Clinica Chimica Acta 438 (2015) 236–240

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Increased plasma soluble CD40 ligand concentration in pelvic inflammatory disease Tsung-chin Ho a, Shun-Fa Yang b, Po-Hui Wang b,c, Long-Yau Lin c,d, Yi-Torng Tee c,d, Wen-Chun Liao e,f, Hsiu-Ju Chang g, Hsiu-Ting Tsai e,f,g,⁎ a

Obstetric and Gynecologic Department, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan d School of Medicine, Chung Shan Medical University, Taichung, Taiwan e School of Nursing, Chung Shan Medical University, Taichung, Taiwan f Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan g School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan b c

a r t i c l e

i n f o

Article history: Received 7 July 2014 Received in revised form 22 August 2014 Accepted 25 August 2014 Available online 2 September 2014 Keywords: Soluble CD40 ligand (sCD40L) Plasma Pelvic inflammatory disease (PID)

a b s t r a c t Background: The role of soluble CD40 ligand (sCD40L) in pelvic inflammatory disease (PID) remains unclear. We sought to determine whether sCD40L was an efficient serum marker as with WBC and CRP in PID patients. Methods: Enzyme-linked immunosorbent assay was used to measure the plasma levels of sCD40L before and after routine protocol treatments in sixty-four PID patients and seventy healthy controls. Results: The level of plasma sCD40L (pg/ml) was significantly elevated in PID patients (1632.83 ± 270.91) compared to that in normal controls (700.33 ± 58.77; p = 0.001) and decreased significantly as compared to that in the same patients (928.77 ± 177.25; p = 0.0001) after they received treatment. The concentration of sCD40L was significantly correlated with the level of plasma C-reactive protein (CRP) in the blood (r = 0.202, p = 0.01, n = 134). When the cutoff level of plasma sCD40L levels was determined to be 1612.26 pg/ml based on ROC, the sensitivity, specificity, and the area under the curve of plasma sCD40L level for predicting PID were 0.26, 0.97, and 0.58 (95% confidence interval: 0.48–0.68), respectively, while the adjusted odds ratio (AOR) with their 95% CI of plasma sCD40L for PID risk was 7.09 (95% CI = 1.14–43.87, p = 0.03). Conclusions: The expression of plasma sCD40L was increased in patients with PID and detection of plasma sCD40L could be useful for the diagnosis of PID. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Pelvic inflammatory disease (PID) is caused by micro-organisms [1] and is related to serious long term consequences including infertility, chronic pelvic pain, and ectopic pregnancy [2–4]. Acute PID is hard to diagnose because of a wide variation in the clinical pictures. Clinical diagnosis alone has only 87% sensitivity and 50% specificity [5]. Therefore, to develop non-invasive adjunctive strategies capable of detecting and controlling pelvic inflammatory disease is strongly recommended. CD 40 ligand (CD40L, formally known as CD154) is a 39 kD transmembrane glycoprotein that belongs to tumor necrosis factor α (TNF-α) family and is expressed on the surface of monocytes, macrophages, T cells, B cells, platelets, and endothelial cells [6–8]. The CD40L receptor, CD40, is a 49 kD membrane glycoprotein of tumor necrosis factor receptor (TNFR) superfamily and is found on monocytes, ⁎ Corresponding author at: School of Nursing, College of Nursing, Taipei Medical University, No. 250, Wu Hsing St., Taipei 11031, Taiwan. Tel./fax: +886 2 2736 1661x6330. E-mail address: [email protected] (H.-T. Tsai).

http://dx.doi.org/10.1016/j.cca.2014.08.030 0009-8981/© 2014 Elsevier B.V. All rights reserved.

macrophages, neutrophils, B cells, T cells, mast cells, dendritic cells, platelets, endothelial cells, smooth muscle cells, and fibroblasts [6,7]. It was reported that CD40 can initiate macrophage antimicrobial activity by rerouting intracellular pathogens to lysosomal compartment to induce fusion between pathogen containing vacuoles and lysosome, this autophagy-dependent fusion resulted in antimicrobial activity against pathogen invasion [9]. The interaction between CD40L and its receptor CD40 has been implicated to mediate inflammatory processes through the induction of various proinflammatory cytokines [6,7] and matrix metalloproteinase (MMP) [10,11] as well as the activation and recruitment of leukocytes [12]. Some of the induced proinflammatory cytokines, including interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and interferon-r (IFN-r), subsequently augment the production of CD40L and CD40, which contribute to the expansion of inflammatory response [6,12]. The increased expression of CD40L has been reported to enhance the production and activity of monocytes and proinflammatory cytokines, such as IL-1, IL-6, IL-8, and TNF-α, and monocyte chemoattractant protein-1 (MCP-1) to mediate inflammatory response [6,13,14]. Interrupting the signaling pathway of CD40–CD40L

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by the administration of anti-CD40L antibody was reported to decrease the risk of inflammatory disease in numerous animal models, including collagen-induce arthritis (CIA) [15], encephalomyelitis [16], thyroiditis [16], and inflammatory bowel disease [17]. We suggest that CD40L plays an important role for controlling the severity of inflammation. A cleavage of CD40L from the surface of cells produces a truncated soluble form of CD40L [18,19]. Soluble CD40L (sCD40L) is detectable in the blood and preserves biologic activity contributing to the mediation of inflammatory process [7,8,18–21]. The increased concentration of sCD40L in the blood has been reported in numerous inflammatoryrelated diseases, including HIV-associated neuroinflammation [20], Behcet disease [21], psoriasis [22], inflammatory bowel disease [23], and pancreatitis [4]. The activation and migration of leukocytes as well as the production of proinflammatory cytokines and MMPs were reported to play a pivotal role in pelvic inflammatory disease [24–31]. We hypothesized that CD40–sCD40L binding could facilitate the amplification of pelvic inflammatory response through the generation of cytokines and MMPs and the activation of leukocytes [7,8,18–21]. Also, the soluble form of CD40L could mediate inflammatory process in pelvic inflammatory disease, and plasma sCD40L level may be related to the severity of PID. However, to date there has been no study on the role of plasma sCD40L in patients with PID. Therefore, we estimated the expressions of sCD40L in plasma of patients with PID to establish a non-invasive strategy on its significance in the diagnosis and treatment of PID. 2. Materials and methods 2.1. Subjects and specimen collection This was a hospital-based case–control study. We cooperated with gynecologists at the Chung Shan Medical University Hospital in Taichung, Taiwan. Sixty-four women, who were diagnosed as having PID by gynecologists (Wang PH, Tee YT, and Lin LY) according to the characteristic criteria of the national guidelines for pelvic inflammatory disease [32,33], between April, 2006 and August, 2011 were recruited as a case group. Seventy healthy women, who visited the Department of Obstetrics and Gynecology or the Department of Family Medicine for health examinations such as cervical Papanicolaou smear and breast examination, were randomly selected to match the sixty-four PID patients with regard to demographical and clinical data such as age matched to within five years, race, ethnicity, resident area, cigarette smoking, and alcohol drinking status. The control group was as similar as possible to the case group, but did not have pelvic inflammatory disease. The diagnosis of PID should conform to all the minimal criteria of the Centers for Disease Control and Prevention (CDC) including lower abdominal pain or pelvic pain of no other origin with one of the following criteria: uterine tenderness or adnexal tenderness or cervical motion tenderness. In order to maximize specificity and reduce the chance of delayed or missed diagnosis, in addition to the criteria mentioned above, the patients should have at least one of the following minor criteria: oral temperature N38.3 °C, abnormal vaginal or cervical mucopurulent discharge, an abundance of white blood cells (WBCs) on microscopic inspection of vaginal secretions, elevated C-reactive protein (CRP), elevated erythrocyte sedimentations, or laboratory documentation for Neisseria gonorrhoeae or Chlamydia trachomatis. Women, who were pregnant, breastfeeding, and taking oral pills or antibiotics for other forms of inflammatory diseases, or who had systemic diseases or cancers which originated from any organs such as cervix and ovary or who had undergone a gynecologic operation within 2 months prior to admission, were excluded from the study. Whole blood specimens were collected from the seventy healthy controls and sixty-four PID patients before and after they received treatment based on the routine protocols suggested by the CDC. The recommended parenteral regimens were cefotetan or cefoxitin plus doxycycline, or clindamycin plus gentamicin. All PID patients were admitted to the ward units in

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the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital. They were given antibiotics intravenously for at least 3 days, or for another 24 h after they were afebrile. Thereafter, oral antibiotics were given until day 14 of treatment. The pre-treatment blood samples were obtained before PID patients received treatment protocols, and post-treatment blood samples were obtained one week after treatment commenced. All blood samples analyzed for nonspecific inflammatory markers, such as WBC and C-reactive protein (CRP) [34, 35], as well as plasma were analyzed for the expressions of sCD40L. Both the technician who measured the levels of sCD40L as well as the clinical laboratory staff who measured WBC, neutrophil counts, lymphocytes, and CRP were blinded to this study. The blood samples obtained for the measurement of sCD40L were placed in tubes containing EDTA and were immediately centrifuged and stored at − 80 °C. The study was performed with the approval of the Chung Shan University Hospital Institutional Review Board and written informed consent was obtained from each patient. 2.2. Sample size and statistical power We focused on the effect size (mean difference) of soluble CD40L expression between groups. Based on data from Erturan et al. [22], assuming α value was set at 0.05, our sample size had at least 80% power to detect a mean difference of 350 pg/ml based on the standard deviation was 700 pg/ml of sCD40L and the alternative hypothesis was two-sided [22]. 2.3. Measurements of sCD40L level by ELISA The sCD40L level in the plasma samples was analyzed by human sCD40L ELISA kits (R&D Systems, Abingdon, UK). From each plasma sample, 100 μl was directly transferred to the microtest strip wells of the ELISA plate and then assayed according to the manufacturer's instructions. The absorbance was measured at 495 nm in a microtest plate spectrophotometer, and the plasma level of sCD40L was quantified with a calibration curve using human sCD40L as a standard [23]. 2.4. Statistical analysis Experimental results are presented as the mean ± SE. An independent t-test was used to compare the differences of plasma levels of sCD40L, WBC and C-reactive protein (CRP) between the healthy women and PID patients before they received the treatment protocols. A paired-sample t test was used to test the difference of these parameters between pre-treatment and post-treatment plasma. Spearman correlation analysis was used to estimate the correlations between plasma level of sCD40L and inflammatory marker C-reactive protein. The adjusted odds ratio (AOR) and their 95% confidence intervals (CIs) of sCD40L, WBC, CRP and PID risk were estimated by utilizing multiple logistic regression models after adjusting for confounding. p value b0.05 was considered significant. The data were analyzed on SAS statistical software (Version 9.1, 2005; SAS Institute Inc., Cary, NC) and SPSS version 13.0 (SPSS Inc., Chicago, IL, USA) statistical software. 3. Results Except for age (p = 0.01), there was no significant difference in the distribution of demographic characteristics between PID patients and healthy controls. Blood cell count regarding WBC was significantly increased in patients with PID (11,391.71 ± 650.15) before they received treatment compared with those in healthy controls (7103.14 ± 302.85, p = 0.0001) and those in PID patients after they received treatment (6462.65 ± 278.37, p = 0.01). Also, plasma CRP-level was significantly increased in patients with PID (6.76 ± 0.80) before they received treatment compared with those in healthy controls (0.38 ± 0.03, p =

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Table 1 The demographical and clinical data of both controls and patients with pelvic inflammatory diseases (PID) before and after treatment with antibiotics. Variable

Control (n = 70) Mean ± SE

Pre-treated (n = 64) Mean ± SE

Post-treated (n = 64) Mean ± SE

p value C/UTa

p value UT/Tb

WBC (/mm3) CRP Age Resident area Race Ethnic

7103.14 ± 302.85 0.38 ± 0.03 40.58 ± 1.23 Mid-Taiwan Asian Taiwanese

11,391.71 ± 650.15 6.76 ± 0.80 35.64 ± 1.53 Mid-Taiwan Asian Taiwanese

6462.65 ± 278.37 2.06 ± 0.32

p = 0.0001 p = 0.0001 p = 0.01

p = 0.01 p = 0.0001

C = control, UT = PID patients before being treated, T = PID patients after being treated. p value b0.05 was considered significant. a The statistical difference was analyzed by an independent t-test. b The statistical difference was analyzed by a paired-sample t-test.

0.0001) and those in PID patients after they received treatment (2.06 ± 0.32, p = 0.0001) (Table 1). The concentrations of plasma sCD40L in the healthy control group as well as in PID patients before and after they received treatment protocols are shown in Fig. 1. Soluble CD40L concentration (pg/ml) of pretreatment plasma in PID patients was significantly elevated compared to that of plasma in normal controls (1632.83 ± 270.91 vs. 700.33 ± 58.77; p = 0.001) and that of post-treatment plasma in the same patients (1632.83 ± 270.91 vs. 928.77 ± 177.25; p = 0.0001). However, there was no significant difference in plasma sCD40L concentration (p = 0.22) between healthy controls and PID patients after they received treatment (Fig. 1). The concentration of sCD40L was significantly correlated (r = 0.202, p = 0.01, n = 134) with the level of plasma CRP in the blood among our recruited subjects (sixty-four PID patients and seventy healthy controls) (Fig. 2), however, there was not a significant correlation between blood sCD40L concentration and the level of plasma CRP among PID patients and healthy controls when we investigated separately in controls and PID patients (data not shown). When the cutoff level of plasma sCD40L level was determined to be 1612.26 pg/ml based on ROC, the sensitivity and specificity for PID are 0.26 and 0.97, respectively. The area under the curve (AUC) of plasma sCD40L level was 0.58 (95% confidence interval = 0.48–0.68). The adjusted odds ratio (AOR) with their 95% CI of plasma sCD40L concentration (≥ 1612.26 pg/ml) for PID risk was 7.09 (95% CI = 1.14–43.87,

Fig. 1. The significantly different expressions (p = 0.001) of soluble CD40 ligand (sCD40L) in blood plasma were shown between the seventy healthy women and the 64 patients with pelvic inflammatory disease before they received treatment; there were significantly different expressions (p = 0.0001) of sCD40L between pre-treatment and post-treatment plasma in PID patients as well. There were no significantly different sCD40L concentrations (p = 0.22) between healthy women and PID patients after receiving treatment. #The significant difference was analyzed by an independent t-test. ##The significant difference was analyzed by a paired-sample t-test.

p = 0.03), after adjusting the WBC in the blood, plasma CRP level, and age (Table 2). We also determined the cutoff level of blood WBC and CRP to be 10,000 cell count and 0.7 mg/l, based on ROC, the sensitivity and specificity for PID are 0.54 and 0.90 for WBC as well as 0.54 and 0.91 for CRP, respectively. The AUCs were 0.76 (95% confidence interval = 0.67–0.84) for blood WBC and 0.90 (95% confidence interval = 0.84–0.95) for plasma CRP. The adjusted odds ratio (AOR) with their 95% confidence intervals (CIs) of WBC and CRP level for PID risk was 3.18 (0.94–10.72, p = 0.06) and 20.34 (6.70–61.78, p = 0.0001), respectively, after adjusting for confounding factors (Table 2). 4. Discussion We suggested that increased plasma sCD40L in PID patients was an important episode during pelvic inflammatory process. sCD40L is an essential mediator of inflammation through stimulating inflammatory properties by autocrine, paracrine, and endocrine activities [8,21,36,37]. Sui et al. demonstrated that sCD40L was increased in both plasma and cerebrospinal fluid of cognitively impaired HIVinfected individuals compared to non-impaired HIV-infected individuals [20]. Erturan et al. recruited 56 patients with chronic plaque-type psoriasis and fifty-three healthy controls to estimate the role of blood sCD40L on psoriasis, and they found that plasma sCD40L levels were significantly elevated in psoriasis patients compared to healthy controls and significantly associated with the levels of blood total cholesterol. They suggested that high levels of serum sCD40L could lead to an increased risk in cardiovascular diseases among psoriasis patients [22].

Fig. 2. There was a significant correlation (r = 0.202, p = 0.01, n = 134) between SCD40L and CRP concentration in the blood. p value b0.05 was considered significant.

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Table 2 The adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) of plasma soluble CD40 ligand concentration (pg/ml) on pelvic inflammatory disease. Variable

Patients (n = 64) (%)

OR (95% CI)

p value

AOR (95% CI)

p value

sCD40 ligand concentration b1612.26 pg/ml 68 (97.1%) ≥1612.26 pg/ml 2 (2.9%)

Controls (n = 70) (%)

47 (73.4%) 17 (26.6%)

1.00 12.29 (2.71–55.75)

p b 0.0001

1.00 7.09 (1.14–43.87)

p = 0.03

White blood count b10,000 ≥10,000

63 (90.0%) 7 (10.0%)

29 (45.3%) 35 (54.7%)

1.00 10.86 (4.31–27.33%)

p b 0.0001

1.00 3.18 (0.94–10.72)

p = 0.06

C-reactive protein b0.7 ≥0.7

64 (91.4%) 6 (8.6%)

14 (21.9%) 50 (78.1%)

1.00 38.09 (13.66–106.21)

p b 0.0001

1.00 20.34 (6.70–61.78)

p b 0.0001

The odds ratios (ORs) with their 95% confidence intervals (CIs) were estimated by logistic regression models. The adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) were estimated by multiple logistic regression models, after controlling for age, WBC, and CRP levels.

In addition, Kayahan et al. enrolled 39 patients with inflammatory bowel disease (20 Crohn's disease and 19 ulcerative colitis patients) and thirty-one healthy controls to investigate the predictor of sCD40L on the progression of early atherosclerosis in patients with inflammatory bowel disease [23]. Significantly increased blood sCD40L concentrations in patients with inflammatory bowel disease as compared to those of controls were found, also finding that plasma sCD40L was significantly negatively correlated with flow mediated dilatation (r = −0.3, p b 0.05) and that sCD40L concentrations significantly predicted the values of flow mediated dilatation (adjusted R2 = − 0.38, p = 0.04). They suggested that increased sCD40L levels were significantly negatively associated with endothelial function and could predict worse vascular outcome among patients with inflammatory bowel disease [23]. To investigate the role of sCD40L on PID, we estimated plasma concentrations of sCD40L in sixty-four patients with PID and seventy healthy controls. In our study, we found that there was a significantly increased plasma sCD40L concentration among patients with PID as compared to that in healthy controls and that these levels decreased significantly when compared with that in PID patients after receiving treatment. Also, the serum markers such as WBCs and the levels of CRP were significantly elevated from before and after treatment as well as showing a significant difference between healthy women and PID patients. Moreover, the concentration of plasma sCD40L was significantly correlated with the level of plasma CRP in the blood among our recruited subjects (sixty-four PID patients and seventy healthy controls), although a significance was not found among PID patients. We suggest that estimating blood sCD40L concentration can be a non-invasive marker to assist the diagnosis of pelvic inflammatory disease. The release of sCD40L from platelets was significantly increased in patients with Crohn's disease [36] or Behcet disease [21] as compared to healthy controls, and suggested that this effect was mediated by MMP9, and MMP9 production was in turn up-regulated by sCD40L. This positive feedback could contribute to inflammatory process in Crohn's disease and Behcet disease [21,36]. The promotion of MMP9 expression from leucocytes or proinflammatory cytokines plays an important role in tissue destruction and inflammation process through degradation of extracellular matrix (ECM) in physiological and pathological conditions [38]. Significantly increased plasma MMP9 level was found in patients with PID compared to healthy controls [29,31]. Also, it has been suggested that elevated sCD40L in plasma and cerebrospinal fluid contributes to the pathogenesis of HIV-associated neurocognitive disorder (HAND) through sCD40L binding to its receptor to stimulate a pro-inflammatory, excitotoxic environment and has been recommended that sCD40L be considered as a potential therapeutic target for the management of HAND [8,20]. We suggested that the increased expression of MMP9 in PID patients was beneficial for initiating the release of sCD40L from platelets and subsequently induced positive feedback for promoting both MMP9 and sCD40L levels. Increased MMP9 and sCD40L make a great benefit to amplify pelvic inflammatory response through the degradation of extracellular matrix by MMP9 and the

binding of sCD40L–CD40 for the production of various proinflammatory cytokines and matrix metalloproteinases and the activation and recruitment of leukocytes to initiate inflammatory processes [6–8,10–12,21, 29,36]. Down-modulating the overexpression of blood sCD40L to prevent the amplification of pelvic inflammatory response could be applied in clinical management of pelvic inflammatory disease. Nonspecific serum markers, including elevated CRP, and elevated WBC, have been reported to be associated with PID [34,35]. However, these laboratory tests had low specificity for predicting PID [39]. In order to provide more beneficial clinical information regarding the diagnosis of pelvic inflammatory diseases, the cutoff level of plasma sCD40L was determined to be 1612.26 pg/ml based on ROC, the AUC, sensitivity, specificity, and the adjusted odds ratio of plasma sCD40L level for PID were 0.58 (95% CI = 0.48–0.68), 0.26, 0.97, and 7.09 (95% CI: 1.14– 43.87, p = 0.03), respectively. In our study, we determined the cutoff level of blood WBC and CRP to be 10,000 cell count and 0.7 mg/l, based on ROC, the AUC, sensitivity, specificity, and AOR for PID are 0.76 (95% CI = 0.67–0.84), 0.54, 0.90, and 3.18 (95% CI = 0.94–10.72, p = 0.06) for WBC as well as 0.90 (95% CI = 0.84–0.95), 0.54, 0.91, and 20.34 (95% CI = 6.70–61.78, p = 0.0001) for CRP, respectively. We found that all of these three blood markers were acceptable discrimination (0.5 b AUC b 1; 9.0 b specificity) for diagnosing PID. Plasma CRP levels were more outstanding discrimination (AUC = 0.9) for their sensitivity to detect PID, however, this plasma CRP level is not specificity for diagnosis of PID [39]. Moreover, we found that there were no significant differences between PID patients and healthy controls at the cutoff level (10,000 cell count/mm3) of WBC after adjusting confounders. Therefore, we suggest that the detection of plasma sCD40L concentration may be a useful adjunctive tool for the diagnosis of pelvic inflammatory disease when the cutoff level of plasma sCD40L level was determined to be ≥1612.26 pg/ml. 5. Conclusion Soluble CD40L was significantly increased in the expression of plasma of patients with pelvic inflammatory disease. Evaluating blood sCD40L concentration can be a non-invasive marker for the diagnosis of the development of pelvic inflammatory disease, and downregulating overexpression of sCD40L level may represent a new therapeutic approach in the management of PID. List of abbreviations CIA collagen-induce arthritis CD40L CD40 ligand ECM extracellular matrix HAND HIV-associated neurocognitive disorder IFN-r interferon-r IL-1β interleukin 1 IL-6 interleukin 1 IL-8 interleukin 1

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MCP-1 MMP PID TNF-α TNFR sCD40L

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monocyte chemoattractant protein-1 matrix metalloproteinase pelvic inflammatory disease tumor necrosis factor α tumor necrosis factor receptor soluble CD40 ligand

Acknowledgment We gratefully acknowledge the physicians of the Chung Shan Medical University Hospital in Taichung, Taiwan, for their assistance in recruiting the study subjects. This study was supported by a research grant from Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan and Chung Shan University, Taichung, Taiwan (CSMU-CYC102-04) and the National Science Council Taiwan (NSC102-2314-B040-002).

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Increased plasma soluble CD40 ligand concentration in pelvic inflammatory disease.

The role of soluble CD40 ligand (sCD40L) in pelvic inflammatory disease (PID) remains unclear. We sought to determine whether sCD40L was an efficient ...
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