Gynaecology & Obstetrics

Embryonic Development in Virtual Reality (Doctoral Thesis)

Rousian, M. — 2011-11-24T00:00:00Z

The overall aim of this thesis is to establish an accurate and reliable description of new in vivo biometric and volumetric measurements in the first trimester of pregnancy using 3D ultrasound datasets, analyzed using an innovative VR system. These new measurements, which make optimal use of all three dimensions, will form a basis for follow-up studies describing the abnormal development of embryonic and early fetal life.

Molecular and immunological mechanisms of epithelial disorders of the vulva (Doctoral Thesis)

Santegoets, L.A.M. — 2011-10-21T00:00:00Z

The vulva is the outer part of the female genital tract, bordered by the symphisis pubis, the labiocrural folds and the anus. It consists of the following structures: the mons pubis, the labia majora and minora, the clitoris, the vestibule of the vagina and the urethral orifice (Figure 1). Embryologically all three germ layers are present at the vulva; the cloacal endoderm, the urogenital ectoderm and the paramesonephric mesoderma. Different epithelia, from keratinized squamous epithelium on the labia majora and minora to squamous mucosa in the vestibule, cover the vulva. Dysplastic changes in the epithelium of the vulva are known as Vulvar Intraepithelial Neoplasia (VIN). In the past, various definitions have been used to describe these dysplastic vulvar lesions: morbus Bowen, Queyrat’s erythroplasia, carcinoma simplex, bowenoid papulosis, early vulvar cancer, vulvar atypia, hyperplastic dystrophy, carcinoma in situ and dysplasia (graded into mild dysplasia (VIN1), moderate dysplasia (VIN2) and severe dysplasia (VIN3)). To simplify this complexity of terms and to enhance diagnostic reproducibility, the International Society for the Study of Vulvovaginal Diseases (ISSVD) defined a new terminology in 2004.7 We nowadays classify two types of VIN: 1. Usual type VIN (uVIN), which is caused by a persistent Human Papilloma Virus (HPV) infection. 2. Differentiated type VIN (dVIN), which is not associated with HPV, but with chronic inflammatory and/or autoimmune processes, such as lichen sclerosus and lichen planus, involving vulvar mucosa and skin. Spontaneous regression of VIN lesions has been described, but malignant transformation into vulvar cancer has also been reported. Vulvar cancer is the fourth most common gynecological type of cancer.11 Worldwide the incidence rate is 1 to 2 per 100.000 women, and around 27.000 women are diagnosed each year.12 In the Netherlands about 200 new cases are identified each year.

Maternal smoking during pregnancy and kidney volume in the offspring: the Generation R Study (Article)

Steegers, E.A.P. — 2011-08-01T00:00:00Z

An adverse fetal environment leads to smaller kidneys, with fewer nephrons, which might predispose an individual to the development of kidney disease and hypertension in adult life. In a prospective cohort study among 1,072 children followed from early fetal life onward, we examined whether maternal smoking during pregnancy, as a significant adverse fetal exposure, is associated with fetal (third trimester of pregnancy, n = 1,031) and infant kidney volume (2 years of age, n = 538) measured by ultrasound. Analyses were adjusted for various potential confounders. Among mothers who continued smoking, we observed dose-dependent associations between the number of cigarettes smoked during pregnancy and kidney volume in fetal life. Smoking less than five cigarettes per day was associated with larger fetal combined kidney volume, while smoking more than ten cigarettes per day tended to be associated with smaller fetal combined kidney volume (p for trend: 0.002). This pattern was not significant for kidney volume at the age of 2 years. Our results suggest that smoking during pregnancy might affect kidney development in fetal life with a dose-dependent relationship. Further studies are needed to assess the underlying mechanisms and whether these differences in fetal kidney volume have postnatal consequences for kidney function and blood pressure.

Interaction between sexhormones and WNT/β-catenin signal transduction in endometrial physiology and disease (Article)

Horst, P.H. van der — 2011-07-14T00:00:00Z

Wnt/β-catenin signalling plays a rate-limiting role in early development of many different organs in a broad spectrum of organisms. In the developing Müllerian duct, Wnt/β-catenin signalling is important for initiation, outgrowth, patterning and differentiation into vagina, cervix, uterus and oviducts. In adult life, sex hormones modulate Wnt/β-catenin signalling in the endometrium to maintain the monthly balance between estrogen-induced proliferation and progesterone-induced differentiation, and enhanced Wnt/β-catenin signalling seems to be involved in endometrial carcinogenesis. However, early in pregnancy enhanced Wnt/β-catenin signalling is prerequisite for proper implantation and invasion of trophoblast cells into endometrium and myometrium thus helping to form a placenta. Overall, it seems that tight control of Wnt/β-catenin signalling in time and space is important for initiation, development and normal function of the female reproductive tract. However, if Wnt/β-catenin signalling is not kept in check, it easily seems to initiate or contribute to development of a number of uterine disorders.

A role for Aurora C in the chromosomal passenger complex during human preimplantation embryo development (Article)

Avo Santos, M. — 2011-07-01T00:00:00Z

Background: Human embryos generated by IVF demonstrate a high incidence of chromosomal segregation errors during the cleavage divisions. To analyse underlying molecular mechanisms, we investigated the behaviour of the chromosomal passenger complex (CPC) in human oocytes and embryos. This important mitotic regulatory complex comprises the inner centromere protein (INCENP), survivin, borealin and Aurora B, or the meiotic kinase Aurora C. Methods: We analysed mRNA expression by quantitative RTPCR of all CPC members in human oocytes, tripronuclear (3PN) zygotes, 2-cell and 4-cell embryos developed from 3PN zygotes, plus good-quality cryopreserved 8-cell, morula and blastocyst stage embryos. Protein expression and localization of CPC members were investigated by immunofluorescence in oocytes and embryos arrested at prometaphase. Histone H3S10 phosphorylation was investigated as an indicator of a functional CPC. Results: INCENP, survivin and borealin were detected at the inner centromere of prometaphase chromosomes in all stages investigated. Whereas Aurora B and C are both present in oocytes, Aurora C becomes the most prominent kinase in the CPC during the first three embryonic cell cycles. Moreover, Aurora C mRNA was up-regulated with Aurora B after activation of the embryonic genome and both proteins were detected in early Day 4 embryos. Subsequently, only Aurora B was detected in blastocysts. Conclusions: In contrast to somatic cells, our Results: point to a specific role for Aurora C in the CPC during human preimplantation embryo development. Although, the presence of Aurora C in itself may not explain the high chromosome segregation error rate, the data presented here provide novel information regarding possible mechanisms.

Genetic ancestry affects the phenotype of normogonadotropic anovulatory (WHOII) subfertility (Article)

Valkenburg, O. — 2011-07-01T00:00:00Z

Introduction: Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. Objective: Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio-geographic ancestry and predict the phenotype of individual patients. Materials and Methods:Astandardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. Results: Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structureona continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. Conclusion: Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility. Copyright

A hinged external fixator for complex elbow dislocations: A multicenter prospective cohort study (Article)

Schep, N.W.L. — 2011-06-09T00:00:00Z

Background: Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures of the radial head, olecranon, or coronoid process. The majority of patients with these complex dislocations are treated with open reduction and internal fixation (ORIF), or arthroplasty in case of a non-reconstructable radial head fracture. If the elbow joint remains unstable after fracture fixation, a hinged elbow fixator can be applied. The fixator provides stability to the elbow joint, and allows for early mobilization. The latter may be important for preventing stiffness of the joint. The aim of this study is to determine the effect of early mobilization with a hinged external elbow fixator on clinical outcome in patients with complex elbow dislocations with residual instability following fracture fixation. Methods/Design. The design of the study will be a multicenter prospective cohort study of 30 patients who have sustained a complex elbow dislocation and are treated with a hinged elbow fixator following fracture fixation because of residual instability. Early active motion exercises within the limits of pain will be started immediately after surgery under supervision of a physical therapist. Outcome will be evaluated at regular intervals over the subsequent 12 months. The primary outcome is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford Elbow Score, pain level at both sides, range of motion of the elbow joint at both sides, radiographic healing of the fractures and formation of periarticular ossifications, rate of secondary interventions and complications, and health-related quality of life (Short-Form 36). Discussion. The outcome of this study will yield quantitative data on the functional outcome in patients with a complex elbow dislocation and who are treated with ORIF and additional stabilization with a hinged elbow fixator. Trial Registration. The trial is registered at the Netherlands Trial Register (NTR1996).

XCI in preimplantation mouse and human embryos: first there is remodelling... (Article)

Berg, I.M. van den — 2011-06-07T00:00:00Z

Female eutherians silence one of their X chromosomes to accomplish an equal dose of X-linked gene expression compared with males. The mouse is the most widely used animal model in XCI research and has proven to be of great significance for understanding the complex mechanism of X-linked dosage compensation. Although the basic principles of XCI are similar in mouse and humans, differences exist in the timing of XCI initiation, the genetic elements involved in XCI regulation and the form of XCI in specific tissues. Therefore, the mouse has its limitations as a model to understand early human XCI and analysis of human tissues is required. In this review, we describe these differences with respect to initiation of XCI in human and mouse preimplantation embryos, the extra-embryonic tissues and the in vitro model of the epiblast: the embryonic stem cells.

Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients (Article)

Vencken, P.M.L.H. — 2011-06-06T00:00:00Z

Background: Because it is insufficiently clear whether BRCA-associated epithelial ovarian cancer (EOC) is more chemosensitive than sporadic EOC, we examined response to chemotherapy, progression-free survival (PFS) and overall survival (OS) in BRCA1- and BRCA2-associated versus sporadic EOC patients. Methods: Data about patient characteristics, response to and outcome after primary therapy, including chemotherapy, were collected from 99 BRCA1, 13 BRCA2 and 222 sporadic patients. Analyses were carried out using a chi-square test and Kaplan-Meier and Cox regression methods. Results: Complete response (CR) or no evidence of disease (NED) was observed in 87% of the BRCA1 patients, progressive disease (PD) in 2%, being 71% and 15%, respectively, in sporadic EOC patients (P = 0.002). In BRCA2 patients, 92% had CR/NED, and none PD (P = 0.27). Median PFS in BRCA1, BRCA2 and sporadic patients was 2.1 [95% confidence interval (CI) 1.9-2.5] years (P = 0.006), 5.6 (95% CI 0.0-11.5) years (P = 0.008) and 1.3 (95% CI 1.1- 1.5) years, respectively. Median OS in the three groups was 5.9 (95% CI 4.7-7.0) years (P < 0.001), >10 years (P = 0.008), and 2.9 (95% CI 2.2-3.5) years, respectively. A trend for a longer PFS and OS in BRCA2 compared with BRCA1 patients was observed. Conclusion: Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy.

Mild versus strong anti-inflammatory therapy during early sepsis in mice: A matter of life and death (Article)

Berg, J.W. van den — 2011-06-01T00:00:00Z

Objective: A recent literature-based study suggested that low-dose corticosteroid treatment has a beneficial effect on mortality in septic patients, whereas high-dose corticosteroid treatment has not. This suggests that mild down-regulation of the inflammatory response during early sepsis may be beneficial while extensive reduction of the inflammatory response is not. To investigate this hypothesis, we examined the effect of dexamethasone in varying doses on cecal ligation and puncture-induced inflammation and mortality. Design: Animal study. Setting: University research laboratory. SUBJECTS:: Male C57BL/6 mice. Interventions: Mice were subjected to cecal ligation and puncture, and dexamethasone was administered intravenously at a dosage of 0.05 (L/DEX), 0.25 (M/DEX), or 2.5 (H/DEX) mg/kg body weight 20 mins postoperatively. Mice receiving phosphate-buffered saline served as controls. Survival was recorded up to 21 days and inflammatory markers were determined in plasma, lungs, liver, and kidney at 6 hrs following cecal ligation and puncture as well as bacterial load in blood and peritoneal fluid. Measurements and Main Results: L/DEX treatment significantly improved survival compared with control mice, whereas treatment with higher concentrations of dexamethasone (M/DEX and H/DEX) did not. Treatment with either M/DEX or H/DEX was associated with significantly (p < .05) reduced cytokine plasma levels as compared with controls at 6 hrs after cecal ligation and puncture. In addition, M/DEX or H/DEX powerfully reduced cytokine messenger RNA expression in the lung, liver, and kidney. In contrast, treatment with L/DEX was associated with a mild, but nonsignificant, reduction of cytokine plasma levels. In addition, L/DEX moderately reduced cytokine messenger RNA expression in lung, liver, and kidney tissue and reduced the occurrence of bacteremia. Conclusions: A modest down-regulation of the early sepsis-associated inflammatory response improves survival in a murine cecal ligation and puncture model. We propose that the success of anti-inflammatory therapies in a septic setting fundamentally depends on finding a treatment balance that reduces the hyperinflammation-induced pathology but still allows adequate defense against pathogens. Copyright

Placental vascularization in early onset small for gestational age and preeclampsia (Article)

Oppenraaij, R.H.F. van — 2011-06-01T00:00:00Z

The objective was to determine whether chorionic villous vascularization is diminished in cases of early onset (<34 weeks) small for gestational age (SGA) and/or preeclampsia (PE). Placental morphometrical measurements were performed in 4 gestational-age-matched groups complicated by SGA, SGA with PE, PE, and spontaneous preterm delivery without SGA or PE as the reference group. Using a video image analysis system, in randomly selected intermediate and terminal villi, the stromal area and the following villous vascular parameters were manually traced and analyzed: number of total, centrally and peripherally localized vessels, vascular area, and vascular area density. No differences were observed in intermediate and terminal villous vascular area. Preeclampsia was associated with smaller terminal villous stromal area (reference 2299 μm2, SGA 2412 μm2, SGA + PE 2073 μm2, and PE 2164 μm2, P =.011), whereas SGA was associated with an increased terminal villous vascular area density (reference 26.1%, SGA 35.7%, SGA + PE 33.4%, and PE 32.0%, P =.029). Compared with preserved flow, lower terminal villous vascular area density was found in cases with absent or reversed end-diastolic (ARED) umbilical artery flow (39.3% vs 30.3%, P =.013). These data demonstrate that villous vascularization was not influenced by PE, whereas in terminal villi an increased vascular area density was associated with SGA. Lower terminal villous vascular area density was associated with ARED flow in SGA pregnancies, indicating an increased risk of fetal compromise.

Nonsteroidal anti-inflammatory drugs do not interfere with imiquimod treatment for usual type vulvar intraepithelial neoplasia (Article)

Terlou, A. — 2011-05-01T00:00:00Z

Imiquimod has been shown to be an effective treatment for usual type vulvar intraepithelial neoplasia (uVIN). Since local inflammation and burning are common side effects, patients often use nonsteroidal anti-inflammatory drugs (NSAIDs). Our study investigated whether NSAID-use, which has been documented to inhibit the cell-mediated immune response, interferes with the outcome of imiquimod treatment. Monocyte-derived dendritic cells (moDCs) and Langerhans cells (moLCs) were cultured in the presence of NSAIDs. The expression of relevant surface markers (CD80, CD86, CD40, HLA-DR, CCR6 and CCR7), stimulatory function, and cytokine production were evaluated. Furthermore, we analyzed in uVIN patients whether frequent NSAID-use had an effect on the clinical response and on immunocompetent cell counts before and after imiquimod treatment. Although an effect was observed on the expression of moDC and moLC maturation markers, NSAIDs did not affect the ability of moDCs and moLCs to stimulate allogeneic T-cell proliferation, or the production of cytokines in an allogeneic T-cell stimulation assay. In agreement with this, in uVIN patients treated with imiquimod, no interference of frequent NSAID-use with clinical outcome was observed. However, we did notice that high CD1a+and CD207+cell counts in frequent NSAID-users before treatment seemed to predict a favourable response to imiquimod treatment. Our data indicate that NSAID-use does not seem to interfere with moDC and moLC function and does not interfere with immunomodulatory properties of imiquimod in uVIN patients. Therefore, NSAIDs can safely be used to reduce imiquimod side effects in uVIN patients during treatment. Copyright

Trauma-related dispatch criteria for Helicopter Emergency Medical Services in Europe (Article)

Wigman, L.D. — 2011-05-01T00:00:00Z

Introduction: Helicopter Emergency Medical Services (HEMS) are used worldwide in order to provide potentially life-saving pre-hospital medical support to trauma patients at the accident scene. It is currently unclear how much overlap exists regarding the number and type of dispatch criteria used by individual HEMS organisations. The aim of the current study was to provide an overview of dispatch criteria for trauma cases used by HEMS organisations within Europe, and search for similarities and differences, between countries and HEMS stations. Materials and methods: HEMS dispatch criteria related to trauma care were obtained from the literature and divided into four groups of criteria and processed in a questionnaire. HEMS providing organisations were identified and contacted by telephone and via email. Results: Fifty-five of the 65 organisations (85%) that were contacted completed the questionnaire. The criteria "Fall from height", "Lengthy extrication and significant injury" and "Multiple casualty incidents" were used most frequently. Criteria from the subgroup "Patient Characteristics - Co-morbidities and Age" were used the least. In 44 of the organisations the Central Dispatch Centre (CDC) was primarily responsible for HEMS dispatch. Conclusion: This overview demonstrates the lack of uniformity in the use of dispatch criteria for trauma assistance on a national and international level. Furthermore, the activation of HEMS is not only depending on dispatch criterion protocols, but is also influenced by organisational factors like the education of the dispatcher, the training of the EMS personnel, the familiarity with the dispatch criteria, and the responses of bystanders. Future research should aim to identify a general set of criteria with the highest discriminating potential.

Advanced maternal age, short interpregnancy interval, and perinatal outcome (Article)

De Weger, F.J. — 2011-05-01T00:00:00Z

Objective: The purpose of this study was to evaluate whether the association between short interpregnancy intervals and perinatal outcome varies with maternal age. Study Design: We performed a retrospective cohort study among 263,142 Dutch women with second deliveries that occurred between 2000 and 2007. Outcome variables were preterm delivery (<37 weeks of gestation), low birthweight in term deliveries (<2500 g) and small-for-gestational age (<10th percentile for gestational age on the basis of sex- and parity-specific Dutch standards). Results: Short interpregnancy intervals (<6 months) was associated positively with preterm delivery and low birthweight, but not with being small for gestational age. The association of short interpregnancy interval with the risk of preterm delivery was weaker among older than younger women. There was no clear interaction between short interpregnancy interval and maternal age in relation to low birthweight or small for gestational age. Conclusion: The results of this study indicate that the association of short interpregnancy interval with preterm delivery attenuates with increasing maternal age.

Defective deacetylation of histone 4 K12 in human oocytes is associated with advanced maternal age and chromosome misalignment (Article)

Berg, I.M. van den — 2011-05-01T00:00:00Z

Background: Chromosome segregation errors during human oocyte meiosis are associated with low fertility in humans and the incidence of these errors increases with advancing maternal age. Studies of mitosis and meiosis suggest that defective remodeling of chromatin plays a causative role in aneuploidy. We analyzed the histone deacetylation pattern during the final stages of human oocyte maturation to investigate whether defective epigenetic regulation of chromatin remodeling in human oocytes is related to maternal age and leads to segregation errors.MethodsHuman surplus oocytes of different meiotic maturation stages [germinal vesicle (GV), metaphase (M)I and MII] were collected from standard IVF/ICSI treatments. Oocytes were analyzed for acetylation of different lysines of histone 4 (H4K5, H4K8, H4K12 and H4K16) and for α-tubulin. ResultsHuman GV oocytes had an intense staining of the chromatin for all four histone 4 lysine acetylations. MI and MII stage oocytes showed either normal deacetylation or various amounts of defective histone deacetylation. Residual H4K12 acetylation was more frequently found in oocytes obtained from older women, with a significant correlation between defective deacetylation and maternal age (r 0.185, P 0.007). Eighty-eight percent of the oocytes with residual acetylation had misaligned chromosomes, whereas only 33 of the oocytes that showed correct deacetylated chromatin had misaligned chromosomes (P < 0.001). Conclusions We conclude that defective deacetylation during human female meiosis increases with maternal age and is correlated with misaligned chromosomes. As chromosome misalignment predisposes to segregation errors, our data imply that defective regulation of histone deacetylation could be an important factor in age-related aneuploidy.

Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: A long-term multi-cohort study (Article)

Kocken, M. — 2011-05-01T00:00:00Z

Background: 15% of women treated for high-grade cervical intraepithelial neoplasia (CIN grade 2 or 3) develop residual or recurrent CIN grade 2 or 3 or cervical cancer, most of which are diagnosed within 2 years of treatment. To gain more insight into the long-term predictive value of different post-treatment strategies, we assessed the long-term cumulative risk of post-treatment CIN grade 2 or 3 or cancer and different follow-up algorithms to identify women at risk of residual or recurrent disease. Methods: Women who were included in three studies in the Netherlands and who were treated for CIN grade 2 or 3 between July, 1988, and November, 2004, were followed up by cytology and testing for high-risk human papillomavirus (hrHPV) at 6, 12, and 24 months after treatment, and subsequently received cytological screening every 5 years. The primary endpoint was the cumulative risk of post-treatment CIN grade 2 or higher by December, 2009. We also assessed the cumulative risk of CIN grade 2 or higher in women with three consecutive negative cytological smears and women with negative co-testing with cytology and hrHPV at months 6 and 24. This study is registered in the Dutch trial register, NTR1468. Findings: 435 women were included, 76 (17%) of whom developed post-treatment CIN grade 2 or higher, of which 39 were CIN grade 3 or higher. The 5-year risk of developing post-treatment CIN grade 2 or higher was 16·5% (95% CI 13·0-20·7) and the 10-year risk was 18·3% (13·8-24·0). The 5-year risk of developing post-treatment CIN grade 3 or higher was 8·6% (95% CI 6·0-12·1) and the 10-year risk was 9·2% (5·8-14·2). Women with three consecutive negative cytological smears had a CIN grade 2 or higher risk of 2·9% (95% CI 1·2-7·1) in the next 5 years and of 5·2% (2·1-12·4) in the next 10 years. The 5-year risk of CIN grade 3 or higher was 0·7% (95% CI 0·0-3·9) and the 10-year risk was 0·7% (0·0-6·3). Women with negative results for co-testing had a 5-year risk of CIN grade 2 or higher of 1·0% (95% CI 0·2-4·6) and a 10-year risk of 3·6% (1·1-10·7). The 5-year risk of CIN grade 3 or higher was 0·0% (95% CI 0·0-3·0) and the 10-year risk was 0·0% (0·0-5·3). Interpretation: The 5-year risk of post-treatment CIN grade 2 or higher in women with three consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24 months was similar to that of women with normal cytology in population-based screening and therefore justifies their return to regular screening. Funding: VU University Medical Center, Erasmus University Medical Center, Netherlands.

Observer agreement in the evaluation of the uterine cavity by hysteroscopy prior to in vitro fertilization (Article)

Kasius, J.C. — 2011-04-01T00:00:00Z

Background Hysteroscopy is known as the most accurate test for diagnosing intrauterine pathology. To optimize fertility treatment, it is increasingly common to perform hysteroscopy as a routine procedure prior to IVF. However, literature on the reproducibility of screening hysteroscopy is lacking. Therefore, the aim of the study was to assess the intra- and inter-observer agreement in the individual evaluation of the uterine cavity using video recordings of hysteroscopy procedures in asymptomatic patients prior to IVF.Methods Screening hysteroscopies of 123 unselected, asymptomatic, infertile women with an indication for IVF/ICSI treatment were recorded on DVD. After editing, the hysteroscopy performer and three other experienced gynecologists independently assessed all recordings, focusing on the appearance of predefined intrauterine abnormalities (i.e. endometrial polyps, myomas, adhesions or septa). The intra- and inter-observer agreement was calculated and expressed as perfect agreement and κ coefficient or intraclass correlation coefficient.Results In total, 123 hysteroscopy procedures were recorded. After editing and selection, based on the record quality, 107 remained for assessment and analysis. The intraobserver agreement on the appearance of any of the predefined intrauterine abnormalities was substantial (κ 0.707), whereas the interobserver agreement was moderate (κ 0.491). Perfect agreement occurred only in 77.6 of the cases. Conclusions Interobserver agreement among experienced gynecologists appeared to be rather disappointing. The latter may have implications for the diagnostic accuracy of screening hysteroscopy prior to IVF, as well as for its clinical significance in IVF programs.

Treatment of vulvar intraepithelial neoplasia with topical imiquimod: Seven years median follow-up of a randomized clinical trial (Article)

Terlou, A. — 2011-04-01T00:00:00Z

Objective: Recently we reported on the efficacy of imiquimod for treating vulvar intraepithelial neoplasia (VIN) in a placebo-controlled, double-blinded randomized clinical trial (RCT). Four weeks after treatment, a complete response was observed in 35% of patients and a partial response in 46%. All complete responders remained disease-free at 12 months follow-up. In the current investigations, we assessed long-term follow-up at least 5 years after the initial RCT. Methods: Twenty-four of 26 imiquimod-treated patients who had participated in the initial RCT were seen for follow-up. Primary endpoint was durability of clinical response to imiquimod assessed by naked eye vulvar examination and histology. Long-term clinical response was correlated to lesion size before start of the initial RCT. Secondary endpoints were mental health, global quality of life, body image and sexual function in relation with long-term clinical response. Results: Median follow-up period was 7.2 years (range 5.6-8.3 years). VIN recurred in one of nine complete responders. Of the initial partial responders, two became disease-free after additional imiquimod treatment. In the other partial responders, VIN recurred at least once after the initial RCT. In long-term complete responders, lesion size at study entry was smaller and these patients had a significantly better global quality of life at follow-up than patients with residual disease and/or recurrence after imiquimod treatment. Conclusions: In case of a complete response, imiquimod is effective in the long-term. Furthermore, patients with a long-term complete response had a significantly better global quality of life than patients who recurred after imiquimod treatment.

Prevalence and prognostic factors of disability after major trauma (Article)

Ringburg, A.N. — 2011-04-01T00:00:00Z

Background: The primary aim of this study was to assess the health-related quality of life of survivors of severe trauma 1 year after injury, specified according to all the separate dimensions of the EuroQol-5D (EQ-5D) and the Health Utilities Index (HUI). Methods: A prospective cohort study was conducted in which all severely injured trauma patients presented at a Level I trauma center were included. After 12 months, the EQ-5D, HUI2 and HUI3 were used to analyze the health status. Results: Follow-up assessments were obtained from 246 patients (response rate, 68%). The overall population EQ-5D (median) utility score was 0.73 (EQ-5D Dutch general population norm, 0.88). HUI2, HUI3, and EQ-5D Visual Analog Scale scores were 0.81, 0.65, and 70, respectively. Eighteen percent had at least one functional limitation 1 year after trauma, and 60% reported functional limitations on two or more domains using the EQ-5D. The female gender and comorbidity were significant independent predictors of disability. Conclusion: Functional outcome and quality of life of survivors of severe injury have not returned to normal 1 year after trauma. The prevalence of specific limitations in this population is very high (40-70%). Female gender and comorbidity are predictors of long-term disability. Copyright

The monocyte transcriptome during pregnancy in multiple sclerosis: Prominent expression of the Fc-receptor CD64 (Article)

Neuteboom, R.F. — 2011-04-01T00:00:00Z

Background: During the third trimester of pregnancy multiple sclerosis (MS) disease activity is reduced. It is not fully understood which factors mediate this disease amelioration. Objective: To study alterations of the monocyte transcriptome during pregnancy in MS patients, using a genomewide approach to identify differentially regulated genes. Methods: Women with MS and healthy controls were longitudinally studied, including a visit before pregnancy. Results: RNA-microarray analysis was performed in six patients. We found a significant increase of CD64 (Fc gamma receptor 1a, FcgR1a) during the third trimester compared with baseline, confirmed by RT-PCR in a group of ten patients. Analysis with Ingenuity software was performed using all genes expression of which was altered at least 1.5-fold in at least five out of six patients. Major networks that were altered during MS pregnancy were: cell-to-cell signalling and interaction, immune response, and cell signalling. From the genes selected for Ingenuity analysis, seven additional candidate genes, selected for their biological interest, were tested using RT-PCR in ten patients with MS and nine controls. We found an increased expression of JAK2 and STAT1 directly postpartum in patients with MS and in controls. Conclusion: The increased CD64 expression during pregnancy is indicative of enhanced innate immune functions.