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|Chantal Ackermann <chantal.ackerm...@biomax.de>
|Re: OutOfMemoryError
|Thu, 29 Nov 2001 09:20:50 GMT
hi Ian, hi Winton, hi all, sorry I meant heap size of 100Mb. I'm starting java with -Xmx100m. I'm not setting -Xms. For what I know now, I had a bug in my own code. still I don't understand where these OutOfMemoryErrors came from. I will try to index again in one thread without RAMDirectory just to check if the program is sane. the problem that the files get to big while merging remains. I wonder why there is not the possibility to tell lucene not to create files that are bigger than the system limit. how am i supposed to know after how many documents this limit is reached? lucene creates the documents - i just know the average size of a piece of text that is the input for a document. or am I missing something?! chantal Am Mittwoch, 28. November 2001 20:14 schrieben Sie: > Were you using -mx and -ms (setting heap size ?) > > Cheers, > Winton > > >As I run the program on a multi-processor machine I now changed the code > > to index each file in a single thread and write to one single > > IndexWriter. the merge factor is still at 10. maxMergeDocs is at > > 1.000.000. I set the maximum heap size to 1MB. > > -- To unsubscribe, e-mail: <mailto:firstname.lastname@example.com> For additional commands, e-mail: <mailto:firstname.lastname@example.com>
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A PEDANTIC clean-freak office policy helped derail the reign of BHP Billiton boss Marius Kloppers, who yesterday announced his resignation from the mining giant.
Staff at BHP were outraged when the company under Mr Kloppers issued an incredible 11-page missive banning office staff from eating smelly lunches at their desks, sticking post-it notes on their monitors and keyboards and placing jackets on chairs.
The draconian "Office Environment Standard" was issued to thousands of staff at two of BHP's Brisbane offices in August 2011. The Australian Financial Review today reported the incident was a "telling sign" Mr Klopper's reign was on the rocks.
Many employees were outraged by the elaborate dossier, which stated:
- Food must not be eaten at workstations
- No food emitting strong odours are allowed
- Mobile phone ring tones must be kept at low volumes
- Post-it notes are to be removed from monitors and keyboards at the end of the day
- Workers are warned to watch the tone and volume of their voices
- In meeting rooms, all whiteboards are to be cleaned, equipment turned off, cables put away, chairs pushed in and cups and bottles thrown away
- iPods and MP3 players must not be brought into work
- Small bags must be stored under work stations during the day
- Clothes must be put in "designated storage areas"
Mr Kloppers will resign as the company's chief executive and director on May 10. He will be succeeded by Andrew Mackenzie, the firm's base metals chief.
At the announcement of the leadership change yesterday, Mr Kloppers said: "There have been milestones along the way, some of them recognised by the media, others not."
At the other times, he added, the "media reports on things that quite frankly we didn't think about."
54 comments on this story
- Brad of Northcote Posted at 21/02/2013 11:36am
BHPB has had this policy for MANY years.. and I love it. No eating at desks not only encouraged people to go away from their desks and take a break for lunch but did stop the odours roaming the office. Cleaning the white board, great - the room is ready for the next user.. All these I see as positives in the workplace.. more companies should take a leaf out of Marius management.
- Gary of Posted at 21/02/2013 11:38am
All have their merits in some way (no one likes a noisy/dirty office), but are a bit much. Hygiene is a common one with food at work stations (crumbs, ants, bacteria, increased costs for cleaners), sticky notes can be a security risks (users tend to write passwords or other sensitive info on them). Cleaning up after yourself should be a given - it's not your home, don't treat it like it. Ipods one is a bit too much imo, at least have a 1 ear policy.
- ReallY? of Posted at 21/02/2013 11:45am
Some of those requests seem quite reasonable to me. The smelly food one is a bit OTT, but cleaning up after yourself and keeping your work station tidy seem like reasonable requests.
- Rebecca of Posted at 21/02/2013 11:45am
No post it notes on computer screens??? But where will I leave all my passowrds??
- Bulldog of Posted at 21/02/2013 11:45am
Just goes to show that private enterprise, isn't any better than the public service
- Chris of Brisbane Posted at 21/02/2013 11:49am
I really don't see the problem with the rules. Everywhere I've worked seems to have similar rules. These to me seem pretty standard, some of which are WH&S.
- Alan of Posted at 21/02/2013 11:49am
The Work Environment Guidelines for the City Square office is actually 12 pages and contains so much drivel about items such as where you can drink soup etc shareholders should have demanded this losers head months ago.
- Bitten of Posted at 21/02/2013 11:50am
People were outraged by courtesy and respect for company property/colleagues? Wow. The parents of today's working population must be so proud of raising a bunch of lazy inconsiderate selfish douches. How about a big thumbs up for human civilsation all round?
- T.J. of Redcliffe Posted at 21/02/2013 11:51am
I see no problem with this list of requirements? I've seen similar, usually at high-end firms. An uncluttered and tidy work area helps with uncluttered and tidy thinking.
- Scotty Mac of Posted at 21/02/2013 11:53am
Fantastic work place. Who wants dirty grubs in their office environment that have not been toilet trained by their parents. A clean safe working environment that complies with OH&S sounds correct for me. We already have many of these in our office environments and no complaints. Happy workers and no infections or virus's. If grubs don't like it then go work for the Labor party.
- Mark of Posted at 21/02/2013 11:56am
Why is this a "telling sign" Mr Klopper's reign was on the rocks???
- Peter C of NSW, Sydney. Posted at 21/02/2013 12:02pm
Truly outrages ideas of workplace etiquette are presented here of not irritating other staff members and keeping a clean work environment. What crazy ideas of treating a workplace as a workplace environment and not an informal home environment. Oh wait, its perfectly fine for an employer as they are employing you within their environment. Find another job if these crazy ideas are too much for you.
- Pauly of Melbourne Posted at 21/02/2013 12:04pm
Seems entirely reasonable to me? Maybe not to those office staff who can't/won't clean up after themselves, yell their heads off all day and eat last night's chicken curry at their desk which looks like a bomb hit it, with their iPod jammed in their ears while they're on Facebook. Don't even get me started on the condition some leave the toilets in.
- Retentive office worker of Sydney Posted at 21/02/2013 12:08pm
I think I would love to work in that environment. Seriously, office etiquette is dying a slow death.
- Darren of Australia Posted at 21/02/2013 12:10pm
Seems reasonable to me
- lee of Posted at 21/02/2013 12:11pm
So apparently asking your staff to act like responsible, considerate adults is not allowed?
- Michael of Posted at 21/02/2013 12:11pm
Marius was quoted at the end of this article "media reports on things that quite frankly we didn't think about" ...this article I'm sure is a prime example.
- Triscott Humberstone of Melbourne Posted at 21/02/2013 12:16pm
To Rebecca: Put the post it note on your dictionary. Why 3 x ? Clutters up the message!
- work slob, noisy inconsiderate type of my Pig Sty offices Posted at 21/02/2013 12:19pm
"Many staff were outraged" never let the facts get in the way of a good story,.... sounds like the standards were perfectly reasonable and a necessary way for management to manage the poor behaviour of some in terms of ettiquite and hygeine
- Soldier of Adelaide Posted at 21/02/2013 12:19pm
When did common sense and self-respect became "draconian"?
- Rob of Australia Posted at 21/02/2013 12:19pm
I have worked at BHPB and found that the rules are just fine. They keep a sense of order in the office and ensure that people behave in the office and leave their rude behaviour at home or somewhere else. It is a simple way to behave and work. What is needed is the greater use of TASER. Teach Adolescents Social Etiquette And Respect
- David of where the money is Posted at 21/02/2013 12:23pm
@Pauly of Melbourne - obviously you don't work there. We're talking about executive staff who earn in excess of $400K per annum - they expect these execs to give their all but will not even allow them to put a picture of their families on their desks. When you are working at this level - you need access to files and reference books, etc. However, everyone in the industry knows it isn't the memo - it's the many other failures under his... um... "leadership" - such as the Rio acquisition....
- CBD worker of Perth Posted at 21/02/2013 12:28pm
I truly wish our office had a "no smelly food" policy. Open plan offices are not the place for yesterdays reheated curry. A tidy desk is really not a big ask people. BHP have spent millions on the new building here in Perth, why shouldnt they expect staff to treat it with respect.
- love a clean desk of Sydney Posted at 21/02/2013 12:29pm
and the problem is ????? I would hate to visit some of the homes of the people I work with...desks filthy, terrible hygiene issues...this is a great idea and should be adopted in more places, music is fine if kept to a minimum so that would be the only no no...one ear policy is fine, then you can hear people speak to you and the phone ring...
- Kelly of Posted at 21/02/2013 12:30pm
I work in an open plan office. If I couldn't bring my mp3 player and headphones in I'd probably go insane. I need my techno to block out the noise and get into the zone so I can program better. A lot of people at at their desks here because of all the staff layoffs Less people means more work so no time for lunch. Plus people are terrified of losing their job and so work through lunch to get more done. Our whiteboards are always clean because there is never any pens.
- Krystal of Sydney Posted at 21/02/2013 12:30pm
Doesn't seem unreasonable at all, the first two have always been rules in all places I have worked and I agree with them! It's horrible when someone has some type of food that stinks out the whole office. Also some people are so allergic to certain foods even just being near them can trigger an allergic reaction.
- Michelle of NSW Posted at 21/02/2013 12:31pm
I think for the most part its pretty reasonable. However, food smells I'm not so sure about. While I have no problem with food being eaten away from the desk, what constitutes 'a good or bad odour' is very subjective depending on the nose of the person. Also what about stinky people (eg bad body odour, perfume, after shave etc)? I
- blair of Posted at 21/02/2013 12:31pm
Nothing to out of the ordinary really! What's all the hoo haa about?
- Post of ItNote Posted at 21/02/2013 12:35pm
This is article is taking the mickey right? Head of the worlds largest mining company resigns because he demands clean offices. April fools day comes early. No one brave enough to put their name to this article, says it all really.
- HC of Posted at 21/02/2013 12:37pm
The BHP "Office Environment Standard" should be applied to all workplaces! The Unions should come up with something similar. Like all unions members should take singing lessons so street protests contain singing not shouting! Federal Labor could implement the same: no sleeping with other cabinet members, get married, be polite, say thankyou.
- kloppers for PM of Posted at 21/02/2013 12:40pm
Anyone whinging about this should resign. if people want to live like pigs at home then thats their bisiness but in the workplace respect for others is needed.
- sjh of vic Posted at 21/02/2013 12:40pm
If you don't think he's a clean freak, you are one. I worked for the company. I think the point should be more like - focus on not losing billions in equity for investors through poor acquisitions rather than whether the office is clean, that is actually what your paid to do kloppers.
- Old Time Miner of Qld Posted at 21/02/2013 12:43pm
Probably a better idea would be to get rid of those who sit behind the desks especially accounting, HR department staff and incompetent supervisors that account for much of money spent and wasted. Get back to the grassroots level and understand that production workers account for profits and should be treated with every social justice whilst letting their voices be heard, listened to and their advice adhered to. The wheel does not need to be reinvented by educated idiots.
- MsElenath of Sydney Posted at 21/02/2013 12:47pm
Comments are funny here, you assume that either people like the rules and are clean or don't and are filthy. I worked in an office that allowed 30 minutes for lunch, which for me was not enough time to go and find food, a place to sit, eat at a slow and healthy rate and be back at my desk. So i would eat at my desk (whilst listening to my mp3's in my ear and scanning facebook, yes) in my lunchbreak. As long as I kept my desk clean and emptied out my bin EVERY DAY I cannot understand why anyone would have a problem with this. Keep your office tidy, yes, but within reason. For example I had post it notes on my computer ALL the time. There were certain things I had to remember but where not always called into question, for example the extra rate we had to charge to deliver to a certain location. So I had that there so that I would not forget. Post it notes do not make an office space look dirty and asking for them to be removed each day is draconian. Some of it is perfectly reasonable, ie wanting gear put away after use. You don't have to choose between slovenly and squeaky clean, there is a rational middle ground.
- Paul of Wollongong Posted at 21/02/2013 12:47pm
.... and the problem is? he's just sick of people turning work into an extension of home and behaving like they ARE at home. More bosses would have the guts to do this if you media people wouldn't turn an entirely reasonable set of requirements into a crime.
- Worker of Posted at 21/02/2013 12:49pm
I simply agree with the policy. Respect for company property and considering your colleagues shouldn't be a stretch for people with little or no sense for hygiene, workplace etiquette and professionalism.
- Mark Grimston of Point Cook, Victoria Posted at 21/02/2013 12:50pm
You mean to tell me that a well-thought out office environment policy (and rules) was the "telling sign" for Mr Kloppers to resign over and above a $58 million fall in profits or an inability to manage the organisation through a severe drop in global ore and metals prices? Seriously? I am going to recommend the rules be implemented where I work. Nothing sinister about these at all.
- Tangles of Posted at 21/02/2013 12:50pm
Is the press really suggesting that the CEO of the world's biggest mining company had a hand in developing the policy about what people can and can't do at work? In any event, most of the items in the policy are pretty much common sense. The company needed to issue formal guidelines/rules because many employees don't display common sense and many don't seem to give a toss about whether what they do impacts on others.
- luke Whitington of florence, italy Posted at 21/02/2013 12:54pm
what you mean we are not allowed to pick each others ears with old paddle pop sticks???
- Rockdoctor of Northern Australia Posted at 21/02/2013 12:58pm
This sums up the problem with BHPB, their management and workplace culture is very poor. I don't reccomend them for anything other than they look good on a CV. Other big miners do it much better without the BS and attitude......
- gerry of sydney Posted at 21/02/2013 1:12pm
seems ok to me. nothing wrong with these rules.
- Michael of Adelaide Posted at 21/02/2013 1:14pm
The rules seem perfectly fine to me. All part of keeping a well run and clean office. Eating at your work desk? Go out and get some fresh air at lunch people.
- Bart of Mexico Posted at 21/02/2013 1:18pm
Haha. Yes, because we're all robots. Has everyone forgotten that "people" actually do the work? Ooh post it notes, how vile... are you people serious? Maybe you've all just never done any work in these environments. Maybe surfed the internet occasionally... hid from the boss, cleaned your desk like good little automatons. Nice one tards.
- Coop of Perth Posted at 21/02/2013 1:22pm
Why is this a telling sign? 18 months, and $16.5 million in salary later, and this memo was a telling sign?? I worked there, it was the most incompetent, corrupt, inefficient place I ever worked. Thankfully they only deal with dirt and rocks, not farm crops, otherwise we would all starve.
- Jz_Dragon of Perth Posted at 21/02/2013 1:23pm
Obviously many of the people commenting the outgoing regime are probably supporting this agenda from within the 'Dark Tower' in Perth. Having contracted within the human services area for this organisation and many others similar I can testify that this behavior is indeed entirely draconian. Not only that, but I think it is grossly 'in-humane'. To me it really epitomizes just how far BHP Billiton has strayed from the path of what can be considered 'normal corporate behavior'. How to create a mindless race of cyclons, nice, BHP. Please, for those supporting this, buy a full length mirror and take day out....
- Pube of canberra Posted at 21/02/2013 1:23pm
Im sick of public servants going to work in the same dirty jeans and loose smelly jumpers everyday. You may not be seen by the public but you are seen by your workmates. errrr
- Starlight of Brizvegas. Posted at 21/02/2013 1:26pm
A clean orderly work environment is more productive and safer. There is nothing worse than trying to work with and around people who seem he'll bent on imposing their peronality quirks on those around them. Kudos to BHP to imposing some discipline and professionalism in the workplace.
- moldor of The InternetZ Posted at 21/02/2013 1:29pm
Well, there go my garlic-laden curries... Seriously, what a complete prat
- Andrew of Perth Posted at 21/02/2013 1:31pm
Talk about adding 2 and 2 together and making 5. If anyone is dumb enough to think that this was even a small part of the reason he had to go, they need to wake up to the realities of big corporate life. Cost management, shareholder value and profit matter for CEO's longevity, not post it notes and fish curry for lunch.
- Pete of Posted at 21/02/2013 1:32pm
He issued the memo in 2011 and they say it was a sign he was about to go.....in 2013. Righto.
- The Judge of Posted at 21/02/2013 1:35pm
I agree that most people don't want to work with pigs, but as I recall, the young turks in the formative halcyon days of the "dotcom" era (Microsoft, Cisco, Apple etc) ate pizzas at their desks, and even slept under them when needed. So excited were they in their "frontier" world of computers, they didn't want to "miss a thing" and so it was that this was commonplace. Didn't seem to bother people then.
- beenTheredoneThat of Posted at 21/02/2013 1:37pm
this doesnt even scratch the surface of it.. we had a quota on pens (eg one red, one blue), no scissors (because you dont need them every day to do your job, so there was communal scissors) and glue/tape. Only one folder and one frame allowed, and even our desk drawers had to look a certain way. There was a strict "no eating" at your desk rule, which led to a lot of people sitting in the kitchen eating morning and afternoon snacks (very inefficient). Basically he doesnt want humans to work for BHP, but faceless robots. The no eating smelly food came from the office they opened in Kuala Lumpur and filtered back down. In Melb you werent allowed to heat anything and they took the microwave away. This is old news, there was an incident a few years ago where he ripped an employee a new one in front of media because he was eating a muffin at this desk, the poor guy had been away on leave and didnt know about the restrictions.
- Alan of Adelaide Posted at 21/02/2013 1:40pm
Time you spend cleaning, is time you waste NOT DOING YOUR JOB... but hey, if you want me to do a cleaner's job and still pay me several multiples of a cleaner's salary, who am I to complain?
- Dani Morena of Adelaide Posted at 21/02/2013 1:42pm
The above list of dot points should be copied, pasted, enlarged then printed to stick on the wall in every workplace everywhere...copyright allowing, lol.

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Domain Group senior economist Dr Andrew Wilson said the median rental price for units in Canberra fell from $385 to $380 per week during the quarter, which was significantly less than the $442 asking price recorded during the December quarter of 2011.
The median asking rent for houses in Canberra remained steady during the September quarter at $450 per week, which was 2.7 per cent lower than the asking price recorded a year earlier.
Despite the falling prices, the rental market in Canberra remains more expensive than in Melbourne, where the median weekly rent for a house is $380 and $370 for a unit.
Dr Wilson said the results were the sign of a pause in the national market; units in Brisbane and houses in Darwin were the only market segments to see an increase in weekly rent.
"Overall, national median weekly asking rents for houses decreased by 0.3 per cent while unit rents fell by 0.4 per cent over the quarter," he said.
Darwin remains the most expensive city to rent in with a median weekly rent of $550 for a unit and $660 for a house, which was still $20 below the asking rate recorded a year earlier.
In Sydney, the median rent for houses remained stable at $510 a week while the weekly rate for units fell by five dollars to $495.
"Unit rents weakened in Sydney over the September quarter, however, the median asking house rent remained steady at the June quarter's record level of $510 per week despite record levels of investor activity in the local market," said Dr Wilson.
But Dr Wilson said demand would continue to put upward pressure on the rental market in Sydney despite the pause in growth.
"In Sydney, yields are holding, asking rents are still strong and there are currently no signs of overshooting market fundamentals," he said.
Rental prices continued to fall in Perth, where the median rent for a house is now $450 and $395 for a unit, which is a yearly decline of 6.3 and 6 per cent respectively.
"Over the quarter, the median asking house rent fell from $460 to $450 a week, which is well down from the $490 recorded over the June quarter last year," Dr Wilson said.
In Brisbane the weekly rent for a unit increased by five dollars to $370 to return to the asking rate recorded 12 months earlier.
"Brisbane continues to deliver the highest yields of the major capitals for houses and Adelaide for units," he said.


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3 weeks PO, I know it's early days but am I bottoming out on my right (your left)? (photos)
Doctor Answers 3
Early results
3 Weeks post op
It is too early to determine how the breasts will ultimately settle. I know it's hard, but try to be patient. Follow the instructions given by your surgeon and be sure to keep up with follow up exams so your progress can be documented. Your final results will not be revealed for a few months and many changes take place in these first early weeks. If you have concerns you should speak with your surgeon, as he/she knows exactly what was involved in your surgery.
Learn more: http://www.camillecashmd.com/breast-enhancement/breast-augmentation.cfm
Bottoming out
Learn more: http://www.roxyplasticsurgery.com
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These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


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Fast. Very Fast.
This is my first SSD and having used it for over a month now I will never go back to old school HDD's. I built a new rig for gaming and although I haven't installed any newer games this drive loads a BF2 map in about 10 seconds. Windows 7 loads in 11 seconds (after mobo boot screen) AMAZING! Pros- Fast! I did drive benchmarks using 3 different programs and READ ranged from 425-550. Kingston has truly delivered. Cons- Expensive, but IMO it's worth it. Other thoughts- If doing a fresh install make sure this is the only drive hooked up and change your SATA contoller in bios to AHCI mode. At first I only got speeds of 200-300 because I was running in IDE mode. You can change this post O/S installation by simply making a change in the registry. AMD 1100T GA-990FXA UD3 Evga GTX 560 ti CORSAIR H60 CORSAIR Vengeance 8GB DDR3 CORSAIR 650w Pro Series PSU 1TB WD HDD for storage
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Layla Mynxx – Hands Of Dai
Released: November 1, 2014
We have another hot hot Asian beauty for you this week. This cutie was all smiles and happy to get right to giving a sensual rubdown. She was pretty quick to find her customers cock to see if he'd like a little rub and tug action. He was all about it and after some money negotiations she went right to work on him. Dont miss this pro showing this guy what a real happy ending is like.


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Pingtan Marine Enterprise Technical Analysis (NASDAQ:PME)
Technical analysis relies on the belief that future price movements of a stock can be forecasted through the study of historical market data and technical charts. The Pingtan Marine Enterprise stock price data and volume are plotted in PME stock charts and these trading charts form the basis of technical analysis.
View technical indicators like moving averages (SMA and EMA), and bollinger bands for Pingtan Marine Enterprise. Technical analysis is used by finance professionals and is popular among traders, especially day traders. Undertaking Pingtan Marine Enterprise stock analysis using these technical indicators helps identify trading opportunities.
Pingtan Marine Enterprise Moving Average:
Moving averages help predict the price direction of PME stock based on certain triggers, but with a lag, and form building blocks for other technical indicators like the MACD and bollinger bands. One needs to choose the duration of a moving average depending on the investment objective and investment horizon. For periods greater than 100, it takes a larger and longer PME stock price movement for the moving average to change course.
Pingtan Marine Enterprise Bollinger Bands:
Bollinger bands comprise of a center line usually PME SMA, and two PME stock price bands above and below it. The stock is considered over brought when the price starts moving closer towards the upper band, and is considered oversold as stock price moves closer towards the lower band. Pingtan Marine Enterprise bollinger bands show that the stock price is $4.11, upper band is 9.76, lower band is 9.38, and the average is 9.57.
Pingtan Marine Enterprise Moving Average Convergence Divergence or MACD:
The moving average convergence divergence or MACD is a technical indicator which helps assess the stock price trend. Traders usually wait for a confirmed crossover signal before entering into a trading position. Divergence implies that the current stock price trend could come to an end, when the stock price diverges from MACD. The Pingtan Marine Enterprise MACD indicator can be used to identify bullish and bearish trends for the stock.
Pingtan Marine Enterprise Relative Strength Index:
The RSI is a valuable tool to determine overbought / oversold stocks and measures the recent performance of a stock in relation to its own stock price history. 67.8 is the RSI value of PME stock. .


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National Lecture Tours are proposed by the Technical Divisions and organized by the National Lecture Tour Coordinator in collaboration with National Office. They provide members with an opportunity to meet and listen to prominent Civil Engineers who have earned wide recognition and respect amongst peers lecture on topics of special importance and interest.
Canadian Infrastructure Report Card National Tour
The second Canadian Infrastructure Report Card (CIRC) was published in January 2016. Guy Félio and Nick Larson presented a detailed overview of the CIRC process and results and provided some ideas for how we can engineer our infrastructure to make sure it can be sustained over the long term. This NLT was offered throughout Canada.
Please click on the title for the brochure
CSCE Advocacy Memo in reponse to CIRC
Development of Sustainable Infrastructure – CSCE Policy Statement and White Paper
For a list of NLTs since 2001, please click here: CSCE Past NLTs


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Zygomycetes are emerging opportunistic molds resistant to most conventional antifungals. We evaluated the in vitro activity of lovastatin (LOV), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, against seven clinical isolates of Zygomycetes by using standard microdilution methods in three different media, disk diffusion testing, and viability dye staining. To further study the in vivo efficacy of LOV against zygomycetes, we developed a Drosophila melanogaster model of zygomycosis. In different experiments, groups of Toll-deficient (Tl) flies fed LOV-containing food were subsequently injected with two representative Zygomycetes isolates (Mucor and Rhizopus spp.). Finally, we examined the effects of LOV on voriconazole (VRC) activity against zygomycetes in vitro by checkerboard dilution, Epsilometer test-based methods, and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining and in vivo in Tl flies fed food containing LOV plus VRC and infected with zygomycetes. LOV exhibited significant, medium, and strain-independent fungicidal activity against all Zygomycetes isolates in vitro by all testing methods (MIC50, 48.0 μg/ml; 50% minimal fungicidal concentration, 56.0 μg/ml; 50% effective concentration, 29.4 μg/ml [6.6 to 38.9 μg/ml]). Tl flies fed LOV-containing food and infected with Mucor had a significantly better 6-day survival rate than did infected Tl flies fed regular food (P= 0.0005). LOV displayed in vitro synergy with VRC against all Zygomycetes isolates (fractional inhibitory concentration index, 0.104 to 0.290) by all methods used. LOV also displayed synergy with VRC in the Drosophila model of zygomycosis (P < 0.01). LOV is significantly active against zygomycetes and synergizes with triazoles inherently resistant to them, such as VRC. The clinical significance of these findings needs to be further explored.
Fungi of the class Zygomycetes, order Mucorales, have been increasingly reported to cause opportunistic infections in a variety of immunocompromised hosts (11, 28). Rhizopus species cause more than 70% of Zygomycetes infections, whereas Mucor, Absidia, Rhizomucor, and Cunninghamella species are less frequently encountered pathogens (11, 16, 28). Importantly, zygomycosis has a particularly unfavorable outcome (11, 16, 28) because of delayed diagnosis as well as the inherent resistance of zygomycetes against most conventional antifungal agents (6, 11, 28, 30). Besides amphotericin B (AMB), only the investigational triazole posaconazole has shown promising activity against zygomycetes (6, 11, 28, 30, 32). Therefore, there is a dire need for development of novel treatment strategies against zygomycosis.
Lovastatin (LOV) is a statin that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme of the mevalonate pathway (26). LOV as well as other statins has activity against a variety of pathogens both in vitro and in vivo (12, 13, 31). Importantly, statins have been shown to have antifungal activity in vitro against both the nonpathogenic yeast Saccharomyces cerevisiae and the pathogenic yeasts Candida spp. and Cryptococcus neoformans (5, 22). In a recent study, LOV induced apoptosis-like cell death in a Mucor racemosus isolate at relatively high concentrations (29). Moreover, statins have been reported to exhibit synergistic interactions with azoles against Candida, even against azole-resistant Candida isolates (5).
In the present study, we evaluated the activity of LOV against a range of clinically important Zygomycetes spp. in vitro by using independent susceptibility methods. We also tested in a Drosophila melanogaster model of zygomycosis the efficacy of LOV in vivo against two representative Zygomycetes isolates (21). We further evaluated whether LOV and voriconazole (VRC), a triazole with an inherent lack of activity against Zygomycetes spp. (6, 11, 30), have synergistic effects in vitro and in vivo (Drosophila model) against zygomycetes. Both these pilot in vitro and in vivo studies against zygomycetes demonstrated that LOV has significant, broad-spectrum fungicidal activity and synergy with VRC.
We used four Rhizopus isolates (two Rhizopus homothallicus isolates and two Rhizopus oryzae isolates), two Mucor circinelloides isolates, and one Cunninghamella bertholletiae isolate collected from patients with cancer who had zygomycosis. We confirmed genus identification of the Zygomycetes isolates as described previously (33). Candida parapsilosis strain ATCC 22019 was used for quality control purposes in all in vitro experiments.
LOV (mevilonin) was kindly provided by Merck (Merck, Sharp, and Dohme Research Laboratories, Rahway, N.J.). LOV was hydrolyzed in active open acid form as described previously (9), and a stock solution (4mg/ml in a 10% alcohol sterile solution) was stored at −20°C until use. Additionally, AMB deoxycholate (Sigma Chemical Co., St. Louis, Mo.), itraconazole (ITC) (Janssen Pharmaceutica, Titusville, N.J.), VRC (Pfizer, Inc., New York, N.Y.), and caspofungin (CAS) (Merck, Rahway, N.J.) were obtained in assay powder form. Drug stock solutions for each antifungal agent (1,280 μg/ml) were prepared in 100% dimethyl sulfoxide (for AMB and ITC) or double-distilled water (for all other agents).
The Clinical and Laboratory Standards Institute (CLSI) M38-A standard medium RPMI 1640 (Sigma Chemical Co.) was buffered with 0.165 M 3-(N-morpholino) propanesulfonic acid (MOPS) to pH 7 according to the manufacturer's instructions. Two other media were used to test the in vitro activity of LOV against the Zygomycetes isolates: RPMI medium plus 2% glucose (RPMI-2) and a yeast nitrogen base (YNB) medium (Difco, Detroit, Mich.).
The MICs of each antifungal agent and LOV against all of the Zygomycetes isolates were determined according to CLSI guidelines (M38-A document [27]). Standardized inoculum suspensions were prepared from 5- to 7-day-old cultures grown on potato dextrose agar slants, filtered twice through sterile syringes filled with glass wool, and adjusted with a hemacytometer to a concentration of 1 × 106 to 5 × 106 conidia/ml in sterile water. Conidial suspensions were further diluted 1:50 in RPMI medium, and 100 μl was dissolved in each well of a 96-well flat-bottomed microtitration plate (Corning, Inc., Corning, N.Y.) containing 100 μl of a serial twofold dilution of each antifungal agent. The final concentrations of the tested drugs ranged from 0.03 to 16.00 μg/ml for AMB, ITC, and VRC; 0.06 to 32.00 μg/ml for CAS; and 2.00 to 64.00 μg/ml for LOV. The MICs of LOV and each antifungal agent were determined at 24 h as the lowest drug concentration at which there was complete inhibition of growth. The minimal effective concentration of CAS was defined as the lowest drug concentration that resulted in the formation of aberrantly growing hyphal tips (3). All of the isolates were tested in triplicate on different days.
The minimum fungicidal concentration (MFC) of each antifungal agent was determined as described previously (8). Briefly, 20-μl suspensions from each well that showed complete inhibition of growth (100%) and from the last positive well (showing growth similar to that in the control well) were subcultured onto YNB plates prepared according to the manufacturer's instructions. The MFC was defined at 24 h as the lowest drug concentration at which fewer than three colonies were observed, which corresponded with a killing activity of approximately ≥99.9%. MFC determinations were done in triplicate on different days.
We performed disk diffusion susceptibility testing on RPMI agar plates previously prepared by using standardized methods (20). Two hundred microliters of a standardized suspension of conidia (106 conidia/ml) of each Zygomycetes isolate was plated. After the plates were allowed to dry, a sterile one-quarter-inch paper disk (Schleicher and Schuell, Keene, N.H.) was placed on the agar surface and inoculated with 125 μl of LOV (4 mg/ml), producing a final LOV concentration in each plate of 20 μg/ml. Plates were incubated at 35°C, and the radius of the zone of inhibition was measured at 24 h by using a micrometer. AMB (final concentration, 10 μg/ml) was used as a control. Three independent experiments were performed at different time points.
We performed the 2,3-bis[2-methyloxy-4-nitro-5-[(sulfenylamino) carbonyl]-2H-tetrazolium-5-carboxanilide] (XTT) colorimetric formazan reduction assay by using the method developed by Meletiadis et al. (25). We initially determined the relationship of formazan production to fungal inoculum by incubating standardized conidial suspensions of each isolate (102 to 105 conidia/ml) in RPMI medium for 12 h at 35°C. After 10 h of incubation, 50μl of an XTT solution (1 mg/ml) containing 125 μg of menadione (Sigma Chemical Co.) was added to each well, and the tray was incubated for an additional 2 h. Formazan absorbance in each well was read at 492 nm and 690 nm (plate absorbance) with the use of a microplate spectrophotometer (Powerwave X; Biotech Instruments, Winooski, Vt.).
We performed XTT-based microdilution studies with CLSI microtiter plates prepared as described above. To evaluate the interaction of LOV with VRC against Zygomycetes, we performed two-dimensional (eight-by-eight) checkerboard studies into microtiter plates as previously described (19). The final concentrations of the drugs ranged from 2.00 to 64.00 μg/ml for LOV and 0.5 to 64.00 μg/ml for VRC. Wells were subsequently inoculated with 100 μl of a standardized conidial suspension of each Zygomycetes isolate (final concentration, 0.4 × 104 to 5.0 × 104 conidia/ml), and trays were incubated for 22 h at 35°C. Next, 50 μl of the XTT solution was added to each well, the tray was incubated for an additional 2 h, and formazan absorbance was determined as described above. The fractional inhibitory concentration (FIC) of each drug was calculated by dividing the MIC of the drug when used in combination by its MIC when used alone. FIC values then were added together to define the interaction of the combination (19). Synergy was defined as an FIC of ≤0.5, whereas antagonism was defined as an FIC of >4; off-scale MICs were raised to the next highest MIC. Control wells containing medium alone were included in each experiment. All experiments were performed in triplicate.
Staining with the fluorescent dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) was performed as described previously by Bowman et al. (3). Briefly, conidia from representative Zygomycetes isolates (one each of R. oryzae, M. circinelloides, and C. bertholletiae) were suspended in RPMI medium at a final concentration of 0.4× 104 to 5.0 × 104 conidia/ml and incubated for 12 h at 35°C to generate hyphae. Aliquots of the hyphae were then mixed with each drug to produce the desired final concentration of LOV alone (4× 50% effective concentration [EC50]), VRC alone (2 μg/ml), VRC in combination with LOV (2 and 4 μg/ml, respectively), and AMB (2 μg/ml). After incubation at 35°C for an additional 6 h, hyphae were washed twice in MOPS (pH 7) buffer solution. DiBAC stain (final concentration, 2 μg/ml) was added accordingly, and samples were incubated for 1 h at room temperature in the dark with shaking (3). Samples were then washed twice again with MOPS, pH 7, and resuspended for photomicrography. Photomicrographs of the hyphae were taken under a triple-band fluorescent microscope (Olympus BX-51; Olympus, Melville, N.Y.) as described previously (3).
To evaluate the effects of LOV on VRC activity against zygomycetes, we used a strategy combining the Epsilometer test (Etest; AB Biodisk, Solna, Sweden) and agar dilution susceptibility methods as described previously (15). We performed Etest susceptibility testing of VRC against each Zygomycetes isolate in RPMI plates containing a standard noninhibitory concentration of LOV (4 μg/ml) (7). As controls, we determined VRC MICs against Zygomycetes by using the Etest method on regular RPMI plates (without LOV). We read the VRC MIC at 24 h as the drug concentration at the point where the growth ellipse intersected the strip (7) and, accordingly, statistically compared the changes in VRC MICs (15). All MIC determinations were carried out in triplicate on different days; the median 24-h MICs were reported.
In different experiments, we infected Toll-deficient flies (Tl flies) (2- to 4-day-old female flies, 30 per experimental group) with two representative Zygomycetes isolates (M. circinelloides 424760 and R. oryzae 557969). We injected the thoraxes of Tl flies with a thin sterile needle that had been dipped into a concentrated solution (108 conidia/ml) of each Zygomycetes isolate, as described previously (17, 20). After injection, we housed the flies at 29°C and transferred them to fresh vials every 2 days. We assessed survival daily until day 6 after injection. We performed each experiment at least in triplicate on different days.
For assessment of LOV protection against lethal infection by each Zygomycetes isolate, different groups of Tl flies (30 per experimental group) were housed in empty vials for 6 to 8 h to starve and then transferred into vials containing LOV-mixed fly food (10 mg/ml) as described previously (2, 20). After 48 h, each group of Tl flies was infected with the corresponding Zygomycetes isolate by injection and transferred daily into fresh LOV-containing vials at 29°C for 6 days. Flies that were starved for 6 to 8 h, transferred to vials containing regular fly food (without LOV), infected, and maintained in regular vials were used as controls. LOV protection was assessed daily until day 6 after infection. For the combination drug experiments, vials containing VRC alone (1 mg/ml), LOV alone (10 mg/ml), or VRC plus LOV (1and 10 mg/ml, respectively) were prepared as described previously (20). Each experiment was performed at least in triplicate on different days.
Median MIC and MFC values were calculated based on experiments performed in triplicate. The Mann-Whitney U test or Kruskal-Wallis one-way analysis of variance with Dunn's test was used when appropriate to assess significant differences in the corresponding MICs and MFCs. Survival curves were plotted by using Kaplan-Meier analysis, and differences in survival rates between the groups were analyzed by using the log rank test. A four-parameter logistic regression model (Hill equation) was fitted to XTT reduction assay data to determine EC50 values and the steepness of inhibitory dose-response curves (Hill slope) with the use of a curve-fitting software program (Prism 4; GraphPad Software, Inc., San Diego, Calif.). P values of less than 0.05 were considered statistically significant.
The MICs and MFCs for AMB, ITC, VRC, and CAS are listed in Table Table1.1. AMB exhibited fungicidal activity against all of the Zygomycetes isolates tested, as the AMB MICs and MFCs (MIC50, 0.5 μg/ml; MFC50, 1 μg/ml) were equal or differed by less than 1 serial dilution in every case. By comparison, only ITC (MIC50, 4 μg/ml; MFC50, 8 μg/ml) demonstrated limited fungistatic efficacy against some Zygomycetes isolates, whereas neither VRC (MIC50, 8 μg/ml; MFC50, 16 μg/ml) nor CAS (MIC50, 32 μg/ml; MFC50, 32 μg/ml) had any activity at the concentrations tested.
The MICs and MFCs of LOV against Zygomycetes isolates in RPMI, RPMI-2, and YNB media are shown in Table Table2.2. LOV exhibited fungicidal activity against all of the isolates (MIC50, 48 μg/ml [range, 32 to 56 μg/ml]; MFC50, 56 μg/ml [range, 48 to 64 μg/ml]) in all media tested. Although there were no significant interspecies differences, there was a trend towards improved activity of LOV against Mucor species.
The activity of LOV against zygomycetes was also clearly observable with disk diffusion susceptibility testing (Fig. (Fig.1A).1A). Notably, LOV produced a clear zone of inhibition of growth against all Zygomycetes isolates (mean radius ± standard deviation for LOV, 12.570 ± 3.861 mm).
We found a linear relationship between XTT reduction to formazan (the colorimetrically assayed product) and starting inoculum of zygomycetes for all of the isolates tested over a range of inocula (Fig. (Fig.2A).2A). Therefore, a reduction of the formazan absorbance from 3.0 to ≤0.5 optical density as a result of LOV activity against zygomycetes correlated with an approximately-2.5-log reduction in hyphal biomass.
LOV exhibited potent antifungal activity against all of the Zygomycetes isolates (median EC50, 29.4 μg/ml [range, 6.6 to 38.9 μg/ml]) in a steep concentration-inhibitory-effect curve (Hill slope range, −1.2 to −4.7). A substantial reduction (≥2.5 log) of the hyphal biomass was evident for all of the isolates as the LOV concentration approached the MFC (Fig. (Fig.2B).2B). Again, LOV appeared to be more effective against Mucor spp. than against Rhizopus and Cunninghamella spp. The in vitro activity of LOV was consistent among all three media tested (Table (Table22).
While control hyphae cells (without drug preexposure) demonstrated absence of fluorescence after DiBAC staining, there was clearly evident Zygomycetes hyphal damage in high concentrations of LOV (4× EC50; 16 μg/ml) of each isolate tested; at a subinhibitory LOV concentration (4 μg/ml), the fluorescence indicative of hyphal damage caused by LOV was minimal to absent (Fig. (Fig.3).3). AMB exhibited a pronounced hyphal damage at a concentration equal to the MFC (2 μg/ml), whereas VRC had no fungicidal activity at a clinically achievable concentration (2 μg/ml).
Injection of a concentrated solution of conidia (108 conidia/ml) of either R. oryzae or M. circinelloides resulted in a hyperacute infection with equally high mortality rates in Tl flies (>80%) within 3 days of infection (Fig. (Fig.4A).4A). LOV-fed flies had a significantly better survival rate 6 days after infection with M. circinelloides (50%) than did control flies (<15%; P = 0.0005) (Fig. (Fig.4A).4A). However, LOV had no activity in Tl flies infected with R. oryzae (Fig. (Fig.4A4A).
By XTT-based checkerboard, the combination of both LOV and VRC was synergistic against all of the Zygomycetes isolates tested (FIC index of ≤0.5), with FIC indices ranging from 0.104 to 0.290 (Table (Table3).3). Importantly, the interaction of LOV with VRC resulted in MICs (VRC MIC50, 1 μg/ml; LOV MIC50, 2 μg/ml) that were in the range of clinically achievable concentrations of both drugs (Table (Table33).
The effects of LOV on VRC MICs against all of the Zygomycetes isolates by Etest/plate dilution method are shown in Table Table33 and Fig. Fig.1B.1B. There was a significant, pronounced reduction in VRC MICs (threefold to sixfold) following concomitant exposure of all of the Zygomycetes isolates to both LOV and VRC (P < 0001).
The combination of VRC and LOV at subinhibitory concentrations for both drugs (2 and 4 μg/ml, respectively) potentiated fungicidal activity against Zygomyceteshyphae, as evidenced by DiBAC staining (Fig. (Fig.3).3). In pilot experiments, VRC alone was shown to cause minimal fluorescence indicative of cellular wall and membrane damage in Zygomycetes hyphae at concentrations up to 8 μg/ml. The effects of VRC combined with LOV on hyphal damage were comparable with those of AMB at concentrations equal to the MFC (2 μg/ml).
Previous studies showed that concentrations of VRC up to 2 mg/ml were not toxic in adult flies (21). We found that Tl flies fed with LOV plus VRC and infected with either R. oryzae or M. circinelloides had a significantly better survival rate than did infected flies fed with LOV alone (P < 0.01). VRC alone had no activity in infected Tl flies (Fig. (Fig.4B4B).
The development of oral antifungal therapeutic strategies is a major unmet medical need for zygomycosis, an opportunistic mycosis for which oral antifungal options are extremely limited (11). In the present study, we found that the in vitro susceptibilities of the Zygomycetes isolates to the antifungal drugs tested were in agreement with those from previous studies (6,11, 30). Indeed, of the antifungal agents tested, only AMB exhibited significant fungicidal activity. Although it has been reported that Zygomycetes spp. might be susceptible to ITC in vitro (6), ITC exhibited marginal fungistatic activities against the isolates tested in our study. However, the Rhizopus, Mucor, and Cunninghamella isolates that we tested were more resistant to ITC than were Absidia and Rhizomucor isolates tested elsewhere (6, 30). Our study also confirmed the well-described in vitro resistance of Zygomycetes spp. to VRC and CAS (6, 11, 30).
We also found that LOV had considerable in vitro fungicidal activity against all seven Zygomycetes isolates tested. Although we did not observe dramatic interspecies differences in susceptibility to LOV, the Mucor isolates appeared to be more susceptible to LOV than the other isolates were. In comparison, a recent study that used nonstandardized methods found that Rhizomucor pusillus strains were remarkably more sensitive to LOV than Rhizomucor miehei strains were according to agar diffusion susceptibility testing (23).
Furthermore, we observed that the activity of LOV against Zygomycetes isolates was consistent across several different culture media. Of note, there was a trend toward lower LOV MICs and EC50s in YNB media. Our group and others have postulated that because enriched YNB medium facilitates fungal growth compared with RPMI and RPMI-2, it might result in increased metabolic activity of fungal cells and better drug penetration into the intracellular sites of drug action (20, 24).
To better characterize the effects of LOV against Zygomycetes spp., we employed a strategy combining different viability dye staining methods (18). We found that the XTT colorimetric assay was able to accurately quantify the Zygomycetes fungal biomass. However, the incubation period was much shorter than with other filamentous fungi (18). In agreement with studies of other filamentous fungi (18, 25), we found that the LOV EC50s correlated better with the MICs for Zygomycetes spp.
We then microscopically confirmed the fungicidal activity of LOV against Zygomycetes spp. by staining LOV-treated hyphae with the fluorescence morbidity dye DiBAC. In correlation with XTT-based analysis, DiBAC staining showed that LOV had minimal fungicidal activity at a low concentration (2μg/ml), whereas it caused prominent hyphal damage at fungicidal concentrations (4× EC50; 16 μg/ml). The fungicidal effects of LOV were comparable with those of AMB at a fungicidal concentration (2 μg/ml).
To examine whether LOV has the same activity against Zygomycetes spp. in vivo, we adapted an established mini-host model of zygomycosis in Drosophila melanogaster. Importantly, this model organism has been successfully used to assess the in vivo effects of LOV in the field of neurological research (2). We found that LOV had a significant protective effect in flies infected with a M. circinelloides strain. However, LOV had no activity in Tl flies infected by a less susceptible in vitro R. oryzae strain. Although Drosophila offers several advantages over conventional, logistically more difficult animal models in the screening of candidate compounds for antifungal activity because of its simplicity and rapidity, it does not allow for quantification of orally absorbed drugs. As a result, pharmacodynamic and pharmacokinetic studies with Drosophila are challenging, whereas little is known of the metabolism of LOV in this model. Thus, our promising findings of LOV activity in Tl flies will need further validation with mammalian models of zygomycosis.
As statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme in ergosterol biosynthesis (26), azoles block a sequential target in the ergosterol biosynthetic pathway (C-14 demethylation) (22). We analyzed the interaction of LOV with VRC, a triazole with no meaningful activity against Zygomycetes spp., because the potential of statins to overcome azole resistance has been shown previously for Candida (5) and might have even greater clinical significance. By employing checkerboard dilution and Etest-based methods, we found that at subinhibitory concentrations, LOV significantly potentiated the activity of VRC against all of the Zygomycetes isolates tested in vitro. We further verified this observation by using DiBAC staining. Importantly, the concentrations of LOV used in synergy studies with VRC were within the range of serum concentrations of LOV reported for mammalian models (2 to 20 μM or 0.5 to 5 μg/ml) and for humans (3.9 μM or 1 μg/ml) (4). Finally, we found that LOV and VRC exhibited synergistic effects against two representative Zygomycetes isolates in vivo in the Drosophila model of zygomycosis. These results are in agreement with studies that reported in vitro synergy of statins with different azoles against Candida and Cryptococcus species (5). Importantly, there is also evidence of in vivo synergy of LOV and azoles against Trypanosoma cruzi, a protozoan parasite in which, similar to fungi, ergosterol is an essential cell membrane component (31).
Although sequential inhibition of sterol biosynthesis may be plausible (22), the mechanisms of the antifungal activity of LOV remain largely unexplored because of the pleiotropic effects of LOV in cellular metabolism. For example, LOV is a well-known inhibitor of protein isoprenylation, a highly conserved essential process for cell proliferation, differentiation, and apoptosis in eukaryotes from fungi to humans (4, 10, 26) as well as in prokaryotes (34). Importantly, LOV was recently shown to induce apoptosis of several human cancer cell lines by mechanisms involving inhibition of Ras and several other isoprenoids (1, 4, 13, 14, 26). Similarly, LOV was recently shown to suppress the expression of three Ras genes in M. racemosus and to induce apoptosis-like cell death (29). However, the exact mechanisms that mediate apoptosis in fungi seem to be complex and have not been elucidated. Exploring the underlying mechanisms of LOV activity against Zygomycetesmight pave the way for the development of compounds with more selective action. This is particularly important in view of the fact that significant toxicity has been reported as a result of statin interactions with azoles or other drugs that are metabolized in the liver by cytochrome P450 (4). Finally, expanding these observations to other members of the statin family with or without other azoles that exhibit activity against Zygomycetes (e.g., posaconazole) or other classes of antifungal agents would be of interest.
In conclusion, the significant antifungal activity of LOV against Zygomycetes as well as its synergy with triazoles may result in significant clinical applications in the near future.
We are grateful to Nathaniel D. Albert for technical assistance and Don Norwood for editorial assistance.
This work was supported by The University of Texas M. D. AndersonCancer Center Faculty E. N. Cobb Scholar Award Research Endowment (to D.P.K.).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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The 2012 Election Roadmap: Chicago Cocktail Hour Discussion with Michael Barone
Illinois Policy
Thursday, January 12, 2012 from 6:00 PM to 8:00 PM (CST)
Event Details
Contrary to popular perception, the underlying trends nationally and in Illinois bode well for liberty and free markets—but the jury is still out on whether this will be manifested in election results. Please join us on January 12 as we host Michael Barone for a cocktail hour discussion on what the 2012 election will look like.
Michael Barone is a renowned and respected political historian who is at the forefront of American political coverage. As senior writer and author of the bi-monthly column, "The National Interest," Barone explores and analyzes political issues with passion and clarity. Barone's work has appeared in The Economist and The New York Times, among many others.
Appetizers and drinks will be served.
When & Where
The Library
190 South LaSalle
40th Floor Library
Thursday, January 12, 2012 from 6:00 PM to 8:00 PM (CST)
Add to my calendar
Illinois Policy
Illinois' comeback story starts here.


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Hi everyone!
I am the mom of Alice and Jane and new to moms.com
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Alice is 8 and dances ballet and tap. She will be doing her grade 1 ballet exam this year!
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We all love to dance and sing. We are the crazy family who sings along to the songs playing in the supermarket haha!
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Justin Bieber Flashes Underwear In Baggy Pants
January 10, 2012 by staff
Justin Bieber Flashes Underwear In Baggy Pants, Justin Bieber stepped out in Paris, France today wearing his usual dogtag/purple tee/black button-down combo.
Except this time? We weren't exactly looking at his outfit. We got to see a little Bieber butt (ok fine, underwear) thanks to those super saggy pants of his. And this isn't exactly the first time we've seen Justin Bieber in his underwear…
Please feel free to send if you have any questions regarding this post , you can contact on
Disclaimer: The views expressed on this site are that of the authors and not necessarily that of U.S.S.POST.


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INSERT INTO sites(host) VALUES('babylon-idiomas.com') 1045: Access denied for user 'www-data'@'localhost' (using password: NO)
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Title:Learn Spanish in Spain, Argentina and Cuba
Description:Learn Spanish in Spain, Argentina and Cuba with Babylon Idiomas, voted Best Spanish Language School in 2011: Courses for adult students in small groups
Keywords: Learn Spanish in Spain, Spanish in Argentina, Spanish in Cuba, Learn Spanish
Learn Spanish in Spain, Argentina and Cuba (+34) 91 4200663 Home Spanish Courses Who We Are Course Overview Intensive 20 20 classes per week Tamara Value 20 new 20 classes per week Super-Intensive 30 30 classes per week DELE Exam Preparation course InmersiУГn Intensive + Private EspaУБol ExprУЉs Spanish 1:1 Immersion Spanish + Xtra Spanish + Dance Mi Profe Homestay Spanish Group Travel Customised courses Tools Spanish Level Test Long Term Courses: See our discounts Our Spanish Schools Spain Barcelona Art, Fun amp; Beach Madrid Capital of the Latin World Salamanca Home of the Spanish Language Sevilla Flamenco amp; Passion Valencia Spain's best kept Secret Latin America Buenos Aires Queen of the South Cuba Vintage Caribbean Accommodation Prices Our Prices Prices Spain Barcelona, Madrid, Sevilla, Valencia Prices Argentina Buenos Aires Prices Cuba Havana, Santiago de Cuba, Trinidad Our Guarantees Price, Quality and Satisfaction Start Dates Photos FAQ Blog Contact Us Learn Spanish in Spain and Latin America Welcome to the Babylon Idiomas website. At the heart of everything we do is our belief that learning Spanish is one of the most rewarding investments you can make in your life. In these pages you'll find all the information you need about our Spanish courses, language schools and services that we offer. We own and operate four schools in Spain and work closely with different partner schools in Argentina and Cuba as well as another school in Spain. Our company was established in 2002 and we've grown ever since to become one of the leading Spanish language learning institutes in the world. Babylon Idiomas was voted best Spanish language school in 2008 and 2011 (and nominated in 2007, 2009, 2010) and we look forward to providing our award winning services to you in the near future. Read the comments from our former students (over 1000 comments and growing every week) to get a good idea of why Babylon Idiomas is the leading Spanish language school in the world. You can easily contact us or simply book online to reserve your seat in one of our classrooms. You can choose to study in any of our Spanish language schools - or even combine a number of different locations. raquo; Study Spanish in Spain [Barcelona, Madrid, Salamanca, Sevilla or Valencia], raquo; Study Spanish in Argentina [Buenos Aires] raquo; Study Spanish in Cuba [Havana, Trinidad or Santiago de Cuba]. raquo; Get your FREE brochure Sit back, relax and watch the video: Our Spanish Courses At the core of our academic program stands the Intensive course which consists of 20 classes per week. We highly recommend to add 5 classes of culture classes to provide you with insights in the Spanish culture, build your vocabulary and train your comprehension skills. You can also choose to add 2 classes of extra conversation and culture classes to this course with our Super-intensive course. If you wish to obtain an official Spanish diploma, you can consider taking the DELE preparation which prepares for the Inicial [A2], Intermedio [B2] or Superior [C2] DELE exam. A very popular course is our Inmersi oacute;n course which combines group classes with individual Spanish lessons. If you need to take a crash course, consider the Espa ntilde;ol Expr eacute;s formula. We offer language courses for adult students in small groups with a maximum of 10 students (6 or less in our Latin American centres). You can choose your own study length from 1 week to a full year and you can start on any Monday. If you want to immerse yourself completely at the home of a teacher, have a look at our Homestay Spanish program. Our website is our business card and you'll find all the information you need here. We have some special information pages if you are an absolute beginner or if you are looking for long term Spanish courses. raquo; Learn more about the range of Spanish programs that we offer Why learn Spanish with Babylon Idiomas? We have been voted Best Spanish language school by readers of Study Travel Magazine in 2008 and 2011 (and we were nominated as well in 2007, 2009 and 2010). Our academic standards have been accredited by Instituto Cervantes which is the national Spanish institution that promotes the Spanish language. Our methodologies are focused on conversation so that you'll learn Spanish in a natural, practical and fast way We only teach Spanish to students 18 years and older so you feel at home with all the other students who come from all over the world. We only teach in small groups of 10 students or less so that you get the attention you need to really make progress. All of our teachers are Spanish native and university trained to teach Spanish as a foreign language All our Spanish schools offer a personal, friendly environment to make it really easy to meet other students and make new friends A Customer Service desk is there to help you 24/7 to make the most of your stay with us. How to choose your Spanish language school? Our website offers a lot of information about the different programs and destinations that we offer. If you don't know yet where you want to go, have a look around first on our Spanish language school pages. Once you know where you want to go, visit the section about our Spanish language programs. Don't forget to use the search function if you are looking for a particular piece of information. To enrol for one of our courses, simply visit our Easy Price Calculator, select the location, course(s) and accommodation (if required) and you'll be automatically shown an overview of your investment. We'd love to hear from you and assist you in choosing a course that is right for you and advise you on the different Spanish language school destinations that we offer. Our team is here to help you. Cursos de inglУЉsAprende inglУЉs en nuestras academias y en extranjero! Sign upEnroll today and join our amazing community Price CalculatorDiscover how much your Spanish Course costs Free BrochureDownload our free brochure now Content 1 Here. Go to 3rd slide Content 2 Here. Content 3 Here. Read more comments Spanish Level TestHow good is your Spanish Today? Visit our BlogSpanish, Culture, News, Reviews Photo GalleryStudents, Destinations, Fun Ask us a question Contact us and we will get back to you within 24 hours Promotions Discover this month's discounts and offers Sign up now Enrol now and join the Babylon Idiomas community Subscribe About Us - Contact Us - Terms amp; Conditions - Privacy Policy - Agencies - Affiliate Program - Sitemap - Cursos de ingl eacute;s


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|Home > Nechamit
♀ Nechamit
What does Nechamit mean?
Nechamit [nechamit] as a name for girls is of Hebrew origin, and the name Nechamit means "comfort, solace". Nechamit is an alternate spelling of Nechama (Hebrew): a male form.
ALTERNATIVE FORMS VIA NECHAMA Nachmanit, Nechamah, NehamahCREATIVE FORMS
(male) MIDDLE NAME PAIRINGS
Nechamit Anika (N.A.), ..
How popular is Nechamit?
Nechamit is a rare given name for women. Nechamit is also a rare surname for both adults and children. (2000 U.S. CENSUS)
Which version is better?with its source form and related girl names. Nechama (#1796 FROM CURRENT RECORDS) is the only prominent related form of Nechamit (NOT RANKED) rated in the Top 2000. Other variants, like Nachmanit, are seldom used. This form of Nechamit was popular as a baby name presently (#1796). (2015 U.S. SSA RECORDS)
Similar NamesRecommended names are Lehavit (see Lehava), Nachuma, Nathalia▲, Nathalie▲, Nathania, Navit, Nehara, Neomi, Nerit, Nesha, Netania, Nethania, Nissanit, Noami, Shanit, Shulamit, Yehudit and Zehavit. These names tend to be more frequently used than Nechamit.See names in meaning and etymology.


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A new study published in the journal Oecologia reveals that California oyster beds are under attack from introduced species, including Atlantic snails and the European green crab.
Labels: California, crabs, crustaceans, marine, mollusks, oysters
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Los Angeles Dorsey offensive guard Jovon Hayes has a lot on his hands right now. He's trying to help his team continue its great season, and he also has to deal with sifting through more scholarshi...
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Data from: Rates of dinosaur body mass evolution indicate 170 million years of sustained ecological innovation on the avian stem lineage
Date Published: May 7, 2014
DOI: http://dx.doi.org/10.5061/dryad.gr1qp
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This campaign will be won one conversation at time. This is why your help is so important to our success. Over here at HKHP, we care a lot about the overall health of our community and are deeply invested in taking steps to make things better for all Portlanders. If you share our values, can you help by spreading the word? Here are some ways you can get involved:
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Fill out the form below to sign up and we'll be in touch. Don't have any time to spare but you care about this issue? Make a donation here.


text: SNSD's popular sub-unit TaeTiSeo made a comeback for the holiday season with the new single "Dear Santa". The jolly track is from the mini-album of the same name, and the album jacket featured a bunch of shots that keep with the season's wintry theme. In one set, each member is styled in a plush angora tank top which is paired with a furry, pearl-embellished choker. The jewelry item is actually a THIERS Kelly Fox Bracelet ($27) that can be extended to wear around the neck as well! Taeyeon, Tiffany an Seohyun wear Ivory, Gray and Brown varieties, respectively. It is also available in Navy or Black.


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Purple Dodge Challenger SRT is Nothing to Laugh at: 2012 SEMA Show
Teaming up with comedian and ventriloquist Jeff Dunham, Mopar built a one-of-a-kind Dodge Challenger SRT that was unveiled late yesterday afternoon at the 2012 SEMA Show.
Under the hood of the Challenger is a Mopar 426 HEMI engine that's further modified with a Mopar cold air intake. A custom side-exhaust was built into the rockers before the Challenger got a two-tone paint job: "Ultraviolet" on the body and "Satin" black on the upper half. The front grille is actually a modified Charger grille, while the headlights got a custom cover to give it a more aggressive look.
Integrated fender flares then gives the Challenger more room for its 22-inch HRE wheels which are wrapped with Pirelli tires. The build was completed by Alan Palmer and Palmer's Customs with Jeff Dunham helping make the tough decisions on the project.


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HMS Queen Caitrin was a King William-class superdreadnought of the Royal Manticoran Navy.
History Edit
She served as Admiral White Haven's flagship in the reinforcement fleet sent to the Yeltsin's Star System shortly before the Third Battle of Yeltsin's Star. (HH3)
In 1918 PD, the ship was part of Task Force 34's 12th Battle Squadron, fighting in the Second Battle of Marsh. (HH10)
Known Crewmembers Edit
- Captain Frederick Goldstein – Commanding Officer in 1905 PD


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