Serpin E1/PAI-1, N-terminal pro-brain natriuretic peptide (NTpro-BNP) and neuropilin-1 are markers which have been associated with endothelial dysfunction. However, data on the levels of these markers in PE is limited. The limited data on the pathophysiology of PE in relation to these markers necessitated the study. This was a multicentre case-control study conducted at the Obstetrics and Gynaecology Department of the Tamale Teaching Hospital, the Bawku Presbyterian Hospital and the Bolgatanga Regional Hospital. Out of 520 consenting pregnant women, 127 pregnant women met the inclusion criteria (53 with PE and 74 controls) and were included in this study. Venous, placental, cord and peripheral blood were collected for biomarker assay, haematological parameters and placental parasite determination. Placental tissue sections were obtained for placental malaria and histopathological lesions associated with hypoperfusion. Maternal heart rate and foetal umbilical artery Doppler impedance indices; resistance index (RI) and systolic diastolic (SD) ratio were determined to confirm utero-placental hypoperfusion. Significantly higher proportions of foeto-maternal complications; eclampsia, low birth weight (LBW), neonatal intensive care unit admissions (NICU), intrauterine growth restriction (IUGR), caesarian deliveries and early gestational age at delivery were associated with PE. Women with PE had lower concentrations of platelet (p = 0.02) whereas red cell distribution width (RDW) was markedly elevated (p = 0.01). NTPro-BNP concentration was markedly elevated (p = 0.01) in women with PE whereas neuropilin-1 concentration was lower (p = 0.03) compared to the non-PE group. Maternal heart rate was elevated in women with PE and Doppler resistance indices (RI and SD) were significantly elevated in foetuses of PE women than foetuses of the controls. Placental mal-perfusion lesions were higher in women with PE compared to the non-PE group. Women with PE had increased risk of adverse foeto-maternal complications, significantly associated with placental mal-perfusion lesions, had reduced platelet concentration and elevated RDW-CV levels. NTPro-BNP, RI and SD are elevated in women with PE whereas neuropilin-1 concentration is reduced. Significant changes in these pathological variables in PE women is indicative of significant derangement in endothelial function culminating in adverse maternal and perinatal outcomes of pregnancy.

Genotype-phenotype analysis of at least 25 individuals with interstitial 16p13.3 duplications defines a recognizable syndrome associated with duplication of a critical Rubinstein-Taybi region encompassing only the CREBBP gene. Nevertheless, variable or incompletely penetrant phenotype has been reported previously. We here report a case of a 5-year old boy with a recognizable phenotype of this syndrome, including intellectual disability, mild arthrogryposis, small and proximally implanted thumbs and characteristic facial features. In addition, growth delay, microcephaly and distinguishable structural brain MRI abnormalities were observed. A de novo 1.5 Mb interstitial duplication of 16p13.3 was detected by SNP-array and fluorescence in situ hybridization (FISH). Short tandem repeat polymorphism (STRP) analysis with marker D16S475 indicated that the duplication was formed before maternal meiosis II. Our findings highlight the variable clinical features and further expand the phenotypic spectrum correlated with this lately proposed syndrome.

Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted.

BACKGROUND: Social networks applied through Web 2.0 tools have gained importance in health domain, because they produce improvements on the communication and coordination capabilities among health professionals. This is highly relevant for multimorbidity patients care because there is a large number of health professionals in charge of patient care, and this requires to obtain clinical consensus in their decisions. Our objective is to develop a tool for collaborative work among health professionals for multimorbidity patient care. We describe the architecture to incorporate decision support functionalities in a social network tool to enable the adoption of shared decisions among health professionals from different care levels. As part of the first stage of the project, this paper describes the results obtained in a pilot study about acceptance and use of the social network component in our healthcare setting.
METHODS: At Virgen del Rocío University Hospital we have designed and developed the Shared Care Platform (SCP) to provide support in the continuity of care for multimorbidity patients. The SCP has two consecutively developed components: social network component, called Clinical Wall, and Clinical Decision Support (CDS) system. The Clinical Wall contains a record where health professionals are able to debate and define shared decisions. We conducted a pilot study to assess the use and acceptance of the SCP by healthcare professionals through questionnaire based on the theory of the Technology Acceptance Model.
RESULTS: In March 2012 we released and deployed the SCP, but only with the social network component. The pilot project lasted 6 months in the hospital and 2 primary care centers. From March to September 2012 we created 16 records in the Clinical Wall, all with a high priority. A total of 10 professionals took part in the exchange of messages: 3 internists and 7 general practitioners generated 33 messages. 12 of the 16 record (75%) were answered by the destination health professionals. The professionals valued positively all the items in the questionnaire. As part of the SCP, opensource tools for CDS will be incorporated to provide recommendations for medication and problem interactions, as well as to calculate indexes or scales from validated questionnaires. They will receive the patient summary information provided by the regional Electronic Health Record system through a web service with the information defined according to the virtual Medical Record specification.
CONCLUSIONS: Clinical Wall has been developed to allow communication and coordination between the healthcare professionals involved in multimorbidity patient care. Agreed decisions were about coordination for appointment changing, patient conditions, diagnosis tests, and prescription changes and renewal. The application of interoperability standards and open source software can bridge the gap between knowledge and clinical practice, while enabling interoperability and scalability. Open source with the social network encourages adoption and facilitates collaboration. Although the results obtained for use indicators are still not as high as it was expected, based on the promising results obtained in the acceptance questionnaire of SMP, we expect that the new CDS tools will increase the use by the health professionals.

OBJECTIVE: We explored possible associations between long-term antimuscarinic use and behavioral problems in children with spinal dysraphism and neurogenic bladder.
METHODS: Children with open and closed spinal dysraphism were recruited from 2 pediatric hospitals, 1 in Amsterdam and 1 in Utrecht, The Netherlands. At the Amsterdam facility antimuscarinics were prescribed in selected patients with detrusor overactivity. At the Utrecht facility antimuscarinics were prescribed from birth onward in patients with spinal dysraphism beginning in the early 1990s. Parents of study participants were asked to fill out a Child Behavior Checklist. Demographics, data on level and type(s) of lesion, and presence of hydrocephalus with a drain (and, if applicable, number of drain revisions) were retrieved for each patient. Cases and controls (8 boys and 8 girls per group) were matched on a 1-to-1 basis.
RESULTS: Data on 32 children were analyzed. Median age was 10.6 years in cases and 10.5 years in controls (p=0.877). In each group 9 of 16 patients had hydrocephalus with a drain. No significant difference in Child Behavior Checklist scores for total problems was found between cases and controls (median 52.0 vs 59.5, p=0.39). No differences were found between the groups on any subdomain of the Child Behavior Checklist.
CONCLUSIONS: No significant differences in behavior were found between children with spinal dysraphism with and without long-term use of antimuscarinics.

The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta-analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81-0.99, p=0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63-0.95, p=0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58-0.94, p=0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07-1.56, p=0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84-2.10, p=0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations.

The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo-controlled, phase III studies that had at least one 600 mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size.

An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose-response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions--Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?--were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment.

OBJECTIVE: There are few prospective studies on fatty acid status in relation to incident stroke, with inconsistent results. We assessed the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with the risk of total stroke and stroke subtypes in Dutch adults.
RESULTS: We conducted a nested case-control study using data from a population-based cohort study in adults aged 20-65 years. Blood sampling and data collection took place during 1993-1997 and subjects were followed for 8-13 years. We identified 179 incident cases of stroke and 179 randomly selected controls, matched on age, gender, and enrollment date. Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated per standard deviation (SD) increase of PUFA in cholesteryl esters using multivariable conditional logistic regression. Cases comprised 93 ischemic, 50 hemorrhagic, and 36 unspecified strokes. The n-6 PUFA linoleic acid and arachidonic acid contributed ~55% and ~6.5% respectively to total plasma fatty acids, whereas the n-3 PUFA alpha-linolenic acid contributed ~0.5% and eicosapentaenoic acid plus docosahexaenoic acid (EPA-DHA) ~1.3%. After adjustment for confounders, n-6 and n-3 PUFA were not associated with incident total stroke or stroke subtypes. The OR (95% CI) for total stroke was 0.95 (0.74-1.23) per SD increase in linoleic acid and 1.02 (0.80-1.30) per SD increase in arachidonic acid. ORs (95% CI) for total stroke were 0.94 (0.72-1.21) for alpha-linolenic acid and 1.16 (0.94-1.45) for EPA-DHA.
CONCLUSIONS: In the present study, plasma n-6 or n-3 fatty acids were not related to incident stroke or stroke subtypes.

An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.