Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death

Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodes-sication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 mug) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; it = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; it = >4 tumors/group) previously established (5-10 mm(3)) on C57BL/6 or Fox1(nu) mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD90 for PEP005 for a panel of tumor cell lines was 180-220 muM. Electron microscopy showed that treatment with PEP005 both ill vitro (230 tot) and ill vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. Cr-51 release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 muM) treatment of tumor cells ill vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Phase shift keyed systems based on a gain switched laser transmitter

Return-to-Zero (RZ) and Non-Return-to-Zero (NRZ) Differential Phase Shift Keyed (DPSK) systems require cheap and optimal transmitters for widespread implementation. The authors report on a gain switched Discrete Mode (DM) laser that can be employed as a cost efficient transmitter in a 10.7 Gb/s RZ DPSK system and compare its performance to that of a gain switched Distributed Feed-Back (DFB) laser. Experimental results show that the gain switched DM laser readily provides error free performance and a receiver sensitivity of -33.1 dBm in the 10.7 Gbit/s RZ DPSK system. The standard DFB laser on the other hand displays an error floor at 10(-1) in the same RZ DPSK system. The difference in performance, between the two types of gain switched transmitters, is analysed by investigating their linewidths. We also demonstrate, for the first time, the generation of a highly coherent gain switched pulse train which displays a spectral comb of approximately 13 sidebands spaced by the 10.7 GHz modulation frequency. The filtered side-bands are then employed as narrow linewidth Continuous Wave (CW) sources in a 10.7 Gb/s NRZ DPSK system.

Cryptographic Primitives with Quasigroup Transformations

AMS Subj. Classification: Primary 20N05, Secondary 94A60

Internet use by patients with bipolar disorder:results from an international multisite survey

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with bipolar disorder diagnosis in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Stable optical vortices in nonlinear multicore fibers

The multicore fiber (MCF) is a physical system of high practical importance. In addition to standard exploitation, MCFs may support discrete vortices that carry orbital angular momentum suitable for spatial-division multiplexing in high-capacity fiber-optic communication systems. These discrete vortices may also be attractive for high-power laser applications. We present the conditions of existence, stability, and coherent propagation of such optical vortices for two practical MCF designs. Through optimization, we found stable discrete vortices that were capable of transferring high coherent power through the MCF.

The functional subdivision of the visual brain : Is there a real illusion effect on action? A multi-lab replication study

Acknowledgements We thank Brian Roberts and Mike Harris for responding to our questions regarding their paper; Zoltan Dienes for advice on Bayes factors; Denise Fischer, Melanie Römer, Ioana Stanciu, Aleksandra Romanczuk, Stefano Uccelli, Nuria Martos Sánchez, and Rosa María Beño Ruiz de la Sierra for help collecting data; Eva Viviani for managing data collection in Parma. We thank Maurizio Gentilucci for letting us use his lab, and the Centro Intradipartimentale Mente e Cervello (CIMeC), University of Trento, and especially Francesco Pavani for lending us his motion tracking equipment. We thank Rachel Foster for proofreading. KKK was supported by a Ph.D. scholarship as part of a grant to VHF within the International Graduate Research Training Group on Cross-Modal Interaction in Natural and Artificial Cognitive Systems (CINACS; DFG IKG-1247) and TS by a grant (DFG – SCHE 735/3-1); both from the German Research Council.

Online information seeking by patients with bipolar disorder:results from an international multisite survey

Background: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. Methods: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. Results: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Conclusion: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Evaluation of a gelatin modified poly(ɛ-caprolactone) film as a scaffold for lung disease

Lung transplantation is a necessary step for the patients with the end-stage of chronic obstructive pulmonary disease. The use of artificial lungs is a promising alternative to natural lung transplantation which is complicated and is restricted by low organ donations. For successful lung engineering, it is important to choose the correct combination of specific biological cells and a synthetic carrier polymer. The focus of this study was to investigate the interactions of human lung epithelial cell line NCl-H292 that is involved in lung tissue development with the biodegradable poly(ϵ-caprolactone) before and after its chemical modification to evaluate potential for use in artificial lung formation. Also, the effect of polymer chemical modification on its mechanical and surface properties has been investigated. The poly(ϵ-caprolactone) surface was modified using aminolysis followed by immobilization of gelatine. The unmodified and modified polymer surfaces were characterized for roughness, tensile strength, and NCl-H292 metabolic cell activity. The results showed for the first time the possibility for NCI-H292 cells to adhere on this polymeric material. The Resazurin assay showed that the metabolic activity at 24 hours post seeding of 80% in the presence of the unmodified and greater than 100% in the presence of the modified polymer was observed. The roughness of the poly(ϵ-caprolactone) increased from 4 nm to 26 nm and the film strength increased from 0.01 kN to 0.045 kN when the material was chemically modified. The results obtained to date show potential for using modified poly(ϵ-caprolactone) as a scaffold for lung tissue engineering.

Discovery and settlement of Alaska coaster

Tsar Peter the Great ruled Russia between 1689 and 1725. Its domains, stretching from the Baltic Sea in the west to the Pacific Ocean in the east. From north to south, its empire stretching from the Arctic Ocean to the borders with China and India. Tsar Peter I tried to extend the geographical knowledge of his government and the rest of the world. He was also interested in the expansion of trade in Russia and in the control of trade routes. Feodor Luzhin and Ivan Yeverinov explored the eastern border of the Russian Empire, the trip between 1719 and 1721 and reported to the Tsar. They had crossed the peninsula of Kamchatka, from west to east and had traveled from the west coast of Kamchatka to the Kuril Islands. The information collected led to the first map of Kamchatka and the Kuril Islands. Tsar Peter ordered Bering surf the Russian Pacific coast, build ships and sail the seas north along the coast to regions of America. The second expedition found equal to those of the previous explorers difficulties. Two ships were eventually thrown away in Okhotsk in 1740. The explorers spent the winter of 1740-1741 stockpiling supplies and then navigate to Petropavlovsk. The two ships sailed eastward and did together until June 20, then separated by fog. After searching Chirikov and his boat for several days, Bering ordered the San Pedro continue to the northeast. There the Russian sailors first sighted Alaska. According to the log, "At 12:30 (pm July 17) in sight of snow-capped mountains and between them a high volcano." This finding came the day of St. Elijah and so named the mountain.

DESCRIBING SLEEP AND SEDATION PRACTICES IN THE ICU: A MULTINATIONAL SURVEY

Introduction Sleep disturbances are common in critically ill patients treated in the intensive care unit (ICU) with the potential for serious consequences and long-term effects on health outcomes and patient morbidity.
Objectives Our aim was to describe sleep management and sedation practices of adult ICUs in ten countries and to evaluate roles and responsibilities of the ICU staff in relation to key sleep and sedation decisions.
Methods A multicenter, self-administered survey sent to nurse managers of adult ICUs across 10 countries. The questionnaire comprised four domains: sleep characteristics of the critically ill; sleep and sedation practices; non-pharmacological and pharmacological interventions used to improve sleep; and the autonomy and influence of nurses on sleeping practices in the ICU.
Results Overall response rate was 66% (range 32% UK to 100% Cyprus), providing data from 522 ICUs. In all countries, the most frequent patient characteristic perceived to identify sleep was lying quietly with closed eyes (N=409, 78%) (range 92% Denmark to 36% Italy). The most commonly used sedation scale was the Richmond Agitation-Sedation Score (RASS) (N=220, 42%) (range 81% UK to 0% Denmark, Cyprus where most ICUs used the Ramsay score). In most ICUs, selection of sleep medication (N=265, 51%) and assessment of effect (N=309, 59%) was performed by physicians and nurses based on collaborative discussion. In a minority of ICUs (N=161, 31%), decisions and assessments were made by physicians alone. The most commonly used (in all countries) non-pharmacological intervention to promote sleep was reducing ICU staff noise (N=473, 91%) (range 100% Denmark, Norway to 78% Canada). Only 95 ICUs (18%) used earplugs on a frequent basis (range 0% Greece, Cyprus, Denmark to 57% Sweden). Propofol was the drug used most commonly for sedation (N=359, 69%) (range 96% Sweden to 29% Canada). Chloral hydrate was used by only 63 (12%) ICUs (range 0% Greece, Cyprus, Denmark, Italy to 56% Germany). Sedation scales were used on a routine basis by 77% of the 522 ICUs. Participants scored nursing autonomy for sleep and sedation management as moderate; median score of 5 (scale of 0 to 10), range 7 (Canada, Greece, Sweden) to 4 (Norway, Poland). Nursing influence on sleep and sedation decisions was perceived considerable; median score 8, range 9 (Denmark) to 5 (Poland).
Conclusions We found considerable across country variation in sleep promotion and sedation management practices though most have adopted a sedation scale as recommended in professional society guidelines. Most ICUs in all countries used a range of pharmacological and non-pharmacological interventions to promote sleep. Most units reported inter-professional decision-making with nurses perceived to have substantial influence on sleep/sedation decisions.

Rutiner i omvårdnad på intensivvårdavdelning av hjärnskadade patienter : Intervjustudie

Bakgrund: Traumatisk hjärnskada (THS) orsakas av våld mot huvud i samband med fallolyckor eller trafikolyckor. Varje år söker 20 000 personer vård på grund av skallskador. Vården för traumatiskt hjärnskadade patienter i Sverige skiljer sig åt, mycket beroende på avstånden som finns till specialistsjukhus, tiden och rätta åtgärder är avgörande faktorer för denna patientgrupp. Syfte: Att undersöka vikten och intensivvårdssjuksköterskors behov av rutiner i samband med vård av patienter med hjärnskador på allmänintensivvårdsavdelningar och på neurointensivvårdavdelningar. Metod: Kvalitativ studie med fokusgruppsintervjuer av tio intensivvårdsjuksköterskor som arbetar på en allmänintensivvårdsavdelning (IVA) och specialistneurointensivvårdavdelningen (NIVA). Resultat: På NIVA finns väl inarbetade rutiner och tydliga riktlinjer nedskrivna. Sjuksköterskornas upplevelse var att det fanns tillräckligt med rutiner, men några rutiner kunde utvecklas. På IVA fanns det inga nedskrivna riktlinjer och inga tydliga rutiner för att vårda denna patientgrupp. Vården och kontrollerna ordinerades av läkare som är i tjänst. Slutsats: Vården kring hjärnskadade patienter är ytterst viktigt då man ständigt måste förebygga sekundära skador/insulter. Rutiner är väl inarbetade på specialistsjukhuset, men vården börjar först på hemsjukhuset på IVA där tydliga rutiner och riktlinjer saknas.

Słownik języka miyako Nikołaja Newskiego: rekonstrukcja oraz analiza etnolingwistyczna rękopisu

Wydział Neofilologii: Katedra Orientalistyki

Panika moralna w dyskursie publicznym. Rosjanie wobec współczesnej imigracji z Chińskiej Republiki Ludowej.

Wydział Nauk Społecznych: Instytut Socjologii