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BackgroundDysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.MethodsA plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTLwith amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTLprotein was employed to study interaction of CERTLwith amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTLwas overexpressed in neurons by adeno-associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety, and locomotion. At week 12, brains were investigated for sphingolipid levels by mass spectrometry, plaques, and neuroinflammation by immunohistochemistry, gene expression, and/or immunoassay.ResultsHere, we report that CERTLbinds to APP, modifies Aβ aggregation, and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTLin vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation, and modulates microglia by decreasing their pro-inflammatory phenotype.ConclusionOur results demonstrate a crucial role of CERTLin regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

We all engage in economic activities on a daily basis, even when are considering how we should use our time. The field which deals with economic activity is, of course, economics. In this textbook, the authors draw on their years of teaching as lecturers at Fontys International Business School in Venlo and the practical experience in management two of them have accumulated in order to facilitate students’ access to its content. The book introduces the reader to the fundamentals of the field, covering aspects ranging from a general introduction to it plus an explanation of economic systems and markets and how they function, to practical analyses, which use up-to-date examples and in-depth information to supplement this explanation.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood-brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial barriers shows great potential as a therapeutic strategy in a wide variety of diseases. Functionalizing nanoparticles with peptides allows for more efficient targeting to specific organs. We have evaluated the hemocompatibilty, cytotoxicity, endothelial uptake, efficacy of delivery and safety of liposome, hyperbranched polyester, poly(glycidol) and acrylamide-based nanoparticles functionalized with peptides targeting brain endothelial receptors, in vitro and in vivo. We used an ELISA-based method for the detection of nanoparticles in biological fluids, investigating the blood clearance rate and in vivo biodistribution of labeled nanoparticles in the brain after intravenous injection in Wistar rats. Herein, we provide a detailed report of in vitro and in vivo observations. (C) 2016 Elsevier Inc. All rights reserved.

RACTICE Guidelines are systematically developed recommendations that assist the practitioner and patient in making decisions about health care. These recommendations may be adopted, modified, or rejected according to clinical needs and constraints and are not intended to replace local institutional policies. In addition, Practice Guidelines developed by the American Society of Anesthesiologists (ASA) are not intended as standards or absolute requirements, and their use cannot guarantee any specific outcome. Practice Guidelines are subject to revision as warranted by the evolution of medical knowledge, technology, and practice. They provide basic recommendations that are supported by a synthesis and analysis of the current literature, expert and practitioner opinion, open-forum commentary, and clinical feasibility data. This document updates the “Practice Guidelines for Management of the Difficult Airway: An Updated Report by

Die BZgA-Studie „Jugendsexualitat 2010“ zeigt den Wandel im Sexual- und Verhutungsverhalten bei Jugendlichen und jungen Erwachsenen in den letzten 30 Jahren. Die Egalisierung der Geschlechter ist bei den deutschen Jugendlichen sowohl beim Alter des ersten Koitus als auch bei der Verhutung festzustellen. Der Anteil der Nicht-Verhutenden beim ersten Koitus ist mit 8% bei den deutschen Jugendlichen so niedrig wie nie zuvor. Die Kommunikation uber Verhutung im Elternhaus und in der Partnerschaft tragt erheblich zu dem verantwortlichen Verhutungsverhalten Jugendlicher und junger Erwachsener bei. Neben familiarer und schulischer Sexualaufklarung beeinflussen aber auch strukturelle Grunde die positive Kontrazeptionsbilanz in Deutschland. Dennoch gibt es noch Zielgruppen, die weniger gut erreicht werden. Viele Migranten und Migrantinnen wissen weniger gut uber korperliche Vorgange Bescheid, verhuten schlechter und sind auch von Informationen aufgrund ihres religiosen Hintergrundes ausgeschlossen. Jugendliche und junge Erwachsene mit Behinderung sind eine Zielgruppe, uber die bislang zu wenig Wissen vorliegt. Bildung und soziale Benachteiligung sind nach wie vor wesentliche Faktoren fur Unterschiede im Sexual- und Verhutungsverhalten. Hier sind weitere Praventionsbemuhungen notwendig.

Introduction Benign epilepsy with centrotemporal spikes (BECTS) is a common epilepsy syndrome in childhood. Besides the occurrence of seizures, mild cognitive impairments and behavioral problems affecting language skills, spatial perception, memory, executive function, and academic achievement might be present. There is no international consensus about the decision whether or not to treat affected children. The influence of treatment on cognitive functions is debated. Methods Patients diagnosed with BECTS were assessed in short term auditory memory, long-term verbal memory, intelligence and behavior using the “number recall” test from the Kaufman assessment battery for children, the “verbal learning memory test”, the “culture free intelligence test” and the “child behavior checklist” prior to a randomized controlled antiepileptic therapy and after a treatment period of 6 months with either sulthiame or levetiracetam. Results 43 of 44 randomized patients were analyzed. One patient had to be excluded due to protocol violation. Patients who completed the study showed a non-significant improvement in parent-reported behavioral problems under therapy. Cognitive skills were not affected. Conclusion The present data suggest that antiepileptic drug treatment of children with BECTS with either sulthiame or levetiracetam does not affect cognitive performance. Behavior improved in a subset of patients though not reaching statistical significance.

Ceramides are lipids that are abundant in brain tissue where they have an important structural role in cellular membranes. Ceramides are also powerful intracellular signalling molecules controlling cell death, growth and differentiation. So far, the ceramide transfer protein (CERT), a shorter splice variant of the Goodpasture antigen-binding protein (GPBP), is the only known protein with the ability to shuttle ceramide from the endoplasmic reticulum to the Golgi apparatus. GPBP/CERT are widely distributed in the central nervous system where they act as key factors for normal brain development and homeostasis. Ceramide accumulates in neurons during acute neurodegeneration. The objective of this study was to define whether levels of the ceramide transfer protein GPBP/CERT are altered in the acute neurodegenerative process. We used design-based stereology to quantify the number of GPBP/CERT immunoreactive cells in the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats as an animal model of Parkinson's disease (PD). In addition, gray value measurement was performed to quantify GPBP/CERT immunoreactivity-levels within individual cells. No difference in the striatal expression levels of GPBP/CERT proteins was found between diseased and control animals, suggesting that the expression pattern of GPBP/CERT in the striatum is not affected in the 6-OHDA rat model of PD.

Background Delirium is a serious postoperative condition for which few pharmacologic prevention trials have been conducted. Objective The authors tested the efficacy of perioperative olanzapine administration to prevent postoperative delirium in elderly patients after jointreplacement surgery. Method The authors conducted a randomized, double-blind, placebocontrolled, prophylaxis trial at an orthopedic teaching hospital, enrolling 495 elderly patients age ≥65 years, who were undergoing elective knee- or hip-replacement surgery; 400 patients received either 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. The primary efficacy outcome was the incidence of (DSM-III-R) delirium. Results The incidence of delirium was significantly lower in the olanzapine group than in the placebo group; this held true for both knee- and hip-replacement surgery. However, delirium lasted longer and was more severe in the olanzapine group. Advanced age, a high level of medical comorbidity, an abnormal albumin level, and having knee-replacement surgery were independent risk factors for postoperative delirium (Clinicaltrials.gov Identifier: NCT000699946). Conclusion Administration of 10 mg of oral olanzapine perioperatively, versus placebo, was associated with a significantly lower incidence of delirium. These findings suggest that olanzapine prophylaxis of postoperative delirium may be an effective strategy.

Viral gene transfer or transgenic animals are commonly used technologies to alter gene expression in the adult brain, although these approaches lack spatial specificity and are time consuming. We delivered plasmid DNA locally into the brain of adult C57BL/6 mice in vivo by voltage-and current-controlled electroporation. The low current-controlled delivery of unipolar square wave pulses of 125 mu A with microstimulation electrodes at the injection site gave 16 times higher transfection rates than a voltage-controlled electroporation protocol with plate electrodes resulting in currents of about 400 mA. Transfection was restricted to the target region and no damage due to the electric pulses was found. Our current-controlled electroporation protocol indicated that the use of very low currents resulting in applied voltages within the physiological range of the membrane potential, allows efficient transfection of nonviral plasmid DNA. In conclusion, low current-controlled electroporation is an excellent approach for electroporation in the adult brain, i.e., gene function can be influenced locally at a high level with no mortality and minimal tissue damage.

In the annular or total eclipses of 3 October 2005, 29 March 2006, 22 September 2006, and 1 August 2008, observational campaigns were organized to record the phenomenon of Baily’s beads. These campaigns were internationally coordinated through the International Occultation Timing Association (IOTA) at both its American and European sections. From the stations in the northern and southern zones of grazing eclipse, the eclipses have been recorded on video. Afterward, as many beads as possible have been identified by analyzing the video data of each observing station. The atlas presented in this paper includes 598 data points, obtained by 23 observers operating at 28 different observing stations. The atlas lists the geographic positions of the observing stations and the observed time instants of disappearance or reappearance of beads, identified by an angle measured relative to the Moon’s axis of rotation. The atlas will serve as a basis for determining the solar diameter.

Summary Studies of human mucosal lymphoid follicles are rare and have been limited to children's Peyer's patches, which are visible at endoscopy. We investigated lymphoid follicles in ileum biopsies of 87 patients and surgical colon specimens from 66 cancer patients, and examined phenotype and function of isolated follicular immune cells. Two (0–10) and 12 (0–117) follicles per patient were found in ileum and colon samples respectively (P

A 48-year-old woman complained of right-sided upper abdominal pain and recurrent vomiting, and had lost 10 kg in 4 months. Ultrasound and computed tomography showed a solid, space-occupying lesion in the head of the pancreas, not separable from the duodenum. Despite thorough investigation the nature of the lesion remained obscure. Operation revealed a divided pancreas with stenosis of the accessory duct at the papilla. Histological examination showed pseudosarcomatous myofibroblastic proliferation within the duodenal wall in the vicinity of a duodenal wall cyst which had been destroyed by inflammation. In cases of divided pancreas it is the accessory duct which drains the main bulk of the pancreas, while the main duct carries little or no secretion; the stenosis of the accessory duct in this patient had therefore led to low-grade pancreatitis involving the head of the pancreas.

The effects of halothane on the cerebral circulation were studied in 23 children during general anaesthesia. Blood flow velocity in one middle cerebral artery was recorded continuously by transcranial Doppler sonography. Furthermore arterial blood pressure, pulse rate, endtidal CO2partial pressure and endtidal halothane concentration were recorded. Mean flow velocities/mean arterial blood pressures were 79 cm x s-1/65 mmHg; 86 cm x s-1/61 mmHg; 78 cm x s-1/54 mmHg and 67 cm x s-1/48 mmHg with 1; 1.5; 2 and 2.5 per cent endtidal halothane concentrations, respectively. Endtidal CO2-partial pressure and pulse rate remained constant throughout the study. The higher cerebral blood flow velocities seen with 1.5 per cent halothane compared with 1 per cent can be explained by an increase in cerebral blood flow. The lower cerebral blood flow velocities and arterial blood pressure with 2.5 per cent halothane compared with 1.5 per cent indicate impaired cerebral autoregulation. However, cerebral blood flow appeared to be sufficient even with low arterial blood pressures.

Transcranial Doppler sonography of basal cerebral arteries is helpful for diagnosis and control of the course of paediatric diseases like patent ductus arteriosus, perinatal brain damage, increased intracranial pressure, cerebral malformations and stenoses and occlusions of main cerebral arteries. The technique also allows control of hyperventilation therapy of cerebral oedema. With a few exceptions, the Doppler results are not specific for a particular disease. However, they do supply important information on the specific pathophysiology of cerebral haemodynamics. The evaluation of the recordings should take into account the clinical condition of the child, the laboratory results, the results of imaging methods and intra- and interindividual comparisons.

Fetal magnetic resonance imaging (MRI) is a reliable method to further evaluate brain anomalies detected on ultrasonography. MRI can reveal additional brain abnormalities which are consequential for counselling parents about the fetal prognosis and subsequently influence the decision about continuing the pregnancy. In case of fatal malformations, MRI can confirm a diagnosis established on ultrasonography, supplying more reliability.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Aims The aim of the current study was to develop a method to detect peptide-linked nanoparticles in blood plasma. Materials & Methods A convenient enzyme linked immunosorbent assay (ELISA) was developed for the detection of peptides functionalized with biotin and fluorescein groups. As a proof of principle, polymerized pentafluorophenyl methacrylate nanoparticles linked to biotin-carboxyfluorescein labeled peptides were intravenously injected in Wistar rats. Serial blood plasma samples were analyzed by ELISA and by liquid chromatography mass spectrometry (LC/MS) technology. Results The ELISA based method for the detection of FITC labeled peptides had a detection limit of 1 ng/mL.We were able to accurately measure peptides bound to pentafluorophenyl methacrylate nanoparticles in blood plasma of rats, and similar results were obtained by LC/MS. Conclusions We detected FITC-labeled peptides on pentafluorophenyl methacrylate nanoparticles after injection in vivo. This method can be extended to detect nanoparticles with different chemical compositions.

ObjectiveThe study aimed to assess the relationship of various types of kindergarten differing in length of care and food availability with the development of overweight in pre-school children.Design, setting and subjectsA cross-sectional study was carried out in 2002 in Stuttgart, Germany, as part of the school entrance examination. Height and weight of 2140 children (participation 70.2%) were measured and information on type of kindergarten and other potential determinants of overweight was collected by a parental questionnaire. Change in relative body mass index (BMI) position between the ages of 4 and 6 years was assessed using medical records.ResultsThe prevalence of overweight or change in relative BMI position did not differ according to the type of kindergarten. For the prevalence of overweight in German children, adjusted odds ratios (OR) comparing institutions that open only in the morning with those opening in the morning and afternoon or for the full day were 0.86 (95% confidence interval (CI) 0.40, 1.83) and 0.63 (95% CI 0.25, 1.58), respectively. Parental BMI and duration of television watching were positively associated, and maternal educational status and duration of breast-feeding were negatively associated, with overweight and/or change in relative BMI position. The prevalence of overweight was substantially higher among non-German than among German children (adjusted OR 2.17 (95% CI 1.53, 3.07)).ConclusionsThese data show no association between different types of kindergarten and the development of overweight in early childhood. Duration of television watching and breast-feeding, as well as the relatively high prevalence of overweight in ethnic minorities, deserve further attention.

Fast 2 Mio. Kinder und Jugendliche in Deutschland stammen aus Migrantenfamilien. Die medizinische Versorgung dieser Bevolkerungsgruppe ist bedingt durch mangelnde Compliance vielfach nicht zufrieden stellend. Neben Sprachproblemen sind unzureichende Information und mangelnde Bildung, aber auch unterschiedliche Weltbilder und Wertvorstellungen der beteiligten Parteien dafur verantwortlich. Die soziale Benachteiligung vieler Migrantenkinder und ihre Biografie gehen mit einer erhohten Pravalenz verschiedener somatischer und psychosozialer Storungen einher. Der gesellschaftspolitische Auftrag der Gleichbehandlung aller Patienten erweist sich fur den einzelnen Padiater als nicht mehr machbar. Neben dem fakultativen individuellen Beitrag jedes einzelnen Arztes muss es einen medizinischen Mindeststandard in Krankenhausern und spezialisierten padiatrischen Ambulanzen geben, der eine sprachlich einwandfreie Kommunikation garantiert. Die padiatrischen Fachgesellschaften mussen diesen medizinischen Mindeststandard vorgeben und fordern, da ein gesundheitspolitischer Auftrag fehlt.

Organised in public or private structures, wastewater services have to cope with different framework conditions as regards planning, construction, financing and operation. This leads quite often to different modes of management. In recent years there has been a push for privatisation on the water sector in general, the reasons for which are manifold, ranging from access to external know-how and capital to synergistic effects through integration of wastewater treatment into other tasks of similar or equal nature. Discussed are various models of public/private partnership (PPP) in wastewater treatment, encompassing for example the delegation of partial tasks or even the proportional or entire transfer of ownership of treatment facilities to private third parties. Decisive for high performance and efficiency is not the legal or organisational form, but rather the clear and unmistakable definition of tasks which are to be assigned to the different parties, customers and all other partners involved, as well as of clear-cut interfaces. On account of the (of course legitimate) profit-oriented perspective of the private sector, some decisionmaking processes in relation to project implementation (design and construction) and to operational aspects will differ from those typically found on the public sector. This does apply to decisions on investments, financing and on technical solutions too. On the other hand, core competencies in wastewater treatment should not be outsourced, but remain the public bodies’ responsibility, even with ‘far-reaching’ privatisation models. Such core competencies are all efforts geared to sustainable wastewater treatment as lifesupporting provision for the future or as contribution to the protection of health and the environment and to the development of infrastructure. Major areas of wastewater treatment and other related tasks are reviewed. The paper concludes with a list of questions on the issue of outsourcing.