Epione application: An integrated web­toolkit of clinical genomics and personalized medicine in systemic lupus erythematosus.

Genome wide association studies (GWAS) have identified autoimmune disease­associated loci, a number of which are involved in numerous disease­associated pathways. However, much of the underlying genetic and pathophysiological mechanisms remain to be elucidated. Systemic lupus erythematosus (SLE) is a chronic, highly heterogeneous autoimmune disease, characterized by differences in autoantibody profile, serum cytokines and a multi­system involvement. This study presents the Epione application, an integrated bioinformatics web­toolkit, designed to assist medical experts and researchers in more accurately diagnosing SLE. The application aims to identify the most credible gene variants and single nucleotide polymorphisms (SNPs) associated with SLE susceptibility, by using patient's genomic data to aid the medical expert in SLE diagnosis. The application contains useful knowledge of >70,000 SLE­related publications that have been analyzed, using data mining and semantic techniques, towards extracting the SLE­related genes and the corresponding SNPs. Probable genes associated with the patient's genomic profile are visualized with several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, to obtain a representative number of the most credible candidate genes and biological pathways associated with the SLE. Furthermore, an evaluation study was performed on a patient diagnosed with SLE and is presented herein. Epione has also been expanded in family­related candidate patients to evaluate its predictive power. All the recognized gene variants that were previously considered to be associated with SLE were accurately identified in the output profile of the patient, and by comparing the results, novel findings have emerged. The Epione application may assist and facilitate in early stage diagnosis by using the patients' genomic profile to compare against the list of the most predictable candidate gene variants related to SLE. Its diagnosis­oriented output presents the user with a structured set of results on variant association, position in genome and links to specific bibliography and gene network associations. The overall aim of the present study was to provide a reliable tool for the most effective study of SLE. This novel and accessible webserver tool of SLE is available at http://geneticslab.aua.gr/epione/.

Demetra Application: An integrated genotype analysis web server for clinical genomics in endometriosis.

Demetra Application is a holistic integrated and scalable bioinformatics web­based tool designed to assist medical experts and researchers in the process of diagnosing endometriosis. The application identifies the most prominent gene variants and single nucleotide polymorphisms (SNPs) causing endometriosis using the genomic data provided for the patient by a medical expert. The present study analyzed >28.000 endometriosis­related publications using data mining and semantic techniques aimed towards extracting the endometriosis­related genes and SNPs. The extracted knowledge was filtered, evaluated, annotated, classified, and stored in the Demetra Application Database (DAD). Moreover, an updated gene regulatory network with the genes implements in endometriosis was established. This was followed by the design and development of the Demetra Application, in which the generated datasets and results were included. The application was tested and presented herein with whole­exome sequencing data from seven related patients with endometriosis. Endometriosis­related SNPs and variants identified in genome­wide association studies (GWAS), whole­genome (WGS), whole­exome (WES), or targeted sequencing information were classified, annotated and analyzed in a consolidated patient profile with clinical significance information. Probable genes associated with the patient's genomic profile were visualized using several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, in an effort to obtain a representative number of the most credible candidate genes and biological pathways associated with endometriosis. An evaluation analysis was performed on seven patients from a three­generation family with endometriosis. All the recognized gene variants that were previously considered to be associated with endometriosis were properly identified in the output profile per patient, and by comparing the results, novel findings emerged. This novel and accessible webserver tool of endometriosis to assist medical experts in the clinical genomics and precision medicine procedure is available at http://geneticslab.aua.gr/.

Endometriosis research in the -omics era.

Endometriosis is a pathological condition extensively studied, but its pathogenesis is not completely understood, since its pathophysiology stems from a broad spectrum of environmental influences and genetic factors. Moreover, the nature of this condition is heterogeneous and includes different anatomical entities. Scientists actively pursue discovery of novel biomarkers in the hope of better identifying susceptible individuals in early stages of the disease. High-throughput technologies have substantially revolutionized medical research and, as a first step, the advent of genotyping arrays led to large-scale genome-wide association studies (GWAS) and enabled the assessment of global transcript levels, thus giving rise to integrative genetics. In this framework, comprehensive studies have been conducted at multiple biological levels by using the "omics" platforms, thus allowing to re-examine endometriosis at a greater degree of molecular resolution. -Omics technologies can detect and analyze hundreds of markers in the same experiment and their increasing use in the field of gynecology comes from an urgent need to find new diagnostic and therapeutic tools that improve the diagnosis of endometriosis and the efficacy of assisted reproductive techniques. Proteomics and metabolomics have been introduced recently into the every day methodology of researchers collaborating with gynecologists and, importantly, multi-omics approach is advantageous to gain insight of the total information that underlies endometriosis, compared to studies of any single -omics type. In this review, we expect to present multiple studies based on the high-throughput-omics technologies and to shed light in all considerable advantages that they may confer to a proper management of endometriosis.

Epidemiological aspects of the outcomes from the treatment of endometriosis: Experience from two different geographical areas.

The purpose of the present study was two-fold: First to review the epidemiological aspects of the experience on the surgical outcomes via laparotomy or laparoscopy, as regards endometriosis from two different academic institutions and, second, to illustrate potential differences in two different geographical areas, New Haven (US) and Greece. This retrospective study included 1,200 patients (15-80 years of age) treated via laparotomy or laparoscopy, at two different institutions, for endometriosis, between 1990 and 2017. Data were collected and analyzed from medical and pathological reports. The statistical methods used included the Student's t-test and χ2 test, as well as the Mann-Whitney U test. A total of 600 women from Yale University and 600 women from Greece participated in this study. Endometrioma was confirmed in 359 (29.9%) cases. Women were compatible in terms of the site of endometriomas. Left-sided cysts were observed (P<0.001) significantly more often compared with right-sided cysts in both groups. The two groups of patients had similar rates of endometriosis stages. A statistically significant positive association (P<0.001) was found for the co-existence of benign gynecological tumors (apart from endometrioma), endometriosis-associated ovarian cancer and for post-menopausal endometriosis in women with endometriosis from Greece. Moreover, similar results were observed as regards endometriosis following in utero exposure to diethylstilbestrol (DES), non-Hodgkin's lymphoma, endometriosis-associated Lyme disease, human immuno-deficiency virus (HIV), melanoma and endometriosis in adolescents, between the two groups. To conclude, the two populations exhibited similar results as regards the surgical outcomes of endometriosis laparoscopic or open surgery. Endometriosis represents a multifactorial entity that depends on complex interactions of hormonal, genetic, immunological and environmental factors. Gynecologists should be aware that there is an association between endometriosis and cancerous diseases. It is thus suggested that the presence of comorbidities in women with endometriosis.

Role of FN1 and GREB1 gene polymorphisms in endometriosis.

Endometriosis is a complex gynecological disorder, affecting up to 10% of women of childbearing age, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic, epigenetic and environmental factors, with an overall heritability estimated at approximately 50%. The aim of the present study was to evaluate the association of rs1250248 and rs11674184 single nucleotide polymorphisms (SNPs), mapping to fibronectin 1 (FN1) and growth regulation by estrogen in breast cancer 1 (GREB1) genetic loci, respectively, with the risk of endometriosis. A total of 166 women with endometriosis (stages I-IV) who were hospitalized for the condition, diagnosed by laparoscopic intervention and histologically confirmed, and 168 normal controls were recruited and genotyped. Genotyping of the rs1250248 and rs11674184 SNPs was performed with TaqMan primer/probe sets. A significant association was detected with the A allele, as well as the AA and AG genotypes of rs1250248 (FN1) in patients with endometriosis, as well as in patients with stage I and II of the disease only. The rs11674184 SNP of the GREB1 gene was not found to be associated with an increased susceptibility to endometriosis either for all patients (stages I-IV) or for subgroups of stage I and II or III and IV of the disease only. Our results demonstrated a genetic association between the rs1250248 (FN1) SNP and endometriosis at both the genotypic and allelic level. However, although rs11674184 of GREB1 constitutes one of the most consistently associated SNPs with endometriosis in European ancestry populations, it was not found to be associated with endometriosis in this study.

Retrospective evaluation of pathological results among women with ovarian endometriomas versus teratomas.

The coexistence of endometrioma with dermoid cyst of the ovaries is an unusual entity, although they are both common and benign gynecological tumors. The present study aimed to investigate the association between ovarian dermoid cyst (teratoma) and endometrioma. We retrospectively, included 315 women with endometrioma and 172 with ovarian teratoma. Data were collected from medical and pathological reports from two different areas between 1995 and 2018. The mean age of cases with endometrioma was similar (35.8±7.2 years) to patients with ovarian teratoma (34.2±6.8 years). Considering the types of dermoid cysts, the observed proportion of mature type was 168/172 (98%), the immature type was 4/172 (2%) and struma ovarii was14/172 (8.1%) respectively. Endometrioma was significantly more frequent in the left ovary [174/266 (65.4%)] than in the right ovary [92/266 (34.6%)], P<0.001. By contrast, ovarian teratoma were predominant in the right ovary, 98/172 (60.6%), compared to the left side, 56/172 (32.5%), P<0.001. Regarding the size of the masses, we detected an inverse distribution between the two groups. Thirteen women were detected with ovarian teratoma and endometriosis, with 6 cases being in the same ovary. Our results indicate a left lateral predispostion of endometrioma and a right of ovarian teratoma and suggest that the pathogenesis between these conditions is different. The coexistence of endometriosis with dermoid cyst of the ovary, presents a challenge to the physicians and the investigators. Further research is required to establish the relationship between endometriosis and ovarian teratoma.

Defining the genetic profile of endometriosis.

Endometriosis is a pathological condition which has been extensively studied, since its pathophysiology stems from a broad spectrum of environmental influences and genetic factors. Familial studies aim at defining inheritance trends, while linkage analysis studies focus on the identification of genetic sites related to endometriosis susceptibility. Genetic association studies take into account candidate genes and single nucleotide polymorphisms, and hence target at unraveling the association between disease severity and genetic variation. The common goal of various types of studies is, through genetic mapping methods, the timely identification of therapeutic strategies for disease symptoms, including pelvic pain and infertility, as well as efficient counselling. While genome-wide association studies (GWAS) play a primary role in depicting genetic contributions to disease development, they entail a certain bias as regards the case-control nature of their design and the reproducibility of the results. Nevertheless, genetic-oriented studies and the implementation of the results through clinical tests, hold a considerable advantage in proper disease management. In this review article, we present information about gene-gene and gene-environment interactions involved in endometriosis and discuss the effectiveness of GWAS in identitying novel potential therapeutic targets in an attempt to develop novel therapeutic strategies for a better management and treatment of patients with endometriosis.

Keeping an Eye on Perimenopausal and Postmenopausal Endometriosis.

Introduction: We aimed to describe and review the epidemiological aspect of the disease pattern of a series of perimenopausal and postmenopausal women with a histology confirmation of endometriosis. Material and Methods: We retrospectively examined the clinical records of 184 perimenopausal and 46 postmenopausal women with endometriosis. Data were collected and analyzed from 1100 patients' charts with confirmed endometriosis and involved cases from two different geographical areas, New Haven (US) and Greece. The statistical methods included ײ and the Mann-Whitney U test. In the perimenopausal group (age 45⁻54 years), there were 184 patients (16.7%) and the postmenopausal group (55⁻80 years) had 46 (4.2%). The average age of diagnosis was (49 ± 2.3) and (61.2 ± 5.1), respectively (p < 0.01). Results: Advanced endometriosis was more aggressive in the perimenopausal group (p < 0.05); in the same group, we observed a higher left-sided predisposition of endometriosis in comparison with the right side (p < 0.01). Endometrioma was the most common gynecological condition among patients with perimenopausal endometriosis in relation to the postmenopausal group (p < 0.001). Additionally, we found uterine leiomyomata more prominent in the perimenopausal group (p < 0.05). In contrast, adenomyosis was found higher in postmenopausal patients (p < 0.05); further, 24 cases with dry eye we observed. Conclusions: Postmenopausal endometriosis is an important underestimated condition. Although the reported situation is not common, various clinicopathological characteristics were observed in both groups. Clinicians should be aware that there is a correlation between endometriosis and endometriosis-associated ovarian cancer in perimenopausal and postmenopausal age.

Whole exome sequencing identifies hemizygous deletions in the UGT2B28 and USP17L2 genes in a three­generation family with endometriosis.

Endometriosis is an enigmatic condition with an unknown etiology and a poorly understood pathogenesis. It is considered to appear from the interplay of many genetic and environmental factors, affecting up to 10% of women and represents a major cause of pain and infertility. The familial association of endometriosis, as demonstrated through monozygotic twin and family studies suggests a genetic contribution to the disease, with further case­control and genome­wide association studies (GWAS) detecting various endometriosis risk factors. In a recent study, we described a unique, three­generation family of Cretan origin (Greece) with 7 females with surgically confirmed endometriosis (grandmother, 3 daughters and 3 granddaughters). All the affected members of this family displayed a variety of clinical manifestations and complications. In the present study, to further analyze the genetic variants conferring the risk of developing endometriosis, whole exome sequencing (WES) was performed, using the AmpliSeq technology on the Ion Proton platform. An initial analysis of 64 variants that were detected across the 14 genes previously confirmed to be associated with endometriosis, did not identify any deleterious exonic variants in these genes. However, further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis of endometriosis, apart from those already identified by GWAS.

Co-existence of endometriosis with 13 non-gynecological co-morbidities: Mutation analysis by whole exome sequencing.

Endometriosis is an enigmatic condition with an unknown etiology and poorly understood pathogenesis and women with endometriosis represent a high-risk population group for a large category of chronic conditions. The study focused on a 67-year-old woman who presented with a 40-year history of familial endometriosis associated with various non-gynecological co-morbidities, thus representing a unique case from a cohort of 1,000 patients with endometriosis. Her family history included infertile members suffering from endometriosis. Thirteen non-gynecological co-morbidities were documented throughout the years, including five autoimmune diseases (i.e., systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis, bronchial asthma and Crohn's disease), urinary bladder diverticulum, osteoporosis, multinodular goiter, cardiovascular diseases, gastroesophageal reflux disease, malignant tumor of urinary bladder, Barrett's esophagus and bilateral cataract. In order to understand the potential role of gene mutations in the development of all those co-morbidities, whole exome sequencing was performed and the presence of various disease-associated, potentially causal missense variants, were observed. These findings are in accordance with the previously suggested common underlying etiologic pathway for some, but not all, autoimmune disorders. This unusual case provides novel insights demonstrating that endometriosis can coexist with various chronic autoimmune diseases and other conditions, including non-gynecological malignancies, which possibly share a common genetic cause, a fact that should be taken into consideration seriously by clinicians.

Endometriosis and in vitro fertilisation.

The aim of the present review was to discuss a matter of concern in the clinical field of obstetrics/gynecology, namely the potency of in vitro fertilization (IVF) in the management of endometriosis-associated infertility. Endometriosis is a medical condition affecting one tenth of women in their fertile years, and accounts for up to 50% of infertile women. Thus, such high prevalence has established the necessity for investigating the effectiveness of available techniques in eradicating the disease and constraining infertility as well as the accompanying pain symptoms of endometriosis. The underlying mechanisms connecting endometriosis with low fecundity have been extensively studied, both in terms of genetic alterations and epigenetic events that contribute to the manifestation of an infertility phenotype in women with the disease. Several studies have dealt with the impact of IVF in pregnancy rates (PRs) on patients with endometriosis, particularly regarding women who wish to conceive. Results retrieved from studies and meta-analyses depict a diverse pattern of IVF success, underlining the involvement of individual parameters in the configuration of the final outcome. The ultimate decision on undergoing IVF treatment should be based on objective criteria and clinicians' experience, customized according to patients' individual needs.

Association between ovarian cancer and advanced endometriosis.

We retrospectively analyzed clinicopathological data in two different countries over the past years on the association between ovarian endometriosis and ovarian carcinoma. Medical and pathological reports were evaluated from 1,000 patients with endometriosis from two different geographical areas. The prevalence and women characteristics of cases were analyzed. Endometriosis-associated ovarian cancer was present in 20 (2%) cases, among the study subjects. The observed prevalence was 12 (60%) for endometrioid carcinoma, 4 (20%) for clear cell ovarian carcinoma, 2 (10%) for serous and 2 (10%) for mucinous adenocarcinoma. A higher proportion of endometrioid carcinoma cases were noted in comparison with other types (P<0.001). We found only 3/20 (15%) postmenopausal cases. In all cases, we reported advanced stage of endometriosis (stage III or IV). Left-sided endometrioid carcinoma were notably more common than right-sided ones (P<0.001). In the majority of cases, malignant transformation of endometriosis was observed in endometrioid carcinoma or clear cell carcinoma of the ovary. Further research is required to establish the relationship between endometriosis and ovarian cancer.

Co-existence of benign gynecological tumors with endometriosis in a group of 1,000 women.

The purpose of this study was two-fold, first to investigate the association between endometriosis and the risk of benign gynecologic tumors and, secondly, to evaluate the distribution of endometrioma and ovarian cysts in women with endometriosis. The medical and pathological reports of 1,000 women with endometriosis were retrospectively reviewed. The incidence of ovarian cysts, uterine leiomyomas and adenomyosis, as well as the side of ovarian cysts were further compared. A total of 295 cases of endometriomas, 172 cases of adenomyosis, 173 cases of ovarian cysts and 89 cases of uterine leiomyomas were confirmed histologically in patients with endometriosis. Serous cysts represented the most frequent diagnosis (n=81, 8.1%) in women with ovarian cysts, followed by dermoid cysts (n=15, 1.2%). In women with unilateral endometriomas, the observed proportion of left-sided cysts was found in 65.6% (164 of 250), significantly higher compared with right-sided cysts (86 out of 250, 34.4%) (P<0.001). Moreover, patients with other ovarian cysts were recognized as left-sided in 60% (96 out of 160) of cases, significantly higher compared with right-sided cysts (64 out of 160, 40%) (P<0.01). On the whole, the current study indicates that endometriosis may be associated with an increased risk of benign gynecological tumors, such as ovarian cysts, adenomyosis and leiomyomas. The results of this study confirm a left lateral predisposition of endometriomas and ovarian cysts.

The role of IL­16 gene polymorphisms in endometriosis.

Endometriosis is one of the most common gynecological diseases affecting up to 10% of the female population of childbearing age and a major cause of pain and infertility. It is influenced by multiple genetic, epigenetic and environmental factors. Interleukin­16 (IL­16) is a proinflammatory cytokine playing a pivotal role in many inflammatory and autoimmune diseases as well as in the pathogenesis of endometriosis. The aim of the present study was to evaluate the association of two IL­16 gene single nucleotide polymorphisms (SNPs), rs4072111 and rs11556218, with the risk of endometriosis in women from Greece as well as to gain insight about the structural consequences of these two exonic SNPs regarding development of the disease. A total of 159 women with endometriosis (stages I­IV) hospitalized for endometriosis, diagnosed by laparoscopic intervention and histologically confirmed, and 146 normal controls were recruited and genotyped. Subjects were genotyped using a polymerase chain reaction restriction fragment length polymorphism (PCR­RFLP) strategy. A significant association was detected regarding the GG and GT genotype as well as 'G' allele of rs11556218 in patients with endometriosis. The rs4072111 SNP of the IL­16 gene was not found to be associated with an increased susceptibility to endometriosis either for all patients (stages I­IV) or for stage III and IV of the disease only. Our results demonstrated that rs11556218 is associated with endometriosis in Greek women, probably by resulting in the aberrant expression of IL­16, as suggested by the bioinformatics analysis conducted on the SNP­derived protein sequences, which indicated a possible association between mutation and functional modification of Pro­IL­16.

The role of gene polymorphisms in endometriosis.

Endometriosis is a benign gynecologic disorder, affecting up to 10% of women, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic and environmental factors, with an overall heritability estimated at approximately 50%. In this study, we investigated whether single nucleotide polymorphisms (SNPs) rs7521902, rs10859871 and rs11031006, mapping to WNT4, VEZT and FSHB genetic loci, respectively, are associated with risk for endometriosis in a Greek population. This study included 166 women with histologically confirmed endometriosis diagnosed through surgery and 150 normal controls. Genotyping of the rs7521902, rs10859871 and rs11031006 SNPs was performed with Taqman primer/probe sets. A significant association was detected with the AC genotype of rs7521902 (WNT4) in patients with stage III and IV disease only. Evidence for association with endometriosis was also found for the AC genotype of the rs10859871 of VEZT. Notably, a significant difference in the distribution of the AG genotype and the minor allele A of FSHB rs11031006 SNP was found between the endometriosis patients and controls. We found a genetic association between rs11031006 (FSHB) SNP and endometriosis. WNT4 and VEZT genes constitute the most consistently associated genes with endometriosis. In the present study, an association of rs7521902 (WNT4) and rs10859871 (VEZT) was confirmed in women with endometriosis at the genotypic but not the allelic level.

Genetic association study in a three-generation family with seven members with endometriosis.

The aim of this study was to investigate whether five single nucleotide polymorphisms (SNPs), associated with endometriosis, may confer new insight towards a genotype­phenotype association with endometriosis. We studied a three-generation family with seven women who had endometriosis. Blood specimens were obtained from all the affected female family members. The entire family was genotyped for five SNPs mapped to WNT4, VEZT, FSHB and IL-16 genetic loci. We further evaluated the members of the family with endometriosis and described all obstetric and gynecological complications caused by the disease in these seven women. The five SNPs analyzed did not reveal any genotype-phenotype correlation with the disease. The members of the family with endometriosis showed a variety of clinical manifestations and complications. None of the five genetic markers examined correlated genotype with phenotype in the case of the Greek three-generation family examined. Therefore, we conclude that more gene polymorphisms must be investigated in the members of this family to gain insight regarding a genotype­phenotype correlation in endometriosis and the potential development of a personalized care for the patients based on these data.

Extra pelvic endometriosis: Retrospective analysis on 200 cases in two different countries.

OBJECTIVE(S): The purpose of the study was to review patients' characteristics and the location of extrapelvic endometriosis. STUDY DESIGN: Out of 1000 women with endometriosis during a 20year period, we found 200 cases with extra pelvic endometriosis. Medical reports were evaluated and the diagnosis was confirmed on the pathological specimen. This study involved cases from two different geographical areas, New Haven and Crete. The age, parity, symptoms, previous surgeries, diagnostic modalities, histopathological evaluation and location of endometriotic implants found in other areas were recorded and analyzed from the patient's charts. MAIN OUTCOME MEASURE(S): Statistical methods included x2 and Mann-Whitney U test s measuring incidence of right-VS left sided endometriosis. RESULTS: 200 patients with extrapelvic endometriosis and 800 patients with pelvic endometriosis were included in the study. The gastrointestinal tract represents the most common location of extrapelvic endometriosis with 104/200(52%) cases (p<0, 01), followed by the urinary system with70/200(35%) cases. We observed the Left-sided ureter being involved in 49/200(24, 5%) cases, significantly higher compare with the right-sided ureter 21/100(10, 5%) (p <0, 01). All women had similar characteristics involving age, weight, main complaints, age of menarche, endometriosis stages, gravid and family history of endometriosis. CONCLUSION(S): The gastrointestinal tract and the urinary system are the most common sites of the extrapelvic endometriosis, which was obvious in both countries. Moreover, we observed that there are no significant differences in demographic variants, menstrual and reproductive characteristics in women with extrapelvic and pelvic endometriosis.

Endometriosis in Adolescent and Young Girls: Report on a Series of 55 Cases.

STUDY OBJECTIVE: The aim of this retrospective study was to evaluate endometriosis in adolescent and young girls and further to review the menstrual, reproductive characteristics, and risk factors. DESIGN AND SETTING: We reviewed the medical records of adolescent and young girls with endometriosis from 2 different countries. Data were collected and analyzed from charts of 900 patients with endometriosis. PARTICIPANTS AND INTERVENTIONS: Fifty-five female adolescents aged between 13 and 21 years (mean age 18.3 years) participated in our series. This study was conducted in the Obstetric and Gynecology Department of Venizeleio General Hospital of Crete and involved all patients diagnosed with endometriosis between 1996 and 2016. MAIN OUTCOME MEASURES: Statistical methods included χ2 and Mann-Whitney U test. RESULTS: Of 900 patients with endometriosis we found 55 female adolescents (6.1%). The mean age was 18.3 ± 2.3 years, significantly younger compared with the advanced endometriosis patients (32.7 ± 7.2; P < .001). Regarding the menstrual reproductive and others characteristics, we observed several differences in adolescent young girls compared with the advanced age endometriosis group. The factors associated with an increased risk for young women include age at menarche, dysmenorrhea, history of asthma, and a positive family history of endometriosis. Additionally, we report on 16 of 55 (32%) adolescent women with endometriosis and congenital malformations (P < .01) and 5 patients who were diagnosed with dry eye syndrome. CONCLUSION: There is an association between endometriosis in adolescent and young women and risk factors including early menarche, early onset of dysmenorrhea, history of asthma, previous surgical procedures, obstructive genital anomalies, and family history of endometriosis.

Peritoneal fluid concentrations of ß-chemokines in endometriosis.

OBJECTIVE: To examine whether the levels of MCP-1, RANTES and MCP-3 in the peritoneal fluid correlate with endometriosis. STUDY DESIGN: Patients with endometriosis were compared with controls. SETTING: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA. SUBJECTS: This study involved 95 women of reproductive age who were undergoing laparoscopy for evaluation of infertility or for pelvic pain. They were divided into an endometriosis group (n=54) and a control group (n=41). INTERVENTIONS: Peritoneal fluid samples were obtained and ß-chemokines (MCP-1, RANTES and MCP-3) were measured using ELISA. STATISTICAL ANALYSIS: Mean and median values were used to present values. Due to the non-normality of chemokines, a log transformation was applied. Differences were examined using independent samples t-test. One-way ANOVA and Tukey HSD multiple comparison post hoc tests were applied. A significance level at 0.05 was set. RESULTS: The levels of MCP-1 are higher (p for log values=0.024) in the control group (mean=687.6, SD=467.7 pg/ml) than those of the endometriosis group (mean=570.4, SD=633.1 pg/ml). The same is true for the median values of MCP-1 (control median=568.5, endometriosis median=384.7 pg/ml). MCP-3 and RANTES do not differ significantly (MCP-3 p=0.787, RANTES p=0.153). The levels of MCP-1 in patients with stage II endometriosis are significantly lower in comparison with stage III (p=0.048) and stage IV (p=0.033) endometriosis. CONCLUSIONS: A decrease in the concentrations of MCP-1 in stage I endometriosis has been observed, which is even larger in stage II, in contrast to stage III and stage IV endometriosis, which exhibit concentrations similar to the controls.

Molecular response of the human diaphragm on different modes of mechanical ventilation.

BACKGROUND: The mechanical stress that the human diaphragm is exposed to during mechanical ventilation affects a variety of processes, including signal transduction, gene expression, and angiogenesis. OBJECTIVES: The study aim was to assess the change in the production of major angiogenic regulators [vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2), and transforming growth factor beta 1 (TGFB1)] on the human diaphragm before and after contraction/relaxation cycles during mechanical ventilation. METHODS: This observational study investigates the diaphragmatic mRNA expression of VEGF, FGF2, and TGFB1 in surgical patients receiving general anesthesia with controlled mechanical ventilation (CMV) with muscle relaxation (group A, n = 13), CMV without muscle relaxation (group B, n = 10), and pressure support of spontaneous breathing (group C, n = 9). Diaphragmatic samples were obtained from each patient at two time points: 30 min after the induction of anesthesia (t1) and 90 min after the first specimen collection (t2). RESULTS: No significant changes in the mRNA expression of VEGF, FGF2, and TGFB1 were documented in groups A and C between time points t1 and t2. In contrast, in group B, the mRNA levels of the above angiogenic factors were increased in time point t2 compared to t1, a finding which was statistically significant (pVEGF = 0.003, pFGF2 = 0.028, pTGFB1 = 0.001). CONCLUSIONS: These findings suggest that the molecular response of the human diaphragm before and after application of diverse modes of mechanical ventilation is different. Angiogenesis via the expression of VEGF, FGF2, and TGFB1 was only promoted in CMV without muscle relaxation, and this may have important clinical implications.