Subcutaneous and Fascial Abdominal Wall Endometriosis in the Setting of Previous Gynecologic Surgeries: Two Case Reportst.

Abdominal wall endometriosis is a rarely reported condition with increasing incidence linked to pelvic surgery, and is also referred to as incisional endometriosis. Here we report two cases of women with previous history of Cesarean section who presented with abdominal wall masses years after surgery. In both cases, CT imaging was used to visualize the masses and surgical exploration and tissue examination revealed the excised masses to be endometriosis of the abdominal wall. Etiology of this ectopic endometrial tissue may be iatrogenic and caused by implantation of endometrial tissue during operative proceedings. This paper aims to highlight the incidence of abdominal wall endometriosis and to discuss differential diagnoses and management.

Influence of acetaminophen consumption and exercise on Achilles tendon structural properties in male Wistar rats.

Chronic consumption of acetaminophen (APAP) during exercise training leads to a reduction in tendon stiffness and modulus compared with a placebo. We explored whether this effect could be due to a reduction in tendon collagen content or cross-linking. Ten-week-old male Wistar rats (n = 50) were divided into placebo or APAP groups and into sedentary or treadmill-exercised groups. APAP (200 mg/kg) or saline was administered once daily by oral gavage. Rats in the exercise groups ran on a treadmill 5 days per week for 8 wk with progression to 60 min per day, 20 m/min, and 8° incline. After 8 wk, lyophilized Achilles tendon samples were assayed for the collagen-specific amino acid hydroxyproline and cross-linking [hydroxylyslpyridinoline (HP)] content by high-performance liquid chromatrography. Collagen content was not influenced by exercise or APAP (P > 0.05). Compared with placebo, tendon water content was 7% (P = 0.006, main effect) lower in animals consuming APAP (placebo: 54.79 ± 0.8%, APAP: 50.89 ± 1.2%). HP in the Achilles tendon was 36% greater (sedentary: 141 ± 15, exercise: 204 ± 26 mmol/mol collagen) in the exercise-trained rats independent of drug treatment (P = 0.020, main effect). Independent of exercise, HP content was 33% lower (P = 0.032, main effect) in the animals consuming APAP (placebo: 195 ± 21, APAP: 140 ± 19 mmol/mol collagen). Our data suggests that chronic consumption of APAP results in a reduction in collagen cross-linking and a loss of tissue water independent of chronic exercise. This reduction in cross-linking and water content could contribute to the decrease in tendon stiffness noted in humans chronically consuming APAP.

Stimulation of murine intestinal secretion by daily genistein injections: gender-dependent differences.

BACKGROUND/AIMS: The effect of daily injections with genistein (naturally occurring phytoestrogen) on intestinal chloride (Cl(-)) secretion was measured with Ussing chamber short circuit current (I(sc), µA/cm(2)), in C57BL/6J male and female mice, using 600 mg/kg genistein/day (600G), 300 mg/kg genistein/day (300G), 150 mg/kg genistein/day (150G) or genistein-free vehicle control (0G) for 1- or 2-weeks. METHODS AND RESULTS: Injecting with 600G elicited significant increases in basal I(sc) in females after 1-week (ñ70 µA/cm(2), n=15, p < 0.05) and in males after 2-weeks (ñ80 µA/cm(2), n=5, p < 0.05) compared to their 0G counterparts. Chloride-free ringer significantly reduced basal I(sc) by 65% in 600G males and 72% in 600G females, suggesting that Cl(-) was the major anion comprising the genistein-stimulated secretion. The forskolin-stimulated (10 µM) I(sc) was significantly inhibited by the CFTR chloride channel inhibitors, glibenclamide (500 µM) and CFTR(inh)-172 (100 µM) in 600G males and females, suggesting some contribution by genistein-dependent CFTR-mediated Cl(-) secretion. We found no associated changes in intestinal morphology, nor change in total CFTR protein with 600G. There was a 5% increase in apical/subapical ratio in 600G males compared to controls (no change in females). CONCLUSION: These data suggest that male and female mice both exhibit increased Cl- secretion with 600G, however, the mechanisms mediating this are gender-dependent.

Exemestane potency is unchanged by common nonsynonymous polymorphisms in CYP19A1: results of a novel anti-aromatase activity assay examining exemestane and its derivatives.

Exemestane (EXE) treats estrogen receptor positive (ER+) breast cancer in postmenopausal women by inhibiting the estrogen-synthesizing cytochrome P450 CYP19A1. Variability in the severity and incidence of side effects as well as overall drug efficacy may be partially explained by genetic factors, including nonsynonymous variation in CYP19A1, also known as aromatase. The present study identified phase I EXE metabolites in human liver microsomes (HLM) and investigated mechanisms that may alter the extent of systemic estrogen deprivation in EXE-treated women with breast cancer, including whether functional polymorphisms in aromatase cause differential inhibition by EXE and whether EXE metabolites possess anti-aromatase activity. The potency of EXE and ten of its derivatives was measured with HEK293-overexpressed wild type aromatase (CYP19A1*1) using a rapid novel UPLC tandem mass spectrometry method. Of the ten compounds assayed, five were poor inhibitors (IC 50 Ëƒ 50 µmol/L) of wild type aromatase while five others, including the major metabolite, 17ß-dihydroexemestane (17ß-DHE), exhibited moderate potency, with IC 50 values ranging between 1.2 and 7.1 µmol/L. The anti-aromatase activity of EXE was also tested with two common allozymes, aromataseThr201Met (CYP19A1*3) and aromataseArg264Cys (CYP19A1*4). Differential inhibition of variant aromatase is unlikely to account for variable clinical outcomes as EXE-mediated inhibition of aromataseThr201Met (IC 50 = 0.86 ± 0.12 µmol/L) and aromataseArg264Cys (IC 50 = 1.7 ± 0.65 µmol/L) did not significantly differ from wild type (IC 50 = 0.92 ± 0.17 µmol/L). Although less potent than the parent drug, these results suggest that active metabolites may contribute to the therapeutic mechanism of EXE.

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17ß-dihydroexemestane.

Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17ß-dihydroexemestane (17ß-DHE), an active major metabolite, as well as two inactive metabolites. 17ß-DHE formation in pooled human liver microsomes subjected to isoform-specific CYP450 inhibition was also monitored using tandem mass spectrometry. 17ß-DHE production in human liver microsomes was unaffected by isoform-specific inhibition of CYP450s 2A6, 2B6, and 2E1 but decreased 12-39% following inhibition of drug-metabolizing enzymes from CYP450 subfamilies 1A, 2C, 2D, and 3A. These results suggest that redundancy exists in the EXE metabolic pathway with multiple hepatic CYP450s catalyzing 17ß-DHE formation in vitro. To further expand the knowledge of phase I EXE metabolism, the impact of CYP450 genetic variation on 17ß-DHE formation was assessed via enzyme kinetic parameters. Affinity for EXE substrate and enzyme catalytic velocity were calculated for hepatic wild-type CYP450s and their common nonsynonymous variants by monitoring the reduction of EXE to 17ß-DHE. Several functional polymorphisms in xenobiotic-metabolizing CYP450s 1A2, 2C8, 2C9, and 2D6 resulted in deviant enzymatic activity relative to wild-type enzyme. Thus, it is possible that functional polymorphisms in EXE-metabolizing CYP450s contribute to inter-individual variability in patient outcomes by mediating overall exposure to the drug and its active metabolite, 17ß-DHE.

Dietary genistein induces sex-dependent effects on murine body weight, serum profiles, and vascular function of thoracic aortae.

BACKGROUND: The influence on, or interaction of, sex and dietary genistein on serum markers of cardiovascular health and cardiovascular function remain unclear. OBJECTIVES: Our purpose was to examine the effects of a genistein-containing diet (600 mg/kg food) (600G) and a genistein-free diet (0G), on cardiovascular risk parameters of male and female mice. METHODS: C57BL/6J mice were fed the diets for 1 month, after which time blood pressure, serum markers, and in vitro vascular reactivity was measured. RESULTS: Males fed the 600G diet gained significantly less weight than males fed the 0G diet (by 1.71 g); diet had no effect on female weight gain. Males fed the 600G diet also exhibited significantly elevated serum insulin (2.9 [0.5] vs 1.8 [0.4] ng/dL), and decreased serum glucose (0.15 [0.01] vs 0.24 [0.02] ng/dL) levels, resulting in a significant increase in the ratio of insulin to glucose; insulin and glucose levels were not changed by dietary genistein in females. Arterial pressure measurements from 0G-fed males were lower than other groups. However, basal vascular reactivity of isolated aortic rings was significantly increased by the 600G diet in both males (from 0.55 [0.03] to 0.94 [0.18] g) and females (from 0.45 [0.04] to 0.78 [0.09] g). Aortic wall thickness was not affected by diet. Norepinephrine-mediated contractility was also greater in aortic rings of male and female mice fed the 600G diet, and differences from the 0G diet persisted in the presence of L-NG-nitroarginine methyl ester but were completely accounted for by increased basal reactivity. CONCLUSION: Our data indicate that 1 month of a 600G or 0G diet significantly alters vascular function independent of sex. In contrast, sex-dependent differences exist in well-established serum markers of cardiovascular health and disease.