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|Publication number
|Publication type
|Application number
|Publication date
|Dec 9, 1997
|Filing date
|Jun 6, 1995
|Priority date
|May 23, 1989
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|Publication number
|Klaus Habenstein
|Original Assignee
|Behringwerke Aktiengesellschaft
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|Patent Citations (11), Non-Patent Citations (35), Referenced by (15), Classifications (32), Legal Events (9)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a division of application Ser. No. 07/526,001, filed May 21, 1990, now U.S. Pat. No. 5,585,247.
The invention relates to fluorogenic compounds for the detection of hydrolyzing enzymes and the use of the fluorogenic compounds.
Hydrolyzing enzymes, the so-called hydrolases, are responsible in the animal organism for a large number of reactions. A distinction is made here between hydrolases of various functions according to their specificity, such as, for example:
--Esterases, such as, for example, acetylcholine esterase, which hydrolyze carbonyl esters.
--Glycosidases, such as, for example, β-D-galactosidase, which hydrolyze the O-glycosidic linkage of sugars to one another or to alcohols.
--Phosphatases, such as, for example, alkaline phosphatase, which hydrolyze phosphoric acid esters.
--Sulfatases, such as, for example, iduronate sulfatase, which hydrolyze sulfuric acid esters.
Hydrolases belong to the most important enzymes of the animal organism. Their absence or reduced or increased occurrence often indicates serious diseases of the organism. A known example is mucopolysaccharidosis; this recessively inherited disease, for which a distinction may be made between 7 different forms of manifestation, is based on a genetically determined defect of hydrolases, for example of β-galactosidase in the case of Morquio's disease and iduronate sulfatase in the case of Hunter's disease. Morquio's disease can be unambiguously diagnosed, for example, by determination of the β-D-galactosidase level of fibroblasts or leukocytes. The level of another glycosidase, amylase, in the blood or urine is used to diagnose pancreatic diseases. Hydrolyric enzymes are moreover used as diagnostic aids, so-called markers, for example in enzyme immunoassays.
Quantification of hydrolyzing enzymes for diagnostic purposes imposes the condition of highly sensitive and specific detection systems so that even low enzyme concentrations can be determined exactly. The naturally occurring substrates are unsuitable for the detection here, since hydrolysis products are already present in the samples before the test is carried out or the hydrolysis products are very difficult to determine. Synthetic substrates of which the hydrolysis products can be detected by physical or chemical means are therefore used in the prior art. As a rule, the detection is carried out by determination of the amounts of fluorescent or highly absorbing coloured substances released during the hydrolyric reaction. Chromogenic substances indeed have the advantage that they can also be perceived visually, that is to say without apparatus aids, and are thus accessible to direct evaluation. On the other hand, the sensitivity of chromogenic tests which can be achieved even with apparatus aids is not always adequate. The fluorescence measurement technique, which in general allows a signal output and therefore test sensitivity which is greater than that of chromogenic tests by a factor of 103 to be achieved, has therefore been used for some time for high-sensitivity detections. The previous radioisotopes used as labels are therefore increasingly being replaced by fluorescence labels, especially in immunoassays (J. Pharm. Biomed. Anal. 5 (7), 1987, 649-58). The enzyme-amplified fluorescence measurement technique in particular opens up new paths for development of highly sensitive test methods here. However, as reported in the above literature citation, pages 651 and 652, and in Clin. Chem. 25 (3), 1979, 353-355, there are considerable difficulties in the general introduction of this promising measurement method as a result of insufficient fluorophores. Thus, for example, fluorescence dyestuffs of the fluorescein, rhodamine or resorufin type have an exceptionally low Stokes shift (difference between excitation and emission wavelength maximum) of about 20 nm. Although fluorophores of the umbelliferone type have a Stokes shift of about 70 nm, they emit at too short a wavelength (450 nm), so that the intrinsic fluorescence of sample constituents and of carrier and vessel materials at about or above 400 nm falsifies the measurement results. Still other fluorophores do not have the hydroxyl group in the molecule which is essential for the above hydrolase substrates.
The present invention was therefore based on the object of providing fluorogenic compounds for the detection of hydrolyzing enzymes, hydrolysis of which leads specifically and highly sensitively to measurable fluorescence signals with maxima at about or above 500 nm. This object is achieved according to the invention by a compound of the general formula I as the fluorogenic compound ##STR1## in which X is O or S,
R is a radical which can be split off by enzymatically catalyzed hydrolysis,
R1 is H, C1 to C4 alkyl or phenyl, which can be substituted by 1 to 3 --CH3, and
A has a molecular structure which lengthens the mesomerism of the benzoheterocyclic ring system, in particular includes aromatic or heteroaromatic and also substituted and optionally benzo-fused 6- and 5-membered ring systems which can also attack in the 2-position of the benzoheterocyclic radical via one or more multiple bonds, or an electron-withdrawing group, such as CN or CF3.
Preferred compounds of the formula I are those in which
A is a phenyl or naphthyl radical, which is optionally substituted by 1 to 3 electronegative groups, such as, for example, --CN, --CF3, thiazole or benzothiazole,
is a thiazole, oxazole, benzothiazole or benzoxazole radical which is optionally substituted by 1 to 3 electronegative groups, such as, for example, --CN or --CF3.
Particularly preferred compounds are those in which
A is phenyl or phenyl which is substituted by up to 3 --CN, --CF3, thiazole or benzothiazole radicals.
Compounds which are furthermore preferred are those in which
R is a carboxylic acid radical, a sugar radical, a phosphoric acid radical or a sulfuric acid radical, and particularly preferred compounds here are those in which the carboxylic acid is a C1 -C10, and especially preferably a C1 -C3, aliphatic carboxylic acid, an amino acid, especially preferably an alanine, which can also be derivatized, or an aromatic carboxylic acid.
Compounds in which the sugar is an α- or β-glucose or an α- or β-galactose are furthermore particularly preferred. Compounds of the formula I in which R1 is hydrogen are also preferred.
Surprisingly, it has been found that the fluorogenic compounds according to the invention react with hydrolysates of varying specificity, depending on the radical R selected. The excitation and emission maxima of the compounds are shifted towards shorter wavelengths by 60-90 nm in comparison with those of the associated free fluorophores. The Stokes shift between the particular excitation and emission maxima is up to 150 nm. The compounds according to the invention are prepared in a manner which is known per se by processes analogous to the literature from the fluorescence dyestuffs (literature: Org. Reactions, 6, 1951, Chapter 8 and Heterocyclic Compounds, Volume 5, 1957, Chapter 6) and the particular enzymatically degradable radical. Fluorogenic substrates for the detection of phosphatases and sulfatases are thus prepared by reaction of the fluorophore with suitable acid halides (for example phosphorus oxychloride or chlorosulfonic acid) by processes which are known per se. The carboxylic acid esters can be prepared from the carboxylic acid chlorides in a corresponding manner.
To prepare glycosides, the fluorescence dyestuffs are glycosylated by processes which are likewise known per se. The preparation of β-galactosides can be carried out, for example, by reaction of the corresponding fluorescence dyestuffs with α-D-acetobromogalactose and subsequent deacetylation. Glycosylation processes are described, for example, in Angew. Chemie 98, 1986, 213-236 and the literature quoted therein. Examples of glycosides which are obtainable by the processes mentioned are, for example, α- and β-D-galactopyranosides, α- and β-D-glucopyranosides and oligosaccharide derivatives derived therefrom and having 2-10, preferably 3-7, monosaccharide units.
The fluorogenic compounds according to the invention are used for the detection of various hydrolyric enzymes, for example carboxyl esterases, phosphatases, sulfatases and glycosidases. To detect the enzyme, the fluorogenic substrate is made available in a reagent mixture which contains any necessary buffer substances, stabilizers, activators, solubilizing agents, auxiliary enzymes or other auxiliary chemicals. These auxiliaries depend specifically on the reaction conditions, such as, for example, on the nature of the enzyme to be determined, as well as the substrate. The particular auxiliaries to be used are familiar to the expert. The various individual chemicals can be present side by side in a solution if they are of sufficient stability and chemical compatibility, but they can also be mixed with one another just before the detection reaction. After the reagent mixture has been brought together with the hydrolyzing enzyme to be detected or the biological sample to be tested the actual detection of the hydrolytically active enzyme takes place by measurement of the fluorescence of the fluorescence dyestuff released from the corresponding fluorogenic substrate by the enzyme-catalyzed hydrolysis.
A reaction in solution, which can be carried out directly in a cell if appropriate and can be immediately evaluated by subsequent fluorescence photometric signal determination, is preferred in this context. Application of the fluorogenic substrates according to the invention to matrix-like, for example fibrous or film-like, reagent carriers which allow fluorescence photometric signal determination after the reaction has been carried out is likewise preferred.
The use of the compounds according to the invention as a substrate for enzyme immunoassays in which the hydrolase to be detected is covalently bonded to one partner of a specific bonding pair, for example to an antibody, a nucleic acid, a hormone and the like, is furthermore preferred. The conjugate can be free or in a form bonded to a solid phase here. Examples of solid phases are particulate phases, preferably latex particles or magnetizable particles.
The fluorogenic compounds according to the invention can be provided in various forms. Embodiments which already contain a combination of the fluorogenic substrates according to the invention with additional reagents needed for the test are preferred here. Examples of these are solutions, reagent tablets, powder mixtures or lyophilisates, if the detection reaction is subsequently to be carried out in solution. Alternatively, the fluorogenic substrates can likewise be absorbed onto an absorbent carrier or incorporated into hydrophilic and hygroscopic films, together with the additional reagents needed for the test.
The invention is illustrated by the following examples.
0.005 mol of 4-aminoresorcinol hydrochloride were dissolved in 7.5 ml of benzoyl chloride, while heating, and the solution was then boiled under reflux for 7 hours. The excess benzoyl chloride was subsequently distilled off in vacuo, 10 ml of ethanol were added to the residue and the mixture was boiled up briefly and, after cooling, rendered alkaline with 10M NaOH solution. The alkaline solution was introduced into 200 ml of water and brought to pH 3 with concentrated hydrochloric acid, using a pH-meter. The crystal mass which precipitated here was filtered off with suction and recrystallized from 15 ml of toluene. The dried product (250 mg) was uniform according to thin layer chromatography (silica gel plate, ethyl acetate/glacial acetic acid 24:1).
Melting point=214� C. (decomposition)
______________________________________Fluorescence data: Excitation (nm) Emission (nm)______________________________________acid 308 480basic 370 480______________________________________
1.5 ml (10 mmol) of 4-trifluoromethylbenzoyl chloride were heated to 190� C. in an oil bath and 1.6 g (10 mmol) of 4-aminoresorcinol were added in portions. After 1 hour the reaction mixture was introduced into 100 ml of 10% strength sodium carbonate solution and heated. The unreacted acid chloride was hydrolyzed during this procedure. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel 60, ethyl acetate or chloroform/glacial acetic acid 9:1).
______________________________________Fluorescence data: Excitation (nm) Emission (nm)______________________________________basic 380 520______________________________________
The following products were obtainable by an analogous routes
______________________________________2-(4'-cyanophenyl)-6-hydroxybenzoxazole (CPHB)basic 390 5402-(4'-pyridyl)-6-hydroxybenzoxazolebasic 370 520______________________________________
Reference is made to Bull. Chem. Soc. Jpn. 36, 332 (1963) for the preparation. Starting from commercially available 2-cyano-6-methoxybenzothiazole, the desired product was obtained by acid hydrolysis (Methods in Enzymology, Volume 13 (1986), page 20-21).
Yield (500 mg of methoxy compound employed): 130 mg of thin layer chromatography-pure product, mobile phase: chloroform/ethyl acetate 20/5.
Melting point: 208� C., decomposition.
______________________________________Fluorescence data: Excitation (nm) Emission (nm)______________________________________basic 380 500______________________________________
A.) Galactosylation of 2-(4'-cyanophenyl)-6-hydroxybenzoxazole (CPHB)
0.01 mol of CPHB, 0.01 mol of acetobromogalactose, 5 mmol of Ag2 O and 0.01 mol of calcium sulfate�1/2 H2 O were heated under reflux in 100 ml of dried toluene in a dry apparatus. (Quinoline can be added to the mixture as a reaction accelerator).
The reaction was carried out with exclusion of light and water (calcium chloride drying tube on the condenser), while stirring.
After a reaction time of 2 hours, the reaction was checked by thin layer chromatography. The CPHB acetogalactoside formed appeared as a dark blue fluorescent spot.
Mobile phase: chloroform/ethyl acetate 4/1 or chloroform/acetone 4/1.
If the reaction was incomplete, further acetobromogalactose and Ag2 O were added and the mixture was again heated under reflux.
When the reaction had ended, the reaction solution was filtered, the filter was washed with toluene and the washing toluene and mother liquor were combined and evaporated on a rotary evaporator at a maximum bath temperature of 40� C. under about 70 mbar.
The residue was dried in a vacuum drying cabinet at room temperature under 200 mbar. The impure product was purified by column chromatography. Separating agent: silica gel 60 or Sephadex RP8. Mobile phase: chloroform/ethyl acetate 4:1. The purified CPHB tetraacetylgalactoside was dried and its purity was checked by thin layer chromatography.
B.) Deacetylation of the acetylglycoside formed
The deacetylation was carried out in anhydrous methanol using sodium methylate. For this, the acetylglycoside (2 mg/dl) was dissolved in methanol and a little sodium methylate was added (5-10 μl of a 30% strength methanolic solution). The course of the deacetylation was monitored by means of thin layer chromatography. Mobile phase: chloroform/ethyl acetate 4:1 and chloroform/methanol 3:1.
When the reaction had ended, the solution was rendered neutral to weakly acid with the ion exchanger Dowex 50�8. The purity was checked by thin layer chromatography. Mobile phase: methanol/chloroform 1:3. The solution was then concentrated and the residue was dried.
C.) Glucosylation of CPHB
0.01 mol of Brigl's anhydride and 0.01 mol of CPHB were heated under reflux in 100 ml of toluene, while stirring and with exclusion of water. Reaction time: 24-48 hours
The reaction was checked by thin layer chromatography. Mobile phase: chloroform/ethyl acetate 4:1.
The deacetylation was carried out as described under B. A β-glucoside with a weak dark blue fluorescence was obtained.
50 mg of a benzoxazole derivative from Example 2 were dissolved in 10 ml of THF, and 1 ml of acetic anhydride and 100 μl of pyridine were added. After a reaction time of 1 hour, the reaction mixture was separated on preparative thin layer chromatography plates. Mobile phase: chloroform/glacial acetic acid 9:1.
The separation showed the acetate with a dark blue fluorescence in addition to unreacted starting substance with a whitish fluorescence. The acetate was obtained by elution of the corresponding silica gel zone.
0.01 mol of 2-phenyl-6-hydroxybenzoxazole were dissolved in 20 ml of methylene chloride with 2 ml of diazabicycloundecene and the solution was cooled to -4� C. This solution was slowly pipetted into a mixture of 20 ml of pyridine and 5 ml of phosphorus oxychloride at -4� C. and the mixture was left to stand at -4� C. for 2 hours, with occasional swirling. The reaction mixture was then introduced into 500 ml of 5% strength sodium bicarbonate solution and the mixture was stirred intensively for 1 hour and then freed from unreacted starting substance by several extractions with ethyl acetate. The aqueous solution was brought to pH 3 and concentrated to dryness and the desired phosphate was extracted from the salt mixture using methanol. Further purification was by chromatography (preparative thin layer chromatography, mobile phase ethyl acetate/water/methanol 100:25:30).
0.01 mol of tosylalanine, 1.1 mmol of hydroxybenzothiazole and 1.1 mmol of dicyclohexylcarbodiimide (DCCI) were dissolved in succession in 2 ml of THF and the solution was stirred at room temperature for 30 minutes. 0.1 mol of CPHB (Example 2) was then dissolved in 1 ml of THF, the above solution was added and the mixture was stirred for 2 hours. A further 2 mmol of DCCI were then subsequently metered in and the reaction mixture was left to stand overnight.
The dicyclohexylurea formed was removed by centrifugation and the clear tetrahydrofuran solution was poured into ice-water. The aqueous phase thus formed was extracted three times with 50 ml of ethyl acetate and the combined extracts were concentrated in vacuo, after drying over sodium sulfate.
The crude product was purified using a preparative thin layer chromatography plate (E. Merck). Mobile phase: ethyl acetate
The methanolic extract, obtained in accordance with Example 7 from the preparative thin layer chromatography plate, of our desired product was applied to a filter paper preimpregnated with a 0.1 mol boric acid-hepes buffer, pH 7.5 and the filter paper was dried. Leukocytes in urine in a concentration of about 100 L/μl were indicated by the occurrence of a yellow fluorescence within 15 seconds after the sample had been dripped onto this indicator paper.
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|U.S. Classification
|436/518, 548/217, 435/805, 548/179, 435/18
|International Classification
|Cooperative Classification
|European Classification
|Sep 4, 1997
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text:
About BHEARD Program
The United States Agency for International Development (USAID), in partnership with the Association of Public and Land-grant Universities (APLU) and the International Maize and Wheat Improvement Center (CIMMYT) in Mexico, has selected Michigan State University (MSU) to implement the Feed the Future Borlaug Higher Education for Agricultural Research and Development (BHEARD) Program. Honoring the legacy of Nobel Peace Prize Laureate Norman Borlaug, this is a major new effort to increase the number of agricultural scientists and strengthen scientific institutions in developing countries.
The program will support long-term training of agricultural researchers at the master's and doctoral levels and will link scientific and higher education communities in Feed the Future countries and the United States.
The program launched with Bangladesh, Cambodia, Ghana, Mozambique, and Uganda, with Malawi, Mali and South Sudan joining in the second cohort and Kenya, Liberia, and Rwanda joining in the third cohort. With future cohorts, the program may expand to include other Feed the Future countries. The design of training programs will be grounded in a strategic planning process facilitated in targeted research institutions. The BHEARD program will focus on training a cadre of BHEARD Fellows at the M.S.[1] and Ph.D. levels, which is indispensable for creating scientific capacity. However, the BHEARD program allows for a broader set of human and institutional capacity‐building, particularly if additional USAID mission or leveraged funds can be mobilized.
The BHEARD program will also support the development, testing and evaluation of new models of capacity development. APLU will develop a knowledge‐sharing system to identify innovative and effective mechanisms for human and institutional capacity development, and to promote shared learning across programs.
[1] M.S. trainees are placed in regional institutions (e.g. within Africa)
Proposed Calendar for Degree Training, 2016 Fall
June 2015 – July 2016: Strategic planning, training design, preparatory work
- Identification of participating institutions by country (USAID, in consultation with MSU)
- Competitive identification of trainee pool (USAID, with local institutions and MSU)
- Competitive identification of U.S., local or third‐country universities to manage training (MSU)
- Selection of universities for training (USAID, in consultation with MSU and local institutions)
- Admission of selected candidates by identified U.S. universities (MSU)
- Coordination of visa application process, medical exams, pre‐departure arrangements (USAID)
- Sub‐agreements with universities to manage the training programs (MSU)
- Possible initiation of a broader strategic planning process by host institution(s) who lack strategic plans
August 2016 – May 2018:
- M.S. and Ph.D. candidates begin degree training; take required courses and plan research
June 2018 – August 2018:
- M.S. students return home for in‐country research, write‐up, defense (finish by late 2018 or early 2019)
- Ph.D. students return home for summer pre‐dissertation or initial dissertation research visit
August 2018 – August 2019:
- Ph.D. students complete final year of courses and exams; prepare research proposal
August 2019 – August 2020:
- Ph.D. students return home for in‐country research, write‐up, defense (finish by mid-2020)
Roles of MSU and USAID Missions
The BHEARD program will be implemented by MSU in close partnership with USAID/BFS, USAID missions, APLU, and CIMMYT. Within that general collaborative framework, a given institution will take lead responsibility for implementing each activity, in close consultation with the other partners, as follows:
- With guidance from USAID missions on priorities, MSU will undertake a process of identifying the local institutions to be supported through M.S. and Ph.D. training and other forms of capacity-building, and of identifying the candidate trainees.
- MSU will manage the process of soliciting expressions of interest from U.S., local, or third‐country universities to implement the training. In concert with USAID/BFS, MSU will conduct an initial technical review of the expressions of interest and communicate a synthesis of that review to USAID missions, along with other summary materials on the university proposals.
- Drawing upon the technical review synthesis provided by MSU, and taking into account preferences of the candidate trainees, USAID missions and target local institutions will make the final decisions in prioritizing the universities and graduate programs that have been proposed to host the candidate trainees.
- Once universities have been selected, MSU will coordinate all aspects of student placement in the appropriate universities, including advice on options for English language training, advice on preparation for and timing of GRE and TOEFL examinations, managing the admission process, initial entry and review of trainee information through the TraiNet system, arrangements for students to travel to the training site, and preparation of sub‐agreements with universities where candidates will be placed.
- USAID missions will facilitate the in‐country visa application steps, medical examinations, and other pre‐departure arrangements, with assistance from MSU in contacting the students.
- During the academic training phase, MSU will monitor and support university training program implementation, provide guidance to mentors on how to support the students, and monitor the progress of candidates in their degree programs.
BHEARD Management Team
This effort is led by three MSU co-directors - Eric Crawford (Agricultural, Food, and Resource Economics; Food Security Group), Fred Derksen (Food Science and Human Nutrition), and Anne Schneller (Agricultural, Food, and Resource Economics). Other project PIs include Mywish Maredia (Agricultural, Food, and Resource Economics). Mitchell Meyle is the Fiscal Officer, Jessica Leigh is the Progam Manager and Matt Milkovich is Communications Manager. Key USAID/BFS personnel are Eric Witte (AOR) and Karen Duca (Activity Manager).
Contact Information
- BHEARD Program
Web site: http://bheard.anr.msu
Phone: +1‐517‐355‐3449
Mailing address: BHEARD Program, Michigan State University, 446 W. Circle Drive, Morrill Hall/Room 401, East Lansing, MI 48824‐1039 USA
Karen Duca
Phone: +1‐202‐712-4203

subset: commoncrawl


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text: Hi guys this might seem a little strange but I'm trying to find the answer to a question for a customer ( I work for a network ) Galaxy -s, able to navigate using google maps, but does not get voice commands for the turn by turn navigation. I've checked the really simply stuff (is it on mute, navigation volume on max). When I first got my android phone I had to download a voice app from the market place but I can't now find this on my phone to advice the guy. Can anyone help me and therefore my customer ? Hoping you might take pity on a call centre working trying to do his best for a customer. Cheers.


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June is Stroke Month, and Sunnybrook Health Sciences Centre has been involved in two new stroke-related initiatives to be unveiled this month.
Fitting with this year's theme, Sunnybrook's Stroke Unit: Leading Innovation and Interprofessional Care, the hospital's new 16-bed stroke unit officially opens on June 5. This will mark a significant change in how stroke care is delivered at Sunnybrook.
"Hospitals with stroke units provide specialized care that improves patient outcomes. Patients will now have access seven days a week to an interprofessional team that includes nurses, physiotherapists, occupational therapists, speech-language pathologists, and social workers, with a focus on earlier integration of rehabilitation into care," says Beth Linkewich, Regional Director, North&EastGTA Stroke Network at Sunnybrook.
Having this enhanced access to care can shorten the length of a hospital stay for persons with stroke, and improves their chances of making a meaningful recovery upon discharge.
Coinciding with Sunnybrook's stroke unit opening, and to support system-wide changes in stroke care in Toronto, the launch of the Toronto Stroke Network's Virtual Community of Practice (VCoP) is geared toward bringing together professionals working with stroke patients across the GTA to share knowledge and resources.
"The VCoP is an interactive forum that brings together healthcare professionals, researchers, students - anyone working in stroke," says Joanne Fortin, Regional Education Coordinator, North&EastGTA Stroke Network at Sunnybrook.
The launch of these initiatives set the stage for system-wide changes in access and delivery of stroke care in Ontario, and has established Sunnybrook as a leader in implementing these best practices. "People from other hospitals across Ontario are interested in how we've accomplished seven days a week rehab on the stroke unit," says Linkewich.
The public can learn about the stroke unit and meet members of the team at a special event on June 12 at 7pm in the McLaughlin Auditorium. Check the special events calendar at www.sunnybrook.ca for more details. An information table will also be set up from June 13 to 15 near the M1 main entrance of the hospital.
A Special Information Feature brought to you by Sunnybrook


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More than any single show, the most significant happening in live music in Portland this year was, to my mind, the door to shows being opened a bit further, a bit more often, to people under 21 thanks to long-overdue Oregon Liquor Control Commission Minor Postings rule changes. Set against that triumphant backdrop, here are six of my favorite local shows of 2008.
1. Chromatics at Rotture (3/14/08)
Night Drive, the Chromatics' 2007 album of spacious doom disco, is the fictitious soundtrack to a nonexistent 1980s highway noir film of the same name. The first track is a skit in which singer Ruth Radelet calls her boyfriend after leaving an all-night dance party whose bass still booms, blocks away, in the background. Well, in my mind this was that party, so fully did it inhabit the Chromatics' dance-the-dreary-night-away aesthetic of 107-BPM elegant despair. Surrounded by admirers in a room that beatmaker Johnny Jewel decorated with balloons and blue-and-pink wall tiles, the Chromatics' energetic, four-piece live incarnation let a smile crack the unwaveringly sexy, sulky expression they wear on record, turning a memorable dance party into the best show of the year.
2. Starfucker at the Doug Fir (9/18/08)
Starfucker was the most consistently enjoyable and life-affirming Portland band in concert this year. This show stands out not only for the performance, but also for two circumstantial reasons: First, it was Starfucker's highly anticipated album release show, a milestone by which one could measure and marvel at how far this little indie-pop band had come in just over a year. Second, Starfucker's most devout fans—Portland music lovers under 21—were able to see a local band at the Doug Fir for the first time.
3. Third Angle at Keller Fountain, Pettygrove Park, Lovejoy Fountain, and Source Fountain (9/14/08)
While the logic linking the postmodern dance, landscape architecture, and contemporary classical music featured in Third Angle's itinerant, interdisciplinary contribution to this year's TBA Festival may have been complex, it was anything but contrived. With this outdoor, site-specific, collaborative ode to downtown Portland's archipelago of pioneering public spaces designed by Lawrence Halprin, our city's premier new music chamber ensemble demonstrated the vitality and under-acknowledged accessibility of 1960s Bay Area composers Riley, Subotnick, and Oliveros, and of Third Angle itself.
4. Explode into Colors at Rotture (9/5/08)
Even with major names lending their glow to MusicfestNW this year, the highlight of my festival experience was happening upon this rhythm-driven, all-female, neo-primitivist trio that connects the dots between Confusion Is Sex and Arular. Playing off her bandmates' minimal melodica, vocals, keyboards, percussion, and guitar, Lisa Schonberg struck me as Portland's most inventive drummer.
5. Eskimo and Sons at Hotel deLuxe rooftop (8/7/08)
Opening for an outdoor screening of Flight of the Navigator on a downtown rooftop at dusk, orchestral twee tribe Eskimo and Sons played what everyone singing along knew would be one of their last shows. Eskimo and Sons had a knack for covers, and riveting vocalist Danielle Sullivan never sounded finer than she did this evening on "Let 'Em In" and "Man on the Frontier." It was a fraught but gorgeous thing to watch the sun set on a beloved city and band simultaneously.
6. Bob Jones Ensemble, Grandfather Claws, Portland, Nick Delffs at Witch's Castle in Forest Park (9/7/08)
A late summer field trip to a crumbling stone building in Forest Park, and an instrumental piece for six acoustic guitars and e-bow in the front niche; a noisy tape loop set sourced from Portland street sounds in the little black cavern; a piece of Jodorowsky-worthy musical theater featuring twins, gongs, and toy piano up top; a solo set of roots rock 'n' roll down below. I like to believe that something like this happens every day in Portland and I'm just not aware of it.


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THE Government yesterday promised to stand by the United States in the campaign against Saddam Hussein despite a wave of protests from the Labour Party.
As tension rose, Baghdad said that it had fired missiles at American and RAF fighters over southern Iraq yesterday, "forcing them to retreat". It also claimed that the allied bombing raid on Friday had killed three people and wounded 30.
George Galloway, the Left-wing Scottish MP, landed in Baghdad on a "solidarity visit" and compared the bombing to "Hitler marching into Czechoslovakia". He said: "What the British and American governments are doing is reckless, lawless and murderous. For every bomb that is dropped, Saddam is getting stronger."
The Government brushed aside criticisms. Tony Blair said: "We had to respond to reduce the chances of one of Saddam's missiles downing a British plane. Operations such as the one on Friday night would not be needed if Saddam stopped attacking us. But as long as he does, I will continue to take the steps necessary to protect our forces and to prevent Saddam from once again wreaking havoc, suffering and death."
Friday's raids against radar installations and air defences south of Baghdad were the first time in two years that the increasingly isolated allies have attacked close to the capital. As thousands marched in Baghdad in support of Saddam, the raids were condemned by Russia, China, France, which is keen to sign contracts with Iraq, and Turkey, a key Nato ally in the Gulf war.
Brian Wilson, the Foreign Office minister responsible for the Middle East, said that Labour should support action to protect RAF and American pilots. He said: "It has never been a credential of the Left to support dictators and weapons of mass destruction."
Robin Cook, the Foreign Secretary, said on BBC1's Breakfast with Frost: "Some of those who ask why we do it would be the very people who would be asking why are we not doing more if we were to abandon it and Saddam was to go back to bombing his own people from the air."
But Bill Morris, the general secretary of the transport union, called for the United Nations to reassess its policy on Iraq. He said: "Sanctions have been running for some 10 years and Saddam Hussein is still in office. You can't bomb a country out of existence."
Glenys Kinnock, the Labour MEP, acknowledged that Saddam was a "terrible tyrant" but expressed concern about the bombing. "I think many people are a little confused about why at this particular time action of this kind was necessary and if there are civilian casualties, as Saddam Hussein claims."
There were calls from both sides of the Commons for the recall of Parliament from its half-term break, which begins today, to discuss the crisis. Tam Dalyell, the Labour MP who has long opposed British policy in the Gulf, accused the Prime Minister of failing to inform the UN about his military plans.
He said: "Not only Russia and China but, for heaven's sake, France as well have condemned our country over this. Parliament should be recalled early next week. We need explanations and we need them at once." Iain Duncan Smith, the shadow defence secretary, said that a recall was necessary to discuss the growing threat posed by Iraq.


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The problem with shotguns is that the ammunition is huge and awkward. As a result, the traditional way to keep a shotgun running has been a tube magazine running along the bottom of the barrel. It works well for things like skeet and hunting, but when you get into "tactical" uses or competition shooting the game becomes a test of who can stuff rounds in their gun faster. The VEPR-12 semi-automatic magazine fed shotgun from Molot seems designed to change the game.
Semi-auto AK-style shotguns aren't new, and we've reviewed them before on the site. My Saiga-12 shtogun review comes to mind, in which I detailed exactly why the gun was a piece of crap and the fan boys retorted with "well, obviously you need to fix the gun before you test it! You didn't give it a fair test!" To which I reply that guns are tested in factory condition, and a gun that needs to be "fixed" before you can actually use it is a pretty piss poor gun. With the VEPR-12, it looks like some of those problems have been fixed.
Most obvious is probably that the gun comes from the factory configured the way you'd want it. Instead of the traditional stock there's a skeletonized tubular stock and a pistol grip. There's a full length rail along the top of the receiver for your optics and other gubbins. And instead of rocking the magazines into place like on a standard AK, they simply slot straight into the receiver.
The bolt is held open after the last round fires. No longer do you have to count your rounds and then muscle the new magazine into place with the bolt forward, it locks open just like an AR-15. It's much more convenient and a lot quicker to reload.
The effect of these changes is that the gun is a lot easier to handle straight out of the box. reloads are quicker, movement is much more fluid, and the manual of arms is much more similar to the AR-15 rifle. But still, there are problems.
First on the list of gripes is the safety. Instead of being a straight AK-style safety, Molot has added a flap that extends down near the pistol grip with the idea that you can then use your trigger finger to manipulate the safety. It's good in theory, but in practice it's annoying and somewhat sharp. I'm not a big fan of thin pieces of metal jutting out off a firearm, especially near my hand, and especially when I'm going to fire slugs through it. It made firing the gun somewhat uncomfortable for me.
In the same area is the bolt release. Positioned about in the same spot that the bolt hold open tab was for the Saiga-12 shotgun, the tab now works as a bolt release allowing you to press this one tab and let the bolt slide home. Ignoring for a minute that it's inside the trigger guard which is a huge safety concern to some people, the role reversal means that there's no easy way to lock the bolt open when the gun runs dry. You need to insert and empty magazine and then rack the action back, which is an extra step for something so crucial.
The sights are nice, and the full length rail along the top is a very nice touch, but it would be more useful if the stock wouldn't get in the way so much. There's a rubber pad on the stock that wallows from one side to the other much like the cheek pad on a SVD rifle, and while it seems like a good idea in practice it tends to move around quite a lot and just get in the way. With the cheek pad in place I couldn't get a good sight picture, and with it removed I couldn't get any kind of cheek or even chin weld on the stock. It's annoying and frustrating, and if this were my gun that would be the first thing to go.
There are some really nifty features on this gun, and it definitely is an improvement from the Saiga-12, but I'm running into the same problem that I ran into with the Saiga: what do you use it for?
If you're thinking about home defense, that's probably the best application I could think of for the gun. Get yourself some higher capacity magazines and prop it by the bedroom door loaded with buckshot and you're nearly guaranteed to kill whatever busts down your door. But the form factor of the magazines limit your capacity, and are you really going to take the time to strap on extra shotgun magazines before checking on what that noise downstairs was?
The gun suffers from the same parallax issues that the Saiga had, since the sights are over an inch above the top of the barrel, and if you're spending this kind of money on a dedicated trap or skeet gun there are much better suited choices out there.
If you're running in open division then this is definitely an option, but consider that for the same price you can have a Mossberg 930 with an XRAIL and have 22 rounds at your disposal before needing to reload, and still have a normal shotgun in every other way. The biggest magazines I've seen fro the VEPR-12 are 12 round magazines, and those require compliance with that pesky Federal statute 922(r) before using them in your gun. Even with the availability of Saiga-12 and VEPR-12 shotguns, the pro 3-gun shooters still don't use them.
The VEPR-12 is definitely an improvement over the Saiga-12, but as far as I can tell it's still a solution looking for a problem. A nifty range gun no doubt, but if I'm spending this much money I'd like to actually be able to use it for something.
VEPR-12 Shotgun
Caliber: 12ga
Barrel: 19 inches
Capacity: 4+1


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Dennis Thompson m.Mary Thompson 1826
Looking for parents of Robert Thompson b c 1807, Darke Co.,Ohio, married Mary Thompson,
dau. of Robert and Mary Thompson in Preble Co. in 1826.Mary died 1836 shortly after
giving birth to Elisha Penny Thompson and
Dennis m. Sarah Biggs in late 1836.Dennis
died 1839 or prior and Robert Thompson apptd.
guardian of children. Other children:Isaac
Garrison Thompson, William, Nancy E., Zimri L.


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With technology found on 98 percent of the world's smartphones, AppsFlyer is the most widely used and trusted mobile attribution and marketing analytics company. The world's leading marketers look to AppsFlyer for unbiased data and cutting-edge tools to attract, engage and retain app users.
AdStage connects marketers quickly and easily to their data across paid search, paid social, web analytics and custom business metrics to gain insight into their campaign performance and take action at scale.
Adlucent is a performance-based digital advertising agency that helps retailers grow online and offline revenue efficiently through a mix of data-driven paid search, product ads, and display services.
Singular enables data-oriented marketers to connect, measure, and optimize siloed marketing data, giving them the most vital insights they need to drive ROI.
Targeto Inc.
Targeto provides an omnichannel cookie-less marketing platform for digital marketers and agencies to create and manage ad campaigns to retarget existing as well as prospective customers on the web and mobile devices.
Brax Software
Brax enables native advertising at scale by providing a single platform for bulk management, unified reporting and rule-based goal optimization across sources. Combine campaign performance with existing engagement, conversion and sales data to automate budget, bid and publisher adjustments.
PMX Agency
PMX Agency is a global independent marketing agency that leads with a data-driven, consumer-centric approach to brand and performance advertising. We provide integrated solutions with specializations in paid search, SEO, affiliates, comparison shopping engines, performance display and paid social.
Bidtellect is the leading paid content distribution platform providing marketers with one platform to execute Native campaigns across all formats and devices including text, imagery and video.
At our core, PulsePoint is a company about making ads matter. We create next-generation programmatic solutions for advertisers and publishers to simplify the marketing process of connecting the right consumer, with the right message, at the right time, in the right environment.
CyberZ has been providing mobile attribution and marketing analytics services in countries throughout the world, including the United States of America, Japan, Korea and Taiwan. In February 2011, CyberZ launched a smartphone advertising analytics tool called F.O.X「Force Operation X」. F.O.X enabled advertisers to measure their smartphone advertising effectiveness for the first time in Japan.
The TUNE Marketing Console unifies measurement across discovery, acquisition, retention, and engagement. Mobile marketers trust TUNE every day to easily find actionable insights and streamline their workflow, helping them focus on driving results.
Adjust combines attribution for advertising sources with advanced analytics and store statistics such as rankings, ratings and reviews.
Kochava (www.kochava.com) offers unique, holistic and unbiased app measurement. From attribution and analytics to fraud abatement and optimization, the Kochava platform provides precise, real-time visualization of campaign and app performance.
AdParlor is the largest social and video advertising platform on the planet, helping large brands and agencies run complex campaigns across multiple social channels like Facebook, Twitter, Instagram and YouTube.
Zemanta One is the only cross-channel media buying platform specifically designed for the promotion and distribution of marketing content.
ESV Digital
ESV Digital (formerly eSearchvision), is a digital performance and consulting agency, specialized in the collection, analysis and the treatment of data in order to improve the marketing performance of our clients. Our agency is structured around 3 complementary axes of expertise: Data Analytics, Digital Consulting and Marketing.
YP is a leading local marketing solutions provider in the U.S. dedicated to helping local businesses and communities grow. YP's flagship consumer brands include the popular YP app and YP.com, which are used by more than 70 million visitors each month in the U.S.
hibu is a leading provider of digital marketing solutions for small businesses. We've helped over a million local businesses get found by their customers and drive leads to their doorstep. Why choose us? Local Experience. Digital Expertise. One-on-one dedicated service. That's what makes us better.
Marin Software
Marin Software Incorporated provides a leading cross channel performance advertising cloud for advertisers and agencies to measure, manage and optimize more than $7 billion in annualized ad spend across the web and mobile devices.
Fiksu is a data-fueled mobile marketing technology company that connects brands, agencies, and app advertisers to precise audiences throughout the customer journey. Fiksu's mobile audience platform combines a massive data set with powerful segmentation tools for awareness, user acquisition, and re-engagement campaigns.
CDK Global
With more than $2 billion in revenues, CDK Global is the largest global provider of integrated information technology and digital marketing solutions to the automotive retail industry.
Driven Local
Driven Local, an award winning digital agency - offers Search Engine Marketing, Display Advertising, Ad Retargeting, Search Engine Optimization, Social Media Management, Responsive Web Design, AnimatedVideo Production, Local Listings Optimization, and more.
ChannelAdvisor (NYSE: ECOM) is a leading provider of cloud-based e-commerce solutions that enable retailers and branded manufacturers to integrate, manage and optimize their merchandise sales across hundreds of online channels including Amazon, Google, eBay, Facebook and more.
Dealer.com is the retail automotive industry's most trusted, inventive, and adaptable provider of digital marketing solutions. Its collection of convention-crushing products and services encompasses advertising, websites, and the increasingly vital digital retailing category, and includes deep integrations with other solutions, including Inventory, CRM, and Sales and F&I.
Tealium is the leader in enterprise tag management and real-time customer data solutions. Tealium enables organizations to power better, more meaningful interactions with their customers across any digital touch point.
Ensighten is the leader in omni-channel data and tag management, helping global brands change the way they collect, own and act on their customer data across all digital touch points.
LBN Partners is a digital media agency utilizing a proprietary platform driving local engagements through search engine advertising. With LBN, clients can gain 3-5 times more search exposure, drive more qualified customers into stores and view in-depth metrics through our client reporting suite.
Sprinklr is the most complete enterprise social media management technology in the world, purpose-built for large companies to drive business outcomes and manage customer experiences across all touch points.
ReachLocal is an award-winning digital marketing company that helps local businesses solve the unique challenges of their online marketing. ReachLocal's total digital marketing system includes search engine advertising, display advertising, mobile advertising, websites, SEO, social and reputation management, and other marketing and lead management software tools.
A digital marketing leader since 1996, Didit provides full-service online advertising and marketing services with award-winning expertise and innovation.
Dex Media
Partnering with Dex Media®, is like getting an entire marketing department working for you. With over 3,000 employees dedicated to our clients' success, we partner with small and medium-sized businesses nationwide to help get them more customers and more sales.
Kenshoo is the global leader in agile marketing software. Kenshoo's mission is to empower every marketer in the world with technology to build brands and generate demand across all media.


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You are here: Household
2016-02-16 11:37:11 —
Healthy House, Healthier Body
Though factors like exercise, lifestyle, and age certainly play a huge role in our bodies' natural immunities, your environment can also help or hurt your chances of getting sick.Read More
2014-08-20 08:32:56 —
The Importance of Grooming Your Puppy
Grooming is not just about maintaining your dog's level of cleanliness, and it is not just about keeping your dog good-looking. Grooming is about maintaining both your dog's physical health as well as her appearance.Read More
2014-08-20 08:25:40 —
Why some people are mosquito magnets
Some folks seem to be magnets for mosquitoes, while others rarely get bitten. What makes the little buggers single you out and not the guy or gal you're standing next to at the Memorial Day backyard barbecue?Read More
2014-08-20 08:13:37 —
Lighten Your Load
"After ecstasy, the laundry," a Zen philosopher once mused. These days, the weekly wash may hit you with more than the soiled thud of earthly reality due to the chemicals packed into many common detergentsRead More


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This event is resting for 2017Sorry, but Linby Open Gardens isn't running this year. We'll keep you posted about next year's event details when they are known, but in the meantime we include below details from a previous year to remind you about the event
Linby, NottinghamshireSunday 26th July 20152.00pm to 5.00pmLinby Leisure Enterprise Group would like to invite you to their annual open gardens event. This year 15 gardens are opening in the beautiful, picturesque village of Linby. A wide variety of gardens are open from cottage gardens to larger landscaped gardens.
Cream teas are being served in the 'secret' cottage garden and there are also plants, handmade cards and hampers to buy.
St Michael's church and Linby Heritage Centre will be open and vintage farm tractors will be on display along the village green. Cream teas and craft stalls at Hanson House.The proceeds of the event are donated to the Linby Millennium Fund.Cost:£3.00How to get event passports:Itinerary and tickets available at the car park.Contact the organisers:Phone: 0115 963 2430Email: Directions:Just north of Hucknall.Location:County: NottinghamshirePostcode for Sat Nav: NG15 8AE (please verify before travelling)Find approximate location on GoogleMaps (new window)
Gardens CounterHow many Open Gardens events are on this website?
Garden Plants QuizHow many cryptic plant clues can you solve?
Cursed StatisticsHow are open gardens events spread through the year?
website design by greenwave


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latest news
Brig Gen Tuohy retiring; Horn is next commander of Washington Air National...
07.07.17 — Brig Gen Tuohy has had a long, accomplished career Read More »
Military Department donates to Tillicum food bank
02.15.17 — Donated: 1,000 pounds of food and cash to buy another 800 pounds Read More »
Guard member flies Black Hawk back to high school
01.06.17 — Guard member was former aviation student at high school Read More »
Featured Story
National Guard Child of Year says father is role model
Trip Landon, 17, of Ellensburg, was recognized as the National Guard's 2016 Military Child of the Year Read More »
JSS/Family Programs
The Joint Services Support (JSS) Directorate is designed to be a one-stop center for all Washington Guard veteran and family readiness services. We oversee transition services, state family programs and a resiliency care team. The JSS manages programs that provide Washington's Warriors, veterans and family members support services that enhance their well-being as well as promote their productive military participation.
Headquartered in Building 3 on Camp Murray, with locations at armories across the state, the JSS can provide assistance no matter where you're located in Washington state.
Need emergency assistance?
Call 1-800-364-7492 (Available 24 hours)
Our mission is to:
Provide support to the Military, and family members of the Washington National Guard.
Be present at unit functions including unit training assemblies.
Provide education about the National Guard, Family Programs and Family Assistance Centers to Military members, families, and the general public.
Support the mission of all National Guard units.
Strive to be the Family Programs model in the United States.
Our purpose is to:
Enhance the quality of life for all Guard members, their families, and the communities in which they live.
Contribute to readiness and retention in the Washington National Guard.
Our vision is that:
Every member of each Washington National Guard family knows and understands the benefits to which they are entitled.
At a minimum, members know that by calling the Family Programs Office at 1-800-364-7492, they can get the answer to their questions or concerns.
Each Washington National Guard family is prepared to meet the challenges of a deployment or disaster, through education, preparedness and the assistance of their Family Support Group, which is postured to provide assistance to every Washington National Guard Family in the event of a deployment or disaster.
Transition Assistance Advisor
VA's Airborne Hazards & Open Burn Pit Registry
Are you getting VA compensation and National Guard pay?
For a full list of contacts, please visit this listing.
video spotlight
What's it like to be a National Guard sniper?
Staff Sgt. Matt Croft, HHC, 3-161st Infantry, describes sniper stalking and what it's like to be a National Guard sniper.View All Videos »
Youth Academy helps Spokane family
KREM2 interviews the Opps, who had two siblings go through the Washington Youth Academy.View All Videos »
Neighbors helping neighbors before the emergency
Our Map Your Neighborhood program really works.View All Videos »


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When you look in the mirror, do you hate seeing your acne scars look back? Unfortunately, scars often affect self-esteem. If you wish there was something that you could do, you can.
It turns out you can get rid of those scars without undergoing painful surgery. There are several treatments available specifically for reducing scars. These treatments are simple and practically pain free. Best of all, they deliver the type of results that you would expect from an extensive procedure. Look at your options and then schedule an appointment to get a step closer to getting rid of your embarrassing scars.
With acne scars, the real issue is not on the surface of your skin but below where pockets form and cause scarring. The Fraxel fractional laser treatment goes below the skin's surface to stimulate the body's collage production. The collagen fills in the pockets that cause scars to form on your face. Because this treatment targets each problem area, your skin fills out and scars go away.
Depending on the severity of your scarring, you might need to go through a series of Fraxel treatments. In addition, your results might not show until after your second treatment. However, your scarring will start to fade more and more from one treatment to the next, until they are gone. At that point, you will feel like a new person and be ready to take on the world.
Micro-needling also stimulates the growth of collagen. The doctor uses tiny needles to penetrate the dermis or top layer of the skin, causing the skin to produce more collagen and elastin. For acne scars, the doctor goes deep into the skin to create the production needed to fill the grooves and pits that cause scarring.
This procedure has very little downtime, and you only need to get it every year or two when dealing with facial acne. That will allow you to reduce your scars without worrying about them coming back.
PicoSure Focus
PicoSure Focus is an easy way to get rid of acne scars for all skin types and it only takes about 15 minutes. This laser stimulates collagen production while leaving all of the overlaying skin cells intact. It is so effective that many people refer to it as a 15-minute face lift.
Although it requires minimal downtime, you may require a series of treatments to achieve optimal results. The best thing to do is come in for a consultation to find out how many treatments you will need for your specific level of scarring. Then, you can schedule the procedure and get started on the road to reducing unwanted scars.
Acne scars can be embarrassing, but you do not have to deal with that embarrassment any longer. Schedule a treatment so you can finally get rid of your scars. Once your scars are gone, you will have your confidence back, and therefore, a new lease on life.


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3DQuickPress v6.0.0 for SolidWorks (2011-2015)(x64) | 1.3 GB
This module is designed for the design of progressive die performing separation (cutting, punching) and shaping (bending, stretching) stamping operation. It allows the designer to use the equipment ready algorithm development of the stamp, special design tools, as well as a library of standard components. The initial data for the development of the stamp is a 3D-model components, developed in SolidWorks or imported from other CAD systems.
Included in the construction of modules 3DQuickPress scans; the formation of the working area of the stamp and the spatial layout of the stamp allows the designer to lead the process of development of the stamp series, based on the results of the previous program modules
Year / Date of Release: 2015
Version: 6.0.0
Developer: 3D QuickTools Ltd.
Bit depth: 64bit
Language: English, Chinese Traditional
Medicine: Present (Team SolidSQUAD)
System requirements: Preset SolidWorks 2011-2015 64bit only!
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Product Code: CEI2.5P
Product Code: CEI2.5P
Platinum Wedding Ring chamfered Edge on a Flat Court Ring - 2.5mm Ladies fully UK manufactured, and comes in a velvetine pouch you can also choose to have it in its own real wood presentation box.
We also send a special ring sizer to everyone who orders a ring to make sure, so you can order with confidence that you will get the right size of ring. The ring is made of solid hallmarked Platinum 950.
You can also change the metal in the options - PLEASE NOTE THE RING DESCRIPTION WONT CHANGE but we will make the ring in the metal of your choice.
Three weights are available each with different depths, Medium of depth 1.5mm, Medium Heavy of depth 1.7mm and Heavy of depth 21.mm
Engraving your Wedding Band
Standard : You can also add engraving on the inside of the ring. Choose the font from the image pick the option you want from the engraving drop down.
Adding Multiple Diamonds
If more than one diamond is required please use the Contact Us to arrange payment and specify diamond placing
To see our full range of platinum wedding rings please click HERE
This item is made from scratch to your specification. Delivery is in 10 to 14 days. If you need it by a specific date please tell us in the special instructions box you will see when checking out. If a return is required please send by Royal Mail Special Delivery.


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"The tour was invaluable in strengthening the girls' capacity to communicate effectively in Italian, particularly through the home-stay experience and the Italian language lessons held in the tranquil yet beautiful town of Mondavio. I'm sure this Italian tour will provide the girls with memories that will last a lifetime. I particularly thank Mario, Gianni, Viny and other members of VITA ITALIAN TOURS for their energy, flexibility and professionalism as tour leaders".
Mrs Anna Dickinson
Bethlehem College Ashfield NSW
"The 2009 trip was such a success and sparked so much interest that we followed it up with a 2011 tour with 20 students! Mario, Viny and now Gianni (their son) are wonderful in terms of leading the tour, catering for our students and their interests, but most of all they're so passionate about what they do, they make the experience come alive and alleviate the pressures of the teachers on tour".
Linda Palermo
Languages Teacher
Cheltenham Secondary College, VIC
"The home stay was just a fantastic experience, it's a once in a lifetime opportunity to stay with an Italian family and live the same way as them!
Tour guides Mario, Viny and Gianni gave us the best experience of our lives over in Italy. We're coming back with all new Italian words and phrases in our head and new gelato and pasta tastes in our mouths.
The tour was made that more special with all the close friends that you make."
Year 9 Student
St John's Regional College, VIC
"With our friendly tour guides Mario and Viny leading the way, we managed to go to so many wonderful places: Rome, Pompeii, Sorrento, Pesaro, Urbania, Siena, Florence and Venice".
Year 10 student
Cheltenham Secondary College, VIC
"Overall, the trip was absolutely amazing and a once in a lifetime experience which I will never forget. We travelled to some of the most amazing places and saw some of the most beautiful things. Thank you Mario and Viny for sharing this delightful experience with us".
Zsa Zsa
Year 10 student
Fitzroy High School, VIC
"Personally, I thought the Italy trip was fantastic. The hotels were great. The tour really catered for everyone which was good. The tour guides were amaqzing and I really enjoyed spending time with Mario and Viny".
Year 10 student
Fitzroy High School, VIC
"Our tour of Italy was a wonderful success. Mario's impeccable organisation and eagerness to meet the needs of our school set the tone for a wonderful trip and this materialised beautifully in Italy. Every day was full of interest and excitement, our students were continually being challenged to extend their understanding of Italian culture and history by our knowledgeable tour leaders. I would like to thank Mario, Gianni and Viny for the smooth running of the tour and for being so gracious, pleasant and accommodating".
Ettore Cinque
Teacher-in-Charge of Languages
Bethlehem College Ashfield, NSW
"The tour has been an immensely enjoyable, satisfying and enriching experience for all of us. Gianni, Viny and Mario have been an absolute pleasure to travel with.".
Lisa Finamore
Language Teacher
St John's Regional College, VIC
"The sights we saw, the people we met, the food we ate, particularly the huge amounts of gelati we consumed were what made our Italian "Study" tour so fantastic. From Rome to the Amalfi Coast, to our challenging Italian speaking home-stay in Mondavio, and from Florence to Venice, it was truly the experience of a lifetime".
Year 10 students
Cheltenham Secondary College, VIC
"The trip was much more than a holiday – it was an educational, cultural and spiritual journey".
Year 10 student
Bethlehem College Ashfield NSW
---FriendTravel AgentAdvertisingInternetOther


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The father of Orlando terrorist Omar Mateen, who killed 49 people and wounded 53 others in a June 12 attack in the Pulse nightclub, attended a recent rally for Democratic presidential candidate Hillary Clinton.
Seddique Mateen was visible seated behind Clinton in the crowd at a rally in Kissimmee, Fla., just south of Orlando.
Mateen, who was spotted by a local news crew at the event, did not want to speak at length when interviewed at the rally.
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"We've been cooperating with the federal government, and that's about it," he said. "Thank you."
However, when the same crew ran into him later in the evening, he wanted to show a sign he had made supporting Clinton.
TRENDING: 'My God is Awesome': Sam's Club Customer Starts Playing Piano and a Worship Service Breaks Out
Mateen, who in the past has voiced support for the Taliban, said he is voting for her over Republican presidential candidate Donald Trump.
"Hillary Clinton is good for United States versus Donald Trump, who has no solutions," he said.
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Mateen was asked whether the Clinton campaign knew he was coming.
"It's a Democratic party, so everyone can join," he said.
Asked whether he thought people would be surprised to see him so close to the community where his son killed so many people, Mateen deflected the question.
"Why should they be surprised? I love the United States, and I've been living here a long time," Mateen said.
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An official with the Clinton campaign said the campaign was not aware Mateen was in attendance until after the event.
Mateen's attendance and open support of Clinton rubbed one commentator the wrong way.
"Not only does Hillary have people who love killing babies supporting her, but she now has family members of Islamic jihadists on her side," wrote John S. Roberts on Young Conservatives. "And some people are still #WithHer?"
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Reverse Engineering Old Estimation Software onto the Salesforce platform
Budget min 50000 $ USD
As a construction company we currently have a Estimation Software (think old windows software). That when you fill out the correct fields it's able to create the layout of the job as a drawing, break down the exact materials needed for the job as well as the pricing for the job. Where this project gets interesting and more complex is that we're looking to build it into the [url removed, login to view] platform, possibly using heroku, in order for it to automatically interact with the objects in Salesforce. I think we might be a couple of months out timeframe for when we wanted to get started however was curious what everyone thinks the ballpark pricing for the project would be as well as a ballpark timeframe. there's really no preference in coding languages but a few possibilities would be python, php, Ruby, etc.
45 freelance ont fait une offre moyenne de 65359 $ pour ce travail
Dear Sir, I have read Project Description & can we see your existing Software or can you update us with the list of features, which you want to develop? Please click on the chat button for further discussion abou Plus
Please accept our bid for your Estimation Software based on SalseForce platform and this can be done on Heroku and Ruby on Rails as well. I have good experience in this area. Thanks Relevant Skills and Experience Skil Plus
Please provide some details on the estimation software to study the possible modules for the new [url removed, login to view] build. Thanks Gopal
Hi Mark here, this sounds like an interesting project and I hope we can make some time to discuss this. Relevant Skills and Experience We currently work on Apps and Development for the likes of Manchester, Birmingham Plus
Hello Sir/Mam, After reading your project description it seems like project description is not enough for understanding such kind of functionality but yes basic idea we got it. Relevant Skills and Experience We have Plus
Hello, we build top quality complex platforms , we have excellent expertise in sales force custom developments so feel confident we can are the best and you have to look no further Relevant Skills and Experience we Plus
Please have a look at our portfolio for Web design projects: Relevant Skills and Experience Graphics design: [url removed, login to view] Plus
We are a London (Shoreditch) based web development studio. Please get in touch to discuss further. Following are some of our recent projects; [url removed, login to view] A social media post scheduler and manager Plus
I have 7+ years in software development with very good experience. Relevant Skills and Experience I am good in CSS, HTML, [url removed, login to view], Software Architecture Proposed Milestones $50000 USD - Cost
I am very good in Reverse Engineer. Let us discuss and move ahead Relevant Skills and Experience Software Architecture Proposed Milestones $52631 USD - cost
Dear Client, Hope you doing well. We are ready to start work immediately on your project. We are very much expertise group of iOS, Android, Website and Design developers. We make the right use of modern techno Plus
We offer solutions on WEB, Slaesforce and Mobile technologies. Please visit our company site www.kennedia.net. Since its an reverse engg. project hence its difficult to give estimates . Relevant Skills and Experience Plus
Hi there, I got an understanding of the workflow of the system but to exactly analyse its working, I need to have a look at the system, can we meet on call where you can travel me through system. Relevant Skills and Plus


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As an MailChimp Expert, working with MailChimp since 2010, I help clients create and manage permission-based email marketing. MailChimp integrates with hundreds of apps and services, like Salesforce, Eventbrite, Google, Twitter, Facebook, Shopify, and SurveyMonkey.
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Get inspired, connect, and improve your online and printed marketing. Sent monthly with occasional discounts offers.


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USA Pro Challenge: Peter Sagan sprints to victory on stage one
Peter Sagan gets off to a winning start at the USA Pro Challenge by outsprinting Greg Van Avermaet in Aspen.
Last Updated: 23/08/13 5:35pm
Sagan (Cannondale) benefited from solid teamwork during the three laps of an undulating circuit, before latching on to Van Avermaet's wheel on the final corner and then passing the BMC rider with ease. The Slovakian champion went on to celebrate his victory with his now customary one-handed wheelie.
That result ensured Sagan was also awarded with the race leader's yellow jersey, although a lack of bonus seconds means he sits level on time with 17 other riders.
Froome (Team Sky) finished 4min 59sec down in 77th place as he continues to build back towards peak fitness in the wake of his Tour de France win last month.
The third edition of the USA Pro Challenge had got off to a lively start with numerous attacks being annulled before Craig Lewis (Champion System) edged ahead after 10km and was joined by Matt Cooke (Jamis-Hagens Berman) and Ian Burnett (Jelly Belly).
Sagan too strong
The trio saw their lead max out at two minutes and 35 seconds before Cannondale took control at the head of the peloton in their new black kit, with Team Sky and Garmin-Sharp also lending a hand.
Cooke earned himself a spell in the King of the Mountains jersey by leading the break over all four categorised climbs, and the American crested the final ascent alone after his two accomplices had failed to match his pace in the closing stages.
Cooke was also swept up in the last 10km as counter attacks came from the field, and Sagan temporarily infiltrated a five-man move before George Bennett (RadioShack) and Carter Jones (Bissell) pressed on as a twosome.
That duo were swept up just 1.5km from home, by which point the sprint trains were in full flight and readying themselves for a flat-out finish. Van Avermaet was the first to kick as the riders swept onto the closing straight, but Sagan bided his time before peeling off to the right and pressing on for his 15th success of the season.
Stage one result and general classification
1 Peter Sagan (Svk) Cannondale Pro Cycling, 2:26:00
2 Greg Van Avermaet (Bel) BMC Racing Team, same time
3 Kiel Reijnen (USA) UnitedHealthcare Pro Cycling Team, st
4 Tony Gallopin (Fra) RadioShack Leopard, st
5 Tejay van Garderen (USA) BMC Racing Team, st
6 Rory Sutherland (Aus) Team Saxo-Tinkoff, st
7 Wilco Kelderman (Ned) Belkin, st
8 Lucas Euser (USA) UnitedHealthcare Pro Cycling Team, st
9 Thomas Danielson (USA) Garmin-Sharp, st
10 Christopher Baldwin (USA) Bissell Pro Cycling, st
Selected other
77 Chris Froome (GB) Team Sky, +4:49


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The U.S. and five Arab nations have struck Islamic State and al-Qaida militant targets in Syria, in a move the Pentagon says is "just the beginning." VOA's Pentagon Correspondent Carla Babb has more.
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On July 18th, 2016, the 4,000th article was added to the SuccuWiki!
Succubus in Need (eBook)
|Succubus in Need
Succubus in Need eBook Cover,
written by J.C. Treeson
|J.C. Treeson
|Amazon Digital Services
|Publication date
|October 23, 2015
|Media type
|125 Pages
|Preceded by
|Succubus in Seven Days
|Followed by
|Succubus in Sin
For other uses of the word Succubus, see Succubus (disambiguation).
Succubus in Need is an eBook written by J.C. Treeson. It is the second work in the Succubus series by this author. In this work the character Emma Wilmot is a Succubus.
- Title: Succubus in Need
- Author: J.C. Treeson
- Published By: Amazon Digital Services
- Length: 125 Pages
- Format: eBook
- Publishing Date: October 23, 2015
Other Works in this Series on SuccuWiki
Plot Summary
Emma Wilmot's new status as the only succubus in the world has just come back to bite her. Politics and plots run afoot in Nashville's supernatural community after a college student is attacked and the blame is laid at Emma's feet. Banned from feeding, she faces death or worse if the investigation proves she committed the crime. The Council is on her tail and familiar faces pop up to tempt her into breaking all the rules.
As she seeks to solve the crime, Emma must juggle between her succubus needs and her own. It doesn't help when she's aching for a touch, any kind of touch, to quench her inner succubus desires. As the old saying goes: water, water, everywhere, and not a drop to drink.
Summer is ending in Nashville, but the nights are only heating up for Emma.
Book Review
At the time of this article's entry in the SuccuWiki, no review was available. Tera has this work on her reading list and will review it shortly.


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Register to Attend
Choose from over 25+ sessions throughout the day. There are 6 time slots with 5+ workshops each time slot. The day starts at 9am and finishes at 5pm. We'll have a "Yoga for Gardeners" during lunch and a drawing for door prizes at the end of the day.
Event registration for Madison Food Camp 2015 powered by Eventbrite


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- Featuring a pluggable surge protection module, the SPM series of Arresters are ideally suited for most industrial applications.
- The pluggable aspect allows the replacement of modules without having to disconnect cabling.
- The units are rated at class 2 protection levels (8/20µs) and can be configured in various formats to cater for most earthing systems (TNS/TNC).
- Have a DIN rail with each module being DIN width the placement of arresters in a consumer unit or Type B Distribution Boards are easily achieved.
- We offer free site visits call 0161 765 3000.


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By Martin W. Schwartz
It's fun to be a little bit scared sometimes, isn't it?
That's the theory behind monster movies and roller coasters and even some practical jokes.
But while being a little scared can be fun, being the one doing the scaring is even more enjoyable. Remember all those nights sharing ghost stories around a bonfire?
If you're not 'fraid of no ghosts, Saint Louis Boo—written by Carolyn Mueller and illustrated by Chris Sharp and Chris Grant—is a great story to share with your little trick or treaters this All Hallows' Eve. Based on actual ghost stories from the Gateway City, Saint Louis Boo follows the adventures of "The Spirit of St. Louis," a friendly little ghost who is perhaps not as brave as he pretends to be. From the ghosts who roam West Cabanne Place to Hickhiker Annie, who likes to flag down rides and then disappear, the stories of fabled St. Louis hauntings are presented with cartoon whimsy to engage the imagination of young readers without making them too scared to turn the lights out.
On the other hand, Moms and dads might find themselves having a sleepless night, Googling the ghost tales told and finding out the real story-behind-the-stories. Turns out, there's a good deal of spectral nightlife to be found on the east side of the state.
This is not the first time author Carolyn Mueller has dipped into real stories for her children's work. She has also written Bubbles the Dwarf Zebu: A Story About Finding a Home at the Saint Louis Zoo and Lily: A True Story of Courage and the Joplin Tornado. When not writing, Carolyn is a zookeeper at the St. Louis Zoo.
So butter the popcorn, warm the apple cider, and get ready for this just-scary-enough story to cap off your Halloween night.
It's probably even better when read by flashlight.


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Quinn Build Guide by SlangforGenitals
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Thank You!
Your votes and comments encourage our guide authors to continue
creating helpful guides for the League of Legends community.
Hard style bird kites
Quinn Build
Starting Items
Farm, Sustain and Kite
Bird flying higher than a kite
Time for more kite, and DMG
Tank blaster
And lastly, chance destruction
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
Quinn is an all around good carry and an even better bruiser, if you are looking for an ADC guide, this isn't it. Yes you can run this build bot lane, if you can do so effectively then do it. Quinn is built to kite and chase, Emphasis on chase. If Quinns was a guy, her name would be Chase. As long as you play smart, and try to burst carries while soaking up damage, then you will be fine in lane.
The lane and you
First of all, Farming is your thing. You are still and ADC so you need farm to deal damage in any notable amount. Rushing an avarice blade helps you immensely. First of all, your hardest lane opponents are people like Pantheon, Talon, or other Assassins and ADC's going top. Flash and Ignite because, well, flash to jump away for kiting purposes or flashing forward to secure kills. Ignite for Securing kills and facing Volibears top. Other possible spells include Ghost instead of flash, or Teleport instead of flash.
Runes and masteries
15/14/1 Masteries for tank and plenty of damage. Flat armor seals, with flat AD Quints, Glyphs and Marks make for a heavy damage early game that is necessary to win the fight with bruisers top.
The playstyle
Because Quinn is an ADC, Kiting is still her main goal. You always want to be out of your enemies range in top lane. The only time you want to be in their range is when you are fighting with other carries, Then you anti-kite. You all in them and kill them before they kill you. Against tops like pantheon or Malphite remember to keep their shields down. If you are going to go for a kill always wait for harrier to mark them, Hit them once, then go in for the kill with an E to mark them again and just chase them do death. If the laner tries to fight, then let them chase you around while you auto-attack now and then. An E once an awhile will keep them from catching up. The key idea is to deny them farm and to farm as much as possible yourself. With the interrupt on her E in the latest patch, Running is very easy by quickly E'ing the target and stopping them in their tracks.
Enemy laners that are hard to deal with
Reason 1: Cleavers, with that slow he can keep you from kiting him and stay in your face, as well as poke you down before the fight.
Reason 2: Sadism, His ultimate again counters you trying to kite, and lets him freely run from you when he needs to.
Counter 1: Ignite during ult.
Counter 2: Early BotRK will allow you drop him and keep him away or chase him down with its active.
Reason 1: Aegis, with his passive it is extremely hard to keep passively poking him with AA, because he will block it though it won't waste harrier.
Reason 2: Spears and the shield bash, With this constant poke and the threat of a shield bash into a Heart-seeker strike, he can easily burst a lot of health off.
Counter 1: Keep AAing him when his passive is up to lock it down.
Counter 2: Same as counter 1 Keep him low enough that taking that initiative to iniate would allow you to kill him.
Reason 1: Yorick
Counter 1: Passive farming, as long as you try to keep at a distance you will be fine, if he plays stupid take the opportunity, but do be watchful of ganks and his ult.
Reason 1: Void spike, with this poke and sustain combo he can keep you lower than you ought to be.
Reason 2: All inning as an assassin, he can and will burst you very soon Post-6.
Counter 1: Rush your Vamp scepter early and sustain as well as you can.
Counter 2: Get an early ruby crystal for tank and get your phage before your frozen mallet.
Reason 1: Stuns, stuns, and more stuns
Counter 2: Be as dodge happy as possible, stay behind minions to escape his Q poke. Remember the little cocaine ball will do his best to beat you down first. If he all ins and you know you can take him from the health, do it.
Pros / Cons
1: Extremely versatile, bursts and tanks carries as well as out does other bruisers
2: Good at pushing, depending on what you build first, you can gank for different laners. if you have a laner with good CC but lacking damage and you can build your damage first. You should. It will allow you to gank the enemy, Vice Versa.


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5/16 Dolby Court North Mackay 4740 QLD
Tidy, Central, Affordable
* Two bedroom unit in North Mackay
* air-conditioning to the main bedroom and living space
* renovated kitchen
* single carport to the front of the complex
* located in a cul de sac within walking distance to North Mackay Bowls Club and the Gooseponds
* only a short drive to Mount Pleasant Shopping Centre and Mount Pleasant Tavern.
Disclaimer; The landlord and/or their agents do not give any warranty as to errors or omissions, if any, in these particulars, which they believe to be accurate when compiled.
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Mackay QLD, 4740
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Real Estate For Rent in North Mackay, QLD 4740 priced between $110 and $200


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Scarlet Dangerfield
Talent Director for Hi-Rez Studios
Scarlet is the Talent Director for Hi-Rez Studios, makers of SMITE, Paladins, JetPack Fighter, Tribes, & Global Agenda. She has 11+ years of progressive Global Human Resource & Recruiting experience, with a passion for the games industry. I received a BS in Business Management with a concentration in Human Resources, and in Information Technology. I also possess a PHR certification as of 2007.
In addition, I am also a regular public speaker in the realms of the millennial workforce, and career development in the game development industry. I have spoken at high volume events like GDC, PAX Prime, & SEIGE. I am devoted to university relations, mentorship, getting Women into Gaming, and growing awesome talent from the ground up.
Talk Description:
What You Can Expect Working in Games!
The video game industry continues to grow and is always on the look out for new talent. But what are new employees to this industry getting themselves into? From in house massages and free lunches to crunch time and reiteration. This presentation will bring insight on the state of studio culture and the best way to navigate it.


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This page contains the various categories for the Microsoft System Center Configuration Manager / ConfigMgr / SCCM 2012 OSD / Operating System Deployment Administration FAQs.
Boot Images
Task Sequences
- How do I find out which Management Point a machine is using when running a Task Sequence?
- How do I check if a Client is in "Provisioning Mode"?
- How do I take a Client out of "Provisioning Mode"?


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The Olsen Gang Never Surrenders Trailer (1979)
26 December 1979 Comedy, Crime, Family 108 mins
Egon plans to exploit knowledge gained during his latest term of incarceration. By stealing the unmanipulated financial records of DanInvest he obtains the majority of the stocks in the department store Magasin du Nord, just in time for their closing sale. The attempt to get the red suitcase that will save the day they rob the main vault at the EEC headquarters in Brussels and end up hijacking a tank.
Watch the official The Olsen Gang Never Surrenders 1979 trailer in HD below or find more The Olsen Gang Never Surrenders videos on Vidimovie.