Archana Dixit MD, MRCOG

• Consultant Obstetrician and Gynaecologist
• West Middlesex University Hospital NHS Trust
• Isleworth, Middlesex, UK

Low-grade lesions characteristically have feathery margins kidney spasms no pain buy discount rumalaya forte 30 pills on-line, whereas high-grade lesions have straighter muscle relaxant with least side effects purchase on line rumalaya forte, sharper outlines muscle relaxant starting with b purchase 30pills rumalaya forte with mastercard. A lesion with an internal border muscle relaxant video order rumalaya forte 30 pills overnight delivery, that is quercetin muscle relaxant generic 30pills rumalaya forte, a lesion within a lesion muscle relaxant 2631 rumalaya forte 30pills visa, is typically high-grade. Atypical vessels with bizarre capillaries with so-called corkscrew, comma-shaped, or spaghetti-like configurations suggest early stromal invasion. Biopsy Ectocervical Biopsy Under direct colposcopic visualization, suspicious lesions on the ectocervix are biopsied using a biopsy forceps. Satisfactory Colposcopy Within a neoplastic lesion, more severe disease tends to be at the proximal limit of the transformation zone. Therefore, with initially unsatisfactory colposcopy, an endocervical speculum may be used to dilate and fully visualize lesions that have extended cephalad into the endocervical canal. Endocervical curettage generally is indicated if: Atypical glandular cell cytology is evaluated Colposcopy is unsatisfactory, which is common in postmenopausal women Ablative treatment is planned. Endocervical curettage is performed by introducing an endocervical curette 1 to 2 cm into the cervical canal. The entire length and circumference of the canal is firmly curetted, carefully avoiding sampling of the ectocervix or lower uterine segment. Condoms Both vaccines are administered in three intramuscular doses during a 6-month period, (0, 2, 6) and are extremely safe, effective and well tolerated. Although these two viral types cause approximately 70% of all cervical cancer, several other viral types (31, 33, 45, and others) are responsible for almost a third of cervical cancer. The objective of all treatment is surgical obliteration of the entire cervical transformation zone, including abnormal tissue. This may be done by use of ablation, that is, tissue destruction with cryosurgery or laser ablation, or by excision of tissue. All treatment modalities, particularly excisional procedures, are suspected of increasing the risk of adverse future reproductive outcomes, such as preterm delivery and premature rupture of membranes. The "see and treat" approach in which loop excision is performed at initial colposcopy is an acceptable option for high-risk, adult patients who present with high-grade cytology and corresponding colposcopic abnormalities. Modalities for the Treatment probe will determine the depth of penetration and subsequent tissue loss. Tissue is sloughed off slowly, over a period of 10 to 14 days, as a watery discharge. The most widely accepted technique for cryotherapy is to freeze the cervix for 3 minutes after formation of an ice ball on the cervix, followed by a 5-minute thaw and a repeated 3-minute freeze. The advantages of cryotherapy include ease of use, low cost, widespread availability, and a low complication rate. Side effects include mild uterine cramping and a copious watery vaginal discharge for several weeks. Carbondioxide Laser Cryotherapy In cryotherapy, an outdoor procedure not requiring anesthesia, nitrous oxide or carbon dioxide is used as the refrigerant for a supercooled probe. Using either carbon dioxide or nitrous oxide under pressure as the coolant, the cervical epithelium is frozen to a depth of 6 to 10 mm. The laser destroys tissue with a very narrow zone of injury around the treated tissue, and is therefore both precise and flexible. The tissue is vaporized to a depth of at least 7 mm to assure that the bases of the deepest glands are destroyed. The technique is expensive and requires significant training and attention to safety, as well as local or general anesthesia. An insulated speculum to prevent conduction of electricity, a grounding pad, and a vacuum to remove the smoke are necessary. Complications are less frequent than with cold knife conization and include bleeding, infection, and cervical stenosis. Cold Knife Conization Cold knife conization of the cervix means the excision of a cone-shaped portion of the cervix using a scalpel. This technique can be individualized to accommodate the cervical anatomy and the size and shape of the lesion. For example, a wide, shallow cone specimen can be obtained from a young patient whose squamocolumnar junction is on the ectocervix. In an older patient, in whom the squamocolumnar junction tends to move more cephalad into the endocervical canal, a narrower, deeper cone is preferable. Endocervical curettage is performed after the conization to assess the remaining endocervical canal. Cervical cone biopsy is generally done in the operating room under local or general anesthesia. Complications include bleeding, infection, cervical stenosis, and cervical incompetence. The need to perform the procedure in the operating room and a higher complication rate are distinct disadvantages of cold knife conization. This becomes particularly important with suspected microinvasive carcinoma and adenocarcinoma in situ. Koilocytic atypia: Koilocytosis or koilocytic atypia are terms used in histology and cytology to describe the presence of koilocytes in a specimen. A Koilocyte is a squamous epithelial cell that has undergone a number of structural changes, which occur as a result of infection of the cell by human papilloma virus. Koilocytes may have the following cellular changes (i) Nuclear enlargement (two to three times normal size), (ii) Irregularity of the nuclear membrane contour, (iii) A darker than normal staining pattern in the nucleus, known as hyperchromasia and (iv) A clear area around the nucleus, known as a perinuclear halo. Carcinoma in situ: A histopathologic diagnosis involving severe epithelial atypia. In the cervix, the full thickness of the cervical epithelium is atypical, but the basement membrane remains intact. Keywords Squamocolumner junctiom: the junction between the squamous and columnar epithelium on the cervix. Although it is found in the area of the external cervical os in most women during the reproductive years, it is a dynamic, ever-changing location. Transformation zone: A colposcopic term for the area of cellular change that is observed adjacent to the squamocolumnar junction. Cervical dysplasia: Dysplasia is a pathologic term to indicate noninvasive epithelial atypia that involves various degrees of the cervical epithelium. By convention, in mild dysplasia, the nuclear atypia, mitoses, and cellular irregularity involved the lower one third of the squamous epithelium. When the atypia involves the middle third, the diagnosis is moderate dysplasia; in severe dysplasia, the upper one third of the epithelial layer is involved. The Bethesda system: Another classification system that was introduced in 1991 for grading cytologic abnormalities. What is the significance of transformation zone in development of cervical neoplasia Name the different types of epithelial cell abnormalities detected during pap screening and what are their significance What are the different techniques of treatment of squamous intraepithelial lesions Cervical intraepithelial neoplasia, current obstetrics and gynecology Mc Grew Hill 2006. Preinvasive lesion of the lower genital tract Williams Gynecology McGrew Hill 2008 9. Programmatic Guidelines for Screening for Cancer of the cervix in Canada Society of Gynecologic Oncologists of Canada. Colposcopy plays an important role in management of abnormal cervical cytology report. Epidemiology Cervical cancer is the second most common malignancy in women worldwide with an estimated 300,000 deaths annually. India has a high incidence of cervical carcinoma, representing the most frequent malignant neoplasm and cancer-related cause of death among women. In the year 2004, national estimate was 1,12,609 new cases cancer cervix, corresponding to an incidence of 26. The highest worldwide mortality rates from cervical cancer are reported in Romania (13. Incidence of cervical cancer correlates with early onset of sexual activity, multiple sexual partners, cigarette smoking, low socioeconomic status, poor nutrition, oral contraceptive use, and immunosuppression (Table 23. Effective screening with the Pap smear in developed countries has reduced the 221 222 Essentials in Gynecology Table 23. Clinical pearl: the main risk factor for cervical cancer is Human papilloma virus infection which is a sexually transmitted infection Pathophysiology incidence and mortality by 75% in the last 50 years. Fact sheet: Cervical cancer disproportionately affects developing countries which have no screening system. In India, over 80% of the cervical cancer present at the fairly advanced stage and around 80,000 deaths are reported annually due to cervical cancer. The research shows an annual rate of progression of high-grade squamous intraepithelial lesion to invasive cancer of 1. About 80 to 85% of all cervical cancers are squamous cell carcinoma; most of the rest are adenocarcinomas. Other high-risk types include 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. In western population, peak infection incidence is in the late teens and early 20s, but in 80% of patients, the infection resolves within 12 to 18 months with a median duration of infection of roughly 8 months. Sites of spread by direct extension include cervical stroma, body of uterus, vagina and parametrium. Then it goes into internal eliac, obturator and external eliac group of lymph nodes. The recommend age for vaccination is 11 to 12 years for girls, but data support immunising as young as 9 years old or up to age 45. The immunogenicity data suggest a high level of persistent antibody titres 5 years after immunization. The vaccine is very safe, with typical adverse effects including pain, itching, irritation, erythema, and low-grade fever. Primary prevention in the low socioeconomic groups would be particularly useful given their increased risk, but advocacy for this often underserved population with poor access to health care has been challenging. Early Symptoms Abnormal vaginal bleeding may take the form of post-coital bleeding, inter menstrual bleeding or postmenopausal bleeding. Serosanguinous discharge or yellowish vaginal discharge, at times foul smelling, may occur. Late Symptoms Pelvic pain-Sciatic or back pain can be related to sidewall extension, hydronephrosis or metastasis. Bladder or rectal invasion by advanced stage disease may produce urinary or rectal symptoms (hematuria, urinary frequency, vaginal passage of urine or stool). Lower extremity swelling from occlusion of pelvic lymphtaics, or thrombosis of external eliac vein. On general and systemic examination, advanced cervical cancer may present with 224 Essentials in Gynecology anemia, plural effusion, ascites and or lower extremity edema. Unilateral lower extremity edema may indicate spread of the disease to pelvic side walls. Groin and supraclavicular lymph nodes may be indurated or enlarged, indicating spread of disease. More advanced tumors have several types of gross appearance: exophytic, endophytic, or infiltrative. Exophytic, lesion generally appears as a friable, bleeding, cauliflower like lesion in the portio vaginalis that characteristically bleeds on touch. In some cases tumor may arise from the endocervix and ecto cervix may appear normal. In these cases, bimanual examination may reveal a firm indurated barrel shaped cervix. Infiltrative lesion produces enlargement, irregularity, and a firm consistency of the cervix and eventually of the adjacent parametria. Rectal examination provides information regarding nodularity of uterosacral ligaments and helps to determine extension of disease into the parametrium. Differential Diagnosis the conditions that may mimic cervical carcinoma may include: Cervicitis: the cervix may be hypertrophied and bulbous in shape. In symptomatic disease all patients require colposcopy and biopsy in the initial work-up. Further tests to stage the disease and check for complications are then carried out if indicated. Colposcopy may show abnormal vascularity, white change with acetic acid, or visible exophytic lesions. These cases cannot be clinically staged, but should be treated according to the characteristics reported by the pathologist 226 Essentials in Gynecology depth and with horizontal spread of 7. Treatment plans are based on clinical acumen, local expertise and practice, and individualised discussion between the patient and physician. In specific circumstances, it may be appropriate to adjust treatment plans if there is a desire to preserve childbearing potential. In more advanced cases, radiation combined with chemotherapy is the current standard of care.

Notochord Morphology Is Perturbed in adamts5 Morphant Embryos Shh signaling from the notochord has been previously demonstrated to be important for adaxial and paraxial mesoderm formation and myod expression during myogenesis [24] muscle relaxant side effects generic rumalaya forte 30 pills with mastercard, while no tail (ntl) is an independent marker for axial mesoderm (notochord) [25] spasms pronunciation purchase rumalaya forte online from canada. Expression of shh and ntl remained unchanged in 12 hpf adamts5 morphants compared to controls [23] spasms during period purchase 30pills rumalaya forte overnight delivery. Skeletal Muscle Formation Is Disrupted in adamts5 Morphant Embryos Notochord perturbation is linked with defective somitic muscle formation and morphogenesis [24] spasms meaning in urdu buy rumalaya forte 30pills amex. Therefore spasms eye order cheap rumalaya forte, the disrupted notochord morphology in the adamts5 morphants suggested that skeletal muscle development might be affected spasms pancreas generic 30pills rumalaya forte. This is also consistent with previous observations indicating a skeletal muscle developmental defect in Adamts5 knockout mice [19]. In addition, myofibril striation within myofibers of adamts5 morphants was 252 Int. Notochord morphogenesis and muscle fiber formation is perturbed in adamts5 morphant embryos. Muscle fibers of control injected larvae feature the typical striation of the myofibril and regular myofibers within chevron-shape somites, indicated by a dashed line (a). Myofibril striation is partially lost within adamts5 morphants (arrowhead in b) and the sarcolemma of the myofibers disrupted (arrow in b). Therefore, cyclopamine, an antagonist of Smoothened (Smo), a receptor in the Shh signaling pathway [28] was used to understand whether Shh signaling through Smo was impaired in adamts5 morphants. Combinatorial inhibition of Shh signaling and adamts5 disrupt paraxial and adaxial myod expression. Scale bar = 200 m; (B) Quantitation of embryos showing present or absent myod patterning represented in (A). Combinatorial activation of Shh signaling and inhibition of adamts5 rescues paraxial myod expression. Scale bar = 100 m; (B) Quantitation of embryos showing present or absent myod patterning represented in (A). Signaling from the notochord specifies slow-twitch muscle precursors in the adaxial mesoderm [24], which migrate laterally after somite formation to the most lateral muscle layer [32]. Myotomes develop following elongation and fusion of somitic cells and their attachment to the somite boundary, with the boundaries between myotome forming the critical myotendenous junctions that are the primary sites of force generation [33]. Shh is an important regulator of musculoskeletal development, given its role in somite and neural tube patterning. Duplication, and presumed overexpression, of Shh is associated with congenital muscular hypertrophy in humans [37]. Shh also enables the formation of the cranial musculature [38] and polarizes the limb during early morphogenesis [39,40]. Shh has the ability to activate myogenesis in vitro and in vivo [43] with expression and secretion of Shh from the notochord able to induce slow muscle fiber formation in vivo via myod [24]. The adamts5 morphants displayed altered myod expression in the paraxial-but not adaxial-mesoderm despite levels of shh expression in the notochord being unaffected. Since the adaxial myod-positive cells represent the slow muscle precursors that subsequently move through the fast muscle region where they impact on fast muscle differentiation [44], it would be of interest to examine the relative distribution of slow and fast twitch muscle fibers in the adamts5 morphants. This suggests that altered morphogenesis as well as disrupted patterning may contribute to the perturbed notochord in adamts5 morphants. Given that treatment options for these diseases are limited, this knowledge could then be applied to the development of novel therapeutics that specifically modulate this interaction to slow the progression of these debilitating conditions. Experiments were approved by the Deakin University Animal Ethics Committees (G14/2013, 15/05/2013). For other studies, injected embryos were treated with 5 M cyclopamine (Sigma-Aldrich, St. Whole-Mount In Situ Hybridization and Immunofluorescence Whole-mount in situ hybridization was performed as described [56]. Statistics Two-tailed paired t-tests were performed between all treatment groups compared to the respective control groups with scoring performed blind. Additional thanks go to Suneel Apte and Sumeda Nandadasa for their helpful discussions regarding this work. Metalloproteinase-dependent and -independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15. A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as sonic hedgehog co-receptors to promote proliferation. Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and -15 facilitates myoblast fusion. The evolutionary conservation of the A Disintegrin-like and Metalloproteinase domain with Thrombospondin-1 motif metzincins across vertebrate species and their expression in teleost zebrafish. The function of the hyalectan class of proteoglycans and their binding partners during vertebrate development. Induction of muscle pioneers and floor plate is distinguished by the zebrafish no tail mutation. Loss of Tropomodulin4 in the zebrafish mutant trage causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy. Sonic hedgehog is not required for the induction of medial floor plate cells in the zebrafish. Identification of separate slow and fast muscle precursor cells in vivo, prior to somite formation. Hanging on for the ride: Adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease. Distinct spatiotemporal roles of hedgehog signalling during chick and mouse cranial base and axial skeleton development. Manifestation of the limb prepattern: Limb development in the absence of sonic hedgehog function. Patterning of mammalian somites by surface ectoderm and notochord: Evidence for sclerotome induction by a hedgehog homolog. Sonic Hedgehog induces proliferation of committed skeletal muscle cells in the chick limb. Developmental regulation of Wnt/-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. Integrinalpha5 and delta/notch signaling have complementary spatiotemporal requirements during zebrafish somitogenesis. Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations. Essential and overlapping roles for laminin alpha chains in notochord and blood vessel formation. Hedgehog signaling and laminin play unique and synergistic roles in muscle development. Laminin and Matrix metalloproteinase 11 regulate Fibronectin levels in the zebrafish myotendinous junction. Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling. The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain. Biosynthesis and expression of a Disintegrin-like and Metalloproteinase domain with Thrombospondin-1 repeats-15: A novel versican-cleaving proteoglycanase. The synthesis and remodelling of a transitional versican-rich matrix is necessary for myogenesis; whether glucocorticoids modulate this transitional matrix is not known. Processed versican (versikine) was detected in wild type and dystrophic muscles, and immunoreactivity was highly associated with newly regenerated myofibres. Glucocorticoids enhanced C2C12 myoblast fusion by modulating the expression of genes regulating transitional matrix synthesis and processing. The addition of exogenous versican impaired myoblast fusion, whilst glucocorticoids alleviated this inhibition in fusion. Keywords: Duchenne muscular dystrophy; fibrosis; glucocorticoids; myogenesis; mdx mouse; versican 1. In skeletal muscle, the V0 and V1 splice variants of versican are the most abundant [9]. Recent studies have highlighted the role of versican in myoblast proliferation and myotube formation, processes critical for regenerative myogenesis [9,27]. In developing chick skeletal muscle, versican is synthesised early in myogenesis [27] and is localised to the pericellular matrix of developing myotubes [28]. These beneficial effects may be due to membrane stabilisation, decreased muscle necrosis and fibrosis, modulation of inflammation, and/or improved regeneration [12,36]. In dystrophic mdx mice, high dose treatment with the glucocorticoid deflazacort increased the proliferation and/or fusion of muscle precursor cells during myotube formation following crush injury, as well as enhancing the growth of intact myotubes [37]. In vitro, glucocorticoids also enhanced myotube formation in primary wild type and dystrophic mdx myoblasts, as well as in C2C12 cells [39,40]. In cultured rat mesangial cells, glucocorticoids decreased secreted and cell associated chondroitin sulphate and dermatan sulphate proteoglycan content by 50% [42]. In cultured airway fibroblasts stimulated with serum, glucocorticoids decreased versican gene and protein expression by 50% [43]. We identify a novel mechanism mediating the glucocorticoid stimulated increase in myoblast fusion and myotube formation in C2C12 cells. This effect is dependent on versican, as glucocorticoid treatment improved myotube formation in the presence of excess versican. As a whole, these findings offer novel insight into the relevance of versican in dystrophic skeletal muscle pathology. In concordance with the more severe pathology, versican immunoreactivity was greatest in the mdx diaphragm. Gene expression analysis was determined from n = 3 wild type mice and n = 3 mdx mice. Immunoreactivity analysis was determined from n = 5 wild type mice and n = 5 mdx mice. Serial cross-sections were stained with versican or versikine and desmin, phase images were captured to confirm localisation and tissue orientation. Glucocorticoids Enhance Myoblast Fusion and Myotube Formation C2C12 myoblasts were used to investigate glucocorticoid mediated effects on transitional matrix synthesis and remodelling during myogenic differentiation. Similar to skeletal muscle development in vivo, the myogenic differentiation of C2C12 myoblasts is associated with an upregulation of transitional matrix genes, such as V1/V0 Vcan, Adamts1, Adamts5, Adamts15, Pcsk6 [9], Has2 and Hyal2 [8,41]. Essential to myogenic differentiation is the fusion of myoblasts into multinucleated myotubes, a multistep process involving migration, alignment, adhesion and membrane coalescence to form nascent myotubes [50]. Subsequent growth of these nascent myotubes occurs through the incorporation of additional myoblasts via secondary fusion [51,52]. Glucocorticoids Regulate the Expression of Genes Associated with Transitional Matrix Synthesis and Processing during Myogenic Differentiation Glucocorticoids may enhance myogenic differentiation by regulating the expression of genes associated with transitional matrix synthesis and processing. Has2 is the primary Has gene involved in hyaluronan synthesis in skeletal muscle [26]. Low dose dexamethasone treatment for 72 h increased myogenic differentiation efficacy in C2C12 myoblasts. The fusion index and myotube number were calculated from n = 3 biological replicates performed in duplicate. The effect of glucocorticoids on versican gene expression was confirmed by western blotting. Versican and versikine protein expression in differentiating C2C12 myoblasts following dexamethasone treatment. Versican and versikine protein expression analysis was calculated from n = 3 biological replicates performed in quadruplicate. Glucocorticoids Rescue Myotube Formation in Differentiating Myoblasts Treated with Exogenous Versican and Versikine In vitro, versican processing facilitates myoblast fusion and myotube formation, whilst an excess of versican appears to be detrimental [9]. Therefore, it is possible that reduced versican synthesis may contribute to the positive effects of glucocorticoids on regenerative myogenesis in dystrophic muscles. To test this hypothesis, differentiating C2C12 myoblasts were treated with V1 versican, versikine or empty vector conditioned media supplemented with 0 nM or 100 nM dexamethasone. The addition of conditioned media made the experimental conditions more challenging, with greater variability in fusion between biological replicates and a blunted response to dexamethasone. Dexamethasone ameliorated the impairment in myogenic differentiation associated with excess versican. In response to 100 nM dexamethasone, the number of nascent myotubes was similar in cells treated with versican or empty vector conditioned media. Migration rate was measured from n = 5 biological replicates performed in duplicate or triplicate. Myoblast proliferation was assessed from n = 3 biological replicates performed in 8 wells. Alignment of myoblasts is essential for fusion, and this depends on carefully regulated migration [50,57,58]. Versican is known to modulate cell migration and depending on the biological context the effects can be stimulatory [59,60] or inhibitory [61]. Thus, excess versican, both the full-length protein and the cleaved bioactive fragment, may also impair regenerative myogenesis through a reduction in myoblast migration. Myoblast viability and number can be a confounding factor in determining the efficacy of myogenic differentiation.

Osteonectin is a Ca2+ -binding protein whose primary function is to contribute to osteogenesis by conducting biomineralization of the bone and cartilage [19] spasms piriformis generic rumalaya forte 30pills. The oligomerization domain can be also found in all family members but it is more variable compared with other shared structures [22] spasms under xiphoid process order rumalaya forte 30pills with amex. The evolutionary analysis showed that the subgroup B is evolutionary younger than the subgroup A [24] spasms pregnancy after tubal ligation buy genuine rumalaya forte. This domain regulates structure and stability of the coiled-coil region and binds heparin muscle relaxant herbs buy 30 pills rumalaya forte. In pathology muscle relaxer 75 generic 30 pills rumalaya forte with amex, formation of neovessels occurs in vascular proliferative diseases such as atherosclerosis and in tumors spasms and cramps purchase rumalaya forte 30 pills online. However, at late atherogenic stages, the plaques developed proinflammatory content and had the same size as lesions in control mice [31,96]. In the proliferative stage of myocardial repair, the collagen amount quickly rises in the injured region while collagen fibers undergo cross-linking in the maturation stage [118]. Collagen can be also accumulated in the non-infarcted area that can initiate reactive myocardial hypertrophy [116]. Lesional erosion that is induced by intimal injury and does not lead to plaque rupture is a frequent cause of sudden death [134]. Fibrosis is resulted from the up-regulation of collagen synthesis, down-regulation of collagen destruction, or both [139]. In the heart, chronic hypertension stimulates apoptosis of cardiomyocytes [142] and inflammation [143]. Degenerative morphological changes in cardiomyocytes were observed due to the sarcomeric loss and rupture of sarcolemma. Cardiac remodeling was abnormal and accompanied with abundant infiltration of defective fibroblasts. Reduced vascularity because of decreased angiogenesis is supposed to promote progression of heart hypertrophy to heart failure [145]. However, it is unclear whether decrease in myocardial capillary density is the effect of fibrosis or angiogenesis. Pressure overload affected cardiac contractility of a whole cardiac muscle, not in separate cardiomyocytes [49]. Structural changes associated with right or left heart failure are differentiated [148]. Right failure is characterized by intensive collagen degradation and cross-linking disruption and off-center hypertrophy. In left failure, cardiomyocyte hypertrophy is concentric while interstitial collagen content and cross-linking is increased [149]. Heart remodeling is accompanied by substantial cardiomyocyte loss, which is supposed to represent one of the major mechanisms of heart failure progression. Importantly, these expression changes occurred only in cardiomyocytes, not in fibroblasts. Interestingly, there were no significant changes in systolic function and expression of genes responsible for Ca2+ homeostasis, neurohumoral regulation, contractility, and cytoskeleton organization during transition from left ventricular hypertrophy to heart failure [158]. This disorder is characterized by increased pressure in the pulmonary artery, pulmonary vein, and lung vasculature. Pulmonary hypertension is accompanied by narrowing of lung-associated vessels due to thickening of the tunica intima and tunica media as a result of pathogenic vascular remodeling. Thrombospondins may contribute to the pathogenesis of congenital heart defects. Depletion of the Hect domain E3 ubiquitin ligase Nedd4 in mice resulted in detrimental abnormalities in heart development associated with the formation of double-outlet right ventricle and atrioventricular cushion defects that was fatal for developing embryos [187]. Nedd4 is involved in the ubiquitination of a variety of ion channels, membrane transporters, growth factors and their receptors [188] followed by proteosomal degradation. In addition, Nedd4 deficiency may induce the premature control loss of the activity of sodium channels such as cardiac voltage-gated channel Nav 1. Some cardiac congenital aberrations such as for example the Holt-Oram syndrome are accompanied by alterations in electrical conduction [192]. Small peptides derived from this region exhibited only weak inhibitory effects on angiogenesis. However, a single D-amino acid substitution (D-isoleucine) of a particular properdin-region heptapeptide was found to strengthen the anti-angiogenic activity by 1000-fold [199]. However, combinational therapy with cytotoxic agents improved the efficiency of anti-cancer therapy. In the context of cardiovascular therapy, anti-angiogenic approaches tested in tumors may be helpful in graft atherosclerosis. Stem cell therapy has emerged as a promising strategy for healing cardiac injury, directly or indirectly, and seems to offer functional benefits to patients. Cardiac stem cell therapy involves using of hematopoietic, mesenchymal, and cardiac stem cells for regenerative purposes. However, a common challenge is to increase the retention and survival of engrafted cells at the injured site in order to strengthen their chances for proliferation and differentiation to functional cardiomyocytes [222]. To enhance the regenerative and prosurvival capacity, stem cells are subjected to ischemic/pharmacological preconditioning before transplantation. This effect of matricryptin has a therapeutic promise and therefore should be further evaluated. Actually, ligand binding is spatially and temporally regulated, and it would be of great interest to reveal these regulatory patterns and recognize their functional significance. Anisotropic strain transfer through the aortic valve and its relevance to the cellular mechanical environment. Factors involved in extracellular matrix turnover in human derived cardiomyocytes. Integrin-substrate interactions underlying shear-induced inhibition of the inflammatory response of endothelial cells. Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure. Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. Distribution of tenascin-C and -X, and soft X-ray analysis of the mandibular symphysis during mandible formation in the human fetus. Tenascin-R distinct domains modulate migration of neural stem/progenitor cells in vitro. Periostin secreted by epithelial ovarian carcinoma is a ligand for V 3 and alphaV beta5 integrins and promotes cell motility. Periostin shows increased evolutionary plasticity in its alternatively spliced region. Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Hierarchies of extracellular matrix and mineral organization in bone of the craniofacial complex and skeleton. Separation of newly formed bone from older compact bone reveals clear compositional differences in bone matrix. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. Phylogenomic analysis of vertebrate thrombospondins, reveals fish-specific paralogues, ancestral gene relationships and a tetrapod innovation. Matricellular proteins as modulators of wound healing and the foreign body response. Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Gender dependent association of thrombospondin-4 A387P polymorphism with myocardial infarction. Thrombospondin-4 1186G>C (A387P) is a sex-dependent risk factor for myocardial infarction: A large replication study with increased sample size from the same population. Replication of the association between the thrombospondin-4 A387P polymorphism and myocardial infarction. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size. Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites. Association between single nucleotide polymorphisms in thrombospondins genes and coronary artery disease: A meta-analysis. Association of thrombospondin-1 and cardiac allograft vasculopathy in human cardiac allografts. Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion. Lack of thrombospondin-2 reduces fibrosis and increases vascularity around cardiac cell grafts. Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection. Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload. Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy. Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Investigation of thrombospondin-1 and transforming growth factor- expression in the heart of aging mice. Valsartan blocks thrombospondin/transforming growth factor/Smads to inhibit aortic remodeling in diabetic rats. Thrombospondin-2 is essential for myocardial matrix integrity: Increased expression identifies failure-prone cardiac hypertrophy. Structural insight into the role of thrombospondin-1 binding to calreticulin in calreticulin-induced focal adhesion disassembly. Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. Novel tissue-specific mechanism of regulation of angiogenesis and cancer growth in response to hyperglycemia. Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Antibody blockade of thrombospondin accelerates reendothelialization and reduces neointima formation in balloon-injured rat carotid artery. Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice. Counterbalancing forces: What is thrombospondin-1 doing in atherosclerotic lesions Effects of cerivastatin on human arterial smooth muscle cell growth and extracellular matrix expression at varying glucose and low-density lipoprotein levels. Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. Thrombospondin-1 activation of signal-regulatory protein- stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. Left ventricular remodeling after myocardial infarction: Past, present, and future. Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough Thrombospondin and apoptosis: Molecular mechanisms and use for design of complementation treatments. Thrombospondin-2 modulates extracellular matrix remodeling during physiological angiogenesis. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity. Metoprolol treatment lowers thrombospondin-4 expression in rats with myocardial infarction and left ventricular hypertrophy. Dissection of thrombospondin-4 domains involved in intracellular adaptive endoplasmic reticulum stress-responsive signaling. Polymorphisms in thrombospondin genes and myocardial infarction: A case-control study and a meta-analysis of available evidence. Thrombospondin-4 A387P polymorphism is not associated with coronary artery disease and myocardial infarction in the Chinese Han population. Genetic association analysis of myocardial infarction with thrombospondin-1 N700S variant in a Chinese population.

Methods to identify abnormal area of the cervix: A cervical biopsy is usually done after a procedure called as colposcopy muscle relaxant gaba buy rumalaya forte 30pills cheap. A colposcopy allows the gynecologist to do a detailed examination of the tissues in the cervix so as to identify abnormal or diseased tissues spasms before falling asleep order rumalaya forte 30pills otc. Colposcopic examination is neither needed nor particularly effective for a gross cervical lesion spasms headache buy discount rumalaya forte 30 pills, but can be helpful when there is a small surface lesion to identify the most abnormal area for directed biopsies spasms icd-9 order rumalaya forte 30 pills without a prescription. There are two well-known methods that can identify an abnormal area of the cervix muscle relaxant ibuprofen order rumalaya forte now. The first method A cervical biopsy is an operative procedure performed to remove tissue from the cervix for histopathological examinations spasms of the esophagus cheap rumalaya forte 30pills. Applying 3- to 5-percent acetic acid to mucosal epithelium results in the acetowhite change characteristic of neoplastic lesions as well as some non-neoplastic conditions. Lugol iodine solution stains mature squamous epithelial cells mahogany in estrogenized women due to high cellular glycogen content. Due to attenuated cellular differentiation, dysplastic cells have lower glycogen content and fail to fully stain, appearing various shades of yellow. The procedure, however, can be done using general, regional, or local block anesthesia. Steps of Operation After emptying bladder patient is placed on the operation table in the lithotomy position. An aseptic solution is applied to the vulva and vagina and appropriate sterile drapes are placed. Alternately an iodine solution may be used to coat the cervix, called the Schiller test. The type of biopsy performed will be determined by the size, shape, location, and other characteristics of the abnormalities. A vulsellum or Allis tissue forceps may be used to hold the cervix so to steady for the biopsy. For a punch biopsy, one or more small samples of tissue will be removed using a punch biopsy forceps. It is important to obtain a specimen where frank stromal invasion can be demonstrated, not from the exophytic portion where no benign stroma is present. Cells from the inside of the cervical canal may be sampled with an endocervical curette or an endocervical brush. For a cone biopsy, a larger cone-shaped piece of tissue is removed from the cervix. With the cold knife cone biopsy, a laser or a surgical scalpel is used to remove tissue. Bleeding from the biopsy site may be treated with electrocauterization (use of a probe with high frequency electrical signals to stop bleeding) or sutures, or packing the vagina with pressure dressing. Possible complications may include: Infection Bleeding In addition, cone biopsies may increase the risk for infertility and miscarriage because of the changes and scarring in the cervix that may occur as a result of the procedure. Identify the instruments and mention their use 356 Essentials in Gynecology Bibliography 1. Surgery in oncology carries more risks as geriatric patients, who may have multiple medical problems. There are two groups of indications for gynecological surgery: absolute-when surgery must be undertaken, when its cancellation is lifethreatening, and relative-when surgery can be postponed till the most appropriate occasion for its performing. Before making a decision on surgery, one of the three requirements must be fulfilled: relief of pain and suffering, preservation of life, correction of an existing deformity. If none of the three goals can be achieved by surgery, the surgery should be given up. The main objective of the preoperative assessment is to make sure that the patient is fit for the appropriate surgery and that the patient understands the indications, benefits, risks, and alternatives for the planned procedure. Preoperative consultation with an anesthesiologist is important for the medically compromised patient. Preoperative testing: Preoperative testing requires some routine preoperative laboratory tests and additional specialist examinations guided mostly by positive findings on the history and physical examination. For patients older than 40 years, laboratory analyses of the blood involves blood group determination, complete blood count, bleeding and coagulation time. Renal function is checked (urea, creatinin) and liver function as well 357 358 Essentials in Gynecology (bilirubin, serum alanine-aminotransferase, serum aspartate aminotransferase). A pregnancy test is usually done for women of reproductive age to exclude pregnancy. Antibiotics before gynecologic surgery: Prophylactic use of antibiotics have been found to be more successful for vaginal compared to abdominal operations. A recommended regimen for patients undergoing vaginal hysterectomy, abdominal or radical hysterectomy consists of a dose of i. Reduction in the number of pathogenic flora in the colon reduces the risk of infection if bowel surgery is performed. Mechanical bowel preparation with oral gut lavage using an agent such as polyethylene glycol electrolyte solution (Peglec) and a clear liquid diet for 24 hours the day before surgery is commonly used. Antihypertensive and thyroid medications should be taken with a sip of water on the morning of surgery. Below-the-knee elastic stockings and pneumatic compression devices may be used for patients undergoing gynecologic surgery. Information regarding the possibility and risk of a blood transfusion must be part of the informed consent procedure. Prophylaxis for subacute bacterial endocarditis: Women undergoing surgery with cardiac disease are candidates for prophylaxis for subacute bacterial endocarditis. Prophylaxis is recommended only for those in the highand moderate-risk categories. Different portions of the uterus, as well as other organs, may be removed at the same time. Types of Hysterectomy Total hysterectomy: It includes the removal of the entire uterus, including the body and the cervix, but not the tubes or ovaries. Subtotal hysterectomy (supracervical hysterectomy): Removal of the body of the uterus while leaving the cervix intact. Hysterectomy with salpingo-oophorectomy: Includes the removal of one or both ovaries, and the fallopian tubes, along with the uterus. Major Operations in Gynecology 359 Radical hysterectomy includes the removal of the uterus, cervix, the top portion of the vagina and parametrium (most of the tissue that surrounds the cervix in the pelvic cavity), and may include the removal of the pelvic lymph nodes. Uterine leiomyomas Symptomatic adenomyosis Symptomatic endometriosis Pelvic inflammatory disease Chronic pelvic pain Pelvic organ prolapse Pregnancy related conditions. Malignant diseases Cervical intraepithelial neoplasia Invasive cervical cancer Atypical endometrial hyperplasia Endometrial cancer Ovarian cancer Fallopian tube cancer Gestational trophoblastic neoplasia. Routes of Hysterectomy procedure is most often used in cases of uterine prolapse, or when vaginal repairs are necessary for related conditions. In a robot-assisted laparoscopic hysterectomy, the surgeon inserts the laparoscope and other instruments, then uses a computer station to control the instruments. Steps of Abdominal Hysterectomy There are different surgical techniques used to perform a hysterectomy. The uterus can be removed via the abdominal route, transvaginally, or laparoscopically. The uterus is removed through the abdomen via a surgical incision about six to eight inches long. The incision can be made either vertically, from the umbilicus to the pubic bone, or transversely, along the top of the pubic hairline. The vagina and perineum are cleaned with antiseptic solutions and a Foley catheter is inserted. The abdomen then is dressed with antiseptic solution from the anterior thighs to the xiphoid, and sterile drapes are applied. After confirming the pathology, the patient is put in a slight Trendelenburg position, a self-retaining retractor is placed, and the bowel packed superiorly to afford good exposure of the pelvis. Straight clamps are placed alongside the uterus near cornu (include the round ligament, fallopian tube and utero-ovarian ligaments. Round ligament transection: the right round ligament is visualised and clamped and divided and tied. Ovarian conservation: the fallopian tube and utero-ovarian ligament are doubly clamped and divided and doubly ligated. The infundibulopelvic ligament is doubly clamped, and the ovarian vessels are cut between the clamps. The proximal pedicle is ligated with a free tie followed by a transfixion suture ligature. Bladder flap: the peritoneal incisions from one round ligament to other are connected from the broad ligament over the bladder at the point of the vesicouterine reflection. The loose connective tissue is pushed down from the bladder to expose the endopelvic fascia over the anterior portion of the cervix. Uterine arteries: Next, the uterine arteries are identified along the lateral aspects of the uterus at the level of the isthmus. Cardinal ligament transection: these ligaments lie lateral to the uterus and are inferior to the uterine vessels. A straight clamp is used to clamp the cardinal ligament A scalpel is used to transect the portion of the cardinal ligament held between the clamp. Uterosacral ligament transection: At this point, attention is directed to the posterior aspect of the uterus and to the uterosacral ligaments. The ligament is divided medial to the clamp, a transfixing suture is placed, and the clamp is removed. Vaginal entry: the vagina is incised and curved clamps are used to grasp the anterior and posterior vaginal walls at the point just below the cervix. Vaginal vault closure: the vaginal vault is sutured, either using figure of eight sutures or as a continuous running suture with careful attention to each angle. The pelvic peritoneum should be included in the suturing of the vagina to aid hemostasis. The pelvis is inspected for hemostasis: Reperitonealisation is not necessary, but may aid hemostasis. Steps of Vaginal Hysterectomy the patient is put under general or regional anesthesia. Injection of vasocontrictors decreases bleeding during dissection and aids in defining tissue planes. To avoid dissection into the cervix, this incision is kept at a depth superficial to the pubocervical fascia. Anterior peritoneal entry: the bladder is dissected off the anterior aspect of the uterus and displaced anteriorly. The Major Operations in Gynecology 361 vesicouterine fold is grasped and elevated to place this peritoneal layer on tension. Posterior entry: the posterior lip of cervix is lifted anteriorly to expose the posterior vaginal vault, and an Allis forceps is placed on the incised edge of the posterior vaginal wall. The Allis tissue forceps is pulled downward to create tension across the exposed posterior peritoneum. The posterior vaginal vault is cut with curved Mayo scissors, and the Douglas cul-de-sac is entered. Curved Kocher clamps are inserted into the pouch of Douglas to take the uterosacral pedicles first vertically angled and then horizontally. The uterosacral ligament is then transected, and ligated with 0-gauge delayed-absorbable suture using a transfixing stitch. After ligation of the uterosacral ligaments, the cardinal ligaments similarly are clamped, cut, and sutured. Clamps are, then, placed across the uteroovarian and round ligaments and fallopian tubes. The peritoneum is then closed in a purse string to include the uterine vessels and uterosacral pedicles and pouch of Douglas peritoneum. Postoperative management of hysterectomy patient: the details of postoperative care are dictated by the indications for hysterectomy, route of hysterectomy, i. Following vaginal hysterectomy, there is faster return of normal bowel function, easier ambulation, and decreased analgesia requirements in comparison to abdominal hysterectomy. The choice will vary from surgeon to surgeon but usually includes pethidine hydrochloride or meperidine sulfate. Once the patient can tolerate a regular diet, she can be switched to oral analgesics. The diet is advanced based on return of bowel sounds and appetite, toleration of the diet, and the passage of flatus. Complications of Hysterectomy Hysterectomy is one of the safe surgical procedures. But as with any surgery complication may occur: Peroperative complications: Injury to the bowel, bladder, ureter or major vessels. Excessive bleeding, complications due to anesthesia Early postoperative complications: Postoperative hemorrhage usually from the angle of vault of vagina, wound infection and febrile morbidity, pelvic hematoma and abscess formation, deep vein thrombosis, wound complications. Indications Myomectomy is indicated for women with symptomatic leiomyoma who are willing for fertility or willing to retain uterus. Following are the situations where myomectomy is indicated: Infertility with distortion of endometrial cavity or tubal occlusion Recurrent pregnancy loss with distortion of endometrial cavity Abnormal uterine bleeding not responding to medical treatment Pain and pressure symptoms that interfere with quality of life Urinary symptoms (frequency and/or symptoms of obstruction) Iron deficiency anemia secondary to menstrual blood loss. Contraindications approach, laparoscopic myomectomy is associated with less blood loss, shorter hospital stay and lower overall complication rate. However laparoscopic myomectomy is more time consuming, larger myoma are more difficult to remove, and may be associated with uterine rupture during pregnancy if inadequately repaired. Myomectomy by hysteroscopy: this is the first line procedure when intracavitory leiomyoma is present and fertility is desired.

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