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PURPOSE: Infectious complications occur following pulmonary resections preceded or not by induction chemoradiotherapy. We aimed to investigate whether bacterial colonization of the bronchial tree at the time of surgery was associated with postoperative complications.PATIENTS AND METHODS: A retrospective analysis of all patients who underwent open anatomical pulmonary resections for malignancies at a single center was performed. Demographical data of the included patients, intraoperative data, and data on the postoperative course of patients were collected. Outcome of patients with a positive intraoperative bronchial culture was compared to patients with a negative bronchial culture. Relations between the presence of potential bacterial pathogens in the bronchial tree and other possible risk factors for the development of postoperative infectious and non-infectious complications, were analyzed using uni- and multivariate analysis.RESULTS: Between January 2010 and January 2012, a total of 121 consecutive patients underwent open anatomical pulmonary resections for malignancy, of whom 45 were preceded by induction chemoradiotherapy and 5 by induction chemotherapy. Intraoperative bronchial cultures were taken from 58 patients (48 %). Patients with a positive bronchial culture developed significantly more infectious (88 % vs. 20 %, p < 0.001) and non-infectious complications (63 % vs. 12 %, p = 0.001). Positive intraoperative bronchial cultures showed the strongest association with the development of infectious and non-infectious postoperative complications (OR 24.8 and 12.2, respectively). After multivariate analysis, only BMI less than 20 kg/m(2) and the presence of a positive intraoperative bronchial culture were found to be independent risk factors for the development of infectious complications. Chemoradiotherapy was not associated with postoperative complications in the present study.CONCLUSIONS: Bacterial colonization of the bronchial tree assessed intraoperatively, appears to be associated with higher rates of infectious and non-infectious complications after pulmonary resection. Whether early starting of appropriate antibiotics based on intraoperative-taken culture findings will reduce the infectious complication rate in a subcategory of patients needs to be investigated.

Mismatch between myocardial innervation and perfusion assessed with positron emission tomography (PET) is a potential risk marker for ventricular arrhythmias in patients with ischemic cardiomyopathy. This mismatch zone originates from residual viable myocardium that has sustained ischemic nerve injury. Heterogenic scar size assessed with late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR) is also a risk marker of ventricular arrhythmias. These two imaging parameters may represent identical morphological tissue features. The current study explored the relation between innervation-perfusion mismatch and heterogenic scar size. Twenty-eight patients (26 males, age 67 ± 8 years) with ischemic cardiomyopathy and a left ventricular ejection fraction below 35%, eligible for ICD implantation were included. All patients underwent both [11C]-hydroxyephedrine and [15O]-water PET studies to assess myocardial sympathetic innervation and perfusion. LGE CMR was conducted to assess total myocardial scar size, scar core size, and heterogenic scar size. Perfusion defect size was 16.6 ± 9.9% and innervation defect size was 33.7 ± 10.8%, which resulted in an innervation-perfusion mismatch of 17.6 ± 8.9%. Total scar size, scar core size, and heterogenic scar size were 21.2 ± 8.6%, 14.7 ± 6.6%, and 6.5 ± 2.9%, respectively. No relation between scar core size and perfusion deficit size was observed (r = 0.18, P = .36). Total scar size was correlated with the innervation defect size (r = 0.52, P = .004) and the heterogenic scar zone displayed a significant correlation with the innervation-perfusion mismatch area (r = 0.67, P

Inflammatory immune disorders such as inflammatory bowel disease and multiple sclerosis are major health problems. Currently, the intestinal whipworm Trichuris suis is being explored in clinical trials to reduce inflammation in these diseases; however, the mechanisms by which the parasite affects the host immune system are not known. Here we determined the effects of T. suis soluble products (SPs) on Toll-like receptor-4 (TLR4)-stimulated human dendritic cells (DCs) using Illumina bead chip gene arrays. Pathway analysis of lipopolysaccharide-stimulated DCs with or without T. suis treatment showed that co-stimulation with T. suis SPs resulted in a downregulation of both the myeloid differentiation primary response gene 88-dependent and the TIR-domain-containing adaptor-inducing interferon-β-dependent signalling pathways triggered by TLR4. These data were verified using quantitative real-time PCR of several key genes within these pathways and/or defining their protein levels. In addition, T. suis SPs induce Rab7b, a negative regulator of TLR4 signalling that interferes with its trafficking, which coincided with a reduced surface expression of TLR4. These data indicate that the mechanism by which T. suis SPs reduce inflammatory responses is through suppression of both TLR4 signalling and surface expression on DCs.

In laparoscopy, specimens have to be removed from the abdominal cavity. If the trocar opening or the vaginal outlet is insufficient to pass the specimen, the specimen needs to be reduced. The power morcellator is an instrument with a fast rotating cylindrical knife which aims to divide the tissue into smaller pieces or fragments. The Food and Drug Administration (FDA) issued a press release in April 2014 that discouraged the use of these power morcellators. This article has the objective to review the literature related to complications by power morcellation of uterine fibroids in laparoscopy and offer recommendations to laparoscopic surgeons in gynaecology. This project was initiated by the executive board of the European Society of Gynaecological Endoscopy. A steering committee on fibroid morcellation was installed and experienced ESGE members requested to chair an action group to address distinct clinical questions. Clinical questions were formulated with regards to the sarcoma risk in presumed uterine fibroids, diagnosis of sarcoma, complications of morcellation and future research. A literature review on the different subjects was conducted, systematic if appropriate and feasible. It was concluded that the true prevalence of uterine sarcoma in presumed fibroids is not known given the wide range of prevalences (0.45–0.014 %) from meta-analyses mainly based on retrospective trials. Age and certain imaging characteristics such as ‘lacunes’ suggesting necrosis and increased central vascularisation of the tumour are associated with a higher risk of uterine sarcoma, although the risks remain low. There is not enough evidence to estimate this risk in individual patients. Complications of morcellation are rare. Reported are direct morcellation injuries to vessels and bowel, the development of so-called parasitic fibroids requiring reintervention and the spread of sarcoma cells in the abdominal cavity, which may possibly or even likely upstaging the disease. Momentarily in-bag morcellation is investigated as it may possibly prevent morcellation complications. Because of lack of evidence, this literature review cannot give strong recommendations but offers only options which are condensed in a flow chart. Prospective data collection may clarify the issue on sarcoma risk in presumed fibroids and technology to extract tissue laparoscopically from the abdominal cavity should be perfected.

In a press release in April 2014, the US Food and Drug Administration [1] discourages doctors from using laparoscopic power morcellators in removing fibroids or myomatotic uteri in order to reduce the risk of sarcomatous cell escape. The USbased company Johnson & Johnson, the largest manufacturer of the devices, halted global sales and distribution of power morcellators, while many hospitals in USA ban the use of morcellation under these circumstances. Patients’ safety and wellbeing especially after surgery is a common and primary concern of surgeons and hospitals; however, there is no reliable way to determine if a uterine fibroid contains a sarcoma prior to removal. Patients should know that the use of laparoscopic power morcellation for hysterectomy or myomectomy may deteriorate their survival rate in case of a sarcoma, and they should discuss the risks and benefits of the available treatment options with their health care professionals. The incidence of uterine sarcomas is extremely low, 0.23% [2], or according to FDA analysis of currently available data (1:350), 0.29 %. They are classified according to histological subtypes in order of decreasing incidence: leiomyosarcomas, endometrial stromal sarcomas (ESS) and ‘other’ sarcomas. The ESS are lesions within the endometrial cavity and diagnosis can be established prior to surgery by endometrial biopsy [3]. The rarity of these tumours has prevented the performance of large epidemiological studies to identify risk factors. Assuming an incidence of uterine sarcomas of 0.23 % by applying the ‘inverse rule of 3’, a surgeonwill need to perform 1304 laparoscopic interventions to observe at least one case of uterine sarcoma with 95 % confidence. Imaging characteristics, tumour markers and other parameters indicating the risk of sarcoma are not available or not specific. In addition, the lack of uniform histologic criteria for diagnosing uterine leiomyosarcoma (ULMS) makes interpretation of the older studies difficult [4]. As the Stanford study [5] was the first to appreciate that the type of necrosis in a uterine smooth muscle tumour was of crucial importance, studies that preceded it did not evaluate the presence or absence of tumour cell necrosis. A leiomyosarcoma usually exhibits diffuse moderate-tosevere atypia, a mitotic count of >10 MFs/10 HPFs and tumour cell necrosis. A tumour with any two of these features V. Tanos :H. Brolmann : R. L. DeWilde : P. O’Donovan :R. Campo Head IVF and Reproductive Surgery, Aretaeio Hospital, Nicosia, Cyprus

Asthma and chronic obstructive pulmonary disease remain a global health problem, with increasing morbidity and mortality. Despite differences in the causal agents, both diseases exhibit various degrees of inflammatory changes, structural alterations of the airways leading to airflow limitation. The existence of transient disease phenotypes which overlap both diseases and which progressively decline the lung function has complicated the search for an effective therapy. Important characteristics of chronic airway diseases include airway and vascular remodeling, of which the molecular mechanisms are complex and poorly understood. Recently, we and others have shown that airway smooth muscle (ASM) cells are not only structural and contractile components of airways, rather they bear capabilities of producing large number of pro-inflammatory and mitogenic factors. Increase in size and number of blood vessels both inside and outside the smooth muscle layer as well as hyperemia of bronchial vasculature are contributing factors in airway wall remodeling in patients with chronic airway diseases, proposing for the ongoing mechanisms like angiogenesis and vascular dilatation. We believe that vascular changes directly add to the airway narrowing and hyper-responsiveness by exudation and transudation of proinflammatory mediators, cytokines and growth factors; facilitating trafficking of inflammatory cells; causing oedema of the airway wall and promoting ASM accumulation. One of the key regulators of angiogenesis, vascular endothelial growth factor in concerted action with other endothelial mitogens play pivotal role in regulating bronchial angiogenesis. In this review article we address recent advances in pulmonary angiogenesis and remodelling that contribute in the pathogenesis of chronic airway diseases.

This study was designed to compare the costs and effects of epidural analgesia (EDA) to those of patient-controlled intravenous analgesia (PCA) for postintervention pain relief in women having uterine artery embolization (UAE) for systematic uterine fibroids. Cost-effectiveness analysis (CEA) based on data from the literature by constructing a decision tree to model the clinical pathways for estimating the effects and costs of treatment with EDA and PCA. Literature on EDA for pain-relief after UAE was missing, and therefore, data on EDA for abdominal surgery were used. Outcome measures were compared costs to reduce one point in visual analogue score (VAS) or numeric rating scale (NRS) for pain 6 and 24 h after UAE and risk for complications. Six hours after the intervention, the VAS was 3.56 when using PCA and 2.0 when using EDA. The costs for pain relief in women undergoing UAE with PCA and EDA were 191 and 355, respectively. The costs for EDA to reduce the VAS score 6 h after the intervention with one point compared with PCA were 105 and 179 after 24 h. The risk of having a complication was 2.45 times higher when using EDA. The results of this indirect comparison of EDA for abdominal surgery with PCA for UAE show that EDA would provide superior analgesia for post UAE pain at 6 and 24 h but with higher costs and an increased risk of complications

To generate novel, objective variables that resemble embryo quality and relate them to ongoing implantation, using multilevel imaging of single-transferred embryos.Retrospective analysis of multilevel images of 659 day 3 single-transferred embryos. Each embryo was photographed on seven different levels, in order to measure the largest diameter of every blastomere within an embryo. The volume of each blastomere was calculated using the equation [Formula: see text]. The blastomere volume index (BVI) represented the ratio between the total blastomeric volume of an embryo and the mean cytoplasmic volume of an oocyte on day 0. The blastomere symmetry index (BSI) represented the ratio between the greatest blastomere volume and the smallest blastomere volume within an embryo. The mean ovality (MO) represented the presence of non-spherical blastomeres. Analyses were performed to compare the BVI, BSI and MO between patients with and without an ongoing implantation.The mean BVI was significantly higher for embryos in the ongoing implantation group compared to the no ongoing implantation group. The mean BSI was associated with ongoing implantation for unevenly cleaved embryos. The MO of blastomeres within an embryo was similar for embryos in the ongoing implantation group compared to the no ongoing implantation group. The association of the BVI and BSI with ongoing implantation was confounded, because only female age and cleavage rate were significantly associated with ongoing implantation in multiple logistic regression analyses.The BVI, BSI and MO are objective variables that resemble embryo quality, but they are not suitable to use as embryo selection tools.

Ureter injuries are the most dreaded complication in gynecological surgery. Some risk factors for the occurrence of urinary tract injuries are known, but clear guidelines to prevent ureter injuries during laparoscopic hysterectomy (LH) are lacking. The aim of this study was to analyze all known ureter injuries that occurred during LH for a benign indication in the Netherlands, in order to identify patient- and surgeon-related risk factors. Ninety-five LH-performing gynecologists were asked to recall all cases of known ureter injuries during LH in their hospital. After identification of ureter injuries, a structured interview was performed with a questionnaire that focused on the identification of predisposing factors which could account for the cause of the injury. Forty-one injuries were detected in 37 patients (4 bilateral ureter injuries) in a 20-year period. The questionnaire could be completed for 31 cases. Predisposing factors were retrospectively assessed and classified into categories: patient-related (i.e., deep infiltrating endometriosis, intraligamentary fibroids) (n = 18), surgeon-related (insufficient experience and/or technique) (n = 16), or both (insufficient experience and difficult case) (n = 8). According to earlier-mentioned recommendations in a Delphi study among experts, in 48.4 % of these ureter injury cases, more than one of the recommended techniques or predisposing conditions were not applied or available. Only one ureter injury was diagnosed during the LH; the mean time to diagnose the injury was 29 days. Incomplete learning curve, insufficient applied technique such as coagulation of the uterine artery without the use of a uterine manipulator, and/or from the contralateral side and/or without previously performed ureterolysis in case of distorted anatomy may be considered as the main predisposing factors.

Osteogenesis imperfecta (OI) comprises a group of inherited disorders characterized by bone fragility and increased susceptibility to fractures. Historically, the laboratory confirmation of the diagnosis OI rested on cultured dermal fibroblasts to identify decreased or abnormal production of abnormal type I (pro)collagen molecules, measured by gel electrophoresis. With the discovery of COL1A1 and COL1A2 gene variants as a cause of OI, sequence analysis of these genes was added to the diagnostic process. Nowadays, OI is known to be genetically heterogeneous. About 90% of individuals with OI are heterozygous for causative variants in the COL1A1 and COL1A2 genes. The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes. These advances in the molecular genetic diagnosis of OI prompted us to develop new guidelines for molecular testing and reporting of results in which we take into account that testing is also used to 'exclude' OI when there is suspicion of non-accidental injury. Diagnostic flow, methods and reporting scenarios were discussed during an international workshop with 17 clinicians and scientists from 11 countries and converged in these best practice guidelines for the laboratory diagnosis of OI.

Obesity is associated with insulin resistance, hypertension, and cardiovascular disease, but the mechanisms underlying these associations are incompletely understood. Microvascular dysfunction may play an important role in the pathogenesis of both insulin resistance and hypertension in obesity. Adipose tissue-derived substances (adipokines) and especially inflammatory products of adipose tissue control insulin sensitivity and vascular function. In the past years, adipose tissue associated with the vasculature, or perivascular adipose tissue (PAT), has been shown to produce a variety of adipokines that contribute to regulation of vascular tone and local inflammation. This review describes our current understanding of the mechanisms linking perivascular adipose tissue to vascular function, inflammation, and insulin resistance. Furthermore, we will discuss mechanisms controlling the quantity and adipokines secretion by PAT.

The costs and efforts for sample preparation of hundreds of individuals, their genomic enrichment for regions of interest, and sufficient deep sequencing bring a significant burden to next-generation sequencing-based experiments. We investigated whether pooling of samples at the level of genomic DNA would be a more versatile strategy for lowering the costs and efforts for common disease-associated rare variant detection in candidate genes or associated loci in a substantial patient cohort. We performed a pilot experiment using five pools of 20 abdominal aortic aneurysm (AAA) patients that were enriched on separate microarrays for the reported 9p21.3 associated locus and 42 additional AAA candidate genes, and sequenced on the SOLiD platform. Here, we discuss challenges and limitations connected to this approach and show that the high number of novel variants detected per pool and allele frequency deviations to the usually highly false positive cut-off region for variant detection in non-pooled samples can be limiting factors for successful variant prioritization and confirmation. We conclude that barcode indexing of individual samples before pooling followed by a multiplexed enrichment strategy should be preferred for detection of rare genetic variants in larger sample sets rather than a genomic DNA pooling strategy.

Exenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus.Patients with type 2 diabetes participated in either a single-dose trial (n = 62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.Exenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6-7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (-42.7 ± 15.7 mg/dL with the 0.8 mg dose and -39.0 ± 9.3 mg/dL with the 2 mg dose; both p 0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC(50)) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2 mg doses of exenatide ER). The 2 mg dose reduced bodyweight (-3.8 ± 1.4 kg; p 0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbA(1c)) levels were reduced with the 0.8 mg dose (-1.4 ± 0.3%; baseline 8.6%) and with the 2 mg dose (-1.7 ± 0.3%; baseline 8.3%) [both p 0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity.These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935].

Objective To characterise the training environment in ICM across Europe, with a particular focus on factors influencing competency-based training. Method A cross-sectional web-based survey completed by the national coordinator for the CoBaTrICE (Competency-Based Training in Intensive Care medicinE) programme in each of 28 European countries. Results Since the last survey in 2004, 50% of EU countries have modified their training programmes. Seven have already adopted the CoBaTrICE programme since its completion in 2006. Multidisciplinary access to ICM training (‘supraspeciality’ model) is available in 57%, most commonly as a 2-year training programme. National examinations are held by 26 (93%); in 24 (86%) this is a mandatory exit exam; ten use the European Diploma of Intensive Care (EDIC). A formal national system for quality assurance of ICM training exists in only 18 (64%) countries. National standards for approving hospitals as training centres vary widely. In 29% there is no designated specialist with responsibility for training at the local level. Time for teaching was cited as inadequate by 93% of respondents; only 21% of trainers receive contractual recognition for their work. In 39% there is no protected teaching time for trainees. Half of countries surveyed have no formal system for workplace-based assessment of competence of trainees. Conclusions There is considerable diversity in pedagogic structures, processes and quality assurance of ICM across Europe. National training organisations should develop common standards for quality assurance, health systems need to invest in educator support, and the EU should facilitate harmonisation by recognising ICM as a multidisciplinary speciality.

Objective A distinctive pattern of physiological symmetrical uptake of 18F-fluorodeoxyglucose (18F-FDG) in the neck and upper chest region is a phenomenon that is sometimes observed on positron emission tomography (PET) scans of some oncologic patients. Initially, it was assumed to be muscle uptake secondary to patient anxiety or tension, which could be prevented by diazepam treatment. However, PET–computed tomography data have shown that 18F-FDG uptake is not restricted to the musculature but is also localised within the non-muscular soft tissue, such as brown adipose tissue. The efficacy of benzodiazepine treatment to reduce this uptake has not been well established. Therefore, a randomised controlled trial was conducted to decide whether diazepam would decrease physiological 18F-FDG uptake in the neck and upper chest region (FDG-NUC). Methods A randomised, double-blind, placebo-controlled trial was conducted to assess the effect on FDG-NUC of 5 mg diazepam, given orally 1 h before 18F-FDG injection. Patients younger than 40 years, having or suspected to have a malignancy, were eligible for inclusion. The primary endpoint was FDG-NUC, as assessed by visual analysis of whole-body PET scans by two independent observers. The secondary endpoint was clinical relevance of FDG-NUC. Results Fifty-two patients were included between September 2003 and January 2005. Twenty-eight patients (54%) received placebo; 24 (46%) received diazepam. FDG-NUC was seen in 25% of the patients in the diazepam group versus 29% in the placebo group. This difference was not statistically significant. Conclusion No beneficial effect of administration of diazepam could be established. Pre-medication with benzodiazepines to diminish physiological uptake of 18F-FDG in the neck and upper chest region is not indicated.

In dit onderzoek hebben wij de huidige vorm van onderwijs over en vaardigheden met neonatale reanimatie bij eerstejaars artsassistenten kindergeneeskunde onderzocht met een enquete onder eerstejaars arts-assistenten kindergeneeskunde cohort 2005. De vragen betroffen relevante werkervaring voor de start van de opleiding, gevolgde reanimatiecursussen, onderwijs over neonatale reanimatie en zelfvertrouwen ten aanzien van neonatale reanimatie uitgedrukt op een schaal van 1-10. Daarnaast werd de ervaring met acute opvang geinventariseerd in theoretisch en praktisch onderwijs, en in reallife met respectievelijk zonder supervisie. Eerstejaars arts-assistenten kindergeneeskunde bleken beperkte competenties te hebben voor neonatale reanimatie bij aanvang van de zelfstandige acute opvang van neonaten. Desondanks blijkt dat eerstejaars arts-assistenten kindergeneeskunde gemiddeld veel zelfvertrouwen hebben, wat kan wijzen op zich onvoldoende bewust zijn van mogelijk nog niet-adequate kennis, vaardigheden en gedrag nodig voor het uitvoeren van neonatale reanimatie. In Nederland is behoefte aan (meer) gestructureerd onderwijs over neonatale reanimatie aan eerstejaars arts-assistenten kindergeneeskunde voordat zij zelf opvang van pasgeborenen gaan doen.

OBJECTIVE: Tight glycaemic control by intensive insulin therapy (IIT) reduces morbidity and mortality in critically ill patients. As potential mechanisms contributing to the clinical benefits we hypothesized that glycaemic control affects regional nitric oxide (NO) bioavailability by changing NO synthases (NOS) activity, NOS transcription, NOS substrate availability or the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) levels. DESIGN: Prospective, randomized experimental study. SETTING: University medical laboratory. INTERVENTIONS: In a rabbit model of prolonged critical illness we assessed the relative impact of maintaining normal insulin/normoglycaemia (n=8), high insulin/normoglycaemia (n=8), normal insulin/hyperglycaemia (n=9) and high insulin/hyperglycaemia (n=8) plasma levels over 7 days on activity and gene expression of endothelial and inducible NOS isoforms in muscle, liver and aorta biopsies, and on plasma levels of NO, arginine and ADMA. MEASUREMENTS AND RESULTS: Compared with normoglycaemic groups, both hyperglycaemic groups revealed 53% higher day-3 NO plasma levels (p

Purpose To measure the refractive properties of the healthy human eye during acute hyperglycemia by means of Scheimpflug imaging and Hartmann-Shack aberrometry. Methods Acute hyperglycemia was induced in five healthy subjects (two males, three females, mean age ±SD 24.8 years ± 4.6) by means of an oral glucose tolerance test (OGTT) after subcutaneous somatostatin injection. Before and every 30 minutes after the OGTT, measurements with Scheimpflug imaging and Hartmann-Shack aberrometry were performed. The main outcome measures were the thickness and shape of the lens, and the ocular refractive error and higher order aberrations. The equivalent refractive index of the lens was calculated from these parameters. Measurements at baseline and during hyperglycemia were analyzed by means of Wilcoxon signed rank sum tests. Results During hyperglycemia (mean blood glucose level at baseline: 4.0 mmol/l; mean maximal blood glucose level: 18.4 mmol/l) no changes could be found in the refractive properties within the group. In one subject, a hyperopic shift (0.4 D) was observed, together with a more convex shape of the anterior lens surface and a decrease in the equivalent refractive index of the lens. Conclusions This study shows that hyperglycemia generally does not cause changes in the refractive properties of the healthy eye. Nevertheless, in one subject a hyperopic shift accompanied by a change in shape and refractive index of the lens was measured. This finding could provide an explanation for the mechanism underlying the refractive changes that are often observed during hyperglycemia.

The formation of new tubular structures from a quiescent endothelial lining is one of the hallmarks of sprouting angiogenesis. This process can be mimicked in vitro by inducing capillary-like tubular structures in a three-dimensional (3D) fibrin matrix. We aimed to analyze the differential mRNA expression in two phenotypically distinct cell populations from the same culture, namely in tubule-forming endothelial cells and monolayer endothelial cells not participating in tubule formation. A fibrin-rich 3D matrix derived from human plasma was used to facilitate tubule formation by human foreskin microvascular endothelial cells (hMVEC). After 7 days of stimulation with VEGF, bFGF, and TNF-α, the culture consisted of a monolayer and capillary-like sprouts that had grown into the fibrinous matrix. A method was developed to separate the monolayer and tubule-forming populations of hMVEC, keeping their cellular integrity intact to ensure mRNA extraction and cDNA production. Subsequent array analysis resulted in an inventory of differentially expressed genes that were associated with either tube-forming (angiogenic) or non-angiogenic capacity. Differential gene expression was verified by real-time PCR on the original RNA samples as well as on RNA obtained from laser-capture microdissected cross sections of monolayers and capillary structures in the 3D fibrinous matrix. The expression of CDC42GAP, an inhibitor of active-state small Rho GTPases, was reduced in tubular hMVEC. Overexpression of CDC42GAP in hMVEC attenuated endothelial tubule formation, while its suppression by siRNA slightly enhanced this process. Thus, CDC42GAP was identified as a counter-regulatory mediator for tubule formation. © 2007 Springer Science+Business Media B.V.

Background Women in pregnancy and postpartum have an increased vulnerability to develop an affective disorder. Affective disorders in pregnancy are associated with an increased risk of prematurity, dysmaturity (foetal weight below the 10th percentile as determined by ultrasound) and the development of postpartum depressive disorder. Untreated affective disorders and their complications may also result in considerable costs. Recent meta-analyses showed that interventions during pregnancy are less effective than postpartum interventions probably because of high attrition due to the barriers pregnant women experience with attending sessions outside their homes. An internet-based self-help intervention may overcome these barriers as it can be followed at home, and also in one’s own time. Such internet interventions showed to be effective for decreasing affective symptoms in general. This randomised clinical trial examines whether an internet-based self-help intervention is effective in the reduction of affective symptoms in pregnancy and postpartum and results in an improvement of the perinatal outcome. We will also determine the cost-effectiveness of the intervention. Methods/design We will investigate the effectiveness of a 6 week internet-based self-help problem solving treatment (PST) for affective symptoms in pregnancy. We aim to include 286 women with mild to severe affective symptoms who will be randomly assigned to the internet-based intervention or a waiting list control group. Primary outcome measures are affective symptoms and the perinatal outcome. Secondary outcome measures are quality of life, and economic costs. All assessments are based on self-report and will take place at baseline (T0), 10 weeks later (after completion of the intervention (T1), 4 weeks before the expected day of birth (T2), and 6 weeks after delivery (T3). The control group will be measured at the same moments in time. Analysis will be based on the intention-to-treat principle. Discussion If shown (cost) effective, internet-based PST will offer new possibilities to treat pregnant women for affective symptoms, to improve their perinatal outcome and to prevent the development of postpartum depressive disorders. Trial registration Nederlands Trial Register: NTR4321

A 14-month-old boy with double aneuploidy and a double aortic arch suffered from frequently recurrent severe feeding and respiratory problems. Chromosomal analysis showed a 48,XXY + 21 karyotype: a double aneuploidy of Down syndrome (DS) and Klinefelter syndrome (KS). Only four cases of double aneuploidy (DS + KS) associated with congenital heart defects have been published of which none had a double aortic arch. Our case report should draw attention to the possibility of a double aortic arch in patients with severe feeding and respiratory problems and a double aneuploidy.

Background Several studies demonstrated an association of homocysteine plasma levels and the plasma lipoprotein profile. This cross-sectional pilot study aimed at analyzing whether blood levels of the two important cofactors of homocysteine metabolism, folate and vitamin B12, coincide with the lipoprotein profile. Methods In a retrospective single center approach, we analyzed the laboratory database (2003-2006) of the University Hospital Bonn, Germany, including 1743 individuals, in whom vitamin B12, folate and at least one lipoprotein parameter had been determined by linear multilogistic regression. Results Higher folate serum levels were associated with lower serum levels of low density lipoprotein cholesterol (LDL-C; Beta = -0.164; p < 0.001), higher levels of high density lipoprotein cholesterol (HDL-C; Beta = 0.094; p = 0.021 for trend) and a lower LDL-C-C/HDL-C-ratio (Beta = -0.210; p < 0.001). Using ANOVA, we additionally compared the individuals of the highest with those of the lowest quartile of folate. Individuals of the highest folate quartile had higher levels of HDL-C (1.42 ± 0.44 mmol/l vs. 1.26 ± 0.47 mmol/l; p = 0.005), lower levels of LDL-C (3.21 ± 1.04 mmol/l vs. 3.67 ± 1.10 mmol/l; p = 0.001) and a lower LDL-C/HDL-C- ratio (2.47 ± 1.18 vs. 3.77 ± 5.29; p = 0.002). Vitamin B12 was not associated with the lipoprotein profile. Conclusion In our study sample, high folate levels were associated with a favorable lipoprotein profile. A reconfirmation of these results in a different study population with a well defined status of health, diet and medication is warranted.

Contains fulltext : 79491.pdf (Publisher’s version ) (Open Access) BACKGROUND: Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands. METHODS/DESIGN: We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80. DISCUSSION: This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies. TRIAL REGISTRATION: Current Controlled Trials: NTR 1858.

Background Glucocorticoids are important in the treatment of childhood acute lymphoblastic leukaemia (ALL). However, cyclic administration of high dose glucocorticoids may cause rapid and substantial changes in quality of life (QoL). The maintenance phase of the Dutch ALL-9 protocol consisted of alternating two weeks on and five weeks off dexamethasone (6 mg/m2/day). The present study was performed to assess the effect of dexamethasone on QoL during treatment for ALL according to this protocol. Methods In a multicentre prospective cohort study, QoL was assessed halfway (T1) and at the end of the two-year treatment (T2). A generic (Child Health Questionnaire) and disease specific (PedsQL™ cancer version) QoL questionnaire were used to assess QoL in two periods: on and off dexamethasone, respectively. Results 41 children (56% males) were evaluated, mean age at diagnosis was 5.6 years. The CHQ physical and psychosocial summary scores were significantly lower than population norms. At T1 and T2, overall QoL showed no significant change. However, regarding specific domains (pain, cognitive functioning, emotion/behaviour and physical functioning) QoL decreased over time. QoL was significantly more impaired during periods on dexamethasone. Conclusion Dexamethasone was associated with decreased QoL. At the end of treatment, reported QoL during dexamethasone deteriorated even more on certain scales (pain, cognitive functioning, emotion/behaviour and physical functioning). Knowledge of the specific aspects of QoL is essential to improve counselling and coping in paediatric oncology. Adverse effects of specific drugs on QoL should be taken into account when designing treatment protocols.

Recent prospective studies highlighted vitamin D deficiency as a significant risk factor for cardiovascular events, but the underlying mechanisms remain unclear [1]. In their recent work among 650 Old Order Amish persons, Michos et al. have demonstrated that 25-hydroxyvitamin D (25[OH]D) levels are not associated with carotid intimamedia thickness (cIMT) and coronary artery calcification [2]. These important findings suggest that the increased cardiovascular risk observed in persons with a poor vitamin D status is unlikely to be mediated by subclinical vascular disease. Considering, however, that 25(OH)D levels were significantly and inversely correlated with cIMT in another study among 390 patients with type 2 diabetes [3], there still exists a need to address further the issue of 25(OH)D levels and cIMT. We therefore evaluated the latter research question in the Hoorn Study, a population-based study among older men and women [4, 5]. 25(OH)D levels were measured in 614 persons during a follow-up visit in 2000–2001 which included ultrasonographic evaluations of the common cIMT [4], and we have recently published that low 25(OH)D serum levels were significantly associated with an increased risk of all-cause and cardiovascular mortality in that study cohort [5]. Consistent with the statistical analyses used by Michos et al. [2] and in order to consider the seasonal variations of 25(OH)D levels, we calculated the residual of each subject’s 25(OH)D level (nmol/l) from the mean of each season and formed quartiles of these residuals. Regression analysis adjusted for age and gender showed no significant association of these seasonally adjusted 25(OH)D levels with cIMT (in mm) (b-coefficient = -0.011, p = 0.794). Regression analysis with multivariable adjustment according to Michos et al. [2], including age (years), gender (female/male), body mass index (kg/m), current smoking (yes/no), hypertension

Sir: Length of red blood cell (RBC) storage has been proposed a contributing factor to adverse outcome after RBC transfusion. This may be explained by an impaired ability to transport or deliver oxygen, or the presence of leukocytes in stored RBC preparations producing potential deleterious pro-inflammatory mediators or bioactive lipids [1]. We hypothesized that length of RBC storage might explain our previously observed independent association between RBC transfusion and increased mortality, duration of mechanical ventilation (MV) and length of paediatric intensive care unit (PICU) stay in critically ill children [2]. For each time a patient was transfused in our previous study, length of RBC storage was retrieved from our hospital’s blood bank [2]. Since we observed a dose-outcome relation between the number of RBC transfusions and mortality, we separately looked at single transfusion and multiple transfusions. The effect of RBC transfusion on oxygenation was assessed by the oxygenation index (OI, mean airway pressure times FiO2 divided by PaO2) and PaO2/FiO2 ratio. RBC preparations were leukocyte-depleted, but not irradiated. Statistical analysis was performed using the Student t-test; linear regression analysis was applied to study correlations. P \ 0.05 was accepted as statistically significant. Data of 295 patients were studied, of whom 67 (22.7%) were transfused; 39 (58.2%) were transfused only once, the remaining 28 received multiple transfusions at different time intervals (range 2–14) (Table 1). Seventeen (5.8%) patients died. The mean length of RBC storage was 16.7 ± 0.6 days [25–75% interquartile range (IQR) 9–23 days]. Length of RBC storage was comparable between survivors and non-survivors. This remained after comparing single versus multiple transfusions. Differences in OI and PaO2/FiO2 ratio between the first day and fifth day after transfusion, duration of MV and length of PICU stay were not correlated with length of RBC storage. Our findings indicate that our previous reported observed independent association between transfusion of leucocyte-depleted RBC preparations and increased morbidity in critically ill children could not be explained by length of RBC storage. Mortality was also not influenced by length of RBC storage, although our study might not be powered to detect this. To our knowledge, although the issue of RBC transfusion has been extensively studied in critically ill adults, no other paediatric data on length of RBC storage and outcome in critically ill children have been reported. Results from retrospective and prospective

A 3-year old girl with a body weight of 15 kg was admitted to our pediatric intensive care unit with acute renal failure. She was the first of a twin pregnancy, born at a gestational age of 28 weeks with a birth weight of 1140 g. There had been no significant neonatal complications. The present history began 5 days before admission with diarrhea and vomiting. She was admitted to a local hospital with signs of severe dehydration and progressive renal failure, which persisted after aggressive fluid therapy. Hemolytic uremic syndrome (HUS) was suspected and she was referred to our hospital. On admission, hemoglobin level was 5.5 mmol/L (9.2 g/dL), serum LDH 4459 U/l and platelets 55×10/L with schistocytes on blood smear. While faeces culture was negative for E. coli 0157, there was a positive PCR for E. coli 0157 on peripheral white blood cells. Complement studies showed no evidence for atypical HUS/thrombotic microangiopathy. Serum creatinine was 458 μmol/L (5.2 mg/dL) and urea 33.1 mmol/L (92.7 mg/dL) in the anuric child. Under the diagnosis of a diarrhea-associated HUS, a Tenckhoff catheter was placed and peritoneal dialysis (PD) begun with a dwell volume of 15 mL/kg of Gambro-Trio (Gambro BCT Europe NV/SA, Zaventem, Belgium) containing 1.9% glucose. Ultrafiltration was 20 mL per hour on day 1. Despite this therapy, the patient remained ventilator-dependent and needed increasing amounts of supplemental oxygen. In order to increase ultrafiltration, the glucose concentration was increased to 2.5% with good effect (ultrafiltration rate 41 mL per hour). A large pleural effusion was noted on the right side (Fig. 1) and about 200 mL of a clear transudate (RBC 5–10/field, WBC 5–10/field, protein concentration 0.594 g/L) was aspirated. Despite this intervention, her respiratory situation deteriorated rapidly and she developed a severe acute respiratory distress syndrome (ARDS). This required highlevel ventilatory support with mean airway pressure values of up to 30 cmH2O. Mechanical ventilation was complicated by subcutaneous and mediastinal emphysema and recurrent pneumothoraces (Fig. 2). During this period, peritoneal dialysis was continued with dwell volumes between 8 and 20 mL/kg and transiently combined with continuous veno-venous hemodiafiltration. When her respiratory situation improved and the ventilator settings could be reduced, leakage of clear fluid of around 150 mL per day was noted from an incision site of a previous thorax-drain on the right side.

Established rheumatoid arthritis (RA) is associated with a doubled cardiovascular risk. However, data about the cardiovascular risk in early RA are scarce. Preclinical atherosclerosis can be reliably assessed with the carotid intima media thickness (cIMT), and the cIMT is a well-validated predictor of cardiovascular events. The cIMT was therefore used in a recent controlled, prospective study in patients with early RA. Surprisingly, an increased cardiovascular risk at baseline could not be demonstrated whereas cIMT progression appeared to be comparable with the general population. Obviously, this study underscores the need for further large-scale investigations to solve the emerging discrepancy with the existing literature.

Background Circulating CD34+ progenitor cells have the potential to differentiate into a variety of cells, including endothelial cells. Knowledge is still scarce about the transcriptional programs used by CD34+ cells from peripheral blood, and how these are affected in coronary artery disease (CAD) patients. Results We performed a whole genome transcriptome analysis of CD34+ cells, CD4+ T cells, CD14+ monocytes, and macrophages from 12 patients with CAD and 11 matched controls. CD34+ cells, compared to other mononuclear cells from the same individuals, showed high levels of KRAB box transcription factors, known to be involved in gene silencing. This correlated with high expression levels in CD34+ cells for the progenitor markers HOXA5 and HOXA9, which are known to control expression of KRAB factor genes. The comparison of expression profiles of CD34+ cells from CAD patients and controls revealed a less naïve phenotype in patients' CD34+ cells, with increased expression of genes from the Mitogen Activated Kinase network and a lowered expression of a panel of histone genes, reaching levels comparable to that in more differentiated circulating cells. Furthermore, we observed a reduced expression of several genes involved in CXCR4-signaling and migration to SDF1/CXCL12. Conclusions The altered gene expression profile of CD34+ cells in CAD patients was related to activation/differentiation by a retinoic acid-induced differentiation program. These results suggest that circulating CD34+ cells in CAD patients are programmed by retinoic acid, leading to a reduced capacity to migrate to ischemic tissues.

Central venous catheters are frequently inserted for various indications. Insertion of a central venous catheter is not without risk; complications occur in more than 15% of the patients. Arterial puncture, hematoma, pneumothorax and hematothorax are among the most well-known and frequently reported complications. In this report, we present a remarkable case of acute diffuse edematous swelling of the thyroid gland as an unexpected and rare complication after attempted subclavian vein catheterization. Acute thyroid swelling rarely occurs after fine needle aspiration, and to our knowledge, we are the first to describe acute thyroid swelling after central venous catheter insertion.

The evidence that severe acute pancreatitis can result in critical illness-related corticosteroid insufficiency following impaired adrenal secretion is accumulating. The study by Peng and coworkers in Critical Care certainly contributes to that idea, even though the question whether relative adrenal insufficiency should prompt for treatment by substitution doses of corticosteroids remains unresolved. The study is discussed in terms of the risk factors, circumstances and significance of impaired corticosteroid secretion by adrenals in severe acute pancreatitis.