Deep endometriosis infiltrating the recto-sigmoid: critical factors to consider before management

Mauricio Simoes Abrao1,, Felice Petraglia2, Tommaso Falcone3, Joerg Keckstein4, Yutaka Osuga5, and Charles Chapron6,7,8 Endometriosis Division, Obstetrics and Gynecological Department – Sao Paulo University, Sao Paulo, Brazil Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Obstetrics, Gynecology andWomen's Health Institute, Cleveland Clinic, Cleveland, OH, USA Department of Obstetrics and Gynecology, Center for Endometriosis, Villach Hospital, Villach, Austria Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo, Tokyo, Japan Universite Paris Descartes, Sorbonne Paris Cite, Faculte de Medecine, Assistance Publique – Hopitaux de Paris (APHP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France Institut Cochin, Universite Paris Descartes, Sorbonne Paris Cite CNRS (UMR 8104), Paris, France Inserm, Universite Paris Descartes, Sorbonne Paris Cite, Unite de recherche U1016, Paris, Franc

Plant Biotechnology in China

expression vector (Invitrogen) were selected using Zeocin (0.5 mg/ml). To release soluble 7BP anchored on the cell surface, we treated cells with thrombin (10 IU/ml) for 3 days under serum-free conditions. The cleaved 6-His-and FLAG epitope-tagged recombinant 7BP in serum-free conditioned media was purified by sequential nickel and anti-FLAG affinity chromatography. For antibody production, 5 mg of purified 7BP emulsified in Freund's adjuvant were injected into rabbits (Strategic BioSolutions Inc., Ramona, CA 2029 (1985). 17. Eight-week-old female mice (strain C57/B6) were treated with equine chorionic gonadotropin (CG) (10 IU, National Hormone and Peptide Program) for 48 hours before ovulation induction with human chorionic gonadotropin (hCG, 10 IU). Mice were mated overnight after ovulation, and pregnant mothers were treated with purified 7BP (500 g, once per day) for 4 days starting from postcoitus day 17. Parturition was monitored at 4-to 6-hour intervals. Five animals per treatment group were used. The pregnancy durations for control and 7BP-treated animals were 508.8 Ϯ 9.0 hours and 536.0 Ϯ 9.1 hours, respectively. The nipple sizes (length ϫ width, mm 2 ) for control and 7BP-treated mice were 1.50 Ϯ 0.05 and 1.07 Ϯ 0.04, respectively

Lipocalin-2 Deficiency Impairs Thermogenesis and Potentiates Diet-Induced Insulin Resistance in Mice

Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low-molecular mass-secreted proteins that bind small hydrophobic molecules. LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents. The objective of this study was to investigate the role of LCN2 in diet-induced insulin resistance and metabolic homeostasis in vivo. Systemic insulin sensitivity, adaptive thermogenesis, and serum metabolic and lipid profile were assessed in LCN2-deficient mice fed a high-fat diet (HFD) or regular chow diet. The molecular disruption of LCN2 in mice resulted in significantly potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance. LCN2(-/-) mice exhibit impaired adaptive thermogenesis and cold intolerance. Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2(-/-) mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition. LCN2 has a novel role in adaptive thermoregulation and diet-induced insulin resistanc

Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue

Delayed Treatment with Systemic (S)-Roscovitine Provides Neuroprotection and Inhibits In Vivo CDK5 Activity Increase in Animal Stroke Models

Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin-dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment.In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms.Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis

Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment. CONCLUSIONS/SIGNIFICANCE: Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism

Evaluation of the treatment patterns and economic burden of dysmenorrhea in Japanese women, using a claims database

Sayako Akiyama,1 Erika Tanaka,2 Olivier Cristeau,3 Yoshie Onishi,4 Yutaka Osuga5 1Health Economics and Outcomes Research, 2Advocacy and External Affairs, Market Access, Bayer Yakuhin, Ltd., Tokyo, Japan; 3Health Economics and Outcome Research, Creativ-Ceutical, Paris, France; 4Creativ-Ceutical K.K., Tokyo, Japan; 5Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Purpose: This study aimed to describe treatment patterns and estimate health care resource utilization and associated costs among Japanese women with dysmenorrhea, using a claims database.Methods: This was a retrospective analysis using health insurance data from the Japan Medical Data Center, assessing female patients aged 18&ndash;49 years with newly diagnosed primary or secondary dysmenorrhea. Treatment pattern analyses focused on hormonal medications, analgesics, hemostatic agents, traditional Chinese medicine (TCM), and gynecological surgeries. Data were collected on health care resource utilization and costs associated with medications, imaging procedures, and inpatient and outpatient care in both patients and matched controls.Results: The analysis included 6,315 women with dysmenorrhea (3,441 primary; 2,874 secondary). The most commonly prescribed initial therapies were low-dose estrogen progestins (LEPs, 37.7%) and TCM (30.0%), with substantial differences between primary (LEPs: 27.4%, TCM: 38.8%) and secondary (LEPs: 50.2%, TCM: 19.5%) dysmenorrhea cohorts. Surgery was conducted in &lt;5% of all patients. Both primary and secondary cohorts of dysmenorrhea had significantly higher mean total health care costs compared to controls within the 1-year period following diagnosis (Case-primary: 191,680 JPY [1,916 USD]; secondary: 246,488 JPY [2,465 USD], Control-primary: 83,615 JPY [836 USD]; secondary: 90,711 JPY [907 USD]) (p&lt;0.0001). After adjusting for baseline characteristics, these costs were 2.2 and 2.9 times higher for primary and secondary dysmenorrhea cohorts, respectively, compared with matched controls, (both p&lt;0.0001). The main driver of these excess costs was outpatient care, with eight additional physician visits per year among dysmenorrhea patients compared to controls (p&lt;0.0001).Conclusion: Considerable heterogeneity in treatment patterns was observed, with relatively low utilization of LEPs in patients with primary dysmenorrhea and those treated by internal medicine physicians. Total annual health care costs were approximately 2&ndash;3 times higher in patients with dysmenorrhea compared to women without the condition. Keywords: dysmenorrhea, women&rsquo;s health, treatment patterns, resource use and costs, economic burden, database analysi