Differences in DNA methylation of insulin-like growth factor 2 and cadherin 13 in patients with preeclampsia.

OBJECTIVES: In a previous mass spectrometry study of our research group, 25 proteins were found to be differentially expressed in cerebrospinal fluid of patients with preeclampsia compared to controls. The objective of the current study was to investigate DNA methylation of the genes encoding for the former mentioned proteins in an independent dataset. STUDY DESIGN: In a nested case-control study of the Rotterdam Periconceptional Cohort, placental tissue, umbilical cord white blood cells and human umbilical vein endothelial cells (HUVEC) were obtained of 13 patients with early-onset preeclampsia, 16 patients with late-onset preeclampsia and 83 normotensive controls (27 patients with fetal growth restriction, 20 patients with spontaneous preterm birth and 36 uncomplicated pregnancies). DNA methylation of 783 CpGs in regions of 25 genes was measured. MAIN OUTCOME MEASURES: DNA methylation of selected candidate genes in early- and late-onset preeclampsia compared to fetal growth restriction, spontaneous preterm birth and uncomplicated controls. RESULTS: From the 783 CpGs of the 25 selected genes, 15 CpGs were differentially methylated between early-onset preeclampsia and spontaneous preterm birth (3.80 E-5 ≤ p ≤ 0.036). Four CpGs were differentially methylated between early-onset preeclampsia and fetal growth restriction (0.0002 ≤ p ≤ 0.037) and 13 CpGs were differentially methylated between early onset preeclampsia and uncomplicated controls (0.0001 ≤ p ≤ 0.04). CONCLUSION: Differences in DNA methylation were found in placental tissue, umbilical cord white blood cells and HUVEC of patients with early onset preeclampsia compared to (un)complicated controls, but not in patients with late-onset preeclampsia. The genes showing the largest differential methylation encode insulin-like growth factor 2 binding protein and receptor and cadherin 13.

A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance.

BACKGROUND: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). OBJECTIVE: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. METHODS: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. RESULTS: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD. CONCLUSION: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity.

The complement system in glioblastoma multiforme.

The human complement system is represents the main effector arm of innate immunity and its ambivalent function in cancer has been subject of ongoing dispute. Glioma stem-like cells (GSC) residing in specific niches within glioblastomas (GBM) are capable of self-renewal and tumor proliferation. Recent data are indicative of the influence of the complement system on the maintenance of these cells. It appears that the role of the complement system in glial tumorigenesis, particularly its influence on GSC niches and GSC maintenance, is significant and warrants further exploration for therapeutic interventions.

First-Trimester Crown-Rump Length and Embryonic Volume of Fetuses with Structural Congenital Abnormalities Measured in Virtual Reality: An Observational Study.

Background. With the introduction of three-dimensional (3D) ultrasound it has become possible to measure volumes. The relative increase in embryonic volume (EV) is much larger than that of the crown-rump length (CRL) over the same time period. We examined whether EV is a better parameter to determine growth restriction in fetuses with structural congenital abnormalities. Study Design, Subjects, and Outcome Measures. CRL and EV were measured using a Virtual Reality (VR) system in prospectively collected 3D ultrasound volumes of 56 fetuses diagnosed with structural congenital abnormalities in the first trimester of pregnancy (gestational age 7+5 to 14+5 weeks). Measured CRL and EV were converted to z-scores and to percentages of the expected mean using previously published reference curves of euploid fetuses. The one-sample t-test was performed to test significance. Results. The EV was smaller than expected for GA in fetuses with structural congenital abnormalities (-35% p < 0.001, z-score -1.44 p < 0.001), whereas CRL was not (-6.43% p = 0.118, z-score -0.43 p = 0.605). Conclusions. CRL is a less reliable parameter to determine growth restriction in fetuses with structural congenital abnormalities as compared with EV. By measuring EV, growth restriction in first-trimester fetuses with structural congenital abnormalities becomes more evident and enables an earlier detection of these cases.

Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAF(V600E)-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAF(V600E)-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.

Next-generation sequencing reveals novel rare fusion events with functional implication in prostate cancer.

Gene fusions, mainly between TMPRSS2 and ERG, are frequent early genomic rearrangements in prostate cancer (PCa). In order to discover novel genomic fusion events, we applied whole-genome paired-end sequencing to identify structural alterations present in a primary PCa patient (G089) and in a PCa cell line (PC346C). Overall, we identified over 3800 genomic rearrangements in each of the two samples as compared with the reference genome. Correcting these structural variations for polymorphisms using whole-genome sequences of 46 normal samples, the numbers of cancer-related rearrangements were 674 and 387 for G089 and PC346C, respectively. From these, 192 in G089 and 106 in PC346C affected gene structures. Exclusion of small intronic deletions left 33 intergenic breaks in G089 and 14 in PC346C. Out of these, 12 and 9 reassembled genes with the same orientation, capable of generating a feasible fusion transcript. Using PCR we validated all the reliable predicted gene fusions. Two gene fusions were in-frame: MPP5-FAM71D in PC346C and ARHGEF3-C8ORF38 in G089. Downregulation of FAM71D and MPP5-FAM71D transcripts in PC346C cells decreased proliferation; however, no effect was observed in the RWPE-1-immortalized normal prostate epithelial cells. Together, our data showed that gene rearrangements frequently occur in PCa genomes but result in a limited number of fusion transcripts. Most of these fusion transcripts do not encode in-frame fusion proteins. The unique in-frame MPP5-FAM71D fusion product is important for proliferation of PC346C cells.

First trimester trophoblast and placental bed vascular volume measurements in IVF or IVF/ICSI pregnancies.

STUDY QUESTION: Are first trimester trophoblast volume (TV) and placental bed vascular volume (PBVV) different in IVF or IVF/ICSI pregnancies in comparison with spontaneously conceived pregnancies? SUMMARY ANSWER: Any possible abnormal placentation in IVF or IVF/ICSI pregnancies in comparison with spontaneously conceived pregnancies is not detected by a difference in PBVV or TV at an early gestational age (GA). WHAT IS KNOWN ALREADY: Assisted reproductive technology pregnancies have been associated with an increased risk of placenta-related adverse pregnancy outcomes. It is unclear whether these effects originate from infertility or from the technique itself. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study in which 154 pregnant patients qualified for participation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Out of 154 pregnant patients, 84 conceived spontaneously and 70 conceived after IVF or IVF/ICSI. We determined the TV at 10 weeks GA by Virtual Organ Computer-aided AnaLysis measuring application and the PBVV at 12 weeks GA by the virtual reality operating system of BARCO I-Space in both subgroups. The investigators were blinded to the mode of conception during the measurements. Analysis was limited to singleton pregnancies with only one sac ever detectable. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in TV (mean 42.7, SD 15.9 versus mean 41.2, SD 13.9, P = 0.70) and PBVV (mean 27.6, SD 16.9 versus mean 24.8, SD 19.9, P = 0.20) between IVF or IVF/ICSI pregnancies and spontaneously conceived pregnancies. There was a significant correlation between TV and PBVV (rs = 0.283, P = 0.004). LIMITATIONS, REASONS FOR CAUTION: The limitations of the present study concern the small size of the study groups. WIDER IMPLICATIONS OF THE FINDINGS: IVF or IVF/ICSI does not seem to be associated with abnormal placentation. STUDY FUNDING/COMPETING INTERESTS: This study was financially supported by the Erasmus Trustfonds, the Meindert de Hoop foundation and the Fonds NutsOhra. No competing interests are declared.

First trimester brain ventricle fluid and embryonic volumes measured by three-dimensional ultrasound with the use of I-Space virtual reality.

STUDY QUESTION: Is it possible to evaluate first trimester brain ventricle development in human pregnancies using an innovative virtual reality (VR) application and to analyze the relation of the embryonic volume (EV) and brain ventricle fluid volume (BVFV) with gestational age (GA), crown-rump length (CRL) and the Carnegie stage? SUMMARY ANSWER: Volumetry and staging of the human embryo using a VR application make it possible to obtain unique information about in-vivo embryonic normal and abnormal development and about the sizes of the ventricles and body. WHAT IS KNOWN ALREADY: Human brain development is complex and has a rapidly changing anatomy during the first trimester of pregnancy. New insights will enable early detection of cerebral pathology. STUDY DESIGN, SIZE, DURATION: In a prospective cohort study, we weekly performed three-dimensional (3D) ultrasound examinations in 112 uncomplicated pregnancies between 6 + 0 and 12 + 6 weeks GA. MATERIALS, SETTING, METHODS: The examinations resulted in 696 3D ultrasound scans that were transferred to the I-Space VR system and analyzed using V-Scope volume rendering software. V-Scope is used to create a 'hologram' of the ultrasound image and allows depth perception and interaction with the rendered objects. The CRL measurements were performed with a tracing tool, and the volume measurements were automatically performed with a segmentation algorithm. The embryos were staged according to the internal and external characteristics of the Carnegie staging system. All longitudinal outcomes were analyzed using repeated measures ANOVA. MAIN RESULTS AND THE ROLE OF CHANCE: CRL could be measured in 91% of the datasets and ranged from 2.5 to 79.0 mm. EV could be measured in 66% of the datasets and ranged from 2.4 to 23 812.0 mm³, whereas the BVFV could be measured in 38% of the datasets and ranged from 10.4 to 226.3 mm³. Finally, in 74% of the datasets, the embryos were staged according to the Carnegie criteria, starting as early as stage 12. Reference charts of volumes versus GA, CRL and stage were constructed. There was no significant relationship between the CRL or EV and the birthweight. LIMITATIONS, REASONS FOR CAUTIONS: The low success rate is a limitation of this study that can be explained mainly by non-targeted scanning of the embryonic head. WIDER IMPLICATIONS OF THE FINDINGS: The I-Space VR system and the V-Scope software enable automatic EV and BVFV measurements and 3D observations of embryonic development in the first trimester. This allows in-vivo staging of human embryos based on both internal and external morphological characteristics. STUDY FUNDING, COMPETING INTERESTS: None.

Human embryonic growth and development of the cerebellum using 3-dimensional ultrasound and virtual reality.

The aim of our study was to evaluate the first trimester cerebellar growth and development using 2 different measuring techniques: 3-dimensional (3D) and virtual reality (VR) ultrasound visualization. The cerebellum measurements were related to gestational age (GA) and crown-rump length (CRL). Finally, the reproducibility of both the methods was tested. In a prospective cohort study, we collected 630 first trimester, serially obtained, 3D ultrasound scans of 112 uncomplicated pregnancies between 7 + 0 and 12 + 6 weeks of GA. Only scans with high-quality images of the fossa posterior were selected for the analysis. Measurements were performed offline in the coronal plane using 3D (4D view) and VR (V-Scope) software. The VR enables the observer to use all available dimensions in a data set by visualizing the volume as a "hologram." Total cerebellar diameter, left, and right hemispheric diameter, and thickness were measured using both the techniques. All measurements were performed 3 times and means were used in repeated measurements analysis. After exclusion criteria were applied 177 (28%) 3D data sets were available for further analysis. The median GA was 10 + 0 weeks and the median CRL was 31.4 mm (range: 5.2-79.0 mm). The cerebellar parameters could be measured from 7 gestational weeks onward. The total cerebellar diameter increased from 2.2 mm at 7 weeks of GA to 13.9 mm at 12 weeks of GA using VR and from 2.2 to 13.8 mm using 3D ultrasound. The reproducibility, established in a subset of 35 data sets, resulted in intraclass correlation coefficient values ≥0.98. It can be concluded that cerebellar measurements performed by the 2 methods proved to be reproducible and comparable with each other. However, VR-using all three dimensions-provides a superior method for the visualization of the cerebellum. The constructed reference values can be used to study normal and abnormal cerebellar growth and development.

Ustekinumab improves psoriasis-related gene expression in noninvolved psoriatic skin without inhibition of the antimicrobial response.

BACKGROUND: Ustekinumab is a fully human anti-p40 monoclonal antibody which neutralizes interleukin (IL)-12 and IL-23, thereby interfering with T-helper (Th)1/Th17 pathways and keratinocyte activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation. OBJECTIVES: To determine whether ustekinumab improves psoriasis-related gene expression and tape-strip responses in noninvolved skin. METHODS: Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape-stripped. After 5 h, biopsies were taken from untouched and tape-stripped skin. The mRNA expression of psoriasis-related markers such as NGF, GATA3 and IL-22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations. RESULTS: Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL-22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation-related serum proteins GPNMB, MST1 and TRADD. The baseline and tape-strip-induced mRNA expression of the AMP human ß-defensin-2 (hBD-2), S100A7 and LL-37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD-2 levels. No changes were noted in total leucocytes, C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: These findings indicate that ustekinumab reduces psoriasis-related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation-related proteins.

First-trimester crown-rump length and embryonic volume of aneuploid fetuses measured in virtual reality.

OBJECTIVES: To examine whether embryonic volume (EV), as measured using three-dimensional (3D) ultrasound and a virtual reality approach, is a better measure of growth restriction than is crown-rump length (CRL) in aneuploid fetuses. METHODS: We retrospectively measured CRL and EV in prospectively collected 3D ultrasound volumes of 55 aneuploid fetuses using the Barco I-Space VR system. The gestational age ranged from 11 + 2 to 14 + 4 weeks. We compared our measured data with previously published reference curves for euploid fetuses. Delta-values were calculated by subtracting the expected mean for euploid fetuses of the same gestational age from observed values. The one-sample t-test was used to test the significance of differences observed. RESULTS: The CRL measurements of fetuses with trisomy 21 (n = 26), trisomy 13 (n = 5) and monosomy X (n = 5) were comparable with those of euploid fetuses, but in fetuses with trisomy 18 (n = 19) the CRL was 14.5% smaller (P < 0.001). The EV in fetuses with trisomies 21, 18 and 13 and monosomy X was smaller than in euploid fetuses (-27.8%, P < 0.001; -39.4%, P < 0.001; -40.9%, P = 0.004; and -27.3%, P = 0.055, respectively). CONCLUSIONS: When relying on CRL measurements alone, first-trimester growth restriction is especially manifest in trisomy 18. Using EV, growth restriction is also evident in trisomies 21 and 13 and monosomy X. EV seems to be a more effective measurement for the assessment of first-trimester growth restriction in aneuploid fetuses.

The effect of smoking on early chorionic villous vascularisation.

The aim of the study was to investigate whether first trimester chorionic villous vascularisation is different in women who smoked cigarettes before and during pregnancy in comparison with women who did not smoke. Placentas of smoking (>10 cigarettes/day, n = 13) and non-smoking women (n = 13), scheduled for a legal termination of a viable first trimester pregnancy for social indications, were retrieved. Placental tissues of 3-5 mm³ were whole mount CD31 immunofluorescence stained. Images of the CD31 immunofluorescence and contour of the villi were captured using an Optical Projection Tomography scanner. An immersive BARCO virtual reality system was used to create an enlarged interactive 3-dimensional hologram of the reconstructed images. Automatic volume measurements were performed using a flexible and robust segmentation algorithm that is based on a region-growing approach in combination with a neighbourhood variation threshold. The villous volume, vascular volume and vascular density were measured for the total chorionic villous tree as well as for its central and peripheral parts. No differences in maternal age and gestational age were found between non-smoking and smoking women. No differences were found in the total, central and peripheral villous tree volume and vascular volume. The central (13.4% vs. 9.5%, p=0.03) and peripheral (8.4% vs. 6.4%, p=0.02) villous tree vascular densities were increased in the smoking women as compared with the non-smoking women. In conclusion, chorionic villous vascularisation is already altered in first trimester of pregnancy in women who smoked cigarettes before and during pregnancy.

Agreement and reliability of pelvic floor measurements during contraction using three-dimensional pelvic floor ultrasound and virtual reality.

OBJECTIVES: Virtual reality is a novel method of visualizing ultrasound data with the perception of depth and offers possibilities for measuring non-planar structures. The levator ani hiatus has both convex and concave aspects. The aim of this study was to compare levator ani hiatus volume measurements obtained with conventional three-dimensional (3D) ultrasound and with a virtual reality measurement technique and to establish their reliability and agreement. METHODS: 100 symptomatic patients visiting a tertiary pelvic floor clinic with a normal intact levator ani muscle diagnosed on translabial ultrasound were selected. Datasets were analyzed using a rendered volume with a slice thickness of 1.5 cm at the level of minimal hiatal dimensions during contraction. The levator area (in cm(2)) was measured and multiplied by 1.5 to get the levator ani hiatus volume in conventional 3D ultrasound (in cm(3)). Levator ani hiatus volume measurements were then measured semi-automatically in virtual reality (cm(3) ) using a segmentation algorithm. An intra- and interobserver analysis of reliability and agreement was performed in 20 randomly chosen patients. RESULTS: The mean difference between levator ani hiatus volume measurements performed using conventional 3D ultrasound and virtual reality was 0.10 (95% CI, - 0.15 to 0.35) cm(3). The intraclass correlation coefficient (ICC) comparing conventional 3D ultrasound with virtual reality measurements was > 0.96. Intra- and interobserver ICCs for conventional 3D ultrasound measurements were > 0.94 and for virtual reality measurements were > 0.97, indicating good reliability for both. CONCLUSION: Levator ani hiatus volume measurements performed using virtual reality were reliable and the results were similar to those obtained with conventional 3D ultrasonography.

Gestational sac fluid volume measurements in virtual reality.

OBJECTIVES: To evaluate a virtual reality (VR) application for gestational sac fluid volume (GSFV) measurements in first-trimester pregnancies and to study the correlation between different embryonic growth parameters. METHODS: This was a prospective cohort study analyzing 180 three-dimensional (3D) ultrasound scans of 42 healthy women, performed between 5 + 5 and 12 + 6 weeks' gestational age (GA). The 3D datasets were transferred to the I-Space immersive VR system. The V-Scope application was used to create a 'hologram' of the ultrasound image, allowing depth perception and interaction with the rendered objects. Volumes were measured semi-automatically using a segmentation algorithm. In addition to the GSFV, the total gestational sac volume (GSV) and its diameter (GSD) were measured. The GSV was also calculated using the ellipsoid formula. Previously obtained measurements of embryonic volume and crown-rump length (CRL) were included in the study. The outcomes were analyzed using repeated-measures analysis of variance. RESULTS: The GSFV was measured in 78 scans, and varied from 434 to 81 491 mm(3). A positive correlation between GSFV and GA, CRL and GSD was found. Comparison of the GSD formula constructed in our study in relation to GA with a formula that is commonly used clinically showed an increasing difference with increasing GA either side of 8 + 5 weeks. The GSFV/embryonic volume ratio showed a decrease with GA. The GSV calculated using the ellipsoid formula was on average 19.8% larger compared with the GSV measured in VR. CONCLUSION: New charts for first-trimester GSFV were constructed using VR. These growth charts could be promising tools for studying normal and abnormal embryonic development.

Second primary malignancies in patients with a gastrointestinal neuroendocrine tumour: a case report and review of the literature.

A second primary malignancy (SPM) is frequently reported in patients with a gastrointestinal neuroendocrine tumour (NET). The majority of SPM are located in the gastrointestinal tract, but malignancies at other sites are described as well. This phenomenon might just be coincidental due to high incidence rates of asymptomatic NET lesions in patients who are operated or who undergo autopsy for another primary malignancy. However, other theories have been developed since the observed incidences rates seem to be double as high as expected. Some authors suggest a common genetic predisposition, while others report tumourigenic properties of various neuroendocrine peptides, including secretin, gastrin and cholecystokinin. This review is illustrated by a case report of a patient in whom the radiological diagnosis of a diffuse liver metastasized adenocarcinoma of the rectum changed dramatically after positron emission tomography and explorative laparoscopy to a curable adenocarcinoma of the rectum with a simultaneous well-differentiated neuroendocrine carcinoma.

Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A.

Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1-q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1-q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation.

An innovative virtual reality technique for automated human embryonic volume measurements.

BACKGROUND: The recent introduction of virtual reality (VR) enables us to use all three dimensions in a three-dimensional (3D) image. The aim of this prospective study was to evaluate an innovative VR technique for automated 3D volume measurements of the human embryo and yolk sac in first trimester pregnancies. METHODS: We analysed 180 3D first trimester ultrasound scans of 42 pregnancies. Scans were transferred to an I-Space VR system and visualized as 3D 'holograms' with the V-Scope volume-rendering software. A semi-automatic segmentation algorithm was used to calculate the volumes. The logarithmically transformed outcomes were analysed using repeated measurements ANOVA. Interobserver and intraobserver agreement was established by calculating intraclass correlation coefficients (ICCs). RESULTS: Eighty-eight embryonic volumes (EVs) and 118 yolk sac volumes (YSVs) were selected and measured between 5(+5) and 12(+6) weeks of gestational age (GA). EV ranged from 14 to 29 877 mm(3) and YSV ranged from 33 to 424 mm(3). ANOVA calculations showed that when the crown-rump length (CRL) doubles, the mean EV increases 6.5-fold and when the GA doubles, the mean EV increases 500-fold (P < 0.001). Furthermore, it was found that a doubling in GA results in a 3.8-fold increase of the YSV and when the CRL doubles, the YSV increases 1.5-fold (P < 0.001). Interobserver and intraobserver agreement were both excellent with ICCs of 0.99. CONCLUSION: We measured the human EV and YSV in early pregnancy using a VR system. This innovative technique allows us to obtain unique information about the size of the embryo using all dimensions, which may be used to differentiate between normal and abnormal human development.

Innovative virtual reality measurements for embryonic growth and development.

BACKGROUND: Innovative imaging techniques, using up-to-date ultrasonic equipment, necessitate specific biometry. The aim of our study was to test the possibility of detailed human embryonic biometry using a virtual reality (VR) technique. METHODS: In a longitudinal study, three-dimensional (3D) measurements were performed from 6 to 14 weeks gestational age in 32 pregnancies (n = 16 spontaneous conception, n = 16 IVF/ICSI). A total of 125 3D volumes were analysed in the I-Space VR system, which allows binocular depth perception, providing a realistic 3D illusion. Crown-rump length (CRL), biparietal diameter (BPD), occipito-frontal diameter (OFD), head circumference (HC) and abdominal circumference (AC) were measured as well as arm length, shoulder width, elbow width, hip width and knee width. RESULTS: CRL, BPD, OFD and HC could be measured in more than 96% of patients, and AC in 78%. Shoulder width, elbow width, hip width and knee width could be measured in more than 95% of cases, and arm length in 82% of cases. Growth curves were constructed for all variables. Ear and foot measurements were only possible beyond 9 weeks gestation. CONCLUSIONS: This study provides a detailed, longitudinal description of normal human embryonic growth, facilitated by a VR system. Growth curves were created for embryonic biometry of the CRL, BPD, HC and AC early in pregnancy and also of several 'new' biometric measurements. Applying virtual embryoscopy will enable us to diagnose growth and/or developmental delay earlier and more accurately. This is especially important for pregnancies at risk of severe complications, such as recurrent late miscarriage and early growth restriction.

Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment.

BACKGROUND This study investigates whether dietary patterns, substantiated by biomarkers, are associated with semen quality. METHODS In 161 men of subfertile couples undergoing in vitro fertilization treatment in a tertiary referral clinic in Rotterdam, the Netherlands, we assessed nutrient intakes and performed principal component factor analysis to identify dietary patterns. Total homocysteine (tHcy), folate, vitamin B12 and B6 were measured in blood and seminal plasma. Semen quality was assessed by sperm volume, concentration, motility, morphology and DNA fragmentation index (DFI). Linear regression models analyzed associations between dietary patterns, biomarkers and sperm parameters, adjusted for age, body mass index (BMI), smoking, vitamins and varicocele. RESULTS The 'Health Conscious' dietary pattern shows high intakes of fruits, vegetables, fish and whole grains. The 'Traditional Dutch' dietary pattern is characterized by high intakes of meat, potatoes and whole grains and low intakes of beverages and sweets. The 'Health Conscious' diet was inversely correlated with tHcy in blood (beta = -0.07, P = 0.02) and seminal plasma (beta = -1.34, P = 0.02) and positively with vitamin B6 in blood (beta = 0.217, P = 0.01). An inverse association was demonstrated between the 'Health Conscious' diet and DFI (beta = -2.81, P = 0.05). The 'Traditional Dutch' diet was positively correlated with red blood cell folate (beta = 0.06, P = 0.04) and sperm concentration (beta = 13.25, P = 0.01). CONCLUSIONS The 'Health Conscious' and 'Traditional Dutch' dietary pattern seem to be associated with semen quality in men of subfertile couples.