The detection of cervical intraepithelial neoplasia by electrical impedance spectroscopy: The effects of acetic acid and tissue homogeneity

Objective. To evaluate the efficacy of an electrical impedance probe (Epitheliometer) in the diagnosis of high grade cervical intraepithelial neoplasia (CIN) in women referred with cervical smear abnormalities and to assess the effect of acetic acid (AA) and tissue boundaries on the measurements. Methods. A prospective observational study was undertaken in the colposcopy clinic. One hundred and sixty-five women, either with a clinical indication or abnormal cervical cytology, were recruited into the study. A pencil type probe was used to record impedance spectra from 12 points on the cervix before and after the application of 5% AA. Spectra were also recorded from tissue boundaries. Colposcopic examinations, including probe positioning, were video recorded to allow for correlations between histopathological diagnosis of colposcopically directed biopsies, colposcopic impression and the diagnosis based on impedance measurements. Results. Receiver operating characteristic (ROC) curves were derived. The areas under the curves (AUCs) to discriminate original squamous from high grade CIN were 0.80 (pre AA) and 0.79 (post AA). Comparison of these curves showed no significant difference, indicating that application of AA does not produce a large change in spectra. The probe Could distinguish tissue boundaries from homogeneous tissue points. Conclusion. The Epitheliometer has the potential to be used as an adjunct to colposcopy in the diagnosis of high grade CIN. It has the advantage of real time results, decreasing the need for diagnostic cervical biopsies, and facilitates a wider use of the 'see and treat' policy without the risk of overtreatment. (C) 2009 Elsevier Inc. All rights reserved

Listening to the patient as a possible route to cost-effective rehabilitation: a case report

<p>Abstract</p> <p>Introduction</p> <p>Adolescents with cerebral palsy often do not need a specific rehabilitative treatment; however, when specific needs are expressed, clinicians should listen and try to answer them.</p> <p>Case presentation</p> <p>We present the case of a 17-year-old Italian male patient with hemiplegia who had received standard physiotherapy and, ultimately, after a period of adapted physical activity performed in a group, was under consideration for discharge. However, due to unsatisfactory hand control, he asked for help to reach a personal goal, the ability to drive a motorbike, without surgery. Functional taping showed efficacy, but was neither cost-effective nor practical for the patient and his family; by contrast, a dynamic orthosis associated with training in a real-life environment was instead successful.</p> <p>Conclusion</p> <p>The present case underlines the importance of considering solutions involving the motivation and compliance of the patient in order to improve his activity and participation.</p

Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients

STUDY QUESTION: Do polymorphisms in the anti-Müllerian hormone (AMH) promoter have an effect on AMH levels in patients with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We have identified a novel AMH promoter polymorphism rs10406324 that is associated with lower serum AMH levels and is suggested to play a role in the mechanism of regulation of AMH gene expression in women. WHAT IS KNOWN ALREADY: Follicle number is positively correlated with serum AMH levels, reflected by elevated AMH levels in women with PCOS. In addition, it is suggested that AMH production per follicle is higher in women with PCOS than in normo-ovulatory women, implying an altered regulation of AMH in PCOS. STUDY DESIGN, SIZE, DURATION: A discovery cohort of 655 PCOS women of Northern European ancestry and both an internal and external validation PCOS cohort (n = 458 and n = 321, respectively) were included in this study. Summary-level data of an AMH genome-wide association study meta-analysis including 7049 normo-ovulatory women was included as a control cohort. A genetic approach was taken through association analysis and in silico analysis of the associated variants in the AMH promoter. In vitro analysis was performed to investigate the functional mechanisms. PARTICIPANTS/MATERIALS, SETTING, METHODS: All common two-allelic single-nucleotide polymorphisms (SNPs) in the region Chr19:2 245 353–2 250 827 bp (Build 37) were selected for the analysis. Linear regression analyses were performed to determine the association between SNPs in the AMH promoter region and serum AMH levels. For the in silico analysis, the webtools ‘HaploReg’ v4.1 for ENCODE prediction weight matrices and ‘atSNP’ were used. In vitro analysis was performed using KK1 cells, a mouse granulosa cell line and COV434 cells, a human granulosa tumor cell line. Cells were transfected with the reference or the variant human AMH promoter reporter construct together with several transcription factors (TFs). Dual-Glo(®) Luciferase Assay was performed to measure the luciferase activity. MAIN RESULTS AND THE ROLE OF CHANCE: Polymorphism rs10406324 was significantly associated with serum AMH levels in all three PCOS cohorts. Carriers of the minor allele G had significantly lower log-transformed serum AMH levels compared to non-carriers (P = 8.58 × 10(−8), P = 1.35 × 10(−3) and P = 1.24 × 10(−3), respectively). This result was validated in a subsequent meta-analysis (P = 3.24 × 10(−12)). Interestingly, rs10406324 was not associated with follicle count, nor with other clinical traits. Also, in normo-ovulatory women, the minor allele of this variant was associated with lower serum AMH levels (P = 1.04 × 10(−5)). These findings suggest that polymorphism rs10406324 plays a role in the regulation of AMH expression, irrespective of clinical background. In silico analysis suggested a decreased binding affinity of the TFs steroidogenenic factor 1, estrogen-related receptor alpha and glucocorticoid receptor to the minor allele G variant, however in vitro analysis did not show a difference in promoter activity between the A and G allele. LIMITATIONS, REASONS FOR CAUTION: Functional analyses were performed in a mouse and a human granulosa cell line using an AMH promoter reporter construct. This may have limited assessment of the impact of the polymorphism on higher order chromatin structures. Human granulosa cells generated from induced pluripotent stem cells, combined with gene editing, may provide a method to elucidate the exact mechanism behind the decrease in serum AMH levels in carriers of the −210 G allele. We acknowledge that the lack of follicle number in the external validation and the control cohort is a limitation of the paper. Although we observed that the association between rs10406324 and AMH levels was independent of follicle number in our discovery and internal validation PCOS cohorts, we cannot fully rule out that the observed effects on serum AMH levels are, in part, caused by differences in follicle number. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that variations in serum AMH levels are not only caused by differences in follicle number but also by genetic factors. Therefore, the genetic context should be taken into consideration when assessing serum AMH levels in women. This may have clinical consequences when serum AMH levels are used as a marker for the polycystic ovarian morphology phenotype. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. J.S.E.L. has received consultancy fees from the following companies: Ferring, Roche Diagnostics and Ansh Labs and has received travel reimbursement from Ferring. J.A.V. has received royalties from AMH assays, paid to the institute/lab with no personal financial gain. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A

Long-term CIN3 risk in women with abnormal cytology; Role of hrHPV testing

Background: Many studies have examined the short-term value of high-risk human papillomavirus (hrHPV) testing in predicting cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3). This study focuses on long-term CIN3 risk after initial wait and see policy. Methods: A total of 342 women with abnormal cytology of borderline/mild dyskaryosis (BMD) or worse (>BMD), included between 1990 and 1992, were followed-up by cytology and hrHPV testing until 1996 and monitored by cytology thereafter. Primary endpoint was cumulative CIN3 risk by December 2009.Results:Women with BMD had a 5-year CIN3 risk of 22.5% (95% confidence interval (CI) 17.0-29.1) and of 0.7% (0.1-4.5) in the subsequent 5 years. High-risk human papillomavirus-negative women with BMD had a 5-year risk of <0.01% (95% CI <0.0-5.1) and of 0.01% (0.0-5.7) in the following 5 years, while for hrHPV-positive women these risks were 37.5% (29.0-46.9) and 1.6% (0.2-9.5), respectively. Women with BMD< had a 5-year risk of 45.1% (36.4-54.1) and of 3.5% (0.9-12.2) in the subsequent 5 years. High-risk human papillomavirus-negative women with < BMD had a 5-year risk of 7.3% (2.0-23.6) and hrHPV-positive women of 56.6% (46.4-66.3). Conclusion: Women with BMD have an elevated CIN3 risk for 5 years only; afterwards their risk is similar to the general population. High-risk human papillomavirus-negative women with BMD may return to regular screening directly. All other women with ≥ BMD should be referred for additional testing and/or colposcopy

Bone morphogenetic proteins and the polycystic ovary syndrome

Background: Polycystic Ovary Syndrome (PCOS) is defined by two out of the following three criteria being met: oligo- or anovulation, hyperandrogenism, and polycystic ovaries. Affected women are often obese and insulin resistant. Although the etiology is still unknown, members of the Transforming Growth Factor β (TGFβ) family, including Bone Morphogenetic Proteins (BMPs) and anti-Müllerian hormone (AMH), have been implicated to play a role. In this pilot study we aimed to measure serum BMP levels in PCOS patients. Methods. Twenty patients, fulfilling the definition of PCOS according to the Rotterdam Criteria, were randomly selected. Serum BMP2, -4, -6 and -7 levels were measured using commercially available BMP2, BMP4, BMP6 and BMP7 immunoassays. Results: Serum BMP2, serum BMP4 and serum BMP6 levels were undetectable. Three patients had detectable serum BMP7 levels, albeit at the lower limit of the standard curve. Conclusions: BMP levels were undetectable in almost all patients. This suggests that with the current sensitivity of the BMP assays, measurement of serum BMP levels is not suitable as a diagnostic tool for PCOS

European Consensus Statement on Expert Colposcopy

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Bone morphogenetic proteins and the polycystic ovary syndrome

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is defined by two out of the following three criteria being met: oligo- or anovulation, hyperandrogenism, and polycystic ovaries. Affected women are often obese and insulin resistant. Although the etiology is still unknown, members of the Transforming Growth Factor β (TGFβ) family, including Bone Morphogenetic Proteins (BMPs) and anti-Müllerian hormone (AMH), have been implicated to play a role. In this pilot study we aimed to measure serum BMP levels in PCOS patients. METHODS: Twenty patients, fulfilling the definition of PCOS according to the Rotterdam Criteria, were randomly selected. Serum BMP2, -4, -6 and −7 levels were measured using commercially available BMP2, BMP4, BMP6 and BMP7 immunoassays. RESULTS: Serum BMP2, serum BMP4 and serum BMP6 levels were undetectable. Three patients had detectable serum BMP7 levels, albeit at the lower limit of the standard curve. CONCLUSIONS: BMP levels were undetectable in almost all patients. This suggests that with the current sensitivity of the BMP assays, measurement of serum BMP levels is not suitable as a diagnostic tool for PCOS

Detection of child abuse in emergency departments: a multi-centre study

Objective: This study examines the detection rates of suspected child abuse in the emergency departments of seven Dutch hospitals complying and not complying with screening guidelines for child abuse. Design: Data on demographics, diagnosis and suspected child abuse were collected for all children aged ≤18 years who visited the emergency departments over a 6-month period. The completion of a checklist of warning signs of child abuse in at least 10% of the emergency department visits was considered to be compliance with screening guidelines. Results: A total of 24 472 visits were analysed, 54% of which took place in an emergency department complying with screening guidelines. Child abuse was suspected in 52 children (0.2%). In 40 (77%) of these 52 cases, a checklist of warning signs had been completed compared with a completion rate of 19% in the total sample. In hospitals complying with screening guidelines for child abuse, the detection rate was higher (0.3%) than in those not complying (0.1%, p<0.001). Conclusion: During a 6-month period, emergency department staff suspected child abuse in 0.2% of all children visiting the emergency department of seven Dutch hospitals. The numbers of suspected abuse cases detected were low, but an increase is likely if uniform screening guidelines are widely implemented

Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.This work was supported by the Medical Research Council [U106179472; MC_U106179472; U106179471; MC_U106179471] and the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981 to 23andMe). The UK Medical Research Council and Wellcome Trust (092731), together with the University of Bristol, provide core support for the ALSPAC study. AMH assays in ALSPAC were funded with a grant from the US National Institute of Health (R01 DK077659). DAL works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_12013/5).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms946

Investigation of Metallized and Nonmetallized Hydroxyl Terminated Polybutadiene/Hydrogen Peroxide Hybrid Rockets

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77070/1/AIAA-22091-612.pd