Hormonal Contraceptive Use and the Prevalence of Endometriotic Lesions at Different Regions within the Peritoneal Cavity.

Endometriosis is an estrogen-dependent disease that can lead to chronic pain and subfertility. Endometriotic lesions found in different locations are heterogeneous and may represent a collection of related but distinct conditions. Whether there is a relationship between hormonal contraceptive (HC) use and endometriosis is still controversial. The purpose of this study was to determine whether HC use affected the prevalence of endometriotic lesions differently based on lesion location. Data was retrospectively collected from 161 patients presenting to the Berne University Women's Hospital between 2008 and 2012 for laparoscopic investigation. Women with histologically proven endometriosis were included in the study and patients were grouped according to lesion location and HC use. The results of the study indicate that HC users are significantly less likely to have endometriotic lesions on the ovaries, although in contrast, no difference was observed in the incidence of lesions in the rectovaginal septum (RVS) or peritoneal region. In addition, women using HC who were diagnosed with endometriotic lesions on the peritoneum were significantly younger than women with lesions in other locations. In conclusion, women with endometriosis who are currently using HC are less likely to have ovarian endometriotic lesions than in alternate locations.

Increased levels of biglycan in endometriomas and peritoneal fluid samples from ovarian endometriosis patients

Abstract In our previous low-density-array gene-expression analysis we found an increased expression of biglycan gene in ovarian endometriosis patients. In the present study we evaluated biglycan expression at the protein level in tissue, serum and peritoneal fluid (PF) from ovarian endometriosis patients, patients with benign ovarian cysts and healthy women. Twenty samples of endometriomas and 27 of control tissues (benign ovarian cysts and eutopic endometrium of healthy women) were obtained laparoscopically or by curettage. Serum and PF samples were collected from 56 ovarian endometriosis patients and 40 controls (patients with benign cysts and healthy women). Tissue biglycan levels and serum and PF biglycan concentrations were determined by Western blotting and ELISA, respectively. Biglycan was detected in endometriomas and in benign cysts tissues but differed in glycosylation levels. The PF biglycan concentrations were significantly increased in ovarian endometriosis patients (mean ± SD = 220.3 ± 190.5 pg/mg protein) compared to the whole control group (101.9 ± 94.7 pg/mg protein, p < 0.001), while serum concentrations did not differ significantly. Biglycan appears to be involved in ovarian pathologies and probably has different roles in benign cysts as compared to ovarian endometriomas.

Assessing Initial Conditions for Chloride Transport Across Low- permeability Argillaceous Rocks, Wellenberg, Switzerland

Information about fluid evolution and solute transport in a low-permeability metamorphic rock sequence has been obtained by comparing chloride concentrations and chlorine isotope ratios of pore water, groundwater, and fluid inclusions. The similarity of d37Cl values in fluid inclusions and groundwater suggests a closed-system evolution during the metamorphic overprint, and signatures established at this time appear to form the initial conditions for chloride transport after exhumation of the rock sequence.

Subcritical Propagation and Coalescence of Oil-Filled Cracks: Getting the Oil Out of Low-Permeability Source Rocks

We use a fracture mechanics model to study subcritical propagation and coalescence of single and collinear oil-filled cracks during conversion of kerogen to oil. The subcritical propagation distance, propagation duration, crack coalescence and excess oil pressure in the crack are determined using the fracture mechanics model together with the kinetics of kerogen-oil transformation. The propagation duration for the single crack is governed by the transformation kinetics whereas the propagation duration for the multiple collinear cracks may vary by two orders of magnitude depending on initial crack spacing. A large amount of kerogen (>90%) remains unconverted when the collinear cracks coalesce and the new, larger cracks resulting from coalescence will continue to propagate with continued kerogen-oil conversion. The excess oil pressure on the crack surfaces drops precipitously when the collinear cracks are about to coalesce, and crack propagation duration and oil pressure on the crack surfaces are strongly dependent on temperature. Citation: Jin, Z.-H., S. E. Johnson, and Z. Q. Fan (2010), Subcritical propagation and coalescence of oil-filled cracks: Getting the oil out of low-permeability source rocks, Geophys. Res. Lett., 37, L01305, doi:10.1029/2009GL041576.

Regression of the inflammatory microenvironment of the peritoneal cavity in women with endometriosis by GnRHa treatment.

OBJECTIVE To investigate the effect of gonadotropin-releasing hormone analogues (GnRHa) on the peritoneal fluid microenvironment in women with endometriosis. STUDY DESIGN Peritoneal fluid was collected from 85 women with severe endometriosis (rAFS stage III and IV) during laparoscopic surgery during the proliferative phase. Prior to surgery clinical data were collected. The concentrations of specific markers for endometriosis in the peritoneal fluid were determined using an ELISA and a comparison between peritoneal fluid markers in women using GnRHa and no hormonal treatment was performed using a non-parametric Mann-Whitney U test. RESULTS The study included peritoneal fluid from 39 patients who had been administered GnRHa (Zoladex(®)) in the three months prior to surgery and 46 from women with no hormonal treatment in this period. Concentrations of IL-8, PAPP-A, glycodelin-A and midkine were significantly reduced in the GnRHa treatment group compared to women receiving no hormonal treatment. RANTES, MCP-1, ENA-78, TNF-α, OPG, IP-10 and defensin showed no significant change between the two groups. CONCLUSIONS GnRHa mediate a significant regression in the inflammatory nature of the peritoneal microenvironment in women with endometriosis.

Correlation between altered central pain processing and concentration of peritoneal fluid inflammatory cytokines in endometriosis patients with chronic pelvic pain

Translational research has not yet elucidated whether alterations in central pain processes are related to peripheral inflammatory processes in chronic pain patients. We tested the hypothesis that the concentration of cytokines in the peritoneal fluid of endometriosis patients with chronic pain correlate with parameters of hyperexcitability of the nociceptive system. The concentrations of 15 peritoneal fluid cytokines were measured in 11 patients with chronic pelvic pain and a diagnosis of endometriosis. Six parameters assessing central pain processes were recorded. Positive correlations between concentration of some cytokines in the peritoneal fluid and amplification of central pain processing were found. The results suggest that inflammatory mechanisms may be important in the pathophysiology of altered central pain processes and that cytokines produced in the environment of endometriosis could act as mediators between the peripheral lesion and changes in central nociceptive processes.

Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

Long-term results of a prospective randomised trial assessing the impact of readaptation of the dorsolateral peritoneal layer following extended pelvic lymph node dissection and cystectomy.

OBJECTIVE To evaluate the long term oncological and functional outcomes after readaptation of the dorsolateral peritoneal layer following pelvic lymph node dissection (PLND) and cystectomy . PATIENTS AND METHODS A randomised, single-center, single-blinded, two-arm trial was conducted on 200 consecutive cystectomy patients who underwent PLND and cystectomy for bladder cancer (peritoneal layer (n=100; 73 male, 27 female; median age 68 yrs, range 35-86 yrs) and group B without readapation (n=100; 66 male, 34 female; median age 65 yrs, range 30-86 yrs). Regular postoperative follow-up was performed at our outpatient clinic. Median follow-up was 59 months (range 3-100 months), five patients were lost to follow-up in group A, seven in group B. Bowel function was evaluated using the validated Gastrointestinal Quality of Life Index questionnaire and an institutional questionnaire regarding post-cystectomy outcome. Local recurrences and distal metastases were evaluated using computed tomography and bone scan at the regular follow-up visits. RESULTS There was no significant difference between the two groups in terms of the rate of local (pelvic) recurrence (5/95 [5.3%] in group A; 7/93 [7.5%] in group B; p = 0.53), the rate of distant metastases (21/95 [22.1%] in group A; 23/93 [24.7%] in group B; p = 0.67), cancer-specific survival (p = 0.37), and overall survival (p = 0.59). Group A had significantly better bowel function at 3 (p < 0.001), 6 (p < 0.006), 12 (p <0.006) and 24 months (p = 0.04), and significantly less postoperative abdominal pain and bloating at 3 (p = 0.002) and 6 months (p = 0.01). CONCLUSION Readaptation of the dorsolateral peritoneal layer following PLND and cystectomy has a beneficial long-term impact on bowel function and postoperative pain without compromising oncological radicality. This article is protected by copyright. All rights reserved.

Phospholipase A2 group IIA is elevated in endometriomas but not in peritoneal fluid and serum of ovarian endometriosis patients.

Our previous gene expression analysis identified phospholipase A2 group IIA (PLA2G2A) as a potential biomarker of ovarian endometriosis. The aim of this study was to evaluate PLA2G2A mRNA and protein levels in tissue samples (endometriomas and normal endometrium) and in serum and peritoneal fluid of ovarian endometriosis patients and control women. One-hundred and sixteen women were included in this study: the case group included 70 ovarian endometriosis patients, and the control group included 38 healthy women and 8 patients with benign ovarian cysts. We observed 41.6-fold greater PLA2G2A mRNA levels in endometrioma tissue, compared to normal endometrium tissue. Using Western blotting, PLA2G2A was detected in all samples of endometriomas, but not in normal endometrium, and immunohistochemistry showed PLA2G2A-specific staining in epithelial cells of endometrioma paraffin sections. However, there were no significant differences in PLA2G2A levels between cases and controls according to ELISA of peritoneal fluid (6.0 ± 4.4 ng/ml, 6.6 ± 4.3 ng/ml; p = 0.5240) and serum (2.9 ± 2.1 ng/ml, 3.1 ± 2.2 ng/ml; p = 0.7989). Our data indicate that PLA2G2A is implicated in the pathophysiology of ovarian endometriosis, but that it cannot be used as a diagnostic biomarker.

Implementation and evaluation of permeability-porosity and tortuosity-porosity relationships linked to mineral dissolution-precipitation

Changes of porosity, permeability, and tortuosity due to physical and geochemical processes are of vital importance for a variety of hydrogeological systems, including passive treatment facilities for contaminated groundwater, engineered barrier systems (EBS), and host rocks for high-level nuclear waste (HLW) repositories. Due to the nonlinear nature and chemical complexity of the problem, in most cases, it is impossible to verify reactive transport codes analytically, and code intercomparisons are the most suitable method to assess code capabilities and model performance. This paper summarizes model intercomparisons for six hypothetical scenarios with generally increasing geochemical or physical complexity using the reactive transport codes CrunchFlow, HP1, MIN3P, PFlotran, and TOUGHREACT. Benchmark problems include the enhancement of porosity and permeability through mineral dissolution, as well as near complete clogging due to localized mineral precipitation, leading to reduction of permeability and tortuosity. Processes considered in the benchmark simulations are advective-dispersive transport in saturated media, kinetically controlled mineral dissolution-precipitation, and aqueous complexation. Porosity changes are induced by mineral dissolution-precipitation reactions, and the Carman-Kozeny relationship is used to describe changes in permeability as a function of porosity. Archie’s law is used to update the tortuosity and the pore diffusion coefficient as a function of porosity. Results demonstrate that, generally, good agreement is reached amongst the computer models despite significant differences in model formulations. Some differences are observed, in particular for the more complex scenarios involving clogging; however, these differences do not affect the interpretation of system behavior and evolution.

Reconstruction of in-situ porosity and porewater compositions of low-permeability crystalline rocks: Magnitude of artefacts induced by drilling and sample recovery

Geological site characterisation programmes typically rely on drill cores for direct information on subsurface rocks. However, porosity, transport properties and porewater composition measured on drill cores can deviate from in-situ values due to two main artefacts caused by drilling and sample recovery: (1) mechanical disruption that increases porosity and (2) contamination of the porewater by drilling fluid. We investigated the effect and magnitude of these perturbations on large drill core samples (12–20 cm long, 5 cmdiameter) of high-grade, granitic gneisses obtained from 350 to 600 m depth in a borehole on Olkiluoto Island (SW Finland). The drilling fluid was traced with sodium–iodide. By combining out-diffusion experiments, gravimetry, UV-microscopy and iodide mass balance calculations, we successfully quantified the magnitudes of the artefacts: 2–6% increase in porosity relative to the bulk connected porosity and 0.9 to 8.9 vol.% contamination by drilling fluid. The spatial distribution of the drilling-induced perturbations was revealed by numerical simulations of 2D diffusion matched to the experimental data. This showed that the rims of the samples have a mechanically disrupted zone 0.04 to 0.22 cm wide, characterised by faster transport properties compared to the undisturbed centre (1.8 to 7.7 times higher pore diffusion coefficient). Chemical contamination was shown to affect an even wider zone in all samples, ranging from 0.15 to 0.60 cm, inwhich iodide enrichmentwas up to 180 mg/kgwater, compared to 0.5 mg/kgwater in the uncontaminated centre. For all samples in the present case study, it turned out that the magnitude of the artefacts caused by drilling and sample recovery is so small that no correction is required for their effects. Therefore, the standard laboratory measurements of porosity, transport properties and porewater composition can be taken as valid in-situ estimates. However, it is clear that the magnitudes strongly depend on site- and drilling-specific factors and therefore our results cannot be transferred simply to other locations. We recommend the approach presented in this study as a route to obtain reliable values in future drilling campaigns aimed at characterising in-situ bedrock properties.

Clinical Validation of a Peritoneal Dialysis Prescription Model in the PatientOnLine Software

Peritoneal transport characteristics and residual renal function require regular control and subsequent adjustment of the peritoneal dialysis (PD) prescription. Prescription models shall facilitate the prediction of the outcome of such adaptations for a given patient. In the present study, the prescription model implemented in the PatientOnLine software was validated in patients requiring a prescription change. This multicenter, international prospective cohort study with the aim to validate a PD prescription model included patients treated with continuous ambulatory peritoneal dialysis. Patients were examined with the peritoneal function test (PFT) to determine the outcome of their current prescription and the necessity for a prescription change. For these patients, a new prescription was modeled using the PatientOnLine software (Fresenius Medical Care, Bad Homburg, Germany). Two to four weeks after implementation of the new PD regimen, a second PFT was performed. The validation of the prescription model included 54 patients. Predicted and measured peritoneal Kt/V were 1.52 ± 0.31 and 1.66 ± 0.35, and total (peritoneal + renal) Kt/V values were 1.96 ± 0.48 and 2.06 ± 0.44, respectively. Predicted and measured peritoneal creatinine clearances were 42.9 ± 8.6 and 43.0 ± 8.8 L/1.73 m2/week and total creatinine clearances were 65.3 ± 26.0 and 63.3 ± 21.8 L/1.73 m2/week, respectively. The analysis revealed a Pearson's correlation coefficient for peritoneal Kt/V of 0.911 and Lin's concordance coefficient of 0.829. The value of both coefficients was 0.853 for peritoneal creatinine clearance. Predicted and measured daily net ultrafiltration was 0.77 ± 0.49 and 1.16 ± 0.63 L/24 h, respectively. Pearson's correlation and Lin's concordance coefficient were 0.518 and 0.402, respectively. Predicted and measured peritoneal glucose absorption was 125.8 ± 38.8 and 79.9 ± 30.7 g/24 h, respectively, and Pearson's correlation and Lin's concordance coefficient were 0.914 and 0.477, respectively. With good predictability of peritoneal Kt/V and creatinine clearance, the present model provides support for individual dialysis prescription in clinical practice. Peritoneal glucose absorption and ultrafiltration are less predictable and are likely to be influenced by additional clinical factors to be taken into consideration.

Ovarian cancer angiogenesis, biology and therapy

The progressive growth of epithelial ovarian cancer tumor is regulated by proangiogenic molecules and growth factors released by tumor cells and the microenvironment. Previous studies showed that the expression of interleukin-8 (IL-8) directly correlates with the progression of human ovarian carcinomas implanted into the peritoneal cavity of nude mice. We examined the expression level of IL-8 in archival specimens of primary human ovarian carcinoma from patients undergoing curative surgery by in situ mRNA hybridization technique. The expression of IL-8 was significantly higher in patients with stage III disease than in patients with stage I disease. To investigate the role of IL-8 in the progressive growth of ovarian cancer, we isolated high- and low-IL-8 producing clones from parental Hey-A8 human ovarian cancer cells, and compared their proliferative activity and tumorigenicity in nude mice. The effect of exogenous IL-8 and IL-8 neutralizing antibody on ovarian cancer cell proliferation was investigated. Finally, we studied the modulation of IL-8 expression in ovarian cancer cells by sense and antisense IL-8 expression vector transfection and its effect on proliferation and tumorigenicity. We concluded that IL-8 has a direct growth potentiating activity in human ovarian cancer cells. ^ The expression level of IL-8 directly correlates with disease progression of human ovarian cancer, but the mechanism of induction is unknown. Since hypoxia and acidic pH are common features in solid tumors, we determined whether hypoxic and acidic conditions could regulate the expression of IL-8. Culturing the human ovarian cancer cells in hypoxic or acidic medium led to a significant increase in IL-8 mRNA and protein. Hypoxic- and acidosis-mediated transient increase in IL-8 expression involved both transcriptional activation of the IL-8 gene and enhanced stability of the IL-8 mRNA. Furthermore, we showed that IL-8 transcription activation by hypoxia or acidosis required the cooperation of NF-κB and AP-1 binding sites. ^ Finally, we studied novel therapies against human ovarian cancer. First, we determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) inhibits the formation of malignant ascites and the progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of nude mice. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinomas. Secondly, we determined whether local sustained production of murine interferon-β could inhibit the growth of human ovarian cancer cells in the peritoneal cavity of nude mice. Our results showed that local production of IFN-β could inhibit the in vivo growth of human ovarian cancer cells by upregulating the expression of the inducible nitric oxide synthase (NOS) in host macrophages. ^