Dexamethasone-induced intrauterine growth restriction modulates expression of placental vascular growth factors and fetal and placental growth.

Prenatal exposure to glucocorticoids (GC) is a central topic of interest in medicine since GCs are essential for the maturation of fetal organs and intrauterine growth. Synthetic glucocorticoids, which are used in obstetric practice, exert beneficial effects on the fetus, but have also been reported to lead to intrauterine growth retardation (IUGR). In this study, a model of growth restriction in mice was established through maternal administration of dexamethasone during late gestation. We hypothesised that GC overexposure may adversely affect placental angiogenesis and fetal and placental growth. Female BALB/c mice were randomly assigned to control or dexamethasone treatment, either left to give birth or euthanised on days 15, 16, 17 and 18 of gestation followed by collection of maternal and fetal tissue. The IUGR rate increased to 100% in the dexamethasone group (8 mg/kg body weight on gestational days 14 and 15) and pups had clinical features of symmetrical IUGR at birth. Dexamethasone administration significantly decreased maternal body weight gain and serum corticosterone levels. Moreover, prenatal dexamethasone treatment not only induced fetal growth retardation but also decreased placental weight. In IUGR placentas, VEGFA protein levels and mRNA expression of VEGF receptors were reduced and NOS activity was lower. Maternal dexamethasone administration also reduced placental expression of the GC receptor, αGR. We demonstrated that maternal dexamethasone administration causes fetal and placental growth restriction. Furthermore, we propose that the growth retardation induced by prenatal GC overexposure may be caused, at least partially, by an altered placental angiogenic profile.

Fibronectin induces capacitation-associated events through the endocannabinoid system in bull sperm.

Mammalian ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, collectively called capacitation, in order to fertilize the oocyte. We reported that fibronectin (Fn), a glycoprotein from the extracellular matrix, and anandamide (AEA), one of the major members of the endocannabinoid family, are present in the bovine oviductal fluid and regulate bull sperm function. Also, AEA induces bovine sperm capacitation, through CB1 and TRPV1 receptors. In this work, we investigated if Fn induces bovine sperm capacitation thought the activation of the endocannabinoid system in this process. We incubated sperm with Fn (100 µg/ml) and/or capsazepine, a TRPV1 antagonist (0.1 µM) and some events related to sperm capacitation such as LPC-induced acrosome reaction, sperm-release from the oviduct, induction of PKA phosphorylated substrates (pPKAs) and protein tyrosine phosphorylation (pY) and nitric oxide (NO) production were assessed. Also, we studied the activity of fatty acid amide hydrolase (FAAH), the enzyme that degrades AEA. We found that Fn, via α5ß1 integrin, induced capacitation-associated events. Also, Fn stimulated signaling pathways associated to capacitation as cAMP/PKA and NO/NO synthase. Moreover, Fn decreased the FAAH activity and this correlated with sperm capacitation. Capsazepine reversed fibronectin-induced capacitation, and pPKAs and NO levels. The incubation of spermatozoa with R-methanandamide (1.4 nM), a stable analogue of AEA, increased cAMP and pPKAs levels. The presence of H89 (50 µM) or KT5720 (100 nM) (PKA inhibitors) prevented AEA-induced capacitation. In addition, R-methanandamide and capsaicin (0.01 µM), a TRPV1 agonist, increased NO production via the PKA pathway. These results indicate that Fn, through α5ß1, supports capacitation in bovine spermatozoa. This effect is dependent on the activation of TRPV1 through cAMP/PKA and NO signaling pathways. We propose that Fn could be considered as a new agent that promotes sperm capacitation in bull sperm. Our findings contribute to better understand the significance of Fn signaling in the capacitating events that lead to successful fertilization and embryo development in mammals including humans.

Sinonasal tumor pathology: what's new?

The sinonasal tract is an anatomical region affected by a wide variety of tumors with different clinical behavior, histologic and molecular features. Substantial advances have been made in the field of sinonasal tumor pathology in recent years, including improvement in the diagnosis, treatment and genetic characterization. In this article, a review of the histological features of new distinctive pathologic entities as well as newly described molecular alterations of these rare tumors is presented.

Thumb carpometacarpal joint denervation for primary osteoarthritis: A prospective study of 31 thumbs.

We present the results of a prospective study of 31 thumbs in 30 patients affected by primary osteoarthritis at the thumb carpometacarpal (CMC1) joint who were treated with denervation of the involved joint. For every operated hand, the Kapandji score, key-pinch strength, grip strength and pain on a visual analogue scale were evaluated preoperatively and postoperatively at 2 weeks, 6 weeks, 3 months, 6 months and 1 year. The patients' satisfaction was determined. The Kapandji score and key-pinch strength improved significantly in all patients. Grip strength improved significantly in 10 hands. Pain was reduced in all cases. Nevertheless, 6 patients were dissatisfied with the operation. Of these 6 patients, 4 had stage IV arthritis in the TMC and scaphotrapeziotrapezoid joints of the thumb. Thumb CMC denervation appears to reduce pain at 1 year with an overall improvement in key-pinch strength. However, patients with stage IV CMC arthritis were not satisfied with the outcome of the procedure.

Uterosome-like vesicles prompt human sperm fertilizing capability.

STUDY QUESTION: Does the rapid transit through the uterine environment modulate the sperm physiological state? SUMMARY ANSWER: The uterosome-like vesicles (ULVs) secreted by endometrial epithelial cells (EECs) in vitro are able to fuse with human spermatozoa, prompting their fertilizing capacity. WHAT IS KNOWN ALREADY: Early studies suggest that sperm capacitation begins in the uterus and ends in the oviduct, and that a synergistic effect of both female organs may accelerate this process. Although it has been reported that co-incubation of human spermatozoa with endometrial cell-conditioned medium (CM) stimulates sperm capacitation, the mechanism mediating this communication is unknown. STUDY DESIGN, SIZE, DURATION: Human ULVs secreted by EECs were characterized and their effect on human sperm physiology was analysed. Spermatozoa were incubated with EEC-derived CM or ULV, after which sperm capacitation was evaluated at different time points. In addition, the interaction of spermatozoa with ULV was analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS: ULVs were isolated by ultracentrifugation and identified using electron microscopy and Western blotting to assess the presence of specific protein markers. Following seminal plasma removal, human spermatozoa were incubated CM or ULV, after which sperm capacitation was evaluated as the ability of the sperm to undergo the induced acrosome reaction and the level of protein tyrosine phosphorylation (PY) determined by Western blot and immunocytochemistry. The interaction of spermatozoa with labelled ULV was analysed by fluorescence microscopy. In all cases, at least three biological replicates from different sperm donors were performed for each set of experiments. Significant differences between mean values were determined by one-way ANOVA followed by Tukey's post hoc test. Differences between treatments were considered statistically significant at P ≤ 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: The level of capacitated spermatozoa and those recruited by chemotaxis increased 3- to 4-fold when spermatozoa were incubated in the presence of CM for 4 h. Even a 15 min incubation of spermatozoa with CM was also enough to increase the level of capacitated cells 3- to 4-fold (P < 0.05). Furthermore, a short co-incubation of spermatozoa with ULV stimulates sperm capacitation, as determined by the increase in the level of induced acrosome reaction and the induction of PY. In addition, after the co-incubation of spermatozoa with fluorescent labelled ULV, the sperm cells acquired the fluorescent staining which indicates that ULV might be transferred to the sperm surface by a fusion mechanism. LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study performed with human biological material, spermatozoa and endometrial derived cells; the latter being a cell line originally isolated from a uterine adenocarcinoma. WIDER IMPLICATIONS OF THE FINDINGS: The capability of spermatozoa to briefly interact with ULVs supports the hypothesis that any step of sperm transport may have physiological consequences, despite the interaction lasting for only a limited period of time. This way of communication of spermatozoa with cell products of uterine origin opens new frontiers of investigation (e.g. the signalling molecules involved), shedding light on the sperm processes that prepare the male gamete for fertilization, which might have implications for human infertility treatment. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTERESTS: The project was financially supported by SECyT-UNC. The authors declare no conflict of interest.

Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1.

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process.

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization.

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

Involvement of hypoxia and inflammation in early pregnancy loss mediated by Shiga toxin type 2.

INTRODUCTION: Symptomatic or asymptomatic Shiga toxin producing Escherichia coli (STEC) infections during early pregnancy may cause maternal or fetal damage mediated by Shiga toxin type 2 (Stx2). The aim of this study is to elucidate the mechanisms responsible for early pregnancy loss in rats treated with Stx2. METHODS: Sprague Dawley pregnant rats were intraperitoneally injected at day 8 of gestation with a sublethal dose (0.5 ng of Stx2/g of total body weight, 250 µl) of purified Stx2. Control rats were injected with the same volume of PBS. The expression of globotriaosylceramide (Gb3) glycosphingolipid receptor for Stx2 was evaluated by thin-layer chromatography (TLC). Regions of hypoxia in decidual tissue were determined by pimonidazole immunohistochemistry and vascular endothelial growth factor (VEGF) expression by Western blot and immunohistochemistry. Tumor necrosis factor-alpha (TNF-α) levels in serum and decidual tissue were evaluated by ELISA. Serum progesterone levels were determined by RIA. RESULTS: Decidual tissue from both, control and Stx2-treated rats showed similar expression of Gb3 receptor. Intrauterine growth restriction was observed in Stx2-treated rats, associated with hypoxia and an increase of decidual TNF-α levels. Decrease of serum progesterone levels and decidual VEGF expression were also demonstrated. DISCUSSION: Our findings indicate that Stx2 reaches the uteroplacental unit, binds Gb3 and triggers damage in decidual tissue. Poor oxygen supply accompanied with damage in the uteroplacental unit and inflammation could be responsible for the early pregnancy loss. Decrease in the pregnancy protective factors, serum progesterone and local VEGF, may contribute to the pregnancy loss.

The sub-occipital transtentorial approach revisited base on our own experience.

UNLABELLED: The surgical experience of the sub-occipital approach for treatment of pineal gland and pineal region tumors is reported. This approach was originally proposed by Jamieson and modified by Lapras who by changing the shape of the bone flap obtained the elevation of the occipital lobe which consequently resulted in a better exposition of this deep region. The reason why this approach became the basis for their treatment is particularly related to the personal experience of Lapras who reported his fantastic experience of surgery in this deep area and demonstrated the advantages of the sub-occipital transtentorial approach. MATERIAL: Out of 277 patients operated from 1982 to 2012 in Lyon for a pineal tumor, 233 were treated by a sub-occipital approach: 153 males, 125 females, 75 patients of pediatric age. The majority of patients were operated on in a sitting position which represents a surgical specialty of the anesthesiological school of Lyon. RESULTS: Complete tumor removal was possible in 135 patients (58%) and partial in 60 patients (26%). For 38 patients, it was not possible to establish the quality of surgical resection. The incidence of hemianopsia decreased to less that 2% of cases while the incidence of severe pneumocephaly which requires a prolonged intensive care hospitalization was less than 4% of cases. Mortality related to this surgical approach in the Lyonnais school series was 0% during this period. CONCLUSION: In our experience the sub-occipital transtentorial approach seems to us the best approach for pineal tumors because it permits a large exposition of the pineal region favoring the removal of the tumor with a lateral extension and also for tumors extending low into the posterior cranial fossa. In fact, this is our preferred approach because it has been used in a large majority of cases. However, surgeons have to be familiar with other possible approaches to obtain the best result in terms of removal and also to decrease the rate of sequelae to improve the quality of life of these patients.

Supracerebellar infratentorial approach for pineal region tumors: Our surgical and technical considerations.

UNLABELLED: The infratentorial supracerebellar approach is most widely used for pineal tumors. We report our own experience and technical considerations using this approach. MATERIAL: From 1982 to 2010, we operated on 232 patients with pineal region tumors. Of these, 201 patients were operated on using a suboccipital transtentorial approach while 31 patients were operated on using a supracerebellar infratentorial approach. The median age of the patients ranged between 8 months and 74 years. There were 19 children and 12 adults. All patients presented with elevated intracranial pressure. There were 6 pinealocytomas, 3 papillary tumors, 7 germinomas, 2 benign teratomas, 4 pineal cysts and 9 gliomas. Adjuvant post-surgical therapy consisted of chemo-radiotherapy in 4 patients, 2 with germinomas and 2 with a grade II/III gliomas. Radiotherapy was performed in the other twelve patients (5 germinomas and 7 gliomas). RESULTS AND COMPLICATIONS: All patients are still alive at a median follow-up of eight years. Twelve of the 19 children are attending normal school classes for their age, 5 are attending classes for special needs children and 2 are not yet of school age at the last follow-up. Seven of the 12 adults are working normally, three are working part-time at the same job and two have retired but are able to lead a normal life. Postoperative complications included symptomatic diffuse cerebellar edema (one patient) completely resolved with a mild residual cerebellar syndrome; double vision secondary to IV nerve palsy (one patient); transitory Parinaud's syndrome (2 patients) and cerebellar gait (2 patients) nearly completely recovered at respectively six and twelve months. CONCLUSION: The supracerebellar infratentorial approach seems to be a safe and effective choice in the treatment of pineal region tumors. In our experience, it permits complete tumor resections with acceptable morbidity and all neurosurgeons should master this approach in order to adapt their surgical choice according to size, extent and the relationship of the lesion with the surrounding anatomical structures.

Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation.

BACKGROUND AND PURPOSE: Uveitis is a prevalent intraocular inflammatory disease and one of the most damaging ocular conditions. Pretreatment with melatonin prevented ocular inflammation induced by an intravitreal injection of bacterial LPS in the Syrian hamster. Here, we have assessed the anti-inflammatory effects of melatonin administered after the onset of ocular inflammation. EXPERIMENTAL APPROACH: The eyes of male Syrian hamsters were intravitreally injected with vehicle or LPS. Melatonin was injected i.p. every 24 h, starting 12 or 24 h after the LPS injection. A clinical evaluation (with a score index based on clinical symptoms), the number of infiltrating cells, protein concentration and PGE2 and PGF2α levels in the aqueous humour, as well as retinal NOS activity, lipid peroxidation and TNF-α levels were assessed. Retinal function was assessed by scotopic electroretinography, and light microscopy and immunohistochemistry were used to evaluate the state of the retinal structure. KEY RESULTS: Both treatment regimens with melatonin decreased clinical symptoms, reduced the leakage of cells and proteins, and decreased PG levels in aqueous humour from eyes injected with LPS. In addition, melatonin treatment blocked the decrease in scotopic electroretinogram a- and b-wave amplitude, protected the retinal structure and reduced the increase in NOS activity, lipid peroxidation and TNF-α levels, induced by LPS. CONCLUSIONS AND IMPLICATIONS: These results indicate that treatment with melatonin, starting after the onset of uveitis, attenuated ocular inflammation induced by LPS in the Syrian hamster and support the use of melatonin as a therapeutic resource for uveitis treatment.

Induction of apoptosis in T lymphoma cells by long-term treatment with thyroxine involves PKCζ nitration by nitric oxide synthase.

Thyroid hormones are important regulators of cell physiology, inducing cell proliferation, differentiation or apoptosis, depending on the cell type. Thyroid hormones induce proliferation in short-term T lymphocyte cultures. In this study, we assessed the effect of long-term thyroxine (T4) treatment on the balance of proliferation and apoptosis and the intermediate participants in T lymphoma cells. Treatment with T4 affected this balance from the fifth day of culture, inhibiting proliferation in a time-dependent manner. This effect was associated with apoptosis induction, as characterized through nuclear morphological changes, DNA fragmentation, and Annexin V-FITC/Propidium Iodide co-staining. In addition, increased iNOS gene and protein levels, and enzyme activity were observed. The generation of reactive oxygen species, depolarization of the mitochondrial membrane, and a reduction in glutathione levels were also observed. The imbalance between oxidants and antioxidants species is typically associated with the nitration of proteins, including PKCζ, an isoenzyme essential for lymphoma cell division and survival. Consistently, evidence of PKCζ nitration via proteasome degradation was also observed in this study. Taken together, these results suggest that the long-term culture of T lymphoma cells with T4 induces apoptosis through the increased production of oxidative species resulting from both augmented iNOS activity and the loss of mitochondrial function. These species induce the nitration of proteins involved in cell viability, promoting proteasome degradation. Furthermore, we discuss the impact of these results on the modulation of T lymphoma growth and the thyroid status in vivo.

Sclerosing variant of PEComa: report of a case and review of the literature.

Tumours of perivascular epithelioid cells (PEComas) are a heterogeneous group of uncommon mesenchymal neoplasms which exhibit a peculiar immunohistochemical co-expression of muscle and melanocytic markers. PEComas occur at various visceral and soft tissue sites, generally with a benign clinical course. Nevertheless, there has been evidence of cases having an unfavourable outcome, thus prompting investigation of pathological criteria for malignancy. A sclerosing variant of PEComa, more frequently encountered in the retroperitoneum of middle-aged women, has been reported. Prognosis has generally been regarded as favourable and complete surgical excision appears to be adequate treatment. To the best of our knowledge, only two cases of sclerosing PEComa displayed high-grade malignant morphology and were associated with adverse outcome. An additional case of retroperitoneal sclerosing PEComa with a two-year follow-up and indolent behaviour is herein described. Light and electron microscopy were performed, along with immunohistochemical analysis. Further studies are needed to clarify the histogenesis and to predict the biological behaviour of this uncommon entity.

Milk fat globule epidermal growth factor 8 (MFG-E8): a novel protein in the mammalian endometrium with putative roles in implantation and placentation.

OBJECTIVES: MFG-E8 is a novel endometrial protein with conserved functions in tissue remodeling and angiogenesis in non-uterine tissues. Our aims were: 1. To examine the presence of MFG-E8 protein in the human endometrium during the window of implantation, in human endometrial cell lines, in human placental tissue at different gestational ages, and in murine implantation sites during early gestation; and 2. To study the regulation of MFG-E8 mRNA expression in mice implantation sites. STUDY DESIGN: MFG-E8 protein and its receptor integrin αvß3 were detected by immunostaining in human endometrial biopsies obtained from normal volunteers, in human endometrial cell lines (epithelial: Ishikawa and HEC-1A, stromal: HESC, and endothelial: HEEC), in human products of conception from all trimesters of gestation, and in murine implantation and inter-implantation sites dissected on days 5 and 8 post-coitus. MFG-E8 gene expression was assessed by RT-PCR. MAIN OUTCOME MEASURES: Immunohistochemical determination of MFG-E8 in endometrium and products of conception as well as relative MFG-E8 mRNA expression in mice implantation sites. RESULTS: MFG-E8 protein was present almost exclusively in the epithelial compartment of human endometrium. It was also expressed in the cytotrophoblasts and syncytiotrophoblasts outlining chorionic villi of the human placenta at all trimesters of gestation, and in murine implantation sites. MFG-E8 mRNA was significantly up-regulated in murine implantation sites and with increased gestational age. CONCLUSIONS: MFG-E8 expression in the endometrial epithelium as well as in chorionic villi suggests its possible role in endometrial reorganization during the receptive phase and in events related to normal pregnancy in mammals.

First bite syndrome as presenting symptom of parapharyngeal adenoid cystic carcinoma.

INTRODUCTION: First bite syndrome refers to the development of pain in the parotid region after the first bite of each meal. CASE REPORT: A man was referred to our institution with first bite syndrome as his only symptom. Magnetic resonance imaging of the head and neck revealed a deep lobe parotid mass in close contact with the external carotid artery. Computed tomography guided fine needle biopsy indicated adenoid cystic carcinoma. Total parotidectomy was performed, with en bloc resection of the infiltrated external carotid artery and a selective neck dissection of levels Ib to III. High-weight ion radiotherapy was administered post-operatively. CONCLUSION: First bite syndrome has hitherto only been described following parapharyngeal space surgery. We present the first case of parotid gland adenoid cystic carcinoma presenting with first bite syndrome as the only symptom. The presence of first bite syndrome should prompt the clinician to investigate the parapharyngeal space and deep lobe of the parotid gland, especially in the absence of other signs or symptoms.

Ultrasoundelastography: Can it provide valid information for differentiation of benign and malignant thyroid nodules?

Ultrasoundelastography (USE) is a new imaging technique that is performed with a normal ultrasound transducer. It provides improved characterization of a tissue or nodule based on the latter's elasticity and stiffness. The aim of the present, prospective study was to assess the validity of USE in characterizing thyroid nodules. USE patterns were analyzed in light of nodule cytology (British Thyroid Association classification) to determine whether these patterns can be used to decide whether or not fine-needle aspiration cytology (FNAC) is indicated. We examined a consecutive series of 617 thyroid nodules in patients referred for the first time to the Endocrinology Unit of Atri Hospital (Atri, [TE]). Patients underwent ultrasonographic and USE examinations of their thyroid nodules, which were then subjected to FNAC. All nodules with Thy 1 cytology were excluded, leaving 567 nodules for analysis. USE findings were classified on the basis of the degree and distribution of elasticity within the lesion: four patterns were identified (1, 2, 3a, 3b, or 4).None of the nodules with Thy 4 cytology (malignant) had USE pattern 1 or 2; patterns 3 and 4 were associated with higher cytologic grades. In conclusion, USE provides additional information on thyroid nodules, which can be used with ultrasound features of the nodules, to decide whether FNAC is indicated. In fact, patterns 1 and 2 do not seem to be associated with Thy 4 cytology.

Spindle cell liposarcoma of the face: case report and literature review.

Liposarcoma is a common soft tissue sarcoma accounting for approximately 20% of all mesenchymal tumours across all ages. Recently, collaborative research in the specialties of pathology and genetics has led to the delineation of several tumour variants with different behaviours and prognoses, one of which includes the very rare spindle cell liposarcoma (SCL) subtype. We present the first case of an SCL arising in the subcutaneous tissue of the forehead of a 78-year-old man. In light of the rarity of this tumour, we describe the tumour and its clinical and pathological characteristics and undertake a literature review to clarify the surgical management and prognosis of SCL, and increase awareness to avoid misdiagnosis of a benign soft tissue neoplasm.

Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus.

In women, the association between chronic marijuana smoking and early miscarriage has long been known. Anandamide, a major endocannabinoid, mimics some of the psychotropic, hypnotic and analgesic effects of Delta(9)-tetrahydrocannabinol, the psychoactive component of marijuana. The uterus contains the highest concentrations of anandamide yet discovered in mammalian tissues and this suggests that it might play a role in reproduction. The production of small amounts of nitric oxide (NO) regulates various physiological events including implantation and myometrial relaxation, but in an inflammatory setting such as sepsis, NO has toxic effects as it is a free radical. The results presented in this study indicate that anandamide modulates NO production induced by lipopolysaccharide (LPS) in an in-vitro murine model. It was shown that LPS-induced NO synthesis and tissue damage were mediated by anandamide, as a cannabinoid receptor type I antagonist could block the effect of LPS (P < 0.001). This endotoxin inhibited anandamide uterine degradation (P < 0.05) and increased the expression of one of its synthesizing enzymes (P < 0.05). Contrary to the known anti-inflammatory and protective effects, in this model anandamide seems to act as a pro-inflammatory molecule modulating the production of NO induced by LPS. This proinflammatory effect of anandamide may be implicated in pathological reproductive events such as septic abortion.