Imaging fetal anatomy.

Due to advancements in ultrasound techniques, the focus of antenatal ultrasound screening is moving towards the first trimester of pregnancy. The early first trimester however remains in part, a 'black box', due to the size of the developing embryo and the limitations of contemporary scanning techniques. Therefore there is a need for images of early anatomical developmental to improve our understanding of this area. By using new imaging techniques, we can not only obtain better images to further our knowledge of early embryonic development, but clear images of embryonic and fetal development can also be used in training for e.g. sonographers and fetal surgeons, or to educate parents expecting a child with a fetal anomaly. The aim of this review is to provide an overview of the past, present and future techniques used to capture images of the developing human embryo and fetus and provide the reader newest insights in upcoming and promising imaging techniques. The reader is taken from the earliest drawings of da Vinci, along the advancements in the fields of in utero ultrasound and MR imaging techniques towards high-resolution ex utero imaging using Micro-CT and ultra-high field MRI. Finally, a future perspective is given about the use of artificial intelligence in ultrasound and new potential imaging techniques such as synchrotron radiation-based CT to increase our knowledge regarding human development

The interplay of microscopic and mesoscopic structure in complex networks

Not all nodes in a network are created equal. Differences and similarities exist at both individual node and group levels. Disentangling single node from group properties is crucial for network modeling and structural inference. Based on unbiased generative probabilistic exponential random graph models and employing distributive message passing techniques, we present an efficient algorithm that allows one to separate the contributions of individual nodes and groups of nodes to the network structure. This leads to improved detection accuracy of latent class structure in real world data sets compared to models that focus on group structure alone. Furthermore, the inclusion of hitherto neglected group specific effects in models used to assess the statistical significance of small subgraph (motif) distributions in networks may be sufficient to explain most of the observed statistics. We show the predictive power of such generative models in forecasting putative gene-disease associations in the Online Mendelian Inheritance in Man (OMIM) database. The approach is suitable for both directed and undirected uni-partite as well as for bipartite networks

Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acidbase regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients

Exploring hypotheses of the actions of TGF-beta 1 in epidermal wound healing using a 3D computational multiscale model of the human epidermis

In vivo and in vitro studies give a paradoxical picture of the actions of the key regulatory factor TGF-beta 1 in epidermal wound healing with it stimulating migration of keratinocytes but also inhibiting their proliferation. To try to reconcile these into an easily visualized 3D model of wound healing amenable for experimentation by cell biologists, a multiscale model of the formation of a 3D skin epithelium was established with TGF-beta 1 literature-derived rule sets and equations embedded within it. At the cellular level, an agent-based bottom-up model that focuses on individual interacting units ( keratinocytes) was used. This was based on literature-derived rules governing keratinocyte behavior and keratinocyte/ECM interactions. The selection of these rule sets is described in detail in this paper. The agent-based model was then linked with a subcellular model of TGF-beta 1 production and its action on keratinocytes simulated with a complex pathway simulator. This multiscale model can be run at a cellular level only or at a combined cellular/subcellular level. It was then initially challenged ( by wounding) to investigate the behavior of keratinocytes in wound healing at the cellular level. To investigate the possible actions of TGF-beta 1, several hypotheses were then explored by deliberately manipulating some of these rule sets at subcellular levels. This exercise readily eliminated some hypotheses and identified a sequence of spatial-temporal actions of TGF-beta 1 for normal successful wound healing in an easy-to-follow 3D model. We suggest this multiscale model offers a valuable, easy-to-visualize aid to our understanding of the actions of this key regulator in wound healing, and provides a model that can now be used to explore pathologies of wound healing

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Immunisation coverage and annual report National Immunisation Programme in the Netherlands 2016

Het RIVM beschrijft jaarlijks de ontwikkelingen binnen het Rijksvaccinatieprogramma (RVP), zowel inhoudelijk als organisatorisch. Vanaf dit jaar zijn de belangrijkste gebeurtenissen en de ontwikkelingen op het gebied van de vaccinatiegraad gebundeld. Belangrijke gebeurtenissen In 2016 waren er geen opvallende uitbraken van RVP-ziekten. Wel stijgt sinds oktober 2015 het aantal patiënten met meningokokkenziekte W, terwijl in het RVP tegen meningokokkenziekte C wordt ingeënt. Opvallend was het stevige debat dat in november 2016 in diverse media is gevoerd tussen voor- en tegenstanders van vaccinatie. Verder heeft het RIVM factsheets gemaakt voor zowel professionals als het publiek met informatie over vaccinaties tegen ziekten die wel beschikbaar zijn maar niet in het RVP zijn opgenomen. Voorbeelden zijn waterpokken, gordelroos en het rotavirus (www.rivm.nl/vaccinaties). Vaccinatiegraad De vaccinatiegraad, oftewel het aandeel zuigelingen, kleuters en schoolkinderen dat de vaccinaties uit het RVP krijgt, is nog steeds hoog. De vaccinatiegraad voor bof, mazelen en rodehond (BMR) daalt al een paar jaar licht. De norm van 95 procent van de Wereldgezondheidsorganisatie (WHO), die nodig is om mazelen uit te bannen, wordt in Nederland bij de eerste BMR-vaccinatie niet meer gehaald. Voor de tweede BMR-vaccinatie was dit al langer zo. Ook bij andere vaccinaties in het RVP is een lichte daling te zien. De deelname aan de HPV-vaccinatie tegen baarmoederhalskanker is voor het eerst afgenomen, van 61 naar 53 procent. Een hoge vaccinatiegraad zorgt ervoor dat kwetsbare en (nog) niet gevaccineerde kinderen tegen ziekten worden beschermd (groepsbescherming). Een dalende vaccinatiegraad vergroot de kans dat in de toekomst ziekten zoals mazelen uitbreken.The RIVM annually describes the developments within the Dutch National Immunisation Programme (NIP), both substantively and organisationally. From this year, the most important events and developments in the field of immunisation coverage have been bundled. Important events In 2016, there were no significant outbreaks of NIP diseases. However, since October 2015, the number of meningococcal disease patients by a different serogroup (W) than the serogroup C which is vaccinated against within the NIP, has risen. Striking was the vigorous debate that was conducted in various media in November 2016 between advocates and opponents of immunisation. Furthermore, the RIVM has made factsheets for professionals as well as the public with information on vaccines against diseases that are available but not included in the NIP. Examples include varicella, herpes zoster and rotavirus (www.rivm.nl/vaccinations). Immunisation coverage The immunisation coverage, i.e. the proportion of newborns, toddlers and schoolchildren who receive vaccinations within the NIP is still high. The immunisation coverage for mumps, measles and rubella (MMR) has declined slightly for a few years. The 95 per cent threshold of the World Health Organization (WHO) needed to eliminate measles is no longer achieved in the Netherlands for the first MMR vaccination. For the second MMR vaccination this has been for longer. Also for other NIP vaccinations there is a slight decrease in participation. The participation in HPV vaccination against cervical cancer has decreased for the first time, from 61 to 53 per cent. A high immunisation coverage ensures that vulnerable and not (yet) vaccinated children are protected against diseases (herd protection). A decreasing immunisation coverage increases the likelihood that diseases such as measles cause outbreaks in the future.Ministerie van VW

Is there a role for CT coronary angiography in patients with symptomatic angina? Effect of coronary calcium score on identification of stenosis

Present guidelines discourage the use of CT coronary angiography (CTCA) in symptomatic angina patients. We examined the relation between coronary calcium score (CS) and the performance of CTCA in patients with stable and unstable angina in order to understand under which conditions CTCA might be a gate-keeper to conventional coronary angiography (CCA) in such patients. We included 360 patients between 50 and 70 years old with stable and unstable angina who were clinically referred for CCA irrespective of CS. Patients received CS and CCTA on 64-slice scanners in a multicenter cross-sectional trial. The institutional review board approved the study. Diagnostic performance of CTCA to detect or rule out significant coronary artery disease was calculated on a per patient level in pre-defined CS categories. The prevalence of significant coronary artery disease strongly increased with CS. Negative CTCA were associated with a negative likelihood ratio of <0.1 independent of CS. Positive CTCA was associated with a high positive likelihood ratio of 9.4 if CS was <10. However, for higher CS the positive likelihood ratio never exceeded 3.0 and for CS >400 it decreased to 1.3. In the 62 (17%) patients with CS <10, CTCA reliably identified the 42 (68%) of these patients without significant CAD, at no false negative CTCA scans. In symptomatic angina patients, a negative CTCA reliably excludes significant CAD but the additional value of CTCA decreases sharply with CS >10 and especially with CS >400. In patients with CS <10, CTCA provides excellent diagnostic performance

Predictive value of coronary calcifications for future cardiac events in asymptomatic patients with diabetes mellitus: A prospective study in 716 patients over 8 years

<p>Abstract</p> <p>Background</p> <p>To establish an efficient prophylaxis of coronary artery disease reliable risk stratification is crucial, especially in the high risk population of patients suffering from diabetes mellitus. This prospective study determined the predictive value of coronary calcifications for future cardiovascular events in asymptomatic patients with diabetes mellitus.</p> <p>Methods</p> <p>We included 716 patients suffering from diabetes mellitus (430 men, 286 women, age 55.2 ± 15.2 years) in this study. On study entry all patients were asymptomatic and had no history of coronary artery disease. In addition, all patients showed no signs of coronary artery disease in ECG, stress ECG or echocardiography. Coronary calcifications were determined with the Imatron C 150 XP electron beam computed tomograph. For quantification of coronary calcifications we calculated the Agatston score. After a mean observation period of 8.1 ± 1.1 years patients were contacted and the event rate of cardiac death (CD) and myocardial infarction (MI) was determined.</p> <p>Results</p> <p>During the observation period 40 patients suffered from MI, 36 patients died from acute CD. The initial Agatston score in patients that suffered from MI or died from CD (475 ± 208) was significantly higher compared to those without cardiac events (236 ± 199, p < 0.01). An Agatston score above 400 was associated with a significantly higher annualised event rate for cardiovascular events (5.6% versus 0.7%, p < 0.01). No cardiac events were observed in patients with exclusion of coronary calcifications. Compared to the Framingham risk score and the UKPDS score the Agatston score showed a significantly higher diagnostic accuracy in the prediction of MI with an area under the ROC curve of 0.77 versus 0.68, and 0.71, respectively, p < 0.01.</p> <p>Conclusion</p> <p>By determination of coronary calcifications patients at risk for future MI and CD could be identified within an asymptomatic high risk group of patients suffering from diabetes mellitus. On the other hand future events could be excluded in patients without coronary calcifications.</p