Chitosan-based nanogels for selective delivery of photosensitizers to macrophages and improved retention in and therapy of articular joints.

Macrophages play key roles in inflammatory disorders. Therefore, they are targets of treatments aiming at their local destruction in inflammation sites. However, injection of low molecular mass therapeutics, including photosensitizers, in inflamed joints results in their rapid efflux out of the joints, and poor therapeutic index. To improve selective uptake and increase retention of therapeutics in inflamed tissues, hydrophilic nanogels based on chitosan, of which surface was decorated with hyaluronate and which were loaded with one of three different anionic photosensitizers were developed. Optimal uptake of these functionalized nanogels by murine RAW 264.7 or human THP-1 macrophages as models was achieved after <4h incubation, whereas only negligible uptake by murine fibroblasts used as control cells was observed. The uptake by cells and the intracellular localization of the photosensitizers, of the fluorescein-tagged chitosan and of the rhodamine-tagged hyaluronate were confirmed by fluorescence microscopy. Photodynamic experiments revealed good cell photocytotoxicity of the photosensitizers entrapped in the nanogels. In a mouse model of rheumatoid arthritis, injection of free photosensitizers resulted in their rapid clearance from the joints, while nanogel-encapsulated photosensitizers were retained in the inflamed joints over a longer period of time. The photodynamic treatment of the inflamed joints resulted in a reduction of inflammation comparable to a standard corticoid treatment. Thus, hyaluronate-chitosan nanogels encapsulating therapeutic agents are promising materials for the targeted delivery to macrophages and long-term retention of therapeutics in leaky inflamed articular joints.

Appropriate management of special situations in Crohn's disease (upper gastro-intestinal; extra-intestinal manifestations; drug safety during pregnancy and breastfeeding): results of a multidisciplinary international expert panel-EPACT II

Introduction: High-grade evidence is lacking for most therapeutic decisions in Crohn's disease. Appropriateness criteria were developed for upper gastro-intestinal, extra-intestinal manifestations and drug safety during conception, pregnancy and breastfeeding in patients with Crohn's disease, to assist the physician in clinical decision making. Methods: The European Panel on the Appropriateness of Crohn's Disease Therapy (EPACT II), a multidisciplinary international European expert panel, rated clinical scenarios based on evidence from the published literature and panelists' own clinical expertise. Median ratings (on a 9-point scale) were stratified into three categories: appropriate (7-9), uncertain (4-6 with or without disagreement) and inappropriate (1-3). Experts were also asked to rank appropriate medications by priority. Results: Proton pump inhibitors, steroids, azathioprine/6-mercaptopurine and infliximab are appropriate for upper gastro-duodenal Crohn's disease; for stenosis, endoscopic balloon dilation is the first-tine therapy, although surgery is also appropriate. Ursodeoxycholic acid is the only appropriate treatment for primary sclerosing cholangitis. Infliximab is appropriate for Pyoderma gangrenosum, ankylosing spondylitis and uveitis, steroids for Pyoderma gangrenosum and ankylosing spondylitis, adalimumab for Pyoderma gangrenosum and ankylosing spondylitis, cyclosporine-A/tacrolimus for Pyoderma gangrenosum. Mesalamine, sulfasalazine, prednisone, azathioprine/6-mercaptopurine, ciprofloxacin, and probiotics, may be administered safety during pregnancy or for patients wishing to conceive, with the exception that mate patients considering conception should avoid sulfasalazine. Metronidazol is considered safe in the 2nd and 3rd trimesters whereas infliximab is rated safe in the 1st trimester but uncertain in the 2nd and 3rd trimesters. Methotrexate is always contraindicated at conception, during pregnancy or during breastfeeding, due to its known teratogenicity. Mesalamine, prednisone, probiotics and infliximab are considered safe during breastfeeding. Conclusion: EPACT II recommendations are freely available online (www.epact.ch). The validity of these criteria should now be tested by prospective evaluation. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.

When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.

Secreted proteases from dermatophytes

Dermatophytes are highly specialized pathogenic fungi that exclusively infect the stratum corneum, nails or hair, and it is evident that secreted proteolytic activity is important for their virulence. Endo- and exoproteases-secreted by dermatophytes are similar to those of species of the genus Aspergillus. However, in contrast to Aspergillus spp., dermatophyte-secreted endoproteases are multiple and are members of two large protein families, the subtilisins (serine proteases) and the fungalysins (metalloproteases). In addition, dermatophytes excrete sulphite as a reducing agent. In the presence of sulphite, disulphide bounds of the keratin substrate are directly cleaved to cysteine and S-sulphocysteine, and reduced proteins become accessible for further digestion by various endo- and exoproteases secreted by the fungi. Sulphitolysis is likely to be an essential step in the digestion of compact keratinized tissues which precedes the action of all proteases.

Nd-, O-, and H-isotopic evidence for complex, closed-system fluid evolution of the peralkaline Ilimaussaq intrusion, South Greenland

Relatively homogeneous oxygen isotope compositions of amphibole, clinopyroxene, and olivine separates (+5.2 to +5.7parts per thousand relative to VSMOW) and neodymium isotope compositions (epsilon(Nd(T)) = -0.9 to -1.8 for primary magmatic minerals and epsilon(Nd(T)) = -0.1 and -0.5 for mineral separates from late-stage pegmatites and hydrothermal veins) from the alkaline to agpaitic llimaussaq intrusion, South Greenland, indicate a closed system evolution of this igneous complex and support a mantle derivation of the magma. In contrast to the homogeneous oxygen and neodymium isotopic data, deltaD values for hand-picked amphibole separates vary between -92 and -232parts per thousand and are among the most deuterium-depleted values known from igneous amphiboles. The calculated fluid phase coexisting with these amphiboles has a homogeneous oxygen isotopic composition within the normal range of magmatic waters, but extremely heterogeneous and low D/H ratios, implying a decoupling of the oxygen- and hydrogen isotope systems. Of the several possibilities that can account for such unusually low deltaD values in amphiboles (e.g., late-stage hydrothermal exchange with meteoric water, extensive magmatic degassing, contamination with organic matter, and/or effects of Fe-content and pressure on amphibole-water fractionation) the most likely explanation for the range in deltaD values is that the amphiboles have been influenced by secondary interaction and reequilibration with D-depleted fluids obtained through late-magmatic oxidation of internally generated CH(4) and/or H(2). This interpretation is consistent with the known occurrence of abundant magmatic CH(4) in the Ilimaussaq rocks and with previous studies on the isotopic compositions of the rocks and fluids. Copyright (C) 2004 Elsevier Ltd.

Une cause exceptionnelle d'hypertension artérielle de l'enfant : l'artérite de Takayasu [An exceptional cause of arterial hypertension in children: Takayasu arteritis].

Takayasu arteritis, a nonspecific inflammatory arteritis, is particularly rare in children. We report the case of a 6-year-old girl presenting with severe arterial hypertension in the upper segment associated with an inflammatory syndrome. Investigations showed coarctation of the abdominal aorta at different levels, due to Takayasu arteritis. The patient was treated with percutaneous dilatation and stent implantation as well as prolonged anti-inflammatory therapy. Arterial hypertension in children needs to be investigated until its cause, which may be rare such as Takaysu arteritis, is determined.

Enregistrement des fluctuations de la pression intraoculaire sur 24 heures par une lentille de contact intégrant un capteur: tolérance et résultats chez 10 sujets sains

AbstractPurpose: to evaluate the tolerability, comfort and precision of the signal transmission of an ocular Sensor used for 24-hour intraocular pressure fluctuation monitoring in humans.Patients and methods: In this uncontrolled open trial involving 10 healthy volunteers an 8.7 mm radius prototype ocular telemetry Sensor (SENSIMED Triggerfish®, Lausanne, Switzerland) and an orbital bandage containing a loop antenna were applied and connected to a portable recorder after full eye examination. Best corrected visual acuity and position, surface wetting ability and mobility of the Sensor were assessed after 5 and 30 minutes, 4, 12 and 24 hours. Subjective wearing comfort was scored and activities documented in a logbook. After Sensor removal a full eye examination was repeated and the recorded signal analyzed.Results: The comfort score was high and did not fluctuate significantly over time. The mobility of the Sensor was limited across follow-up visits and its surface wetting ability remained good. Best corrected visual acuity was significantly reduced during Sensor wear and immediately after its removal (from 1.07 before, to 0.85 after, P-value 0.008). Three subjects developed a mild, transient corneal abrasion. In all but one participant we obtained usable data of a telemetric signal recording with sufficient sensitivity to depict ocular pulsation.Conclusions: This 24-hour- trial has encouraging results on the tolerability and functionality of the ocular telemetric Sensor for intraocular pressure fluctuation monitoring. Further studies with different Sensor radii conducted on a larger study population are needed to improve comfort, precision and interpretation of the telemetric signal.

Sex differences: From mental rotation to object location memory, an ERP study

Sex differences in cognition have been largely investigated. The most consistent sex differences favoring females are observed in object location memory involving the left hemisphere whereas the most consistent sex differences favoring males are observed in tasks that require mental rotation involving the right hemisphere. Here we used a task involving these two abilities to see the impact of mental rotation on object location memory. To that end we used a combination of behavioral and event-related potential (ERP) electroencephalography (EEG) measures.A computer screen displayed a square frame of 4 pairs of images (a "teddy" bear, a shoe, an umbrella and a lamp) randomly arranged around a central fixation cross. After a 10-second interval for memorization, images disappeared and were replaced by a test frame with no image but a random pair of two locations marked in black. In addition, this test frame was randomly displayed either in the original orientation (0° rotation) or in the rotated one (90° clockwise - CW - or 90° counterclockwise - CCW). Preceding the test frame, an arrow indicating the presence or the absence of rotation of the frame was displayed on the screen. The task of the participants (15 females and 15 males) was to determine if two marked locations corresponded or not to a pair of identical images. Each response was followed by feedback.Findings showed no significant sex differences in the performance of the original orientation. In comparison with this position, the rotation of the frame produced an equal decrease of male and female performance. In addition, this decrease was significantly higher when the rotation of the frame was in a CCW direction. We further assessed the ERP when the arrow indicated the direction of rotation as stimulus-onset, during four time windows representing major components C1, P1, N1 and N2. Although no sex differences were observed in performance, brain activities differed according to sex. Enhanced amplitudes were found for the CCW compared to CW rotation over the right posterior areas for the P1, N1 and N2 components for men as well as for women. Major topographical differences related to sex were measured for the CW rotation condition as marked lateralized amplitude: left-hemisphere amplitude larger than right one was measured during P1 time range for men. These similar patterns prolonged from P1 to N1 for women. Early distinctions were found in interaction with sex between CCW and CW waveform amplitudes, expressing over anterior electrode sites during C1 time range (0-50 ms post-stimulus).In conclusion (i) women do not outperform men in object location memory in this study (absence of rotation condition); (ii) mental rotation, in particular the direction of rotation, influences performance on object location memory; (iii) CCW rotation is associated with activity in the right parietal hemisphere whereas the CW rotation involves the left parietal hemisphere; (iv) this last effect is less pronounced in males, which could explain why greater involvement of right parietal areas in men and of bilateral posterior areas in women is generally reported in mental rotation tasks; and (v) the early distinctions between both directions of rotation located over anterior sites could be related to sex differences in their respective involvement of control mechanisms.

The molecular basis of social behavior: models, methods and advances.

Elucidating the molecular and neural basis of complex social behaviors such as communal living, division of labor and warfare requires model organisms that exhibit these multi-faceted behavioral phenotypes. Social insects, such as ants, bees, wasps and termites, are attractive models to address this problem, with rich ecological and ethological foundations. However, their atypical systems of reproduction have hindered application of classical genetic approaches. In this review, we discuss how recent advances in social insect genomics, transcriptomics, and functional manipulations have enhanced our ability to observe and perturb gene expression, physiology and behavior in these species. Such developments begin to provide an integrated view of the molecular and cellular underpinnings of complex social behavior.

Preoperative immunonutrition in patients at nutritional risk: results of a double-blinded randomized clinical trial.

Background/Objectives:To evaluate the impact of preoperative immunonutrition (IN) on postoperative morbidity in patients at risk of malnutrition undergoing major gastrointestinal (GI) surgery.Subjects/Methods:The combination of malnutrition and major GI surgery entails high morbidity. The Nutritional Risk Score (NRS) reliably identifies patients who need preoperative nutrition; the optimal nutritional formula for these patients still needs to be defined. In all, 152 patients with a NRS3 and undergoing elective major GI surgery were randomized between IN or isocaloric-isonitrogenous nutrition (ICN) given for 5 days preoperatively. Patients and caregivers were blinded for the allocated intervention. Thirty days complication rate was the primary endpoint. Infections, length of hospital stay and compliance were considered as secondary outcomes.Results:Overall, 145 patients were available for analysis; the 73 patients in the IN group matched well with the 72 ICN patients with regards to patient's and surgical characteristics. In all, 39 IN and 33 ICN patients experienced a total of 48 and 50 postoperative complications, respectively (P=0.723). Both groups did not differ significantly concerning infectious (13 vs 9) complications. Independent risk factors for overall complications were malignant disease (odds ratio (OR)=4.304; confidence interval (CI) 1.317-14.002) and operative time (OR=1.004; CI 1.000-1.008).Conclusion:In patients at nutritional risk, complications, infections and hospital stay after major GI surgery were comparable regardless of preoperative supplementation with IN or ICN.

How to manage the left subclavian artery during endovascular stenting of the thoracic aorta.

We performed a systematic review of the literature to establish whether revascularisation of the left subclavian territory is necessary when this artery is covered by a stent. We retrieved data from 99 studies incorporating 4906 patients. Incidences of left-arm ischaemia (0.0% vs 9.2%, p=0.002) and stroke (4.7% vs 7.2%, p<0.001) were significantly less following revascularisation, although mortality (10.5% vs 3.4%, p=0.032) and endoleak incidence (25.8% vs 12.6%, p=0.008) were increased. No significant differences in spinal-cord ischaemia were seen. Revascularisation may reduce downstream ischaemic complications but can cause significant risk. Indications must be carefully considered on an individual patient basis.

Simultaneous determination of antidementia drugs in human plasma: Procedure transfer from HPLC-MS to UPLC-MS/MS.

A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([(2)H(7)]-donepezil, [(13)C,(2)H(3)]-galantamine, [(13)C(2),(2)H(6)]-memantine, [(2)H(6)]-rivastigmine) were extracted from 250μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1mm×50mm; 1.7μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4mL/min and an overall run time of 4.5min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300ng/mL for donepezil, galantamine and memantine, and 0.2-50ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients' samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.

Efficacy of clinical guideline implementation to improve the appropriateness of chest physiotherapy prescription among inpatients with community-acquired pneumonia

BACKGROUND: Although there is no strong evidence of benefit, chest physiotherapy (CP) seems to be commonly used in simple pneumonia. CP requires equipment and frequently involves the assistance of a respiratory therapist, engendering a significant medical workload and cost. AIM: To measure and compare the efficacy of two modalities of chest physiotherapy (CP) guideline implementation on the appropriateness of CP prescription among patients hospitalised for community-acquired pneumonia (CAP). PATIENTS AND METHODS: We measured the CP prescription rate and duration in all consecutive CAP inpatients admitted in a division of general internal medicine at an urban teaching community hospital during three consecutive one-year time periods: (1) before any guideline implementation; (2) after a passive implementation by medical grand rounds and guideline diffusion through mailing; (3) after adding a one-page reminder in the CAP patient's medical chart highlighting our recommendations. Death and recurrent hospitalisation rates within one year after hospitalisation were recorded to assess whether CP prescription reduction, if any, impaired patient outcomes. RESULTS: During the three successive phases, 127, 157, and 147 patients with similar characteristics were included. Among all CAP inpatients, the CP prescription rate decreased from 68% (86/127) to 51% (80/157), and to 48% (71/147), respectively (P for trend <0.01 for trend). A significant reduction in CP duration was observed after the active guideline implementation (12.0, 11.0, 7.0days, respectively) and persisted after adjustment for length of stay. Reductions in CP prescription rate and duration were also observed among CAP patients with COPD CP prescription rate: 97% (30/31), 67% (24/36), 75% (35/47), respectively (P<0.01 for trend). The mean cost of CP per patient was reduced by 56%, from $709 to $481, and to $309, respectively. Neither the in-hospital deaths, the one-year overall recurrent hospitalisation nor the one-year CAP-specific recurrent hospitalisation significantly differed between the three phases. CONCLUSION: Both passive and active implementation of guidelines appear to improve the appropriateness of CP prescription among inpatients with CAP without impairing their outcomes. Restricting CP use to patients who benefit from this treatment might be an opportunity to decrease CAP medical cost and workload.