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Barcelona Card Review- What is Included: Unlimited Public Transport and Discount Entry for Attractions in Barcelona City Centre.
This page will give you a review of the Barcelona Card - the discount tourist card issued by the Barcelona tourism board. The card offers a range of discounts, unlimited trips on the public transport system and the convenience of not having to queue to buy your transport tickets in a foreign language. Simply whip out your Barcelona Card and you're away!
7 Reasons for considering the Barcelona Tourist Card
1. Unlimited transport on Barcelona public transport network in the city centre is included in the Barcelona Card. No more lost holiday time queuing for travel tickets. Once you have the Barcelona Card public transport within the city centre (Zone 1) is included on the public transport system.
- No need to buy metro, tram or bus tickets. The area covered for public transport travel is zone 1 which covers the entire city centre and all the main tourist attraction areas in Barcelona. Here is the transport that is included:
- Airport train, Airport metro line L9 from both T1 and T2, or TMB bus from Barcelona airport to the city centre.
- You can travel without charge on the RENFE train, the airport metro link or the TMB N46 bus (but not the Aerobus) from the airport to the city centre.
The Barcelona Card will save you time and makes your holiday more enjoyable as most of your transport cost is included at no additional charge.
2.Save money on entrance fees for many major attractions. You can also enter for free to some attractions with the card. We have not listed which ones here because the offers change frequently. You will be informed which ones when you are presented with the card.
3. Discount Souvenirs: You are also entitled to special discounts in the official Barcelona Turisme souvenir shop which you will find in Plaça de Catalunya square tourist information office.
4. Restaurant discounts: Discounts can also be had on some specific restaurants (see below)
5. Performance/show discounts: You will also receive discount tickets to shows at Palau de la Musica and Theatre Liceu which are important music venues in the city (see below for more details)
6. Improved personal security. If you've read our article on personal safety in Barcelona you would have learned that petty theft and pick pocketing in Barcelona is a problem particularly at stations where tourists have to purchase transport tickets. The reason is that pickpockets can see where tourists keep their money. With the Barcelona Card you do not need to take out your wallets / purses to purchase tickets - your transport has been all paid for in advance and if you keep your Barcelona card in a separate location to your purse or wallet no pickpocket will know where you keep your money.
7. Barcelona map and Barcelona guide are included with the Barcelona Card. Along with your Barcelona Card you will have a map and guide which is useful to help you navigate around the main points of interest and Barcelona attractions. However if you want to have a more detailed map you would probably need to supplement this with a good guide book.
If you want entry tickets for the Sagrada Familia by Gaudi (Barcelona's No.1 tourist attraction) we recommend you consider the BCN Essentials Pass instead of the Barcelona Card. The BCN Essentials pass includes entrance tickets to Sagrada Familia, Park Guell and includes unlimited transport on the Barcelona public transport system. You also get a downloadable audio guide of the city of Barcelona along with interactive maps so you can easily plan your own guided tours of the city. The other great feature of the BCN Essentials pass is it is sent to you by email immediately after you order so you don't need to visit a tourist information office to pick it up.
Here's a little more detail on what the Barcelona Card offers you.
Unlimited public transport at no charge
The card gives you unlimited travel on the Barcelona public transport system including the Metro underground system, the buses around the city centre, the tram system and the train service from the city centre to Barcelona airport. No need to buy any tickets for public transport it is included in the price of the Barcelona Card .
Discounts on entry to many museums and art galleries.
The Barcelona card will give you good discounts on entry to many popular museums and art galleries. Here are just a few of the discounts you will get:
Museum de Historia de Catalunya: 15%
MNAC museum: 15%
Maritime Museum: 15%
Casa Batlló: 15%
Save Money on Barcelona Original Souvenirs
Buy your Barcelona original souvenirs from the souvenirs shop in Barcelona tourist office in Plaça de Catalunya and receive a discount with the Barcelona Card.
Tourist Discount on Specific Restaurants
Enjoy 10% discounts on specific Barcelona restaurants that will be listed when you purchase your card.
Savings on Shows And Music
Obtain a saving on Palau de la Musica (A beautiful classical music venue) and Gran Teatre del Liceu (Opera, theatre and musicals venue).
Tourist guide and map of Barcelona
When you pick up your Barcelona card you will receive a basic street map of the city, metro map and a simple but comprehensive guide to Barcelona's main attractions along with details on where you will obtain discounts.
How much is the Barcelona Card?
The Barcelona card price varies depending on 2 factors:
1. How many days you choose the card to be valid for.
2. Whether the Barcelona Card is for an adult or for a child.
To find out up to date prices for the Barcelona Card see the link below.
How can I buy the Barcelona Card?
You have 2 options for buying your travel and discount card:
Purchase Online: You can purchase your Barcelona Card online which is the easiest and simplest way.
When you pay for your discount card online you can pick it up from Barcelona airport tourist information and then obtain free travel on the RENFE train to the city centre. You will need both the voucher you purchased online and photographic identification to be able to pick up you card.
Opening hours Tourist Office Barcelona Airport:
|02 January - 23 December||Monday - Sunday||08:30 - 20:30|
|24 December||Sunday||08:30 - 18:30|
|26 December||Tuesday||08:30 - 19:30|
|27 December - 30 December||Wednesday - Saturday||08:30 - 20:30|
|31 December||Sunday||08:30 - 19:30|
Tourist office: Alternatively you can purchase the Barcelona Card from the Tourist information offices in Barcelona city centre when you visit.
How many days is the Barcelona Card valid for?
You can buy a Barcelona cards valid from 2 to 5 days. The price of the card varies depending on the number of days of validity you choose.
It is worth thinking about what you intend to use the Barcelona Card for and figure out how much you would be saving before you purchase the card. This would mean taking some time to do some advanced planning before your trip. Once you know what you want to see and do you can more easily figure out if the card will be value for money. Bear in mind that you can use the card not only for free transport and discounted entrance fees but also souvenir shopping, and attending many key cultural venues and entertainments.
Another important factor to consider is the convenience of booking the ticket in advance knowing your transport tickets are covered - which can help you with budgeting your holiday. You can forget about most of your transport costs once you have the Barcelona Card because most of your public transport cost are covered and you can travel on the entire metro system that cover all of Zone 1 which is were all the main attractions are situated.
An exception is the card will not cover you for train journeys that go outside of Barcelona city centre but it does entitle you to free transport on the RENFE train between BCN international airport and the city centre. Alternatively you can use it on the TMB bus from the airport to the city centre but it does not cover you for the Aerobus (express bus) from the airport.

domain: travel


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By Marcia Pilgeram
Reader Food Columnist
As the westbound Empire Builder ground to a halt at the Williston, N.D., train station, Miley, my 11-year-old granddaughter, gave me one last hug on the vestibule of our sleeping car before stepping onto the platform and waving goodbye before I returned to the cozy (and lonely) little roomette to complete my trip to home.
Miley and I were returning from a long-awaited trip to Chicago, where we split our nights between a fancy girl’s stay at the historic Palmer House Hotel and my daughter Casey’s home for Easter. And though many 11-year-old girls visiting the Windy City would have visions of the flagship America Girl doll store on the Magnificent Mile, Miley was keen on picking up a few pastry-making supplies and shopping at Eataly, the Italian food mecca.
As a single parent raising four children, my son Zane has his hands full, and though she’s just barely 11, Miley prepares many of the meals and all the desserts for her family. She’s been my shadow in the kitchen since she was 5 years old. I don’t see her nearly as often as I’d like, but we always look forward to the coveted time we spend together in the kitchen, where she loves hearing childhood stories about her daddy while we whip up some of his favorite foods, like twice-baked potatoes and extra-gooey cinnamon rolls.
I’d secretly like to take culinary credit for her baking skills, and it is possible some of these skills seeped into her DNA, but to be honest, a lot of credit for her baking expertise goes to her country school in Savage, Montana, where they offer a program that is, well, genius.
Genius Hour is a project-based learning movement where Miley and other students explore their own passions and curiosities for a set amount of time, usually ranging from one hour per week to 20 percent of their total class time. This approach allows for self-directed learning and passion-based work, such as photography or music (or baking).
This was Miley’s first foray into Genius Hour, and in the past couple of months she has mastered the art of Eclairs, from scratch, including the Pâte à Choux pastry (for the shells), which, containing only four ingredients, can be a daunting project, especially for a beginner. Flour, water and butter are boiled until thickened and then tempered eggs are added one at a time and beaten by hand before the dough is piped onto baking sheets, egg washed and baked.
Miley’s dream is to someday own her own bakery, and a couple of months ago I decided I would try and plan something bakery-related to both reward and encourage my aspiring young chef during our trip to the city. The perfect tour would have been my own alma mater, The French Pastry School of Chicago, but they were closing for spring break. So I placed a call to HotChocolate Café, the eatery of James Beard Award-winning pastry chef and author of Cookie Love, Mindy Segal.
I met Mindy a couple of years ago at the Montana Master Chef program at Paws Up Resort, a luxury guest ranch near Missoula. She’s a badass, tattooed baker, known as the godmother of Chicago pastry chefs (who now also peddles a sophisticated line of edibles). At the time, she autographed a copy of her recently-released cookbook for Chicago-based Casey, and we spent some time discussing our favorite restaurants there.
HotChocolate Café, in Bucktown/Wicker Park, will forever top my list. After we met up with Casey for a delicious lunch of classic Americana comfort foods (and, according to Miley, the best vanilla milkshake in the universe), Miley got an autographed copy of Cookie Love and then a tour of the lively, urban bakery/kitchen.
I will forever be indebted to Mindy’s incomparable kitchen staff, who treated Miley not as a kid, but as a professional pastry-making peer. It was a transcending experience in the life of an impressionable young lady who has a lot of life decisions coming her way the next 10 years.
I’m not sure which recipes in Mindy’s book will become Miley’s favorites, but I have no doubt that Miley will use that book as an inspiration and her baking bible for many years to come. And we’ll both covet those sweet memories even longer!
I am sure that, after our indulgent week of sugared-coated bliss, Miley and I were happy to prep some savory veggies to serve at Aunt Casey’s Easter spread. Miley’s pastries were a big hit, but my roasted Brussels sprouts (with mushrooms, peppers and garlic) recipe faired well, too.
Roasted Brussels Sprouts with Mushrooms, Peppers and Garlic Recipe • serves 6
• 1 lb Brussels sprouts
• 8 ounces sliced mushrooms
• 1 orange pepper, diced
• 4 cloves garlic, crushed and
• 3 tablespoons olive oil
• 2 tbs soft butter
• 2 tsp fresh minced rosemary
• 1/2 teaspoon salt
• 1/4 teaspoon coarse black pepper
• Age balsamic vinegar
Preheat the oven to 400° F.
Wash the Brussels sprouts then trim the stems and cut the Brussels sprouts in half.
Add the sprouts, mushrooms, pepper and garlic to a large bowl.
Drizzle with the olive oil, add soft butter, rosemary, salt and pepper.
Toss well by hand to coat. Pour onto a baking sheet and bake for 20 to 25 minutes or until the Brussels sprouts are nicely browned and tender when pierced with a knife.
Drizzle with aged balsamic and serve hot.
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domain: food


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An earthwork enclosure of post medieval date, centred at SK36982722, has been identified on good quality aerial photographs as a rectangular enclosure, 30m by 20m, defined by a bank. This enclosure is attached to ridge and furrow, seen as an interrupted random, mixed shape system with 'blocks' on average 160m by ??m. (1)
Index: RCHME. 1995. New National Forest Project: 931695. 931695. p1023-4.
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Centred SK 3698 2706 (10m by 330m) (Centred on)
STANTON BY BRIDGE, SOUTH DERBYSHIRE, DERBYSHIRE
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Record last edited
Mar 29 2010 4:16PM
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domain: geography


Popular now on KPCC
Archive for August 9th, 2018
The federal government will overhaul accountable care organizations, an Obama-era innovation. The change could lead to a dramatic decrease in hospitals and doctors participating in the program.
The president blamed the intensity of the fires on state environmental policies, incorrectly claiming water that could be used to fight the fires is being pumped into the Pacific Ocean.
In recent weeks, dozens of military recruits had their enlistment contracts canceled. They had joined the military as part of a program to recruit foreign nationals with critically needed skills.
The founder of WikiLeaks received a request to testify in person before the Senate intelligence committee about Russian interference in the 2016 presidential election, his lawyer says.
Vice President Pence said in a speech Thursday that the Space Force, which would be the military's sixth branch, will "prepare for the next battlefield" and "a new generation of threats."
Damaging aftershocks continue to shake the island of Lombak, which suffered a deadly earthquake on Sunday. Rescue workers are struggling to reach the injured in some remote areas.
Many doctors never find out when a patient dies from an overdose. A new study shows that when find out, it can alter the way they prescribe addictive drugs.
Atlantic writer Franklin Foer says President Trump has "radicalized" Immigration and Customs Enforcement (ICE), opening the door for the agency to deport any undocumented immigrant.
New research finds that stomach infections, like norovirus and rotavirus, have a special way to get to us hard — and fast. That knowledge could lead to new, more effective treatments.
At the beginning of this year, Bejuique "Bay" Shambow and Bobby Austin were sleeping in a tent along the Santa Ana riverbed in Orange County. Then, in February, they and hundreds of their fellow campers were kicked out of the encampment by OC officials and given temporary shelter.
Linguist Geoff Nunberg says it's common for citizens of democracies to express concerns about the government. But the term "deep state" refers to something more nefarious — and conspiratorial.
The New York City Council voted to put new licenses for Uber and Lyft cars on hold for a year to study the services' effect on traffic congestion and look at how drivers are paid.
Tribune CEO Peter Kern said Thursday that the deal unraveled because Sinclair chose to follow a strategy that was only in its own self-interest.
At least three people are reportedly dead and a dozen injured in the Gaza Strip, while at least 11 people reportedly wounded when Hamas rockets landed in the southern Israeli city of Sderot.
James Loewen's 1995 book explained how history textbooks got the story of America wrong. Now, in a new edition, Loewen champions critical thinking in the age of fake news.
The Trump administration has proposed a rule that would prohibit some home health workers from having union dues deducted from their paychecks. The rule would likely undercut unions' power, all agree.
The new Netflix series Insatiable got early attention for stereotyping its fat-to-skinny lead character, but it's not as bad as all that. It's worse.
The move, which comes months after the attack in the U.K. on Russian ex-spy Sergei Skripal and his daughter, follows pressure on the Trump administration from lawmakers in both parties.
Tenants typically represent themselves in eviction cases and face off with their landlord's attorney in unlawful eviction cases.
There were no blog entries published on this date.
On Wednesday, the NCAA announced new college basketball policies meant to overhaul the system in light of the FBI probe into recruiting practices.
Have you ever wondered who Hollywood’s good guys and gals really were? Or what it was like to work for Cecil B. DeMille? Or what about how Errol Flynn hid liquor while filming on location in New Mexico mountains?
A company in United Arab Emirates is looking to haul a giant iceberg from the Antarctic to either Australia or Africa in an effort to provide drinking water to one of these two water-starved places.
Why rent control initiatives have failed to take hold in Pasadena, Glendale and other local municipalities| August 09 2018, 9:42 AM
Some residents are facing a severe housing affordability crisis in California.
Los Angeles City Council transportation committee refined a new set of regulations Wednesday for electric scooters.
The Oscars announced yesterday that they are looking to add a new category to honor popular films.


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AuNP-DG: Deoxyglucose-Labeled Gold Nanoparticles as X-ray Computed Tomography Contrast Agents for Cancer Imaging
- First Online:
- Cite this article as:
- Aydogan, B., Li, J., Rajh, T. et al. Mol Imaging Biol (2010) 12: 463. doi:10.1007/s11307-010-0299-8
- 522 Downloads
To study the feasibility of using 2-deoxy-d-glucose (2-DG)-labeled gold nanoparticle (AuNP-DG) as a computed tomography (CT) contrast agent with tumor targeting capability through in vitro experiments.
Gold nanoparticles (AuNP) were fabricated and were conjugated with 2-deoxy-d-glucose. The human alveolar epithelial cancer cell line, A-549, was chosen for the in vitro cellular uptake assay. Two groups of cell samples were incubated with the AuNP-DG and the unlabeled AuNP, respectively. Following the incubation, the cells were washed with sterile PBS to remove the excess gold nanoparticles and spun to cell pellets using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifugation. The reconstructed CT images were analyzed using a commercial software package.
Significant contrast enhancement in the cell samples incubated with the AuNP-DG with respect to the cell samples incubated with the unlabeled AuNP was observed in multiple CT slices.
Results from this study demonstrate enhanced uptake of 2-DG-labeled gold nanoparticle by cancer cells in vitro and warrant further experiments to study the exact molecular mechanism by which the AuNP-DG is internalized and retained in the tumor cells.

domain: medical


CHILE (CBS SF ) — The U.S. Geological Survey says a strong and shallow earthquake has struck the Pacific-Antarctic ridge in the middle of the southeastern Pacific, but a tsunami is unlikely.
The USGS says the quake’s epicenter was located 1337 miles north of Mount Siple, Antarctica and 2,418 miles southwest of Puerto Natales, Chile at a depth of 7.5 miles. The quake hit at 8:25 a.m. PDT Tuesday.READ MORE: UPDATE: News Crew Security Guard Shot in Oakland Dies From Injuries; Photo of Suspect Vehicle Released
There is no tsunami threat from this earthquake, according to NOAA’s Pacific Tsunami Warning Center in Hawaii and the Japan Meteorological Advisory.
COMPLETE QUAKE COVERAGE: CBS Earthquake Resource CenterREAD MORE: UPDATE: 2 Men Shot Outside South Bay High School Football Playoff GameMotorist Arrested on Suspicion of DUI, Gun, Drug Offenses in Suisun City
Strong earthquakes with an epicenter off the coast can trigger tsunamis, depending on the size and type of the fault movement. The Pacific Tsunami Warning Center tracks earthquake data for the West Coast.
WEST COAST TSUNAMI TRACKING:
Tsunami Alerts & Maps


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- This event has passed.
In Conversation: On Baggage: Tales from a Fully Packed Life
Saturday, November 20, 2021 @ 6:00 pm
300 NE Second Ave., Miami, FL 33132 United States
Writing about his memoir Baggage: Tales from a Fully Packaged Life, actor and author Alan Cumming warns us that “No one ever fully recovers from their past. There is no cure for it. … that is what this book is about, and for: to remind you not to buy into the Hollywood ending.” Moderated by author Julio Capó Jr., associate professor of history, Steven J. Green School of International & Public Affairs.
To livestream this event visit MiamiBookFairOnline.com.
This event requires a ticket for admission.
All in-person events at MBF 2021 will require a ticket for entry. Tickets will be available to Friends of the Fair October 18 and to the general public November 3.

domain: literature


Why a Visit to La Crosse Scientific Instruments A family vacation gave me the opportunity to find La Crosse instruments. In the Summer of 2018, I was going on a road trip vacation with my wife. Our starting point was western, NY State, and our goal was Colorado Springs, Colorado. We were going to drive […]
These Are Various Articles about Weather Collection and Weather Education As a Whole
I have written various posts about weather and you.
These posts are usually light-hearted yet very informative for the reader.
Many weather subjects of many different weather subjects are discussed.
Tornado Alley Season Starts Soon The tornado alley season is fast approaching. If you know about this, this is a time to get prepared for the tornado season. But if you don’t know what tornado alley is you really will not even know the tornado season will be starting in a couple of weeks. The […]
Why Would You Use Weather Alerts As an active weather lover, you need to keep up on your current weather conditions. It gives you a certain peace of mind knowing that you have a handle on what your weather is doing. There are many individuals who feel much peace and comfort when they know what […]
We All Check the Weather You will need to check your local weather forecast if you have any outdoor plans. This would apply if you are in the process of planning a barbeque in your backyard, or maybe a long awaited snowmobiling trip, then you know all of your plans may be affected by changes […]
Celsius Compared to Fahrenheit It has been many years since I studied Centigrade versus Fahrenheit in school. Over the years as I wasn’t around nor did I ever Iearn to use Centigrade for any reason. Celsius seems like a distant memory to me. So as I have been building this site I have stopped many […]
What About Weather Station Stations Just about everyone has checked the weather first thing in the morning, dressed accordingly, and then found that things did not turn out as predicted. That’s because more traditional sources of daily climate information provide data that applies to a wider area. I am sure almost everyone interested in the […]
Questioning the Accuracy of Personal Weather Stations Weather is very important to you. Collecting the climate instrument data from around you, is important to you. You are not a novice with the elements nor are you a geek for the climate information. You are a seriously interested in the daily climate changes that are in […]
What Does a Weather Anemometer Look Like Most people who are unfamiliar with weather instruments will ask what does an anemometer look like? They do not know that many meteorological stations today are equipped with an anemometer–a device that measures information about currents of air-so on your station’s display you have access to the current […]
Welcome to George Loves Weather! If you are like me, you also have an avid interest in weather, or maybe you have a passion for weather observation, then you have arrived at the home of great informative weather equipment reviews. You probably also you have a more than casual relationship with the weather and it’s […]


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My kids have never noticed that I’m sneaking carrots and yams into their sauce! I mix the healthy puree right into the bottled tomato sauce, then I let the kids add the toppings. You can even prepare this pizza ahead of time without cooking it, and then refrigerate for a day or two. Simply bake when you’re ready to eat.
Makes 1 large pizza or 4 smaller pizzas:
1 store-bought pizza dough or 4 “ Greek style” pocketless pitas (whole wheat preferred)
1 cup store-bought tomato sauce
1 cup Orange Puree (see recipe above)
1 to 2 cups low-fat shredded mozzarella cheese
Preheat oven to 400 degrees and preheat a pizza stone or spray a baking sheet with oil.
Stretch pizza dough, or roll out with floured rolling pin on floured surface, to form a pie. Transfer to stone or baking sheet. If using pocketless pitas, place them on the prepared baking sheet. Combine tomato sauce with Orange Puree. Mix well. Spread 1/2 to 1 cup of the sauce mixture across the large pizza dough (1/4 cup for each pita), then top with 1 cup of mozzarella (1/2 cup per pita). Cover and refrigerate at this point, or bake for 15 to 20 minutes until bubbly and lightly browned. Allow to cool a few minutes, then cut into triangles and serve.
For more information visit www.thesneakychef.com.


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Minecraft Socks 3 Pack - Green Posters
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domain: design


Aegithina lafresnayei, Gustav Hartlaub, 1844
The great iora (Aegithina lafresnayei) is a species of bird in the family Aegithinidae. It is found in Cambodia, China, Laos, Malaysia, Myanmar, Thailand, and Vietnam. Its natural habitat is subtropical or tropical moist lowland forest.
This article uses material from Wikipedia released under the
Creative Commons Attribution-Share-Alike Licence 3.0. Eventual photos shown in this page may or may not be from Wikipedia, please see the license details for photos in photo by-lines.
Category / Seasonal Status
Recorded in an apparently wild state within the last 50 years BCST Category:
Resident or presumed resident BCST Seasonal status:
Kingdom Animalia Phylum Chordata Class Aves Order Passeriformes Family Aegithinidae Genus Aegithina Species Aegithina lafresnayei
English: Great iora Thai: นกขมิ้นน้อยปีกสีเรียบ
No photo for this species yet
Ban Bueng District, Chonburi Bang Lang National Park Bang Phra Non-Hunting Area Chaloem Rattanakosin National Park Chiang Dao District, Chiang Mai Chiang Dao Wildlife Sanctuary Doi Inthanon National Park Doi Pha Hom Pok National Park Doi Saket District, Chiang Mai Doi Suthep - Pui National Park Hala-Bala Wildlife Sanctuary Hat Yai District, Songkhla Huai Kha Khaeng Wildlife Sanctuary Huai Yang Waterfall National Park Kaeng Krachan District, Phetchaburi Kaeng Krachan National Park Kaeng Krung National Park Kantharawichai District, Maha Sarakham Kaset Sombun District, Chaiyaphum Khao Ang Rue Nai Wildlife Sanctuary Khao Banthat Wildlife Sanctuary Khao Khiao - Khao Chomphu Wildlife Sanctuary Khao Khitchakut National Park Khao Laem National Park Khao Lak - Lam Ru National Park Khao Luang National Park Khao Nam Khang National Park Khao Phra - Bang Khram Wildlife Sanctuary Khao Phra Thaeo Wildlife Sanctuary Khao Soi Dao Wildlife Sanctuary Khao Sok National Park Khao Yai National Park Khlong Saeng Wildlife Sanctuary Khuan Khanun District, Phatthalung Khun Chae National Park Kui Buri National Park Mae Rim District, Chiang Mai Mae Wong National Park Muak Lek District, Saraburi Mueang Chiang Mai District, Chiang Mai Mueang Chumphon District, Chumphon Mueang Kanchanaburi District, Kanchanaburi Mueang Krabi District, Krabi Mueang Nakhon Nayok District, Nakhon Nayok Mueang Nan District, Nan Nam Nao National Park Op Khan National Park Pachee River Wildlife Sanctuary Pak Thale Pang Sida National Park Pha Daeng National Park Pha Nam Yoi Forest Park Phi Phi Islands Phu Khiao Wildlife Sanctuary Phu Suan Sai National Park Phu Wiang National Park Ramkhamhaeng National Park Sai Yok National Park Sakaerat Environmental Research Station San Kala Khiri National Park San Sai District, Chiang Mai Sangkhla Buri District, Kanchanaburi Si Racha District, Chonburi Sri Phang-nga National Park Tai Rom Yen National Park Thale Ban National Park Tham Pla - Namtok Pha Suea National Park Tham Sakoen National Park Thung Salaeng Luang National Park Ton Nga-Chang Wildlife Sanctuary Wang Mai Forest Restoration Project Yan Ta Khao District, Trang Range map of Aegithina lafresnayei in Thailand
About our range maps
Our range maps are based on limited data we have collected. The data is not necessarily accurate nor complete.
Special thanks to Ton Smits, Parinya Pawangkhanant, Ian Dugdale and many others for their contributions.
It is free to use this map on various media. See the creative common license terms by clicking "CC" icon below the map. But remember, again; the map may not be accurate or complete.


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Life expectancy seems to have been quite short.
Life expectancy may have been quite low in the Roman period, although scholars have recently questioned the reliability of statistics taken from archaeological and other sources. However, it is clear that many women died in childbirth and many young children also died. More
Plague was, at times, a threat during the Roman Empire
At certain times in Rome's history, plagues swept the empire, killing large numbers of people. At such times, all the people’s life chances were affected by the dreaded disease, the Bubonic Plague. More
The baths were important to the Romans but their impact on health is hard to measure.
Public baths were to be found in every city throughout the Roman Empire and were the focus of the social life of the city. More
Systems of pipes or aqueducts brough fresh water to the cities.
The quantity of fresh water available in the average Roman town was far greater than in later centuries, right up to Victorian times. In Roman Britain, large aqueducts were not needed, as water could be found close to most places in rivers or wells. More
Physical exercise was much prized in Greek and Roman times.
It was the Greeks, after all, who started the Olympic Games, which continued right throughout Roman times. Sports such as wrestling were also popular. Public baths also contained gymnasiums. More
There were sewers and public toilets to help keep the cities clean.
Roman towns contained several healthy features such as sewers and even public toilets. Drainage was an important part of Roman town planning. More
In richer homes, there was central heating to keep people warm and healthy in cold winter months.
This central heating was provided by fires, whose heat was directed under the floors of the house, thus warming the rooms above. More
The practice of medicine was largely in the hands of Greek doctors.
The Greeks had developed many theories about medicine, most of which are regarded as nonsense today. More
Although many of their ideas have been disproved, the Greeks introduced the idea of careful observation.
Greek doctors developed techniques of careful observation of patients’ symptoms, and how to deal with these by such practical remedies as keeping warm, taking fresh air, herbal medicines and so on. More
War and conflict cost the lives of many Roman soldiers.
In conquering their empire, Roman soldiers fought many battles, and uprisings could see both soldiers and civilians perish. More
The towns the Romans built in Britain were actually healthier than Rome itself.
The city of Rome had grown up over the course of many centuries and, unlike many of the cities that the Romans later built (in Britain, for example), their home city was completely unplanned, with many people crowded together. More
Religion was import in every aspect of daily life, including health.
In the early period of Roman rule in Britain, the Romans worshipped many gods; there were many minor gods connected with health and childbirth to whom people would make offerings. More

domain: history


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domain: hobby


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Jacksboro Elementary Principal Joan Crutchfield took the floor to a hearty round of applause Thursday night during a special meeting at the Campbell County Board of Education office.
LAFOLLETTE—City Council is looking at leasing out part of the parking lot at the former post office on South Tennessee Avenue.
JELLICO—Town officials must secure $10,000 or jeopardize a $500,000 grant for new utility meters.
JELLICO—Board newcomer Wanda Perkins is now responsible for the town’s community meeting halls.
JACKSBORO—Friends of Campbell County Animals reports the local shelter is full.
• Lucas Zana Baker, 456 Disney Lane, Caryville, possession of schedule VI controlled substance, possession of drug paraphernalia
• Bobby Lee Barnes, 908 S. Fourth St., LaFollette, fourth offense driving while revoked, violation of seatbelt law, violation of registration law
Copyright © 2013
The LaFollette Press is your source for local news, sports, events, and information in Campbell County and LaFollette, TN, and the surrounding area.

domain: news


Remember Giraffe’s are selfish
Michael Moore Gets the Giraffe award this month. The Gosnell story is ripe with selfishness, but that kind of selfishness is so evil the “Giraffe” award hardly suffices. Moore, however, was drooling all over twitter, hoping against hope that somehow the terrorists attacks yesterday could be blamed on the Tea Party. The same Tea Party that held hundreds of events all over the nation, without one arrest. The same Tea Party whose event policy seems to be ‘leave it better than you found it,’ when in comes to the physical location, while the environmentally conscious left invariably leaves nothing but filth in its wake. Whether Occupy Wall Street or an Obama Inaugural .
Michelle Malkin documents how Moore selfishly decides to use the horrific attack to score cheap political points with his goofiest twitter followers by pointing fingers at the Tea Party. His evidence? Why, yesterday was April 15th, “Tax Day.” Stay Classy Michael.


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5564 Meat Camp Road
Todd, NC 28684
GPS: 36.332586, -81.690640
November - February: 7am - 6pm
March, April, May, September and October: 7am - 8pm
June - August: 7am - 9pm
Closed Christmas Day
Park Office Hours
8am - 5pm weekdays
Closed state holidays
Half inch of snow on the ground as of 10:15 a.m. It is snowing now and may throughout the day. Foot traction devices are recommended on trails.Last updated on: Tuesday, January 7, 2020
Less than one inch of snow/ice is on all roads, trails and walkways. Four wheel drive and foot traction devices are highly recommended.Last updated on: Sunday, January 5, 2020
Elk Knob State Park
Elk Knob State Park features one of the highest peaks in North Carolina’s high country at 5,520 feet and one of the parks system’s finest trails to the spectacular views from the summit. Other trails are being developed at this relatively new park. Despite its location in an area known for winter weather, the park attempts to stay open throughout the winter and is the only one in the system offering cross-country skiing (although skiers must provide their own equipment). At lower elevations, there are primitive, backcountry campsites for individuals and for groups. Elk Knob is an outstanding park for experiencing all seasons in the mountain environment.
Notices and alerts
Master Plan public meeting
The Division of Parks and Recreation is currently working on the Master Plan for Elk Knob State Park.
The next public meeting is:
Tuesday, December 17 from 5 to 7 p.m.
Optimist Park Clubhouse
1012 State Farm Road, Boone, NC


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NEWYou can now listen to Fox News articles!
MEMPHIS, Tenn. – Some progressive district attorneys “may have tarnished the brand,” Memphis’ new top prosecutor told Fox News, noting that he’s taken lessons from their mistakes.
Shelby County District Attorney Steve Mulroy was sworn in on Aug. 31, making him the first Democrat to hold the position in decades. He campaigned on a progressive agenda, vowing to prioritize violent crime, fix the “broken bail system,” implement restorative justice and expand Juvenile Court jurisdiction to age 25, among other policies.
“I think that there have been a few high profile reform DAs or progressive DAs that have gotten into trouble that may have tarnished the brand for your viewers,” Shelby County District Attorney Steve Mulroy told Fox News. “I want them to know that me and a lot of other people who consider themselves reform DAs also think that violent crime needs to be punished severely.”
“We also think that quality of life matters and that crime matters,” Mulroy continued. “We just think that there’s a better way of doing it.”
Steve Mulroy is the

domain: sociology


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The Adventures of Baron Munchausen (1988) by El Bicho
The films of Terry Gilliam are some of the most imaginative in terms of story ideas and visual effects in the history of the art form, and Adventures of... is no different. Based on a real 18th Century German nobleman who told outrageous tales of his adventures, which have been written about, this fantastic film delivers exactly what the title states.
During the Age of Reason, an unnamed European city is at war with the Turks. In the city, a traveling theater troupe is performing the story of Baron Munchausen, when an elderly man (John Neville) claiming to be the Baron takes to the stage, angered at the play's inaccuracies. He begins to tell the correct version of the events but the war outside makes its presence known, frightening everyone away. The Baron is resigned to die until a young girl named Sally (Sarah Polley) tells him he's the only one who can save them.
But to do so the Baron needs to locate his friends speedster Berthold (Eric Idle); marksman Adolphus (Charles McKeown, who co-wrote the script with Gilliam); the diminutive Gustavus (Jack Purvis), whose strengths are hidden in his ears and lungs; and strong man Albrecht (Winston Dennis). The Baron, with Sally stowing away, heads to the Moon, the Underworld, and the belly of a whale to reunite his team who have not escaped Father Time.
The special effects are special indeed as they show the Baron sailing to the moon and dancing in air with the Goddess Venus (Uma Thurman). Most importantly, the story is special as well with its stories layered upon stories as it speaks to the power of stories and imagination.
Solaris (1972) by Dusty Somers
Andrei Tarkovsky's cerebral and spiritual sci-fi film Solaris doesn't revel in the glories of technology or the wonder of the unknown like a lot of science fiction. Rather, it's a film that's positively homesick for earth. The opening shots of lush greenery and grass gently swaying underwater are hypnotically beautiful, setting up the mesmerizing quality of the nearly three hours to come.
Russian cosmonaut Kris Kelvin (Donatas Banionis) is being sent to the Solaris space station to find out what's become of the failed enterprise, but he's met with a lot more than he bargained for -- two fellow cosmonauts on the brink of sanity and the specter of his dead wife, who he can't prevent from appearing.
Solaris is filled with Tarkovsky's trademark languid pacing and long takes, and it makes for a film that you seemingly just sink to. Sci-fi is known to be a genre that's rigorously intellectual when it's at its best, but Tarkovsky also imbues Solaris with a deep emotional core.
Aliens (1986) by Amanda Salazar
This is a difficult category because personally I would separate the two and write about a favorite science fiction and also a favorite fantasy film, so the decision was a little difficult but I went the sci-fi route and chose James Cameron's second film the Alien series, Aliens. This film does such a wonderful job of picking up where the previous one left off, but developing a story that wasn't trite. Ripley wakes after being in hyperspace for over fifty years. When she tries to explain what has happened with the aliens, no one believes her, and they are sending out another mission to see why they have lost contact with one of their colonies.
She decides to go on the mission with a group of Marines and while there she encounters Newt, a small girl that has lost all of her family. When they find out that the colony has been taken over by aliens, a whole different mission comes into play, survival. The film is packed with great one-liners, wonderful set design, and some great scenes of alien attacks. Cameron does such a great job at maintaining a sense of fear and tension in the unknown, making for a science fiction masterpiece. The whole series is worth a look but when it comes to great science fiction films, this one did it right and to this day remains a classic.
Liquid Sky (1982) by Shawn Bourdo
For portions of my life, this was about the only genre I watched. Oh wait, it's still about the most watched genre in my watching life. It would be easy to just sort through the kings of the genre and pick Lord Of The Rings or Empire Strikes Back or Blade Runner. But I want to delve a bit deeper for my love. I see that "horror" is coming up later, so that part of sci-fi is going to come up in the future. Thinking of about my fandom of the genre - there have been some highlights. By 1983, I had done every space-related film I could find and Battlestar Galactica had rocked my TV world. I thought I was quite avant-garde as a teen - I was watching quite a few art films along with science fiction. Imagine my delighted surprise to find this mesmorizing piece showing at the local Arthouse theater in Kalamazoo.
Liquid Sky is almost indescribable. An alien ship lands on a building in Manhattan. I guess an alien gets inside of the very androgynous model Anne Carlisle. The alien can only get what he/she needs by killing a sex partner during orgasm. I wish it was easier to describe or that a description could do it justice. It certainly plays up the symbolic relationship of heroin to the alien inhabiting her body. There's also quite a bit to be parodied of the New York art crowd. Much of this feels like performance art or really more like watching someone watch performance art. The disconnect lets the viewer really step back and think about what is happening.
I think I saw The Man Who Fell To Earth in the same time frame and they make interesting companions. This is sci-fi bending the genre - expanding the possibilites. There's no two ways about it - you're either going to love or hate this film. I used to recommend it when I worked at Liberty Street Video in Ann Arbor and would often get confused, panic looks from people when they returned it. Or thanks and praise and requests for more like it. Certainly Lady Gaga uses this film as a career manual. It's not the best science fiction but it's one of my favorites that deserves a mention.

domain: entertainment


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Location: Devalsari, Tehri Garhwal, Uttarakhand
Distances: 80 km from Dehradun, 55 km from Mussoorie
Dates: 5th Devalsari Titli Utsav@ Devalsari 6th June (Thursday) to 11th June 2024 (Tuesday)
Start: First trail will begin at 1000 hrs on 6th June 2024
End: Drop off at Dehradun Railway Station by 1830 hrs on 11th June 2024
Boarding, lodging & activities costs:
Background: Uttarakhand with 65% forest area is home to some terrific biodiversity. With more than 500 species of butterflies, and innumerable moth species, it is a haven for butterfly and moth watchers. The Devalsari Society, with support from NGO’s, local communities and the Uttarakhand Forest Department, has been conducting the Devalsari Titli Utsav for 4 years now, and this year, the 5th Devalsari Titli Utsav will be held in June
Purpose: The primary purpose of the Titli Utsavs is to promote lesser-known destinations in Uttarakhand, ensure benefits to local communities through community ecotourism and to support the conservation of butterflies and moth through citizen science.
Introduction: Devalsari, tucked away in the Aglar Valley, in Tehri Garhwal District, Uttarakhand, is the home of the Jaunpuris. The snow-capped peaks of the Middle Himalayas, looming in the distance, marvelous deodar, oak and rhododendron forest, surrounded by terrace fields. The Pali Gad stream flows through Bangsil into the Aglar River, winding its way through a forest landscape with altitudes varying from 1,200 m at Thatyur up to 3,048 m at Nag Tibba, the highest peak in the area. It is 80 km from Dehradun by road (55 km from Mussoorie).
About the Society: The Devalsari Environment Protection and Technology Development Society, a rural community not-for-profit organisation, was set up to promote ecotourism and conservation at involving local youth in Devalsari and surrounding villages. The main aim of the Society is to promote village-linked livelihoods while conserving the area’s natural resources and retaining its traditional and cultural practices. The Society aims to promote ecotourism with nature tourism as its focus. The Society also promotes bee keeping and supports bee colony development by providing technical training and holding camps. Finally, the Society promotes production and marketing of local organic produce and natural honey. It markets its pure, natural honey under the brand name “Deodar”. Arun Gaur of the Society was selected for the Sanctuary Asia Wildlife Service Award in 2019. In addition, the Society made it to the Top 3 in Outlook Responsible Tourism Award (Wildlife Conservation) in Dec 2019.
About the Devalsari Titli Utsav: It is proposed to establish an annual butterfly festival at Devalsari. The festival is targeted towards visitors who have some interest and enthusiasm to watch butterflies and moths, but also targeting more serious butterfly and moth enthusiasts, who may prefer only to watch butterflies and moths. It is planned to host the festival annually.
More than 160 species of butterflies, 250 species of moths, 201 species of birds, 41 species of odonates and 13 species of bats have been recorded and identified at Devalsari.
The area is home to some stunning butterflies such as the Woolly-branded Peacock (Uttarakhand’s State Butterfly), Hairy Angle, Golden Emperor, Bluetail Jester, Brown Argus, Siren, Grand Duchess, Western Courtier, Wonderful Hairstreak, Water Hairstreak, Fawn Hairstreak, Dark Blue Royal and Walnut Blue amongst many others. The butterfly and bird checklists of Devalsari are available on request.
Proposed workshops & activities
Planned Nature trails
Accommodation: A total of 40 visitors can be accommodated in dormitory type accommodation at the Deodar Ecotourism and Research Centre (DERC), tents and homestay-based accommodation in other nearby villages (Moldhar, Udalsu, etc). Attached Western toilet with the dormitory and common Western and Indian toilets exist onsite.
How to get to Devalsari
Nearest railhead: Dehradun. Devalsari is an 80 km, 3.5 hours drive from Dehradun. Road transport is the only way to get to Devalsari.
Nearest airport: Jolly Grant, Dehradun, 115 km, 4 hours from Devalsari
Nearest town to Devalsari: Thatyur, 13 km from Devalsari
We can organise a pick up and drop off from Dehradun. then pick up and drop off charges (around Rs.4500) paid extra.
Please advise us on the date/time/pick up point for your requirement through email. Pick up/drop off point: Dehradun Railway Station. Pick up time from Dehradun: 630 am (linked to Nanda Devi Express arrival time in Dehradun). Please add this to your payment.
For your return journey, shared taxis operate from Devalsari-Dehradun every morning. This can be availed on arrival at Devalsari.


Former aide-de-camp to former president Goodluck Jonathan, Col. Ojogbane Adegbe has said another Dasukigate may be imminent if he reveals what transpired in that administration.
The Economic and Financial Crimes Commission (EFCC) picked up Adegbe on Wednesday in Lagos where he was interrogated before he was flown to Abuja yesterday.
It was gathered that ongoing interrogation of the former ADC by operatives of the EFCC could open up a new can of worms, which “could surpass what is now called Dasukigate.”
EFCC sources said the former ADC may soon give details of all he knows with regards to financial transactions and the dramatic personae involved in the last administration.
Preliminary findings, including recovered documents, were said to have hinted of large-scale questionable expenditure with funds sourced from and outside the arms purchase deals.
Another source said “most of the funds were reportedly diverted soon after the election was postponed from the originally scheduled date of February 14, 2015 to March 28, 2015…”
Among the active participants in the alleged sleaze, was a top official of an agency set up to discourage militancy in the South-South, who is currently outside the country.
At the centre of the interrogation of the former ADC, who has been moved to Abuja, Daily Sun gathered, was the “mind-boggling spending” during the two weeks’ extension of the general election, “which runs into several trillions of naira, when converted from foreign currency.”
Sources said many top Nigerians, “including some very close persons” to the former president, may likely be called to explain and defend their roles in the handling of the funds, a chunk of which was sourced from the agency.


South African cricket officials officially complained about racial abuse by small groups of fans at the WACA during the drawn first test which ended on Tuesday.
The &to=http://english.pravda.ru/main/2002/07/22/32940.html' target=_blank>South Africans reported the verbal abuse and chants by the crowd directed at Ashwell Prince, Garnett Kruger, Shaun Pollock, Justin Kemp and Makhaya Ntini during the third day of the match. Security was stepped up at South Africa's request for the remainder of the match.
The Proteas' management called for enforcement of the International Cricket Council's anti-racism rules, which also apply to spectators.
Cricket Australia said on Wednesday any fans caught making racist remarks would be removed from any ground.
The British Prime Minister cuts a sociopathic figure, isolated, stubborn beyond belief, totally wrong and convinced that the world gravitates around her feet
The Basmanny Court of Moscow arrested Michael Calvey, the founder of Baring Vostok investment fund, on allegations of embezzling 2.5 billion rubles from Vostochny Bank. Calvey will be held in custody until April 13


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Print version ISSN 0074-0276
Mem. Inst. Oswaldo Cruz vol.106 no.7 Rio de Janeiro Nov. 2011
Naglaa Mohamed El-LakkanyI, +; Sayed Hassan Seif el-DinI; Abdel-Nasser Abdel-Aal SabraI; Olfat Ali HammamII
IDepartment of Pharmacology
IIDepartment of Pathology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba PO Box 30, Giza 12411, Egypt
Praziquantel (PZQ) is currently the only drug widely used for the treatment of schistosomiasis, but the antimalarial drug mefloquine (Mef) possesses interesting antischistosomal properties. Combination therapy with these two drugs has been suggested as a strategy for transmission control, as PZQ is active against adult worms and Mef is active against schistosomula. To examine the efficacy of combination therapy, Schistosoma mansoni-reinfected mice were separated into seven groups: untreated (I), treated with PZQ in doses of 200 mg/kg (II) or 1,000 mg/kg (III), treated with Mef in doses of 200 mg/kg (IV) or 400 mg/kg (V); each dose was divided equally and given on two consecutive days. Group VI was treated with doses of PZQ + Mef as in groups II and IV, respectively, while group VII was treated with PZQ + Mef as in groups III and V, respectively. PZQ + Mef at the reduced doses of 200 mg/kg each enhanced the therapeutic efficacy over the reduced PZQ dose alone as shown by a very high reduction in the total numbers of mature worms (95% vs. 49%), immature worms (96% vs. 29%) and the complete eradication of immature females, mature females and immature eggs. The reduction in worm burden was associated with the healing of hepatic granulomatous lesions and the normalisation of all liver enzymes. Therefore, the use of Mef with PZQ is more effective than PZQ alone and should be considered for clinical trials in humans as a potential treatment regimen to prevent treatment failures in areas with high rates of schistosomiasis.
Key words: Schistosoma mansoni - praziquantel - mefloquine - reinfection - therapeutic efficacy
Schistosomiasis remains a major health problem in many tropical areas. It is currently estimated that over 200 million people are infected and nearly 800 million others are at risk of infection. Schistosomiasis causes 280,000 deaths annually and more than 20 million individuals experience high morbidity from the disease (King et al. 2005, Steinmann et al. 2006, Sayed et al. 2008). Praziquantel (PZQ) is currently the drug of choice for the treatment of schistosomiasis, but its widespread use has led to concern that the emergence of PZQ-resistant schistosomes may eventually render it obsolete (Botros & Bennett 2007, Caffrey 2007). However, it is unclear whether schistosomes have developed clinically relevant levels of resistance to PZQ. Botros et al. (2005) has cast some doubt on previous reports of resistance (Ismail et al. 1996, 1999) because no significant resistance was observed in the same region after 10 years of therapeutic pressure. While the likelihood of the development and spread of PZQ resistance is uncertain, the slightest possibility of resistance occurring reinforces the need for alternative treatments.
Various studies have sought to identify new drugs to use as alternatives to PZQ or in conjunction with PZQ (Fenwick & Webster 2006, Abdulla et al. 2007, Caffrey 2007, Keiser & Utzinger 2007, Xiao et al. 2007, Sayed et al. 2008). Several promising leads have been identified, including analogues of the antimalarial artemisinin and the synthetic derivatives trioxane and trioxolane (Caffrey 2007, Keiser & Utzinger 2007). The artemisinins artemether and artesunate, which are essential components of malaria treatment and control (White 2008), also possess antischistosomal properties (Xiao et al. 2000, Seif el-Din 2007, Utzinger et al. 2007). Detailed in vivo studies revealed that schistosomula are particularly susceptible to the artemisinins and that a moderate reduction in worm burden can still be achieved for adult worms (Xiao et al. 2002). A number of clinical trials carried out in different African settings confirmed that both artemether and artesunate are effective against Schistosoma haematobium and Schistosoma mansoni infections (Keiser & Utzinger 2007, Utzinger et al. 2007). Interestingly, the antimalarial drug mefloquine (Mef) and its analogues have also been shown to have schistosomicidal activity (Keiser et al. 2009). Any shared mechanism of action that underlies the effects of the artemisinins and Mef on schistosomes and malaria parasites is still unclear.
Egypt has employed PZQ-based chemotherapy to control schistosomiasis at the community level and has sustained a national control program for a prolonged period and an impressive reduction in morbidity has been achieved (WHO 2000). The renewed impetus for extending schistosomiasis control throughout sub-Saharan Africa will likely rely on a greater use of PZQ than ever before (Engels 2002, Fenwick 2003). However, despite the success in controlling schistosomiasis with PZQ, there is a significant deficiency in the therapeutic profile of PZQ; the drug targets the adult worm but has only minor activity against the young developing stages (schistosomula) (Doenhoff et al. 2008, Keiser et al. 2009). Therefore, a second treatment with PZQ is necessary to kill any parasites that matured after the first treatment. The need for retreatment presents an economic burden to poorer nations that will require external support to allow them to prioritise the control of schistosomiasis. Even with retreatment, the peculiar stage-specificity of PZQ means that some immature parasites will remain unaffected by the drug. These parasites can later mature to egg-producing adult worms and thus lead to apparent treatment failure. Treatment failure occurs most often in areas of high transmission and in individuals harbouring large numbers of maturing worms that escape the effects of PZQ (Sabah et al. 1986). It is possible that drug combinations could prove useful by offsetting the shortcomings of individual agents (such as stage or species-dependence). Combination therapy may also provide mutual protection against the development of resistance (Geary et al. 2010).
It should also be recognised that the use of artemisinin analogues and perhaps Mef, for the treatment of malaria might have additional benefits in areas that are also endemic for schistosomiasis (Keiser & Utzinger 2007, Keiser et al. 2009). A preliminary study by Xiao et al. (2011) on a Mef/PZQ combination therapy revealed that treating Schistosoma japonicum-infected mice with each of Mef or PZQ alone at single dose of 50 mg/kg has no apparent improvement in efficacy relative to that of the untreated infected control. The authors added that increasing the dose of both drugs to 100 mg/kg resulted in a statistically significant difference in female worm burdens between the PZQ group and combined treatment group. Moreover, Mef exhibits a direct killing effect against adult and juvenile S. japonicum in vitro, but juvenile schistosomes are more susceptible to in vitro exposure to Mef than the adult worms (Xiao et al. 2009). In this study, we tested the potential of Mef/PZQ combination therapy in two dose regimens in animals harbouring both immature and mature S. mansoni worms by examining parasitological criteria of cure represented by worm burden and distribution, tissue egg load and oogram pattern. The histopathology and function of the livers of the infected and uninfected animals after treatment were also investigated.
MATERIALS AND METHODS
Drugs and doses - Mef HCl (Mephaquin®) tablets were obtained (Mepha Ltd, Aesch-Basel, Switzerland, lot 0850074) and were administered orally as a fresh suspension in 7% (v/v) Tween-80 and 3% (v/v) ethanol. Mef was administered as a high dose of 400 mg/kg or a reduced dose of 200 mg/kg (Keiser et al. 2009); each dose was divided in half and given on two consecutive days. PZQ tablets (Distocide®, EIPICO, El-Asher Men Ramadan, Egypt) were administered orally as a suspension in 2% cremophore-El (Sigma-Aldrich Chemical Co, St. Louis, MO) in a high dose of 1,000 mg/kg (Gonnert & Andrews 1977) or a reduced dose of 200 mg/kg (Fallon & Doenhoff 1995), which were also divided in half and given on two consecutive days.
Animals - One hundred and twelve male CD1 Swiss albino mice, average weight of 20 g ± 2, were bred and maintained at the Schistosome Biology Supply Center (SBSC) of Theodor Bilharz Research Institute (TBRI), Giza, Egypt. Animals were housed in a controlled temperature and light environment and were given water and commercial chow ad libitum. The animal experiments were conducted in the animal unit according to the international ethical guidelines after approval by the Institutional Review Board of TBRI.
Infection of animals - Cercariae of S. mansoni (Egyptian strain) were obtained from infected intermediate host snails maintained at the SBSC. Animals were infected with 80 ± 10 cercariae/mouse using the body immersion technique (Liang et al. 1987) and then reinfected 35 days after the first infection with 40 ± 5 cercariae/mouse.
Animal groups - Reinfected, untreated mice (I), reinfected mice treated with PZQ at a reduced dose of 200 mg/kg divided equally and administered on two consecutive days (II), reinfected mice treated with PZQ at a high dose of 1,000 mg/kg divided equally and administered on two consecutive days (III); reinfected mice treated with Mef at a reduced dose of 200 mg/kg divided equally and administered on two consecutive days (IV), reinfected mice treated with Mef at a high dose of 400 mg/kg divided equally and administered on two consecutive days (V), reinfected mice treated concomitantly with the reduced doses of both PZQ and Mef as in groups II and IV, respectively (VI), and reinfected mice treated concomitantly with the high doses of both PZQ and Mef as in groups III and V, respectively (VII).
Animals in all infected groups were treated with both Mef and PZQ 49 days after the first infection (14 days post reinfection) and were killed by rapid decapitation nine weeks after the first infection (28 days post reinfection). Comparable groups of uninfected mice were subjected to the same treatment schedule to evaluate the safety of PZQ/Mef combination therapy. After decapitation, blood was collected and sera were separated by centrifugation at 1,850 g for 10 min and stored frozen at -70ºC.
Assessment of parasitological criteria - To recover mature and immature worms for subsequent counting and determination of sex, the hepatic and mesenteric vessels of infected animals were perfused according to Duvall and De Witt (1967) without using general anaesthesia. The number of ova per gram of liver or intestinal tissue (tissue egg load) was counted according to the method of Cheever (1968) in which a piece of small intestinal or hepatic tissue was weighed before digestion in 5% KOH. The percentage of eggs in the different developmental stages (oogram pattern) was studied according to the method of Pellegrino et al. (1962), in which eggs at different stages of maturity were identified (from I-IV) according to the size of the embryo and were counted. In addition, mature eggs containing fully developed miracidium and dead eggs (granular, dark and semi-transparent) from three fragments of the small intestine were counted and the mean numbers of eggs each stage were calculated.
Histopathology and granuloma measurement - Livers were harvested from the mice, fixed in 10% buffered formalin and processed to paraffin blocks. Sections (4 µm thick) were cut every 250 µm to avoid measuring the same granuloma. Five liver sections were prepared from each animal and stained with the haematoxylin and eosin and Masson trichrome stains. Measurements of the granulomas were conducted on non-contiguous granulomas, each containing a single egg (with intact or degenerated miracidia), using an ocular micrometre. The mean diameter of each granuloma was calculated by measuring two diameters of the lesion at right angles to each other (Von Lichtenberg 1962). Thirty granulomas were measured from each mouse. Granuloma structural configurations, including cellular components and associated hepatic histopathological changes, were studied and the percentages of viable and dead eggs were also calculated.
Serum enzymes - The concentrations of alanine aminotransferase (ALAT), total proteins, albumin and urea in the collected sera were estimated using the available commercial kits.
Statistical analysis - Results were analysed with the use of the Statistical Package for the Social Sciences software (version 9.0). The values are expressed as the means ± standard error of the mean. The means of groups were compared with the use of an unpaired t-test. For comparisons of more than two groups, an Analysis of Variance test was used. Data were considered significant at a p value < 0.05.
Parasitological studies - Table I shows that administering Mef to S. mansoni-reinfected mice in split oral doses of 200 mg/kg or 400 mg/kg for two consecutive days significantly (p < 0.001) reduced the numbers of immature male worms, immature female worms and total immature worms by 61.4% and 84.2%, 74.8% and 96.8% and 67.4% and 89.9%, respectively, compared with the untreated reinfected group. Mef administration at the above doses also significantly reduced the number of mature males, mature females and total mature worms by 28.3% (p < 0.01) and 56.7% (p < 0.001), 57.6% and 80.3% (p < 0.001) and 41.9% (p < 0.01) and 67.7% (p < 0.001), respectively. Moreover, significant decreases in the hepatic (28.7%, p < 0.05 and 50.9%, p < 0.001, respectively) and intestinal (79.8% and 87.5%, p < 0.001, respectively) tissue egg loads and in the percentage of immature eggs concomitant with a significant increase (p < 0.001) in the percentage of dead eggs were observed (Table II).
Administering PZQ in split oral doses of 200 mg/kg or 1,000 mg/kg to S. mansoni-reinfected mice for two consecutive days significantly reduced the numbers of immature males, immature females and total immature worms by 31.1% (p < 0.05) and 48.2% (p < 0.001), 18.5% (p > 0.05) and 43.7% (p < 0.01) and 29.2% and 46.2% (p < 0.001), respectively, compared with the untreated S. mansoni-reinfected group. PZQ administration at the above doses also significantly reduced the total mature males, females and total mature worms by 55.2% and 96.6% (p < 0.001), 43% (p < 0.01) and 88.1% (p < 0.001) and 49.6% and 92.6% (p < 0.001), respectively (Table I). This was accompanied by significant decreases in the hepatic (41.5%, p < 0.05 and 77.9%, p < 0.001) and intestinal (84.3% and 94.2%, p < 0.001) tissue egg loads, respectively, and in the percentage of immature eggs and a significant increase (p < 0.001) in the percentage of dead eggs was also found (Table II).
The co-administration of PZQ and Mef in both reduced and high doses significantly enhanced (p < 0.001) the killing of immature and mature males, immature and mature females and total immature and mature worms and also reduced hepatic (p < 0.05; p < 0.001) and intestinal (p < 0.001) tissue egg burdens when compared with S. mansoni-reinfected groups treated with PZQ alone at either dose. Treatment of reinfected mice with PZQ + Mef at the reduced doses killed all immature females, while treatment with the high doses of each drug killed all mature and immature females. This was accompanied by a complete loss of immature eggs and an increase in the percentage of dead eggs (94.22% and 99.25%) in the groups treated with PZQ + Mef in reduced or high doses, respectively (Tables I, II). No remarkable differences were observed between the groups treated with reduced doses of PZQ + Mef and the groups treated with high doses of PZQ + Mef in most of the assessed parameters.
Histopathological studies - Liver sections of untreated and treated uninfected mice showed normal hepatic lobular architecture with hepatocytes arranged in thin plates. The portal tracts were within normal limits and contained arteries, veins and bile ducts. The hepatocytes contained rounded, regular nuclei with lymphocytes scattered between hepatocytes and the sinusoids. Moreover, no hydropic, steatotic, feathery or ballooning changes, degeneration or apoptosis were observed (Fig. 1A-E). Only scattered or focal collections of lymphocytes in between hepatocytes (focal spotty necrosis) were observed in liver sections of uninfected mice treated with either Mef alone at high dose (Fig. 1C) or combined with PZQ at high dose (Fig. 1E).
Liver sections from S. mansoni-reinfected mice killed nine weeks after the first infection (28 days post reinfection) showed a typical large fibrocellular granuloma centred around living ova, including living miracidium and surrounded by lymphocytes, epithelioid cells, eosinophils, polymorphonuclear cells and fibrous tissue (Fig. 2A). Compared to the reinfected untreated group, treatment with PZQ or Mef alone reduced the diameters of the granulomas by 28.08% and 26.26% (p < 0.01), respectively, with the reduced doses of each drug and reduced granuloma diameters by 39.39% and 32.53% (p < 0.001), respectively, with the higher concentration of each drug (Fig. 2B-E, Table III). Moreover, we observed a significant reduction in the granuloma diameters in groups treated with PZQ + Mef at the reduced dose (p < 0.01) or high dose (p < 0.05) in comparison with groups treated with the different doses of PZQ alone (Fig. 2F, G, Table III). All treated groups showed size-variable, well-demarcated or circumscribed fibrocellular granulomas with central ova encircling living or dead miracidia, surrounded by lymphocytes, epithelioid cells, neutrophils, eosinophils and collagen bundles. All treatment regimens significantly increased (p < 0.01) the percentage of dead ova in the examined liver sections compared to the infected untreated group. Moreover, the percentage of ova degeneration was significantly increased in the liver sections from groups treated with PZQ + Mef at the reduced (p < 0.05) or high (p < 0.01) doses when compared to PZQ alone at its reduced or high dose, respectively (Table III).
Enzyme assessments - Treatment of uninfected mice with PZQ, Mef or PZQ + Mef at the reduced and high doses did not alter the enzyme levels, which were measured to assess liver and kidney function (Table IV). Reinfection of mice with S. mansoni significantly increased serum levels of ALAT (p < 0.001) and significantly decreased the levels of albumin (p < 0.001) and total protein (p < 0.01) and the albumin/globulin (A/G) ratio (p < 0.05) in comparison with the uninfected untreated group. Compared to reinfected untreated group, the ALAT level was significantly decreased in the groups treated with either PZQ (p < 0.01, p < 0.001) or Mef (p < 0.05, p < 0.01) alone at their reduced or high doses, respectively. Additionally, total protein levels were significantly elevated (p < 0.05) in groups treated with either PZQ or Mef at high doses and albumin was significantly elevated (p < 0.01) in the group treated with a high dose of Mef. Treatment with PZQ + Mef in reduced and high doses completely normalised the total protein and albumin levels and the A/G ratio, while ALAT was still higher than normal (Table IV).
In the present study, we found that a dose of 200 mg/kg of Mef resulted in moderate reductions in the total number of mature and immature worms (41.9% and 67.4%, respectively) and 57.6% and 74.8% reductions in the number of mature and immature female worms, respectively. By increasing the dose of Mef to 400 mg/kg, the reductions in the number of total mature and immature worms were increased to 67.7% and 89.9%, respectively, with an 80.3% reduction in the number of mature females and a 96.8% reduction in the number of immature females. Nwaka and Hudson (2006) reported that Mef exceeds the benchmark criteria set forth by the World Health Organization (WHO) for highly active lead compounds, as they found a greater than 80% reduction in worm burden using the adult S. mansoni model and five consecutive Mef doses given intraperitoneally or subcutaneously. Keiser et al. (2009) exceeded the WHO criteria and showed that a single dose of Mef (200 mg/kg or 400 mg/kg) administered orally to mice infected with either young developing or adult S. mansoni (Liberian strain) resulted in a high or complete reduction of the total and female worm burden (72.3-100%). In contrast, Nassauw et al. (2008) reported that a dose of 150 mg/kg of Mef had no effect on worm burden, but reduced egg fecundity in the first three developmental stages of S. mansoni in the murine model. The discrepancy between our study and the previous investigations may be due to differences in the strain of S. mansoni used and should be examined further.
It has been shown that female S. mansoni worms become fully mature, egg-producing worms on day 35 if they are paired on day 28 (Clegg 1965). Egg granulomas in livers and intestines are frequently detected from day 42 post infection onwards in mice (Miller et al. 1994). Therefore, at the time Mef was administered to S. mansoni-reinfected mice, adult schistosomes had been producing eggs for two weeks and granulomas had been present for one week. All mice were sacrificed 28 days after reinfection (56 days after the first infection) to ensure that all eggs and granulomatous reactions observed were due to the first infection. This allowed us to avoid confusion due to the presence of sub-patient and patient infections. Administration of Mef alone at both the reduced and high doses resulted in a remarkable decrease in the percentage of immature eggs and a reduction in the hepatic and intestinal egg counts with a corresponding increase in the percentage of dead eggs. This was associated with greater granuloma circumscription, more ova degeneration and fewer inflammatory cells. In addition, the serum levels of ALAT, total protein and albumin were significantly improved.
Administration of PZQ alone at both reduced and high doses resulted in a decrease in the mature worms (49% and 92%, respectively) that was greater than the decrease in immature worms (29% and 46%, respectively) and a greater reduction was found in the number of males than females. These observations were associated with a high reduction of immature hepatic and intestinal eggs, an increase in the percentages of dead eggs and granuloma circumscription and improved ALAT and total protein serum levels. In this investigation, the therapeutic efficacy of PZQ was slightly higher than Mef with regard to all parameters studied, except for the lower efficacy of PZQ against young worm stages when used in its reduced (29%) or higher (46%) dose. Although there was an advantage for treatment with Mef over PZQ because it reduces both mature and immature worms (68% and 90%, respectively) with female reduction reaching 80-97%, respectively, the efficacy of Mef against adult worms was not satisfactory (42-68%) when used in its reduced and higher dose respectively. This may be due to the use of a dose that is sublethal to adult worms of the Egyptian strain, for which higher doses may be more effective. Additionally, Keiser et al. (2009) reported that the Mef treatment consistently resulted in a greater reduction in worm burden than PZQ when used against all development stages of the schistosome worms in the rodent model.
The use of Mef in combination with schistosomicidal agents that affect other stages of the parasite's life cycle may improve the treatment and control of schistosomiasis. Previous studies on the treatment of schistosomiasis with a combination of artemether and PZQ in humans and animals showed that combination therapy resulted in a significantly higher reduction in worm burden than administration of either drug alone (Utzinger et al. 2001, Xiao et al. 2002, Botros et al. 2007). In the present study, concomitant administration of PZQ + Mef at reduced doses exceeded the effect of the reduced PZQ dose alone, with combination therapy resulting in a very high reduction in the numbers of total mature (95% vs. 49%) and immature worms (96% vs. 29%) and the complete eradication of immature and mature females as well as immature eggs. We also observed a high level of reduction in both hepatic and intestinal tissue egg loads and healing of hepatic granulomatous lesions, as evidenced by the presence of more degenerated eggs, more granuloma circumscription, fewer inflammatory cells and normal levels of all tested liver enzymes. These effects are likely due to the dual actions of both the antimalarial Mef on the schistosomula and adult stages of the worm and the schistosomicidal PZQ on the adult stages of schistosome worms.
Interestingly, no noticeable differences in the therapeutic efficacy were observed between the reduced and high doses of PZQ + Mef. Previous investigations on the morphology of schistosomes recovered from host animals after administration of PZQ (Mehlhorn et al. 1981) and observations made with schistosomes recovered from Mef-treated mice indicate different mechanisms of action (Keiser et al. 2009). Mef rapidly affects schistosomes, resulting in marked alterations of the digestive tract and the reproductive system of the adult worms. However, a direct effect of Mef on S. mansoni eggs cannot be excluded (Von Lichtenberg 1962). Although nothing is known about the presence or expression of P-glycoprotein (P-gp) in S. mansoni eggs, P-gp has been observed in the external layers of the shells of eggs of the red stomach worm Haemonchus contortus, a parasitic nematode of ruminants, suggesting that P-gp inhibition might contribute to the elimination of parasitic eggs (Riou et al. 2005).
Concerning the safety of both drugs, no side effects were observed for either dose of both drugs in the host animals. Animal behaviour was normal with 0% mortality. Liver and kidney function tests remained within the normal limits and liver histology showed no hydropic, steatotic, feathery or ballooning changes, degeneration or apoptosis. Only scattered or focal collections of lymphocytes between the hepatocytes (focal spotty necrosis) were observed in liver sections of uninfected mice treated with a high dose of Mef alone or combined with a high dose of PZQ. In general, the toxicity of PZQ was very low in both short and long-term experiments (Frohberg 1984). Some adverse reactions are likely due to the release of cellular contents from dying schistosomes. This may well be the case with the most severe side effects, such as bloody diarrhoea or oedematous urticarial, which are encountered mainly in endemic areas (Polderman et al. 1984). Mef is generally well tolerated by adults and children; however, there is evidence that Mef may harm the gastrointestinal and central nervous systems (AlKadi 2007). Adverse reactions to Mef include insomnia, nausea, vomiting, diarrhoea, headache, dizziness, rash, pruritus and abdominal pain (AlKadi 2007). In addition, Nassauw et al. (2008) reported that Mef induces a severe mastocytosis in the intestinal wall, leading to intestinal inflammation and gastrointestinal disturbances due to mast cell recruitment to the intestine. This can result in visceral pain and disturb the motor and secretory functions of the intestine. Moreover, the neurotoxicity of Mef cannot be explained (Pham et al. 1999). Another aspect worth mentioning when considering PZQ-Mef combination therapy is the argument that the antimalarial drugs should not be recommended for chemoprophylaxis or treatment of schistosomiasis in areas where malaria is co-endemic because of the risk of resistance development in the malaria parasites. This warrants further investigation into the mechanisms of Mef resistance.
In conclusion, Mef significantly reduces both worm burden (immature and mature) and egg production and returns liver histology and function to normal levels. The concomitant use of PZQ with Mef in reduced doses showed enhanced therapeutic efficacy compared with that of each drug alone. This was evidenced by the nearly complete eradication of immature worms, mature worms and eggs, healing of hepatic granulomatous lesions and normalisation of liver serum enzyme levels. Mef is safe at both doses (200 mg/kg and 400 mg/kg) whether used alone or in combination with PZQ. Accordingly, Mef could be used at a low dose in combination with a reduced dose of PZQ for the treatment of human schistosomiasis, thus potentially preventing treatment failures in areas with high rates of transmission. Therefore, the combination therapy may represent a cost-effective treatment regimen in developing countries.
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Received 5 April 2011
Accepted 10 October 2011
Financial support: TBRI

domain: biology


text:
It appears that Nike will be the big benefactor of the MEAC’s decision to allow teams to negotiate their own apparel deals. Florida A&M confirmed that it has reached a deal with the apparel giant and at least two other schools appear to be headed in that direction as well.
FAMU confirmed that it has reached a three-year deal with Nike over the weekend, according to the Tallahassee Democrat. AD Milton Overton, Jr. didn’t give figures but did indicate that the deal will be more financially beneficial than the previous one negotiated by the conference with Russell.
“Most of the conference moved to Nike,” Overton said. “Some of the conference members when to a different apparel company. I won’t necessarily say numbers. What I’ll say it was a 50-percent increase in value from Russell to Nike.”
Sources tell HBCU Gameday that North Carolina A&T and Savannah State will wear Nike as well. Delaware State announced a deal with Nike last month. Howard has been the only school to go elsewhere so far, reaching a deal with Under Armour earlier this month. |
FAMU plans on releasing new uniforms for football soon.
“We’ll release new uniforms,” Overton said. “We’ll also release new apparel. That’ll be in the next couple of weeks. We’re going to push it out to the fans. We’ll show what the new uniforms will look like for football and a couple of other sports. Then we’ll show what some of the new Nike polos will look like.