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By: F. Rhobar, M.A., M.D., M.P.H.

Vice Chair, University of Iowa Roy J. and Lucille A. Carver College of Medicine

The quiescent primordial follicles are recruited to further growth and differentiation through a highly regulated process that limits the size of the developing cohort to ensure that folliculogenesis can continue throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells. The theca interna cells that surround the developing follicle begin to form as the primary follicle grows. Acquisition of a zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary follicles. In murine models, genes that regulate ovarian development and follicle formation have been identified. Bidirectional signals between the oocyte and its surrounding somatic cells are essential for normal follicular development. These steps require the cooperative interaction of signals from the oocyte and the somatic cells. Accumulation of follicular fluid between the layers of granulosa cells creates an antrum that divides the granulosa cells into two functionally distinct groups: mural cells that line the follicle wall and cumulus cells that surround the oocyte. Differential exposure to these factors may explain why one follicle is selected for continued growth to the preovulatory stage. The sequence of steps and the enzymes involved in the synthesis of steroid hormones are similar in the ovary, adrenal, and testes. However, the specific enzymes required to catalyze specific steps are compartmentalized and may not be abundant or even present in all cell types. Within the developing ovarian follicle, estrogen synthesis from cholesterol requires close integration between theca and granulosa cells-sometimes called the two-cell model for steroidogenesis. Androstenedione and testosterone are transferred across the basal lamina to the granulosa cells, which receive no direct blood supply. The hilar interstitial cells of the ovary are functionally similar to Leydig cells and are also capable of secreting androgens. Gonadotropin levels are cyclic during the reproductive years and increase dramatically with the loss of negative feedback that accompanies menopause. The Female Reproductive System: Infertility and Contraception with the production of pituitary gonadotropins. Thus, like the ovary, the hypothalamic and pituitary components of the reproductive system are present before birth. However, the high levels of estradiol and progesterone produced by the placenta suppress hormonal secretion in the fetus. The mechanisms responsible for the childhood quiescence and pubertal reactivation of the reproductive axis remain incompletely understood. Metabolic signals, such as adipocyte-derived leptin, also play a permissive role in reproductive function (Chap. Theca lutein cells produce 17-hydroxyprogesterone, a substrate for aromatization by the luteinized granulosa cells. While the major secretory product of the corpus luteum is progesterone, estradiol and 17-hydroxyprogesterone are also produced. Estrogen promotes development of the ductule system in the breast, whereas progesterone is responsible for glandular development. In the reproductive tract, estrogens create a receptive environment for fertilization and support pregnancy and parturition through carefully coordinated changes in the endometrium, thickening of the vaginal mucosa, thinning of the cervical mucus, and uterine growth and contractions.

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When acutely deoxygenated, an erythrocyte may partially polymerize which reverses when reoxygenated. Prophylactic chronic transfusions and hydroxyurea are used to decrease the rate of cerebral infarction. Infection is the most common cause of death in the first decade, followed by sequestration and cerebrovascular infarction. Due to diminished phagocytosis and splenic function, children are at high risk for osteomyelitis (particularly Salmonella). Infants between 6 and 24 months are at risk of an infarction of the small bones of the hands and feet ("hand-foot syndrome"). Painful soft tissue swelling of the hands and feet present for several weeks before radiographic changes are evident. Ischemic infarcts predominate in younger children while hemorrhagic stroke occurs in older S Sickle Cell Disease. A bone scan demonstrates increased uptake in numerous bones including ribs, humeri, and radii. When stenosis becomes irreversible, lenticulostriate collateral develop forming a pattern of moyamoya "puff of smoke. Radiographs are important for evaluating the lungs and bones for infections and infarctions. When chest pain develops, there often is a lag time in radiographic changes so close follow-up radiographs are necessary. The most common pneumonias are Streptococcus pneumoniae, Hemophilus influenzae, and Staphylococcus aureus. Skeletal: Skeletal changes include marrow hyperplasia and bony infarction from vasoocclusive crisis. Expansion of the marrow is notable in the skull with widening of the diploic space creating a "hair-on-end" appearance. Avascular Necrosis is a common with up to 50% of patients developing osteonecrosis by the age of 35. The epiphyses of the long bones have a limited vascular supply with minimal collaterals. Stasis and occlusion lead to ischemia and infarction most commonly of the hips and shoulders. Nuclear bone scans can demonstrate early decreased perfusion prior to radiographic changes. Within the spine, infarcts involve the vessels supplying the central vertebral end plates. Central end plate depressions result in a "fish mouth" appearance to the vertebral bodies. Compression fractures are common due to marrow hypertrophy and end plate collapse. Dactylitis or "hand-foot syndrome," is an infarction of red marrow of the tubular bones of the hands and feet with associated periosteal inflammation. Differentiating from osteomyelitis can be difficult but bones tend to reconstitute after several months without residual deformity. Epiphyseal infarction of the hands and feet may produce cone-shaped epiphysis or premature fusion of epiphysis resulting in abnormal shortening of involved bones. Both may present with pain, swelling, fever, leukocytosis, and elevated sedimentation rate.

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Safety, effectiveness, or pharmacokinetics of mangafodipir injection in pediatric patients below the age of 12 years has not been established. Gadobenate Dimeglumine A known allergic or hypersensitivity reactions to gadolinium or any other ingredients, including benzyl alcohol represents a contraindication. Further contraindications are sickle cell anemia or other hemoglobinopathies and hemolytic anemias. Gadobenate should not be administered to patients who may be using medications or who may have underlying metabolic, cardiac, or other abnormalities that may predispose them to cardiac arrhythmias. Gadobenate is not recommended in patients with severely impaired renal function (creatinine clearance <30 mL/min). Therefore, gadobenate should not be used in patients with history of sensitivity to benzyl alcohol. Contraindication Safety and effectiveness have not been established in pediatric patients for any of the contrast agents. Specific contraindications and precautions for the three contrast agents are as follows. Gadoxetic Acid Hypersensitivity to the active substance or to any of the excipients represents a clear contraindication. Caution should be exercised in patients with severe renal impairment due to reduced elimination capacity of gadoxetic acid. Caution should also be exercised when gadoxetic acid is administered to patients with severe cardiovascular problems because only limited data are available so far. It cannot be excluded that of gadoxetic acid may cause torsade de points arrhythmias in an individual patient. Mangafodipir Mangafodipir is contraindicated in patients with known allergic or hypersensitivity reactions to manganese, fodipir or any of the inert ingredients. Pregnancy/Lactation It is recommended that breastfeeding be discontinued before administration of any of the contrast agents and not reinitiated until 24 h after administration. Use is recommended only if potential benefit to the pregnant woman outweighs the potential risks to the fetus. However, it is recommended not to use mangafodipir since this may cause harm to the fetus when administered to a pregnant woman. Animal studies have shown that 54Mn manganese crosses the placenta and locates in the fetus. At least 24 h after injection, radioactivity is detected in liver and bones of the fetus. It has been reported that manganese enters nerve terminals, accumulates in nervous tissue, and could be associated with neurotoxicity in fetuses. If mangafodipir is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be told of the potential hazard to the fetus. Near maximal enhancement is achieved at 20 min after the start of the infusion, and persists for several hours. Postcontrast imaging may start as soon as 20 min after the start of the infusion, but longer time intervals are possible because of a plateau-like enhancement up to and several hours. This approach exploits the differences in blood flow between lesions and normal liver parenchyma. The fraction of gadobenate dimeglumine taken up into the hepatocytes manifests itself as a strong enhancement of the liver parenchyma signal intensity in T1-weighted images between 40 and 120 min postinjection. Gadoxetic acid is administered as a bolus injection at a dose of 25 mmol Gd/kg body weight. Near maximal enhancement is achieved at 20 min after the start of the injection, and persists for several hours. The portalvenous system (b) shows weak enhancement following Primovist compared to plain T1 (a). Caution should be exercised in patients with deoxygenated sickle erythrocytes in all paramagnetic contrast agents. Mangafodipir showed warmth or flush, nausea, heart pounding (increase in blood pressure and heart rate), and dizziness as the most frequent side effects in clinical studies with facial flushing in 55% of patients. The majority (93%) of adverse events were of mild to moderate intensity: chest pain, dizziness, hot flushes, hypersensitivity, hypertension, palpitation, pruritus, rash, taste perversion, urticaria.

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B Stereotactic Localization Stereotactic lesion localization is carried out according to stereotactic biopsy as described in the previous section. Following exact needle placement, wire placement and/or dye injection is performed. Misplacement of just a few millimeters under compression may equal considerable misplacement following tissue decompression. It is thus recommended to advance the needle about 5 mm beyond the calculated target. If these rules are observed, stereotactic localization proves to be a very reliable method. Sonographic Localization Lesion access should be chosen according to the shortest possible skin lesion distance, but it should not interfere with surgical transection pathways. However, to sufficiently visualize the needle and wire during placement, it should be kept parallel to the linear transducer. In circumscribed findings, the marker should penetrate the lesion center and the tip of the wire should be placed and fixed in the tissue distal to the lesion, the maximum tolerable distance being 1 cm. The orientation of the wire as well as the distance between the skin and lesion, the depth of the tip of the wire, and the location of the wire relative to the lesion must be documented. Moreover, information should be given concerning the general extent of the excision and the dimensions in relation to the marker. Specimen Radiography/Specimen Ultrasound Localization by Perforated or Tagged Compression Needle Depending on the lesion site, a craniocaudal, mediolateral, or lateromedial mammogram will be obtained using a perforated compression panel. Needle placement is carried out under tissue compression and according to the lesion is coordinated via the perforated/fenestrated compression panel. In doing so, the needle should perforate the lesion to a certain extent, so that after decompression and relaxation of the tissue it still perforates or at least reaches the lesion. If necessary, the needle position may be adjusted In all lesions subjected to presurgical labeling and excision, postsurgery sample X-ray (two planes) or ultrasound must be performed to assure complete removal. Sample compression may be helpful to increase contrast and facilitate delineation of the resected lesion. In addition, the most suspicious areas (calcifications/solid lesions) should be marked for the pathologist with additional tags/needles. Microcalcifications always warrant additional magnification views, as those will usually give further information about morphology and about more, even smaller, calcifications. The the the the lesion lesion lesion lesion has been removed completely; might be incomplete; is definitely incomplete; is not contained in the sample. In lesions that could be seen and tagged on ultrasound only, additional sample ultrasound may increase confidence concerning successful excision; evaluation obeys the same standards as in sample X-rays. Raven Press, New York Rissanen T, Typpo T, Tikkakoshki T, Turunen J, Myllymaki T, Suramo, I (1993) Ultrasound-guided percutaneous galactography. In addition to postsurgical changes, changes following axillary node dissection and radiotherapy can also occur. The changes induced by breastconserving treatment with irradiation affect the entire breast and are superimposed on the changes at the surgical site. Depending on whether a hematoma, a seroma, or fat necrosis is present, postsurgical changes can have variable radiologic presentations. Therapy effects are also seen following reconstruction, augmentation, and reduction of the breast. Augmentation refers to enlargement of the breast for to correct congenital or acquired anisomastia or micromastia, or for cosmetic reasons. Reduction is performed to achieve symmetry in anisomastia or following mastectomy. Neoadjuvant systemic chemotherapy is used to enable breast-conserving surgery in patients with large primary operable breast cancers. It is important to be able to assess response to systemic therapy, both for assisting the surgeon and for prognostic purposes (1). Postmenopausal hormone therapy has been associated with an increased risk of breast cancer, and an increase in mammographic breast density has been reported to occur in a significant proportion of women during such treatment (3). On the other hand, tamoxifen is a widely used antineoplastic agent, not only for early adjuvant therapy but also for prophylaxis and treatment of breast cancer. It has antiestrogenic effects in the female reproductive organs, especially breast parenchyma (4).

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