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"Head in, hands on": Ram Charan on How to Lead Now
Renowned business adviser Ram Charan's latest book is Leadership in the Era of Economic Uncertainty: The New Rules for Getting the Right Things Done in Difficult Times (McGraw-Hill, 2008). He recently spoke with Christina Bielaszka-DuVernay, a HarvardBusiness.org editor, about the challenges — and opportunities — this downturn presents to companies and their leaders. In this […]
Christina Bielaszka-DuVernay
Renowned business adviser Ram Charan's latest book is Leadership in the Era of Economic Uncertainty: The New Rules for Getting the Right Things Done in Difficult Times (McGraw-Hill, 2008). He recently spoke with Christina Bielaszka-DuVernay, a HarvardBusiness.org editor, about the challenges — and opportunities — this downturn presents to companies and their leaders. In this edited record of their conversation, Charan gives leaders at all levels advice on guiding their organizations and people through this crisis and coming out stronger on the other side.
CBD: What's most important for leaders — not just CEOs and senior executives but leaders throughout the ranks — to focus on right now?
RC: In these times more than other times, first and foremost is demonstrating personal integrity and maintaining your personal credibility. They are so important in tough times, yet many leaders lose their integrity and destroy their credibility by giving into the temptation to cut corners when they have to do unpleasant tasks like downsizing. For example, a business-unit head, instead of being transparent about why he needs to cut 10 jobs, gives a partial truth or makes an excuse. That's a way of cutting corners, and it's destructive. In the Google era, people will find out the truth and that leader will lose credibility, making his job even more difficult.
Tell people the truth. Gather information — from customers, from your customer-facing employees, from sources outside the firm. Talk to employees throughout the company; listen to their viewpoints and engage them. When you have a firm picture of reality, share it. Tell people the reality — if the company doesn't take action now and cut some jobs, even more good people will lose jobs later. In this environment, the entire company could fail as a result of a leader failing to make hard decisions when they're needed.
If you have to make layoffs, make them in a fair, open way. Be frank; explain what's happening on the outside and why layoffs are necessary to protect good people and good jobs.
Authenticity is always important but now it's absolutely critical. Leaders, wherever they sit in the organization, have to demonstrate rock-solid integrity, honesty, and the ability to confront reality. The way to inspire courage and optimism in your employees is by mapping a credible path forward. If you soft-pedal bad news, they won't trust you. Worse, they'll miss the urgency of the situation and won't follow you.
In your book you advise leaders to practice "management intensity." What is this and why is it so important now?
I define management intensity as a deep immersion in the business's operational details and the day-to-day competitive climate the business is facing, along with hands-on involvement and follow-through.
It's so important now because of the accelerating speed at which things are changing. Surviving a volatile environment requires frequent operational adjustments. You hear every day about new layoffs and downward projections. Keeping up with news like that and tracking its effects is crucial, because a cut today will initiate cuts elsewhere tomorrow. It's not enough to sit in your office and read reports and issue directives. You've got to know what's happening daily, and adjust plans and processes accordingly.
Big-picture strategic thinking is still important, but it must take a back seat to this operational immersion — leaders need to be involved and visible, and communicating all the time. As I explain in the book, your guiding principle should be this: Head in, hands on. Only in this way will you be able to anticipate what's coming next and respond quickly and appropriately.
Does management intensity place a greater emphasis on execution than what's called for in more flush times?
Yes — management intensity calls for a sharper and more frequent focus on execution. The DuPont story I tell in my book is a good example of what I mean. When Chad Holliday [then DuPont's CEO; now its chairman] determined that the global banking crisis had spread beyond the financial sector and could seriously affect his company, he called a meeting of DuPont's crisis teams. Over four days, they put together a plan to deal with the growing economic downturn. Conserving cash was the top priority.
Within two weeks, every one of DuPont's 60,000 employees had had a face-to-face meeting with a manager who explained the plan for keeping DuPont viable. Each employee was asked to name three things he could do immediately to save money and conserve cash. Then a few days later, the company polled employees to assess their understanding of the crisis, their psychological response to it, and their follow-through on conserving cash.
After this first round of communication with DuPont employees, you report in your book, Holliday had the sense that people hadn't grasped the urgency of the situation. You quote him as saying that "maybe we were too good at giving [employees] the reassurance and confidence that we could come through this." What balance should leaders strike right now between realism and optimism?
Realism is not negotiable. It's absolutely essential to anyone who leads. You need to have a clear picture of how bad things are and how bad things could get, then put that reality in front of people.
Realism also includes determining under what conditions the business will improve, and communicating those scenarios. That's optimism grounded in solid realism.
People through the centuries have gone through some very difficult times. Those who succeeded despite challenging conditions did so because they were tough and tenacious. You have tough and tenacious people working for you; engage them by putting the hard issues right in front of them. They will be motivated to overcome the challenges.
Isn't there a danger that people will become demoralized by the enormity of the challenges? How does a leader prevent that from happening?
Give them the problems in bite sizes. Put a challenge in front of them that's specific and concrete enough to deal with. For instance, if your competitor has a 20% win ratio, challenge them to get 30%. Even though the total market is declining, even though your company's revenues will be smaller, you and your employees still have a chance to compete and to beat somebody.
These are anxious times. How should leaders manage their own emotions?
Actually, in a crisis most leaders tend to be too optimistic rather than the contrary. They overestimate how well their company will fare because they want to believe everything will turn out well. This misplaced optimism allows them to think that they don't have to make painful decisions or take drastic action.
To guard against this, I advise all leaders to map out worst-case scenarios. If you deliberately plan for the worst, you'll probably encounter something less dire and come out ahead when it's all over.
In your book you say that surviving this downturn requires intense coordination across the company. What can the CEO do to pull down silos and foster companywide coordination? What can midlevel leaders do?
Any leader at any level can figure out what key decisions must be made and what coordination is required to implement them. Say your unit aims to launch a new product by July. You know what decisions you will have to make around that goal. So move swiftly to get the best information you can, then make the best decisions you can.
You know there will be three or four silos involved. Check in with people from those areas frequently, asking questions and exploring issues with an open, informal tone. Remind them of your shared purpose: to win with customers. Human beings like to win, and in companies, no one wins alone.
It might help to think that the situation you and your colleagues face is akin to a basketball game. Players make judgments constantly about the game as it's in progress, instinctively passing the ball to a teammate to counter the defense, without worrying about who's going to get the credit. Basketball is a sport of speed, flexibility, and synchronization. The same qualities are demanded of cross-functional teams in this recession. What department or function teammates come from doesn't matter; what matters is that they're united against the competition.
You teach a class at Wharton for high potentials. What's your advice to high potentials in this downturn?
If you're a high potential, act like one and keep building your capabilities; this recession doesn't have to slow you down. In fact, it offers you opportunities that normal times don't. Wherever you work, it's likely that there is a shortage of really talented, motivated people with the flexibility and resilience to weather these tough times. So step forward and get noticed. Get on cross-functional teams. Learn and lead. Build social networks. Set benchmarks for yourself — use the next two years to double your capacity and triple your capabilities.
What will the best companies do during this recession?
They'll get ahead the curve and conserve their cash. They'll take out frills and focus on the core. And then they'll think of how the market will have changed in two or three years and what innovation they will need to have done to compete successfully, and they'll do that innovation now.
Read more on Leadership or related topics Economics, Strategy execution, Leadership development and Recessions


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Ready for Dessert
My Best Recipes: A Baking Book
By David Lebovitz
Category: Baking & Desserts | Cooking Methods
About Ready for Dessert
Pastry chef David Lebovitz is known for creating desserts with bold and high-impact flavor, not fussy, complicated presentations. Lucky for us, this translates into showstopping sweets that bakers of all skill levels can master. In Ready for Dessert, elegant finales such as Gâteau Victoire, Black Currant Tea Crème Brûlée, and Anise-Orange Ice Cream Profiteroles with Chocolate Sauce are as easy to prepare as comfort foods such as Plum-Blueberry Upside-Down Cake, Creamy Rice Pudding, and Cheesecake Brownies.
With his unique brand of humor—and a fondness for desserts with "screaming chocolate intensity"—David serves up a tantalizing array of more than 170 recipes for cakes, pies, tarts, crisps, cobblers, custards, soufflés, puddings, ice creams, sherbets, sorbets, cookies, candies, dessert sauces, fruit preserves, and even homemade liqueurs. David reveals his three favorites: a deeply spiced Fresh Ginger Cake; the bracing and beautiful Champagne Gelée with Kumquats, Grapefruits, and Blood Oranges; and his chunky and chewy Chocolate Chip Cookies. His trademark friendly guidance, as well as suggestions, storage advice, flavor variations, and tips will help ensure success every time.
Accompanied with stunning photos by award-winning photographer Maren Caruso, this new compilation of David's best recipes to date will inspire you to pull out your sugar bin and get baking or churn up a batch of homemade ice cream. So if you're ready for dessert (and who isn't?), you'll be happy to have this collection of sweet indulgences on your kitchen shelf—and your guests will be overjoyed, too.
Also by David Lebovitz
See all books by David Lebovitz
About David Lebovitz
DAVID LEBOVITZ has been a professional cook and baker for most of his life; he spent nearly thirteen years at Chez Panisse until he left the restaurant business in 1999 to write books. He moved to Paris in 2004 and… More about David Lebovitz
Published by Ten Speed Press
Sep 18, 2012 | 304 Pages | 7-1/2 x 10 | ISBN 9781607743651
People Who Read Ready for Dessert Also Read
"Lebovitz's chatty, down-to-earth tone is sure to steady any rattled nerves as you turn the oven on and get the measuring cups out. And for seasoned cooks and bakers, Lebovitz's recipes are classics worth revisiting."
—Epicurious.com, The Best Cookbooks of 2010: Best Dessert
"David Lebovitz, blogging phenom and former pastry chef at Chez Panisse has written several cookbooks, but this might be his best yet. It's a compilation of all his favorites–from ice cream to cookies to cake and fruit desserts. You will also enjoy the notes with each recipe that tell stories, share tips and often produce giggles. Why? You've read his blog, and probably tried his recipes for free. Now it's time to pay the man!"
—Cooking with Amy, Top Cookbooks 2010, 12/18/10
"If there's one person you can trust to write a good recipe, it's David. My copy of Ready for Dessert is already dogeared and vandalized with all manner of sweet ingredients. His chocolate chip cookies are my go-to and his ice creams, for which he is well-known, are all outstanding. The man worked as as a pastry chef at Chez Panisse then moved to Paris. Need I say more?"
—TheKitchn.com, Favorite Baking Books of 2010, 12/16/10
"And finally, I want to mention a book from earlier in the year, highly recommended if you're looking for a sweets book: Ready For Dessert: My Best Recipes by David Lebovitz who writes the excellent and popular blog, "Living the Sweet Life in Paris" at DavidLebovitz.com. This is a compendium of his favorite recipes that he's reworked and rewritten. As ever, superb and recommended."
—Michael Ruhlman, Books for the Holidays, 12/13/10
"You'll want to make everything in this book."
—Washington Post's Top Cookbooks of 2010, 11/30/10
"An elegantly-composed collection of classics and contemporary riffs, former Chez Panisse pastry chef David Lebovitz's (The Perfect Scoop) latest effort hits the sweet spot. Artfully balancing accessible recipes for novices (the simple four-ingredient Chocolate Orbit Cake, the three-ingredient Peaches in Red Wine and Pistachio, Almond and Dried Cherry Bark) with ambitious-but -worth-it desserts like Banana Cake with Mocha Frosting and Salted Candied Peanuts and White Nectarine Sorbet with Blackberries in Five-Spice Cookie Cups, Lebovitz truly has something for everyone. Can't-miss combinations like Guinness-Gingerbread Cupcakes, Cherry-Almond Cobbler, and Orange-Almond Bread Pudding are sure to inspire a trip to the market, and riffs on classics like a French apple galette (updated here with frangipane, a rich almond pastry cream) and a lush Fresh Ginger Cake will appeal to bakers whose bookshelves are already groaning with cookbooks. The inclusion of Coconut Layer Cake, Vanilla Ice Cream, Meyer Lemon Sorbet, Chocolate Chocolate-Chip Cookies, and Gingersnaps (including a fat-free variety) shows that Lebovitz also knows when not to mess with a good thing. Given its breadth, depth, and accessibility, readers with a passion for baking will be hard pressed to find a better guide to desserts this year. Photos. (May)"
—Publishers Weekly, Web-Exclusive Reviews, STARRED REVIEW, 6/14/10
"Each section is more of a collection of surprises than a tour of the usual baking suspects you might find in a greatest hits sort of book by another author (cheesecake, muffins, angel cake etc.). There are unusual flavour combinations as well as intriguing takes on classic desserts."
—Cookbooker.com, 6/2/10
"Lebovitz brings his writing to life with wit and humor and offers expert advice on everything from cake to cutting boards. Plus, his recipes have that irresistible combination of simplicity and elegance."
—Portland Oregonian, 6/1/10
"Life is short, always eat dessert first." If you're a follower of that profound precept or just the owner of an active sweet tooth, David Lebovitz's Ready for Dessert is a must. . . . His header notes are chatty, his directions thorough and supportive and his take on the sweet side of life inspired and inspiring."
—BookPage, Cookbook of the Month, May 2010
"Here's what I love about this book. Lebovitz has gathered a selection of 170 recipes that is both complete and eclectic, including classics and innovations. David's voice is candid, sometimes conspiratorial, often funny, and always enabling. It's the same authentic voice that has made his blog one of the most popular food sites on the web. Enjoy the sweetness."
—The City Cook, 5/27/10
"Ready for Dessert promises visceral satisfaction starting with the cover, which invites you to drag a greedy finger through a cake's thick chocolate icing."
—Associated Press, 5/17/10
"You know the real reason I love David Lebovitz so much and tell you about him over and over again? Because he's a baking god. David's new book, Ready for Dessert: My Best Recipes is his best yet. . . . Now, I know that we'll have this book in our house for decades, until the spine falls apart and we have to put it together with duct tape. I'm never letting go of this baking book because every single recipe works. It is one of the few baking books I will keep forever in our home. This is my baking bible now. You should buy it too."
—Gluten-Free Girl, 5/11/10
"This is recipe writing at its best my friends."
—In Jennie's Kitchen, 5/4/10
" I have a sweet tooth for Lebovitz, a terrific writer and dessert whiz who has updated his favorite recipes for this lavish book. If you bake, do yourself a favor and buy this book."
—Houston Chronicle, 5/4/10
"Lebovitz has outdone himself with his latest recipe collection, offering readers the very best of his best."
—FineCooking.com, 5/3/10
"If you're looking for a new best friend in the kitchen, one that'll stay a best friend for life, Ready for Dessert might just be the one for you."
—Epicurious.com, 4/30/10
"Part of David's genius is the way he delivers the goods. He's clench-your-legs hilarious but with a strong foundation of serious culinary knowledge. A rare gem in the ever-growing field of food writers — if you haven't gotten to know his books yet, start with this one."
—Apartment Therapy's TheKitchn.com, 4/29/10
"With a bloggers tone and a skilled baker's sensibility, pastry chef David Lebovitz shares his deliciously simple yet refined recipes in his latest cookbook Ready for Dessert. Sprinkled with endearing anecdotes, each recipe reveals Lebovitz' compulsion with chocolate and seasonality. There's a charming unfussiness about the book, which includes recipes like the flourless chocolate orbit cake, which was previously named the chocolate idiot cake for it's easy-to-execute recipe. There are also some more involved recipes—like the kiwifruit, pineapple and toasted coconut baked alaska—making it a great book for beginners and experts alike."
—Los Angeles Times, 4/28/10
"Flipping through our copy, we were entranced by fudgy smudges on the plate under his banana cake, seduced by the simplicity of his red-wine raspberry sorbet, curious about the impression his chocolate chip cookies made on Parisians, and desperate to taste his best-ever brownies."
—BonAppetit.com, 4/26/10
"This is the Lebovitz book that has it all: an elite selection of cakes, fruit desserts, custards, frozen desserts, cookies and candies that encompass all the techniques you'll ever need to make dessert. The large-format color photos are ridiculously seductive and the design and tone of the book make you believe that your fresh ginger cake, banana butterscotch cream pie or tangy lemon frozen yogurt will taste as luscious as they look here. Based on my experience with Lebovitz's recipes, they will."
—Patricia Unterman, San Francisco Examiner, 4/23/10
"I think these just might be my new favorite chocolate chip cookie, sorry Thomas Keller but Lebovitz's cookies have got yours beat."
—SeriousEats.com, 4/19/10
"This is the Slinky of cookbooks. I've been paging back and forth, back and forth, mesmerized, spurred on each time I land on a silvery endpaper. It's an enticing, beautiful book with charm and know-how. But this book is not for a coffee table; I'd put it on a pedestal. . . . This book; buy it and bake the living daylights out of it."
—AOL Slashfood.com Cookbook Spotlight, 4/16/10
"An absolutely gorgeous book filled with pages upon pages of recipes and photos that will motivate you to get in the kitchen and start baking."
—SeriousEats.com Cook the Book, 4/12/10
"It's a good sign for a new cookbook when the food-lovers at the table keep passing it around. . . David Lebovitz is one of a handful of authors whose books are pure gifts in the kitchen. . . . But the proof is in the pudding — in this case, that includes coconut tapioca, orange-almond bread pudding, and kumquat sticky toffee — and I find his recipes both unintimidating to prepare and impressive to eat."
—Amazon.com Al Dente blog, 4/12/10
"This book is the perfect Starter Lebovitz, if you ask me; for those of you who've heard about him or read his blog and laughed at his jokes and comments but didn't know which of his cookbooks to buy first. With this, he's retested everything, added weights and pretty pretty photographs so you get a little taste of everything he does well without having to clear out an entire bookshelf to accommodate his awesomeness. (Though he'd like me to let you know that he does not mind one bit if you do that too.)"
—smittenkitchen.com, 4/12/10
"My copy of Lebovitz's book is already stained (with coffee) from just looking at it. It's the best type of food porn available: high production values (great recipes and gorgeous photography by Maren Caruso); a cast of stars (Chocolate Orbit Cake, Kumquat Sticky Toffee Pudding, Apple-Quince Tarte Tatin) that are hot, but not out of reach; and a writer who supplies, if not a story line, then enough anecdotes to keep me interested (The Racine's Cake recipe was, after all, found written on a men's room wall). It's one sexy book."
—Bay Area Bites, KQED.org, 4/9/10
"His headnotes are as bon-vivant engaging as his Tweets and blog. He proves that it is possible to bake and laugh at the same time. But more importantly, you'll find that his best recipes are, in fact, your favorites as well. Lebovitz is solidly among the pantheon of modern bakers."
—Washington Post, All-We-Can-Eat, 4/15/10
"Dessert Genius David Lebovitz's Opus."
—Condé Nast Traveler, 4/5/10
"A gorgeous new offering full of homey (Cherry-Almond Cobbler) and haute (Pistachio-Cardamom Cake) recipes."
—Ladies' Home Journal, LHJ.com, Ladies' Lounge blog, 4/3/10
"Bring any of David's desserts forward at the close of a meal, and you'll have a hard time remaining humble under showers of praise. But what I especially like about David's book, aside from the results his recipes promise, is David himself—that he and his desserts are so approachable, relaxed, and friendly."
—Deborah Madison, author of Seasonal Fruit Desserts from Orchard, Farm, and Market
"David's recipes are always delicious and, even more importantly, fun and approachable. They're the kind of recipes you make in a pair of comfortable sweatpants and a T-shirt. And by comfortable sweatpants, we mean the kind with an elastic waistband so you can eat more than just one slice of the heavenly Banana Cake with Mocha Frosting and Salted Candied Peanuts. David is our dessert idol and Ready for Dessert is our guidebook."
—Matt Lewis and Renato Poliafito, pastry chefs and owners of Baked and authors of Baked: New Frontiers in Baking
"If you already know David and love his simple, straightforward style and his full-flavored desserts, you'll be delighted to see his favorites polished and brought up to the moment. And if you're just discovering David's recipes, all I can say is 'Lucky you!' This collection brings you the best of his best and hours of sweet pleasure."
—Dorie Greenspan, author of Baking: From My Home to Yours
"David has put into his fantastic new book all of the ingredients that make him so great: 1 part talented pastry chef + 1 part comic + 1 part great writer. I'm excited to try his best-of recipe collection!"
—Elizabeth Falkner, chef/owner of Citizen Cake and Orson and author of Demolition Desserts

redpajama_set_name: RedPajamaCommonCrawl


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Explore Tourist Spots Galore for the Twin City of Haridwar and Rishikesh
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Haridwar and Rishikesh are holy cities in the Uttarakhand district of North India and are thronged by people from all over the world. Since they are the best choice to soak in spirituality, the cities are also meat and alcohol free. They are also known as the twin cities of national heritage. Haridwar literally means "Abode of Lord Vishnu". Both these cities are important Hindu pilgrimage places. The world famous Kumbh Mela takes place in Haridwar once every twelve years.The cities of Haridwar and Rishikesh have many pilgrimage spots and a trip to Haridwar Rishikesh is incomplete without visiting them.
Read on to find out some of the most important pilgrimage spots you need to explore on a tour to Haridwar and Rishikesh.
•	Har Ki Pauri(Ghat)
The literal meaning of Har Ki Pauri is "The footsteps of God." The Har Ki Pauri is the bank of the River Ganga which as per Hindu religion is the most auspicious river. Many pilgrims come to the river bank to take a dip in the holy waters. The evening Ganga Aarti at sunset is a magical sight with the lamps swaying to the sounds of the holy chants and bells. The light of the lamp being reflected in the holy waters of the mighty Ganga gushing down is a lovely sight to behold.
•	LakshmanJhula
This is a suspension bridge built in 1939 in Rishikesh. The Lakshman Jhula is about 450 feet in length and is at a height of about 70 feet from the river that rushes past under the bridge. Mythology has it that this was the exact place where Lord Lakshmana crossed the River Ganges on a jute rope.
•	Ashrams
There are many Ashrams in Haridwar and Rishikesh. The largest ashram in Rishikesh is the Parmarth Niketan.Parmarth Niketan literally means "House for helping others". The Parmarth Niketan is an ashram builtby Pujya Swami Sukhdevji Maharaj in the year 1942. As the name suggests, the Parmarth Niketan helps the thousands of pilgrims who throng to Rishikesh, by providing a clean and sacred atmosphere through its 1000 rooms and beautiful green gardens.
Apart from this ashram, there are other ashrams like the Patanjali Yogpeeth, which is a haven for the Yoga enthusiasts. Another very popular ashram that is visited by tourists is the Shanti Kunj or the "Peaceful garden". The stay at Shanti Kunj is reasonable, clean and spiritual.
•	Temples:
Situated at a distance of about 19 kilometers from Rishikesh is the temple of Shivapuri dedicated to Lord Shiva. The temple is located on the banks of the River Ganges and is an important pilgrim spot. The Mansa Devi temple at the top of a hill is also an important pilgrim spot. There are two ways to reach the temple. A walk up the hill may prove to be on the lines of a short trek. However, if you are not feeling too energetic and would like to expend your energy just soaking in the sights, smells and sounds around the temple periphery then take the cable car to the hilltop temple of Mansa Devi.
The Maya Devi temple on the banks of the river and the Chanda Devi temple on the Neel Parvat are the other important temples in Haridwar.
•	Swarg Ashram:
This ashram deserves special mention as it is popular for the solitude that visitors feel here unlike many pilgrim spots which are bustling with people. A quiet evening looking at the waters of the Ganges when the sun rays play on the glistening water as the sun goes dipping down into the horizon is a magical and serene feeling. You can try your hand at scenic photography as it is a splendid sight. Spend hours meditating in the green gardens of the Ashram and enjoy the spiritual vibes that the city exudes.
The twin city is plush with yoga centres, ashrams, temples and offers and unparalleled spiritual experience. At Haridwar, the river and ghat coming alive with huge gathering of people and dancing flames of diyas floating over the river makes the Haridwar Rishikesh tour, a memory of the lifetime.
Sofia Lemon
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Haridwar Rishikesh tour
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Last October, we attended the congress Waste Meetings held in Lyon, where we could share experiences related to waste management and learn about the work being done by some companies.
We had the opportunity to share the table with Triadis Seche, among others Innoveox and Sita group exchanged views and knowledge and we revealed synergies that could benefit mutually.
Attendance at the conference was hugely successful as we could learn more about the latest technologies for waste management.
Certainly, we will participate in this interesting meeting next year.


The European Commission will give conditional approval for Turks to travel without visas to Europe's passport-free Schengen area.
The move is part of a deal in which Turkey is taking back migrants who have crossed over the Aegean Sea to Greece, sources have told the BBC.
But Turkey must still meet EU criteria and the deal must be approved by the European Parliament and member states. The EU fears that without a visa deal, Turkey will not control migration.
The large influx of migrants and refugees arriving in Europe from Turkey and from North Africa has caused a political crisis among EU states.
A formal announcement from the European Commission is due on Wednesday.
If the European Commission (the EU's executive body) does make the recommendation this Wednesday that Turks be granted visa-free travel in Europe's Schengen area, as whispers from well-placed EU sources suggest, then it will be doing so holding its nose and its breath.
The freedom of speech; the right to a fair trial; and revising terrorism legislation to better protect minority rights—these are just some of the criteria demanded by the EU countries before it lifts visa requirements, even for short-term travel.
It is hard to see how Turkey could be described as meeting these conditions. The government in Ankara increasingly cracks down on its critics in a manner more autocratic than democratic.
But these are desperate times for the EU. The European Commission and most EU governments are under huge public pressure to ease the migrant crisis.
BBC's sources say the commission will keep to the agreed script. But they insist this is no blank check. Turkey will get the green light over visas this week to keep it sweet. But it will also be informed of the outstanding criteria it still needs to meet.
Under the EU-Turkey agreement, migrants who have arrived illegally in Greece since 20 March are to be sent back to Turkey if they do not apply for asylum or if their claim is rejected.
For each Syrian migrant returned to Turkey, the EU is to take in another Syrian who has made a legitimate request.
Under the agreement, Turkey must meet 72 conditions by 4 May to earn access to the EU's Schengen area by the end of June, subject to full EU approval. Diplomats have suggested that fewer than 10 still need to be met.
Human rights groups question the deal's legality and argue that Turkey is not a safe place to return people to.
Last month, however, European Council President Donald Tusk said the deal had begun to produce results. He praised the Turkish government as "the best example in the world on how to treat refugees", despite criticism by rights groups of the agreement.
At the same time, Turkish Premier Ahmed Davutoglu said his country had fulfilled its part of the agreement and that the issue of the visa waiver for the EU's Schengen area was "vital" for Turkey.


As the USSA Masters Manager of the U.S. Ski Team Masters Program, I have been in this sport and racing since 1969. Junior racing, NCAAA racing, Pro racing and for the past 35 year Masters racing and coaching at the PC Masters program. I have seen it all. I run the Park City Masters program that started in 1990. Bootworks and Ernie were there then and are still there, Really what else has to be said? Sure I have looked around and had some boot work done here and there but in the end Ernie knows the deal and fixed me again and again as he did today, canting and pressure points. If I have Master racer who is in Park City to train and needs a proper fit (boots last a lot longer than skis) I send them to Ernie & the team at Bootworks.
"Bootworks understands my feet. They know which shell is best for my foot and they punch and align my boots to perfection. I can wear my race boots all day with comfort. Bootworks is the best."
"Purchasing a new pair of ski boots is a big decision. Getting them customized to your foot is an even bigger decision. I had the good fortune of spending over 40 years in the business and I can say, without question, getting your new boots customized at Bootworks will pay huge dividends in both comfort and performance! Skiing boots "out of the box" would be like driving your car on 4 spare tires!!!"
"I have been going to Bootworks for 20 plus years. Ernie and his staff have the experience and technology to optimize my boots so I can ski my best. They will put you in the right boot, build a contemporary foot bed and then fine tune your fit and alignment."
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Display of any trademarks, tradenames, logos and other subject matters of intellectual property belong to their respective intellectual property owners. Technology is gifting easy life for us day-to-day. This scheme was to help indigenous machinery manufacturers and their purchases. This is not an example of the work written by our professional academic writers. Enter both the main points in the option that follows. Energy consumption information is disaggregated into fuels and electricity categories. The loan amount which they had provided was sufficient and there has been processing fee which was nominal.
The units which have been assisted by State Financial Corporation or State Industrial Development Corporations and are classified as sick are eligible under this scheme. Government Loans for Small Scale Businesses Small Scale Businesses or industries need better support and financial aid in order to have proper growth and flourish well in the face of stiff competition from companies or organisation that are privately funded or have an established presence in the market. A non-public code means added safety against unauthorized use of your card while you shop at collaborating on-line retailers. However in this case we would appreciate more information from your behalf regarding which bank schemes you applied to? Hi, There are many discussion of Loan for a manufacturing setup. In case of mortgaging immovable property then process of home loan is to be followed. Premier Institutions Under Non Vocational Courses, comes the other segment where the students of premier education institutes who are doing full time courses are also eligible.


text:
Shooting outside Fla. nightclub kills 2, injures more than a dozen others
WFTX

Fort Myers-based WFTX

FORT MYERS, Fla. (AP) — Gunfire erupted at a nightclub hosting a swimsuit-themed party for teens in Florida, leaving two teens dead and at least 17 other people wounded, officials said Monday.
It was not immediately clear what triggered the violence, but Fort Myers police Capt. Jim Mulligan said the shooting was not an act of terror. Police detained three people and said the area around Club Blu had been deemed safe, Mulligan said.
The slain teens were 14-year-old Sean Archilles and 18-year-old Stef'an Strawder, police said. Archilles lived about a mile from the nightclub, said his father, Jean Archilles. Archilles said his son loved to play football and basketball.
"He liked to make people laugh. He's a funny kid. He's always joking," Jean Archilles said.
He said he doesn't wish bad for the shooter.
"When he lays down in his bed, how is he feeling about what he did? A 14-year-old kid!" Archilles said. "Is he thinking about his family, his friends? Because everybody has family and friends. Does he feel good about himself?"
Four people were in the hospital. Two were in critical condition and two in fair condition, said Lisa Sgarlata, the chief administrative officer at Lee Memorial Health System.
All of the other patients were treated and released. The victims ranged in ages from 12 to 27.
Police said they want to talk to some of the victims who were treated and released from the hospital and haven't yet spoken with investigators.
"It is imperative that all persons who were involved with this incident come forward so that this incident can be properly documented and statements obtained from all involved," Mulligan said.
There were two active crime scenes — the club and a street in the area, which also remained closed as police investigated.
The club is in a strip mall that includes a daycare center and is across the street from a large apartment complex. The shooting happened about 12:30 a.m. Monday, just as the club was closing and parents were arriving to pick up their children.
Syreeta Gary told WFTX-TV her daughter ran to avoid being shot. Her daughter was OK, but her daughter's friend "got hit in the leg and luckily it's just her leg," she said.
"Her dodging bullets and running, dropping in between cars, it's ridiculous that these kids have to go through this," Gary said. "They can't enjoy themselves because you have other people that have criminalistic minds and they just want to terrorize things."
A post on Club Blu's Facebook page said there was armed security at the event.
"We are deeply sorry for all involved," the post read. "We tried to give teens what we thought was a safe place to have a good time."
Law enforcement removed some of police tape by Monday morning, allowing the media and public to get closer to the entrance to Club Blu.
There were bullet holes in concrete planters and wooden support beams. Sheriff's evidence markers were still affixed to the holes. The letter "A'' was attached near a post, while nearby "L," ''M," ''N" and "O'' we're marked near a planter filled with scraggly foliage.
"It breaks my heart. No family should have to endure this kind of pain," said Sylvia Bargouthi, a mother who didn't know any of the victims. "Children should be able to enjoy their life without being brutally murdered."
Bargouthi carried a small stuffed animal with her and placed it near the club's entrance.
State records online show the alcohol license for Club Blu was revoked June 7 because of an incident that occurred a year ago, but there were no additional details available, according to records from the Department of Business and Professional Regulation. The same records show that a complaint was filed in 2014 for "criminal activity" and that the club was given an official notice.
The shooting comes more than a month after a nightclub shooting in Orlando that was the deadliest shooting in modern U.S. history. The shooting at the Pulse nightclub on June 12 left 49 victims dead and 53 others wounded.
Associated Press writers Tamara Lush and Gary Fineout contributed to this report.
This story has corrected the hospital official's title to chief administrative officer, not CEO. It also has corrected the victim's first name to Stef'an, not Ste'fan.
Copyright 2016 Scripps Media, Inc. The Associated Press contributed to this report. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


text:
Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs Academic research paper on "Chemical sciences"
Asian Journal of Pharmaceutical Sciences
{Extended-release / Chitosan / "Anionic polymers" / "Sodium valproate–Valproic acid"}
Abstract of research paper on Chemical sciences, author of scientific article — Yang Shao, Liang Li, Xiangqin Gu, Linlin Wang, Shirui Mao
Abstract The objective of this study is to develop chitosan–anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS) and valproic acid (VPA) were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG), carrageenan (CG), sodium carboxymethyl cellulose (CMC-Na) and sodium alginate (SA). The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan–anionic polymers based system caused a further slowdown of drug release rate. Among them, CS–xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan–anionic polymers based system.
Similar topics of scientific paper in Chemical sciences , author of scholarly article — Yang Shao, Liang Li, Xiangqin Gu, Linlin Wang, Shirui Mao
Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression
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Effect of formulation variables on in vitro release of a water-soluble drug from chitosan–sodium alginate matrix tablets
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2017 / Rawan A. Fitaihi, Fadilah S. Aleanizy, Samar Elsamaligy, Hanaa A. Mahmoud, Mohsen A. Bayomi
Drug release behavior of polymeric matrix filled in capsule
2015 / Thawatchai Phaechamud, Wanwilai Darunkaisorn
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2016 / Wael Samy, Ayman Elnoby, Hanan M. El-Gowelli, Nazik Elgindy
Academic research paper on topic "Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs"
Accepted Manuscript
Evaluation of chitosan-anionic polymers based tablets for extended-release of highly water soluble drugs
Yang Shao, Liang Li, Xiangqin Gu, Linlin Wang, Shirui Mao
PII: S1818-0876(14)00051-8
DOI: 10.1016/j.ajps.2014.08.002
Reference: AJPS 84
To appear in: Asian Journal of Pharmaceutical Sciences
Received Date: 1 May 2014
Revised Date: 8 July 2014
Accepted Date: 4 August 2014
Please cite this article as: Shao Y, Li L, Gu X, Wang L, Mao S, Evaluation of chitosan-anionic polymers based tablets for extended-release of highly water soluble drugs, Asian Journal of Pharmaceutical Sciences (2014), doi: 10.1016/j.ajps.2014.08.002.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Evaluation of chitosan-anionic polymers based tablets for extended-release of
highly water soluble drugs
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China To be submitted to: Asian JPharm Sci
* To whom correspondence should be addressed.
Shenyang Pharmaceutical University
103 Wenhua Road, 110016, Shenyang, China
Tel and Fax: +86-24-23986358
E-mail\ maoshirui@syphu.edu.cn
The objective of this study is to develop chitosan-anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS) and valproic acid (VPA) were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG), carrageenan (CG), sodium carboxymethyl cellulose (CMC-Na) and sodium alginate (SA). The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan-anionic polymers based system caused a further slowdown of drug release rate. Among them, CS-xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 hours. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan-anionic polymers based system.
Keywords: Extended-release; Chitosan; Anionic polymers; Sodium valproate-Valproic acid
Hydrophilic gel-forming matrix tablets are widely used as oral extended-release dosage forms due to their simple preparation process and cost-effectiveness. The key factors controlling drug release are the capacity of the gel-forming polymers to imbibe large amount of water or biological fluids and forming three-dimensional, hydrophilic networks [1]. Since the gel layer formation, which defines the kinetics of drug release from the matrix system, is controlled by the concentration, viscosity and chemical structure of the polymers, it is of greatly importance to select appropriate hydrophilic polymers for the design of extended-release tablets.
Chitosan, a cationic biopolymer, derived from chitin by partial deacetylation, is well known for its good biocompatibility, biodegradability, low toxicity and relatively low production cost from abundant natural sources [2, 3], and it has been wildly applied as a polymeric drug carrier in the field of pharmaceutics. However, although chitosan is a very promising biopolymer as a release-controlling agent in drug delivery, it has limited capacity for controlling drug release when used alone due to its easy disintegration characteristics at neutral pH [4, 5]. Thus, combination of CS with anionic polymers as the carrier of oral controlled-release preparations has been suggested, with increased controlled-release capability and reduced pH dependence [6-8]. In most cases, extended-release effect of the combination system was achieved by forming the polyelectrolyte complexes (PECs) between CS and anionic polymers in solution first and then the PECs was further used for tablet preparation. Since PECs preparation was an energy-consuming and lengthy process with complicated operations [9], the superiority of simple preparation process of this type of hydrophilic matrix tablets was greatly discounted.
In order to avoid this drawback, some new strategies have been taken. It was reported that when CS-sodium alginate (SA) physical mixture was used as the matrix to prepare tablets, in situ PECs could be formed on the surface of the tablets in the simulated gastrointestinal fluid due to self-assembly or spontaneous association [10]. However, drug release from this CS-SA based system presented obvious drug solubility dependence and it is not suitable to control the release of highly water-soluble drugs [11]. Thus, it was absolutely essential to search for alternative drug delivery system with better extended-release ability for highly water-soluble drugs. We assume that
by changing the type of anionic polymers used in combination with chitosan, it is possible to change the strength and permeability of the PECs formed on the tablet surface, therefore making the release of highly water soluble drugs under control as well. This hypothesis was tested in this study.
Valproic acid (VPA) and sodium valproate (VPS) are generally regarded as the first-line antiepileptic drugs [12]. Sodium valproate (VPS) is the sodium salt of 2-propyl pentanoic acid with a high solubility (1000 mg/ml) in neutral pH. They are usually used in combination [13]. Despite their efficacy for controlling epilepsy, they both suffer from relative short half-life [14]. Thus, an extended-release preparation of the combination has attracted considerable attention in order to minimize plasma peak-related adverse effects and reduce the inconvenience caused by frequent dosing of conventional products. In addition, to meet the clinical needs for once-daily administration, they were usually formulated into extended-release dosage forms with high loading (500mg/tablet).
Therefore, in this study, by using VPA and VPS combination as the model highly soluble drugs, the feasibility of using CS and other anionic polymers based system for controlling the release of highly water soluble drugs with high drug loading was tested, and influence of the type of anionic polymers, CS: anionic polymer ratio, molecular weight of CS, on the drug release behavior was screened, and drug release mechanism from CS and anionic polymers based tablets were further explored.
2.1. Materials
Chitosan (50kDa, lOOkDa and 400kDa) were all purchased from Weifang Kehai Chitin Company, Ltd. (Weifang, Shandong, China) with degrees of deacetylation of 86.5%, VPA and VPS were purchased from Yan Cheng Lang De chemicals Company, Ltd. Sodium Alginate (SA, LF 200M, G/M=40:60) and carrageenan (CG, GP 209NF) were gifts from FMC Biopolymer Company, Ltd (Drammen, Norway). Sodium carboxymethyl cellulose (CMC-Na) was from Anhui Shanhe Pharmaceutical excipients Co., Ltd (Anhui, China). Xanthan gum was from Zibo Zhongxuan Biological Products Co., Ltd (Shandong, China). Magnesium stearate was from Tianjin Bo di Chemical Company, Ltd. (Tianjin, China). Colloidal Silicon Dioxide was purchased from Hubei ZhanWang Pharmaceuticals Company, Ltd. (Hubei, China). All other chemicals were of analytical
grade.
2.2. Preparation of compound VPA and VPS extended-release matrix tablets
The matrix tablets containing drug (500 mg calculated by VPS and the mole ratio of VPS to VPA was 2/1), CS-anionic polymers (200 mg), colloidal silicon dioxide (80 mg as adsorbent and 11mg as antisticking agent), magnesium stearate (11mg) as lubricants were prepared using conventional wet granulation method. All the components used were passed through 80-mesh sieve and mixed for at least 15 min, then 70% ethanol was used as wetting agent to prepare the damp mass, the granules were prepared by passing through 16 mesh sieve and dried at 55oC. The dried granules were mixed with lubricants and compressed using single punch tableting machine (ZDY-8, Shanghai far-east-pharmach company, Ltd, Shanghai, China) with a caplet punch. Hardness of all the tablet formulations was adjusted to 120-140 N (Shanghai huanghai Instruments Company, Ltd, Shanghai, China; hardness tester; n=6). The weight of each tablet was controlled within 780 ± 0.5% mg.
2.3. In vitro Drug release study
Drug release from the tablets was tested using a dissolution apparatus (ZRD6-B, Shanghai Huanghai Instruments Company, Ltd, Shanghai, China), ChP Apparatus II (paddle method) operating at 50 r/min and 37±0.5 °C. Unless specially indicated, the tablets were immersed in dissolution vessels (n=6) with simulated gastrointestinal conditions (500 ml of pH 1.2 HCl solutions for the first hour, 900 ml of pH 6.8 phosphate buffer for additional 23 h) as dissolution medium. Aliquots of 10 ml were withdrawn at different time intervals (0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15, and 24 h) for analysis and were replenished with equal amounts of fresh release medium. The amount of drug released at different time intervals was determined using high-performance liquid chromatography (HPLC) method [15].
The differences in release profiles of the designed formulations were compared using similarity factor f2). The similarity factor was calculated using the Eq. (1) [16].
where n is the number of time points, Rt is the dissolution value of the reference at time t, and Tt is the dissolution value of the test at time t. The release profiles were significantly different iff2<50.
2.4 Differential scanning calorimetry (DSC)
Thermal analysis was performed using a Mettler Toledo model 30TC 15 equipment (Mettler, Zurich, Switzerland). The samples (2-4 mg) were scanned in sealed aluminum pans under nitrogen atmosphere. The samples were cooled to room temperature and then reheated from 25-320 °C at a constant rate of 10 °C/min.
2.5 Fourier transforms infrared (FTIR) spectroscopy
The infrared absorption spectra of the samples were analyzed using an FTIR spectrophotometer (IFS-55, Bruker Co., Ltd, Switzerland, Faellanden). The tablets were prepared by compressing the samples with potassium bromide. The peak variation of adsorption between 400 and 4000 cm"1 was detected.
2.6 Erosion and swelling behavior of the combined matrix
The erosion and swelling behaviors of the developed matrix system were evaluated simultaneously by measuring the amount of water uptake and weight loss in a dissolution tester. Briefly, the weighed tablets were placed in the dissolution vessels and were taken out of the vessels at predetermined time intervals and weighed after removing the excess liquid. Swollen tablets were dried at 50 °C for 2 days and then the weight of dried tablets was determined. The erosion and swelling ratios were calculated according to Eq. (2) and Eq. (3), the remaining ratio was calculated according to Eq (4) [17, 18].
Where ER is erosion ratio, SR is swelling ratio, RM is remaining ratio, Wo is the initial weight of the dry tablet, Wj is the weight of drug released at time i, IV, is the weight of remaining dry tablet after swelling at time t, Wt is the weight of the swollen matrix tablet at time t. The erosion and swelling studies were carried out in triplicate for all the samples tested.
ER{%) = (W0 - Wr - Wd)/W0 x 100 SR(%) = (Wt - Wr)/Wr x 100 RM(%) = 100 - ER
3.1. Evaluation of CS-anionic polymers as extended-release system
The anionic polymers were indispensable components in this matrix system and the choice of anionic polymers type was of special importance in developing the controlled-release system. In this study, three other kinds of anionic polymers including xanthan gum (XG), carrageenan (CG), and sodium carboxymethyl cellulose (CMC-Na) were chosen to combine with CS (400kDa) to explore their extended-release capability for VPA-VPS, and compared with that of CS-sodium alginate (SA) based system.
First of all, by keeping the total amount of polymer in each formulation 200mg, influence of single anionic polymers on drug release was investigated. As shown in Fig.1, these polymers presented diverse release behavior when used alone. Among them, SA and CMC-Na could only control drug release for 8-10 h due to their swelling and erosion characteristics [19]. When CG or XG was used as the matrix, controlled drug release up to 14 h can be achieved. However, none of these anionic polymers has the capacity to extend drug release up to 24 h when used alone. This phenomenon can be explained by the fact that drug release from conventional hydrophilic matrix is mainly controlled by drug solubility, swelling and erosion properties of the polymer [20]. For single anionic polymer based matrix tablets, due to the poor gel forming ability and large extent of polymer erosion, together with the high drug solubility (1000p,g/ml) at neutral pH, a large amount of drug was released in a short period of time.
Thus, in order to further prolong drug release to 24 h, combination of these anionic polymers with CS was subsequently investigated. Figure 2 shows the drug release profiles from the combined matrix systems at CS and anionic polymers ratio 1:1. Compared with the results in Fig.1, when CS and these anionic polymers were used in combination, the drug release behaviors were improved to different degrees and the extended-release characteristics became more remarkable. In agreement with the previous report [11], release of highly water soluble drugs from CS-SA system was the fastest, with 93.8% of the drug released within 6 hours. For the CS-CMC-Na and CS-CG based systems, although the drug release was slower than that of single polymer based systems, most of the
drugs were released in 12 h. In contrast, 24 h sustained drug release was obtained by using CS-XG-based matrix system. The mechanism for this extended release behavior was further explored in the followed studies.
3.2 Effect of CS and XG ratio on drug release
The ratio between CS and anionic polymers might greatly influence the hydration property and drug diffusion coefficient in the extended-release system. Since drug release from CS-XG-based tablets exhibited the best extended-release behavior, therefore the CS-XG system was selected for this investigation. By keeping the total amount of CS (400 kDa) and XG being 200 mg in each formulation, effect of CS/XG ratio at 3/1,1/1,1/3, on drug release was evaluated and the results are shown in Figure 3.
No significant difference in release was found when changing the ratio of CS to XG from 3/1 to 1/1 (/2=92). Although a slight fluctuation in drug release occurred when CS to XG ratio was 1/3, the similarly factors were still larger than 50 (f (3/1-1/3) = 71, f2 (1/1.1/3) = 67), indicating that the weak fluctuation did not lead to large deviation from the whole trend. Thus, drug release was less influenced by CS to XG ratio in the range studied. CS: XG ratio 1:1 was selected for the followed studies.
3.3 Effect of CS molecular weight on drug release
The molecular weight (MW) of the polymer is directly related to gel strength and is of great importance in drug release since it is decisive for the passage of water through the gel layer during swelling. In this study, keeping CS-XG ratio 1:1, effect of chitosan molecular weight on drug release was investigated by using three kinds of CS with low (50kDa), medium (100kDa) and high (400kDa) molecular weights. The release profiles are presented in Figure 4.
It was noted that no apparent difference in drug release was found in the first 6 h and thereafter slightly decreased release rate was observed with the increase of chitosan molecular weight. On the whole, the drug release profiles from these three kinds of CS based systems was similar to each other
(f (CS LMW-MMW) =67 > 50,_f (CS lmw-hmw) =69 > 50,f2 (cs mmw-hmw) = 74 > 50). It was reported that,
for hydrophilic matrices, gel strength determines the erosion capacity of the polymer, while solubility of the drug incorporated into the polymer matrix will govern the release mechanism [21]. Due to the high solubility of VPS and its high loading, it might be released from the tablets mainly by diffusion through the gel layer [22]. This is in good agreement with the comparable drug release profiles from different molecular weight chitosan based systems.
3.4. Characterization of the CS/XG PECs
In our previous study, it was found that the self-assembled PECs film was formed on the tablet surface of CS-SA based system during the dissolution process [10]. Therefore, based on the structure properties of the polymers, it was reasonably to assume that in situ PECs can be formed on the tablet surface of CS-XG based system. Indeed, insoluble white film (shell structures) was observed visually on the outer surface of the tablets during the dissolution test, similar phenomenon was reported in CS-SA based system [11]. In order to identify the composition of the film, FIIR and DSC were applied to characterize the physicochemical properties of the films collected from tablet surface.
Figure 5 shows DSC curves of CS, XG, physical mixtures of CS and XG, and the outer layer of CS-XG-based matrix tablets after 24 h of release test. An exothermic peak appeared at approximately 310 °C (Fig. 5a) corresponding to the degradation of CS [23]. Similarly, XG (Fig. 5b) presented the exothermic peak of decomposition at 288 °C [24]. As for the physical mixture of CS-XG (Fig. 5c), due to the overlap of the exothermic peaks of CS and XG, only a peak at 303 °C was found,indicating no obvious interaction between each other. However, compared with the single polymers and physical mixture, the outer layer of CS-XG-based matrix tablets showed different properties (Fig. 5d). On one hand, although the exothermic peak at 288 °C was still visible, it was very weak. On the other hand, a new broad peak ranging from 150 to 280 °C appeared, which was significant distinguished with the single exothermic peaks of CS and XG and similar to the exothermic peak of PECs reported in the literature [11]. These results implied the in situ PECs were formed on the surface of the tablets during drug release process.
Moreover, FIIR was further used to demonstrate the formation of PEC on the tablet surface. In the spectrum of CS (Fig. 6a), the band situated at 1659 cm-1 and 1605 cm-1 were assigned to the
amine groups of the 2-aminoglucose unit and the carbonyl group of the 2-acetaminoglucose unit, respectively [25]. Meanwhile, the characteristic peak of XG at 1725 cm-1 corresponding to C=O stretching vibration of carboxylic groups was presented in the spectrum of XG (Fig. 6b) [26, 27]. In comparison with IR spectra of the single polymers, no new characteristic peak was found in the physical mixtures (Fig. 6c). However, in the spectrum of the outer shell of the CS-XG-based tablets, the characteristic peaks of XG were not apparent or even disappeared. Meanwhile, a new weak peak at 1542 cm-1 was observed, which might be attributed to the ionic interaction between the ionized carboxylic groups and the protonated amino groups(-NH3+) of CS [8, 28]. These results were in accordance with previous observations from the PECs formed between poly(acrylic aid) or carrageenan with CS [29, 30].
Therefore, both visual observation and DSC, FTIR studies suggested that PEC was formed in situ on the CS-XG based matrix tablets.
3.5. Drug release mechanism
For traditional hydrophilic matrices, the erosion and swelling of the polymeric carrier play an important role in controlling drug release [4, 31]. This study demonstrated that PECs can be formed on the surface of CS-XG based matrix tablets. It is not clear how this PEC can influence drug release mechanism. Therefore, the erosion and swelling properties of the selected CS-XG based system were further evaluated by weighing method during the release process.
As shown in Fig.7a, the remaining ratio was quite high in the initial stage, 82.66 % in 0-1 h, and then slowed down gradually with erosion rate 2.38 %/h in 1-6 h. The remaining ratio was 68.07 % at 6 h and no significant decrease was observed in the followed time period. This is in great agreement with our previous study indicating that the formation of PEC on the tablet surface may prevent erosion in the later stage [10, 11], leading to further prolonged drug release.
Similarly, three-stage swelling processes were observed in Fig.7b. Initially, the tablets exhibited fast swelling behavior and the swelling ratio increased almost linearly at a rate of 57.96 % /h, and swelling ratio reached 474 % at 6 h. Thereafter, the swelling rate slowed down gradually with the average rate being approximately 16.76 % /h during 6-24 h. After 12 h, the swelling ratio was almost leveled off and it was 775.4 % at 24 h.
Taken together, it was found that swelling ratio increased slightly with limited change in
remaining ratio of the tablet after 6 hour. This can probably be explained by the preventing function of the PEC formed on the surface of CS-XG based tablets during drug release process. Meanwhile, this result implied that complete PEC was formed in 6 h. Similarly, it has been demonstrated that polyion complex formation in chitosan and xanthan gum gel layer prevented over-swelling, strengthened the wet matrices and sustained the drug release [32]. Since the formation of the PECs was a progressive and gradual process, significantly decreased erosion and swelling was only observed after its complete formation at 6 h. Based on the above analysis, it can be concluded that later stage drug release from CS-XG matrix based tablets were greatly dependent on the properties of PECs on the tablet surface.
In this study the feasibility of using CS-anionic polymers based matrix system for sustained release of highly water-soluble drugs, the combination of sodium valproate and valproic acid were demonstrated. Among them, drug release from CS-XG based matrix system exhibited the best extended release behavior and was less influenced by the change of CS: XG ratio and CS molecular weights. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface. The PECs played an important role on retarding erosion and swelling of the matrix, and therefore drug release in the later stage. In conclusion, CS-anionic polymer system was suitable for developing extended-release preparations of highly water-soluble drugs with high drug loading and this broadened current views on hydrophilic polymers based matrix tablets.
[1] Hennink WE, van Nostrum CF. Novel crosslinking methods to design hydrogels. Adv Drug Deliver Rev 2002; 54: 13-36.
[2] Ding J, Na L, Mao S. Chitosan and its derivatives as the carrier for intranasal drug delivery. Asian J Pharm Sci 2012; 7: 349-361.
[3] Hamman JH. Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Mar Drugs 2010; 8: 1305-1322.
[4] Huanbutta K, Cheewatanakornkool K, Terada K, et al. Impact of salt form and molecular weight of chitosan on swelling and drug release from chitosan matrix tablets. Carbohydr Polym 2013; 97: 26-33.
[5] Rasool BKA, Fahmy SA, Galeel OWA. Impact of Chitosan as a disintegrant on the bio-ava ilability of furosemide tablets: In vitro evaluation and in vivo simulation of novel formulations. Pak J Pharm Sei 2012; 25.
[6] Andrews GP, Laverty TP, Jones DS. Mucoadhesive polymeric platforms for controlled drug delivery. Eur J Pharm Biopharm 2009; 71: 505-518.
[7] Gömez-Burgaz M, Torrado G, Torrado S. Characterization and superficial transformations on mini-matrices made of interpolymer complexes of chitosan and carboxymethylcellulose during in vitro clarithromycin release. Eur J Pharm Biopharm 2009; 73: 130-139.
[8] Park SH, Chun MK, Choi HK. Preparation of an extended-release matrix tablet using chitosan /Carbopol interpolymer complex. Int J Pharm 2008; 347: 39-44.
[9] Li X, Xie H, Lin J, et al. Characterization and biodégradation of chitosan-alginate polyelectrolyte complexes. Polym Degrad Stab 2009; 94: 1-6.
[10] Zhang T, Mao S, Sun W. Design and In vitro evaluation of a film - controlled dosage form self-converted from monolithic tablet in gastrointestinal environment. J Pharm Sei 2010; 99: 4678-4690.
[11] Li L, Wang L, Shao Y, et al. Drug release characteristics from chitosan-alginate matrix tablets based on the theory of self-assembled film. Int J Pharm 2013; 450: 197-207.
[12] Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695-714.
[13] Bialer M. Extended-release formulations for the treatment of epilepsy. CNS drugs 2007; 21: 765-774.
[14] Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 1999; 58: 31-59.
[15] Fujisaki Y, Tsukune T, Funyu M, et al. Development of sustained-release tablets containing sodium valproate: In vitro and in vivo correlation. Drug Dev Ind Pharm 2006; 32: 207-217.
[16] Gohel M, Panchal M. Novel Use of Similarity Factors f 2 and S d for the Development of
Diltiazem HCl Modified-Release Tablets Using a 32 Factorial Design. Drug Dev Ind Pharm
2002; 28: 77-87.
[17] Efentakis M, Stamoylis K. A study of dimensional, swelling, and gel changes in hydrophilic and hydrophobic polymer mixtures of chitosan and their possible use as carriers for sustained release drug delivery. Adv Polym Tech 2011; 30: 110-121.
[18] Sokar M, Hanafy A, El-Kamel A, et al. Pulsatile core-in-cup valsartan tablet formulations: In vitro evaluation. Asian J Pharm Sci 2013; 8: 234-243.
[19] Sriamornsak P, Thirawong N, Korkerd K. Swelling, erosion and release behavior of alginate -based matrix tablets. Eur J Pharm Biopharm 2007; 66: 435-450.
[20] Hardy IJ, Windberg-Baarup A, Neri C, et al. Modulation of drug release kinetics from hydroxypropyl methyl cellulose matrix tablets using polyvinyl pyrrolidone. Int J Pharm 2007; 337: 246-253.
[21] Maderuelo C, Zarzuelo A, Lanao JM. Critical factors in the release of drugs from sustained release hydrophilic matrices. J Control Release 2011; 154: 2-19.
[22] Tahara K, Yamamoto K, Nishihata T. Overall mechanism behind matrix sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910. J Control Release 1995; 35: 59-66.
[23] Neto CdT, Giacometti J, Job A, et al. Thermal analysis of chitosan based networks. Carbohyd Polym 2005; 62: 97-103.
[24] Darzi HH, Larimi SG, Darzi GN. Synthesis, characterization and physical properties of a novel xanthan gum/polypyrrole nanocomposite. Synthetic Met 2012; 162: 236-239.
[25] Le Tien C, Lacroix M, Ispas-Szabo P, et al. N-acylated chitosan: hydrophobic matrices for controlled drug release. J Control Release 2003; 93: 1-13.
[26] Fukuda M, Peppas NA, McGinity JW. Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum. Int J Pharm 2006; 310: 90-100.
[27] Kumar A, Singh K, Ahuja M. Xanthan-g-poly (acrylamide): Microwave-assisted synthesis, characterization and in vitro release behavior. Carbohyd Polym 2009; 76: 261-267.
[28] Moustafine RI, Margulis EB, Sibgatullina LF, et al. Comparative evaluation of inter -polyelectrolyte complexes of chitosan with Eudragit® L100 and Eudragit® L100-55 as potential carriers for oral controlled drug delivery. Eur J Pharm Biopharm 2008; 70: 215-225.
[29] Li L, Wang L, Shao Y, et al. Elucidation of release characteristics of highly soluble drug trimetazidine hydrochloride from chitosan-carrageenan matrix tablets. J Pharm Sci 2013; 102:
[30] Torre PM, Enobakhare Y, Torrado G, et al. Release of amoxicillin from polyionic complexes of chitosan and poly (acrylic acid). Study of polymer/polymer and polymer/drug interactions within the network structure. Biomaterials 2003; 24: 1499-1506.
[31] Lamberti G, Galdi I, Barba AA. Controlled release from hydrogel-based solid matrices. A model accounting for water up-take, swelling and erosion. Int J Pharm 2011; 407: 78-86.
[32] Phaechamud T, Ritthidej GC. Sustained-release from layered matrix system comprising chitosan and xanthan gum. Drug Dev Ind Pharm 2007; 33: 595-605.
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Guy Grantham
Guy Grantham net worth, birthday, age, height, weight, wiki, fact 2021-22! In this article, we will discover how old is Guy Grantham? Who is Guy Grantham dating now & how much money does Guy Grantham have?
Date of Death August 31, 1992
Place of Birth Skegness, Lincolnshire
Guy Grantham Biography
Guy Grantham is a famous , who was born on January 09, 1900 in Skegness, Lincolnshire. According to Astrologers, Guy Grantham's zodiac sign is Capricorn.
Admiral Sir Guy Grantham, GCB, CBE, DSO (9 January 1900 – 8 September 1992) was a senior Royal Navy officer who served as Commander-in-Chief, Portsmouth from 1957 to 1959.
Many peoples want to know what is Guy Grantham ethnicity, nationality, Ancestry & Race? Let's check it out! As per public resource, IMDb & Wikipedia, Guy Grantham's ethnicity is Not Known. We will update Guy Grantham's religion & political views in this article. Please check the article again after few days.
Educated at Rugby School, Grantham joined the Royal Navy in 1918.
Guy Grantham Net Worth
His net worth has been growing significantly in 2021-2022. So, how much is Guy Grantham worth at the age of 92 years old? Guy Grantham's income source is mostly from being a successful . He is from . We have estimated Guy Grantham's net worth, money, salary, income, and assets.
Grantham served in the Second World War, initially as commander of the cruiser HMS Phoebe and was involved in the evacuation from Greece, for which he was awarded the Distinguished Service Order. After a period as a liaison officer in the Western Desert, he became Commander of the cruiser HMS Naiad, which was sunk by a torpedo in March 1942. He then became commander of the cruiser HMS Cleopatra, in which he was involved in the defeat of the Italian Fleet at the second Battle of Birte. His last wartime command was of the aircraft carrier HMS Indomitable, which was involved in the landings in Sicily. He went on to be Director of Plans at the Admiralty.
Guy Grantham Height, Weight & Measurements
At 92 years old, Guy Grantham height not available right now. We will update Guy Grantham's Height, weight, Body Measurements, Eye Color, Hair Color, Shoe & Dress size soon as possible.
After the war, Grantham became Chief of Staff to the Commander-in-Chief, Mediterranean Fleet in 1946. He was appointed Flag Officer Submarines in 1948, Flag Officer, Second in Command of the Mediterranean Fleet in 1950 and Vice Chief of the Naval Staff in 1951. He became Commander-in-Chief, Mediterranean Fleet and NATO Commander Allied Forces Mediterranean in 1954 and then Commander-in-Chief, Portsmouth and Allied Commander-in-Chief, Channel and southern North Sea in 1957. He retired in 1959.
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Grantham was also First and Principal Naval Aide-de-camp to the Queen from 1958 to 1959.
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Do you have difficulty passing your stool because they are hard and dry? Do you even dread going to the bathroom because you have difficulty with bowel movements? This causes constipation and in this case you really need good stool softener home remedy.
I know for a fact that the underlying reasons why people have this problem are mainly due to poor eating habit. Having too much processed, fried, greasy food, not drinking sufficient water and not consuming enough fiber will lead to constipation as well as many other health related issues.
So, what is the most effective constipation home remedy? There are many over the counter products that can be taken however most people prefer stool softening home remedy because they are easier and have no undesired side effects.
Hope these will help ease the problem you are experiencing and help make bowel movements painless.
Eat fiber rich foods such as unprocessed bran, whole wheat bread, brown rice, fruits and vegetables. You should also try those baby carrots they are good in helping moving the bowel.
Drinking aloe vera juice as they contain substances that are found in many laxatives. Drink about half a cup of aloe vera juice each day then follow with a glass of water.
Any physical activity that will get your metabolism going and move things around in your body will aid in keeping your digestive system healthy and help prevent constipation.
Kiwi as been found to help regulate the digestive system and keep it in balance. A properly balanced digestive system will help give you free bowel movement.
Purchase senna and make a cup of hot tea. Drinking this tasty brew will help initiate bowel movement.
Lastly, a classic yet effective stool softener home remedy is to consume prunes. Prunes whether blended into juice or eaten directly is an excellent home made laxative. So, start by drinking prune juice daily or just eating several prunes each day will make you feel amazed on how easy it is to go soon enough. Read also foods that help with digestion here.
Find more quick constipation remedies here.


text:
Drivers from France shocked by London low emission zone penalties
The ULEZ does not automatically detect if foreign-registered vehicles are exempt. 'Perhaps TfL should reconsider how it communicates with visitors from abroad,' said one driver
Connexion readers have received London ULEZ penalty charges, despite the fact that their vehicles are exempt, because Transport for London cannot detect when they were made Pic: Lorna Roberts / Shutterstock
Several Connexion readers have contacted us about penalty charges – some of them amounting to thousands of euros – that they have received recently as drivers of French-registered cars travelling within the London Ultra Low Emissions Zone (ULEZ). Many of them are exempt from the associated charge.
Previously such penalties had not been sent out to French addresses, but in recent days this has changed. If you drive a French-plated vehicle which is exempt from ULEZ charges, you must pre-register it with Transport for London (TfL) or you will also receive a penalty charge. We explain.
Read more: Register French-plated cars for London driving to avoid penalties
TfL consults the UK's DVLA database to determine whether UK-registered cars are exempt or not, but when this is not possible the owner must provide paperwork proving that their vehicle is not concerned by the charge.
It means that people with foreign-registered cars need to enter their vehicle details to avoid receiving a penalty charge but many drivers are unaware of this.
What is ULEZ and how does it work?
The Ultra Low Emissions Zone – introduced in 2019 – is an area of London in which the most polluting cars are charged. It currently covers the Inner London area inside the North and South Circular roads, which are not affected by the charges themselves.
You can check whether different London postcodes fall inside or outside the zone using this TfL search tool.
The owners of the most polluting cars must pay £12.50 a day to drive in the zone in addition to the daily Congestion Charge of £15, which applies in the city centre.
ULEZ generally affects pre-Euro 6 diesel vehicles – manufactured before 2016 – and pre-Euro 4 petrol vehicles produced before 2006, although there may be some exceptions.
The Euro6 or Euro4 label refers to the vehicles emissions standards which came into force in 2015 and 2005 respectively.
Car drivers who forget to pay the ULEZ will receive a penalty charge notice of £160, reduced to £80 if paid within 14 days. However, if the fee is still not paid, the charge will continue to increase.
You can check if your vehicle is subject to the ULEZ charge using this TfL tool.
From August 29, 2023, the ULEZ area will extend to cover the whole of Greater London.
How to register a vehicle and appeal a charge
Chris Harris, a retired business director in the vehicle safety industry who has lived near Paris for over 20 years, told The Connexion: "This week I received a letter containing five separate fines for not paying the ULEZ charges dating back to December 2021.
"My diesel vehicle is Euro6 compliant and therefore exempt from the ULEZ charges.
"The problem is that the system that captures you entering these zones does not automatically recognise foreign number plates and therefore applies a charge.
"TfL have subcontracted the management of these fines and collection to Euro Parking Collections Ltd (EPC) who have access to the vehicle registration for France and can then send out the fines.
"I challenged the fines directly with EPC and after submitting a copy of my carte grise they have cancelled them.
"It is necessary to go on the TfL/EPC website to register your vehicle, again with a copy of carte grise, to ensure that you are not fined again."
It is possible to register your vehicle on this EPC page, and appeals can be started here.
An EPC spokesperson told The Connexion that it has only just started sending out ULEZ penalty charges to drivers in France because TfL only shared details of the relevant vehicle number plates in the last week.
This may explain why several Connexion readers have received multiple penalty notices dating back as far as 2020 over the past few days.
Registering is 'easy'
Marie McEnroe Lexa said that she has registered her car on the website and driven many times to London. "I have not had any problems or received any fines," she said.
Lynette Beardwood also said: "I registered my car on the ULEZ site, which refers you to EPC. It was an easy process, and I received a confirmatory email promptly."
Up to €2,634 in fines
Several Connexion readers who did not pre-register their vehicles report having received penalty charge notices over the last few days.
Trevor Roper said: "My wife and I visited London last December with our year-old Hybrid Peugeot. A couple of days ago we received four penalty notices with a total of around £1,000 in fines.
"The letter also arrived three weeks after posting, so not allowing us to pay a reduced fee. We also had extreme difficulty finding out how to appeal.
"The whole experience has been stressful and frustrating. We now just need to see if our appeal is successful."
Another reader, who preferred not to be named, said: "I have just got off the phone to TfL, who tell me that the four €97.56 [penalty charges we have had], due to increase by €100-€200 each just two or three weeks after we received them, are not enforceable if my car is low emissions.
"It's been a stressful couple of days, especially when we tried to challenge the penalties on the TfL website, it refused to send all our information, citing 'technical problems' (though we tried on more than one device).
"We are awaiting their decision but I do think other visitors should be warned about this and perhaps TfL should reconsider how it communicates with visitors from abroad."
Online form is 'not user-friendly'
Colin Bell said he has "just received nine fines for not being ULEZ compliant. These fines, with early payment within 14 days, amount to €878.04, due on December 5 or December 8. If not paid, the full amount is due: €2,634.12.
He said that when he went online to register his car, he "ended up with '502 Bad Gateway'. I spoke with EPC – they are having problems with their website (maintenance) and cannot do anything. You need to register yourself with TfL first."
A "helpful TfL representative" told Mr Bell that a carte grise is enough to register the vehicle via the TfL website, but he said that when he tried it was "very awkward" and "not user-friendly".
"Once registered as an individual it then redirects you to EPC to register the vehicle: 520 Bad Gateway.
"I assume the bad gateway message was because many citizens of Europe are receiving these multiple fines and everyone is logging on – so the system has crashed. But I could be wrong.
"I finally managed to get logged on to the EPC site and register my car. Now "pending". Still have to contest the fines!"
TfL 'omits information about what the alleged offence is'
Colin Campbell, an early retiree who lives in Alpes-Maritimes, said that TfL are "dressing up the ULEZ as a 'toll road' and then omitting information about what the alleged offence is.
"They are accessing foreign vehicles databases to get addresses, but not bothering to check those same databases for the emissions class of the vehicles concerned.
"Any reasonable person would conclude that TfL is hoping foreigners will just pay up because they're confused about the various TfL charging zones, their own whereabouts three months earlier and are being taken in by the blatantly false offence description in the notices themselves.
"Today I received three penalty notices from TfL. I used my French-registered car in SW6 in August. The vehicle is a petrol car manufactured and first registered in 2020 – so it meets the Euro6 standard and therefore no ULEZ charge is due. They're asking for €97-€292 for each of the three alleged infringements.
"TfL appears to be in breach of Sections 2 and 4 of the Fraud Act (2006). The issuing of the notices for payment is unlawful, regardless of whether I paid-up or not."
Reader tips on appealing
If you do need to appeal a penalty charge, you probably need to pay it to avoid the total increasing while you await a response, a reader, who preferred not to be named in this article, observed.
Another reader said: "It is also worth noting that the emissions category is shown under V9 on the carte grise so I have sent a copy of this with my appeal."
Snow tyre law could be used by French car insurers to refuse claims
Bikers protest in France against new two-wheeler contrôle technique
reader experiences
driving fine


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