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OBJECTIVES: The role of lymphadenectomy in the management of early endometrial cancer remains controversial. The aim of our study was to evaluate risk factors associated with nodal metastases in endometrial cancer and to devise a predictive risk model based on the significant risk factors in predicting node metastasis. MATERIALS AND METHODS: A retrospective study was conducted on women diagnosed with uterus-confined endometrial cancer, and who underwent surgical staging with pelvic and/or paraaortic lymphadenectomy from our center during July 1, 2017 to June 30, 2019. Clinical details, Magnetic Resonance imaging (MRI)-detected myometrial invasion, and pre and post-operative histological details of tumor were correlated with pelvic and/or para-aortic lymph node metastasis. Risk factors were assessed using logistic regression model and risk models devised. RESULTS: 128 patients were included in the study. Paraaortic lymphadenectomy was done in 72.7% patients. Nodal metastasis was seen in 14.8% of patients. Logistic regression analyses revealed lymphovascular invasion (P = 0.002), parametrial involvement (P = 0.017) and nonendometrioid histology (P = 0.004) to be significant risk factors. Tumor size >2 cm, grade 3 and deep myometrial invasion had higher risk for nodal metastasis, although non-significant. Risk models were derived with sensitivity of 79-89.5%, specificity of 58.7-69.7%, Negative predictive value (NPV) of 95-97% and accuracy of 63-71%. CONCLUSION: Lymphovascular invasion, nonendometrioid histology and parametrial involvement are independent predictors of lymph node metastasis in endometrial cancer. Risk models using these risk factors can better predict the risk of nodal metastasis and thus avoid lymph node dissection in low risk patients. Our risk models had reasonably good sensitivity in nodal metastasis prediction and require further validation.

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MPNSTs (malignant peripheral nerve sheath tumours) arise rarely from the female genital tract, even more rarely from the uterus. A literature review showed 18 cases affecting the uterine cervix, but only four affecting the uterus per se, making our present case the fifth to be involving the uterus, specifically round ligament. It was the first time a uterine lesion (not uterine cervix) was defined in a neurofibromatosis patient. This was a young patient who initially underwent a uterus-sparing surgery for a round ligament tumour which was finally diagnosed to be MPNST. She received adjuvant chemotherapy but recurred with pelvic vascular involvement. A challenging surgery was performed, and the tumour was resected without morbidity. She was followed up with radiotherapy; however, she quickly developed extensive peritoneal disease and succumbed to the disease. High-grade nature of MPNST along with the background of NF could have made the tumour more aggressive, highlighting the importance of suspecting MPNST in spindle cell tumours of pelvis and performing total resection in the first setting.

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Inflammatory mediators have been implicated as a cause of reversible myocardial depression in septic shock. We previously reported that the release of lysozyme-c (Lmz-S) from leukocytes from the spleen or other organs contributes to myocardial dysfunction in Escherichia coli septic shock in dogs by binding to a cardiac membrane glycoprotein. However, the mechanism by which Lzm-S causes this depression has not been elucidated. In the present study, we tested the hypothesis that the binding of Lzm-S to a membrane glycoprotein causes myocardial depression by the formation of nitric oxide (NO). NO generation then activates soluble guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP), which in turn triggers contractile impairment via activation of cGMP-dependent protein kinase (PKG). We examined these possibilities in a right ventricular trabecular preparation in which isometric contraction was used to measure cardiac contractility. We found that Lzm-S's depressant effect could be prevented by the non-specific NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA). A guanylyl cyclase inhibitor (ODQ) and a PKG inhibitor (Rp-8-Br-cGMP) also attenuated Lzm-S's depressant effect as did chemical denudation of the endocardial endothelium (EE) with Triton X-100 (0.5%). In EE tissue, we further showed that Lzm-S caused NO release with use of 4,5 diaminofluorescein, a fluorescent dye that binds to NO. The present study shows that the binding of Lzm-S to EE generates NO, and that NO then activates the myocardial guanosine 3',5' monophosphate pathway leading to cardiac depression in sepsis.

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PURPOSE: In sepsis, reversible myocardial depression has been ascribed to the release of mediators of inflammation. We previously found that lysozyme released from leukocytes from the spleen and other organs mediated myocardial depression in an Escherichia coli model of septic shock in dogs. We hypothesize that lysozyme binds to or cleaves a cardiac surface membrane N-glycoprotein to cause depression. The objectives of the present study were: 1) to determine whether the binding of lysozyme is reversible; 2) to assess the N-glycan structure to which lysozyme binds; 3) to examine whether nonenzymatic proteins, termed lectins, with a binding specificity similar to that of lysozyme could also cause depression; and 4) to assess whether the membrane to which lysozyme binds is affected by the enzymes protease type XIV and collagenase A, that are used to prepare single cell myocyte experiments. METHODS: We measured isometric contraction in a right ventricular trabecular preparation. RESULTS: We found that lysozyme binds in a reversible manner to the Man beta(1-4) GlcNAc beta(1-4)GlcNAc moiety in the tri-mannosyl core structure of high mannose/hybrid and tri-antennary carbohydrate classes where GlcNAc is N-acetylglucosamine and Man is mannose. Lectins with a specificity similar to that of lysozyme also caused depression, and lysozyme's depressant activity was eliminated by protease type XIV and collagenase A. CONCLUSIONS: These results indicate that lysozyme reversibly binds to a membrane glycoprotein to cause myocardial depression in sepsis. We further localize its binding site to a variant of the chitotriose structure in the tri-mannosyl core of the membrane glycoprotein.

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OBJECTIVE: Reversible myocardial depression in sepsis has been ascribed to the release of inflammatory mediators. We recently found that lysozyme c (Lzm-S), consistent with that originating from the spleen, was a mediator of myocardial depression in an Escherichia coli model of septic shock in dogs. We further showed in a right ventricular trabecular (RVT) preparation that Lzm-S's depressant activity could be blocked by N,N',N" triacetylglucosamine (TAC), a competitive inhibitor of Lzm-S. We hypothesized that Lzm-S binds to or cleaves a cardiac membrane glycoprotein, thereby interfering with myocardial contraction in sepsis. In the present study, we examined whether TAC could prevent myocardial depression in an in vivo preparation and whether other related N-acetylglucosamine (NAG) structures could also inhibit Lzm-S's effect in RVT. DESIGN: Randomized experimental study. SETTING: University laboratory. SUBJECTS: Anesthetized, mechanically ventilated dogs. INTERVENTIONS: We produced sepsis by infusion of E. coli over an approximately 6-hr period. MEASUREMENTS AND MAIN RESULTS: We examined the effect of TAC on stroke work, our primary index of myocardial function, when treatment was administered before sepsis (pretreatment) and after 1.5 hrs (early treatment study) and 3.5 hrs of sepsis (late treatment study; LTS). In the pretreatment study and early treatment study, myocardial depression would have not yet occurred but would have already been present in the late treatment study. In RVT, we assessed the effect of other NAG oligosaccharides and variants to the NAG structure on Lzm-S's depressant activity. In pretreatment and the early treatment study, TAC prevented the reduction in stroke work observed in nontreated septic groups but did not reverse the reduction found in the late treatment study. In RVT, of the compounds tested, only N,N'-diacetylglucosamine showed an inhibitory effect. CONCLUSIONS: We found that TAC, a competitive inhibitor of Lzm-S, prevented myocardial depression in experimental sepsis. Only specific NAG structures are inhibitory to Lzm-S's depressant activity. TAC may be useful in attenuating cardiovascular collapse in sepsis.

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The objective of the present study was to identify the nature of a filterable cardiodepressant substance (FCS) that contributes to myocardial dysfunction in a canine model of Escherichia coli septic shock. In a previous study, it was found that FCS increased in plasma after 4 h of bacteremia (Am J Physiol 1993;264:H1402) in which FCS was identified by a bioassay that included a right ventricular trabecular (RVT) preparation. In that study, FCS was only partially identified by pore filtration techniques and was found to be a protein of molecular weight between 10 and 30 K. In the present study, FCS was further purified by size exclusion high-pressure liquid chromatography, until a single band was identified on one-dimensional gel electrophoresis. This band was then subjected to tandem mass spectrometry and protein-sequencing techniques and both techniques identified FCS as lysozyme c (Lzm-S), consistent with that originating from the canine spleen. Confirmatory tests showed that purified Lzm-S produced myocardial depression in the RVT preparation at concentrations achieved during sepsis in the in vivo preparation. In addition, Lzm-S inhibited the adrenergic response induced by field stimulation and the beta- agonist isoproterenol in in vitro preparations, these results suggesting that Lzm-S may inhibit the sympathetic response in sepsis. The present findings indicate that Lzm-S originating from disintegrating leukocytes from organs such as the spleen contributes to myocardial dysfunction in this model. The mechanism may relate to its binding or hydrolysis of a cardiac membrane glycoprotein thereby interfering with myocardial excitation-contraction coupling in sepsis.

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OBJECTIVE: Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level. METHODS: In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect. RESULTS: We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma. CONCLUSION: We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

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OBJECTIVE: Lactic acidosis is an important complication of septic shock. Alkali treatment such as sodium bicarbonate is often used to treat the low pH level that develops in sepsis. The effect of this treatment on lactate (Lac) clearance is not clear. In the present study, the objective was to examine whether blood pH level alters Lac metabolism in sepsis. Measurements were determined in a canine model of Escherichia coli sepsis after bolus infusion (5 mmol/kg) of either lactic acid (LA) or sodium lactate (NaL). In one preparation, Lac uptake by the splanchnic organs (SP), liver, lung, kidneys (Kid), and soft tissues of the lower extremity (SOL) was primarily determined, whereas in another preparation, Lac uptake by the head and neck region and lung was obtained. METHODS: The dogs were studied while anesthetized and ventilated. After 4 hours of sepsis, either LA or NaL was given through a catheter positioned in the abdominal aorta in respective sepsis (SepLA, SepNaL) and nonsepsis groups (ConLA, ConNaL) (n approximately equal to 6 in each preparation). Catheters and flow probes were used to measure organ Lac uptake. Measurements were obtained at end infusion and at 15-minute intervals after infusion until 75 minutes after infusion. RESULTS: Arterial clearance of Lac in the sepsis groups was slower as compared with the nonsepsis groups. In the liver, sepsis inhibited the uptake of LA as compared with the nonseptic group. In SP, both sepsis and pH affected Lac uptake in which an increase in uptake was found only after NaL infusion in the nonseptic group. In the head and neck region, Lac uptake was pH-level dependent and was found after LA infusion in the sepsis and nonsepsis groups. In the lung, Lac was produced after either LA or NaL infusion in all groups. Neither Kid nor SOL contributed to Lac uptake in any of the groups. CONCLUSION: Lactate clearance was reduced in sepsis. Both effects of pH level and sepsis modulated the organ uptake of Lac in septic shock. Only a small amount of the total Lac infused could be accounted for by the organs measured in the present study. This suggests that additional organs may account for lactate removal in sepsis.

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OBJECTIVE: In the heart, histamine H3 receptors may function as inhibitory presynaptic receptors that decrease adrenergic neural norepinephrine release in conditions of enhanced sympathetic tone. In a previous study, we found that H3 receptor blockade improved cardiac contractility and systemic hemodynamics in experimental bacteremia in dogs. Because histamine H3 receptors have been found in the splanchnic circulation in other animal models, it was not clear the extent to which H3 receptor blockade may have altered splanchnic hemodynamics, and variables of venous return, that in turn contributed to the overall improvement in systemic hemodynamics observed in the previous experiment. In the present study, we examined splanchnic hemodynamics in the presence of H3 receptor blockade in a canine model of Escherichia coli bacteremia. DESIGN: Bacteremia was produced by intravenous infusion of live E. coli administered throughout the experiment. Variables of venous return included mean systemic pressure, resistance to venous return, and mean right atrial pressure. Splanchnic measurements included hepatic and portal pressures and flows. Measurements were obtained before and after H3 receptor blockade with thioperamide maleate. The animals were studied while ventilated and anesthetized. RESULTS: H3 receptor blockade caused a decrease in mean right atrial pressure from 5.9 mm Hg pretreatment to 3.5 mm Hg posttreatment (p < .05), although it did not affect mean systemic pressure or resistance to venous return. There were no changes in portal or hepatic flows after H3 receptor blockade. The cardiac function curve after H3 receptor blockade was shifted upward and to the left compared with the pretreatment curve. CONCLUSIONS: The results showed that the primary effect of H3 receptor blockade in experimental bacteremia was attributable to an increase in inotropy. There was no evidence to indicate that H3 receptor activation contributed to altered splanchnic hemodynamics in this model.

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