Leon A. Assael, DMD

• Professor of OMFS and Surgery
• Department Chair
• Medical Director, Hospital Dentistry
• Oregon Health and Science University
• Portland, Oregon

The prostate supplies about one-third of the ejaculate anxiety symptoms constipation 50 mg fluvoxamine amex, and this includes prostate-specific antigen anxiety 34 weeks pregnant 50 mg fluvoxamine purchase with visa, a proteolytic enzyme that cleaves seminogellin anxiety medication side effects order 50 mg fluvoxamine with amex, effecting liquefaction anxiety exhaustion cheap fluvoxamine on line. Finally anxiety 2 calm order fluvoxamine 100 mg amex, the bulbourethral glands contribute a small amount of clear mucoid discharge, released mainly during sexual stimulation before ejaculation. Testosterone, a C19 steroid, is synthesized from cholesterol by the interstitial (Leydig) cells of the testes and from androstenedione secreted by the adrenal cortex. The remainder is loosely bound to albumin and is available for target tissue action. The albumin-bound and free fractions make up the "bioavailable" testosterone in circulation. Estradiol is produced by aromatization of testosterone in the peripheral circulation. Thus, obesity can increase conversion of testosterone, with resultant hyperestrogenemia, downregulation of the hypothalamic-pituitary-gonadal axis, and hypogonadism. In the fetus, androgens are necessary for normal differentiation and development of the internal and external male genitalia. During puberty, androgens are needed for normal growth of the male genital structures, including the scrotum, epididymis, vas deferens, seminal vesicles, prostate, and penis. Androgens are also responsible for development of the secondary sex characteristics summarized in Table 23Ͳ. Specifically, androgens stimulate erythropoiesis, preserve bone structure and muscle mass, and maintain libido and erectile function. What are the roles of the two major cell populations in the testis, the Leydig cells and the Sertoli cells? What are the relative concentrations of testosterone in the peripheral circulation and the testicular tissue? Next, the spermatozoa must be able to travel to the uterine tubes, and they must undergo functional changes that allow them to fuse with the oolemma (plasma membrane of oocyte). Infertility is defined as the inability of a couple to achieve pregnancy despite unprotected intercourse for a period of more than 12 months. About 15% of all couples are infertile, and it is estimated that a male factor plays a role in about half of the cases. Finally, neglecting to examine the infertile man properly risks overlooking serious conditions such as testicular cancer that may coexist with infertility. A comprehensive list of etiologies is presented in Table 23ͳ, genetic male infertility causes are listed in Table 23ʹ, and causes of testicular atrophy are in Table 23͵. These endocrinopathies are most often caused by mutations in genes involved in the biosynthesis of the hormones, growth factors or receptors, and associated signal transduction pathways. The deficiencies result in a loss of intratesticular testosterone production and cessation of spermatogenesis. Hypogonadotropic hypogonadism is an uncommon cause of male infertility but is important to recognize because replacement therapy can be initiated. Disorders without a known cause are termed idiopathic hypogonadotropic hypogonadism. In addition, patients tend to be tall and can have congenital deafness, asymmetry of the cranium and face, cleft palate, cerebellar dysfunction, cryptorchidism, or renal abnormalities. However, some Kallmann syndrome patients present only with isolated gonadotropin deficiency, manifesting as infertility. With clinical implications for diagnosis and treatment of infertility and related disorders, this ligand/receptor pair has proven to be one of the key mediators of pubertal onset. Mutations of the X-linked Dax1 gene are associated with hypogonadotropic hypogonadism and congenital adrenal hypoplasia. Dax1 is a nuclear receptor that plays a critical role in the development of the hypothalamus, pituitary, adrenal, and gonads. Prader-Willi syndrome is caused either by mutations or deletions of a specific locus within paternal chromosome 15 or, less commonly, by maternal uniparental disomy (two maternal copies) of this locus. Symptoms include obesity, mild or moderate mental retardation, infantile hypotonia, and hypogonadotropic hypogonadism. Hemochromatosis is associated with treatable hypogonadotropic hypogonadism; some men with hemochromatosis develop primary testicular failure. The mutations result in a spectrum of dysfunction from complete virilization failure to less severe hypogonadism. Pituitary mass lesions are uncommon but are recognized causes of hypogonadotropic hypogonadism and male infertility. Adenomas of the pituitary can cause hyperprolactinemia (due to infundibular compression and resultant inhibition of hypothalamic dopamine that tonically inhibits prolactin synthesis and secretion), together with headaches and visual field impairment (due to direct compression on the optic chiasm). Androgen deficiency results in a spectrum of phenotypic abnormalities ranging from incomplete virilization to completely feminized genitalia and cryptorchid testes. In less severe cases, the phenotypic spectrum ranges from simple male infertility to ambiguous genitalia and hypospadias. The phenotype of men with Klinefelter syndrome varies but can include increased height, female hair distribution, gynecomastia, decreased level of intelligence, diabetes mellitus, obesity, increased incidence of leukemia and nonseminomatous extragonadal germ cell tumors, small firm testes, and infertility. Affected individuals can have male, female, or ambiguous genitalia, streak gonads, or normal testes. Microdeletions of the Y chromosome have been shown to be of great importance in male infertility. Y chromosome microdeletions are detected by polymerase chain reaction΢ased mapping of molecular markers and genes. Decreased testicular size and gynecomastia can also be seen in association with long-time anabolic steroid abuse. The extent and reversibility of these detrimental effects depend on dose and duration of use. Testicular Causes A number of conditions damage spermatogenic potential by direct effects on the testicles. A varicocele is present in about 15% of the normal male population, but in approximately 40% of men presenting with infertility. Possible pathogenic mechanisms in varicocele formation include the anatomical configuration of the left internal spermatic vein, incompetent or absent valves, and potential for a partial left renal vein compression between the aorta and the superior mesenteric artery. An acute varicocele can also be caused by retroperitoneal malignancies with arteriovenous shunting into the venous system. The pathophysiology of the impaired spermatogenesis is likely multifactorial in many cases. However, the evidence for a clinical benefit of varicocele repair in improving fertility is controversial. Genetic disorders are characterized as (a) abnormalities of entire chromosomes (abnormalities of the karyotype), (b) deletions of specific areas of chromosomes, or (c) specific mutations within genes. These disorders can alter spermatogenesis and impair normal development of the genital tract, thus decreasing fertilization capacity. Numerical chromosome abnormalities include deletion or duplication of whole chromosomes. Structural chromosome abnormalities include deletion, inversion, or duplication of a portion of a chromosome, or translocation of part of one chromosome to another chromosome. Such abnormalities occur with much greater frequency in infertile men than in the general population. Cryptorchidism is the term used if testicular descent does not proceed normally during development, and the testis remains in the abdominal cavity or groin. The prevalence of cryptorchidism is approximately 3% in full-term newborns, but only 1Ͳ% by age 6 months. About 50ͷ0% of unilaterally cryptorchid men are oligospermic or azoospermic, and almost 100% of bilaterally cryptorchid men are azoospermic. While numerous substances and occupations have been suspected, inadequate study sample size and confounding factors make causal relationships difficult to confirm. The different germ cell populations display unique sensitivities to different toxins. Spermatogonia are located outside the blood-testis barrier and are exposed to any toxins in the interstitial fluid. Conversely, spermatocytes and spermatids are located inside the blood-testis barrier, which offers them some protection. Toxins that injure Sertoli cells can also impair spermatogenesis, whereas injury to the Leydig cells can reduce testosterone levels. Toxins may also interfere with hormone balance by causing alterations in androgen or gonadotropin receptor binding, alterations in circulating gonadotropin levels, and alterations in the metabolism of androgens. The effects of toxins may be reversible if the agents are removed before azoospermia occurs. Cigarette smoking has been associated with a reduction in sperm count and motility and an increase in abnormal forms. A meta-analysis of 21 studies examining the effects of cigarette smoking on semen quality revealed that smoking lowered sperm concentration by 13ͱ7% in 7 studies but had no adverse spermatogenic outcome in 14 studies. Therefore, it remains controversial whether smoking actually decreases male fertility rates. Also controversial is whether second-hand smoke from a male partner can affect female fertility. There is, however, some evidence that maternal smoking may be related to decreased sperm counts in the male offspring. Finally, the risk of developing erectile dysfunction is almost doubled for smokers compared with nonsmokers, and this can limit male fertility. Testicular temperatures are approximately 2у below core body temperature, and spermatogenesis is dependent on this 661 cooler temperature. Factors such as clothing, lifestyle, season, and fever can cause increases in scrotal temperature. Chemotherapy and radiation therapy, used in men with testicular cancer, Hodgkin disease, or leukemia, are potent gonadotoxins. For example, both radiation therapy and chemotherapy can cause damage to the germinal epithelium, and spermatogenesis may not recover. If the semen quality is good, specimens can be preserved in aliquots large enough for intrauterine insemination. For example, although mumps is generally a self-limited disease in children, mumps may result in orchitis in postpubertal males. Necrosis from acute swelling and increased intratesticular pressure can cause permanent testicular atrophy and infertility. Epididymitis can lead to scarring of the tubules and obstruction of sperm flow (discussed below). In the absence of ductal obstruction, however, the role of infection in causing infertility is controversial. Potential deleterious effects of infection on male fertility include decreases in spermatogenesis, breaches in the blood-testis barrier leading to sperm autoimmunity, and seminal oxidative stresses due to an increase in seminal fluid oxidant levels or a decrease in seminal fluid antioxidant levels. Torsion of the spermatic cord with interruption of testicular blood flow results in acute, intense testicular pain. If untreated, the absence of blood flow after 4Ͷ hours of torsion causes irreparable damage. Torsion may also induce sperm autoimmunity due to a breakdown of the blood-testis barrier during the ischemic event. Testicular trauma can lead to scrotal or testicular edema, hematoma, hematocele, hydrocele, torsion, fracture, or rupture. These may result in testicular atrophy as well as the development of antisperm antibodies. In both testicular rupture and torsion, early surgery is needed to ensure testicular salvage. The ruptured testicle can be restored in up to 90% of patients if the rupture is treated within 72 hours, but torsion of the testicle must be treated within 6 hours to obtain a similar result. Post-testicular Causes Ductal obstruction can occur anywhere along the male reproductive system, and results of semen analysis vary with the site of obstruction. Complete obstruction of the ejaculatory duct results in a low-volume, acidic, fructose-negative ejaculate. Acquired cases may be due to prostatic nodule formation or inspissated secretions in the ejaculatory ducts causing calculi. Symptoms from ejaculatory duct obstruction include infertility, decreased ejaculate volume, reduced ejaculatory force, hematospermia, pain with ejaculation, and dysuria. The physical examination of patients with ejaculatory duct obstruction is usually normal. However, some may have a palpable seminal vesicle or mass on rectal examination, or prostatic or epididymal tenderness. Clinically, ejaculatory duct obstruction must be considered in patients with azoospermia, low ejaculate volume, absence of fructose in the ejaculate, and normal hormone profiles. Seminal vesicle aspiration after ejaculation may aid in diagnosing partial ejaculatory duct obstruction. Immunologic infertility may result from a breach in the blood-testis barrier, exposing the mature spermatozoa to the immune system with the formation of antisperm antibodies. Risk factors for the formation of antisperm antibodies include trauma to the testes, epididymitis, congenital absence of the vas deferens, and vasectomy. It may also be caused by dysregulation of normal immunosuppressive activities within the male reproductive tract. Antisperm antibodies are found in 5ͱ0% of infertile couples but are also present in 1ͳ% of fertile men. Antisperm antibodies react with all of the major regions of sperm and can impair sperm motility, sperm penetration through the cervical mucus, acrosome reaction, and sperm-oocyte interactions and fertilization. The disorders can be divided into premature ejaculation, anejaculation, and retrograde ejaculation. Premature ejaculation is the inability to control ejaculation for a satisfactory length of time during intercourse. Premature ejaculation causes distress as a sexual dysfunction for both partners but seldom leads to infertility, as ejaculation usually occurs intravaginally. Anejaculation describes the complete absence of seminal emission into the posterior urethra.

In patients with chronic kidney disease anxiety tattoo discount 100 mg fluvoxamine with amex, there are many causative factors that contribute to the often dramatic enlargement of the parathyroid glands anxiety symptoms upon waking up discount fluvoxamine 50 mg with visa. This is shifted to the right in the majority of parathyroid adenomas compared to normal tissues anxiety symptoms children buy fluvoxamine online from canada, in which the set-point is approximately 1 anxiety vest for dogs buy fluvoxamine 50 mg with mastercard. Dispersed cells prepared from human parathyroid glands: distinct calcium sensitivity of adenomas vs primary hyperplasia anxiety symptoms or heart problems buy discount fluvoxamine 100 mg line. This qualitative regulatory defect is more common than truly autonomous secretion. How these two defects interact in the pathogenesis of the disease remains to be fully elucidated. The genetic defects responsible for primary hyperparathyroidism have received considerable attention. Genes that regulate the cell cycle are thought to be important in the pathogenesis of a significant subset of parathyroid tumors. If this second mutation confers a growth advantage on the descendant cells, there is clonal outgrowth of cells bearing the second mutation, and eventually a tumor results. Menin localizes to the nucleus, where it binds to the transcription factor JunD in vitro and suppresses transcription. The role of menin in normal physiology and the mechanisms by which it promotes tumor formation in the pituitary, pancreas, and parathyroid glands are unknown. Mice with targeted deletion of both genes encoding the murine menin homologues (or Men1) die in utero. Patients with this disease may be asymptomatic, and their diagnosis is made by screening laboratory tests. Because calcium affects the functioning of nearly every organ system, the symptoms and signs of hypercalcemia are protean (Table 17ͳ). Depending on the nature of the complaints, the patient with primary hyperparathyroidism may be suspected of having a psychiatric disorder, a malignancy, or, less commonly, a granulomatous disease such as tuberculosis or sarcoidosis. Recurrent stones containing calcium phosphate or calcium oxalate occur in 10ͱ5% of patients with primary hyperparathyroidism. Nephrolithiasis may be complicated by urinary outflow tract obstruction, infection, and progressive renal insufficiency. This is reflected in subperiosteal resorption, osteoporosis (particularly of cortical bone), and even pathologic fractures. These patients may experience no clinical deterioration if their hyperparathyroidism is monitored rather than treated surgically. Because it is difficult to identify these patients with certainty when the diagnosis of hyperparathyroidism is made, regular follow-up is mandatory. Recent studies indicate that bone mass may deteriorate significantly, especially at cortical sites (ie, hip, forearm) after conservative follow-up beyond 8ͱ0 years. These observations have reopened the issue about the advisability of long-term medical observation in this condition. By comparison, patients with mild disease who undergo definitive parathyroid surgery will experience improvements in bone mass over time. These data raise the question as to how a presumed innocuous mild primary hyperparathyroidism may be deleterious to the skeleton. These include subperiosteal resorption (evident most strikingly in the clavicles and distal phalanges), generalized low bone mass, and the classic but now rare brown tumors. Abdominal films or computed tomography may show nephrocalcinosis or nephrolithiasis. The complete differential diagnosis of hypercalcemia should be considered in all patients with this abnormality (Table 17Í´). Primary hyperparathyroidism accounts for most cases of hypercalcemia in the outpatient setting (>90%). Patients with secondary hyperparathyroidism may have normal or subnormal calcium levels (see below). In families with this form of benign hypercalcemia, there are rare occurrences of neonatal severe primary hyperparathyroidism. In familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, the ability to detect serum calcium is faulty in both the kidney and parathyroid. Familial hypocalciuric hypercalcemia is due to a partial reduction - and neonatal hyperparathyroidism to a marked reduction - in the ability to sense extracellular calcium. In the kidney, serum calcium concentrations are also detected (inappropriately) as low, and calcium is retained. Depending on the mutant gene dosage, the clinical symptoms tend to be mild in familial hypocalciuric hypercalcemia and profound and life-threatening in neonatal severe hyperparathyroidism. Clinical Manifestations Patients with familial hypocalciuric hypercalcemia typically have lifelong asymptomatic elevations in serum calcium. However, they are not thought to suffer the consequences of end-organ dysfunction characteristic of long-standing hyperparathyroidism and hypercalcemia. These individuals are generally spared the nephrolithiasis, low bone mass, and renal dysfunction that can occur in patients with primary hyperparathyroidism. Individuals with familial hypocalciuric hypercalcemia do not benefit from parathyroidectomy. Can also be low depending on the dietary calcium and the filtered load of calcium. These infants usually require total parathyroidectomy in the newborn period for survival. In the asymptomatic hypercalcemic patient, a careful family history should be obtained in an effort to document hypercalcemia or the occurrence of failed parathyroidectomies in other family members. Simultaneous serum and urinary calcium and creatinine levels should be measured to rule out familial hypocalciuric hypercalcemia. In this condition, urinary calcium levels are typically low and almost always less than 100 mg/24 h (Table 17͵). The calcium-creatinine clearance ratio derived from 24-hour urine collections is often below 0. The ratio is calculated as urine calcium (mg/dL) × serum creatinine (mg/dL)/serum calcium (mg/dL) × urine creatinine (mg/dL). Multiple myeloma produces hypercalcemia by a different mechanism; myeloma cells induce local bone resorption or osteolysis in the bone marrow, probably by releasing cytokines with bone-resorbing activity, such as interleukin-1 and tumor necrosis factor. Finally, even though many hypercalcemic patients have bone metastases, these may not contribute directly to the pathogenesis of hypercalcemia. Clinical Manifestations Unlike patients with primary hyperparathyroidism, who often are minimally symptomatic, patients with hypercalcemia of malignancy are typically very ill. Hypercalcemia typically occurs in advanced malignancy - the average survival of hypercalcemic patients is usually several weeks to months - and the tumor is almost invariably obvious on examination of the patient. In addition, hypercalcemia is often severe and symptomatic, with nausea, vomiting, dehydration, confusion, or coma. These findings, together with the differences in clinical presentation, usually make the differentiation of this syndrome from primary hyperparathyroidism relatively easy. What is the occurrence of hyperparathyroidism in the multiple endocrine neoplasia syndromes? How can primary hyperparathyroidism be distinguished from familial hypocalciuric hypercalcemia? It is commonly seen in solid tumors, particularly squamous cell carcinomas (eg, lung, esophagus), renal carcinoma, and breast carcinoma. Hypercalcemia occurs in more than one third of patients with multiple myeloma but is unusual in lymphomas and leukemias. It should be recognized, however, that symptoms of hypocalcemia occur only if the ionized fraction of calcium is reduced. Furthermore, only patients with low ionized calcium levels should be evaluated for the possibility of a hypocalcemic disorder. To determine whether a hypoalbuminemic patient has a low ionized calcium, this parameter can be measured directly. If this laboratory test is not readily available, a reasonable alternative is to correct the serum total calcium for the low serum albumin. This simple correction usually brings the adjusted serum total calcium into the normal range. Most cases are the result of inadvertent trauma to , removal of, or devascularization of the parathyroid glands during thyroid or parathyroid surgery. Abnormal development of the glands resulting in varying degrees of severity of hypoparathyroidism is seen in the DiGeorge syndrome. This syndrome can present in infancy, childhood, or even adulthood and may be accompanied by defective cell-mediated immunity and other congenital anomalies (Table 17Í·). Autoantibodies to adrenal and parathyroid tissue are seen in most of these patients. The pathogenesis of hypocalcemia in this clinical setting relates to a functional and reversible state of hypoparathyroidism. Magnesium depletion may occur from a variety of causes, including chronic alcoholism, diarrhea, and drugs such as loop diuretics, aminoglycoside antibiotics, amphotericin B, and cisplatin (Table 17Ͷ). These individuals rarely experience symptoms of their often mild hypocalcemia, but if given vitamin D, they are prone to develop marked hypercalciuria, nephrocalcinosis, and even renal failure. Clinical Manifestations the symptoms and signs of hypocalcemia are similar, regardless of the underlying cause (Table 17͸). Painful carpal spasms and laryngeal stridor are striking manifestations of tetany. A positive Trousseau sign is demonstrated by inflating the sphygmomanometer with the cuff around the arm above the systolic blood pressure for 3 min. If hypocalcemia is severe and unrecognized, airway compromise, altered mental status, generalized seizures, and even death may occur. Chronic hypocalcemia can produce intracranial calcifications that have a predilection for the basal ganglia. Chronic hypocalcemia may also enhance calcification of the lens and the formation of cataracts. In addition to the symptoms and signs of hypocalcemia, patients with pseudohypoparathyroidism type 1a may have a constellation of features collectively known as Albright hereditary osteodystrophy. They include short stature, obesity, mental retardation, round facies, shortened fourth and fifth metacarpal and metatarsal bones, and subcutaneous ossifications. In considering the differential diagnosis of hypocalcemia, one must be guided by the clinical setting. A positive family history is very important in supporting a diagnosis of pseudohypoparathyroidism and other hereditary forms of hypoparathyroidism (Table 17Í·). The patient with hypocalcemia, hyperphosphatemia, and a normal serum creatinine most likely has hypoparathyroidism. There may be a long latent period before symptomatic hypocalcemia presents in postsurgical hypoparathyroidism. Patients with pseudohypoparathyroidism type 1a often have other endocrine abnormalities such as primary hypothyroidism or gonadal failure. In the differential diagnosis of hypocalcemia, laboratory findings are extremely useful (Table 17͹). Serum phosphate is often (not invariably) elevated in hypoparathyroidism and pseudohypoparathyroidism. In secondary hyperparathyroidism not due to renal failure, serum phosphate is typically low. In patients with secondary hyperparathyroidism resulting from defects in the production or bioavailability of vitamin D, the clinical setting often suggests a problem with vitamin D (eg, regional enteritis, bowel resection, liver disease). Measurement of serum magnesium is the first step in ruling out magnesium depletion as the cause of hypocalcemia and should be part of the initial evaluation. If urinary magnesium is inappropriately high relative to the serum magnesium, renal magnesium wasting is present. Hypoparathyroidism may vary in its severity and, therefore, in the need for therapy. In some patients with decreased parathyroid reserve, only situations of increased stress on the glands, such as pregnancy or lactation, induce hypocalcemia. All patients so treated should have periodic monitoring of serum calcium, urinary calcium, and renal function. Fineneedle aspiration biopsy shows the characteristic C-cell lesion with positive immuno-staining for calcitonin. Fine needle aspiration may be nondiagnostic in more than half of individuals with medullary thyroid carcinoma. Staining for calcitonin may improve diagnostic sensitivity; however, the diagnosis of medullary thyroid carcinoma may not be evident until examination of frozen section specimen slides during surgery or, later, of final pathological slides from the resected thyroid. The tumor has the propensity to contain large calcifications, which can be seen on x-ray films of the neck. Bone metastases may be lytic or sclerotic in their appearance, and pulmonary metastases may be surrounded by fibrotic reactions. The most important laboratory test in determining the presence and extent of medullary carcinoma is the calcitonin level. Circulating calcitonin levels are typically elevated in most patients, and serum levels correlate with tumor burden. Intravenous calcium gluconate (2 mg/kg of elemental calcium) is injected over 1 minute, followed by pentagastrin (0. Provocative testing is based on the ability of calcium and the synthetic gastrin analogue pentagastrin to hyperstimulate calcitonin release in patients with increased C-cell mass resulting from either hyperplasia or carcinoma. An increase in serum calcitonin, more than twice the normal response, is considered abnormal. It must be borne in mind that false-positive provocative testing for calcitonin can occur. Serial calcitonin levels are a useful parameter for monitoring therapeutic responses in patients with medullary carcinoma or for diagnosing a recurrence, along with clinical examination and imaging procedures.

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Lipolysis is increased anxiety symptoms preschooler fluvoxamine 100 mg buy line, and adipocytes show an increase in -adrenergic receptor density and increased responsiveness to catecholamines anxiety symptoms 6 year molars fluvoxamine 100 mg purchase without prescription. With the rise in metabolic rate anxiety and nausea buy cheap fluvoxamine 50 mg online, there is also an increased need for vitamins; if dietary sources are inadequate anxiety symptoms 5 yr old 100 mg fluvoxamine purchase mastercard, vitamin deficiency syndromes may occur anxiety 13 year old buy 50 mg fluvoxamine otc. In addition, because of enhanced osteoblastic and osteoclastic activity, overtly hyperthyroid patients frequently exhibit accelerated bone turnover and negative calcium and phosphorus balance, resulting in low bone mineral density and increased skeletal fragility. Normalization of thyroid function is associated with a significant attenuation of increased bone turnover followed by an increase in bone mineral density. Accelerated small bowel transit may be caused by increased frequency of bowel contractions and of giant migrating contractions. In severe thyrotoxicosis, abnormal liver function tests may be observed, reflecting malnutrition. Anorexia in untreated hyperthyroidism is associated with older age, anxiety, and abnormal liver function but not with hypercalcemia. In addition, autoantibodies against G2s, a 55-kDa protein found in both thyroid and eye muscle tissue, are definitely associated with Graves ophthalmopathy. For instance, antibodies reactive with G2s are identified in significantly more patients with active thyroid ophthalmopathy than in patients with Graves disease without ophthalmopathy, those with Hashimoto thyroiditis or nonimmunologic thyroid disorders, and those without thyroid disease. It is postulated that cytokines released from these sensitized lymphocytes cause inflammation of orbital tissues, resulting in the proptosis, diplopia, and edema. For unknown reasons, Graves ophthalmopathy is worse in smokers and may be exacerbated by radioiodine therapy. Hyperpigmentation can be seen on the lower extremities, most strikingly on the shins, the backs of the feet, and the nail beds. The hyperpigmentation is due to basal melanosis and heavy deposition of hemosiderin around dermal capillaries and sweat glands. Its distribution, hemosiderin deposition, and poor response to treatment distinguish it from the hyperpigmentation seen with Addison disease. In Graves disease, the pretibial skin may become thickened, resembling an orange peel (pretibial myxedema or thyrotoxic dermopathy). The dermopathy is usually a late manifestation of Graves disease, and affected patients invariably have ophthalmopathy. The most common form of the dermopathy is nonpitting edema, but nodular, plaque-like, and even polypoid forms also occur. The pathogenesis of thyroid dermopathy may also involve lymphocyte cytokine stimulation of fibroblasts. Patients so affected have tachycardia, fever, agitation, nausea, vomiting, diarrhea, and restlessness or psychosis. The condition is usually precipitated by an intercurrent illness or by a surgical emergency. The most common cause is Hashimoto thyroiditis, which results from an autoimmune destruction of the thyroid, although the precipitating cause and exact mechanism of the autoimmunity and subsequent destruction are unknown. Hypothyroidism may also be caused by lymphocytic thyroiditis after a transient period of hyperthyroidism. Thyroid ablation, whether by surgical resection or by therapeutic radiation, commonly results in hypothyroidism. Congenital hypothyroidism, a preventable cause of mental retardation, occurs in approximately 1 in 4000 births; girls are affected about twice as often as boys. The most common cause of sporadic congenital hypothyroidism is thyroid dysgenesis, in which hypofunctioning ectopic thyroid tissue is more common than thyroid hypoplasia or aplasia. The most common problems causing hereditary congenital hypothyroidism are inborn errors of thyroxine (T4) synthesis. Finally, a variety of drugs, including the thioamide antithyroid medications propylthiouracil and methimazole, may produce hypothyroidism. The thioamides inhibit thyroid peroxidase and block the synthesis of thyroid hormone. In addition, propylthiouracil, but not methimazole, blocks the peripheral conversion of T4 to T3. Deiodination of iodinecontaining compounds such as amiodarone, releasing large amounts of iodide, may also cause hypothyroidism by blocking iodide organification, an effect known as the Wolff-Chaikoff block. Lithium is concentrated by the thyroid and inhibits the release of hormone from the gland. Lithium-associated clinical hypothyroidism occurs in about 10% of patients receiving the drug. It Pathogenesis Hypothyroidism is characterized by abnormally low serum T4 and T3 levels. The hypernormal response is caused by absence of feedback inhibition by T4 and T3. Pathology In the early stages of Hashimoto thyroiditis, the gland is diffusely enlarged, firm, rubbery, and nodular. In the late stages, the gland is atrophic and fibrotic, weighing as little as 10Ͳ0 g. Microscopically, there is destruction of thyroid follicles and lymphocytic infiltration with lymphoid follicles. The surviving thyroid follicular epithelial cells are large, with abundant pink cytoplasm (H𲴨le cells). Again, it is possible that a defect in suppressor T lymphocytes allows helper T lymphocytes to interact with specific antigens on the thyroid follicular cell membrane. Once these lymphocytes become sensitized to thyroidal antigens, autoantibodies are formed that react with these antigens. Serum levels of these antibodies do not correlate with the severity of the hypothyroidism, but their presence is helpful in diagnosis. In general, high antibody titers are diagnostic of Hashimoto thyroiditis; moderate titers are seen in Graves disease, multinodular goiter, and thyroid neoplasm; and low titers are found in the elderly. A polyglandular failure syndrome has been defined in which two or more endocrine disorders mediated by autoimmune mechanisms occur (Chapter 17). Affected patients frequently have circulating organ- and cell-specific autoantibodies that lead to organ hypofunction. Clinical Manifestations the clinical consequences of thyroid hormone deficiency in the adult are summarized in Table 20Ͷ. The decreased basal metabolic rate leads to weight gain despite reduced food intake. In hypothyroid infants, synapses develop abnormally, myelination is defective, and mental retardation occurs. Hypothyroid adults have several reversible neurologic abnormalities, including slowed mentation, forgetfulness, decreased hearing, and ataxia. Some patients have severe mental symptoms, including reversible dementia or overt psychosis ("myxedema madness"). Paresthesias are common, often caused by compression neuropathies resulting from accumulation of myxedema (carpal tunnel syndrome and tarsal tunnel syndrome). Study of the bioenergetic abnormalities in hypothyroid muscle suggests a hormone-dependent, reversible mitochondrial impairment. However, the pulmonary capillary wedge pressure, right atrial pressure, heart rate, left ventricular ejection fraction, and left ventricular systolic pressure-volume relation (a measure of contractility) are not significantly different from the euthyroid state. Thus, in early hypothyroidism, alterations in cardiac performance are probably primarily related to changes in loading conditions and exercise-related heart rate rather than to changes in myocardial contractility. In chronic hypothyroidism, echocardiography shows bradycardia and features that suggest cardiomyopathy, including increased thickening of the intraventricular septum and ventricular wall, decreased regional wall motion, and decreased systolic and diastolic global left ventricular function. These changes may be due to deposition of excessive mucopolysaccharides in the interstitium between myocardial fibers, leading to fiber degeneration, decreased contractility, low cardiac output, cardiac enlargement, and heart failure. Pericardial effusion (with high protein content) may lead to findings of decreased electrocardiographic voltage and flattened T waves, but cardiac tamponade is rare. Hypothyroid patients exhibit decreased ventilatory responses to hypercapnia and hypoxia. There is a high incidence of sleep apnea in untreated hypothyroidism; such patients sometimes demonstrate myopathy of upper airway muscles. In hypothyroid children, bone growth is slowed and skeletal maturation (closure of epiphyses) is delayed. Pituitary secretion of growth hormone may also be depressed because thyroid hormone is needed for its synthesis. Hypothyroid animals demonstrate decreased width of epiphysial growth plate and articular cartilage and decreased volume of epiphyseal and metaphyseal trabecular bone. These changes are not solely due to lack of pituitary growth hormone, because administering exogenous growth hormone does not restore normal cartilage morphology or bone remodeling, whereas administering T4 does. If unrecognized, prolonged juvenile hypothyroidism results in a permanent height deficit. A normochromic, normocytic anemia may occur as a result of decreased erythropoiesis. Alternatively, a moderate macrocytic anemia can occur as a result of decreased absorption of cyanocobalamin (vitamin B12) from the intestine and diminished bone marrow metabolism. Normally, the skin contains a variety of proteins complexed with polysaccharides, chondroitin sulfuric acid, and hyaluronic acid. The hair is brittle and lacking in luster, and there is frequently loss of body hair, particularly over the scalp and lateral eyebrows. If thyroid hormone is administered, the protein complexes are mobilized, a diuresis ensues, and myxedema resolves. Carotenemia (manifested as yellow-orange discoloration of the skin) may occur in hypothyroidism because thyroid hormones are needed for hepatic conversion of carotene to vitamin A. In the absence of sufficient hormone, carotene accumulates in the bloodstream and skin. Alternatively, menses may become scanty or disappear secondary to diminished secretion of gonadotropins. Because thyroid hormone normally has an inhibitory effect on prolactin secretion, hypothyroid patients may exhibit hyperprolactinemia, with galactorrhea and amenorrhea. In men, hypothyroidism can cause infertility and gynecomastia from enhanced release of prolactin. Long-standing severe untreated hypothyroidism may lead to a state called myxedema coma. This condition is usually precipitated by an intercurrent illness such as an infection or stroke or by a medication such as a sedative-hypnotic. The mortality rate approaches 100% unless myxedema coma is recognized and treated promptly. A goiter may also develop from ingestion of goitrogens (factors that block thyroid hormone synthesis) either in food or in medication. Dietary goitrogens are found in vegetables of the Brassicaceae family (eg, rutabagas, cabbage, turnips, cassava). Medications that act as goitrogens include thioamides and thiocyanates (eg, propylthiouracil, methimazole, and nitroprusside), sulfonylureas, and lithium. A congenital goiter associated with hypothyroidism (sporadic cretinism) may occur as a result of a defect in any of the steps of thyroid hormone synthesis (Table 20͵). Defective transport of iodide Defective organification of iodide due to absence or reduction of peroxidase or production of an abnormal peroxidase Synthesis of an abnormal thyroglobulin Abnormal interrelationships of iodotyrosine Impaired proteolysis of thyroglobulin Defective deiodination of iodotyrosine Pituitary and peripheral resistance to thyroid hormone? The exact mechanism underlying this transition to autonomous growth and function is unknown. However, mutations of the gsp oncogene have been found in nodules from many patients with multinodular goiter. Consequently, the serum T3 may be normal or increased, and the patient may remain clinically euthyroid. Later, there are enlarged follicles with flattened follicular epithelial cells and accumulation of thyroglobulin. This accumulation occurs particularly in iodine deficiency goiter, perhaps because poorly iodinated thyroglobulin is less easily digested by proteases. These nodules often vary from "hot" nodules that can trap iodine and synthesize thyroglobulin to "cold" ones that cannot. The enlarged gland may weigh 1͵ kg and may produce respiratory difficulties secondary to obstruction of the trachea or dysphagia secondary to obstruction of the esophagus. Some patients with multinodular goiter also develop hyperthyroidism late in life (Plummer disease), particularly after administration of iodide or iodine-containing drugs. The most common neoplasm, accounting for 30% of all solitary thyroid nodules, is the follicular adenoma. It is a solitary, firm, gray or red nodule, up to 5 cm in diameter, completely surrounded by a fibrous capsule. Microscopically, the adenoma consists of normal-appearing follicles of varying size, sometimes associated with hemorrhage, fibrosis, calcification, and cystic degeneration. Occasionally, only ribbons of follicular cells are present, without true follicles. Most are derived from the follicular epithelium and, depending on their microscopic appearance, are classified as papillary or follicular carcinoma. The major risk factor predisposing to epithelial thyroid carcinoma is exposure to radiation, but genetic factors have also been recognized. Most papillary and follicular cancers pursue a prolonged clinical course (15Ͳ0 years). Papillary carcinoma typically metastasizes to regional lymph nodes in the neck, whereas follicular cancer tends to spread via the bloodstream to distant sites such as bone or lung. Medullary carcinoma is an uncommon neoplasm of the C cells (parafollicular cells) of the thyroid that produce calcitonin (see Chapter 17). In the third, there are alterations in transthyretin, a tetrameric protein that transports 15Ͳ0% of circulating T4. The alterations in transthyretin structure produced by different point mutations can markedly increase its affinity for T4.

There is perihilar and anterior right middle lobe and lingula ground glass opacity anxiety symptoms eyesight fluvoxamine 100 mg order online. Note slightly greater conspicuity of perihilar and anterior ground glass opacity as well as patchy lower lobe air trapping anxiety meds fluvoxamine 50 mg purchase free shipping. Plain chest radiographs with the addition of inspiratory/ expiratory or decubitus films as needed are often the only imaging studies required in the evaluation of a suspected endobronchial foreign body anxiety symptoms restless legs cheap fluvoxamine 100 mg overnight delivery. The spectrum of findings includes normal; visible foreign body or interruption of the air column; asymmetry with air trapping or atelectasis; lung consolidation; and airleak anxiety symptoms depression fluvoxamine 100 mg buy lowest price, both pneumomediastinum and pneumothorax anxiety disorder key symptoms buy fluvoxamine 100 mg overnight delivery. Fluoroscopic observation of lung inflation/deflation along with diaphragmatic and mediastinal motion may be helpful in some cases. Esophagrams are rarely utilized in foreign body evaluation currently but may occasionally be useful in differentiating between an endobronchial or esophageal foreign body, tracheobronchomalacia, or an impinging mediastinal lesion such as vascular ring or sling. Imaging description this previously healthy 10-month-old infant presented with coughing and wheezing. A right mainstem foreign body was diagnosed and food material was removed at a subsequent bronchoscopy. Importance Endobronchial foreign body aspiration most often occurs in children between the ages of one and three years. In normal respiration, negative intrathoracic pressure expands the intrathoracic airways slightly upon inhalation, with relatively decreased caliber upon expiration. A partially obstructive intraluminal airway foreign body may form a oneway valve since air may be able to move past it on inspiration when the airway expands, but not on expiration. A foreign body that is too small to affect air movement in either inspiration or expiration (two-way valve) may be missed radiographically, resulting in delayed diagnosis until secondary findings such as associated infection manifest. Differential diagnosis the differential diagnosis of an endobronchial foreign body is quite large. Considerations include other intraluminal, mural, and extraluminal lesions that can impinge on the intrathoracic airway. Consideration of the age of the patient and anatomic location of the lesion help in further narrowing the likely diagnoses. Possible differential considerations include common childhood respiratory conditions, such as tracheobronchomalcia and acute airway inflammation (bronchiolitis and bronchitis), as well as pneumonia and asthma. Less common entities include an endobronchial granuloma or neoplasm (carcinoid is most common), tracheobronchial stenosis, bronchial atresia, vascular compression (including vascular ring), extrinsic mass (including infectious adenopathy, especially tuberculosis), congenital malformation. The differential diagnosis of an asymmetric hyperlucent lung on a chest radiograph includes ipsilateral air trapping, interstitial emphysema, pneumothorax, congenital lobar emphysema, bronchiolitis obliterans and hypoplastic lung. The latter two conditions are associated with a smaller rather than increased lung volume, hyperlucency, and oligemia rather than air trapping or airleak. Typical clinical scenario the pediatric patient with foreign body aspiration classically presents with a triad of coughing, choking, and wheezing (often unilateral), but a history of choking is the most reliable clue for diagnosis. In many cases there is no clear-cut history of aspiration, and non-specific symptoms can make early diagnosis difficult. A normal inspiratory chest radiograph should not rule out foreign body aspiration. Similarly, lateral decubitus films can be used for the same purpose in an uncooperative pediatric patient. Prompt diagnosis and treatment can obviate prolonged symptoms, superimposed infection, and other long-term complications. Frontal chest radiograph demonstrates subtle hyperlucency of the right lung compared to the left side. The right lung remains hyperinflated on both decubitus views while the left lung deflates appropriately on the left down decubitus view (c) and inflates on the opposite decubitus view. An eight-year-old female presented with a choking episode­aspiration of an earring. An 18-month-old with chronic endobronchial foreign body (peanuts) and three-week history of cough and low grade fever. This finding may not be apparent when the foreign body is not radiographically visible. If a chronic esophageal foreign body is suspected, a contrast esophagram is typically diagnostic of the location of the foreign body, extent of airway narrowing, and condition of the esophagus. Imaging description A 16-month-old male infant presented with persistent symptoms of croup, unresponsive to treatment. This density did not correspond to any anatomic landmark but was located in the area of the esophagus. The overall appearance led to the suggestion by the radiologist that there was likely a chronically impacted esophageal foreign body with surrounding mediastinal inflammation, probably resulting from penetration or perforation of the esophagus. At a subsequent endoscopy an upper esophageal foreign body was found to be embedded in the esophageal wall with marked surrounding inflammation and granulation tissue. The child did well post operatively on antibiotic treatment with rapid improvement of respiratory symptoms. There was a small anterior esophageal diverticulum at the thoracic inlet, likely the site of perforation/ penetration of the esophageal wall by the foreign body. Typical clinical scenario Esophageal foreign bodies may be either acute or chronic (approximately 10%) and typically occur in young preschool age children. Acute esophageal foreign bodies account for the majority of cases and may be asymptomatic or present with drooling or swallowing difficulty. Foreign bodies tend to lodge at the level of the cricopharyngeus, thoracic inlet, level of the aortic arch, gastroesophageal junction, or in areas of pathologic esophageal stenosis. The most commonly ingested items are swallowed coins, batteries, small toys, pieces of household items, or bulky food material. Smaller foreign bodies can become lodged in the esophagus but may not produce swallowing difficulty and can escape notice in small children who eat a largely liquid or soft solid diet, particularly if the ingestion was not witnessed. Over time, a more chronic esophageal foreign body incites adjacent inflammation and granulation tissue forms. The foreign body tends to become surrounded by granulation tissue and incorporated into the esophageal wall. Erosion of the esophagus with contained or free perforation may occur with extensive surrounding mediastinal inflammation or abscess formation. The extensive periesophageal inflammation displaces and compresses the trachea with the result that respiratory symptoms (stridor or wheezing depending on location) are often more prominent than dysphagia. Additionally the nature of the foreign body may contribute to inflammatory changes. In particular, ingested batteries may leak corrosive Importance An esophageal foreign body should be included in the differential diagnosis of a child with respiratory symptoms. Radiographs should be carefully scrutinized to establish the location, nature, and number of foreign bodies present and any possible secondary complications. Most esophageal foreign bodies can be extracted endoscopically; occasionally thoracotomy is required for removal. Even when there is pre-existing esophageal perforation or esophageal tear associated with foreign body extraction, treatment is usually conservative, with a good outcome in most cases. Since esophageal foreign bodies are more common when there is underlying esophageal abnormality, such as prior repair of a tracheoesophageal fistula and congenital or acquired esophageal stenosis, a contrast esophagram may be helpful after removal to evaluate the integrity of the esophageal wall and presence of underlying abnormality. Teaching point Lesions of the esophagus in children, especially a chronic esophageal foreign body, tend to present clinically with respiratory rather than esophageal symptoms due to displacement and narrowing of the adjacent airway. The radiologist should be vigilant regarding this possibility; making the correct diagnosis has important therapeutic and prognostic implications. Chronic esophageal foreign bodies are associated with significant morbidity and even mortality. Pearls and perils in the management of prolonged, peculiar, penetrating esophageal foreign bodies in children. Chronic inspiratory stridor secondary to a retained penetrating radiolucent esophageal foreign body. Differential diagnosis Differential diagnostic considerations are those entities that produce subacute or chronic respiratory or swallowing symptoms. These include croup, asthma, airway foreign body, middle mediastinal masses (common entities include bronchogenic or esophageal duplication cyst and inflammatory or neoplastic adenopathy), vascular ring/sling, and other obstructive esophageal lesions (stenosis, diverticulum, and achalasia). Because of airway compression, anesthesia was considered a very high risk in this infant. The study was therefore obtained with the infant fed, swaddled, and breathing quietly. Parts (c) (axial mediastinal window), (d) (axial lung window), and (e) (coronal reconstruction, mediastinal window) demonstrate increased low-density tissue in the mediastinum with marked tracheal narrowing along with rightward and anterior displacement. In addition there is a thin linear density on the axial image (c, arrow) that is rounded on the coronal image [(e) arrow] behind and to the left of the trachea. This 15-month-old boy was brought to the pediatrician with a 24-hour history of drooling and emesis. In retrospect, he and his older brother had been playing with a flashlight the day before but no ingestion was witnessed. Note widening of the soft tissues between the trachea and esophagus and focal upper tracheal narrowing indicative of adjacent inflammatory changes. This appearance suggests that the foreign body is subacute or chronic and predicts that removal may be difficult and should not be attempted without direct visualization of the esophagus and foreign body. The foreign body could easily be mistaken for a coin in this view although it is somewhat thick. The marked inflammatory changes that were present in this case were likely due to leakage of the battery as well as the subacute nature of the foreign body. The battery was extracted endoscopically with great difficulty and there was an extensive burn and possible perforation of the esophagus. Subsequent follow-up on endoscopy and esophagram showed good healing without evidence of stricture or diverticulum. A 13-month-old male with aspiration pneumonia in the right upper lobe and left lower lobe status post removal of an ingested esophageal button battery that had eroded through the esophagus to form a traumatic tracheoesophageal fistula just above the carina. One-third of the patients present with atypical symptoms, which results in delayed diagnosis. Imaging description A 19-month-old child presented with symptoms of difficulty in walking, abnormal eye and limb movements, and irritability. It can be idiopathic, postinfectious, or a paraneoplastic manifestation of neuroblastoma. The primary tumor is often very small in size, low grade, and quite frequently located in the chest and can be metabolically less active. Outcome and prognostic features in opsoclonus­myoclonus syndrome from infancy to adult life. This is accompanied by severe irritability, involuntary rapid eye movements, myoclonic limb jerking, and behavioral changes such as sleep problems and developmental regression. While removal of the tumor may result in reversal of clinical symptoms and signs, chronic neurologic sequelae including motor, speech, and cognitive deficits occur in as many as 70% of cases and may result in long-term steroid dependence. Encasement of adjacent mediastinal vessels and displacement and compression of the airway in children is common in lymphoma and cross-sectional imaging studies requiring sedation or anesthesia must be undertaken with great care. Diffuse or nodular pulmonary involvement by leukemia is uncommon and most often seen in acute myelocytic or monocytic leukemia. Imaging description A 16-year-old girl presented with a two-month history of night sweats, weight loss, and cough. The mechanism of spread of the disease to the lungs is typically by hematogenous or lymphangitic channels and less commonly by direct or endobronchial spread. Pleural effusion can occur without pleural tumor and may be due to nodal lymphatic obstruction; pericardial effusion typically denotes tumor involvement. Infection, pulmonary edema, hemorrhage, and drug reactions are all confounding causes of pulmonary abnormality in children with lymphoma, especially after initiation of therapy. It is a B-cell lymphocyte proliferation associated with immunosuppression and Epstein­Barr virus infection or reactivation. When the lymphoma is limited to the chest, the most common symptoms are chest pain, fever, dry cough, hemoptysis, dyspnea, and pneumonia. Imaging findings of other pulmonary metastatic disease can mimic a wide range of benign, infectious, and noninfectious diseases and both parenchymal nodules and mediastinal adenopathy may occur. However, alveolar infiltration or nodules with air bronchograms is a specific characteristic of lymphoma as opposed to other metastatic lung disease. Mediastinal and hilar adenopathy are common in bacterial pneumonias in children although the extent is usually not as marked as that seen with lymphoma. Tuberculosis and atypical mycobacterial infection are typified by the presence of prominent adenopathy (usually low-density) and adjacent lung infiltrate, nodules, or masses. Pulmonary nodules and mediastinal lymphadenopathy also occur in other granulomatous diseases such as histoplasmosis. The presence of central calcifications and history of residence in or visit to an endemic area may help to differentiate granulomatous disease from lymphoma. In addition, presence of mediastinal or splenic calcifications may indicate a granulomatous process but does not exclude lymphoma. Teaching point Pulmonary parenchymal involvement is a characteristic of more advanced lymphoma. The finding of pulmonary involvement can significantly alter therapy and prognosis and hence it is important to keep in mind the various manifestations of pulmonary lymphoma involvement and correctly differentiate benign from malignant pulmonary disease. Multiple small pulmonary nodules are noted in the right middle lobe, lingula, and left lower lobe. Reticular changes are noted in the right upper lobe with interlobular septal thickening and small pulmonary nodules (c). Patchy ill-defined ground glass opacities in the lung may represent early infection or leukemic infiltration. This eight-year-old boy presented with cough, fever, and rising Epstein­Barr virus titers, 3 months post bone marrow transplant. In most cases chest radiographs are the only imaging study needed to help guide management of acute or subacute pneumonia. Acute suppurative lung parenchymal complications include cavitary necrosis, lung abscess, pneumatocele, and bronchopleural fistula. Pneumonia was diagnosed and the child was admitted and given intravenous antibiotics for 24 hours.

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