By: Dirk B. Robertson MD
This inhibitor gains access to the oocyte via gap junctions connecting the oocyte and its surrounding cumulus of granulosa. Follicular Development Follicular development is a dynamic process that continues from menarche until menopause. The process is designed to allow the monthly recruitment of a cohort of follicles and, ultimately, to release a single, mature, dominant follicle during ovulation each month. Primordial Follicles the initial recruitment and growth of the primordial follicles is gonadotropin independent and affects a cohort over several months (73). The stimuli responsible for the recruitment of a specific cohort of follicles in each cycle are unknown. This process signals the shift from gonadotropin-independent to gonadotropin-dependent growth. The first changes seen are growth of the oocyte and expansion of the single layer of follicular granulosa cells into a multilayer of cuboidal cells. The enlarging oocyte secretes a glycoprotein-rich substance, the zona pellucida, which separates it from the surrounding granulosa cells (except for the aforementioned gap junction). With transformation from a primordial to a preantral follicle, there is continued mitotic proliferation of the encompassing granulosa cells. Simultaneously, theca cells in the stroma bordering the granulosa cells proliferate. Both cell types function synergistically to produce estrogens that are secreted into the systemic circulation. At this stage of development, each of the seemingly identical cohort members must either be selected for dominance or undergo atresia. It is likely that the follicle destined to ovulate was selected before this point, although the mechanism for selection remains obscure. Two-Cell, Two-Gonadotropin Theory the fundamental tenet of follicular development is the two-cell, two gonadotropin theory (73,75,76) (Fig. This theory states that there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle. Granulosa cells lack several enzymes that occur earlier in the steroidogenic pathway and require androgens as a substrate for aromatization. These locally produced estrogens create a microenvironment within the follicle that is favorable for continued growth and nutrition (80). Within the ovary, androgens promote granulose cell proliferation, aromatase activity, and inhibit programmed death of these cells (81). This process continues until all members of the initial cohort, with the exception of the single dominant follicle, have suffered atresia. Clinically, androgen excess results in chronic anovulation, as is seen in polycystic ovarian syndrome. Preovulatory Follicle Preovulatory follicles are characterized by a fluid-filled antrum that is composed of plasma with granulosa cell secretions. The granulosa cells at this point have further differentiated into a heterogenous population.
Thus , it excludes the last void before going to bed but includes the first void after rising in the morning. Nocturia can be the result of nocturnal polyuria potentially related to delayed mobilization of fluid especially in the elderly, sleep problems. Nocturnal polyuria is present when an increased proportion of the 24-hour output occurs at night. Risk Factors for Urinary Incontinence Most of the data about risk factors for urinary incontinence come from clinical trials or cross-sectional studies using survey design. Thus, the information available is limited in its general applicability and one cannot infer causality from it. Despite these limitations, there is some evidence that age, pregnancy, childbirth, obesity, functional impairment, and cognitive impairment are associated with increased rates of incontinence or incontinence severity (16). For example, in studies of older women, childbirth no longer increases the risk of incontinence, possibly because of the presence of comorbidities and other factors that promote incontinence. Medical diagnoses that were associated with urinary incontinence include diabetes, strokes, and spinal cord injuries. Other factors about which less is known or findings are contradictory include hysterectomy, constipation, occupational stressors, smoking, and genetics. Pregnancy and delivery predispose women to stress urinary incontinence, at least during their younger years. Of women who have not borne children, those who are pregnant leak more often than their nonpregnant counterparts; about half of women report symptoms of stress urinary incontinence during pregnancy, but in most, the symptom resolves after delivery. In a prospective study, 32% of 305 primiparas developed stress urinary incontinence during pregnancy and 7% after delivery. However, 5 years later, 19% of women with no symptoms after the first delivery had stress urinary incontinence. Of women reporting stress urinary incontinence 3 months postpartum (in most of whom it had resolved by 1 year), 92% had such leakage 5 years later. Various changes happen after delivery that may predispose women to stress urinary incontinence. About 20% of women develop a visible defect in the levator ani muscles after vaginal delivery (26). The bladder neck descends, and the pelvic muscles undergo partial denervation with pudendal neuropathy (27). In most studies, parity is strongly associated with urinary incontinence in younger women (28). In studies of women 60 years and older, parity is no longer an independent risk factor for incontinence (29).
Finally , plastic surgery techniques that include advanced tissue transfer procedures are being used more frequently in patients with high-risk wounds, and this can achieve a high success rate (>90%) of healed wounds from a single-stage operation. Chemotherapy Despite improvements in the local control rate, metastasis and death remain significant problems for patients with high-risk soft-tissue sarcomas. This high-risk group includes localized sarcomas in nonextremity sites, tumors which show an intermediate or high-grade histology, or large (T2) tumors. The treatment regimen for patients with high-risk localized disease, metastatic disease, or both, usually includes chemotherapy. Systemic chemotherapy is a particularly important component of several sarcomas that occur predominantly in children, such as rhabdomyosarcoma, Ewing sarcoma, and osteogenic sarcoma. It is also well recognized that myxoid liposarcoma and synovial sarcoma are chemosensitive soft-tissue sarcomas. Only three drugs, doxorubicin, dacarbazine, and ifosfamide, have consistently achieved response rates of at least 20% as single-agent treatments in patients with advanced soft-tissue sarcomas. The majority of active chemotherapeutic trials have included doxorubicin as part of the treatment regimen. The response rate to ifosfamide has been found to vary from 20% to 60% in single-institution series in which higher-dose regimens have been used or in which ifosfamide was given in combination with doxorubicin. Eribulin is a microtubule inhibiting agent approved in the treatment of liposarcoma. However, there are several criticisms of these individual trials that may explain why they failed to demonstrate improvement in survival. First, the chemotherapy regimens used were suboptimal, in that single-agent drugs (most commonly doxorubicin) were studied and dosing schedules were less intensive. Second, the sample sizes in these trials were 250 not large enough to allow the detection of clinically significant differences in survival. Finally, most studies included patients at low risk for metastasis and death, that is, those with small (<5 cm) and low-grade tumors. Hence, the role of postoperative chemotherapy in soft-tissue sarcomas has been controversial. Since then, multiple randomized trials have been conducted with conflicting results. A formal meta-analysis was conducted by the Sarcoma Meta-Analysis Collaboration in 1997; this group analyzed data from 1,568 patients in 14 trials of doxorubicin-based postoperative chemotherapy to determine the effect of postoperative chemotherapy on localized, resectable soft-tissue sarcomas. The same group updated the analysis by adding several subsequent randomized trials. Based on these analyses, a chemotherapy regimen including ifosfamide is generally recommended. Preoperative Chemotherapy the potential advantages to preoperative chemotherapy over a postoperative approach include tumor reduction (which may enable more limited resection), early treatment of potential micrometastases, patient selection for surgery in cases with borderline resectable tumors or tumors with questionable metastases, and most importantly, in vivo evaluation of treatment effectiveness. Given that only 30% to 50% of patients respond to standard chemotherapeutic regimens, a preoperative approach enables the oncologist to identify patients who respond to specific regimens, as shown radiographically and pathologically.
Since nearly 60% of morphologically normal cleavage embryos but only 30% of blastocysts are chromosomally abnormal , extended culture allows for better selection of embryos with improved quality (364,367). Blastocyst versus Cleavage Transfer Outcomes Comparisons involving equal numbers of transferred embryos demonstrate that blastocyst transfer is associated with lower implantation failure, a higher pregnancy rate, and a 7% higher live birth rate than cleavage stage transfer. This is of particular interest in programs that offer elective single embryo transfer (364,367,368). Given that blastocyst formation rates range from only 28% to 60%, disadvantages of extended culture include the possibility that no embryos will survive to transfer (8. Monozygotic twinning rates may be higher with blastocyst culture, although this has not been a consistent finding (364,369). Criteria for Extended Culture There are no established guidelines or criteria that determine when to utilize extended culture. Embryo Transfer Embryo Morphology Embryo morphology guides the choice of embryo for transfer. Pronuclear embryos are assessed by their distribution and number of nucleoli, the position of the second polar body relative to the first, and cleavage rates (abnormal rates are too fast, too slow, or arrested) (365). Preferred cleavage stage embryos have a normal developmental pattern characterized by early cleavage on day 1, four cells on day 2, and eight cells on day 3. Embryo fragmentation should be 10% or less, the blastomere size should be regular, and there should be no multinucleation (362). The Gardner and Schoolcraft system for scoring blastocysts uses a scale from 1 (worst) to 6 (best), with grades 1 to 3 indicating growth of the blastocele until it completely fills the embryo. Grade 4 blastocysts are expanded with a larger blastocele volume and a thinning zona pellucida. The trophectoderm in a grade 5 blastocyst is starting to hatch though the zona, and the grade 6 blastocyst has completely escaped or hatched from the zona. The inner cell mass is graded A to C based on tightness and cellularity (A is best), and the trophectoderm is assessed from A to C based on cohesiveness and cellularity (A is best) (361). Number of Embryos to Transfer High-order multiple pregnancy (three or more fetuses) increases complications for mothers and fetuses, so guidelines have been developed to minimize this adverse outcome (371). Otherwise, transfer should be limited to two embryos in women under 35 years of age. For older women, the maximum number of transferred cleavage-stage embryos should be three in women aged 35 to 37, four in women aged 38 to 40, and five in women older than 40 years of age. Because of their high implantation potential, no more than three blastocysts should be transferred to any woman regardless of her age.
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