20mg free shipping. There may also be disease-causing genotypes or genetic factors affecting expression of immune factors. For example, the lymphoid protein tyrosine phosphatase nonreceptor type 22 gene is associated with type 1 diabetes and other autoimmune disease. Environmental Triggers Chronic or multiple viral or bacterial infections may trigger the development of autoimmune disease in susceptible persons. Viruses can activate B cells, decrease the function of T cells, contribute to the development of antigenic mimicry, or insert viral components on cell surfaces and trigger immune reactions. For example, Epstein-Barr virus, cytomegalovirus, and bacteria such as Campylobacter jejuni and Helicobacter pylori have been frequently cited as potential triggers of autoimmune disease. Environmental stress and occupational stress can affect the immune system because of their relationship to the neuroendocrine system, Genetic Factors Genetic predisposition seems to be an important factor in the development of autoimmune disorders. Gender, which is genetically determined, also inluences the expression of autoimmune disorders. Therapeutic plasmapheresis is another type of therapy occasionally used in the management of autoimmune diseases. Plasmapheresis is analogous to dialysis and involves the selective iltering or removal of plasma or a plasma cell type as well as protein-bound toxic substances. According to the American Society for Apheresis, this type of therapy has been effective in the management of diseases such as myasthenia gravis, thrombocytopenia purpura, multiple sclerosis, and Rh-negative hemolytic disease of the newborn. Plasmapheresis is generally well tolerated; however, there are both major and minor risks involved in the process. Neuroendocrine and immune system interaction during life stress, such as shift work or workplace stress, promotes the synthesis and overproduction of proinlammatory cytokines. Although the etiology of autoimmunity continues to be investigated, the mechanisms whereby autoantibodies injure tissues are better understood. Pharmacotherapies Immunosuppressive therapy is a common treatment for autoimmune disease. Because autoimmunity is expressed in different ways, the immunosuppressive treatment for each type of autoimmune disease is individualized, depending on disease expression. Immunosuppressive therapy, including corticosteroids and certain cytotoxic chemotherapeutic agents, has become an increasingly important treatment choice. The ideal immunosuppressive medication would be an agent that inhibits only the abnormal immune response without limiting the positive and protective functions of the immune system or causing any organ toxicity. Unfortunately, no immunosuppressive medication with these speciic properties yet exists. Immunosuppressive agents include corticosteroids, tumor necrosis factor inhibitors, immunomodulators, and cytotoxins. Corticosteroids decrease the number of lymphocytes and decrease antibody formation, as well as alter the functional activities of lymphocytes. They also have many other activities as a result of their glucocorticoid function. Corticosteroids tend to be used in the treatment of many autoimmune diseases and are the oldest of the immunosuppressive drugs. The adverse effects that occur during corticosteroid use often limit their extended use over time. Cytotoxins, such as methotrexate, are used to manage autoimmune disorders because of their ability to kill actively proliferating lymphocytes after they are transformed from their resting G0 state. The key to the use of cytotoxins is to effectively apply their killing activity without damaging the rest of the body. Cyclosporine (Sandimmune) is a more selective immunosuppressant that reversibly suppresses T-helper cells in the G0 or G1 phase of the cell cycle without killing them. As a result, it inhibits the development of killer or cytotoxic T cells without decreasing the numbers of cells. It also impairs the ability of T cells to respond effectively to foreign antigens. Frequent side effects include edema, hypertension, headache, hirsutism, elevated triglyceride levels, gastrointestinal effects, nephropathy, infection, emotional changes, gynecomastia, leukopenia, anemia, and hepatotoxicity. These disorders are thought to be polygenic and multifactorial; however, the exact etiologic process is unknown. The basic mechanism that triggers hypersensitivity is a speciic antigenantibody reaction or a speciic antigen-lymphocyte interaction. Hypersensitivity reactions are speciic to a particular antigen and usually do not occur on irst exposure to the antigen. Although the diseases or syndromes associated with each type differ in their clinical signs and symptoms, the underlying pathophysiologic process is similar within each type. The complex interactions between immune system inlammatory mediators, cytokines, T cells, B cells, and mast cells characterize hypersensitivity reactions. Genetic mechanisms inluence type I hypersensitivity with strong genetic or hereditary linkage regarding the IgE response to antigens (allergens). This genetic component involves both the ability to respond to an allergen and the general ability to produce an IgE antibody response. For example, children born to two allergic parents have a 50% chance of being allergic. Children born to one nonallergic and one allergic parent have a 30% chance of being allergic. It has been identiied that total IgE concentration is higher in patients with atopic rhinitis or asthma compared to nonatopic patients. Type I hypersensitivity is also known as immediate hypersensitivity, because the reaction is immediate. It is a sensitization reaction characterized by signs and symptoms of an allergic reaction that usually occurs 15 to 30 minutes after exposure to an antigen (allergen). At the cellular level, immunoglobulin E (IgE) is the principal antibody mediating this reaction. IgE is produced by specialized plasma B cells and circulates in very small amounts in the blood. When an individual is exposed to an allergen, selected plasma B cells produce allergen-speciic IgE. It usually takes repeated exposures to the allergen to cause signiicant levels of IgE to be present in the blood. Environmental pollutants may play a role by increasing mucosal permeability and enhancing antigen (allergen) entry in to the body. Mast cells and basophils are the principal effector cells, although there are many other cells with histamine and other inlammatory mediators that can be involved in the reaction. These may include neutrophils, eosinophils, lymphocytes, macrophages, epithelial cells, and endothelial cells. They are covered with IgE receptors-up to 500,000 on their cell surfaces-and they are illed with vesicles or granules containing potent vasoactive, proinlammatory chemical mediators (especially histamine) that produce inlammation when they are released. Cross-linking of IgE and the antigen causes an increase in intracellular calcium (Ca2+) concentration that results in immediate, massive, local mast cell degranulation of preformed and newly formed proinlammatory mediators. Some of the mediators are preformed and stored in vesicles, such as histamine, heparin, proteolytic enzymes, and chemotactic factors. Examples of newly formed mediators include superoxide, prostaglandins, thromboxanes, leukotrienes, bradykinin, and interleukins (see Chapter 9). Histamine binds to H1 (histamine 1), H2, H3, and H4 receptors, which are located on many types of cells. Mast cells have receptors for H1, H2, and H3, with H1 receptors being the most active. Basophils express predominantly H2 receptors, whereas neutrophils and eosinophils have both H1 and H2 receptors. Recent evidence shows that H1 and H2 receptors are present on monocytes and macrophages, with an increase in H1 receptors when monocytes differentiate in to macrophages. The activation of H2 receptors has opposing effects to H1 receptors in some tissues and causes smooth muscle relaxation in the lower airways, augments gastric acid secretion from parietal cells, and in high concentrations has an inhibitory effect on inlammatory cells, decreasing degranulation and decreasing neutrophil chemotaxis. The H3 receptors are located in the brain, in the spinal cord, and on sensory neurons such as postganglionic cholinergic nerves in lung bronchi. The H4 receptors are found on immune system cells such as dendritic cells, eosinophils, T cells, monocytes, macrophages, and natural killer cells as well as in hematopoietic cells such as the spleen, thymus, bone marrow, and blood leukocytes. H4 receptors are highly attracted to histamine and are also involved in chemotaxis and inlammatory responses. The proteolytic enzymes kininogenase and tryptase activate the kinin pathway and C3 activates the complement cascade via the alternative pathway. Manifestations of an immediate hypersensitivity reaction vary in severity and intensity. For many people, type I hypersensitivity reactions are annoying, such as hives (urticaria), seasonal allergic rhinitis, eczema, or mild bronchoconstriction. In other people, the symptoms are more problematic, including tightening of the throat, localized edema, wheezing, and tachycardia, such as is associated with localized angioedema reactions or severe airway reactions. In a very small number of highly allergic people, the type I hypersensitivity reaction can be expressed as a life-threatening allergic reaction known as anaphylaxis such as that associated with bee stings and seafood or peanut allergic reactions. Common allergenic medications, insects, and foods that can trigger type I hypersensitivity reactions are listed in Box 10-1. Treatment for type I hypersensitivity primarily involves pharmacologic management with antihistamines, -adrenergics, corticosteroids, anticholinergics, and anti­immunoglobulin E therapy (IgE blocker therapy). Antihistamines such as diphenhydramine (Benadryl) are used to block the effect of histamine. Epinephrine is an adrenergic agent (, 1, and 2) given subcutaneously or intravenously during acute allergic reactions, especially after food or bee sting reactions. Most patients with severe allergies to food or insect bites are given prescriptions for epinephrine in the form of EpiPen with an autoinjector. Anticholinergics are used to block the parasympathetic system and thus allow greater sympathetic activity. Anti­immunoglobulin E therapy (omalizumab) may be used for persons with severe persistent asthma. Omalizumab (Xolair) is a subcutaneously injected, monoclonal anti-IgE antibody that binds to the IgE molecule, thus inhibiting the binding of IgE to mast cells and basophils and promoting downregulation of IgE receptors. It is used to improve asthma control in patients with moderate to severe persistent asthma not controlled with inhaled corticosteroids. Some protective, proactive actions taken during pregnancy are thought to decrease the likelihood that type I hypersensitivity will develop in children from families with a history of allergies. Another avenue for prevention of type I hypersensitivity reactions involves the use of desensitization therapy (immunotherapy). Desensitization, or immunotherapy, is more successful in patients with hay fever than in those with other types of allergies. It involves both environmental control of external allergens and titrated pharmacologic exposure to allergens. Environmental control involves a systematic plan to decrease exposure to house dust, molds, and animal dander. The person must avoid food allergens, wool carpets, goose down or feather pillows, dried plants, and exposure to other animal and vegetable products. Pharmacologic desensitization involves injecting a person with suficient antigen (allergen) on a regular basis over a course of months or years, followed by periodic maintenance or booster therapy. Gradually the dose is increased until the person can tolerate the allergen without a type I hypersensitivity reaction. The goal of this therapy is a change in immunoglobulins so that there is an increase in IgG- and IgA-blocking antibodies, no increase in IgE during allergy season, decreased basophil reactivity, and decreased lymphocyte reactivity to allergens. The reaction is mediated by the complement system and a variety of effector cells, including tissue macrophages, platelets, natural killer cells, neutrophils, and eosinophils. Transfusion reactions, hemolytic disease of the newborn, and graft rejection are examples of isoimmunity (alloimmunity), a condition in which the immune system reacts against antigens on tissues from other members of the same species. The Fc region then acts as a bridge between the antigen and complement or the effector cells. This antigen-antibody binding with Fc bridging is the key and leads to lysis of the cell by one of several mechanisms. Complement-mediated lysis occurs through the classical pathway for activation of complement. The classical pathway of complement generates the activated complement component C3b via splitting of C4 and C2 by C1 (Chapter 9). The activated complement component C3b is bound to the target cell by the Fc region of IgG or IgM. C3b increases opsonization, which in turn increases the capacity of the system to allow lysis by other effector cells or by complement itself. Often the reaction is immediate (15 to 30 minutes after Transfusion Reaction An example of this type of mechanism is an acute hemolytic blood transfusion reaction. It occurs when a person receives blood from someone with a different blood group type (Table 10-4). For example, if a person with type A blood having type A antigens and anti-B antibodies incorrectly receives type B blood with B antigens and anti-A antibodies, the anti-B antibodies will attach to the surface of the infused type B red blood cells and the anti-A antibodies in the infusion will attach to the surface of the circulating type A red blood cells. The resulting signs and symptoms of this major blood group reaction include fever, chills, lushing, tachycardia, hypotension, low back pain, pleuritic chest pain, nausea, vomiting, restlessness, anxiety, oliguria, and headache. They may be delayed from a few days to 2 weeks especially in persons requiring periodic transfusions such as in sickle cell anemia or thalassemia. Once this bridging occurs, the foreign cell is phagocytized and destroyed by lysosomes within the effector cell. An example of this type of mechanism is hemolytic disease of the newborn (erythroblastosis fetalis).

These defects depression definition dictionary purchase line escitalopram, as well as large structural defects (involving more than 5 to 10 million base pairs) depression symptoms of buy escitalopram 20 mg without a prescription, can be detected using traditional genetic testing methods such as karyotyping depression documentary buy escitalopram in united states online. When the abnormal germ cell combines with a normal germ cell containing 23 chromosomes anxiety symptoms in women 5 mg escitalopram order visa, the resulting zygote will either be deicient by one chromosome (45) or have an extra chromosome (47) depression during pms 20mg escitalopram buy with amex. In anaphase lag, one chromosome lags behind and is therefore left out of the newly formed cell nucleus. This results in one daughter cell with the normal number of chromosomes and one with a deiciency of one chromosome, a condition called monosomy. The causes of aneuploidy are poorly understood; however, advanced maternal age, abnormalities in parental chromosome structure, and abnormalities in crossing over are known to increase the risk of abnormalities in chromosome number in humans. Disorders involving extra or missing sex chromosomes are more common and less debilitating. Abnormal Chromosome Structure Alterations in chromosome structure are usually due to breakage and loss or rearrangement of pieces of the chromosomes during meiosis or mitosis. During meiosis, the homologous chromosomes normally pair up and exchange genetic alleles in a process called crossing over. When the normal process of crossing over goes awry, portions of chromosomes may be lost, attached upside down, or attached to the wrong chromosome. The severity of the chromosomal rearrangement ranges from insigniicant to lethal, depending on the number and importance of the gene loci involved. Gene locations can be described by their position on the long arm (q arm) or the short arm (p arm) of the chromatid. Aneuploidy refers to an abnormal number of chromosomes-in humans, either more or less than 46. If no genetic material is lost, as in a reciprocal translocation, the individual may have no symptoms or disorder. However, an individual with a reciprocal translocation is at increased risk of producing abnormal gametes. This is called a robertsonian translocation and is responsible for a rare hereditary form of Down syndrome, discussed later in the chapter. Isochromosomes occur when the sister chromatids separate incorrectly at the centromere such that the two identical short arms remain together, as do the two long arms. Like balanced translocations, inversions involve no net loss or gain of genetic material and are often without consequence to the individual. Dificulties result, however, when homologous chromosomes attempt to pair up during meiosis. The chromosome with an inverted section may not pair up properly, resulting in duplications or loss of genes at the time of crossing over. Chromosomal deletions have been associated with some forms of cancer, including retinoblastoma (see Chapter 7). Deletions at both ends of a chromatid may cause the free ends to attach to one another, forming a ring chromosome. The consequences of duplications are generally less severe than those from loss of genetic material. Gene loci are described by the chromosome number, location on short (p) or long (q) arm, region, and band. Examples of Autosomal Chromosome Disorders Trisomy 21 (Down Syndrome) Trisomy 21 is a chromosomal disorder in which individuals have an extra copy of chromosome 21. It is the most common of the chromosomal disorders and a leading cause of mental disability, occurring in about 1 in 700 live births. Children with Down syndrome often are aflicted with congenital heart deformities and an increased susceptibility to respiratory tract infections and leukemia. Precise causes of these signs and symptoms are unknown, although the genedosage hypothesis relates them to overexpression of certain genes contained on chromosome 21. The reason for increased susceptibility of the ovum to nondisjunction with age remains unknown. A rare form of Down syndrome (occurring in about 4% of cases) is due to a chromosomal translocation of the long arm of chromosome 21 to another chromosome. This form of Down syndrome is not associated with increased maternal age but is passed from parent to offspring. Therefore, testing for translocations in newborns with Down syndrome is recommended to determine recurrence risk for families. Trisomies involving chromosomes 8, 9, and 22 also have been described but are extremely rare. Cri du Chat Syndrome Deletion of part of the short arm of chromosome 5 results in a syndrome characterized by severe mental retardation, round face, and congenital heart anomalies. The syndrome was so named because of the characteristic cry of the affected infant, which is caused by laryngeal malformation and resembles a cat crying. Some children aflicted with this syndrome survive to adulthood, and they generally thrive better than those with the trisomies. Examples of Sex Chromosome Disorders Klinefelter Syndrome the incidence of Klinefelter syndrome is about 1 in 600 liveborn males, making it the most common sex chromosome abnormality. The presence of the Y chromosome determines the sex of these individuals to be male; however, the extra X chromosomes result in abnormal sexual development and feminization. The condition is rarely diagnosed before puberty, when lack of secondary sex characteristics may become apparent. Turner Syndrome Also known as monosomy X, Turner syndrome is associated with the presence of only one normal X chromosome and no Y chromosome. The absence of the Y chromosome results in a female phenotype; however, the ovaries fail to develop or fail prematurely. In some cases of Turner syndrome, the second X chromosome is not entirely missing but is structurally abnormal. An individual has two copies or alleles of each gene (one allele from each parent). A recessive gene is expressed only when the individual is homozygous for the gene; that is, the individual has two identical copies. Mendelian disorders are generally classiied according to the location of the defective gene (autosomal or sex chromosome) and the mode of transmission (dominant or recessive). The great majority of mendelian disorders are familial (attributable to mutant genes inherited from the parents), but 15% to 20% represent new mutations. For example, new mutations for Huntington disease are rare, whereas 80% of individuals with achondroplasia represent new mutations. It is important to note that there are many exceptions to these rules, but they generally are useful in predicting transmission patterns for a number of single-gene disorders. Autosomal Dominant Disorders Autosomal dominant disorders are due to a mutation of a dominant gene located on one of the autosomes. In general, autosomal dominant disorders involve key structural proteins or regulatory proteins, such as membrane receptors. Marfan syndrome and Huntington disease are commonly cited examples of autosomal dominant disorders and are briely described here. Most fetuses with monosomy X are lost during pregnancy, and the incidence is about 1 in 3000 live female births. Marfan Syndrome Marfan syndrome is a disorder of the connective tissues of the body. Because of the long, thin ingers, this syndrome has also been called arachnodactyly ("spider ingers"). It is commonly suggested that President Abraham Lincoln may have had this disorder. Although skeletal and joint deformities are problematic, the cardiovascular lesions are the most life threatening. The medial layer of blood vessels, particularly the aorta, tends to be weak and susceptible to dilation and rupture. Marfan syndrome has been traced to hundreds of different mutations in the ibrillin 1 gene on chromosome 15. Most individuals appear normal; however, females may experience menstrual abnormalities, and males will generally be taller than average. A tendency toward mental retardation has been noted in females with more than four X chromosomes. It provides important scaffolding for deposition of other matrix proteins such as elastin. Marfantype ibrillin 1 appears to be more susceptible to proteolytic degradation than normal ibrillin, leading to the weakened connective tissues typical of the disease. Huntington Disease Huntington disease is an autosomal dominant disease that primarily affects neurologic function. The symptoms of mental deterioration and involuntary movements of the arms and legs do not appear until approximately age 40 years. The disease was formerly called Huntington chorea (from the Greek khoreia, meaning "dance") because of the uncontrolled movements of the limbs. The delayed onset of symptoms means that the disease may be transmitted to offspring before the parent is aware that he or she harbors the defective gene. Triplet repeats of more than 40 are reliably associated with development of the disease, and the greater the number of triplet repeats, the earlier the onset of symptoms. The protein forms aggregates in brain tissue, which are thought to contribute to the pathogenesis of neurodegeneration. Autosomal Recessive Disorders Autosomal recessive disorders are due to a mutation of a recessive gene located on one of the autosomes. The gene for a particular enzyme may be absent or present in a mutated, and therefore nonfunctional, form. The enzyme deiciency usually is not apparent in heterozygotes carrying one normal gene and one mutated gene because the normal gene produces enough of the necessary enzyme. In the homozygous state, neither gene for the enzyme is functional, resulting in an enzyme deiciency. A partial list of the large number of autosomal recessive disorders that have been identiied is given in Table 6-3. Many of these diseases involve the inability to metabolize nutrients (inborn errors of metabolism) or to synthesize cellular components because of enzyme deiciencies. Albinism, phenylketonuria, and cystic ibrosis are described here as representative examples. Other disorders are described in the discussions of system pathophysiology in later chapters. Albinism Albinism refers to a lack of pigmentation of the hair, skin, and/or eyes. There are several types of albinism; all types involve disruption of melanin synthesis. In oculocutaneous albinism, which is inherited in an autosomal recessive fashion, pigmentation of the skin, hair, and eyes is decreased. From Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 8, Philadelphia, 2010, Saunders, p 141. It is estimated that nearly everyone carries several mutated recessive genes, and related individuals are more likely to carry the same recessive genes. More than 1300 different mutations of this gene have been identiied, all of which cause a defect in chloride transport across the cell membrane; however, the severity of chloride channel dysfunction varies widely with different mutations. Clinical trials have been published; however, eficiency for delivering genes to target cells has been low. Sex-Linked (X-Linked) Disorders Sex-linked disorders occur because of a mutation of the sex chromosomes. Disorders linked to the Y chromosome are extremely rare, and for that reason the terms sex-linked and X-linked are often used interchangeably. Females express the X-linked disease only in the rare instance in which both X chromosomes carry the defective gene. Males, however, do not have the safety margin of two X chromosomes and express the disease if their one and only X chromosome is abnormal. Several X-linked recessive disorders have been identiied, as presented in Table 6-4. Skeletal deformities such as pectus excavatum and abnormal curvature of the thoracic spine are common indings. It is one of several enzyme deiciencies that are often referred to as inborn errors of metabolism. The symptoms of the disorder are due to the accumulation of dietary phenylalanine in the body, which primarily affects the nervous system. Excess phenylalanine is excreted in the urine in the form of phenylketones, hence the name phenylketonuria. Infants typically have a musty odor because of excess phenylalanine by-products in the sweat and urine. The enzyme deiciency can be detected soon after birth and managed with a low-phenylalanine diet. Individuals aflicted with hemophilia A bleed easily and profusely from seemingly minor injuries (see Chapter 14). About 4% of Caucasian Americans harbor the defective gene, and the incidence of cystic ibrosis is approximately 1 in 3200 live births. The alteration in chloride transport is associated with production of abnormally thick secretions in glandular tissues. The lung bronchioles and pancreatic ducts are primarily affected, often resulting in progressive destruction of these organs (see Chapter 22). Triplet Repeat Mutations Fragile X syndrome is a prototypical example of disorders characterized by long repeating sequences of three nucleotides, called triplet (or trinucleotide) repeat mutations.

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References

• Rahnamaii MS, de Wachter SG, van Koeveringe GA, et al: The relationship between prostaglandin E receptor 1 and cyclooxygenase I expression in guinea pig bladder interstitial cells: proposition of a signal propagation system, J Urol 185(1):315n322, 2011.
• Qin Q, Xu X, Wang X, et al: Obesity and risk of bladder cancer: a meta-analysis of cohort studies, Asian Pac J Cancer Prev 14:3117n3121, 2013.
• Proffit WR, Phillips C, Dann C IV, Turvey TA. Stability after surgical orthodontic correction of skeletal Class III malocclusion. I. Mandibular setback. Int J Adult Orthodon Orthognath Surg 1991;6:7-18.
• Chan DY, Jeffs RD, Gearhart JP: Determinates of continence in the bladder exstrophy population after bladder neck reconstruction, Urology 165:1656, 2001.