Brandi Page, M.D.

• Associate Residency Program Director, Radiation Oncology Residency, Johns Hopkins University School of Medicine
• Assistant Professor of Radiation Oncology and Molecular Radiation Sciences

https://www.hopkinsmedicine.org/profiles/results/directory/profile/10000789/brandi-page

B medicine 8 letters buy generic aricept 10 mg, Computed tomography confirmed a soft tissue mass in the rectosigmoid region (arrow) and peritoneal implants elsewhere (asterisk) treatment innovations purchase aricept master card. Computed tomography of the abdomen with intravenous and enteric contrast material demonstrates extensive confluent soft tissue attenuation within the upper peritoneum anterior to the liver (so-called omental caking) (arrows) treatment tinea versicolor order aricept with amex. Axial T1-weighted precontrast (A) medicine jar purchase generic aricept on line, T1-weighted fat-saturated postcontrast (B) medications and grapefruit order aricept 10mg on line, and fat-saturated T2-weighted (C) images show an enhancing peritoneal deposit anterior to the liver medications hair loss purchase aricept 10mg fast delivery, near the falciform ligament. Note the decreased conspicuity of the same implant on the corresponding computed tomography scan (D). Ultrasonography Ultrasonography is of limited use in the evaluation of patients with neoplasms involving the mesentery and omentum. Ultrasonography is widely used to guide diagnostic paracentesis or occasionally to guide peritoneal biopsy. Imaging Algorithm As previously discussed, plain radiographs, ultrasonography, and general nuclear medicine are not suited for the evaluation of neoplasms of the omentum and mesentery. However, they can give clues to a peritoneal malignancy, which can be confirmed by the use of another cross- sectional imaging modality Table 82-5). There is also abnormal diffuse uptake in the abdomen, suggesting peritoneal spread (arrow), which was confirmed at surgery. B, Iodine images show increased conspicuity of omental nodules (arrow), with iodine uptake helping to characterize the nodule and differentiate from surrounding ascites. When considering a focal lesion of the omentum or mesentery, one should keep non-neoplastic or inflammatory causes in the differential diagnosis. Imaging plays a key role in guiding biopsy to obtain tissue for histologic analysis. Immunohistochemical analysis and study of various tissue-specific cytokeratins also allude to a particular pathologic entity. Medical treatment usually consists of intraperitoneal chemotherapy; however, response varies depending on the cause of the malignancy. Surgical Treatment Many institutions combine surgical therapy with chemotherapy as treatment for omental and mesenteric cancer. The combination of surgical debulking or cytoreductive surgery and intraperitoneal chemotherapy has been shown to increase survival to a greater extent than intraperitoneal chemotherapy alone. When carcinoma is diagnosed, but a primary site is not found, the diagnosis of carcinoma of an unknown primary tumor is established. Ghosh L, Dahut W, Kakar S, et al: Management of patients with metastatic cancer of unknown primary. Puvaneswary M, Proietto T: Primary papillary serous carcinoma of the peritoneum: four cases and review of computed tomography findings. Facchiano E, Scaringi S, Kianmanesh R, et al: Laparoscopic hyperthermic intraperitoneal 12. Bourdillon L, Lanier-Gachon E, Stankovic K, et al: Lofgren syndrome and peritoneal involve- ment by sarcoidosis: case report. Ultrasonography is frequently used as the first imaging modality to explore a palpable abdominal mass. Conventional radiographs have no role in assessing infection and collections of the abdominal wall. Necrotizing fasciitis can be seen as soft tissue gas dissecting fascial planes in a characteristic appearance. Abscesses are often heterogeneous but generally appear hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences with peripheral enhancement and inflammatory changes in the adjacent tissues. Fluid collections complicated by infection or hemorrhage have a complex appearance on ultrasound with echoes and internal septa. It is more commonly seen in patients with diabetes mellitus, immunosuppressant therapy, sepsis, surgery, trauma, atherosclerosis, alcoholism, obesity, and malnutrition. Imaging Infectious involvement of the abdominal wall may manifest as cellulitis with poorly defined inflammatory changes in the Differential Diagnosis Differential diagnosis of abdominal wall collections includes uninfected seroma, hematomas, and abscess. Axial contrast-enhanced computed tomography image of the abdomen shows diffuse subcutaneous fat stranding in a 32-year-old woman 2 days after abdominoplasty. Axial contrast-enhanced computed tomography image of the abdomen shows a complex pelvic collection extending into the abdominal wall in a 41-year-old woman that was secondary to pelvic inflammatory disease. Axial unenhanced computed tomography image of the abdomen shows an abdominal wall fluid collection (seroma, asterisks), located superficial to a renal transplant in the right iliac fossa. Axial contrastenhanced computed tomography image of the abdomen demonstrates a well-defined ventral wall seroma (asterisks), manifesting after ventral hernia repair with mesh (arrowheads), in a 51-year-old man. Surgical management is usually required in severe conditions or in cases of necrotizing fasciitis. Abdominal wall hematomas may be associated with trauma, anticoagulation therapy, and blood dyscrasias. Abdominal wall hematomas commonly involve the anterior or anterolateral muscle groups. Axial contrast-enhanced computed tomography image demonstrating traumatic rupture of the right posterolateral abdominal wall (arrowheads) in a 23-year-old man after blunt trauma to the abdomen. Axial contrastenhanced computed tomography image in a 36-year-old man showing rupture of the right rectus abdominis muscle (arrowheads) after blunt abdominal trauma, with herniation of extraperitoneal fat into the subcutaneous tissue. Axial unenhanced computed tomography images of the abdomen through the (A) lower pole of the kidneys and (B) level of the umbilicus in a 62-year-old anticoagulated patient that show a left rectus abdominis muscle hematoma. Note heterogeneous density of the hematoma with multiple fluid-fluid levels and moderate stranding in the subcutaneous fat. Axial unenhanced computed tomography image of the abdomen in a 59-year-old man demonstrating a rectus sheath hematoma occurring below the arcuate line. Acute hematomas appear isointense relative to muscle on T1-weighted images and hypointense on T2-weighted images. Subacute hematomas demonstrate high signal intensity on both T1- and T2-weighted images. Hematomas appear as a nonspecific complex fluid collection with internal echoes and septations. Rectus sheath hematomas occurring above the arcuate line are contained within the muscular fascia. Axial contrast-enhanced computed tomography image of the abdomen demonstrates a hematoma in the anterior abdominal wall in a 32-year-old woman after cesarean section. The hematoma is below the arcuate line, demonstrates hematocrit effect (asterisks), and is associated with extraperitoneal extension of the hematoma into the space of Retzius (arrowheads). Axial contrast-enhanced computed tomography image of the abdomen demonstrating a homogeneous fluid collection in the midline anterior abdominal wall (asterisk) in a 42-year-old woman after left colectomy. Note the homogeneous density of the fluid collection and absence of inflammatory changes in adjacent subcutaneous tissue. Differential Diagnosis Abdominal wall hematoma may mimic other pathologic processes leading to acute abdomen. Prevalence and Epidemiology In most cases, ectopic endometrial tissue is located within the pelvis, associated with the ovaries, uterine ligaments, and pelvic peritoneal folds. One hypothesis suggests that mesenchymal cells with multipotential properties may undergo metaplasia into endometriosis. The other theory states that endometrial cells may be transported to ectopic sites, forming an endometrioma. When these cells are stimulated by estrogens, they may proliferate and become symptomatic. Endometriomas appear as a solid mass in the abdominal wall with hypervascular component. On ultrasonography, endometriomas tend to be solid, hypoechoic lesions within the abdominal wall; they show internal vascularity on Doppler studies. Cystic changes may occur and are probably secondary to intralesional bleeding during menstruation. Ultrasonography is the primary modality in the evaluation of abdominal wall masses (see Table 83-1). Differential Diagnosis Imaging findings of abdominal wall endometrioma are nonspecific, and a wide spectrum of disorders should be considered in the differential diagnosis, including neoplasms. If medical treatment of abdominal wall endometriosis fails, surgical excision is the treatment of choice. Pathophysiology Cirrhosis is the most common cause of intrahepatic portal hypertension and accounts for the majority of cases of portal hypertension in the West. Postsinusoidal and posthepatic causes of portal hypertension include portal and splenic vein thrombosis or hepatic diseases, Budd-Chiari syndrome, and inferior vena cava obstruction. Pathology the left portal vein communicates with the systemic epigastric veins near the umbilicus via paraumbilical venous channels (Cruveilhier-Baumgarten syndrome). Abdominal wall varices appear as subcutaneous, enhancing tubular structures near the umbilicus. Axial contrast-enhanced computed tomography image of the abdomen demonstrating multiple periumbilical varices (arrow) in a 48-year-old man with cirrhosis man. On Doppler ultrasonography, abdominal wall varices appear as fluid-filled dilated tubular structures, with intraluminal venous flow near the umbilicus. Radiotracer localization may mimic scintigraphic findings of acute gastrointestinal hemorrhage. Clinical suspicion and careful evaluation of scintigraphic gastrointestinal bleeding studies will avoid false-positive interpretations. Axial contrast-enhanced computed tomography image of the abdomen demonstrates a soft tissue nodule in the ventral abdominal wall (arrow) in a 55-year-old patient after spigelian hernia repair. A pseudoaneurysm is a pulsatile hematoma in the soft tissues with persistent communication between the artery and the extraluminal space. Imaging Femoral artery pseudoaneurysm causes a localized groin mass with heterogeneous appearance on unenhanced images due to blood products communicating with the arterial lumen. Angiography remains the standard of reference for the diagnosis of pseudoaneurysms despite the advent of new imaging technologies. The donor artery adjacent to the pseudoaneurysm can usually be seen communicating with it. A pseudoaneurysm is a cystic structure that typically demonstrates direct communication with the arterial lumen. Treatment Abdominal wall varices are incidental findings and generally do not require medical treatment; however, these varices may bleed and require surgical ligation. To-and-fro flow between the artery and the pseudoaneurysm also is usually evident. Ultrasonography is the mainstay for detection and visualization of pseudoaneurysms and associated hematoma (see Table 83-1). Moreover, it permits evaluation of the neck and lumen of the pseudoaneurysm; and, in most cases, ultrasound-guided compression results in complete thrombosis of the pseudoaneurysm. Ultrasonography Although ultrasonography is highly operator dependent, it is relatively inexpensive, noninvasive, and widely available, playing an important role in the evaluation of patients with suspected abdominal wall masses. Ultrasonography provides important information regarding lesion location and extent and may be used for percutaneous image-guided biopsy or percutaneous treatment. The primary limitation of ultrasonography is that it does not demonstrate deep extension of large abdominal wall lesions and may not accurately delineate the relationship of these lesions to underlying bowel. Differential Diagnosis A hematoma or any inflammatory or neoplastic process may produce a groin mass and local mass effect. Ultrasound-guided percutaneous injection of thrombin is an alternative procedure that many authors suggest as the therapeutic method of choice. Technical success rates with this method in the setting of postcatheterization pseudoaneurysms are greater than 90%. Endovascular management permits exclusion of pseudoaneurysms from the circulation and includes two broad categories: embolization and stent placement. Benign primary tumors include lipoma, neuroma, neurofibroma, and desmoid tumor, which do not typically metastasize but can be locally aggressive. Metastases to the abdominal wall are more common than primary malignancy, and periumbilical involvement may occur secondary to intraperitoneal spread. Some subcutaneous lesions may be a manifestation of systemic disease, such as neurofibromas in neurofibromatosis or lipomas in lipomatosis. The most common primary neoplasm of the abdominal wall is a desmoid tumor, a benign entity with aggressive local behavior. Axial nonenhanced computed tomography images of (A) the lower thorax and (B) abdomen demonstrate multiple soft tissue cutaneous nodules in the anterior abdominal wall (arrows), representing neurofibromas in a 32-year-old man with type 1 neurofibromatosis. Ultrasonography may be used as the primary imaging modality in patients with suspected abdominal wall lesions. Benign abdominal wall tumors are frequent incidental findings on abdominal imaging. This category includes lipoma, neuroma, neurofibroma, and other less common tumors, such as hemangioma and lymphangioma. When there is a soft tissue component or an increase in size, malignant degeneration (liposarcoma) should be suspected.

Occasionally medicine upset stomach buy on line aricept, air may be found within a collection owing to fistulous communication to bowel symptoms 9 weeks pregnant buy cheap aricept online. Ultrasonography may be used for a large peritoneal collection in which the superficial surface of the collection is clearly visible by ultrasonography medicine 54 543 5 mg aricept overnight delivery. Ultrasonography is also used for transrectal treatment 3 antifungal 10 mg aricept sale, transvaginal medication 3 checks discount aricept 10 mg overnight delivery, and transperineal drainage medications in checked baggage order cheapest aricept. Conscious sedation also may be employed in children undergoing percutaneous abscess drainage. If ultrasonography is used, subsequent wire and catheter placement is visualized fluoroscopically. When performing a transgluteal approach, choose a path that is as medial as possible to reduce the risk for injury to the sciatic nerve. A direct trocar approach may be used for large superficial collections, with no organs close to the catheter track. A report comparing multiple drainage catheters, ex vivo, indicated that nitinol-reinforced catheters had better flow rates. Complications of abscess drainage are uncommon and include bleeding or transient symptomatic bacteremia. Intracavitary fibrinolytic drugs are safe and help break down septa and hemorrhagic debris to improve drainage, obviating the need for surgery in some cases. Axial computed tomography shows diffuse omental nodularity (arrowhead), loculated peritoneal fluid (dashed arrow), and smooth peritoneal enhancement (solid arrow). In our experience, patients with peritoneal tuberculosis typically present with mixed "wet" and "dry" forms and this differentiation is not clinically useful. The prognosis of advanced sclerosing encapsulating peritonitis is poor, with mortality as high as 80%. Peritoneal Abscess Imaging tests cannot reliably differentiate an uninfected fluid collection from an early abscess. Mild thickening and enhancement of the wall of a peritoneal collection does not necessarily indicate infection, and the finding may be due to inflammation, as seen in pancreatitis and the postoperative state. Axial (A) and coronal reformatted (B) images show foci of peritoneal calcification (solid arrows) and moderate amount of ascites (dashed arrows). Bowel (arrowheads) is displaced posteriorly by the dense ascites and does not freely float. If a procedure needs to be performed emergently, the guidelines may be waived after discussion with the referring team. The increased risk for bleeding is discussed with the patient or guardian during informed consent. An 18-year-old man presented after a gunshot wound to the abdomen and subsequent surgical resection of bowel. During several types of surgery, including hysterectomy and partial resection of liver or kidneys, Gelfoam sponges are used to reduce hemorrhage. These are intentionally left after surgery and expected to be absorbed in a few days. The distinction among peritoneal tuberculosis, mesothelioma, and carcinomatosis is usually not possible on imaging studies. Sclerosing encapsulating peritonitis is almost always a complication of peritoneal dialysis and is characterized by peritoneal thickening and eventually bowel obstruction. Tsujimoto F, Miyamoto Y, Tada S: Differentiation of benign from malignant ascites by sonographic evaluation of gallbladder wall. George C, Al-Zwae K, Nair S, et al: Computed tomography appearances of sclerosing 25. However, in most cases, it is not possible to make a categorical diagnosis based on the imaging findings alone and it is necessary to correlate with clinical findings and laboratory tests. In this section we discuss peritoneal diseases that are not classified as infectious diseases or neoplasms. This diverse group of diseases may be categorized as peritoneal fat-based lesions, peritoneal involvement in multiple-organ disease, and fibrosisrelated conditions. The disease is thought to be a continuum of mesenteric lipodystrophy (where fat necrosis predominates), to mesenteric panniculitis (with chronic inflammation), to retractile mesenteritis (where fibrosis predominates). The typical manifestation is one of chronic abdominal pain, fever, and weight loss. In some patients (reports range from 1% to 70%), the presence of mesenteric panniculitis is a sign of malignancy elsewhere. Mesenteric panniculitis involving the mesocolon has been suggested to have a more aggressive course, and surgical treatment is often required. Epiploic Appendagitis, Segmental Omental Infarction, and Omental Torsion Epiploic appendices are pedunculated protuberances of adipose tissue arranged in parallel rows along the antimesenteric border of colon. Each appendage is supplied by one or two small arteries from the colonic vasa recta and drained by a single vein. Given the tenuous vascular supply and narrow neck, these appendages are at risk for ischemia or torsion, resulting in inflammation and infarction. Epiploic appendagitis is usually primary without an associated bowel pathologic process. Like epiploic appendagitis, segmental omental infarction belongs to the spectrum of fat-based peritoneal and mesenteric conditions. Differentiation between epiploic appendagitis and segmental omental infarction is not clinically necessary because conservative therapy with analgesics is all that is required for both conditions. Rarely, laparoscopic surgery may be required in persistently symptomatic segmental omental infarction. Infrequently, segmental omental infarction may be mistaken for a fatty tumor such as liposarcoma. The lack of a well-defined outline and typical site of segmental omental infarction, as well as the clinical presentation, usually help differentiate this entities. However, the "whirl" sign is not always present, and, if not, differentiation from omental infarction is difficult. Contrast-enhanced axial computed tomography images in a 52-year-old woman with abdominal pain (A) and a 58-year-old man with known lung cancer (B). In both cases, the root of the mesentery is expanded and has a misty appearance (arrowheads). There are small lymph nodes (arrows) with a ring of low-density fat around them ("fat ring" sign). The mesenteric vessels (dashed arrows) have increased density fat around them but are not stenosed. The patient underwent laparotomy and was found to have ischemic small bowel, which was resected. Axial computed tomography images in a 50-year-old woman undergoing staging for known breast cancer (A) and a 69-year-old man with pelvic pain (B). Epiploic appendagitis appears as a fat density ovoid lesion with peripheral soft tissue rim (arrows). There may be central hyperdensity as a result of a thrombosed epiploic vein (arrowhead, B). The lesions are found on the antimesenteric border of the colon, usually anterior or lateral to the colon. Amyloidosis associated with chronic dialysis shows immunoglobulin (beta-2 microglobulin) deposition. In less common cases of amyloidosis, neuroendocrine peptides such as calcitonin or cytoskeleton proteins such as keratin may be deposited. The causative organism is a grampositive bacillus, Tropheryma whippelii, which is usually found in soil. An area of the omentum (arrowhead) shows a thickened outline and increased central density. B, A 65-year-old man presented with metastatic renal cancer requiring regular staging. There is calcification within the omentum (arrowheads) that had been stable for 4 years, indicating chronic omental infarction. Extramedullary Hematopoiesis Extramedullary hematopoiesis is an ectopic hematopoiesis that occurs as a compensatory response to insufficient bone marrow hematopoiesis. Although any tissue of mesenchymal origin may show extramedullary hematopoiesis, the liver and spleen are the most common sites in the abdomen. Eosinophilic Gastroenteritis Eosinophilic gastroenteritis is an uncommon disorder with eosinophilic infiltration of different layers of the abdominal gastrointestinal tract. To make the diagnosis of eosinophilic gastroenteritis it is necessary to have gastrointestinal symptoms, eosinophilic infiltration of the gastrointestinal tract (20 eosinophils per high power field), lack of eosinophilic infiltration in other organs, and no evidence to support other conditions associated with eosinophilia, such as drug allergy, parasitic infection, or malignancy. The stomach is the most affected organ in eosinophilic gastroenteritis, followed by the duodenum. Eosinophilic gastroenteritis may be classified into mucosal, muscular, and subserosal subtypes. Axial computed tomography image in a 39-year-old woman with acute right lower quadrant pain. The omentum is swollen (arrowhead) with a central hyperdense structure (dashed arrow) and whirling pattern of curvilinear streaks (solid arrows). Systemic Mastocytosis Mastocytosis is a rare disease characterized by excessive proliferation of mast cells in the skin, bone marrow, and other organs. The 2001 World Health Organization classification of mastocytosis divides this disease into at least five groups. Imaging of systemic mastocytosis includes a skeletal scintigraphic survey and radiographic and endoscopic gastrointestinal evaluation. A, Axial computed tomography shows mixed lowdensity and higher density mesenteric adenopathy (arrowheads). B, Small bowel follow-through was performed for investigation of concomitant malabsorption. C, Abdominal radiograph on same patient shows asymmetric sacroiliitis, worse on the left (arrow). A, Axial computed tomography shows hepatomegaly (solid arrow), splenomegaly (dashed arrow), moderate-volume adenopathy (arrowhead), and ascites. These features are highly suggestive of systemic mastocytosis, which was proved on bone marrow and skin biopsies. Coronal reformatted abdominal computed tomography image shows numerous small low-density lesions in the liver and spleen (arrows), as well as moderate-volume adenopathy (arrowhead). They are consistent with sarcoidosis and represent the most common presentation of this disease in the abdomen. Axial computed tomography shows dense mesenteric soft tissue (arrowhead) enveloping bowel loops, which show thickened folds (arrow). Axial computed tomography scan (A) and coronal T2-weighted magnetic resonance image (B) show several peritoneal masses of low density and high signal intensity (solid arrows) around the celiac artery and the hepatic hilum and retroperitoneal masses (arrowheads). Note the absence of spleen from autosplenectomy and moderately enlarged liver (dashed arrow, B). In the abdomen, the retroperitoneum, mesentery, porta hepatis, and pancreas are affected. Approximately half of these patients present with fever and have anemia or an elevated erythrocyte sedimentation rate. A and B, Axial computed tomography images of the abdomen and pelvis show enhancing lymph nodes (arrows) in the retroperitoneum and inguinal region. There is a spiculated mass (arrowhead) in the mesentery with adherent bowel loop (arrow) anteriorly. A smooth, rounded soft tissue mass in the mesentery (arrowhead) was proved at biopsy to be desmoid. Mesenteric Fibromatosis (Abdominal Desmoid) Mesenteric fibromatosis is a locally aggressive fibroproliferative process that has the capacity to infiltrate or recur but is considered benign because it does not metastasize. Sporadic abdominal desmoids are associated with somatic mutations of the beta-catenin gene. In patients with familial adenomatosis coli there is an inactivating germline mutation in the adenomatous polyposis coli gene. Both gene mutations result in increased transcription of betacatenin protein, which causes cellular adherence and explains the biology of desmoid tumors. The lesions are usually of low signal intensity on T1-weighted precontrast sequences and show variable signal on T2-weighted sequences. Inflammatory Pseudotumor Inflammatory pseudotumor (also called inflammatory myofibroblastic tumor or plasma cell granuloma) is a benign, chronic inflammatory disorder of unknown cause that may manifest as a mesenteric mass indistinguishable from a neoplasm. Mesenteric and omental pseudotumor accounts for approximately 40% of extrapulmonary cases. Small bowel mesentery (distal ileum), transverse mesocolon, and greater omentum are the most common sites in the abdomen. Solid abdominal organs including the liver, kidneys, and pancreas may be affected less commonly. Primary peritoneal neoplasms arise from the peritoneum itself, whereas secondary peritoneal neoplasms originate from adjacent or remote organs. The most common of these is peritoneal mesothelioma, which has a reported incidence of two cases per million. Secondary neoplasms of the peritoneum are more common than primary tumors but are uncommon overall. The most common primary tumors to metastasize to the peritoneum are ovary, breast, and gastrointestinal tract tumors. Peritoneal metastases are often discovered by imaging or at surgery and require biopsy for definitive diagnosis. When biopsy yields poorly differentiated adenocarcinoma and a primary tumor site is not found, the tumor is usually categorized as adenocarcinoma of an unknown primary tumor rather than primary peritoneal adenocarcinoma.

A tuft of hair in the median plane of the back in the lumbosacral region usually indicates spina bifida occulta symptoms you have cancer buy 5mg aricept free shipping. It is the most common developmental defect of vertebrae medications safe for dogs aricept 10 mg without a prescription, and it occurs in L5 or L1 symptoms hyperthyroidism order generic aricept on-line, or both symptoms 9dpiui purchase aricept amex, in approximately 10% of otherwise normal people treatment math definition order generic aricept line. Spina bifida occulta usually has no clinical significance medicine valley high school purchase 10 mg aricept free shipping, but some infants with this vertebral defect may also have a birth defect of the underlying spinal cord and nerve roots. The superficial layers of the epidermis of infants with lamellar ichthyosis, resulting from excessive keratinization, consist of fish-like, grayish brown scales that are adherent in the center and raised at the edges. Fortunately, the condition is rare; it is inherited as an autosomal recessive trait. Between 7% and 10% of birth defects are caused by drugs, environmental chemicals, and infections. It is difficult for clinicians to assign specific defects to specific drugs for several reasons: the drug may be administered as therapy for an illness that itself may cause the defect. The physician caring for a pregnant 41-year-old woman will recommend chorionic villi sampling and amniocentesis to determine whether the fetus had a chromosomal disorder such as trisomy 21 or trisomy 13. A 41-year-old woman can have a normal baby; however, the chances of having a child with Down syndrome are 1 in 85 (see Table 20-2). Penicillin has been widely used during pregnancy for more than 35 years without any suggestion of teratogenicity. Small doses of aspirin and other salicylates are ingested by most pregnant women, and when they are consumed as directed by a physician, the teratogenic risk is very low. Chronic consumption of large doses of aspirin during early pregnancy may be harmful. Alcohol and cigarette smoking should be avoided, and illicit drugs such as cocaine must be avoided. The physician told the mother that there was no danger that her child would develop cataracts and cardiac defects because she has rubella infection (German measles). However, the physician also explained that cataracts often develop in embryos whose mothers contract the disease during early pregnancy. They occur because of the damaging effect the rubella virus has on the developing lens. Oocysts of these parasites appear in the feces of cats and can be ingested during careless handling of litter. If the woman is pregnant, the parasite may cause severe fetal defects of the central nervous system, such as mental deficiency and blindness. Smarter, Faster Search for Better Patient Care Unlike a conventional search engine, ClinicalKey is specifically designed to serve doctors by providing three core components: Comprehensive Content Trusted Answers Unrivaled Speed to Answer 1 2 3 the most current, evidence-based answers available for every medical and surgical specialty. Faster, more relevant clinical answers, so you can spend less time searching and more time caring for patients. Cells migrate from the mesonephros (M) into the developing gonad (G), which develop in close association with each another. F, Distinctive segmentation of the S-shaped body defines the patterning of the nephron. A vascular cleft develops and separates the presumptive podocyte layer from more distal cells that will form the proximal tubule. Initially the podocytes are connected by intercellular tight junctions at their apical surfaces. They develop microtubule-based primary processes and actin-based secondary foot processes. Together, these components provide a size- and charge-selective barrier that permits free passage of small solutes and water but prevents the loss of larger molecules such as proteins. The tubular portion of the nephron becomes segmented in a proximalto-distal order, into the proximal convoluted tubule, the descending and ascending loops of Henle, and the distal convoluted tubule. Increased expression levels of transporters, switch in transporter isoforms, alterations in paracellular transport mechanisms, and the development of permeability and biophysical properties of tubular membranes have all been observed to occur postnatally. Asdescribedinthetext,nephrons are continually produced in the nephrogenic zone throughout fetallife. Water and salt resorption and excretion, ammonia transport, and H+ secretion required for acid-base homeostasis also occur in the collecting ducts, under different regulatory mechanisms and using different transporters and channels from those that are active along tubular portions of the nephron. Ultimately, they form a funnel-shaped structure in which cone-shaped groupings of ducts or papillae sit within a funnel or calyx that drains into the ureter. The mouse kidney has a single papilla and calyx, but a human kidney has 8 to 10 papillae, each of which drains into a minor calyx, with several minor calyces draining into a smaller number of major calyces. Thus, within the developing kidney, the most mature nephrons are found in the innermost layers of the cortex, and the most immature nephrons in the most peripheral regions. Indeed, whether there are significant molecular differences between the induction of the original nephrons and these subsequent inductive events is not known. Vasculogenesis and angiogenesis have been described as two distinct processes in blood vessel formation. Vasculogenesis refers to de novo differentiation of previously nonvascular cells into structures that resemble capillary beds, whereas angiogenesis refers to sprouting from these early beds to form mature vessel structures including arteries, veins, and capillaries. At 13 dpc capillaries form networks around the developing nephric tubules, and by 14 dpc the hilar artery and first-order interlobar renal artery branches can be identified. These branches will form the corticomedullary arcades and the interlobular arteries that branch from them. The efferent arterioles carry blood away from the glomerulus to a system of fenestrated peritubular capillaries that are in close contact with the adjacent tubules and receive filtered water and solutes reabsorbed from the filtrate. In comparison, the vasa recta, which surround the medullary tubules and are involved in urinary concentration, are also fenestrated but have more pericytes. However, in later years, interest has arisen in the stromal cell as a key regulator of nephrogenesis. Loose and condensed mesenchymal cells are also observed around the stalk of the ureteric bud in B. B, Scanning electron micrograph of a glomerulus withanexposedendotheliallumen(dashed outlined)showingfenestrations. In these cases, the mesenchyme can be placed in contact with neural tube to determine whether it has the intrinsic ability to differentiate. Most often, when renal agenesis is due to the mutation of a transcription factor gene, tubular induction is not rescued by neural tube, as could be predicted for transcription factors which would be expected to act in a cell-autonomous fashion. As chemical inhibitors specific for various signal transduction pathways have been synthesized and become available, it has been possible to add them to organ cultures and observe effects that are informative about the roles of specific pathways in development of the kidney. A subsequent study could not duplicate this phenotype,34 although there were possible differences in experimental techniques. C, Epithelial derivatives of the metanephric mesenchyme stained for E-cadherin (Cdh6). Additionally, many genes are expressed in multiple cell types, and the resulting knockout phenotypes can be complex and difficult or impossible to dissect. A number of mouse lines may be used to target specific kidney cell lineages Table 1. As with any experimental procedure, numerous caveats must be taken into account in the interpretation of data. In spite of these issues, tissue-specific conditional gene targeting strategies remain powerful tools to study gene functions. In contrast to gene targeting experiments in which the gene is known at the beginning of the experiment (reverse genetics), random mutagenesis represents a complimentary phenotype-driven approach (forward genetics) to study the physiologic relevance of certain genes. Random mutations are introduced into the genome at high efficiency by chemical or gene trap mutagenesis. Consecutively, large numbers of animals are screened systematically for specific phenotypes of interest. As soon as a phenotype is identified, test breeding is used to confirm the genetic nature of the trait. Chromosomal mapping and positional cloning are then used to determine the identity of the culprit mutant gene. First, most knockouts lead to major gene disruptions, which may not be relevant to the subtle gene alterations that underlie human renal disease. Second, many of the complex traits underlying congenital anomalies and acquired diseases of the kidney are unknown, making predictions about the nature of the genes that are involved in these diseases difficult. It acts through random alkylation of nucleic acids, inducing point mutations in spermatogonial stem cells of injected male mice. Mutations may be complete or partial loss of function, gain of function, or altered function and can have either dominant or recessive effect. Assuming a total number of 25,000 to 40,000 genes in the mouse genome, a single treated male mouse should have between 25 and 40 different heterozygous mutagenized genes. In the case of multigenic phenotypes, segregation of the mutations in the next generation allows the researcher to focus on monogenic traits. In each generation, 50% of the mutations are lost, and only the mutation underlying the selected phenotype is maintained in the colony. Screening for dominant phenotypes is popular because breeding schemes are simple and a great number of mutants can be recovered through this approach. About 2% of all firstgeneration offspring mice display a heritable phenotypic abnormality. For example, in renal glomerular development, the phenotype of a genetic mouse strain with a tendency to development of congenital nephrosis. This approach has been successfully used to identify genes involved in neural development. The advent of genetically modified mice that express fluorescent proteins revolutionized cell lineage and mapping studies allowing high-resolution live visualization of morphogenetic events both in situ and in cultured organ explants. Targeted labeling of cells with fluorescent proteins can be achieved by driving expression of fluorescent proteins under direct control of a cell-specific promoter. This Cre-driven strategy is particularly valuable in cell lineage tracking and fate mapping analysis because both the progenitor and its subsequent derivatives become fluorescently labeled. This third method allows for the incomplete and pulse labeling of certain cell lineages, permitting the tracking of the fate and migratory behavior of individual cells in real time. This continuing feature stems from the facts that all of these organisms possess excretory organs designed to remove metabolic wastes from the body and that genetic pathways involved in other aspects of invertebrate development may serve as templates to dissect pathways in mammalian kidney development. Major contributions to our understanding of the function of polycystic and cilia-related genes have been made from studying C. Furthermore, studies on myoblast fusion and neural development in Drosophila-two processes that may not appear to be related to kidney development at first glance-have provided major clues to the development and function of slit diaphragms. The pronephros found in larval stage zebrafish (Dario rerio) consists of two tubules connected to a fused, single, midline glomerulus. The zebrafish pronephric glomerulus expresses many of the same genes found in mammalian glomeruli. The pronephros of the clawed frog Xenopus laevis has also been used as a simple model to study early events in nephrogenesis. As in the fish, the pronephros consists of a single glomus, paired tubules, and a duct. Together, the phenotypes of these knockout mice have provided an initial molecular hierarchy of early kidney development. Although Six1 and Eya1 may act in a complex together, the Six1 phenotype is somewhat different, in that a histologically distinct mesenchyme is present at 11. This understanding has been gained primarily through the phenotypic analysis of mice carrying targeted mutations that affect kidney development. Additional information has been gained by identification and study of genes expressed in the developing kidney, even though the targeted mutation, or knockout, either has not yet been performed or has not affected kidney development or function. This section categorizes the genetic defects on the basis of the major phenotype and stage of disrupted development. It must be emphasized that many genes are expressed at multiple points of renal development and may play pleiotropic roles that are not entirely clear. As previously mentioned, the organ culture system has been in use since the seminal experiments, beginning in the 1950s, of Grobstein, Saxen, and their colleagues. The embryonic neural tube was found to be able to substitute for the epithelial bud, and experiments involving the placement of the inducing agent on the opposite side of a porous filter from the mesenchyme provided information about the degree of contact required between them. A large series of experiments using organ cultures provided information about the timing of appearance of different proteins normally observed during the induction of nephrons and about the intervals that were crucial in maintaining contact between the inducing agent and the mesenchyme to obtain induction of tubules. Mice carrying mutations in any one of these genes do not have kidney abnormalities; however, triple-mutant mice for these genes demonstrate a complete absence of metanephric kidney induction. A novel approach to the organ culture system involving microinjection and electroporation has also yielded insights as to a possible function of the Wt1 gene in early kidney development. Blockade of Flk1 after the organ had been in culture for 48 hours had no effect, indicating that the angioblast-derived signal was required to initiate kidney development but not to maintain continued development. Flk1 signaling is also required to initiate hepatocyte differentiation during liver development. Nephric duct specification fails in Pax2/Pax8 mutants but not in the case of Lhx1 deficiency, in which only the caudal portion of the nephric duct degenerates. Nephronectin gene (Npnt) knockout mice exhibit renal agenesis or severe hypoplasia. Hence, dysregulation of mesenchymal cell adhesion causes the failure to attract and induce the ureteric epithelia. This fact is another example of how signaling through the extracellular matrix intersects with growth factor signaling to influence morphogenesis. The importance of basement membrane assembly in the development of other renal structures is emphasized by genetic studies on the genes Lama5 and Lamb2, which encode for laminins 5 and 2, respectively. Loss of Lama5 causes either renal agenesis or disruption of glomerulogenesis, whereas deficiency of Lamb2 leads to a defective glomerular filtration barrier. The formation of patent lumens within epithelial tubules of the kidney also depends on coordinated cell adhesion. Thus, cell adhesion molecules may suppress cell division to regulate distinctive aspects of renal branching and tubulogenesis.

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