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Rupture of unstable atherosclerotic plaque that leads to stroke and myocardial infarction may be induced by macrophage infiltration and neovessel formation. A tracer that selectively binds to integrin αvβ3 a protein expressed by macrophages and neovascular endothelium may identify rupture prone plaque. 18F-labeled “R-G-D” containing tripeptide (Flotegatide), a click chemistry derived radiotracer that binds to integrin αvβ3 was injected in ApoE knockout mice fed a high fat diet. Uptake of Flotegatide by atherosclerotic plaque was visualized by micro-PET, autoradiography, and correlated to histologic markers of inflammation and angiogenesis. We found that Flotegatide preferentially binds to aortic plaque in an ApoE knockout mouse model of atherosclerosis. The tracer’s uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects with atherosclerosis and may have potential for detecting vulnerable plaque.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808. © 2014 A IOS Press and the authors. All rights reserved.

A novel caspase-3 substrate-based probe [(18)F]-CP18 was evaluated as an in vivo positron emission tomography (PET) imaging agent for monitoring apoptosis in tumors.Uptake of [(18)F]-CP18 in cell assays and tumors was measured. Caspase-3/7 activities in cell lysates and tumor homogenates were determined. Autoradiography,Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and cleaved caspase-3 immunostaining were performed on adjacent tumor sections to identify areas of apoptosis.The in vitro cell assays showed caspase-3-dependent uptake of [(18)F]-CP18 in tumor cells when treated with an apoptosis inducer. The in vivo microPET imaging signal of [(18)F]-CP18 in xenograft tumors correlated with the ex vivo caspase-3/7 activities in these tumors. Furthermore, tumor autoradiographies of [(18)F]-CP18 in tumor sections matched adjacent sections stained by TUNEL and caspase-3 immunohistochemistry (IHC).[(18)F]-CP18 demonstrated high affinity and selectivity for activated caspase-3 both in vitro and in vivo, and the results support [(18)F]-CP18 as a promising new PET imaging agent for apoptosis.

We identified and validated [18F]-CP18, a DEVD (the caspase 3 substrate recognition motif) containing substrate-based compound as an imaging tracer for caspase-3 activity in apoptotic cells. CP18 was radiolabeled with fluorine-18 using click chemistry. The affinity and selectivity of CP18 for caspase-3 were evaluated in vitro. The biodistribution and metabolism pattern of [18F]-CP18 were assessed in vivo. [18F]-CP18 positron emission tomography (PET) scans were performed in a dexamethasone-induced thymic apoptosis mouse model. After imaging, the mice were sacrificed, and individual organs were collected, measured in a gamma counter, and tested for caspase-3 activity. In vitro enzymatic caspase-3 assay demonstrated specific cleavage of CP18. In vivo, [18F]-CP18 is predominantly cleared through the kidneys and urine, and is rapidly eliminated from the bloodstream. There was a sixfold increase in caspase activity and a fourfold increase of [18F]-CP18 retention in the dexamethasone-induced thymus of treated versus control mice. We report the use [18F]-CP18 as a PET tracer for imaging apoptosis. Our data support further development of this tracer for clinical PET applications.

Fragestellung: Welche ethischen und juristischen Rahmenbedingungen und Problemsituationen bestehen in der Anwendung pflegerischer und arztlicher Masnahmen der kunstlichen Ernahrung? Material und Methodik: Die Literaturrecherche erfolgte zu den Stichworten kunstliche Ernahrung, enterale Ernahrung, orale Ernahrungssupplemente, parenterale Ernahrung, Ethik und Recht. Eine Evidenzbewertung der Literatur war mit den im klinischen Bereich ublichen Methoden nicht moglich. Der Textentwurf der Arbeitsgruppe wurde sowohl bei der ersten Konsensus-Konferenz als auch dem gesamten Plenum der Leitliniengruppe zur Diskussion gestellt. Die Ruckmeldungen wurden berucksichtigt und der Text schlieslich von allen Mitgliedern der Arbeitsgruppe und den Mitgliedern des DGEM Steering Committee konsentiert. Ergebnisse: Die Hilfe bei der naturlichen Nahrungsaufnahme ist integraler Bestandteil einer angemessenen pflegerischen Fursorge. Fur ernahrungstherapeutische Masnahmen stehen verschiedene Substrate und unterschiedliche Wege der kunstlichen Nahrungszufuhr zur Verfugung. Wie bei jeder arztlichen Intervention bedarf es sowohl einer entsprechenden Indikation, welche vor dem Hintergrund eines angemessenen Behandlungszieles beurteilt werden muss als auch einer Einwilligung des Patienten bzw. seines Stellvertreters. Schlussfolgerung: Das Kapitel „Ethik und Recht“ behandelt ubergreifende Regeln, Probleme und Grenzfragen, die fur die Sicherheit und Orientierung des Entscheidens und Handelns bei der Anwendung kunstlicher Ernahrung in allen medizinischen Gebieten von Bedeutung sind. Es verweist auf die Notwendigkeit der Festlegung von Therapiezielen sowie der Indikationsstellung im Einzelfall und auf die Bedeutung des Patientenwillens.

Objectives While the use of St John's wort extracts as treatment for mild to moderate depression is well established the mode of action is still under investiation. Individual constituents of St John's wort extract were tested for possible effects on the β1AR density and a subsequent change in downstream signalling in rat C6 glioblastoma cells. Methods The effect of compounds from St John's wort extract on the downregulation of β1-adrenergic receptor-GFP fusion proteins (β1AR-green fluorescent protein (GFP)) of transfected rat C6 gliobastoma cells (C6-β1AR-GFP) was investigated by means of confocal laser scanning microscopy (LSM). The influence on the lateral mobility of β1AR-GFP in C6-β1AR-GFP was investigated by fluorescence correlation spectroscopy. The formation of second messenger was determined by c-AMP-assay. Key findings Confocal LSM revealed that pretreatment of cells with 1 μm of hyperforin and hyperoside for 6 days, respectively, led to an internalization of β1AR-GFP under non-stimulating conditions. Observation by fluorescence correlation spectroscopy showed two diffusion time constants for control cells, with τdiff1 = 0.78 ± 0.18 ms and τdiff2 = 122.53 ± 69.41 ms, similarly distributed. Pretreatment with 1 μm hyperforin or 1 μm hyperoside for 3 days did not alter the τdiff values but decreased the fraction of τdiff1 whereas the fraction of τdiff2 increased significantly. An elevated level of β1AR-GFP with hindered lateral mobility was in line with β1AR-GFP internalization induced by hyperforin and hyperoside, respectively. A reduced β1-adrenergic responsiveness was assumed for C6 gliobastoma cells after pretreatment for 6 days with 1 μm of both hyperforin and hyperoside, which was confirmed by decreased cAMP formation of about 10% and 5% under non-stimulating conditions. Decrease in cAMP formation by 23% for hyperforin and 15% for hyperoside was more pronounced after stimulation with 10 μm dobutamine for 30 min. Conclusions The treatment of C6 gliobastoma cells with hyperforin and hyperoside results in a reduced β1AR density in the plasma membrane and a subsequent reduced downstream signalling.

Demenzpatienten sind oftmals eine Irritation fur die Organisation Akutkrankenhaus. Professionelle haben im Klinikalltag wenige Moglichkeiten, auf die speziellen Bedurfnisse, Herausforderungen und Kommunikationsanforderungen im Umgang mit an Demenz erkrankten Menschen einzugehen. An der Klinik fur Innere Medizin und Geriatrie am Klinikum Nurnberg gibt es seit 2 Jahren ehrenamtliche Demenzbegleiter, die Menschen mit Demenz auf den Stationen begleiten und den strukturierten Klinikalltag mit Zeit und Alltaglichkeit unterbrechen. In diesem Beitrag werden die Organisation des Pilotprojekts am Zentrum fur Altersmedizin, die Schulung der Ehrenamtlichen sowie erste Ergebnisse der wissenschaftlichen Begleitforschung vorgestellt. Als Studiendesign wurde ein Mixed-Methods-Ansatz gewahlt. Evaluiert werden Baseline-Daten, die Motivation fur ehrenamtliche Tatigkeit, die Selbsteinschatzung sowie Haltung, Kompetenzen und theoretisches Wissen vor und nach den Schulungen. Haltungen, Kompetenzen und Wissen konnen nach Selbsteinschatzung der Teilnehmenden durch das Training positiv beeinflusst werden. Strukturelle Rahmenbedingungen aufseiten der Professionellen und Ehrenamtlichen ermoglichen eine gelingende Integration in das Betreuungsteam. Der stationare Alltag ist fur Demenzpatienten oftmals verwirrend und beangstigend. Geschulte ehrenamtliche Begleiter konnen dazu beitragen, das Akutkrankenhaus zu einem „demenzfreundlicheren“ Ort zu machen.

In diesem gemeinsamen Konsensuspapier der Deutschen Rontgengesellschaft und der Deutschen Gesellschaft fur Kardiologie werden der MR-physikalische und elektrophysiologische Hintergrund sowie das prozedurale Management fur MR-Untersuchungen von Patienten mit Herzschrittmachern und implantierbaren Kardioverter-Defibrillatoren dargestellt. Es werden detaillierte Handlungsanweisungen bezuglich Indikationsstellung, den spezifischen Untersuchungsbedingungen mit Umprogrammierung des SM/ICD- Systems, Modifikation der MR-Sequenzen und Monitoring gegeben sowie die Verantwortlichkeiten und Aufklarungsnotwendigkeiten zwischen Radiologie und Kardiologie definiert. Ziel ist es, ein Maximum an Patientensicherheit zu gewahrleisten sowie Rechtssicherheit fur die beteiligten Arzte herzustellen, um insgesamt den Zugang von Patienten mit aktiven kardialen Implantaten zu notwendigen MR-Untersuchungen zu verbessern. Die Kernaussagen dieses Konsensus-Papiers sind wie folgt: 1. Konventionelle SM- und ICD-Systeme sind nicht mehr als eine absolute, sondern als eine relative Kontraindikation fur die Durchfuhrung einer MR-Untersuchung anzusehen. Entscheidend bei Indikationsstellung und Untersuchungsdurchfuhrung sind die Abschatzung des individuellen Nutzen/Risiko-Verhaltnisses, eine umfassende Aufklarung uber „off-label use“ und spezifische Risiken, dezidierte SM-/ICD-bezogene und MR-bezogene Sicherheitsmasnahmen zur weitestgehenden Reduzierung dieser Risiken sowie adaquate Monitortechniken wahrend der MR-Untersuchung. 2. Bedingt MR-sichere („MR conditional“) SM- und ICD-Systeme sind fur eine MR-Untersuchung unter dezidierten Rahmenbedingungen getestet und zugelassen. Entscheidend fur die Patientensicherheit sind hier die genaue Kenntnis und die Einhaltung der fur das jeweilige SM/ICD-System spezifischen Nutzungsbedingungen. 3. Das Risiko eines ICD-Patienten wahrend einer MR-Untersuchung ist aufgrund der hoheren elektrophysiologischen Vulnerabilitat des per se strukturell geschadigten Myokards sowie des hoheren Risikos irreversibler Funktionsstorungen konventioneller ICD-Systeme im Vergleich zu SM-Patienten als deutlich hoher einzuschatzen. Die Indikationsstellung zu einer MR-Untersuchung eines ICD-Patienten sollte somit strenger erfolgen und kritisch hinterfragt werden, ob der zu erwartende Nutzen der MR-Untersuchung in einem adaquaten Verhaltnis zum Risiko steht. 4. Die komplexe Thematik erfordert eine enge und abgestimmte Kooperation zwischen Radiologie und Kardiologie.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation between the density and neocortical spread of neurofibrillary tangles (NFTs) and the severity of cognitive impairment offers an opportunity to use a noninvasive imaging technique such as positron emission tomography (PET) for early diagnosis and staging of the disease. PET imaging of NFTs holds promise not only as a diagnostic tool but also because it may enable the development of disease-modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to identifying high-affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitor medications are a class of antihyperglycemic agents that increase urinary glucose excretion by interfering with the reabsorption of glucose in the proximal renal tubules. In May of 2015, the U.S. Food and Drug Administration released a warning concerning a potential increased risk of ketoacidosis and ketosis in patients taking these medications. Case Report We present a case of a 57-year-old woman with type 2 diabetes mellitus taking a combination of canagliflozin and metformin who presented with progressive altered mental status over the previous 2 days. Her work-up demonstrated a metabolic acidosis with an anion gap of 38 and a venous serum pH of 7.08. The serum glucose was 168 mg/dL. The urinalysis showed glucose > 500 mg/dL and ketones of 80 mg/dL. Further evaluation demonstrated an elevated serum osmolality of 319 mOsm/kg and an acetone concentration of 93 mg/dL. She was treated with intravenous insulin and fluids, and the metabolic abnormalities and her altered mental status resolved within 36 h. This was the first episode of diabetic ketoacidosis (DKA) for this patient. Why Should an Emergency Physician Be Aware of This? Diabetic patients on SGLT2 inhibitor medications are at risk for ketoacidosis. Due to the renal glucose-wasting properties of these drugs, they may present with ketoacidosis with only mild elevations in serum glucose, potentially complicating the diagnosis. Acetone is one of the three main ketone bodies formed during DKA and it may be present at considerable concentrations, contributing to the serum osmolality.

CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses (19) F-bearing fragments as (18) F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.

Objective Hypoxia is an important negative prognostic factor for radiation treatment of head and neck (HN P> 0.05). A total of 12 lesions were identified. Among them, eight lesions were positive and two lesions were negative on both 18F-HX4 and 18F-FMISO images; one of the other two lesions was positive only on 18F-HX4, whereas the other one was positive only on 18F-FMISO. The CA-IX expression result correlated with the hypoxia imaging but not with 18F-FDG imaging. Conclusion 18F-HX4 is a safe and feasible agent in hypoxia imaging of H&N cancer patients. We could assume that 18F-HX4 may have higher sensitivity and specificity, faster clearance, and shorter injection–acquisition time compared with traditional 18F-FMISO. Additional evaluations need to be carried out to validate the assumption. Further development of 18F-HX4 for eventual targeting of antihypoxia therapies is warranted.

Remote magnetic navigation systems are used for catheter navigation in cardiac electrophysiological ablation procedures. In this setting, ferromagnetic particles will be moved by changes in the magnetic field. It is unknown to what extent cardiac implantable electronic devices (CIED) are affected by the magnetic field when using magnetic navigation, and whether these forces may exceed the limit of 5 N that is set forth by German and European norms for implanted electrodes. A total of 121 rhythm devices were examined in a magnetic field of 0.1 T using the NIOBE II® Magnetic Navigation System (Stereotaxis, St. Louis, USA). Forces acting on the devices were measured with the force measurement tool Futek LRF 400 (Futek Advanced Sensor Technology Inc., Irvine, CA, USA). A standardized protocol of different movements of the magnetic field including all three dimensions was performed and maximal forces on the CIED were assessed. Out of 121 devices, 78 different pacemakers (54 different model families from 11 manufacturers) and 43 different cardioverter-defibrillators (26 different model families from 6) were examined. The mean force that could be observed was 0.33 ± 0.13 N for pacemakers (range 0.16–1.12 N) and 1.05 ± 0.11 N for cardioverter-defibrillators (range 0.86–1.38 N) when exposed to the magnetic field. Exposure of pacemakers or implantable cardioverter-defibrillators to a magnetic field of 0.1 T does not result in a force exceeding the regulatory demanded 5 N that could damage the connected leads.

Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-β positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process. A competitive autoradiography assay was set up to test compounds for binding to native tau tangles and amyloid-β plaques on human brain tissue sections. In our in vitro assays, the 18F labeled compound [18F]-T808 displayed a high level of binding affinity and good selectivity for tau aggregates over amyloid-β plaques. [18F]-T808 showed rapid uptake and washout in rodent brains. Our in vitro and preclinical in vivo studies suggest that [18F]-T808 possesses suitable properties and characteristics to be a specific and selective PET probe for imaging of paired helical filament tau in human brains.

2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-18F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid (18F-RGD-K5) has been developed as an αvβ3 integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from 18F-RGD-K5 using whole-body PET/CT scans in monkeys and humans. Methods: Successive whole-body PET/CT scans were obtained after intravenous injection of 18F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of 18F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions. Results:18F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased 18F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model. Conclusion: The biodistribution profile of 18F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of 18F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. 18F-RGD-K5 can be used safely for imaging αvβ3 integrin expression in humans.

OBJECTIVE: To determine the effectiveness of a quality improvement program to improve pediatricians' adherence to existing, evidence-based, attention-deficit/hyperactivity disorder (ADHD) practice guidelines. METHODS: Forty-nine community-based pediatricians at 8 practices participated in a cluster-randomized trial. Practices were matched according to the numbers of pediatricians and the proportions of patients receiving Medicaid. The medical charts for a random sample of patients with ADHD for each of the participating pediatricians were examined at baseline and 6 months. All practices participated in 4 sessions of training, including didactic lectures and office flow modification workshops. Practices were then given access to an ADHD Internet portal that allowed parents, teachers, and pediatricians to input information (eg, rating scales) about patients, after which information was scored, interpreted, and formatted in a report style that was helpful for assessment and treatment of patients with ADHD. Physicians evaluated their practice behaviors quarterly and addressed underperforming areas. RESULTS: Pediatricians in the intervention group, compared with those in the control group, demonstrated significantly higher rates of many American Academy of Pediatrics–recommended ADHD care practices, including collection of parent (Cohen's d = 0.69) and teacher (d = 0.68) rating scales for assessment of children with ADHD, use of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria (d = 0.85), and use of teacher rating scales to monitor treatment responses (d = 1.01). CONCLUSION: A quality improvement intervention that can be widely disseminated by using Internet-based information technology significantly improved the quality of ADHD care in community-based pediatric settings.

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [ 18 F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [ 18 F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly ( P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [ 18 F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [ 18 F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [ 18 F]HX4 tumor uptake was shown by a strong and significant relationship ( r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction ( P < 0.001) in [ 18 F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake ( P < 0.05). [ 18 F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

We present numerical modeling and experimental studies of flow optimization inside a batch microfluidic micro-reactor used for synthesis of human-scale doses of Positron Emission Tomography (PET) tracers. Novel techniques are used for mixing within, and eluting liquid out of, the coin-shaped reaction chamber. Numerical solutions of the general incompressible Navier Stokes equations along with time-dependent elution scalar field equation for the three dimensional coin-shaped geometry were obtained and validated using fluorescence imaging analysis techniques. Utilizing the approach presented in this work, we were able to identify optimized geometrical and operational conditions for the micro-reactor in the absence of radioactive material commonly used in PET related tracer production platforms as well as evaluate the designed and fabricated micro-reactor using numerical and experimental validations.

The batch microfluidic technology is a promising system for sequential chemical steps combining the advantages of micro-scale reactions, while addressing some shortcomings of flow-through systems. We report herein the convenient three-step, one-pot synthesis and purification of [ 18F]SFB. [ 18F]SFB is a radiolabelling agent that can be used to label sensitive biomolecules, which are not accessible by direct nucleophilic 18F-fluorination. Five sequential steps were performed with a batch microfluidic device to obtain the short-lived positron-emitter- labelled molecule. Aqueous [ 18F]fluoride was concentrated and further eluted to a microreactor for evaporation. Nucleophilic 18F- fluorination of the precursor was carried out at high temperature, prior to hydrolysis and subsequent activation of the 4-[ 18F]fluorobenzoyl group. Purification on miniaturized solid-phase finally afforded [ 18F]SFB in 25 min and 55±6% yield (not decay-corrected) and >98% radiochemical purity. In this study, microfluidic prepared [ 18F]SFB could be further successfully used for labelling the epidermal growth factor protein. These results illustrate how microfluidic batch devices are advantageous for producing radiotracers for molecular imaging, e.g. Positron emission tomography. The technology offers many benefits such as the possibility to use much smaller quantities of starting material, reduced reaction time combined with improved efficiency, and easier purification. Copyright © 2010 John Wiley and Sons, Ltd.

A Monte-Carlo model of exospheres ( Wurz and Lammer, 2003 ) was extended by treating the ion-induced sputtering process, photon-stimulated desorption, and micro-meteorite impact vaporisation quantitatively in a self-consistent way starting with the actual release of particles from the mineral surface of Mercury. Based on available literature data we established a global model for the surface mineralogy of Mercury and from that derived the average elemental composition of the surface. This model serves as a tool to estimate densities of species in the exosphere depending on the release mechanism and the associated physical parameters quantitatively describing the particle release from the surface. Our calculation shows that the total contribution to the exospheric density at the Hermean surface by solar wind sputtering is about 4×10 7 m –3 , which is much less than the experimental upper limit of the exospheric density of 10 12 m –3 . The total calculated exospheric density from micro-meteorite impact vaporisation is about 1.6×10 8 m –3 , also much less than the observed value. We conclude that solar wind sputtering and micro-meteorite impact vaporisation contribute only a small fraction of Mercury’s exosphere, at least close to the surface. Because of the considerably larger scale height of atoms released via sputtering into the exosphere, sputtered atoms start to dominate the exosphere at altitudes exceeding around 1000 km, with the exception of some light and abundant species released thermally, e.g. H 2 and He. Because of Mercury’s strong gravitational field not all particles released by sputtering and micro-meteorite impact escape. Over extended time scales this will lead to an alteration of the surface composition.

The long-term sustainability of a quality improvement project was examined. The ADHD Collaborative was designed to assist community-based pediatricians in adhering to the American Academy of Pediatrics evidence-based assessment and treatment guidelines for attention deficit hyperactivity disorder (ADHD). Patient chart reviews were completed out to 2 years post training for 14 practices (N = 38 pediatricians), who received the ADHD Collaborative intervention to assess whether improvements made immediately post training were sustained. Pediatricians maintained significant improvements in their use of evidence-based assessment and treatment practices for a period of 2 years. The majority of the improvements occurred quickly, within 6 months of training. Pediatricians focused most of their continuous quality improvement (CQI) efforts on improving follow-up care for their patients with ADHD. Systematic monitoring and follow up of ADHD patients who were prescribed medication improved considerably from pre-train...

OBJECTIVES To evaluate the use of the CorTemp ingestible sensor system to monitor athletes in the prevention of thermal injuries, 3 objectives were established: (1) to determine the agreement between the system and a mercury thermometer and quantify the effect of exceeding the recommended yearly manufacturer calibration, (2) to establish the effect of individual sensor correction on agreement, and (3) to determine the quantity of data required for effective correction. DESIGN Validation study. PARTICIPANTS Ninety-four ingestible sensors. INTERVENTIONS (1) Five comparisons were made between each sensor and a mercury thermometer across the range of 33 to 41 degrees C. This was performed immediately, and 14 to 18 months, after factory calibration. (2) Linear regression equations were created and used to correct sensor readings at approximately 37 degrees C; the corrected value was compared with the mercury thermometer. (3) Linear regression equations were created for each sensor using 2 to 5 data points. MAIN OUTCOME MEASURES Systematic bias and random error (95%). RESULTS (1) Systematic bias + or - random error (95%) was 0.73% + or - 0.23% ( approximately 0.27 + or - 0.09 degrees C) and 0.54% + or - 0.28% ( approximately 0.22 + or - 0.11 degrees C) immediately and 14 to 18 months post factory calibration, respectively. (2) Regression correction improved agreement through reductions in systematic bias. (3) Individualized equations using a minimum of 3 comparisons were required to reduce agreement to + or - 0.10 degrees C; the use of 5 comparisons minimized the number of readings exceeding + or - 0.10 degrees C. CONCLUSIONS (1) The CorTemp system inflates temperature measurements compared with a mercury thermometer. (2) Individual sensor calibration is warranted. (3) Correction equations should use a minimum of 3, preferably 5, comparisons. After regression correction, the system displays satisfactory accuracy for preventative monitoring.

OBJECTIVE Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT). RESEARCH DESIGN AND METHODS The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[18F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor–positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. RESULTS Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor–expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3–kinase inhibitor. CONCLUSIONS Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus.

Introduction Dysregulated MMP expression or activation is associated with several diseases. To study MMP activity in vivo by means of PET a radiolabeled MMP inhibitor (MMPI) functioning as radiotracer has been developed by our group based on the lead structure CGS 25966. Materials and methods Aiming at the modification of the pharmacokinetics of this lipophilic model tracer a new class of MMPIs has been discovered, consisting of additional fluorinated hydrophilic substructures, such as mini- PEG and/or 1,2,3-triazole units. To identify the best candidate for further clinical applications, radiofluorinated compounds of each subgroup have been (radio) synthesized and evaluated regarding their biodistribution behavior and their metabolic stability. Results Radiosyntheses of different triazole based MMPIs could be realized using two step "click chemistry" procedures. Compared to lead structure [ 18 F]FEtO-CGS 25966 ( [ 18 F]1e , log D (exp) =2.02, IC 50 =2–50nM) all selected candidates showed increased hydrophilicities and inhibition potencies (log D (exp) =0.23–1.25, IC 50 =0.006–6nM). Interestingly, despite different hydrophilicities most triazole based MMPIs showed no significant differences in their in vivo biodistribution behavior and were cleared predominantly via the hepatobiliary excretion route. Biostability and metabolism studies in vitro and in vivo revealed significant higher metabolic stability for the triazole moiety compared to the benzyl ring in the lead structure. Cleavage of ethylene glycol subunits of the mini -PEG chain led to a faster metabolism of mini -PEG containing MMPIs. Conclusion The introduction of hydrophilic groups such as mini -PEG and 1,2,3-triazole units did not lead to a significant shift of the hepatobiliary elimination towards renal clearance. Particularly the introduction of mini -PEG chains led to an intense metabolic decomposition. Substitution of the benzyl moiety in lead structure 1e by a 1,2,3-trizole ring resulted in an increased metabolic stability. Therefore, the 1,2,3-triazole-1-yl-methyl substituted MMPI [ 18 F]3a was found to be the most stable candidate in this series and should be chosen for further preclinical evaluation.

The clinical course of multiple sclerosis (MS) is heterogeneous, varying between patients as well as over time. Classification criteria define the relapsing and progressive forms of MS as well as active and stable disease. Prior to the advent of disease-modifying therapies (DMTs), the majority of patients developed a secondarily progressive course. Randomized clinical trials, long-term extension trials, and observational trials provide data on the impact of DMTs on relapses and progression; however, use of these currently available studies to assess the effect on MS disease course is limited by duration or selection bias. Further analysis of a large populations of MS patients is needed to ascertain the long-term effects of DMTs on MS clinical course.

We have extended our Monte Carlo model of exospheres [Wurz, P., Lammer, H., 2003. Icarus 164 (1), 1–13] by treating the ion-induced sputtering process from a known surface in a self-consistent way. The comparison of the calculated exospheric densities with experimental data, which are mostly upper limits, shows that all of our calculated densities are within the measurement limits. The total calculated exospheric density at the lunar surface of about 1 × 10 7 m −3 as result of solar wind sputtering we find is much less than the experimental total exospheric density of about 10 12 m −3 . We conclude that sputtering contributes only a small fraction of the total exosphere, at least close to the surface. Because of the considerably larger scale height of atoms released via sputtering into the exosphere, sputtered atoms start to dominate the exosphere at altitudes exceeding a few 1000 km, with the exception of some light and abundant species released thermally, e.g. H2, He, CH4, and OH. Furthermore, for more refractory species such as calcium, our model indicates that sputtering may well be the dominant mechanism responsible for the lunar atmospheric inventory, but observational data does not yet allow firm conclusions to be drawn.

Catheter ablation, notably the electric isolation of pulmonary veins, has become a well-established therapeutic approach in symptomatic atrial fibrillation. The NavX navigation system has been described to facilitate pulmonary vein isolation in patients with AF. EnSite NavX (Endocardial Solutions, St. Jude Medical, Inc., St. Paul, MN, USA) is a novel navigation system that measures the local voltage on every standard intra-cardiac electrode and calculates the electrode position in three-dimensional (3D) space. Any individual electrode of each catheter in 3D-space can be displayed and labelled individually. The geometry of any cardiac chamber can be reconstructed and additional information, e.g. electrical activation spreading, can be displayed colour coded on the surface. Recent studies investigating the possible advantages of this system in the ablation of persistent or paroxysmal atrial fibrillation are summarized. All reports showed a significant reduction in fluoroscopy and procedure time by the use of the NavX system compared to conventional fluoroscopic catheter guidance. This benefit can be obtained with simple visualisation of all intracardiac catheters alone or with additional reconstruction of the left atrium and pulmonary veins.

Objectives To determine how nursing staff evaluate nonverbal behavior related to hand and tube feeding of residents with dementia. Design Cross-sectional survey. Setting A stratified sample of nurses and nursing assistants in residential nursing homes in a major German city. Participants Nursing staff members (N = 131) in 12 nursing homes. Measurements Nursing staff perception of nonverbal behavior of residents with dementia in response to hand and tube feeding. Results Ninety-three percent of survey participants considered the nonverbal behavior of residents with advanced dementia crucial for decisions about artificial nutrition and hydration (ANH). The same percentage had at some point encountered residents who did not open their mouths when feeding was attempted. Fifty-three percent of the participants interpreted residents’ expressions of pleasure while eating as a will to live. The most frequent interpretation of residents’ aversive behavior was discomfort. When residents did not open their mouth during nurse's hand feeding, 41% of the participants inferred a will to die. Conclusion Most nurses and nursing assistants consider residents’ behavior during hand or tube feeding to be important, but their interpretations are heterogeneous. Various professional caregivers assume a will to live or die. Further reflection is necessary to determine how behavioral expressions should be factored into treatment decisions.

Purpose Hypoxia is an important factor influencing tumor progression and treatment efficacy. The aim of this study was to investigate the repeatability of hypoxia PET imaging with [18F]HX4 in patients with head and neck and lung cancer. Methods Nine patients with lung cancer and ten with head and neck cancer were included in the analysis (NCT01075399). Two sequential pretreatment [18F]HX4 PET/CT scans were acquired within 1 week. The maximal and mean standardized uptake values (SUVmax and SUVmean) were defined and the tumor-to-background ratios (TBR) were calculated. In addition, hypoxic volumes were determined as the volume of the tumor with a TBR >1.2 (HV1.2). Bland Altman analysis of the uptake parameters was performed and coefficients of repeatability were calculated. To evaluate the spatial repeatability of the uptake, the PET/CT images were registered and a voxel-wise comparison of the uptake was performed, providing a correlation coefficient. Results All parameters of [18F]HX4 uptake were significantly correlated between scans: SUVmax (r = 0.958, p

Background: The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future. Objectives: To determine the cost-effectiveness of trametinib plus dabrafenib. Methods: A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone. Results: Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib. Conclusions: The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment.

Previous interpretations of the Pioneer Venus mass spectrometer data of the deuterium to hydrogen ( D / H ) ratio of 1.9 × 10 - 2 or 120 ± 40 times the terrestrial value indicate that Venus may have had at least an H 2 O content of the order of about 0.3% of a terrestrial ocean (TO), and even much more during and shortly after the accretion period of ⩽ 300 Myr , depending on the unknown ratio of a continuous supply of H 2 O by comets to a hydrogen blow-off loss and impact erosion of the early atmosphere. In view of the low H 2 O abundance in the present atmosphere, several studies suggest that the planet should have lost most of its H 2 O during the early high X-ray, EUV and solar wind period of the active young Sun. Because oxygen did not accumulate in Venus’ atmosphere it is commonly believed that a part of the oxygen from dissociated H 2 O vapor was dragged off to space along with the escaping hydrogen during a blow-off period, or could have oxidized the surface minerals to produce FeO and Fe 2 O 3 to the depths of a few kilometers to tens of kilometers depending on the initial amount of H 2 O . We use in the present study, for the first time, multi-wavelength X-ray and EUV (XUV) observations by the ASCA, ROSAT, EUVE, FUSE and IUE satellites and stellar winds inferred from mass loss observations by the Hubble Space Telescope of solar proxies with ages 4.6 Gyr for the investigation of how efficiently the radiation and particle environment of the young Sun could have influenced the evolution of the early Venusian atmosphere and its H 2 O inventory due to the removal of oxygen picked up by the solar wind. For modelling the Venusian thermosphere over the planetary history we apply a diffusive-gravitational equilibrium and thermal balance model and investigate the heating of the early thermosphere by photodissociation and ionization processes, due to exothermic chemical reactions and cooling by CO 2 IR emission in the 15 μ m band. Our model simulations result in expanded thermospheres with exobase levels between about 200 km at present and about 2200 km 4.5 Gyr ago. Moreover, our results yield high exospheric temperatures during the active phase of the young Sun even if we assume a “dry” CO 2 atmosphere with similar composition that is observed on present Venus of more than 8000 K after the Sun arrived at the zero-age-main-sequence (ZAMS). Exospheric temperatures above about 4000 K lead to diffusion-limited escape and high loss rates for atomic hydrogen. The duration of this blow-off phase for atomic hydrogen essentially depends on the mixing ratios of CO 2 , N 2 and H 2 O in the early Venusian atmosphere and could last between about 150 to several hundred Myr, which could result in a large thermal loss of hydrogen from Venus. For studying how much of the H 2 O -related oxygen could have been lost to space by the ion pick up process due to the stronger solar wind and higher XUV fluxes of the young Sun we used our modelled atmospheric density profiles and studied the loss of O + ion pick up from the upper atmosphere of Venus over the planet's history by applying a numerical test particle model. Depending on the used solar wind parameters, our model simulations show that ion pick up by a strong early solar wind on a non-magnetized Venus could erode during 4.6 Gyr more than about 250 bar of O + ions, that corresponds to an equivalent amount of one terrestrial ocean. Finally, we discuss the implications of our findings for the formation of the Venusian atmosphere and discuss our results in the frame of previous studies.