Endometriosis: Age at diagnosis and the severity of the disease.

BACKGROUND: Endometriosis is often described as a progressive disease beginning with menarche and menstrual bleeding. However, this is controversial, as the origin of the disease remains unknown. The objective of this study was to investigate the association between the severity of endometriosis and age at initial diagnosis. MATERIAL AND METHODS: This prospective multicenter cohort study included 964 patients, newly and histologically diagnosed with endometriosis during laparoscopic treatment. The main outcome measures were diagnostic lesions with staging according to rAFS (revised American Fertility Society) scores, intensity of pain based on VAS (Visual Analog Scale) scores and quality of life from SF-36 questionnaire results. Age was treated as a categorical variable. Univariate and multivariable analyses (linear and multinomial ordinal) were conducted taking into account two by two multiple comparisons. The results were expressed with effect sizes and 95 % confidence intervals. MAIN FINDINGS: No significant association between age and rAFS stage was found (p = 0.053). The percentage of patients with a deep nodule ≥ 2 cm was respectively 20 %, 25 %, 21 %, 18 % and 9 % for patients aged ≤ 25, 26-30, 31-35, 36-40 and >40 years respectively (p = 0.005). For dysmenorrhea, 64 %, 61 %, 54 %, 51 % and 32 % of patients aged ≤25, 26-30, 31-35, 36-40 and >40 years respectively reported a VAS score of ≥7 (p ≤ 0.001). CONCLUSION: Prospective data obtained in patients newly diagnosed with endometriosis, revealed that the rAFS score is not related to patient age, and that the percentage of patients with a nodule ≥ 2 cm and severe dysmenorrhea did not increase with age. These percentages were significantly lower in patients aged > 40.

Benefits of Premaquick® Combined Detection of IL-6/Total IGFBP-1/Native IGFBP-1 to Predict Preterm Delivery.

We conducted a prospective double-blind study to compare two vaginal diagnostic methods in singleton pregnancies with threatened preterm labor (TPL) at the University Hospital of Clermont-Ferrand (France) from August 2018 to December 2020. Our main objective was to compare the diagnostic capacity at admission, in terms of positive predictive value (PPV) and negative predictive value (NPV), of Premaquick® (combined detection of IL-6/total IGFBP-1/native IGFBP-1) and QuikCheck fFN™ (fetal fibronectin) for delivery within 7 days in cases of TPL. We included 193 patients. Premaquick® had a sensitivity close to 89%, equivalent to QuikCheck fFN™, but a higher statistical specificity of 49.5% against 38.6% for QuikCheck fFN™. We found no superiority of Premaquick® over QuickCheck fFN™ in terms of PPV (6.6% vs. 7.9%), with NPV being equivalent in predicting childbirth within 7 days in cases of TPL (98.6% vs. 98.9%). Nevertheless, the combination of positive native and total IGFBP-1 and the combination of all three positive markers were associated with a higher PPV. Our results, though non-significant, support this combined multiple-biomarker approach to improve testing in terms of predictive values.

Cannabis Use in Physicians: A Systematic Review and Meta-Analysis.

Background: Cannabis use by physicians can be detrimental for them and their patients. We conducted a systematic review and meta-analysis on the prevalence of cannabis use by medical doctors (MDs)/students. Method: PubMed, Cochrane, Embase, PsycInfo and ScienceDirect were searched for studies reporting cannabis use in MDs/students. For each frequency of use (lifetime/past year/past month/daily), we stratified a random effect meta-analysis depending on specialties, education level, continents, and periods of time, which were further compared using meta-regressions. Results: We included 54 studies with a total of 42,936 MDs/students: 20,267 MDs, 20,063 medical students, and 1976 residents. Overall, 37% had used cannabis at least once over their lifetime, 14% over the past year, 8% over the past month and 1.1 per thousand (‱) had a daily use. Medical students had a greater cannabis use than MDs over their lifetime (38% vs. 35%, p < 0.001), the past year (24% vs. 5%, p < 0.001), and the past month (10% vs. 2%, p < 0.05), without significance for daily use (0.5% vs. 0.05%, NS). Insufficient data precluded comparisons among medical specialties. MDs/students from Asian countries seemed to have the lowest cannabis use: 16% over their lifetime, 10% in the past year, 1% in the past month, and 0.4% daily. Regarding periods of time, cannabis use seems to follow a U-shape, with a high use before 1990, followed by a decrease between 1990 and 2005, and a rebound after 2005. Younger and male MDs/students had the highest cannabis use. Conclusions: If more than a third of MDs tried cannabis at least once in their lifetime, this means its daily use is low but not uncommon (1.1‱). Medical students are the biggest cannabis users. Despite being common worldwide, cannabis use is predominant in the West, with a rebound since 2005 making salient those public health interventions during the early stage of medical studies.

Factors of Non-Compliance with a Protocol for Oral Administration of Misoprostol (Angusta®) 25 Micrograms to Induce Labor: An Observational Study.

We set out to identify factors of non-compliance with a protocol for the oral administration of misoprostol 25 µg (Angusta®) every 2 h (up to eight tablets), for the induction of labor (IOL). We conducted a retrospective study on IOL at term, on singleton pregnancies from 2019 to 2021, in a university hospital. The study included 195 patients, comprising 144 compliant protocols. Pain was statistically more frequent in the non-compliance group (92.2% vs. 62.5%, p < 0.001), and when a midwife was unavailable (15.7% vs. 0.7%, p < 0.001). A multivariable analysis found factors of good response (defined as going into labor before the administration of the median number of tablets, i.e., six) to be an indication for PROM (OR: 12.03, 95% CI: 5.42-26.71), and gestational age at induction (OR: 1.54, 95% CI: 1.19-2.01), independently of BMI, initial Bishop score, and parity. Patients with pain who were able to follow the protocol delivered 9 h earlier than patients with pain who interrupted the protocol and 16 h earlier than patients who experienced no pain. We identified two key elements that favored compliance: (i) providing the next tablet in advance; and (ii) offering patients early epidural analgesia when in pain in order to continue the protocol and go into labor promptly.

SurgAI3.8K: A Labeled Dataset of Gynecologic Organs in Laparoscopy with Application to Automatic Augmented Reality Surgical Guidance.

STUDY OBJECTIVE: We focus on explaining the concepts underlying artificial intelligence (AI), using Uteraug, a laparoscopic surgery guidance application based on Augmented Reality (AR), to provide concrete examples. AI can be used to automatically interpret the surgical images. We are specifically interested in the tasks of uterus segmentation and uterus contouring in laparoscopic images. A major difficulty with AI methods is their requirement for a massive amount of annotated data. We propose SurgAI3.8K, the first gynaecological dataset with annotated anatomy. We study the impact of AI on automating key steps of Uteraug. DESIGN: We constructed the SurgAI3.8K dataset with 3800 images extracted from 79 laparoscopy videos. We created the following annotations: the uterus segmentation, the uterus contours and the regions of the left and right fallopian tube junctions. We divided our dataset into a training and a test dataset. Our engineers trained a neural network from the training dataset. We then investigated the performance of the neural network compared to the experts on the test dataset. In particular, we established the relationship between the size of the training dataset and the performance, by creating size-performance graphs. SETTING: University. PATIENTS: Not available. INTERVENTION: Not available. MEASUREMENTS AND MAIN RESULTS: The size-performance graphs show a performance plateau at 700 images for uterus segmentation and 2000 images for uterus contouring. The final segmentation scores on the training and test dataset were 94.6% and 84.9% (the higher, the better) and the final contour error were 19.5% and 47.3% (the lower, the better). These results allowed us to bootstrap Uteraug, achieving AR performance equivalent to its current manual setup. CONCLUSION: We describe a concrete AI system in laparoscopic surgery with all steps from data collection, data annotation, neural network training, performance evaluation, to final application.

Success to reach 3cm of dilation with a Dinoprostone Vaginal Insert in primiparous women with a previous cesarean section versus nulliparous: A retrospective case-control study.

Background The best methods of labour induction have still been controversial because of an increased risk of uterine rupture, especially in exposed women of labour induction with prostaglandins. We here attempted to determine, after Dinoprostone Vaginal Insert, previous cesarean women (exposed women), compared with nulliparous women (non-exposed women), are more likely 1) to have the dilated cervix (up to 3 cm or more), and 2) to require cesarean after cervix being dilated 3 cm or more. Methods This retrospective observational study included 43 exposed women and 188 non exposed women . A propensity score was calculated to balance the background differences including age, BMI, Bishop. Main findings Exposed women were significantly less likely to reach 3 cm of cervix dilation than non exposed women (62.8 and 67.6% [study] vs. 83 and 81.3% [control] before and after propensy score analysis, respectively (p < 0.05)). However exposed women were significantly less likely to require cesarean than non exposed women (4.9 vs. 17.2% p = 0.03) after inverse probability of treatment weighting once 3 cm dilation was reached. Conclusion After Dinoprostone Vaginal Insert, women with scarred uterus were less likely to reach 3 cm of cervix dilation but once 3 cm of dilation was achieved, they were less likely to require cesarean.

Autism spectrum disorder and air pollution: A systematic review and meta-analysis.

Despite the widely-known effects of air pollution, pollutants exposure surrounding pregnancy and the risk for autism spectrum disorder (ASD) in newborns remains controversial. The purpose of our study was to carry out a systematic review and meta-analyses of the risk of ASD in newborns following air pollution exposure during the perinatal period (preconception to second year of life). The PubMed, Cochrane Library, Embase and ScienceDirect databases were searched for articles, published up to July 2020, with the keywords "air pollution" and "autism". Three models were used for each meta-analysis: a global model based on all risks listed in included articles, a pessimistic model based on less favorable data only, and an optimistic model based on the most favorable data only. 28 studies corresponding to a total of 758 997 newborns were included (47190 ASD and 703980 controls). Maternal exposure to all pollutants was associated with an increased risk of ASD in newborns by 3.9% using the global model and by 12.3% using the optimistic model, while the pessimistic model found no change. Each increase of 5 µg/m3 in particulate matter <2.5 µm (PM2.5) was associated with an increased risk of ASD in newborns, regardless of the model used (global +7%, pessimistic +5%, optimistic +15%). This risk increased during preconception (global +17%), during pregnancy (global +5%, and optimistic +16%), and during the postnatal period (global +11% and optimistic +16%). Evidence levels were poor for other pollutants (PM10, NOx, O3, metals, solvents, styrene, PAHs, pesticides). PM2.5 was associated with a greater risk than PM10 (coefficient 0.20, 95CI -0.02 to 0.42), NOx (0.29, 0.08 to 0.50) or solvents (0.24, 0.04 to 0.44). All models revealed that exposure to pollutants, notably PM2.5 during pregnancy, was associated with an increased risk of ASD in newborns. Pregnancy and postnatal periods seem to be the most at-risk periods.

Long-Term Evolution of Quality of Life and Symptoms Following Surgical Treatment for Endometriosis: Different Trajectories for Which Patients?

Many studies have shown a global efficacy of laparoscopic surgery for patients with endometriosis in reducing painful symptoms and improving quality of life (QoL) in the short and long-term. The aim of this study was to analyze the different trajectories of long-term evolution in QoL and symptoms following surgical treatment for endometriosis, and to identify corresponding patient profiles. This prospective and multicenter cohort study concerned 962 patients who underwent laparoscopic treatment for endometriosis. QoL was evaluated using the Short Form (SF)-36 questionnaire and intensity of pain was reported using a visual analog scale prior to surgery and at 6, 12, 18, 24 and 36 months after surgery. Distinctive trajectories of pain and QoL evolution were identified using group-based trajectory modeling, an approach which gathers individuals into meaningful subgroups with statistically similar trajectories. Pelvic symptom trajectories (models of the evolution of dysmenorrhea, dyspareunia and chronic pelvic pain intensity over years) correspond to (1) patients with no pain or pain no longer after surgery, (2) patients with the biggest improvement in pain and (3) patients with continued severe pain after surgery. Our study reveals clear trajectories for the progression of symptoms and QoL after surgery that correspond to clusters of patients. This information may serve to complete information obtained from epidemiological methods currently used in selecting patients eligible for surgery.

Indocyanine green in deep infiltrating endometriosis: a preliminary feasibility study to examine vascularization after rectal shaving.

OBJECTIVE: To evaluate the feasibility of using indocyanine green (ICG) to estimate the vascularization of the resected zone during a laparoscopic rectal shaving. DESIGN: Indocyanine green can highlight blood vascularization when injected intravenously. There is no relevant, objective, intraoperative method to assess the vascularity of the resected zone during a laparoscopic rectal shaving for deep infiltrating endometriosis (DIE) to prevent fistula. We conducted a registered clinical trial examining the feasibility of the use of ICG to evaluate the bowel vascularization after endometriosis rectal shaving (Institutional Review Board number 2016-002773-35). SETTING: Tertiary university hospital. PATIENT(S): Twenty-one patients underwent laparoscopic surgery for DIE with a rectal shaving. INTERVENTION(S): Patients undergoing laparoscopic surgery for DIE received ICG intravenously at the end of the endometriosis resection. MAIN OUTCOME MEASURE(S): The main evaluation criteria was the fluorescence degree in the operated rectal area and in the vaginal suture. We used a visual assessment with a Likert-type scale from 0 to 4 (0 = no fluorescence; 4 = very good fluorescence). RESULT(S): No adverse reaction was recorded. Most of the patients (81%) showed very good fluorescence levels at the rectal shaving area. The protocol did not increase the operating time. In one patient we changed the surgical strategy making two stitches to bring the rectal muscularis closer together, which improved the degree of fluorescence. There was no case of digestive fistula. CONCLUSION: Indocyanine green fluorescent imaging is feasible in endometriosis surgery and may be considered as a potential candidate to further enhance patient safety in endometriosis bowel surgery. CLINICAL TRIAL REGISTRATION NUMBER: NCT03080558.

Letter to the Editor: Comment on "Maternal exposure to air pollution and risk of autism in children: A systematic review and meta-analysis".

Comment on "Maternal exposure to air pollution and risk of autism in children: A systematic review and meta-analysis". Some points and/or limitations of their review and meta-analysis should be discussed.

Identification of Predictive Factors in Endometriosis for Improvement in Patient Quality of Life.

STUDY OBJECTIVE: To investigate predictive factors for change in quality of life (QOL) between pre- and postoperative periods in patients with endometriosis. DESIGN: A prospective and multicenter cohort study. SETTING: Five districts including a tertiary referral center and private and general public hospitals. PATIENTS: Nine hundred eighty-one patients aged 15 to 50 years underwent laparoscopic treatment (preferred approach) for endometriosis between January 2004 and December 2012. INTERVENTIONS: Laparoscopic treatment for endometriosis. All revised American Fertility Society stages were included. MEASUREMENTS AND MAIN RESULTS: QOL was evaluated using the 36-Item Short Form Survey questionnaire. Factors influencing changes for each 36-Item Shorty Form Survey domain score between t0 (before surgery) and 1 year after surgery were predicted on the basis of univariate and multivariable analyses. The effect size (ES) method was used to measure changes in QOL. Univariate analysis revealed that 47% of stage IV endometriosis patients presented an improvement in the postoperative Physical Component Summary (PCS) score (ES ≥ 0.8) versus 26%, 31.3%, and 27.5% of patients with stage I, II, and III, respectively (p <.001). Forty-four percent and 38% of patients with chronic pelvic pain (CPP) presented an improvement in postoperative PCS and Mental Component Summary scores (ES>0.8) versus 23% and 24% of patients without CPP, respectively (p <.001). Multivariable analysis (ES > 0.8 vs ES < 0) revealed that women with CPP were more likely to experience greater improvement in postoperative PCS and Mental Component Summary scores than women without CPP (relative risk [RR] = 2.7; 95% confidence interval [CI], 1.7-4.4; p <.001 and RR = 1.8; 95% CI, 1.2-2.8; p <.01, respectively). Accordingly, fertile patients were more likely to show higher rates of improvement in the postoperative PCS score than infertile patients (RR = 1.8; 95% CI, 1.1-3.1; p <.05). CONCLUSION: Patients presenting with severe endometriosis and who experience higher levels of pain are more likely to show improvement in QOL after surgery. CPP is the most significant independent predictive factor for changes in QOL scores.

Minilaparoscopic Total Hysterectomy in Current Practice Feasibility and Benefits: A Unicentric, Randomized Controlled Trial.

STUDY OBJECTIVE: To investigate whether mini-instrumentation may be used for hysterectomy (HT) by all surgeons (assistants and seniors) without increasing the operative time or altering surgeon working conditions. DESIGN: A unicenter, randomized controlled, single blind, parallel, noninferiority trial comparing 2 surgical techniques. SETTING: A tertiary referral center. PATIENTS: Thirty-two patients undergoing HT for a benign gynecologic disease were enrolled in this study in our center between April 2, 2015, and June 1, 2018. Sixteen patients were randomized in group A and 16 patients in group B. INTERVENTIONS: HT with bilateral annexectomy or ovarian conservation using 3-mm instruments (group A) or conventional 5-mm instruments (group B). MEASUREMENTS AND MAIN RESULTS: Concerning the primary outcome, the operative time for the HT 3-mm group was 128 minutes (range, 122-150 minutes) versus 111 minutes (range, 92-143 minutes) for the HT 5-mm group (i.e., δ = 17 [90% confidence interval, -6 to 39]), with rejection of the noninferiority threshold at 35 minutes. Thirty-one percent of HTs initially performed using 3-mm instruments were completed with conventional instruments. HTs performed with mini-instruments required more concentration (p = .02) with surgeons reporting higher levels of frustration (p = .009) and sense of failure (p = .006). Patients tend to experience greater satisfaction regarding scars with a significant difference noted during the postoperative visit both for scar pain (1 vs 4 patients with moderate pain [30-50 mm on the Patient Scar Assessment Scale) in the HT 3-mm group and the HT 5-mm group, respectively) and scar firmness (p = .021; 3 vs 7 patients with moderate firmness [30-50 mm on the Patient Scar Assessment Scale] in the HT 3-mm group and the HT 5-mm group, respectively). CONCLUSION: Total minilaparoscopic HT appears inferior to standard laparoscopy in terms of operative time and surgeon working conditions; only the short-term cosmetic appearance was in favor of the 3-mm approach.

Repetitive Transcranial Magnetic Stimulation Therapy (rTMS) for Endometriosis Patients with Refractory Pelvic Chronic Pain: A Pilot Study.

Endometriosis concerns more than 10% of women of reproductive age, frequently leading to chronic pelvic pain. Repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) induces an analgesic effect. This effect on chronic pelvic pain is yet to be evaluated. The objective of this study was to assess the feasibility and effect of rTMS to reduce pain and improve quality of life (QoL) in patients with chronic pelvic pain due to endometriosis. This pilot, open-labelled prospective trial examined treatment by neuronavigated rTMS over M1, one session per day for 5 consecutive days. Each session consisted of 1.500 pulses at 10 Hz. We assessed tolerance, pain change and QoL until 4 weeks post treatment with a primary endpoint at day 8. Twelve women were included. No patients experienced serious adverse effects or a significant increase in pain. Nine women reported improvement on the Patient Global Impression of Change with a reduction in both pain intensity and pain interference (5.1 ± 1.4 vs. 4.1 ± 1.6, p = 0.01 and 6.2 ± 2.1 vs. 4.2 ± 1.5, p = 0.004, respectively). rTMS appears well tolerated and might be of interest for patients suffering from chronic pelvic pain for whom other treatments have failed. A randomized controlled trial is mandatory before proposing such treatment.

Patient Quality of Life and Symptoms after Surgical Treatment for Endometriosis.

STUDY OBJECTIVE: To assess the impact of surgical treatment of endometriosis on quality of life and pain over a 3-year period of postoperative follow-up. DESIGN: Prospective and multicenter cohort study (Canadian Task Force classification II-2). SETTING: Five districts including a tertiary referral center and private and general public hospitals. PATIENT: Patients (n = 981), aged 15 to 50years, underwent laparoscopic treatment (preferred approach) for endometriosis between January 2004 and December 2012. INTERVENTION: Laparoscopic treatment for endometriosis. All revised American Fertility Society stages were included. MEASUREMENTS AND MAIN RESULTS: The mean visual analog scale score for dysmenorrhea fell from 5.3 ± 3.7 (time 0) to 2.6 ± 3.3 at 6 months, and 2.3 ± 3.3 at 36 months of follow-up (p <.001). Mean visual analog scale scores for chronic pelvic pain and dyspareunia fell from 2.6 ± 3.5 and 2.7 ± 3.2, respectively, before surgery to 1.4 ± 2.5 and 1.1 ± 2.2 at 6 months and then 1.3 ± 2.5 and 1.2 ± 2.3 at 36 months of follow-up. The Short Form 36-Item survey analysis revealed the greatest increases linked to physical domains (i.e., bodily pain and role limitations) from 54.6 ± .9 and 63.3 ± 1.3, respectively, at time 0 to 74.4 ± .9 and 81.9 ± 1.1 at 6 months of follow-up (p <.001), with scores subsequently remaining stable. Among mental domains the most favorable results involved social functioning and role limitations due to emotional problems, which increased from 66 ± .8 and 65.7 ± 1.3 at time 0 to 75.6 ± .9 and 77.4 ± 1.3 at 6 months of follow-up, respectively (p <.001), with scores remaining stable over time. CONCLUSIONS: Surgical treatment of endometriosis improves pelvic and sexual pain postoperatively in many women with endometriosis. Improvement later plateaus and remains stable, allowing patients to experience the beneficial effects over a period of years.

Feelings and expectations in endometriosis: Analysis of open comments from a cohort of endometriosis patients.

INTRODUCTION: Endometriosis symptoms may have a negative effect on health-related quality of life (HRQoL). Analyses of open comments are known to be a key source of information and support. The authors aimed to analyse open comments associated with a validation scale study, in order to ascertain whether the questionnaires allowed an adequate exploration of patient preoccupations and in so doing define important quality of life themes not assessed in HRQoL scales. MATERIAL AND METHODS: Analysis of open comments, following two questionnaires (SF-36 and EHP-30) as part of a national study evaluating the EHP-30, was performed. Questionnaires were distributed online, via a link to the RedCap Internet platform. The association EndoFrance, a support group for endometriosis patients, notified women of the launching of the study. Women were asked to complete the questionnaire and had the opportunity to comment. Comments were gathered, coded systematically, and categorised by theme. RESULTS: Of the 1156 women who responded to the questionnaire, 913 (79.0%) declared having a confirmed surgical diagnosis of endometriosis, and 265 comments were analysed. Comments were classified in 20 themes. Correspondence between the themes and items for both questionnaires and the open comments was investigated for all topics, including those non-addressed by the questionnaires. 8 themes are not mentioned in both questionnaires, 9 themes are covered by EHP-30, two by SF-36 and only one by both. CONCLUSION: Anonymous data collection and subsequent analysis proves to be an effective and practical way of obtaining patient opinion on their pathology. Analysis of comments may provide additional and useful information to the classical HRQoL Scale.

Long-term evaluation of painful symptoms and fertility after surgery for large rectovaginal endometriosis nodule: a retrospective study.

INTRODUCTION: Optimal surgical treatment of rectovaginal endometriosis remains a controversial topic. The objective of this study was to evaluate long-term postoperative outcomes after rectal shaving or colorectal resection for rectovaginal endometriosis. MATERIAL AND METHODS: 195 patients underwent surgery (172 managed by shaving, 23 by colorectal resection) between January 2000 and June 2013 for rectovaginal endometriosis (>2 cm) involving at least the serosa of the rectum. Primary outcome measures were pain and fertility. Secondary outcome measures were complications, recurrence rates and quality of life. RESULTS: Mean follow-up was 60 ± 42 months in the shaving group and 67 ± 47 months in the resection group. The mean VAS score for pelvic pain between the pre and postoperative period decreased from 5.5 ± 3.5 (shaving group) and 7.3 ± 2.9 (resection group) to 2.3 ± 2.4 (p < 0.001) and 2.0 ± 1.8 (p < 0.001), respectively. For dysmenorrhea, the mean baseline VAS score fell postoperatively from 7.7 ± 2.8 (shaving group) and 8.2 ± 2.6 (resection group) to 3.3 ± 2.9 (p < 0.001) and 2.7 ± 2.7 (p < 0.001), respectively. Pregnancy rates were 73% for shaving and 69% for resection. Major complications occurred in 4% of patients in the shaving group and in 26% in the resection group (p = 0.001). Thirteen patients (7.6%) from the shaving group and none from the resection group were reoperated for suspicion of endometriosis recurrence (p = 0.37). Postoperative quality of life scores revealed no differences between the two groups. CONCLUSION: Our study demonstrates that rectal shaving, when feasible for rectovaginal nodule (>2 cm) infiltrating the digestive serosa, has equal impact on pain and pregnancy rates compared with colorectal resection at long-term follow-up, with low complication and favorable pregnancy rates.

Cigarette smoke condensate affects the retinoid pathway in human amnion.

INTRODUCTION: The preterm premature rupture of membranes (PPROM) is a frequent pathology responsible of more than 30% of preterm births. Tobacco smoking is one of the most frequently described risk factors identified and contributes to the pre term weakening of fetal membranes. As previously demonstrated, all-trans retinoic acid (atRA) regulates several genes involved in the extracellular matrix dynamics, an essential actor in fetal membrane ruptures. We hypothesized that cigarette smoke may affect this pathway in human amnion. METHODS: Amnion was obtained from full-term fetal membranes collected from non-smoking women after cesarean births and used either as explants or for the isolation of derived epithelial cells. The pro-healing and transcriptomic effects of atRA were studied by a scratch assay experiment and quantitative RT-PCR, respectively, after treatment with dimethyl sulfoxyde (DMSO), atRA, DMSO + cigarette smoke condensate (CSC), or atRA + CSC. RESULTS: Our results show a strong alteration of the retinoid pathway after CSC treatment on amnion-derived epithelial cells and explants. We first demonstrated that CSC inhibits the activity of the RARE reporter gene in amnion-derived epithelial cells. Then, atRA's effects on both the transcription of its target genes and wound healing were demonstrated to be inhibited or at least decreased by the CSC in human amnion epithelial cells. DISCUSSION: Here, we demonstrated that CSC altered the retinoid signal, already known to have roles in fetal membrane physiopathology. These results highlight a potential negative action of maternal smoking on the retinoid pathway in human amnion and more generally on pregnancy.

Retinoic Acid Engineered Amniotic Membrane Used as Graft or Homogenate: Positive Effects on Corneal Alkali Burns.

Purpose: Alkali burns are the most common, severe chemical ocular injuries, their functional prognosis depending on corneal wound healing efficiency. The purpose of our study was to compare the benefits of amniotic membrane (AM) grafts and homogenates for wound healing in the presence or absence of previous all-trans retinoic acid (atRA) treatment. Methods: Fifty male CD1 mice with reproducible corneal chemical burn were divided into five groups, as follows: group 1 was treated with saline solution; groups 2 and 3 received untreated AM grafts or grafts treated with atRA, respectively; and groups 4 and 5 received untreated AM homogenates or homogenates treated with atRA, respectively. After 7 days of treatment, ulcer area and depth were measured, and vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) were quantified. Results: AM induction by atRA was confirmed via quantification of retinoic acid receptor ß (RARß), a well-established retinoic acid-induced gene. Significant improvements of corneal wound healing in terms of ulcer area and depth were obtained with both strategies. No major differences were found between the efficiency of AM homogenates and grafts. This positive action was increased when AM was pretreated with atRA. Furthermore, AM induced a decrease in VEGF and MMP-9 levels during the wound healing process. The atRA treatment led to an even greater decrease in the expression of both proteins. Conclusions: Amnion homogenate is as effective as AM grafts in promoting corneal wound healing in a mouse model. A higher positive effect was obtained with atRA treatment.

Myocilin expression is regulated by retinoic acid in the trabecular meshwork-derived cellular environment.

Glaucoma is the leading cause of irreversible blindness and is usually classified as angle closure and open angle glaucoma (OAG). Primary open angle glaucoma represents the most frequent clinical presentation leading to ganglion cell death and optic nerve degeneration as a main consequence of an intraocular pressure' (IOP) increase. The mechanisms of this IOP increase in such pathology remain unclear but one protein called Myocilin could be a part of the puzzle in the trabecular meshwork (TM). Previously described to be transcriptionally regulated by glucocorticoids, the comprehension of the trabecular regulation of Myocilin' expression has only weakly progressed since 15 years. Due to the essential molecular and cellular implications of retinoids' pathway in eye development and physiology, we investigate the potential role of the retinoic acid in such regulation and expression. This study demonstrates that the global retinoids signaling machinery is present in immortalized TM cells and that Myocilin (MYOC) expression is upregulated by retinoic acid alone or combined with a glucocorticoid co-treatment. This regulation by retinoic acid acts through the MYOC promoter which contains a critical cluster of four retinoic acid responsive elements (RAREs), with the RARE-DR2 presenting the strongest effect and binding the RARα/RXRα heterodimer. All together, these results open up new perspectives for the molecular understanding glaucoma pathophysiology and provide further actionable clues on Myocilin gene regulation.