Light-induced racemization: artifacts in the analysis of the diastereoisomeric pairs of thioridazine 5-sulfoxide in the plasma and urine of patients treated with thioridazine.

The ring sulfoxidation of thioridazine (THD), a widely used neuroleptic agent, yields two diastereoisomeric pairs, fast- and slow-eluting (FE and SE) thioridazine 5-sulfoxide (THD 5-SO). Until now, studies in which concentrations of these metabolites were measured in THD-treated patients have revealed no significant differences in their concentrations. Preliminary experiments in our laboratory had shown that sunlight and, to a lesser extent, dim daylight led to racemization and probably also to photolysis of the diastereoisomeric pairs as measured by high-performance liquid chromatography. Similar results were also obtained with direct UV light (UV lamp). In appropriate light-protected conditions, THD, northioridazine, mesoridazine, sulforidazine, and FE and SE THD 5-SO were measured in 11 patients treated with various doses of THD for at least 1 week. Significantly higher concentrations of the FE stereoisomeric pair were found. The concentration ratios THD 5-SO (FE)/THD 5-SO (SE) ranged from 0.89 to 1.75 in plasma and from 1.15 to 2.05 in urine. Because it is known that the ring sulfoxide contributes to the cardiotoxicity of the drug even more potently than the parent compound does, these results justify further studies to determine whether there is stereoselectivity in the cardiotoxicity of THD 5-SO.

Polymorphisms in fibronectin binding protein A of Staphylococcus aureus are associated with infection of cardiovascular devices.

Medical implants, like cardiovascular devices, improve the quality of life for countless individuals but may become infected with bacteria like Staphylococcus aureus. Such infections take the form of a biofilm, a structured community of bacterial cells adherent to the surface of a solid substrate. Every biofilm begins with an attractive force or bond between bacterium and substratum. We used atomic force microscopy to probe experimentally forces between a fibronectin-coated surface (i.e., proxy for an implanted cardiac device) and fibronectin-binding receptors on the surface of individual living bacteria from each of 80 clinical isolates of S. aureus. These isolates originated from humans with infected cardiac devices (CDI; n = 26), uninfected cardiac devices (n = 20), and the anterior nares of asymptomatic subjects (n = 34). CDI isolates exhibited a distinct binding-force signature and had specific single amino acid polymorphisms in fibronectin-binding protein A corresponding to E652D, H782Q, and K786N. In silico molecular dynamics simulations demonstrate that residues D652, Q782, and N786 in fibronectin-binding protein A form extra hydrogen bonds with fibronectin, complementing the higher binding force and energy measured by atomic force microscopy for the CDI isolates. This study is significant, because it links pathogenic bacteria biofilms from the length scale of bonds acting across a nanometer-scale space to the clinical presentation of disease at the human dimension.

Analysis of Existing Work-Zone Devices with MASH Safety Performance Criteria, TPF-5(018), 2009

Crashworthy, work-zone, portable sign support systems accepted under NCHRP Report No. 350 were analyzed to predict their safety peformance according to the TL-3 MASH evaluation criteria. An analysis was conducted to determine which hardware parameters of sign support systems would likely contribute to the safety performance with MASH. The acuracy of the method was evaluated through full-scale crash testing. Four full-scale crash tests were conducted with a pickup truck. Two tall-mounted, sign support systems with aluminum sign panels failed the MASH criteria due to windshield penetration. One low-mounted system with a vinyl, roll-up sign panel failed the MASH criteria due to windshield and floorboard penetration. Another low-mounted system with an aluminum sign panel successfully met the MASH criteria. Four full-scale crash tests were conducted with a small passenger car. The low-mounted tripod system with an aluminum sign panel failed the MASH criteria due to windshield penetration. One low-mounted system with aluminum sign panel failed the MASH criteria due to excessive windshield deformation, and another similar system passed the MASH criteria. The low-mounted system with a vinyl, roll-up sign panel successfully met the MASH criteria. Hardware parameters of work-zone sign support systems that were determined to be important for failure with MASH include sign panel material, the height to the top of the mast, the presence of flags, sign-locking mechanism, base layout and system orientation. Flowcharts were provided to assist manufacturers when designing new sign support systems.

Benefits of endoscopic vein harvesting.

The purpose of this study was to evaluate and compare the benefits of endoscopic saphenous vein harvesting (EVH) with the traditional incision technique (TIT) for coronary artery bypass grafting (CABG) in respect to the technical procedure and clinical outcome. In a prospective nonrandomized, case-matched study the greater saphenous vein was harvested for CABG in 22 patients using the endoscopic technique and in 18 patients with the traditional method. Comparisons were made for the operating time, length of incision and vein harvested, graft quality, postoperative complications, and pain assessment. Patient demographics were well matched. EVH required smaller incisions than did the TIT (10.5 +/- 6.6 vs. 31.2 +/- 7.8 cm, respectively; p < 0.0001). Harvest time and vein quality were comparable in the two groups. Total vein operating time was shorter following the endoscopic technique (60 +/- 24 vs. 100 +/- 35 minutes, respectively; p < 0.0001). EVH had fewer complications (NS), and postoperative pain was significantly less (p = 0.0034). The major advantages of endoscopic vein harvesting are a significant reduction of postoperative pain and strikingly better cosmetic results. Wound complications seem to be less frequent.

The PEDRO (Pocketable Electronic Devices in Radiation Oncology) project: how clinical practice is changing among young radiation oncologists.

Purpose. To evaluate the impact of mobile devices and apps on the daily clinical activity of young radiation oncologists. Methods. A web-based questionnaire was sent to 382 young (≤40 years) members of the Italian Association of Radiation Oncology (AIRO). The 14 items investigated the diffusion of mobile devices (smartphones and/or tablets), their impact on daily clinical activity, and possible differences perceived by the participants over time. Results. A total of 158 questionnaires were available for statistical evaluation (response rate 41%). Up to 75% of respondents declared they used an electronic device during their clinical activity. Conversely, 82% considered the impact of smartphones/tables on daily practice low to moderate. Daily device use increased significantly from 2009 to 2012, with high daily use rates rising from 5% to 39.9%. Fulfillment of professional needs was declared by less than 42% of respondents and compliance with app indications by 32%. Almost all physicians desired in 2012 a comprehensive website concerning a variety of apps covering radiation oncologists' needs. Conclusions. Mobile devices are widely used by young Italian radiation oncologists in their daily clinical practice, while the indications so obtained are not always followed. Nevertheless, it would be important to verify the consistency of information found within apps, in order to avoid potential errors that might be detrimental to patients.

Looking for factors involved in the light-dependent degradation of phytochrome A

SUMMARY : Phytochromes constitute a family of red/far-red photoreceptors regulating all the major transitions during the life cycle of plants. In Arabidopsis, five members: phyA,_ B, C, D and E, were identified. Phytochromes are synthesized in their inactive red-light absorbing form called Pr. Upon light absorbance they convert to the far-red light absorbing Pfr form. The Pfr form is the active conformer which converts back to the Pr form either rapidly upon far-red perception or in a slower process called dark reversion. ph~A represents an exception, in that it does not significantly dark-revert and two specific processes have been developed by the plants to decrease the amount of biologically active phyA. The first one is alight-dependent repression of the PHYA gene expression and the second one is alight-dependent degradation of the phyA protein. The latter is the most efficient process to rapidly decrease the level of active phyA. The ability of plants to regulate the amount of active phyA is critical in a far-red rich environment, a situation observed under a canopy. In these conditions, phyA is essential to induce the germination and the deetiolation of the young seedling. Later in the development the ability of phyA to repress growth counteracts the shade avoidance response. Therefore decreasing the amount of phyA allows stem growth and to compete with neighbours for the light. In this thesis, I investigate the light-dependent degradation of phyA. I developed a reverse genetic approach based on the systematic analysis of the light-dependent accumulation of phyA in the different cullin mutant cull, cul3a; cul3b and cul4. This analysis allowed me to show that CUL1 and CUL3A-based E3 ligase complexes are involved in the regulation of phyA degradation. Surprisingly, our results also demonstrate that cu14 is not affected in the degradation of phyA whereas constitutive Photomorphogenic 1 (COP1) a subunit of one CUL4based E3 complex was reported to be involved. Further investigations showed that the phenotype of cop1 is conditional, the mutant being defective in phyA degradation only in the presence of metabolisable sugars. I also showed that phyA is degraded by a proteasome-dependent mechanism both in the cytoplasm and in the nucleus using mutants and transgenic lines affected in the localization of phyA. Interestingly, I observed that phyA degradation was faster in the nucleus than in the cytosol and that rapid degradation of Pr also occurred in the nucleus suggesting that cytosolic accumulation of phyA in the dark is a way to regulate its proteolysis. Finally, we identify a short region similar to a PEST sequence required for phyA stability and we developed a unbiased genetic screen to identify new components involved in the regulation of the light-dependent degradation of phyA. The significance of these results are discussed. RESUME : Les phytochromes (phy) constituent une famille de photorécepteurs absorbant la lumière rouge et rouge lointaine et régulant toutes les étapes de transitions majeures dans la vie des plantes. Chez Arabidopsis, cinq membres : phyA, B, C, D et E ont été identifiés. Les phytochromes sont synthétisés sous une forme inactive appelée Pr absorbant la lumière rouge. Après perception de lumière ils passent sous une forme active Pfr absorbant dans le rouge lointain. La forme Pfr peut retourner sous la forme Pr après absorption de lumiëre rouge lointaine ou dans un processus lent appelé «réversion à l'obscurité ». phyA représente une exception à cette règle car il ne retoune pas significativement sous sa forme inactive dans le noir. Deux processus spécifiques ont donc été développés pour diminuer le taux de phyA actif. Le premier consiste en la répression du gène PHYA en condition de lumière et le second en une dégradation induite par la lumière de la protéine phyA. Ce dernier processus est le plus efficace pour diminuer rapidement le niveau de phyA. La capacité des plantes à réguler le taux de phyA actifs est critique dans un environnement riche en lumière rouge lointaine, une situation observée sous une canopée. Sous une canopée, phyA est essentiel pour induire la germination et la dé-étiolation de la jeune pousse. Plus tard dans le développement la capacité de phyA de réprimer la croissance freine la «réponse à l'évitement de l'ombre ». Par conséquent diminuer le taux de phyA permet la croissance de la tige et donc de rentrer en compétition pour la lumière avec les plantes avoisinantes. Dans cette thèse, j'ai étudié la dégradation de phyA. J'ai développé une approche génétique inverse basée sur l'analyse systématique de l'accumulation de phyA en condition de lumière dans les différents mutants cullin, cul1, cul3a, cul3b et cul4. Ces analyses nous ont permis d'identifier qu'un complexe E3 ligase CUL1 et un complexe E3 ligase CUL3A sont impliqués dans la régulation de la dégradation de phyA. Mes résultats démontrent aussi que le mutant cul4 n'est pas affecté dans la dégradation de phyA alors que Çonstitutive Photomorphogenic 1 (COPI) une sous unité d'un complexe CUL4 à été identifier dans la régulation de cette dégradation. Des analyses supplémentaires suggèrent que l'effet de la mutation cop1 est dépendante dë la présence de sucres métabolisables. J'ai aussi montré que phyA est dégradé dans le noyau et dans le cytoplasme par un mécanisme dépendant du protéasome et que la dégradation dans le.noyau est non seulement aspécifique de la forme Pr ou Pfr mais aussi est plus rapide que dans le cytoplasme. Ceci suggère que l'accumulation de phyA dans le cytoplasme permet son accumulation à des niveaux élevés à l'obscurité. Enfin j'ai identifié une région similaire à un motif PEST requise pour la stabilité de phyA et j'ai aussi développé un criblage génétique non biaisé pour identifier de nouveaux composants impliqués dans la régulation de la dégradation de phyA. L'importance de ces résultats est discutée dans le dernier chapitre de cette thèse.

Light-emitting diodes (LED) for domestic lighting: any risks for the eye?

Light-emitting diodes (LEDs) are taking an increasing place in the market of domestic lighting because they produce light with low energy consumption. In the EU, by 2016, no traditional incandescent light sources will be available and LEDs may become the major domestic light sources. Due to specific spectral and energetic characteristics of white LEDs as compared to other domestic light sources, some concerns have been raised regarding their safety for human health and particularly potential harmful risks for the eye. To conduct a health risk assessment on systems using LEDs, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), a public body reporting to the French Ministers for ecology, for health and for employment, has organized a task group. This group consisted physicists, lighting and metrology specialists, retinal biologist and ophthalmologist who have worked together for a year. Part of this work has comprised the evaluation of group risks of different white LEDs commercialized on the French market, according to the standards and found that some of these lights belonged to the group risk 1 or 2. This paper gives a comprehensive analysis of the potential risks of white LEDs, taking into account pre-clinical knowledge as well as epidemiologic studies and reports the French Agency's recommendations to avoid potential retinal hazards.

Phototropism: Translating light into directional growth.

Phototropism allows plants to align their photosynthetic tissues with incoming light. The direction of incident light is sensed by the phototropin family of blue light photoreceptors (phot1 and phot2 in Arabidopsis), which are light-activated protein kinases. The kinase activity of phototropins and phosphorylation of residues in the activation loop of their kinase domains are essential for the phototropic response. These initial steps trigger the formation of the auxin gradient across the hypocotyl that leads to asymmetric growth. The molecular events between photoreceptor activation and the growth response are only starting to be elucidated. In this review, we discuss the major steps leading from light perception to directional growth concentrating on Arabidopsis. In addition, we highlight links that connect these different steps enabling the phototropic response.

Light intensity modulates the regulatory network of the shade avoidance response in Arabidopsis.

Plants such as Arabidopsis thaliana respond to foliar shade and neighbors who may become competitors for light resources by elongation growth to secure access to unfiltered sunlight. Challenges faced during this shade avoidance response (SAR) are different under a light-absorbing canopy and during neighbor detection where light remains abundant. In both situations, elongation growth depends on auxin and transcription factors of the phytochrome interacting factor (PIF) class. Using a computational modeling approach to study the SAR regulatory network, we identify and experimentally validate a previously unidentified role for long hypocotyl in far red 1, a negative regulator of the PIFs. Moreover, we find that during neighbor detection, growth is promoted primarily by the production of auxin. In contrast, in true shade, the system operates with less auxin but with an increased sensitivity to the hormonal signal. Our data suggest that this latter signal is less robust, which may reflect a cost-to-robustness tradeoff, a system trait long recognized by engineers and forming the basis of information theory.

Different colors of light lead to different adaptation and activation as determined by high-density EEG.

Light adaptation is crucial for coping with the varying levels of ambient light. Using high-density electroencephalography (EEG), we investigated how adaptation to light of different colors affects brain responsiveness. In a within-subject design, sixteen young participants were adapted first to dim white light and then to blue, green, red, or white bright light (one color per session in a randomized order). Immediately after both dim and bright light adaptation, we presented brief light pulses and recorded event-related potentials (ERPs). We analyzed ERP response strengths and brain topographies and determined the underlying sources using electrical source imaging. Between 150 and 261ms after stimulus onset, the global field power (GFP) was higher after dim than bright light adaptation. This effect was most pronounced with red light and localized in the frontal lobe, the fusiform gyrus, the occipital lobe and the cerebellum. After bright light adaptation, within the first 100ms after light onset, stronger responses were found than after dim light adaptation for all colors except for red light. Differences between conditions were localized in the frontal lobe, the cingulate gyrus, and the cerebellum. These results indicate that very short-term EEG brain responses are influenced by prior light adaptation and the spectral quality of the light stimulus. We show that the early EEG responses are differently affected by adaptation to different colors of light which may contribute to known differences in performance and reaction times in cognitive tests.

Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability.

Light toxicity is suspected to enhance certain retinal degenerative processes such as age-related macular degeneration. Death of photoreceptors can be induced by their exposure to the visible light, and although cellular processes within photoreceptors have been characterized extensively, the role of the retinal pigment epithelium (RPE) in this model is less well understood. We demonstrate that exposition to intense light causes the immediate breakdown of the outer blood-retinal barrier (BRB). In a molecular level, we observed the slackening of adherens junctions tying up the RPE and massive leakage of albumin into the neural retina. Retinal pigment epithelial cells normally secrete vascular endothelial growth factor (VEGF) at their basolateral side; light damage in contrast leads to VEGF increase on the apical side - that is, in the neuroretina. Blocking VEGF, by means of lentiviral gene transfer to express an anti-VEGF antibody in RPE cells, inhibits outer BRB breakdown and retinal degeneration, as illustrated by functional, behavioral and morphometric analysis. Our data show that exposure to high levels of visible light induces hyperpermeability of the RPE, likely involving VEGF signaling. The resulting retinal edema contributes to irreversible damage to photoreceptors. These data suggest that anti-VEGF compounds are of therapeutic interest when the outer BRB is altered by retinal stresses.

Consumer Advisory: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones, June 2014

The Attorney General’s Consumer Protection Division receives hundreds of calls and consumer complaints every year. Follow these tips to avoid unexpected expense and disappointments. This record is about: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones

Evaluation of Air Pollution Control Devices for Asphalt Pavement Recycling Operations, HR-188, Progress Report, 1977

This report discusses the asphalt pavement recycling project designated Project HR-188 in Kossuth County, Iowa. Specific objectives were: (a) to determine the effectiveness of drum mixing plant modifications designed to control air pollution within limits specified by the Iowa Department of Environmental Quality; (b) to assess the impact of varying the proportions of recycled and virgin aggregates, (c) to assess the impact of varying the production rate of the plant, and (d) to assess the impact of varying the mixing temperature. The discussion includes information on the proposed use of research funds, project location and description, the project planning conference, plan development, bid letting, asphalt plant configuration, actual plant operation, why this method is successful, probable process limitations, pollution results, recycled pavement test results, and the cost of virgin vs. recycled asphalt pavements.