The Treatment of Tubal Inflammatory Infertility using Yinjia Tablets through EGFR/MEK/ERK Signaling Pathway based on Network Pharmacology.

Background: Salpingitis obstructive infertility (SOI) refers to infertility caused by abnormal conditions such as tubal adhesion and blockage caused by acute and chronic salpingitis. SOI has a serious impact on women's physical and mental health and family harmony, and it is a clinical problem that needs to be solved urgently.

Objective: The purpose of the present study was to explore the potential pharmacological mechanisms of the Yinjia tablets (Yin Jia Pian, YJP) on tubal inflammation.

Methods: Networks of YJP-associated targets and tubal inflammation-related genes were constructed through the STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of YJP were identified using Cytoscape and Database for Annotation, Visualization, and Integrated Discovery (metascape). E. coli was used to establish a rat model of tubal inflammation and to validate the predictions of network pharmacology and the therapeutic efficacy of YJP. H&E staining was used to observe the pathological changes in fallopian tubes. TEM observation of the ultrastructure of the fallopian tubes. ELISA was used to detect the changes of IL-6 and TNF-α in fallopian tubes. Immunohistochemistry was used to detect the expression of ESR1. The changes of Bcl-2, ERK1/2, p-ERK1/2, MEK, p-MEK, EGFR, and p-EGFR were detected by western blot.

Results: Through database analysis, it was found that YJP shared 105 identical targets with the disease. Network pharmacology analysis showed that IL-6, TNF, and EGFR belong to the top 5 core proteins associated with salpingitis, and EGFR/MEK/ERK may be the main pathway involved. The E. coli-induced disease rat model of fallopian tube tissue showed damage, mitochondrial disruption, and increased levels of the inflammatory factors IL-6 and TNF-α. Tubal inflammatory infertility rats have increased expression of Bcl-2, p-ERK1/2, p-MEK, and p-EGFR, and decreased expression of ESR1. In vivo, experiments showed that YJP improved damage of tissue, inhibited shedding of tubal cilia, and suppressed the inflammatory response of the body. Furthermore, YJP inhibited EGFR/MEK/ERK signaling, inhibited the apoptotic protein Bcl-2, and upregulated ESR1.

Conclusion: This study revealed that YJP Reducing tubal inflammation and promoting tissue repair may be associated with inhibition of the EGFR/MEK/ERK signaling pathway.

The H9N2 avian influenza virus increases APEC adhesion to oviduct epithelia by viral NS1 protein-mediated activation of the TGF-ß pathway.

H9N2 avian influenza is a low-pathogenic avian influenza circulating in poultry and wild birds worldwide and frequently contributes to chicken salpingitis that is caused by avian pathogenic Escherichia coli (APEC), leading to huge economic losses and risks for food safety. Currently, how the H9N2 virus contributes to APEC infection and facilitates salpingitis remains elusive. In this study, in vitro chicken oviduct epithelial cell (COEC) model and in vivo studies were performed to investigate the role of H9N2 viruses on secondary APEC infection, and we identified that H9N2 virus enhances APEC infection both in vitro and in vivo. To understand the mechanisms behind this phenomenon, adhesive molecules on the cell surface facilitating APEC adhesion were checked, and we found that H9N2 virus could upregulate the expression of fibronectin, which promotes APEC adhesion onto COECs. We further investigated how fibronectin expression is regulated by H9N2 virus infection and revealed that transforming growth factor beta (TGF-ß) signaling pathway is activated by the NS1 protein of the virus, thus regulating the expression of adhesive molecules. These new findings revealed the role of H9N2 virus in salpingitis co-infected with APEC and discovered the molecular mechanisms by which the H9N2 virus facilitates APEC infection, offering new insights to the etiology of salpingitis with viral-bacterial co-infections.IMPORTANCEH9N2 avian influenza virus (AIV) widely infects poultry and is sporadically reported in human infections. The infection in birds frequently causes secondary bacterial infections, resulting in severe symptoms like pneumonia and salpingitis. Currently, the mechanism that influenza A virus contributes to secondary bacterial infection remains elusive. Here we discovered that H9N2 virus infection promotes APEC infection and further explored the underlying molecular mechanisms. We found that fibronectin protein on the cell surface is vital for APEC adhesion and also showed that H9N2 viral protein NS1 increased the expression of fibronectin by activating the TGF-ß signaling pathway. Our findings offer new information on how AIV infection promotes APEC secondary infection, providing potential targets for mitigating severe APEC infections induced by H9N2 avian influenza, and also give new insights on the mechanisms on how viruses promote secondary bacterial infections in animal and human diseases.

Effects of salpingitis simulation on the morphology and expression of inflammatory-related genes of oviduct in laying hens.

This study was conducted to simulate salpingitis of laying hens by observing the morphology and expression of inflammatory genes in the oviduct. A total of one hundred twenty 81-wk-old Roman Pink laying hens in good physical condition without the oviduct disease with an average egg production rate of 76% were fed a basal diet for 2 wks and then randomly allocated into 4 groups (6 replicates/group, 5 birds/replicate). The experimental treatments were as follows: 1) Control group (treated with PBS); 2) Organic chemical reagent (OCR) group; 3) Lipopolysaccharide (LPS) group; 4) LPS + OCR group. First, the chickens were kept upside down to make ectropion and exposure of the apertura uterinae; then prepared reagents were poured into the uterine part of the fallopian tube by using the chicken vas deferens (1 mL/layer); finally, the chickens were kept in the inverted position for 5 to 10 min. The fallopian tube samples (the magnum, isthmus, and uterus) were collected after 48 h of treatment. Compared with the control, treatment with LPS+OCR decreased (P < 0.05) the secondary villus length and primary villus area in magnum and villus length in isthmus (P < 0.05). An increase (P < 0.05) of the intervillous space of uterus was observed in LPS + OCR group compared with the control. The expressions of interleukin-6 mRNA of magnum and interferon-γ (IFN-γ) of isthmus in the LPS and LPS+OCR treatments were higher (P < 0.05) than that in control. Compared with the control, treatment with LPS+OCR increased (P < 0.05) the expressions of IFN-γ mRNA of magnum and IFN-γ, tumor necrosis factor-α and inducible nitric oxide synthase mRNA of uterus in laying hens. In conclusion, the results of morphological damage of fallopian tube tissue and increased expression of inflammatory factors in LPS + OCR treatment group suggested that LPS+OCR treatment can provide data basis to establish salpingitis model in laying hens for studying the pathogenesis of it.

Characterization of Pathogenic CD8+ T cells in Chlamydia-Infected OT1 Mice.

Chlamydia trachomatis is a leading infectious cause of infertility in women due to its induction of lasting pathology such as hydrosalpinx. Chlamydia muridarum induces mouse hydrosalpinx because C. muridarum can both invade tubal epithelia directly (as a first hit) and induce lymphocytes to promote hydrosalpinx indirectly (as a second hit). In the current study, a critical role of CD8+ T cells in chlamydial induction of hydrosalpinx was validated in both wild type C57BL/6J mice and OT1 transgenic mice. OT1 mice failed to develop hydrosalpinx partially due to the failure of their lymphocytes to recognize chlamydial antigens. CD8+ T cells from naive C57BL/6J mice rescued the ability of recipient OT1 mice to develop hydrosalpinx when naive CD8+ T cells were transferred at the time of infection with Chlamydia. However, when the transfer was delayed for 2 weeks or longer after the Chlamydia infection, naive CD8+ T cells no longer promoted hydrosalpinx. Nevertheless, CD8+ T cells from mice immunized against Chlamydia still promoted significant hydrosalpinx in the recipient OT1 mice even when the transfer was delayed for 3 weeks. Thus, CD8+ T cells must be primed within 2 weeks after Chlamydia infection to be pathogenic, but, once primed, they can promote hydrosalpinx for >3 weeks. However, Chlamydia-primed CD4+ T cells failed to promote chlamydial induction of pathology in OT1 mice. This study optimized an OT1 mouse-based model for revealing the pathogenic mechanisms of Chlamydia-specific CD8+ T cells.

Adrenomedullin insufficiency alters macrophage activities in fallopian tube: a pathophysiologic explanation of tubal ectopic pregnancy.

Ectopic pregnancy is the major cause of maternal morbidity and mortality in the first trimester of pregnancy. Tubal ectopic pregnancy (TEP) accounts for nearly 98% of all ectopic pregnancies. TEP is usually associated with salpingitis but the underlying mechanism in salpingitis leading to TEP remains unclear. Adrenomedullin (ADM) is a peptide hormone abundantly expressed in the fallopian tube with potent anti-inflammatory activities. Its expression peaks at the early luteal phase when the developing embryo is being transported through the fallopian tube. In the present study, we demonstrated reduced expression of ADM in fallopian tubes of patients with salpingitis and TEP. Using macrophages isolated from the fallopian tubes of these women, our data revealed that the salpingistis-associated ADM reduction contributed to aggravated pro-inflammatory responses of the tubal macrophages resulting in production of pro-inflammatory and pro-implantation cytokines IL-6 and IL-8. These cytokines activated the expression of implantation-associated molecules and Wnt signaling pathway predisposing the tubal epithelium to an adhesive and receptive state for embryo implantation. In conclusion, this study provided evidence for the role of ADM in the pathogenesis of TEP through regulating the functions of tubal macrophages.

B cell activation factor (BAFF) induces inflammation in the human fallopian tube leading to tubal pregnancy.

BACKGROUND: Tubal pregnancy is recognized as one of the most common ectopic pregnancy types. Salpingitis may result in tubal pregnancy by causing fallopian tube occlusion and hydrosalpinx. B cell activation factor (BAFF) is a proinflammatory cytokine that helps regulate both innate and adaptive immune responses. Our previous study firstly showed that BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells, and both BAFF protein and mRNA in human inflamed fallopian tubes had higher expression levels than those in normal fallopian tubes. This study aimed to elucidate the association between the expression of BAFF gene and the inflammation in the human fallopian tube leading to tubal pregnancy. METHODS: We examined 70 patients undergoing salpingectomy for salpingitis (n = 35) and tubal pregnancy (n = 35). Twenty patients with benign uterine diseases undergoing complete hysterectomy and salpingectomy were recruited into control group. BAFF mRNA and protein in tissue samples were detected by qPCR and Western blotting methods. Furthermore, serum levels of BAFF, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured using ELISA kits. RESULTS: We found statistically significantly elevated expressions of BAFF mRNA or protein in whole tissue samples, and serum levels of BAFF, TNF-α and IL-6 in whole blood samples from patients with salpingitis and tubal pregnancy, in comparison to the control group. CONCLUSION: Based on the results, high expression of BAFF gene might induce inflammation in the human fallopian tube, suggesting its possible role in the tubal pregnancy process.

Telocytes in Inflammatory Gynaecologic Diseases and Infertility.

Women suffered with inflammatory gynecologic diseases, such as endometriosis (EMs) and acute salpingitis (AS) often complained of sub- or infertility, even in those women without obvious macroscopic anatomical pelvic abnormalities also have unexplained infertility. Generally, besides the well-known impairment of classically described oviduct cells caused by inflammatory diseases, such as the ciliated cells, fibroblasts and myofibroblasts, the involvement of the newly identified telocytes (TCs) in disease-affected oviduct tissues and potential pathophysiological roles in fertility problems remain unknown. In this chapter, TCs was investigated in rat model of EMs- and AS-affected oviduct tissues. Results showed inflammation and ischaemia-induced extensive ultrastructural damages of TCs both in cellular body and prolongations, with obvious TCs loss and interstitial fibrotic remodelling. Such in vivo pathological alterations might contribute to structural and functional abnormalities of oviduct tissue and potentially engaged in sub- or infertility. And especially, TCs connected to various activated immunocytes in both normal and diseased tissues, thus might participate in local immunoregulation (either repression or activation) and serve a possible explanation for immune-mediated pregnancy failure. Then, in vitro cell co-culture study showed that uterine TC conditioned media (TCM) can activate mouse peritoneal macrophages and subsequently trigger its cytokine secretion, thus providepreliminary evidence that, TCs are not simply innocent bystanders, but are instead potential functional players in local immunoregulatory and immunosurveillance.

Aberrant expression of leukemia inhibitory factor receptor (LIFR) and leukemia inhibitory factor (LIF) is associated with tubal pregnancy occurrence.

BACKGROUND/AIM: Tubal pregnancy is a major cause of maternal death in the first trimester and exploration of its underlying molecular mechanism is of great importance. This study aimed to explore the association of tubal pregnancy with leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) expression in oviduct tissues. MATERIALS AND METHODS: Immunohistochemistry was performed to probe the differential expression of LIF and LIFR in oviduct tissues among a control group (including NP group, n = 11; and IP group, n = 12), tubal pregnancy group (Ect-N group, n = 31; and Ect-A group, n = 40), and chronically inflamed group (including Inf-S group, n = 11; and Inf-P group, n = 9), followed by semiquantitative analysis. RESULTS: Semiquantitative immunohistochemical analysis demonstrated that there was no significant difference in LIF expression in either the epithelial or stromal cells of oviduct tissues between the tubal pregnancy group and the control group (P < 0.05). However, LIF expression was remarkably elevated in the Inf-S and Inf-P group compared to the other groups (P < 0.05). In the epithelial cells of the fallopian tubes, LIFR expression was highest in the chronically inflamed group, followed by the tubal pregnancy group, outnumbering the control group (P < 0.05). More interestingly, an opposite expression trend of LIFR was observed in the stromal cells of the fallopian tubes among these groups (P <0.05). CONCLUSION: Aberratn expression of LIF and LIFR might be associated with the occurrence of tubal pregnancy.

[THE ROLE OF NO AND MEXIDOL IN CONTRACTILITY OF OVARIAN AND CERVICAL PARTS OF UTERUS UNDER THE CONDITION OF IMMUNE-MEDIATED INJURY IN MICE].

Contractility of ovarian (OP) and cervical parts (CP) of uterus under the condition of immune-mediated injury which was induced by immunization with bovine serum albumin (BSA) was investigated. It was shown that under the activation of energy-synthesizing function of mitochondria with Mexidol the frequency of reductions in both uterine parts decreased, the amplitude and contractility index in the OP and CP as well as the duration of the active state in CP increased. Mexidol under the condition of immunization with BSA leads to the decrease in amplitude in 2,6 time and contractility index in 2,2 time in OP and to the increase of them in CP. It was shown that contractility features of ovarian and cervical parts of uterine under the condition of BSA- induced immunization were caused by changes of mitochondria functional state and were associated with nitric oxide.

Elafin expression in mucosa of fallopian tubes is altered by hydrosalpinx.

Elafin is a natural antimicrobial molecule and a member of the antileukoproteinase (Trappin) family. It is normally expressed in the mucosae of fallopian tubes. Hydrosalpinx is a chronic inflammatory process of the fallopian tubes. The objective of this study is to compare the localization of elafin protein and levels of elafin messenger RNA (mRNA) in the mucosa of oviducts with and without hydrosalpinx. Immunohistochemical analysis was performed on tissue sections of hydrosalpinx (n = 10) and normal tubes (n = 22) from paraffin-embedded blocks, obtained from patients who underwent salpingectomy for benign conditions. The main outcome measure was the intensity of staining with 3,3'-diaminobenzidine calculated by ImageJ software and mRNA expression by real-time polymerase chain reaction. The mean intensity of elafin (mean ± standard deviation) in mucosae of the fallopian tubes was 69.68 ± 24.55 in controls and 32.03±18.16 in patients with hydrosalpinx (P < .0001). Elafin mRNA levels were reduced in hydrosalpinx, although not significantly (P = .05, n = 9 from each group). Therefore, tubal epithelium of women with hydrosalpinx seems to have a lower expression of elafin, an elastase inhibitor and a natural antimicrobial molecule, compared to normal tubes.

Loss of nerve fibers in the oviduct isthmus in women with hydrosalpinx.

Apart from the abnormalities of tubal anatomy, the main concern linked to infertility is impaired tubal motility associated with hydrosalpinx, which is thought to be controlled by hormones and nerves. The objective of this study was to determine the distribution of nerve fibers in the oviduct isthmus in women with and without hydrosalpinx. Histological sections of the oviduct isthmus tissue were obtained from 18 women undergoing salpingectomy for hydrosalpinx, and from 15 women undergoing hysterectomy and salpingectomy for benign gynecologic diseases. The tissues were immunohistochemically stained for protein gene product (PGP) 9.5, protein S100, neuropeptide tyrosine (NPY), and vasoactive intestinal peptide (VIP) to reveal all nerve fibers, as well as sympathetic and parasympathetic nerve fibers, in the oviduct isthmus. We detected the presence of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus in all study subjects. However, the densities of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus were all significantly decreased in women with hydrosalpinx compared with those in women without hydrosalpinx (P<0.01). Our results suggest that reduced nerve fibers in the oviduct isthmus in women with hydrosalpinx compared with women without hydrosalpinx may have an important function in the mechanism of hydrosalpinx-associated infertility.

NF κB expression increases and CFTR and MUC1 expression decreases in the endometrium of infertile patients with hydrosalpinx: a comparative study.

BACKGROUND: Hydrosalpinx are associated with infertility, due to reduced rates of implantation and increased abortion rates. The aims of this study were to investigate the expression of cystic fibrosis transmembrane conductance regulator (CFTR), nuclear factor kappa B (NF KappaB) and mucin-1 (MUC-1), and analyze the correlation between the expression of CFTR and NF KappaB or MUC1, in the endometrium of infertile women with and without hydrosalpinx. METHODS: Thirty-one infertile women with laparoscopy-confirmed unilateral or bilateral hydrosalpinx and 20 infertile women without hydrosalpinx or pelvic inflammatory disease (control group) were recruited. Endometrial biopsy samples were collected and the expression of CFTR, NF KappaB and MUC1 were analyzed using immunohistochemistry and quantitative real-time PCR. RESULTS: CFTR, NF KappaB and MUC1 mRNA and protein expression tended to increase in the secretory phase compared to the proliferative phase in both groups; however, these differences were not significantly different. The endometrium of infertile patients with hydrosalpinx had significantly higher NF KappaB mRNA and protein expression, and significantly lower CFTR and MUC1 mRNA and protein expression, compared to control infertile patients. A positive correlation was observed between CFTR and MUC1 mRNA expression (r = 0.65, P < 0.05); a negative correlation was observed between CFTR mRNA and NF KappaB mRNA expression (r = -0.59, P < 0.05). CONCLUSIONS: Increased NF KappaB expression and decreased CFTR and MUC1 expression in the endometrium of infertile patients with hydrosalpinx reinforce the involvement of a molecular mechanism in the regulation of endometrial receptivity.

[The relationship between HalphaD-5 and HbetaD-2 in infertile women's fimbriae tubes with adhesions and atresias].

OBJECTIVE: To investigate the expression and relationship of human alpha defensin-5 (HalphaD-5) and human beta defensin-2 (HbetaD-2) in human fimbriae tubes with adhesions and atresias. METHODS: The tissue samples were collected from 30 human fimbriae tubes with adhesions and atresias, and 30 cases without adhesions and atresias. The expression of HalphaD-5 and HbetaD-2 in fimbriae tube tissue were measured by immunohistochemical SP methods. Image pro-plus 6.0 software was used to test the average IOD value of positive staining. Differences of HalphaD-5 and HbetaD-2 expressions were analyzed by independent-samples T test. The relationship between HalphaD-5 and HbetaD-2 was analyzed by Pearson correlation. RESULTS: We found that HalphaD-5 and HbetaD-2 mainly expressed in the epithelial cells which face to lumen, mostly in the cytochylema. Both two groups expressed HalphaD-5 and HbetaD-2, but the degrees were different. Compared with human fimbriae tubes without adhesions or atresias, the expressions of HalphaD-5 and HbetaD-2 increased significantly in adhesion cases (P(HalphaD--5) = 0.000, P(HbetaD--2) = 0.02). In the group without adhesion, there was a positive correlation between HalphaD-5 and HbetaD-2 (r = 0.404, P = 0.027), while in the adhesion group, there was no correlation between HalphaD-5 and HbetaD-2 (P = 0.089). CONCLUSION: HalphaD-5 and HbetaD-2 may protect fimbriae tubes during the pathological process of microorganisms attack.

Locally elevated leukemia inhibitory factor in the inflamed fallopian tube resembles that found in tubal pregnancy.

OBJECTIVE: To investigate the association between the expressions of leukemia inhibitory factor and the occurrence of tubal pregnancy. DESIGN: Prospective observational study. SETTING: University-based obstetrics and gynecology hospital. PATIENT(S): Thirty women undergoing salpingectomy for tubal pregnancy and 30 nonpregnant patients with benign uterine or appendix disease. INTERVENTION(S): Oviduct tissues with ectopic gestation were separated into implantation sites and nonimplantation sites. Samples of ampullary fallopian tubes during midsecretory phase were collected as control groups. Immunohistochemical and Western blot analysis were performed. MAIN OUTCOME MEASURE(S): The differences of leukemia inhibitory factor expression between the implantation and nonimplantation sites of oviduct tissues and the normal and chronically inflamed fallopian tubes. RESULT(S): The expression of leukemia inhibitory factor in the implantation group is significantly higher than that in the nonimplantation group or in the normal group. A statistically significant difference was also found for leukemia inhibitory factor between the chronic inflammation group and the normal group by Western blot analysis but no difference between the chronic inflammation group and the implantation group or the nonimplantation group. CONCLUSION(S): Leukemia inhibitory factor might be one of the reasons that cause patients with salpingitis to be more susceptible to tubal pregnancy and might be involved in the implantation process of tubal pregnancy.

Positive staining for p53 and expression of c-erbB-2 in endosalpinx hyperplasia: analysis of 48 cases and review of literature.

To establish the diagnostic value of p53 and c-erbB-2 expression, forty-eight cases of endosalpinx hyperplasia were analyzed. p53 protein and c-erbB-2 oncoprotein expression was examined using an avidin-biotin peroxidase complex method. The accumulation of p53 protein and c-erbB-2 oncoprotein was used as objective evidence to support morphologic differential diagnosis of endosalpinx hyperplasia and early cancer. In all cases various forms of endosalpinx hyperplasia were seen. Only in 4 cases staining for p53 showed positive reaction without staining for c-erbB-2. In one case positive reaction for c-erbB-2 was showed and no expression of p53 protein was detected. It is concluded that immunohistochemical detection of the mutant p53 protein and c-erbB-2 oncoprotein might be useful tools in differential diagnosis among various forms of hyperplastic changes of endosalpinx. The presence of these markers may be associated with the risk of malignant transformation in various forms of the tubal hyperplasia.

Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells.

BACKGROUND AND OBJECTIVES: An experimental model consisting of gonococcal infection of human fallopian tube mucosa in organ culture has proven useful in studying the molecular pathogenesis of acute gonococcal salpingitis and postsalpingitis sequelae. Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa. This damage to the mucosa can be quantified on fallopian tube pieces by an assay of the percent of the periphery that has ciliary activity (PPCA) remaining at specific time points after infection. Although assay of the PPCA has been quite valuable, it is labor-intensive, somewhat subjective, and requires that the observers have training and experience. A more practical assay for genital mucosal damage is desirable for further investigations that employ the fallopian tube experimental model. Gonococcal infection of fallopian tube mucosa in organ culture also results in the production of easily quantified tumor necrosis factor-alpha (TNF-alpha) by the mucosa. Furthermore, treatment of the organ cultures with recombinant human TNF-alpha (rHuTNFalpha) alone also causes sloughing of ciliated cells from the mucosa. These findings strongly suggest that TNF-alpha is a mediator of the mucosal damage that attends gonococcal infection. GOALS OF THE STUDY: To determine: (1) whether the PPCA values and the TNF-alpha concentrations in fallopian tube mucosal tissues correlate closely enough to allow prediction of the PPCA from a measurement of the mucosal tissue TNF-alpha concentration; and (2) whether the correlation of the TNF-alpha mucosal tissue concentration with the sloughing of ciliated cells (measured by the PPCA) supports the hypothesis that induction of TNF-alpha by gonococcal infection, with resultant sloughing of ciliated cells, is likely to be a major pathogenic mechanism of gonococcal salpingitis and might mediate postsalpingitis infertility and ectopic pregnancy. STUDY DESIGN: A metaanalysis was performed on studies from three research groups (two laboratories in the United States and one in the United Kingdom, using identical techniques for quantifying the PPCA, TNF-alpha, or both. RESULTS: There was a close and statistically significant correlation between the TNF-alpha mucosal tissue concentration and the proportion of ciliated cells lost from the mucosa as measured by the PPCA (r = 0.95, p < 0.001). Therefore, as the mucosal tissue concentration of endogenous TNF-alpha increased, the loss of ciliated cells from the epithelium increased proportionately. CONCLUSIONS: During gonococcal infection of human fallopian tube mucosa in organ culture, the mucosal tissue concentration of TNF-alpha can be used to predict the PPCA, and therefore, the extent of mucosal damage. This finding should facilitate studies of the molecular pathogenesis of infectious diseases involving human genital mucosa. Further, the close correlation of mucosal TNF-alpha concentration with genital mucosal damage, evaluated by the PPCA, supports the hypothesis that induction of the proinflammatory cytokine, TNF-alpha, by gonococcal infection, with resultant inflammation and sloughing of ciliated cells, is an important pathogenic mechanism of gonococcal salpingitis and may mediate postsalpingitis infertility and ectopic pregnancy as well.

C-reactive protein and the treatment of pelvic inflammatory disease.

OBJECTIVE: The significance of C-reactive protein (CRP) in assessing the treatment of pelvic inflammatory disease (PID) was established and compared with body temperature (BT), erythrocyte sedimentation rate (ESR) and serum leukocyte concentration (L). METHOD: In 51 patients with PID, 20 (39%) of them with tubo-ovarial abscess (TOA), measurement of BT and laboratory investigations were carried out on admission and during treatment on days 3-4, 6-8 and 18-21. The changes in these values were compared with the changes in clinical condition. RESULT: Prior to treatment, the majority--49 patients or 96.1%--had increased CRP values. In successful treatment, the CRP values decreased significantly in PID patients without TOA on day 3-4, in patients with TOA on day 6-8 and reached normal values in both groups on day 18-21. Changes in clinical condition were most concurrent with changes in CRP. CONCLUSION: In assessing PID treatment, the determination of CRP has precedence over L, ESR and BT as the percentage of patients with increased CRP is higher and because the changes in value follow the changes in clinical condition more reliably.

[Enterobius vermicularis localized to the internal female genitalia]. / Enterobius vermicularis lokaliseret til genitalia femininae interna.

Enterobius vermicularis is one of the most common helminthic infections in humans. It normally inhabits the large intestine and is of low pathogenecity. The ova are, however, occasionally found in ectopic sites in the peritoneal cavity, usually as asymptomatic granulomas, though in rare cases they may cause chronic lower abdominal pain. Two cases of ectopic enterobius vermicularis are presented in this paper.

Increased inducibility of inflammatory mediators from peripheral blood mononuclear cells of women with salpingitis.

To investigate whether immune system activation may contribute to the tissue damage observed in salpingitis, we isolated peripheral blood mononuclear cells and quantitated production of the monocyte activation products tumor necrosis factor-alpha, interleukin-1, and interleukin-6. Unstimulated cells from 7 of 20 women with salpingitis spontaneously released tumor necrosis factor at a concentration greater than 2 SD above the mean value produced by cells from 29 healthy donors. Interferon gamma (200 U/ml) further induced production of tumor necrosis factor from mononuclear cells of 11 women with salpingitis. In contrast, production of tumor necrosis factor by each of 23 other patients who lacked laparoscopic or clinical evidence of salpingitis was similar to that of the controls. In a subset of women whose cells were tested for production of other monokines, three of nine women with salpingitis spontaneously released interleukin-1 but none of the others did so. Four of nine patients with salpingitis also produced interleukin-6, but none of the others did so. None of the monokines were detected in serum from any subject. The results suggest that monocytes from women with salpingitis are primed in vivo and produce inflammatory mediators under conditions where monocytes from other women are poorly responsive. This increased monokine inducibility may contribute to the tubal damage that is the hallmark of salpingitis.