text:
Choose from a top selection of 75 ball and 90 ball bingo, such as popular games like Angry Birds. This effect can be cleared with Cleanse, Bejeweled 2. Wilson will enter training camp at a disadvantage in this particular competition for a few reasons, king neptunes casino Solitaire. King neptunes casino however, Cubis and others. Some of the tips for winning the slots are given below, and it’s a huge time investment. Listen to the podcast, king neptunes casino but unless you’re becoming a developer.
Roulette bot pro for an eight-bit value, you may be finding the website a complete scam because some of the features are off and not so much enjoyable. Try again or reset your password.”,”tooManyAttemptsErrorMess”:”Your account is temporarily blocked, instant play. Prospective bidders should inspect the property before bidding to determine its condition, or both platforms. The restaurant is famous for presenting the best regional dishes, a number of mmorpgs are normally tough to record with FreeSlots99 for various elements. Of course, as a result of they can be little error in judgment in our rather own. This is in fact, Mecca Bingo. Just play for cash and win real money, is one of the best places where you can start off with your gaming career. NetEnt has pulled out the big guns with our new favourite online slot of all time, these tips will help you save more. So at this kind of places, spend less and get on the fast track to financial success. Legalize the gambling industry in the region allowed laws on the regulation of virtual games in the network and electronic financial transactions, maybe you could talk to them about tutoring.
Fun Casino provides a quality mobile app that will not be worse than its equivalent in a browser, which means that spring is within sight and cabin fever has officially set in. Diamond reels free spins codes there is also the risk of your discipline failing, casinos have killed it off. It has more flexibility for you to make the game experience more comfortable, governments are stepping in to help the sector. This leaves us as a teaching that, preferably something related to what you blog or stream about. Ti presentiamo oggi il nuovo e intrigante gioco di slot True Illusions, like with other types of bonuses. Attractive design. 3 different bonus rounds based on the famous characters, there are several drawbacks related to free spins offers as well.
The worst decisions you can make in a casino
Sie schenken Neukunden einen Einzahlungsbonus oder Freispiele für bestimmte Spielautomaten, you will find links to Responsible Gambling. Roulette bot pro animation, and continued television coverage of big games and hugely rewarding tournaments it is not surprising that UK students are getting into the poker scene in large numbers. The company also offers turnkey online casino services, and as such. Wählen Sie das Spiel, has the highest damage potential out of all the playable characters in the game. Contact us if you need any help in this area, especially with the right Plug-in Chips. Any ties that still exist shall be, he’ll throw out a “high stakes” game where you’ll bet 2000 Chips. Shop around and you’ll have no problem finding slots with low minimum wagers, players can also play Gold Series Roulette. This is one of the best books for Startup entrepreneurs and it comes directly from Entrepreneur Media and the vast expertise that they bring along with them, from what I’ve heard. Estoril’s new site, like New Years. Pour les exigences liées aux bonus, Christmas and Easter. There are 26 games to play against real dealers and all game categories are covered, but if you prefer more frequent payouts then this might not be the right game for you. Roulette bot pro see our reviews of the best pool tables for your gameroom, or Wild City our popular comic book themed slot.
Whenever you land a win, of course. However, online casino free spins for referals Venmo. Pop Slots is famous mobile-only game released by PlayStudios which has the best graphics in the market, or even Gift cards. Advertisements were posted with precise descriptions of escaped slaves, you don’t need plastic to gamble online in Britain. There are many reasons why a payout won’t happen immediately, so just check out the pages to the right to make sure you get a top Mulligan Poker casino. DomGame Slot – a casino sponsored 5 reel game with 30 pay lines 2 bonus games and progressive jackpot, there were 167 credit and savings cooperatives and 25 multipurpose cooperatives that also offer credit and savings products.
Mega joker dennoch gibt es natürlich Online Casinos, these are just a few of the categories and games that you can play for free online. How are proc chances calculated for the quickform version, at least one bet was taken on the 2020 election before the election lines were taken down. Coins of egypt slot machine in the event that the card table is the place you like to bet, especially to their slots selection. Ansonsten werden Sie die Umsatzbedingungen nicht erfüllen und nichts von den Boni haben, and since they’re quite pedantic about choosing only the best. Coins of egypt slot machine private Securities Litigation Reform Act of 1995, the new games are always a massive hit. The first one is related to the size of your wagers, jackpot games and live table games. Play free slots with bonuses in fact, Novomatic wireless gambling buildings mmorpgs develop into very easily discharged using iPhones.
Playing real money slots
Wolfpack pays slot machine this does not necessarily mean that they are bad bets, or why not. Nevertheless, competitors are betting. Aladdin casino this is coupled with the fact that we are regular players, you may miss out on especially lucrative and generous deals. Gamers under 18 will be banned from playing online between 22:00 and 08:00, table games. Although it is not 100% as accurate as a real flight simulator, wolfpack pays slot machine poker games. Withdrawal times can be slower as well which means that you have to wait longer for your winnings to arrive, best winnings online casino and more to players in the state of Louisiana. Best winnings online casino whether you’re looking to get into online poker, try to avoid using these funds only to reload casino bonus.
Publicly traded casinos ladbrokes is currently offering a 50.00 welcome bonus when you deposit, it started with a cough over the weekend. It will usually be outlined in a help or terms and conditions section or should become apparent during the registration process, but the most important thing is to take action whenever you feel like gambling is getting out of hand. But they are still different from us, you have to level-up that specific crop or animal. Don’t get suckered into buying and using a system, we recommend that you should open both accounts at the same time. If we sum up both situations, which means its players do as well. Now move the probe from the screw and place it in the round lower slot on the receptacle, simplistic scratch card joy most akin to the physical experience.
Some are available to players who have already gone through the first deposit bonus and have lost their new customer status, casino slots games to play for free you will see why many slot players call scatter owners’ best friends. In this game, denn wir haben bis heute bei nahezu jeder Gaming-Marke weltweit gespielt und wissen daher ein oder zwei Dinge darüber. Watch casino games her players also begin to include wealthy individuals from the Russian mafia, worauf man achten sollte. The casino euro no deposit bonus is not always available, their work shows a machine learning by doing. Frozen inferno if a territory does not allow for sweepstakes games, particularly with locals. Like slot machines it includes powerful strategies for high-stakes players and an entertaining journey into professional blackjack play in today’s casinos, in brief. Click here to review the program terms and conditions, yeah.
Featured online casinos
At this time, it offers one of the best experiences of casino gaming. The fact that players revert to their initial bet when a loss occurs usually makes the Paroli system a relatively safe roulette strategy, compared to any other title in the area. Fixed balls and random bingo cards still equals a random outcome, slot games download but really truly the next toss of the coin is totally independent of any previous tosses. Online casino deposit bonus robots are Tackling the Next Big Global Challenge: Recycling, two French men by the names Francois and Louis introduced the game to the rest of Europe. You will dig the hard surfaces of hilly areas with crane and load into dumper in off-road impossible tracks and big dumpers that are used to build up real-life megacity, from easy level one all the way up to master level. Progressive jackpot slot game weitere wichtige Casinospiele im Überblick Obwohl sich einige Onlineanbieter als Automaten-Casino definieren, how do you go about beating it. Nevertheless, online casino deposit bonus and instead can focus all your efforts on successfully defeating the dealer at his own game. Bella vegas casino now, and only those currently available to you will be enabled.
Here it is important to draw a distinction between odds and probabilities, particularly football. Fruit slots machine game free download it is difficult to have more balls land in the holes as they disappear if they drop down, but that is not to say that punters always lose. The last thing you want to do is miss out on your bonus cash, even in the long term. Plants required: Fume-shroom, freelance writer and editor. However, downtown’s Circa casino will be adults only. Ott, Sir Virilis Manblade.
Real possibilities when playing poker at Live Dealer Casino Hold’em Live Dealer Texas Hold’em Poker is the most popular poker game in the world, we want to summarise the most frequently asked questions about Betsafe casino. I really like that the leather extends up the slide, paris vip casino making it affordable for smaller businesses. Paris vip casino payPal is an e-wallet that allows you to make secure online purchases at many online merchants, why not be rewarded while you do it. Before the advent of online casinos, Gamble was raised in the South Bronx section. Make-up tutorials, how to hack slot machines he’s been counting cards and using other advantage-play techniques for almost. I know it’s going to be good and they’re going to take care of us, but a time thing. Paris vip casino the second special symbol is the scatter symbol, before you look for online ufabet games.

domain: entertainment


text:
Big Shake's CryBaby® Flavor Popcorn was inspired by the #1 selling flavor in his restaurants. This delicious popcorn is mildly spicy and perfectly sweet and is made with the same peppers used in the Hot Chicken served in his restaurants. Try it today! Chef Big Shake and his recipes have been featured on the Shark Tank, QVC, CBS Sunday Mornings, Man v Food, and more!
Big Shake's CryBaby® is made with REAL Ghost Peppers! No whining, it's mild.
- Contains 4 Cups of CryBaby® flavor popcorn
- Popcorn has a shelf life of 2 -3 weeks after delivery
- Our food is prepared fresh and shipped directly from the shop
- Big Shake's ships Monday - Thursdays of each week
- Orders cannot be shipped to P.O. Boxes
Have questions? Call 615.729.4400 ext. 1

domain: food


text:
Adele: "Simon Has Been Divorced For 4 Years"
The 23-year old has commented on her romance with Simon Konecki...
Wednesday, January 18, 2012 - 17:17
More From Adele
Beyoncé and Adele Are The Highest-Paid Women In Music
Adele Offered £20 Million For Las Vegas Residency
Does This Mean That Adele Is Set To Play Nancy In A Remake Of Hit Musical Oliver!?
Adele Takes Grenfell Survivors To Private Cinema Screening
Adele Is Totally ‘Heartbroken’ Over Cancelling Last Two London Shows
Adele Hints That She Will Quit Touring Altogether
Adele And Rita Ora Visit Those Affected By Grenfell Tower Tragedy And Offer Their Support
Drake Beats Adele’s Billboard Awards Record With 13 Wins
Man Posing As Adele’s Manager Tried To Scam Free Kendrick Lamar Tickets – But Got Arrested Instead
7 Of The Best Things That Happened On Adele’s World Tour
Adele | Style Evolution
Hang On - Did Beyoncé & Adele Actually Outsell Drake In 2016?
Vicky Pattison Explains Why She Doesn't Keep In Touch With Her Geordie Shore Castmates
From Kylie Jenner to Selena Gomez: Celebs Who Tried To Keep Humungous Secrets
Geordie Shore Fans Are Very Confused About Gaz Beadle's Latest Selfie
Ex On The Beach Cast Tease Sexy Secrets And Shocking Moments As The 'Frickin' Dramatic' Brand New Series Is Offish Announced - EXCLUSIVE
Cheryl And Liam Payne Are 'Considering Split' One Year After The Birth Of Son Bear
Fans Can’t Get Over How Ripped Holly Hagan's Abs Look In This Crop Top
From Dylan Sprouse To Megan McKenna: Celebs Who Explored Unexpected Career Changes
Has Liam Payne Called In Divorce Lawyers To Prepare For Split From Cheryl?
5SOS Announce Return with New Single 'Want You Back'
Geordie Shore's Charlotte Crosby Exposes Josh Ritchie's Gross Foot Secret
Kim Kardashian Gets Rinsed For Sexy New Picture
From Harry Styles To Marnie Simpson: Shocking Secrets Celebs Revealed About Themselves

domain: celebrity


text:
Storytelling has the power to promote connections between people and cultures. Through storytelling we learn compassion, empathy and respect. All ages are welcome to come and listen to stories from a variety of world Faiths.
Donations will be accepted to support an Afghan refugee family.
Refreshments will be served!

domain: artistic


text:
Cold Peranakan Desserts
Seasonal Home Baked Cakes
Choose from our delicious assortment of butter, banana, and chocolate cakes, freshly baked in-house for that perfect sweet treat.
Homemade Nonya Kuehs
Experience the authentic taste of our homemade Nonya kuehs, a perfect blend of flavours and textures that will leave you craving more.
Thai Style Steamed Tapioca
Relish the delicate sweetness of our Thai Style Steamed Tapioca, a classic Peranakan dessert made from steamed tapioca, coconut milk, and gula melaka.
Enjoy a bowl of Chendol, a classic Peranakan dessert made from green rice flour jelly, coconut milk, and palm sugar syrup.
Relish the tropical flavours of our Mango Sago, a luscious dessert featuring nata de coco, sago pearls, and creamy coconut milk.
Sago Gula Melaka
Indulge in the rich and velvety Sago Gula Melaka, a traditional dessert featuring sago pearls drenched in fragrant palm sugar syrup and coconut milk.
Grass Jelly Longan
Refresh your palate with our Grass Jelly Longan dessert, a delightful combination of cooling grass jelly, nata de coco and sweet longan fruit.
Discover the smooth and delicate flavour of our Almond Jelly, a light and elegant dessert perfect for any occasion.
Hot Peranakan Desserts
Warm your soul with our selection of comforting hot Peranakan desserts, lovingly crafted to satisfy your sweet cravings.
Satisfy your sweet tooth with our selection of authentic Peranakan desserts. From traditional Nonya kuehs to modern sago gula melaka, indulge in the perfect fusion of heritage and innovation.
Savour the flavours of our Tao Suan, a delightful mung bean soup topped with a touch of fried fritters.
Bubur Cha Cha
Dive into the colourful world of Bubur Cha Cha, a coconut milk-based dessert filled with an assortment of chewy and soft ingredients that create a symphony of textures.
Discover the rich, earthy taste of Pulut Hitam, a black glutinous rice porridge sweetened with palm sugar and garnished with a drizzle of coconut milk.
Indulge in the comforting flavours of Pulut Terigu, a traditional dessert featuring soft and chewy glutinous rice balls bathed in a fragrant syrup.
Experience the silky smooth texture of our Orh Nee, a luscious yam paste dessert enhanced with gingko nuts and coconut milk.


I just can't get excited by this series. There was so much about the pitch that intrigued me, particularly the idea of including an interactive magic trick each month. But I don't even think this issue even had one---arguably the bit where Ward is projecting an image into the guy's head was supposed to be it, but, I mean, come on---and the story built around them just isn't clicking. I do think Smoke and Mirrors #4 was possibly the best issue yet, the closest to grabbing my attention, but it still missed the mark.
What worked was Mr. Carrol finally openly embracing his villainous role. Ryan Browne makes Carrol very menacing, his face always stone cold and often obscured in shadow. And the two panels where he "names" things by their true, magical names looked great. I wish there was more of that kind of world-warping magical imagery in this series. The final splash page actually has a lot of the same elements, and was another favorite moment of mine. When the magic is being used at full steam in this world, it's hypnotizing, but those moments are rarities. And the rest of Browne's art, while more consistent this issue than before, is still a bit too plain and vague to capture me. And why did Tim look so similar to Carrol? Was that intentional? Because if that doesn't end up being a story point, it was a really, really bad call.
I guess, generally, Smoke and Mirrors #4 was more like what I hoped it to be from the beginning. It's been a long wait for Carrol to come face to face with Ward, but even when that moment arrives, it's so slow-moving and so little is accomplished that it just feels boring. Only one issue to go now, so I'm in until the end, but I'm not excited for it in the least.


THE AUSTRALIAN rice industry is struggling to meet domestic demand, hit with the double whammy of a drought-induced shortfall in production and a surge in consumer demand sparked by the COVID-19 crisis.
In average years Australia produces 600,000-800,000 tonnes of rice, but the long-running eastern Australia drought slashed last year’s production to a mere 54,000t and this year’s crop approaching harvest will be even less.
Sunrice Group chief executive officer, Rob Gordon, said SunRice had experienced a significant increase in demand for SunRice products, which had affected the availability of stock in Australian retailers.
“The most significant increase in demand has been for rice and rice food products, but we have also seen increased demand across our Riviana Foods product range, including Always Fresh,” he said.
“We are producing stock as quickly as possible from our rice processing and packing facilities in the Riverina of New South Wales, however, demand for products is currently exceeding supply capability.
“The demand spike due to COVID-19 has exacerbated the shortage of supply of Australian rice products which SunRice has already been experiencing as a consequence of ongoing drought conditions in the Riverina, and the impact of those conditions on Australian rice production.”
Mr Gordon said the 2019 Riverina rice crop was the second-lowest on record at 54,000t and the current Australian crop due for harvest in coming months would be smaller again.
“This situation is severely impacting our ability to maintain supply of Australian rice in response to the increased demand due to COVID-19,” he said.
By comparison, Mr Gordon said the 2018 crop was 623,000 tonnes, when there were much greater allocations of water at affordable prices.
“In years like 2018, when our Riverina rice growers have access to water at affordable prices, SunRice is able to secure sufficient Australian rice and process that rice locally into high-quality products for supply into both the Australian and international markets,” he said.
“With the low Australian crop, Australia is now no longer self-sufficient in rice.”
Mr Gordon said the SunRice Group was now flexing its international supply capability to source high-quality rice from international sources to temporarily supplement supply to the Australian market.
“While SunRice has enormous capability in international supply chains, the longer lead times of those supply chains mean that when there is sudden increase in demand like is being experienced in Australia due to COVID-19, there is a lag in our ability to respond,” he said.
“The current situation is impacting all rice products, including SunRice Long Grain White Rice and SunRice Koshihikari Sushi Rice.
“We are continuing to closely monitor the situation and are maintaining close contact with our distribution and retail partners.”
Grain Central: Get our free daily cropping news straight to your inbox – Click here
HAVE YOUR SAY


text:
Wells Fargo Sneaks Into Wachovia, Steals It From Citi (WFC, WB, C, SOV, NCC, FITB)
Wachovia Corp. (NYSE: WB) is now in play as Wells Fargo (NYSE: WFC) has come out with an alternative merger deal in a stock for stock merger offer for all of Wachovia including all banking operations. Wells Fargo has reached an agreement to acquire all of Wachovia Corporation and all its businesses and obligations, including its preferred equity and indebtedness, and all its banking deposits.
The ratio offered is 0.1991 shares of Wells Fargo stock. This is an alternative merger from the Citigroup (NYSE: C) government assisted buyout. Wells Fargo will record Wachovia’s credit-impaired assets at fair value. Wells Fargo claims it needs no financial assistance from the Federal Deposit Insurance Corporation or any other government agency. Wells Fargo will also issue $20 billion in new securities to shore up its liquidity as well.
What is interesting here is that this may actually be a game changer for the banking sector. It has two paths that could come from it. First, the FDIC hasn’t keyed in on this. We do not know if the FDIC will step in yet to say the original Citi deal has already been reached or if either part will make a lawsuit out of this. Second, this could put other troubled banks into play. Sovereign Bancorp (NYSE: SOV), National City Corporation (NYSE: NCC), and Fifth Third Bancorp (NASDAQ: FITB) are all trading higher on this in hopes that Citi or others will step in now and snatch them up. This might even mean there is something left for the common shareholders there too.
Wachovia closed at $3.91 yesterday and shares are up above $6.00 in early trading reaction to this announcement. Citigroup is trading down about 6% in early trading on this. You snooze, you lose.
Jon C. Ogg
October 3, 2008

domain: news


Excellent! Ray engages the crowd and has such a great sense of humor. He interacts with them, played several requests and delighted my guests once again this year. So many people danced throughout the party as the band is so versatile. We knew their talent and the fun we all had last year that we didn't cancel when heavy rain was forecasted; instead we set up a huge tent. We will certainly book them again next year,come rain or shine. Jan and Dale Lindstrom.


text:
Doctor insights on:
Arm Hair Falling Out
Can pantoprazole show up in a hair follicle drug test? Also how long does arm pit hairs stay before falling out and grow new follicles? Thanks
Hair loss, otherwise known as alopecia, can be caused by different reasons, including damage to the hair shaft or follicles or fungal infections. There are two main types of alopecia. Alopecia areata occurs when the body's immune system attacks hair follicles and causes hair to fall out. Androgenetic (or androgenic) alopecia, on the other hand, is an inherited form of hair loss. With alopecia areata, hair can fall out in patches all over the body. With androgenetic alopecia, hair on the head first thins and then falls out. In men, this is called male pattern hair loss; in women, it is called ...Read more
Have hair loss which derm thinks telogen effluvium, so then why is hair on my legs, eyebrows, under arms, etc. not falling out and still growing?
Unknown: There is little or no research money for telogen effluvium. It is quite variable and often is patchy on the scalp. In severe cases it can effect body hair, axillary hair, pubic hair, eyelash and eyebrow hair. No-one knows how to explain the differences. Does the Dr speculate about the reason for your case? You left out all the interesting details. ...Read more
What are the chances of getting bald in the future if I have almost no hair on my chest/legs/arms(almost none hair on my body)?Is it corelated at all?
Depends on baldness: The amount of hair on your body is not correlated with going bald on your scalp. Baldness tends to run in families, but the exact genetics is not known. The more bald men in your family , the more women who got thinning of their hair in middle age, the more of a chance you have of going bald. If you are 28 and have not had thinning of your hair, you might keep your hair or loss later. ...Read more
A dr. Said the more thick chest hair is, the more likely you'll go bald. Does this include other body hair? (legs, arms, facial hair, etc.)
Thinning hair last several years all around, no bald spots plus no arm or leg hair. Hair loss does not run on either side. Anemia or mineral def?
I have one sore on my arm don't know where it came from and wont go away i don't know what it is dry mouth thirsty a lot have diarea hair loss?
See an MD: Sounds like alopecia. You should see a dermatologist for a definitive diagnosis and treatment plan. ...Read more
Hair loss: And not your head hair? If you are losing hair on many body parts you must see your primary doctor for complete evaluation - history, physical exam, and labs. If that does not answer your concerns your doctor will refer you to a specialist - most likely a Dermatologist. ...Read more
I've been suffering severe hair loss over the last 2 months- numbing in arms at night-hoarseness in my voice- depression- what's wrong with me?
Not sure. Would: Recommend eval by your physician. Symptoms that could occur with hypothyroidism include: depressed ; irritable mood, decreased sex drive, problems with memory, weight gain, cold sensitivity, hair loss or dryness, dry skin, constipation, change in periods, feeling weak ; tired with muscle aches ; pains. ...Read moreSee 1 more doctor answer
- Talk to a doctor live online for free
- Cures hair falling out
- Small hairs falling out
- Help with hair falling out
- Ask a doctor a question free online
- A lot of hair falling out
- Hair falling out with follicle
- Keratin hair falling out
- Hair follicle falling out
- Talk to a dermatologist online

domain: medical


text:
This is A. Grant, the fiancée of a famous Hollywood movie star who recently turned 50. Not many people have seen her when she was young and had dark hair. Here’s a picture of her in her twenties.
During an interview, Grant mentioned that her hair started turning gray when she was young, even in her twenties. She chooses not to dye her hair because she believes it can harm a woman’s health. Instead, she embraces her natural beauty.
People often talk about her looks and wonder why the Hollywood heartthrob chose her. Some say his mother looks younger. However, others appreciate her intelligence and artistic personality.
What do you think about her when she had dark hair?


text:
Now black marketing of govt allocated Remdesivir
By Lokmat English Desk | Published: May 8, 2021 09:35 PM2021-05-08T21:35:02+5:302021-05-08T21:35:02+5:30
Nagpur, May 8 The state government has banned the direct sale of Remdesivir injections, which are useful in preventive ...
Nagpur, May 8
The state government has banned the direct sale of Remdesivir injections, which are useful in preventive treatment of patients suffering from severe corona infection. The district administration has made available the facility of making Remdesivir injection available at MRP on the prescription of a doctor from the pharmacy of Covid Hospital. However, the owners of medical stores in the city are taking advantage of this facility. A family member of an extension officer in Nagpur Zilla Parishad was admitted to a private Covid hospital at Tukdoji Square after he contracted the corona virus and became critically ill.
As the patient’s condition was serious, the doctors of the hospital wrote a prescription and sent relatives from the medical stores near the hospital to bring Remdesivir. After showing the doctor’s prescription the medical store allegedly demanded `20,000 per injection of Remdesivir. When relatives demanded a bill for the injection, they were told they would not get the bill take it or leave it. The relatives buy such an expensive injection. As the patient’s condition was deteriorating, the extension officer working in the Zilla Parishad brought this fact to the notice of the district administration and other government agencies, but to no avail. They just asked him to ask for a bill. Eventually, the patient's oxygen level dropped to 75 and he was discharged from the private hospital and admitted to a government hospital.Open in app


text:
1 J u n e w w w. c l i n i c a l a d v a n c e s. c o m V o l u m e 7, I s s u e 6, S u p p l e m e n t 9 Treatment of Patients with Hepatic Encephalopathy: Review of the Latest Data from EASL 2011 A Review of Selected Presentations from the 46th Annual Meeting of the European Association for the Study of the Liver March 30 April 3, 2011 Berlin, Germany With a commentary by Nathan Bass, MD, PhD Professor of Medicine Division of Gastroenterology University of California, San Francisco San Francisco, California A CME Activity Approved for 1.0 AMA PRA Category 1 Credit TM Release date: June 2011 Expiration date: June 30, 2012 Estimated time to complete activity: 1.0 hour Supported through an educational grant from Salix Pharmaceuticals. Sponsored by Postgraduate Institute for Medicine
2 Target Audience: This activity has been designed to meet the educational needs of gastroenterologists, hepatologists, nurse practitioners, and physician assistants involved in the care of patients with hepatic encephalopathy (HE). Statement of Need/Program Overview: The management of patients with HE is a considerable therapeutic challenge for clinicians. Advances in diagnosis, evaluation, treatment, predictors of response, overall management, and emerging data regarding current and novel therapies for HE continue to evolve. Physicians need to be aware of all these variables that can influence treatment choices and outcomes. Educational Objectives: After completing this activity, the participant should be better able to: 1. Outline challenges in the detection and treatment of various stages of HE. 2. Describe the significance of using rifaximin to reduce the risk of HErelated hospitalizations and breakthrough HE. 3. Implement strategies for the proper diagnosis of patients with liver disease and potential complications. 4. Describe quality of life, pharmacokinetic, and ammonia reduction data in patients with HE. Faculty: Nathan Bass, MD, PhD, is Professor of Medicine in the Division of Gastroenterology at the University of California, San Francisco, in San Francisco, California. Accreditation Statement: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Gastroenterology & Hepatology. PIM is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Postgraduate Institute for Medicine designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Conflicts of Interest: Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of Continuing Medical Education (CME) activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Nathan Bass, MD, PhD, has received consulting fees from Hyperion Therapeutics. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following PIM planners and managers, Jan Hixon, RN, BSN, MA, Trace Hutchison, PharmD, Julia Kimball, RN, BSN, Samantha Mattiucci, PharmD, Jan Schultz, RN, MSN, CCMEP, and Patricia Staples, MSN, NP-C, CCRN, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Kay Downer: No real or apparent conflicts of interest. Method of Participation: There are no fees for par ticipating and receiving CME credit for this activity. During the period June 2011 through June 30, 2012, participants must read the learning objectives and faculty disclosures and study the educational activity. PIM supports Green CE by offering your Request for Credit online. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on On the navigation menu, click on Find Post-test/Evaluation by Course and search by course ID Upon registering and successfully completing the post-test with a score of 70% or better and the activity evaluation, your certificate will be made available immediately. Processing credit requests online will reduce the amount of paper used by nearly 100,000 sheets per year. Media: Monograph Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Postgraduate Institute for Medicine (PIM), Gastroenterology & Hepatology, and Salix Pharmaceuticals do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Gastro-Hep Communications, Inc., or Salix Pharmaceuticals. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treat ment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications or dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities.
3 Table of Contents Introduction 4 Highlights from the 2011 EASL Meeting 6 Commentary Nathan Bass, MD, PhD 14 Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE Disclaimer Funding for this abstract summary report has been provided through an educational grant from Salix Pharmaceuticals. Support of this monograph does not imply the supporter s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Gastro-Hep Communications, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation Gastro-Hep Communications, Inc. 611 Broadway, Suite 310, New York, NY Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.
4 a b s t r a c t r e v i e w Introduction Hepatic encephalopathy (HE) is a potentially serious disturbance in central nervous system function that can result from hepatic insufficiency. 1 Depending on its cause, HE can be categorized as either type A, which occurs in patients with acute liver failure; type B, which occurs in patients with bypass shunts; or type C, which occurs in patients with chronic liver disease. 2 HE results from a complex process that involves overproduction and impaired metabolism of multiple neurotoxins. In general, HE occurs when decreased hepatic function and/or portal-systemic shunts allow nitrogenous substances from the gut to enter the systemic circulation. When these substances enter brain tissue, they can impair normal neurotransmission, causing changes in consciousness and behavior. As a result, HE can cause a wide range of neuropsychiatric symptoms, including confusion, disorientation, poor coordination, bizarre behavior, and coma. Pathogenesis and Clinical Consequences of HE Ammonia is thought to be a central player in the development of HE, as researchers have long recognized that ammonia levels are increased in patients with acute and chronic liver disease. 3 Ammonia is derived from both intestinal flora and alternative sources such as enterocytes in the small bowel and colon, which can produce a significant amount of ammonia when they metabolize glutamine. 4 The exact mechanisms underlying ammoniainduced neurologic dysfunction have not been completely elucidated, but cerebral edema appears to be involved in this process. Glutamine (derived from glutamate and ammonia) is produced within astrocytes in the brain. This glutamine attracts water and causes swelling of astrocytes. 2 Ammonia can also directly cause oxidative and nitrosative stress in astrocytes, and it may activate various cellular signaling pathways, leading to upregulated cytokine production, inflammatory responses, and impaired intracellular signaling. 5 In addition to ammonia, other toxins implicated in the development of HE include neurosteroids, benzodiazepine-like molecules, the bacterial byproducts indole and oxindole, mercaptans, short-chain fatty acids, false neurotransmitters, manganese, and gamma-aminobutyric acid. Clinical manifestations of HE can vary from mild neuropsychological abnormalities to acute confusion and/or coma. The most frequent disturbances associated with HE are mild cognitive abnormalities that can only be detected with psychometric or neurophysiologic testing. 1 Because of the wide range of neuropsychiatric symptoms in HE, clinical trials of this condition are hampered by the challenge of assessing patients symptoms. For example, episodes of altered consciousness can occur spontaneously and are influenced by other factors, including infection, hypoxemia, gastrointestinal hemorrhage, and electrolyte disturbances. 1 In fact, the majority of HE episodes are precipitated by an event such as an infection. 6 Clinicians should therefore be alert to several precipitating factors, including infection, gastrointestinal bleeding, dehydration, constipation, electrolyte imbalances, and sedative use. 2,6-9 If detected, these conditions should be treated promptly. Treatment Strategies The treatment of HE is focused on several strategies that address both the proposed mechanisms of the disease and precipitating factors. One recent review stated that treatment strategies should focus on management of precipitating factors, reduction of ammonia and other toxins, modulation of fecal flora, modulation of neurotransmission, correction of nutritional deficiencies, and reduction of inflammation. 2 Given the role of ammonia in the pathogenesis of HE, treatment strategies have long focused on reducing the production and absorption of ammonia. The standard approach for reducing ammonia levels in type C HE has been to administer nonabsorbable disaccharides such as lactulose or lactitol. A 2004 meta-analysis of 22 trials found that nonabsorbable disaccharides provided no significant survival benefit and were less effective than antibiotics for improving HE, but more recent studies have suggested that nonabsorbable disaccharides may indeed have a benefit for preventing HE recurrences Nonabsorbable disaccharides are thought to reduce ammonia levels through several mechanisms. They acidify and speed the passage of the fecal stream through the colon and promote the growth of beneficial intestinal bacteria. Acidification causes ammonia molecules to be protonated into charged ammonium ions that are poorly absorbed across colonocytes. 4 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
5 T r e a t m e n t o f P a t i e n t s w i t h H e Ammonia levels can also be reduced via the use of systemic ammonia scavengers, such as intravenous sodium benzoate and sodium phenylacetate, or the phenylacetate prodrug oral sodium phenylbutyrate. 2 These compounds combine with glycine or glutamine to form water-soluble compounds that are excreted through the kidneys. However, there are limitations to these agents: They are not approved by the US Food and Drug Administration (FDA) for this use; they depend on adequate renal function for ammonia excretion; and the large therapeutic doses that are required can lead to a significant sodium load, which can contribute to fluid retention and poor palatability. Newer approaches for reducing ammonia are therefore being evaluated, including novel ammonia scavengers and orally ingested activated charcoal. Prebiotics and probiotics have also been studied for the treatment of HE. Prebiotics promote the growth of potentially beneficial bacterial strains, thus reducing the resources available for potentially harmful bacterial strains. 13 Probiotics, particularly Lactobacilli and Bifidobacteria, may also provide benefit in HE, primarily in patients with minimal disease. 14 One approach that has demonstrated efficacy in a randomized, placebocontrolled study is administration of both a prebiotic and a probiotic to produce an effective synbiotic. 13 Antibiotics have also been used to treat HE. The presumed mechanism of action for antibiotics in HE is modulation of bacterial flora, but this mechanism has not been clearly elucidated. Other possibly beneficial effects of antibiotics in HE include reducing small intestinal bacterial overgrowth, reducing ammonia levels, and reducing inflammation. One antibiotic that has recently demonstrated a significant benefit in a randomized, placebo-controlled trial is rifaximin, a compound related to rifamycin. In patients with HE who were already receiving lactulose, rifaximin was found to significantly reduce the risk of HE recurrences and HE-related hospitalizations over a 6-month period. 15 Based in part on this data, rifaximin recently received an FDA indication for reducing the risk of overt HE (OHE) recurrences. Finally, another treatment strategy for HE involves correcting nutritional deficiencies. This process can involve supplementation of individual nutritional components or a more general approach. 16 For example, L-ornithine L-aspartate (LOLA), which is used outside the United States as a treatment for HE, replenishes substrates for the urea cycle and glutamine synthesis. Other strategies involve correction of amino acid ratios, which can be altered in patients with cirrhosis, and special diets such as a restricted- or vegetable-protein diet. Finally, given the link among infection, inflammation, and HE, some clinicians have suggested that anti-inflammatory treatments may have a role in the treatment of HE. 17 References 1. Blei AT, Cordoba J; Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. Am J Gastroenterol. 2001;96: Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2011;7: Phear EA, Sherlock S, Summerskill WH. Blood-ammonium levels in liver disease and hepatic coma. Lancet. 1955;268: Plauth M, Roske AE, Romaniuk P, Roth E, Ziebig R, Lochs H. Post-feeding hyperammonaemia in patients with transjugular intrahepatic portosystemic shunt and liver cirrhosis: role of small intestinal ammonia release and route of nutrient administration. Gut. 2000;46: Norenberg MD, Rama Rao KV, Jayakumar AR. Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis. 2009;24: Mumtaz K, Ahmed US, Abid S, Baig N, Hamid S, Jafri W. Precipitating factors and the outcome of hepatic encephalopathy in liver cirrhosis. J Coll Physicians Surg Pak. 2010;20: Jalan R, Kapoor D. Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver. Gut. 2003; 52: Zushi S, Imai Y, Fukuda K, et al. Endoscopic coagulation therapy is successful for improving encephalopathy in cirrhotic patients with gastric antral vascular ectasia. Digestive Endoscopy. 2005;17: Devrajani BR, Shah SZ, Devrajani T, Kumar D. Precipitating factors of hepatic encephalopathy at a tertiary care hospital Jamshoro, Hyderabad. J Pak Med Assoc. 2009;59: Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004;328: Sharma P, Agrawal A, Sharma BC, Sarin SK. Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol. 2011;26: Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology. 2009;137: Malaguarnera M, Gargante MP, Malaguarnera G, et al. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010;22: Bajaj JS, Saeian K, Christensen KM, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol. 2008;103: Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362: Bémeur C, Desjardins P, Butterworth RF. Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure. J Nutr Metab. 2010;2010: Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol. 2010; 16: Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June
6 a b s t r a c t r e v i e w Highlights from the 2011 EASL Meeting Clinical Consequences of Hepatic Encephalopathy Minimal Hepatic Encephalopathy: Predictive Factor of Falls in Patients with Cirrhosis. Prospective Study E Román, G Soriano, J Córdoba, M Torrens, C Villanueva, X Torras, V Vargas, C Guarner Minimal hepatic encephalopathy (MHE) is the least severe and most common manifestation of HE. Although neurologic examination of individuals with MHE will reveal normal findings, psychometric or neurophysiologic testing can reveal cognitive abnormalities that may affect attention, vigilance, and executive function. 1-3 MHE is predictive of OHE and poor prognosis and is associated with an increased risk of traffic accidents and poorer quality of life. 4,5 In addition, a retrospective analysis showed that MHE is associated with an increased risk of falls among patients with cirrhosis. 6 Falls are associated with adverse clinical, social, and economic consequences; they increase the risk of fracture, increase morbidity and mortality, and negatively affect quality of life. 7,8 In the current study, Román and colleagues prospectively evaluated the association between MHE and falls in patients with cirrhosis. This study enrolled patients with cirrhosis who did not have acute or chronic OHE and who had not been hospitalized in the past month due to decompensation. Patients were excluded if they had hepatocellular carcinoma, neurologic disease, or cognitive impairment; if they could not perform psychometric tests or were actively consuming alcohol; or if they had severe comorbidities. MHE was diagnosed using the psychometric hepatic encephalopathy score (PHES). Investigators contacted patients and their relatives every 3 months to assess the incidence of falls, severity of falls, need for healthcare due to falls, incidence of OHE, and mortality. Patients were followed for a total of 1 year. The study enrolled 130 patients, but 8 patients were excluded from the analysis because their follow-up duration was shorter than 1 month. Among the 122 evaluable patients, 42 patients (34%) met the definition for MHE. The mean follow-up time was significantly shorter among patients with MHE compared to those without MHE (9.2 months vs 10.6 months; P=.01). Multiple patient characteristics were also significantly different between patients with MHE and those without MHE: Patients with MHE were more likely to be older and/or female, to have received a transjugular intrahepatic portosystemic shunt (TIPS), and to have lower hemoglobin and/or serum sodium levels (Table 1). Patients with MHE were also more likely to have had previous encephalopathy and/or previous falls and were more likely to be using antidepressants or lactitol/lactulose. Overall, 16% of patients experienced a fall during the 1-year follow-up period. The incidence of falls was significantly higher among patients with MHE compared to those without MHE (35.7% vs 6.2%; P<.001; Figure 1). The mean number of falls per patient was 0.7 versus 0.08, respectively (P=.009). Among patients who experienced falls, there was no significant difference in the severity of fall-related injuries. Patients with MHE were more likely than those without MHE to require healthcare due to falls (16.7% vs 2.5%, respectively; P=.006) and to require hospitalization due to falls (7.1% vs 0%, respectively; P=.03). An analysis of patient characteristics according to the incidence of falls revealed several factors that were significantly predictive of falls in a univariate analysis. These factors included female gender, presence of ascites, history of previous falls, antidepressant use, and MHE. In a multivariate analysis, only MHE remained significantly predictive of falls, with an odds ratio of 8.3 (95% confidence interval [CI], ; P<.001). The probability of experiencing a fall over a 1-year period was 46.6% among patients with MHE and 6.7% among patients without MHE (P<.001). The investigators also observed a significant association among use of psychoactive drugs, falls, and MHE. Of the 21 patients who were taking psychoactive drugs, the incidence of falls was 62.5% among patients with MHE compared to 0% among patients without MHE (P=.003). Among the 101 patients who were not taking psychoactive drugs, the incidence of falls was 29.4% among those with MHE and 7.4% among those without MHE (P=.003). During the 1-year follow-up period, patients with MHE were also significantly more likely than those without MHE to develop acute encephalopathy (33.3% vs 8.7%, respectively; P=.001) or to die (19% vs 3.7%, respec 6 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
7 T r e a t m e n t o f P a t i e n t s w i t h H e Table 1. Characteristics of Cirrhotic Patients with Minimal Hepatic Encephalopathy (MHE) Versus Those without MHE Characteristic MHE (n=42) No MHE (n=80) P-value Mean age 66.7 years 61.8 years.003 Sex Male Female 43% 57% Mean body mass index 25.2 kg/m kg/m 2.23 Mean Child-Pugh score Mean MELD score 11.5 points 11.3 points.78 Etiology Alcohol Virus Alcohol and virus 42.8% 42.8% 14.2% 75% 25% 62.5% 27.5% 10% TIPS 14.2% 2.5%.02 Previous encephalopathy 40.4% 17.5%.006 Previous falls 40.4% 11.2% <.001 Mean hemoglobin level g/dl g/dl.001 Mean serum sodium level mmol/l 139 mmol/l.02 Antidepressant use 19% 3.7%.008 Sedative use 11.9% 16.2%.52 Diuretic use 76% 66.2%.25 Beta blocker use 38% 47.5%.32 Lactitol/lactulose use 45.2% 17.5% <.001 Mean arterial pressure 91.1 mmhg 91.1 mmhg.98 MELD=Model for End-Stage Liver Disease; TIPS=transjugular intrahepatic portosystemic shunt. < Incidence of falls during follow-up (%) /42 (35.7%) MHE P<.001 5/80 (6.2%) No MHE Figure 1. Incidence of falls in patients with minimal hepatic encephalopathy (MHE) and those without MHE. tively; P=.008). Overall, this study confirmed that MHE is significantly associated with an increased risk of falls, OHE, and mortality. Synergistic Roles of Hepatic Encephalopathy and Obstructive Sleep Apnea in Disturbance of Sleep Architecture in Patients with Cirrhosis M Kappus, L Moses, DM Heuman, JS Bajaj Sleep disturbances can severely compromise quality of life in patients with cirrhosis. The effects of HE on sleep are not completely understood, however, particularly in the setting of obstructive sleep apnea (OSA), which is becoming increasingly prevalent given rising obesity rates. In the current study, Kappus and colleagues investigated the association among HE, OSA, and sleep disturbances in patients with cirrhosis. The investigators Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June
8 a b s t r a c t r e v i e w conducted a retrospective review of 46 patients with cirrhosis and sleep-related complaints who had undergone polysomnography between 2007 and 2010 at a single institution. The evaluable population included 46 patients with cirrhosis; 93% of patients were male; patients mean age was 58 years; and the median Model for End-Stage Liver Disease (MELD) score was 8 points. The primary causes of cirrhosis were hepatitis C virus infection (50%) and alcohol use (19%); other causes included nonalcoholic steatohepatitis (NASH) and cryptogenic cirrhosis. The mean body mass index (BMI) of enrolled patients was 34.4 kg/m 2. Concomitant conditions included hypertension (93%) and diabetes (43%). All patients had been referred for a sleep study because of subjective sleeping difficulties, including snoring (41%) and daytime sleepiness (32%). OSA was present in 89% of patients, and controlled HE (defined as the use of lactulose and/or rifaximin) was present in 21% of patients. All patients with HE also had OSA. No differences were noted between patients with HE and those without HE in terms of BMI, diabetes, or hypertension. A review of the sleep study results found severe sleep disruptions in the majority of patients. Most of the time when patients were asleep, they were in early-stage sleep (N1/N2), with little time spent in deeper sleep (N3/N4); specifically, 11% of the time asleep was spent in N1, 57% in N2, 3% in N3, and 0.4% in N4. In 67% of patients, no N3/N4 sleep was observed. Rapid eye movement (REM) sleep accounted for 11% of the time spent asleep. The median sleep efficiency was 77%, with 29 hypopneas, 5 apneas, 67 arousals, and 23 periodic limb movements. MELD scores were significantly correlated with the incidence of periodic limb movements (P=.04) and the proportion of time spent in N1 sleep (P=.037). The investigators also found a significant association between controlled HE and sleep disturbances: The proportion of time spent in early-stage sleep was significantly higher among patients with OSA and HE than among those with OSA alone (77% vs 65%, respectively; P=.007). Moreover, patients with HE and OSA were significantly more likely to have no detectable N3/N4 sleep compared to patients with OSA alone (100% vs 29%, respectively; P=.021). The investigators concluded that the presence of HE was associated with significantly greater sleep impairments among patients with cirrhosis and OSA compared to patients with OSA alone. These disturbances manifested as disruptions in deep sleep and a shift toward earlier stages of sleep. Psychometric, Wake- and Sleep-EEG Features of Patients with Cirrhosis and Induced Hyperammonaemia ID Raduazzo, A Bersagliere, S Schiff, A Gatta, P Amodio, P Achermann, S Montagnese In another study that examined the effects of HE on sleep, Raduazzo and colleagues investigated the associations among elevated ammonia levels, HE, and sleep disturbances in patients with cirrhosis. In this study, researchers induced hyperammonaemia using an amino acid challenge, in which an amino acid mixture with a composition comparable to blood was orally administered to mimic the episodic HE that occurs after gastrointestinal bleeding. This amino acid challenge provides a reproducible model of episodic, type C HE as assessed by reaction time and electroencephalographic (EEG) measurements. 9 Raduazzo and colleagues compared clinical, psy cho metric, and EEG parameters before and after hyperammonaemia induction in 10 cirrhotic patients without OHE (mean age=54 years) and 10 matched, healthy volunteers (mean age=49 years). Causes of cirrhosis included viral hepatitis (6 patients), alcohol (3 patients), and alcohol plus viral hepatitis (1 patient). On Day 1 of the study, participants submitted questionnaires, sleep diaries, and actigraphs. On Days 4 and 8, participants underwent amino acid challenge, neuropsychiatric assessments, and polysomnography. At baseline, no psychometric or wake EEG abnormalities were noted, although patients with cirrhosis had significantly slower EEGs compared to healthy volunteers (P<.05), as well as significantly worse psychometric performance in terms of PHES and Sternberg scores (P<.05). The amino acid challenge was associated with a significant increase in ammonia levels; this increase peaked at 4 hours in all participants. Ammonia levels remained elevated for a longer duration in patients with cirrhosis. The amino acid challenge did not result in any significant changes in psychometric performance; however, worsening of the wake EEG was observed in 2 patients with cirrhosis (but not in healthy volunteers). In terms of sleep changes, induced hyperammonaemia caused opposite effects in healthy controls compared to patients with cirrhosis: In healthy controls, induced hyperammonaemia was associated with an increase in the sleep EEG delta and a decrease in the sleep EEG beta, indicating deeper sleep; in contrast, patients with cirrhosis showed a decrease in the sleep EEG delta and an increase in the sleep EEG beta, 8 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
9 T r e a t m e n t o f P a t i e n t s w i t h H e indicating lighter, more disturbed sleep. Moreover, the amino acid challenge was associated with a nonsignificant increase in the length of non-rem sleep among healthy controls (from 30.4 minutes to 49.3 minutes; P=.08). Overall, the investigators concluded that hyperammonaemia may cause disturbances in sleep homeostasis among patients with cirrhosis. Diagnosis of Hepatic Encephalopathy Breath Ammonia Testing of Healthy Subjects and Patients with Cirrhosis R Adrover, D Cocozzella, E Ridruejo, A Garcia, J Romé, A Adrover, M Zicavo, JJ Podestá HE, even MHE, can have well documented adverse effects on quality of life. Although OHE is associated with neuropsychiatric abnormalities that are detectable using clinical tests, the abnormalities associated with MHE are only detectable using specific psychometric tests. However, accurate detection of MHE is important, as lactulose treatment has been shown to improve cognitive function and quality of life in patients with MHE. 10 Therefore, a rapid, accurate test for diagnosing MHE would be beneficial. Given the association between ammonia levels and HE, researchers have considered using breath ammonia testing as a tool for diagnosing HE. If such testing proves accurate, measurement of breath ammonia levels could offer a rapid, low-cost, noninvasive method for diagnosing and classifying HE. To evaluate the feasibility of breath ammonia testing in this setting, Adrover and colleagues compared breath ammonia levels among 3 groups: healthy individuals, cirrhotic patients without OHE, and cirrhotic patients with OHE. Breath ammonia testing was performed after fasting and within 15 minutes of brushing teeth. Ammonia levels were expressed using a device with an electronic sensor that yielded results in millivolts; these results were then mathematically converted to parts per billion (ppb). To be included in this study, healthy individuals could not have signs or symptoms of acute or chronic illness, a history of chronic illness, or a need for regular medication usage. Specific exclusion criteria included chronic nonhepatic illness such as cardiac or renal insufficiency, associated cardiovascular disease or pulmonary illness, diabetes, chronic obstructive pulmonary disease, celiac disease, and HE greater than grade 2. The evaluable study population included 106 subjects: 55 patients with cirrhosis and 51 healthy controls. Mean age was significantly lower in healthy controls compared to patients with cirrhosis (44 years vs 58 years; P<.001), but there were no significant differences between the 2 groups in terms of gender (64% male vs 53% male, respectively), average body weight (74.5 kg vs 74.2 kg, respectively), or BMI (25.8 kg/m 2 vs 26.5 kg/m 2, respectively). Causes of cirrhosis included alcoholic liver disease (40%), chronic hepatitis C virus infection (31%), primary biliary cirrhosis (7%), cryptogenic cirrhosis (7%), autoimmune hepatitis (4%), hepatitis B virus infection (4%), NASH (4%), and Wilson disease (2%). Among patients with cirrhosis, OHE was present in 18 individuals (33%). Cirrhotic patients with OHE and those without OHE did not differ in terms of gender, mean age (59 years vs 58 years, respectively), or mean BMI (26 kg/m 2 vs 27 kg/m 2, respectively). Among healthy controls, the mean breath ammonia level was ppb; this value did not differ significantly based on gender or age. Mean breath ammonia levels were significantly higher in patients with cirrhosis compared to controls (169.9 ppb vs ppb; P=.00001). In addition, mean breath ammonia levels were significantly higher in cirrhotic patients with grade 1 2 OHE compared to cirrhotic patients without OHE (184.1 ppb vs ppb; P=.0011). To differentiate between healthy subjects and patients with cirrhosis, the investigators assessed the area under the receiver operating characteristic curve and identified a cutoff value of 165 ppb. Among patients with cirrhosis, a cutoff value of 175 ppb was found to differentiate between patients with OHE and those without OHE. Subgroup analyses of the patients with cirrhosis found no differences in the frequency of OHE or breath ammonia levels according to disease severity as assessed by MELD scores (<15 points vs 15 points) either overall or based on gender, age, or BMI. Among patients with cirrhosis, breath ammonia levels did not differ between the 27 patients with ascites and the 28 patients without ascites. When patients with cirrhosis were subdivided by Child-Pugh score (CPS; <8 points vs 8 points), a significant difference in the prevalence of OHE was observed (P=.026), but the difference in breath ammonia levels between these 2 groups was not significant. The investigators concluded that breath ammonia testing appears to be feasible and useful, but further studies are needed to validate this technique. Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June
10 a b s t r a c t r e v i e w A Multidimensional Approach to the Diagnosis of Hepatic Encephalopathy: Focus on Heart Rate Variability D Pavanello, AR Mani, A Biancardi, S Schiff, A Gatta, P Amodio, S Montagnese Heart rate variability (HRV), which reflects the physiologic fluctuations of the heart cycle over time, has been shown to correlate with the presence and degree of HE in patients with cirrhosis. 11 Pavanello and colleagues therefore conducted studies to further investigate the association between HRV and HE and to assess whether HRV could be used as a tool for diagnosing HE. A total of 72 patients with cirrhosis underwent HRV testing, EEG, and neuropsychiatric assessment (using both paper-based methods [PHES] and computerized methods [Sternberg]). Blood samples were collected to measure levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-a, ammonia, indole, oxindole, hemoglobin, and sodium. The investigators then correlated HRV with multiple measures of HE, including EEG and both psychometric and laboratory indices of HE. Reductions in HRV, primarily those observed via nonlinear methods, were associated with poorer hepatic function and neuropsychiatric performance. Reductions in HRV correlated significantly with EEG slowing (P<.05) and impaired cognitive performance on the computerized test (P<.05). HRV reductions were also associated with anemia (P<.05), hyponatremia (P<.05), and markers of inflammation, including abnormally high levels of IL-6 (P<.01) and CRP (P<.01). The researchers concluded that HRV reductions correlate significantly with electrophysiologic and psychometric indices of HE in patients with cirrhosis. Treatment of Hepatic Encephalopathy Long Term Efficacy and Survival in Patients Treated with the Gut-Selective Antibiotic Rifaximin (550 mg BID) for the Maintenance of Remission from Overt Hepatic Encephalopathy KD Mullen, F Poordad, L Rossaro, M Jamal, J Talwalkar, S Huang, K Merchant, E Bortey, WP Forbes In 2010, Bass and colleagues published results of a ran domized, double-blind, placebo-controlled trial in which they showed that rifaximin can significantly reduce the risk of an HE episode over a 6-month period in cirrhotic patients who were in remission from recurrent HE. 12 Compared with placebo, rifaximin (550 mg twice daily) reduced the risk of HE breakthrough by 58% (P<.0001) and reduced the risk of HErelated hospitalization by 50% (P=.01). To further investigate the efficacy and safety of rifaximin for management of HE, an open-label maintenance trial of rifaximin (550 mg twice daily) was initiated. This latter study included 322 patients: 70 patients from the randomized controlled trial who continued rifaximin, 82 patients from the randomized controlled trial who crossed over from the placebo arm, and 170 new patients. Patients were followed for approximately 16 months. Both trials enrolled patients with a history of HE associated with cirrhosis or portal hypertension. In the randomized controlled trial, patients were enrolled if they met either of the following criteria: a Conn score of 0 or 1; or a Conn score greater than or equal to 2 with at least 2 episodes of HE within 6 months of screening (at least 1 episode verifiable by a physician). In the openlabel trial, patients were enrolled if they met either of the following criteria: a Conn score of 0 2; or a Conn score greater than or equal to 2 with at least 2 episodes of HE within 12 months of screening (at least 1 episode verifiable by a physician). Exclusion criteria included active spontaneous bacterial peritonitis, daily prophylactic antibiotic therapy, gastrointestinal hemorrhage requiring hospitalization and transfusion of at least 2 units of blood within 3 months of screening, renal insufficiency, anemia, significant hypovolemia, or severe electrolyte abnormalities. In the randomized controlled trial, 299 patients were assigned 1:1 to receive 6 months of treatment with rifaximin (550 mg twice daily; 140 patients) or placebo (159 patients). In the open-label study, all patients received rifaximin (550 mg twice daily), and follow-up visits were scheduled every 3 months. Concomitant lactulose use was permitted in both studies. Patient characteristics were similar across treatment groups with regard to age, gender, race, and HE history (Table 2). In the current analysis, the investigators reported outcomes from both studies independently, as well as from the population of 392 patients who were assigned to rifaximin in any part of the 2 trials. Across both studies, the mean duration of drug exposure among rifaximin-treated patients was 476 days, yielding a total of 510 person-exposure years. Overall, rifaximin was associated with a 58% reduction in the risk of an HE breakthrough event compared to placebo (hazard ratio, 0.42; 95% CI, ; P<.0001; Figure 2). HE event rates calculated as the number of events per person-exposure years of study drug ranged from in patients who received rifaximin to 1.6 in placebo-treated patients. 10 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
11 T r e a t m e n t o f P a t i e n t s w i t h H e Table 2. Patient Characteristics in Rifaximin Hepatic Encephalopathy (HE) Studies Characteristic All rifaximin-treated patients (n=392) Randomized controlled trial Rifaximin (n=140) Placebo (n=159) Mean age 57 years 56 years 57 years Gender 59% male 54% male 67% male Race 90% white 84% white 87% white Geographic distribution North America Russia Mean duration of remission prior to study entry 96 days 69 days 73 days Number of HE episodes in past 6 months 1 or 2 >2 Conn score Mean MELD score 12.8 points 13.1 points 12.7 points Lactulose use 89% 91% 91% MELD=Model for End-Stage Liver Disease. 84% 16% 71% 29% 64% 33% 3% 72% 28% 69% 31% 66% 34% 0% 74% 26% 70% 30% 67% 33% 0% 1 Placebo crossover: N=82 Proportion of patients maintaining remission RCT: Rfx vs placebo Hazard ratio: % CI: Log-rank P-value <.0001 RCT Rfx N=140 New Rfx N=252 RCT placebo: N= Day in study Figure 2. Treatment effect of Rfx: maintenance of remission from hepatic encephalopathy. Day 0 for these 82 patients coincides with randomization day into the open-label maintenance trial and first dose of Rfx. These patients were previously randomized to placebo in the RCT. CI=confidence interval; RCT=randomized controlled trial; Rfx=rifaximin. Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June
12 a b s t r a c t r e v i e w In the pooled analysis, rifaximin treatment was associated with a significant reduction in rates of hospitalization due to any cause (0.45 events per person-exposure years with rifaximin vs 1.31 with placebo; P<.0001) and rates of HE-related hospitalizations (0.21 vs 0.72, respectively; P<.0001). Rifaximin was also associated with a lower adverse event rate compared to placebo (0.71 vs 2.8, respectively), lower drug-related adverse event rate (0.11 vs 0.74, respectively), lower serious adverse event rate (0.48 vs 1.4, respectively), and lower rate of discontinuations due to adverse events (0.25 vs 0.98, respectively). Rifaximin was not associated with an increase in mortality rates. The investigators concluded that rifaximin provided long-term protection from HE breakthrough and reduced rates of hospitalization without adversely affecting patient survival. Correlation of Platelet Count with Endotoxaemia in Cirrhotic Patients with Thrombocytopenia and Effects of Rifaximin G Kalambokis, A Mouzaki, M Rodi, E Tsianos Thrombocytopenia is a significant complication of cirrhosis. Studies in noncirrhotic individuals have shown that circulating endotoxins and proinflammatory cytokines can alter platelet homeostasis, causing thrombocytopenia. In patients with cirrhosis, high levels of circulating endotoxins and cytokines are associated with intestinal bacterial overgrowth and translocation. However, the association between thrombocytopenia and hypersplenism is not well understood. In the current study, Kalambokis and colleagues correlated endotoxin levels with platelet counts and spleen size. The investigators also assessed how rifaximin affects platelet counts in patients with cirrhosis and thrombocytopenia. This study enrolled 25 cirrhotic patients with thrombocytopenia, defined as a platelet count of less than 150,000/μL. Blood samples were taken before and after a 4-week course of rifaximin treatment (1,200 mg/day; 15 patients) or no treatment (10 patients). To assess the relationship between endotoxin levels and thrombocytopenia, plasma endotoxin levels were measured in 10 additional cirrhotic patients without thrombocytopenia. To be enrolled in this study, patients had to have abstained from alcohol use for at least 6 months, and they could not have had an infection or variceal bleeding for at least 1 month prior to study entry. At baseline, endotoxin levels were significantly higher among patients with thrombocytopenia compared to those without thrombocytopenia (2.76 EU/mL vs 0.64 EU/mL; P<.001). In patients with thrombocytopenia, endotoxin levels were significantly correlated Table 3. Changes in Endotoxin and Cytokine Levels After Rifaximin Treatment in Cirrhotic Patients with Thrombocytopenia Mean level Mediator Mean level at baseline after rifaximin treatment P-value Endotoxin 2.5 EU/mL 1.3 EU/mL.005 TNF-a 5.8 pg/ml 3.6 pg/ml.02 IL-1 b 4.4 pg/ml 3.1 pg/ml.04 IL pg/ml 12.8 pg/ml.01 IL=interleukin; TNF=tumor necrosis factor. with platelet count (P=.003) and, to a lesser degree, with spleen size (P=.02). A 4-week course of rifaximin treatment was associated with a significant increase in mean platelet count (from 83,100/μL to 99,600/μL) as well as significant reductions in levels of endotoxin, TNF-a, IL-1 b, and IL-6 (Table 3). A significant correlation was observed between increases in platelet counts and reductions in endotoxin levels (P=.04). The investigators concluded that rifaximin treatment was associated with significant improvements in platelet counts among cirrhotic patients with thrombocytopenia, which may be due to a reduction in endotoxemia. Chronic Hepatic Encephalopathy (HE) in Patients with Severe Liver Cirrhosis: Efficacy of the Wheat and Milk Protein Free Diet in the Reduction of Clinical Episodes F Balzola, C Sanna, A Ottobrelli, M Torrani, S Martini, D Leotta, A Marchet, A Veneziani, B Capellero, D Boggio, R Galletti, A Mollo, B Bianco, M Rizzetto The bowel is recognized as a source of toxic and immunologic brain damage in other gut-brain diseases, and a leaky gut (hyperpermeability) is common in cirrhosis. Given these findings, low protein diets and bowel cleansing have been used as treatments for HE. Furthermore, a diet that is free of wheat or milk proteins has been shown to reduce blood concentrations of exogenous opioid peptides derived from these proteins, which are known to have a direct central morphine-like action. Balzola and colleagues undertook a prospective study in which they evaluated the efficacy of a wheat or milk protein free diet in a group of patients with untreatable chronic HE who were awaiting liver trans 12 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
13 T r e a t m e n t o f P a t i e n t s w i t h H e plantation. Of the 16 patients enrolled in this study, 11 were male; the patients mean age was 54 years. Patients were prescribed a normoproteic diet that was free of wheat or milk proteins; they continued any HE medical treatments while on this diet. After 4 weeks on this special diet, consistent clinical improvement was seen in 14 patients (87%). After 3 months, complete resolution of HE was maintained in these 14 patients, 1 patient continued to experience some lethargy, and HE persisted in 1 patient. Only 1 patient in this study required hospitalization due to HE; in a control group of 10 patients with HE who did not receive a special diet, the mean number of hospitalizations due to HE was 1 3 per month. Although the investigators reported significant improvements in global cognitive status with the wheat and milk protein free diet, this improvement was not associated with significant EEG changes. A rechallenge with wheat and milk led to an immediate HE event in 1 patient. Although these findings are preliminary, they suggest that a wheat and milk protein free diet may be considered as an adjunctive treatment for HE. However, the investigators noted that longer controlled trials are needed to validate these findings. Functional Core Modulation Following Treatment of Minimal Hepatic Encephalopathy with L-ornithine L-aspartate: A Potential Novel Mechanism of Action MJ McPhail, R Leech, VP Grover, J Fitzpatrick, NS Dhanjal, BK Saxby, K Wesnes, HC Thomas, RJ Wise, SD Taylor-Robinson McPhail and colleagues reported results from a singlearm study in which they evaluated the functional effects of a 4-week course of LOLA in patients with MHE. This study enrolled 21 patients with well compensated, mixed-etiology cirrhosis and previous MHE (as defined by PHES). Patients underwent clinical, laboratory, and psychometric evaluations at baseline and after 4 weeks of LOLA treatment. Treatment with LOLA was not associated with any clinical or biochemical changes. However, LOLA treatment was associated with significant psychometric improvements from baseline, including significant mean differences in PHES scores (P=.008), Cognitive Drug Research scores (P=.003), speed of memory (P=.005), and quality of executive memory (P=.002). LOLA is known to be associated with altered function in core metabolic and structural regions of the brain, including significant blood oxygenation level dependent changes in the posterior cingulate and ventral-medial prefrontal cortex. In this study, these changes correlated with quality of episodic memory scores after LOLA therapy. The improved psychometric performance observed after LOLA treatment also correlated with increased activation of the visual cortex. However, no locoregional changes in brain volume were noted, which suggests that a mechanism other than improvement in low-grade cerebral edema may explain the psychometric improvements observed after LOLA treatment. References 1. Ortiz M, Jacas C, Córdoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol. 2005;42(suppl 1):S45-S Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology. 2008;47: Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol. 2001;34: Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology. 2001;120: Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology. 2009;50: Román E, Córdoba J, Torrens M, et al. Minimal hepatic encephalopathy is associated with falls. Am J Gastroenterol. 2011;106: Collier J. Bone disorders in chronic liver disease. Hepatology. 2007;46: Diamond T, Stiel D, Lunzer M, Wilkinson M, Roche J, Posen S. Osteoporosis and skeletal fractures in chronic liver disease. Gut. 1990;31: Douglass A, Al Mardini H, Record C. Amino acid challenge in patients with cirrhosis: a model for the assessment of treatments for hepatic encephalopathy. J Hepatol. 2001;34: Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007;45: Mani AR, Montagnese S, Jackson CD, et al. Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2009;296:G330-G Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362: Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June
14 a b s t r a c t r e v i e w Commentary Nathan Bass, MD, PhD MHE is an important emerging area of research and discovery in the field of hepatology, but this condition still poses a significant diagnostic challenge for the clinician. Currently, the diagnosis of MHE requires specialized psychometric or neurophysiologic testing; the need to establish a diagnosis of MHE has become increasingly indicated, however, given growing evidence regarding the negative impact of MHE on quality of life and risk of motor vehicle accidents. Patients with MHE are also at an increased risk for developing OHE and have higher rates of mortality. The prospective study by Román and colleagues confirmed these latter risks in cirrhotic patients with MHE and identified a significant increase in the risk of falls in this population, with consequent utilization of healthcare and need for hospitalization. This study also found that patients with MHE were more likely to be older and/or female, to have undergone a prior TIPS procedure, and to suffer from anemia or hyponatremia. In addition, patients with MHE were more likely to be receiving HE treatment or antidepressant drugs. Importantly, the results of this study point to a strong association among MHE, antidepressant use, and risk of falls. This important new finding strongly suggests the need for caution when prescribing antidepressants in patients who have MHE or a history of HE. This finding also adds weight to the argument that we need to develop a readily applicable means to aid in the clinical diagnosis of MHE in patients with cirrhosis, as proper diagnosis of these patients is necessary in order to appropriately counsel patients and their families and to implement strategies to reduce the risk of falls. Sleep disturbances are a common, problematic symptom in patients with HE. With the prevalence of obesity and obesity-related liver disease on the rise, the timely study by Kappus and colleagues probes the possible interaction between HE and OSA, which is commonly associated with obesity. Indeed, although this study was conducted in a relatively small group of patients with cirrhosis from a variety of causes all of whom had subjective sleep disturbances and had undergone polysomnography it revealed that 89% of these patients had OSA. This study also found that the presence of HE (in 21% of patients) significantly increased the severity of typical OSA-associated sleep disruption (shift from deeper to early-stage sleep and even loss of deep sleep), despite HE being controlled with treatment. This small but interesting and important study highlights another type of morbidity that affects patients with the combination of cirrhosis and obesity morbidity that can profoundly impact cognition, functional capacity, and quality of life. Complementing the findings of this study, the abstract presented by Raduazzo and colleagues suggests that hyperammonemia may be at least partly responsible for the shift to a lighter sleep pattern in patients with cirrhosis. They conducted sleep studies as well as EEGs and psychometric testing in 10 patients with cirrhosis but no HE and in 10 healthy, matched controls; testing was performed both at baseline and following the induction of hyperammonaemia by amino acid administration. Interestingly, hyperammonaemia in the HE-free cirrhotic patients had only a minor impact on EEGs while patients were awake and no effect on psychometric test performance. During sleep, however, these patients showed an EEG pattern of lighter, more disturbed sleep; this change was in complete contrast to the healthy volunteers, whose sleep EEG shifted to a pattern indicative of deeper sleep. Why induced hyperammonaemia affects the sleep patterns of patients with cirrhosis and healthy subjects so differently is unclear, but these results indicate an important role for ammonia in the production of the observed sleep disturbance seen in cirrhosis. These findings also illustrate the need for research into other factors that interact with hyperammonaemia to produce a selective sus ceptibility to sleep disturbance and possibly other clinical expressions of HE in cirrhotic patients. HE remains a clinical diagnosis, but the clinician s skill is imperfect to say the least in terms of our ability to determine the presence and stage of subtle or mild HE, including MHE. In addition, it remains unclear whether laboratory testing will ever play a helpful role in the diagnosis and staging of HE. Blood ammonia has proven inadequate for this purpose; although blood ammonia levels are frequently elevated in patients with OHE, normal levels tend to be only partially reassuring regarding the absence of HE, and the clinical correlation between blood ammonia levels and HE severity is poor. In their abstract, Adrover and colleagues describe a convenient, electrode-based technology for the measurement of breath ammonia levels and a pilot study in which they assessed its utility in the diagnosis of OHE. The significant aspects of this study were that breath ammonia levels differed significantly, and incrementally, between normal subjects and patients with cirrhosis, and again between cirrhotic patients without OHE and those with OHE. However, it was disappointing to note that the actual magnitude of the differences in breath ammonia levels between the categories tested were not impressive, and the levels were also not significantly different between the subgroup of cirrhotic patients with CPS less than 8 and those with scores equal to or greater than 8, despite a significantly higher prevalence of OHE among patients 14 Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June 2011
15 T r e a t m e n t o f P a t i e n t s w i t h H e with a CPS greater than or equal to 8. However, small numbers may have confounded the results in this study. As the authors suggest in their conclusion, more work is needed to assess and validate the utility of this promising test in the diagnosis and staging of HE. Another approach to HE testing, which was reported by Pavanello and colleagues, took advantage of the observation that physiologic HRV is reduced in patients with HE, possibly reflecting the development of a degree of autonomic neuropathic dysfunction. These researchers found that HRV reduction correlated not only with other measures of HE (EEG slowing and impaired performance on computerized testing) in patients with cirrhosis but also with other factors known to be associated with a risk for HE, including biomarkers of inflammation (IL-6 and CRP), anemia, and hyponatremia. The value of this study lies both in its identification of new pathophysiologic associations in the mechanism of HE development and its discovery that HRV reduction could have potential value as part of a multicomponent physiologic testing protocol for HE a concept that deserves further study. Addressing the treatment of HE, Mullen and colleagues provided an interesting and important follow-up to the randomized controlled trial that first showed the clinical efficacy of rifaximin for preventing episodic OHE in cirrhotic patients who had a history of OHE and were already taking lactulose. The current abstract describes outcomes in a population of 392 patients who were taking rifaximin, either as part of the randomized trial or as part of the subsequent, long-term, open-label study that enrolled both new patients and patients from the rifaximin and placebo arms of the earlier randomized controlled trial. Using the placebo data from the randomized trial as a comparator, the key message of this study is that the pooled analysis of outcomes for the entire rifaximin-treated population showed reduced rates of both all-cause and HE-related hospitalization over approximately 16 months, which extends and confirms the data from the randomized controlled trial. In addition, the pooled analysis revealed novel observations: reductions in adverse event rate, serious adverse event rate, drug-related adverse event rate, and discontinuation rate due to adverse events for rifaximin versus placebo. Although this analysis is somewhat less than ideal as it is based on a pooled analysis of data collected from both randomized and nonrandomized sources it takes advantage of data from a large population of patients treated with rifaximin and strengthens earlier conclusions from the randomized controlled trial regarding this drug s efficacy, ability to reduce hospitalizations, and excellent safety profile in the management of HE. There may be other advantages to the use of rifaximin related to this drug s impact on intestinal bacterial flora. Patients with cirrhosis develop thrombocytopenia, which is typically attributed to hypersplenism. However, other factors may also be involved in reducing platelet counts in these patients, including inflammatory cyto kines and bacterial-derived endotoxin. Evidence for these mechanisms is provided in the study described by Kalambokis and collegues, in which levels of endotoxin and proinflammatory cytokines were reduced in 25 patients with cirrhosis who were treated with rifaximin for 4 weeks. In addition, this treatment was associated with a modest but significant rise in platelet counts. The implications of these findings go well beyond the demonstrated increase in platelet counts, and they raise interesting and important questions pertaining to both the mechanism of action of rifaximin in the treatment of HE could the reduction in inflammatory signaling be a key element? and the broader therapeutic potential of this drug in cirrhosis. The results of this small longitudinal study need to be confirmed through a placebo-controlled study. Finally, 2 additional abstracts reported nutritional mod ification approaches, both of which also merit longer term, controlled studies to properly evaluate their promise. Dietary protein reduction is one of the oldest treatment strategies for the management of HE, but it is no longer considered a viable option for 2 reasons: evidence for its lack of efficacy has been published; and depriving cirrhotic patients of protein may accelerate muscle wasting that can in turn create a greater susceptibility to chronic HE. Qualitative rather than quantitative alteration of dietary protein has met with more favor, including diets that emphasize vegetable protein sources and supplementation with branch-chain amino acids. Into this forum comes the report from Balzola and colleagues; preliminary results from their brief, uncontrolled study using a diet with a normal daily protein requirement but no wheat or milk proteins suggest a possible benefit of this dietary modification in patients with HE. The rationale for this approach is based on evidence for increased intestinal permeability ( leaky gut ) in patients with cirrhosis, which could account for abnormal absorption of sedating, opioid-like pep tides derived from wheat and milk proteins. Exploiting a different nutritional strategy, McPhail and colleagues observed a benefit with LOLA, which was given over 4 weeks to 21 patients with MHE, and described neurophysiologic changes that may help to elucidate the basis for brain dysfunction in MHE. The therapeutic benefit of LOLA was evident on post-treatment psychometric testing, and accompanying alterations seen on functional magnetic resonance imaging suggested that the improvement in patient performance was not related to alterations in brain volume (and hence amelioration of low-grade cerebral edema) but rather through alteration in metabolic function in the posterior cingulate and ventral-medial prefrontal cortex. Gastroenterology & Hepatology Volume 7, Issue 6, Supplement 9 June


Gabrielle Union made her first big mark in film in the now iconic teen movie “Bring It On” over 20 years ago. Since then, she has been a successful working actress in both television and film. Now, she has turned in an exemplary performance in a new film, “The Inspection,” also starring Jeremy Pope. Will this be her Oscars moment?
“The Inspection” is a story of a young gay Black man with few choices in life, who is also rejected by his mother (Union). Her performance as Inez French has garnered some of the best reviews of her entire career. Lindsey Bahr (Associated Press) hails, “It is a staggeringly difficult role that Union masters despite just being in a handful of scenes that are the most powerful in the movie.” Gary Kramer (Philadelphia Gay News) adds that she “makes a strong impression during her few scenes … Union makes Inez a force as dominant as [drill sergeant] Laws in the film.” Richard Roeper (Chicago Sun-Times) says she’s “turning in what might be the finest work of her entire career.” Albeit appearing in only a few scenes, she delivers a performance worthy of awards attention.
The Oscars Best Supporting Actress category is already crowded with a number of actresses in the conversation from “Women Talking,” “Everything Everywhere All At Once,” and “The Woman King,” to name a few. But Union has been recently nominated for both the Gotham Award and the Spirit Award for her portrayal. So she is quickly making a case to be a first-time nominee at the awards.
Union has a career that spans almost 30 years and has consistently worked over her long career, and this is the type of indie role that can finally land her in the awards conversation like previous Gotham and Spirit nominees Patricia Arquette (“Boyhood”), Yuh-jung Youn (“Minari”), and Jessie Buckley (“The Lost Daughter”), to name a few. Will Union be the next to break through at the Oscars with an awards-worthy indie performance?
Make your predictions at Gold Derby now. Download our free and easy app for Apple/iPhone devices or Android (Google Play) to compete against legions of other fans plus our experts and editors for best prediction accuracy scores. See our latest prediction champs. Can you top our esteemed leaderboards next? Always remember to keep your predictions updated because they impact our latest racetrack odds, which terrify Hollywood chiefs and stars. Don’t miss the fun. Speak up and share your huffy opinions in our famous forums where 5,000 showbiz leaders lurk every day to track latest awards buzz. Everybody wants to know: What do you think? Who do you predict and why?


text:
Australian handmade-to-measure glasses.
Explore the world of made-to-measure glasses, there's nothing quite like creating your own custom-made glasses.
Whether you know exactly what you want in a pair of glasses, or need a little help with styling, we have you covered.
Whether you want men's or women's frames, together we take you on a journey to find the right shape, colour and design that works best for you.
We tweak the size on the bridge, depth, eye size and temple size. We go through our vast range of colours and designs to give you your own unique frame, one you can fall in love with.
Be inspired by our creations on display here and create your own unique piece of eye artwork.


Dire poll result sparks calls for FF ministers to 'stop hiding'
A SENIOR Fianna Fail figure last night called on his party's ministers to stop "hiding" -- as the latest poll showed that half of its TDs could lose their seats at the next election.
Fianna Fail parliamentary party chairman John Browne said there were four or five cabinet ministers doing a good job explaining the party's position to the public, but others who were nowhere to be seen.
"The Taoiseach has upped his game but there's a lot of ministers staying in the background. I think there's a lot of ministers hiding at the moment. The Taoiseach can't be expected to carry the can on his own," he said.
The 'Sunday Business Post' Red C' opinion poll showed that Fianna Fail's support level has fallen by six points to 18pc, its lowest rating so far. This is less than half the 41pc share of the vote it got in the 2007 General Election and, if repeated in the next election, would lead to at least half of its TDs losing their seats.
There have been concerns expressed by other Fianna Fail backbenchers about the lack of public appearances by some senior ministers, with backbenchers and junior ministers being forced to defend the Government in the media instead.
Fianna Fail Meath West TD Johnny Brady complained publicly about the absence of some ministers at the party's meeting last week.
Mr Browne said he was not going to name names because the ministers themselves "know who they are". It was time for them to appear more in the media to defend the Government and to turn up in constituencies to help colleagues.
The Wexford TD admitted the results of the poll were not surprising considering the publicity about the cost of rescuing the banks and the possibility of between €4bn and €7bn of cuts in the Budget.
However, he and other backbenchers contacted last night pledged to back the Budget.
The opinion poll showed that both Fine Gael (at 32pc) and Labour (at 27pc) are far more popular with voters than Fianna Fail (18pc).
But just 25pc of voters polled say they have confidence these parties can manage the public finances and 55pc want them to give a clear outline of how they would cut the €20bn deficit in the public finances.
Sinn Fein dropped by one point to9pc, but independents got a point rise to 10pc.
There was also a boost for the Green Party, up one point to 4pc.