text:
Zelboraf (Oral)
Generic Name: vemurafenib (Oral route)
Commonly used brand name(s)
In the U.S.
- Zelboraf
Available Dosage Forms:
- Tablet
Therapeutic Class: Antineoplastic Agent
Pharmacologic Class: BRAF Inhibitor
Uses For Zelboraf
Vemurafenib is used to treat melanoma (a type of skin cancer) that has spread or that cannot be removed by surgery. It is only used if the melanoma cells have the BRAF V600E mutation. Your doctor will use a special test to look for this mutation. Vemurafenib belongs to the group of medicines called antineoplastics (cancer medicines).
This medicine is available only with your doctor's prescription.
Before Using Zelboraf
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of vemurafenib in the pediatric population. Safety and efficacy have not been established.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of vemurafenib in the elderly. However, elderly patients are more likely to have unwanted effects (eg, skin problems, decreased appetite, fast heartbeat, nausea, or swelling of the hands, feet, or legs) which may require caution in patients receiving vemurafenib.
Breast Feeding
Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.
Interactions with Medicines
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
- Amifampridine
- Amisulpride
- Bepridil
- Cisapride
- Colchicine
- Dronedarone
- Fluconazole
- Ketoconazole
- Measles Virus Vaccine, Live
- Mesoridazine
- Mumps Virus Vaccine, Live
- Pimozide
- Piperaquine
- Posaconazole
- Rubella Virus Vaccine, Live
- Saquinavir
- Sparfloxacin
- Terfenadine
- Thioridazine
- Varicella Virus Vaccine
- Ziprasidone
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
- Adenovirus Vaccine
- Alfuzosin
- Amiodarone
- Amitriptyline
- Anagrelide
- Apomorphine
- Aripiprazole
- Arsenic Trioxide
- Asenapine
- Astemizole
- Atazanavir
- Azithromycin
- Bacillus of Calmette and Guerin Vaccine, Live
- Bedaquiline
- Boceprevir
- Buserelin
- Carbamazepine
- Chloroquine
- Chlorpromazine
- Cholera Vaccine, Live
- Ciprofloxacin
- Citalopram
- Clarithromycin
- Clomipramine
- Clozapine
- Cobicistat
- Conivaptan
- Crizotinib
- Cyclobenzaprine
- Dabrafenib
- Dasatinib
- Degarelix
- Delamanid
- Desipramine
- Deslorelin
- Digoxin
- Disopyramide
- Dofetilide
- Dolasetron
- Domperidone
- Donepezil
- Doxepin
- Droperidol
- Ebastine
- Efavirenz
- Enzalutamide
- Eribulin
- Erythromycin
- Escitalopram
- Famotidine
- Felbamate
- Fingolimod
- Flecainide
- Fluoxetine
- Formoterol
- Foscarnet
- Fosphenytoin
- Galantamine
- Gatifloxacin
- Gemifloxacin
- Gonadorelin
- Goserelin
- Granisetron
- Halofantrine
- Haloperidol
- Histrelin
- Hydroquinidine
- Hydroxychloroquine
- Hydroxyzine
- Ibutilide
- Idelalisib
- Iloperidone
- Imipramine
- Indinavir
- Influenza Virus Vaccine, Live
- Itraconazole
- Ivabradine
- Lapatinib
- Leuprolide
- Levofloxacin
- Lopinavir
- Lumefantrine
- Mefloquine
- Methadone
- Methotrimeprazine
- Metronidazole
- Mifepristone
- Mitotane
- Mizolastine
- Moricizine
- Moxifloxacin
- Nafarelin
- Nefazodone
- Nelfinavir
- Nilotinib
- Norfloxacin
- Octreotide
- Ofloxacin
- Olanzapine
- Ondansetron
- Paliperidone
- Panobinostat
- Papaverine
- Paroxetine
- Pasireotide
- Pazopanib
- Pentamidine
- Perflutren Lipid Microsphere
- Perphenazine
- Phenytoin
- Pimavanserin
- Pipamperone
- Pitolisant
- Poliovirus Vaccine, Live
- Probucol
- Procainamide
- Prochlorperazine
- Promethazine
- Propafenone
- Protriptyline
- Quetiapine
- Quinidine
- Quinine
- Ranolazine
- Rifampin
- Risperidone
- Ritonavir
- Sertindole
- Sevoflurane
- Smallpox Vaccine
- Sodium Phosphate
- Sodium Phosphate, Dibasic
- Sodium Phosphate, Monobasic
- Solifenacin
- Sorafenib
- Sotalol
- St John's Wort
- Sulpiride
- Sunitinib
- Tacrolimus
- Tamoxifen
- Telaprevir
- Telavancin
- Telithromycin
- Tetrabenazine
- Theophylline
- Tizanidine
- Tolterodine
- Toremifene
- Trazodone
- Trimipramine
- Triptorelin
- Typhoid Vaccine
- Vandetanib
- Vardenafil
- Venlafaxine
- Vilanterol
- Vinflunine
- Voriconazole
- Vorinostat
- Yellow Fever Vaccine
- Zuclopenthixol
Interactions with Food/Tobacco/Alcohol
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
- Grapefruit Juice
Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
- Caffeine
Other Medical Problems
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
- Bradycardia (slow heartbeat) or
- Congenital long QT syndrome (abnormal heart rhythm) or
- Congestive heart failure or
- Mineral imbalance (eg, blood levels of potassium, calcium, magnesium) or
- QT prolongation (abnormal heart rhythm) or
- Skin cancer, history of—May cause side effects to become worse.
Proper Use of Zelboraf
Medicines used to treat cancer are very strong and can have many side effects. Before using this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.
Take this medicine exactly as directed even if you feel well. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
This medicine comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.
Swallow the tablet whole with a glass of water. Do not crush, break, or chew it.
You may take this medicine with or without food.
If you vomit after taking this medicine, do not take an extra dose. Wait and take your next dose at the normal time.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablet):
- For melanoma (skin cancer):
- Adults—960 milligrams (mg) (four 240 mg tablets) two times a day. The first dose should be taken in the morning, and the second dose in the evening. The 2 doses should be taken 12 hours apart.
- Children—Use and dose must be determined by your doctor.
- For melanoma (skin cancer):
Missed Dose
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
If you miss a dose and it is less than 4 hours until your next regular dose, skip the missed dose and take your next dose at the regular time.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Precautions While Using Zelboraf
It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests and an ECG (electrocardiogram) may be needed to check for unwanted effects.
Using this medicine while you are pregnant can harm your unborn baby. This medicine may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Women should use an effective form of birth control during treatment and for 2 weeks after stopping it. Men should use condoms during sexual intercourse during treatment and for 2 weeks after stopping it. If a pregnancy occurs while using this medicine, tell your doctor right away.
This medicine may increase your risk of having new skin cancers such as cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. It may also cause other cancers like noncutaneous squamous cell carcinoma of the head and neck. This is more likely to occur if you are more than 65 years of age, have too much sun exposure, or have a history of skin cancer. Your doctor may want to check for new skin lesions before treatment and every 2 months while you are using this medicine.
This medicine may cause serious types of allergic reactions, including anaphylaxis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, lightheadedness or dizziness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth with this medicine.
Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loose skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills with this medicine.
This medicine may cause changes to your heart rhythm, such as a condition called QT prolongation. Contact your doctor right away if you feel dizzy or faint, or have fast, pounding, or uneven heartbeats.
Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.
This medicine may make your skin more sensitive to sunlight. Use sunscreen or sunblock lotions and lip balms with a sun protection factor (SPF) of at least 30 on a regular basis when you are outdoors. Wear protective clothing and hats and stay out of direct sunlight, especially between the hours of 10 AM and 3 PM. Avoid sunlamps and tanning beds.
Check with your doctor right away if blurred vision, difficulty with reading, eye pain, or any other vision change occurs with this medicine. Your doctor may want an ophthalmologist (eye doctor) to check your eyes.
Kidney failure may occur while you are using this medicine. Tell your doctor right away if you have bloody urine, decrease in how much or how often you urinate, lower back or side pain, swelling of the face, fingers, or lower legs, trouble breathing, or weight gain.
It is important to tell your doctor if you have had or are planning to receive radiation treatment while you are taking this medicine.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Zelboraf Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
More common- Blistering, peeling, or loosening of the skin
- bloating or swelling of the face, arms, hands, lower legs, or feet
- bloody urine
- blurred vision or other change in vision
- chills
- cough
- decreased frequency or amount of urine
- diarrhea
- dizziness
- eye pain
- fainting
- fast or irregular heartbeat
- fever
- increased sensitivity of the skin to sunlight
- increased thirst
- itching or skin rash
- joint or muscle pain
- loss of appetite
- lower back or side pain
- lump or growth on the skin
- nausea or vomiting
- pain in the ankles or knees
- painful, red lumps under the skin, mostly on the legs
- paralysis of the nerves
- rapid weight gain
- rash with flat lesions or small raised lesions on the skin
- red skin lesions, often with a purple center
- red, irritated eyes
- redness or other discoloration of the skin
- redness, soreness, swelling, or itching skin
- scaling of the skin on the hands and feet
- sensitivity of the eye to light
- severe sunburn
- sore throat
- sores, ulcers, or white spots in the mouth or on the lips
- sores, welting, or blisters
- tearing
- tingling of the hands and feet
- tiredness
- trouble breathing
- ulceration of the skin
- unusual tiredness or weakness
- unusual weight gain or loss
- weight gain
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common- Back or bone pain
- burning, itching, and pain in the hairy areas, or pus at the root of the hair
- change in taste
- cough
- decreased appetite
- decreased weight
- diarrhea
- difficulty having a bowel movement (stool)
- difficulty with moving
- dry skin
- hair loss or thinning of the hair
- headache
- lack or loss of strength
- loss of taste
- muscle stiffness
- nausea
- pain in the arms or legs
- rash
- sunburn
- vomiting
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Side effects (in more detail)
The information contained in the Truven Health Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Truven Health products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Truven Health and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, TRUVEN HEALTH MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Truven Health does not assume any responsibility or risk for your use of the Truven Health products.
Copyright 2016 Truven Health Analytics, Inc. All Rights Reserved.
More about Zelboraf (vemurafenib)
- Side Effects
- During Pregnancy
- Dosage Information
- Drug Images
- Drug Interactions
- Support Group
- Pricing & Coupons
- En Español
- 3 Reviews – Add your own review/rating
- Drug class: multikinase inhibitors


text:
Learn about this topic in these articles:
role in Byzantine Empire
...victim to assassination, but before his death events beyond his control had improved the empire's situation. Krum died suddenly in 814 as he was preparing an attack upon Constantinople, and his son,
Omortag, arranged a peace with the Byzantine Empire in order to protect the western frontiers of his Bulgar empire against the pressures exerted by Frankish expansion under Charlemagne and his...
treaty conclusion with Leo V
Meanwhile, Krum, the Bulgarian khan, had reached the walls of Constantinople. Leo succeeded in drawing him back and concluded a treaty with Krum's successor,
Omortag, that determined the boundary between the two countries and provided a 30-year peace. In the ʿAbbāsid caliphate the troubles following the death of the caliph Hārūn al-Rashīd in 809 continued to provide...

subset: commoncrawl


text:
Bat Ecology and Conservation
Designed for those new to bat work, this course gives a comprehensive foundation to bat biology, ecology and conservation. You will learn about the different UK species, range, distribution, bat conservation and threats, bat taxonomy, physiological adaptations, life histories, foraging ecology, life cycle, roosting requirements and bat identification.
Course Content Includes:
- Bat taxonomy
- UK species, range and distribution
- Bat species identification (in the hand) – with live bats
- Bat physiology including adaptations to flight, echolocation, energetics
- Life histories including life-cycle, mating strategies, pup development, roost composition and requirements, social behaviour
- Feeding behaviour
- Bat conservation and threats
Prior knowledge: None
This course is approved by the Royal Society of Biology for purposes of CPD, this event may be counted as 24 CPD credits.
These credits are valid only if attendees are registered on the Royal Society of Biology CPD Scheme.
Key Information
Start date:
£165 (£5 discounts for BCT members)
Bat Conservation Trust
Biodiversity, Ecology
Juniper Hall FSC, Surrey
Contact Details:
Naomi Webster 020 7820 7169 firstname.lastname@example.com More Information
Please mention ConservationJobs.co.uk when enrolling in this Course!


text:
Blank: Shakespeare and the Mismeasure of Renaissance Man
We are happy to report that Paula Blank's latest book, Shakespeare and the Mismeasure of Renaissance Man, has just been published (8/06) by Cornell University Press. From the Publisher Shakespeare's poems and plays are rich in reference to "measure,
number, and weight," which were the key terms of an early modern
empirical and quantitative imagination. Shakespeare's investigation of
Renaissance measures of reality centers on the consequences of applying
principles of measurement to the appraisal of human value. This is
especially true of efforts to judge people as better or worse than, or
equal to, one another. With special attention to the Sonnets, Measure
for Measure, Merchant of Venice, Othello, King Lear, and Hamlet, Paula
Blank argues that Shakespeare, in his experiments with measurement,
demonstrates the incommensurability of the aims and operations of
quantification with human experience. Reviews "Shakespeare and the Mismeasure of Renaissance Man succeeds in
combining wide-ranging interdisciplinary comment with minute scrutiny
of language and verse. It is a satisfying read and one that will yield
a wealth of interesting observations to scholars of Shakespeare and of
early modern culture." -Héloïse Sénéchal, Times Literary Supplement,
June 22 2007 "The framing idea for this book--the way that the concept of
measurement quantifies social and political aspects of human
experience--is brilliant. Paula Blank relates measurement to ideas of
justice in ways that are likely to be groundbreaking for early modern
studies in general and for Shakespeare studies in particular."
-Elizabeth D. Harvey, University of Toronto
From scales and spans to squares and levels to ratings and rules,
Shakespeare's rhetoric of measurement reveals the extent to which
language in the Renaissance was itself understood as a set of
alternative measures for figuring human worth. In chapters that explore
attempts to measure human feeling, weigh human equalities (and
inequalities), regulate race relations, and deduce social and economic
merit, Blank shows why Shakespeare's measures are so often exposed as
"mismeasures"-equivocal, provisional, and as unreliable as the men and
women they are designed to assess.
"Shakespeare and the Mismeasure of Renaissance Man is a smart, subtly
argued, and consistently interesting contribution to our understanding
not just of Shakespeare but of Renaissance culture itself in England
and elsewhere throughout Europe. Paula Blank asserts that the
Renaissance concern with measurement and quantification, when applied
to the human realm, created more problems than it solved." -Wayne
Rebhorn, University of Texas at Austin, author of Renaissance Debates
on Rhetoric
"In this beautifully nuanced and trenchant account, Paula Blank
demonstrates how troubled Shakespeare's works are by the inadequacy yet
necessity of measurement to all forms of knowledge, feeling, and
value—indeed to poetic language itself." -Margreta de Grazia,
University of Pennsylvania


text:
Related Regions: Colorado, Denver, Boulder, United States, North America
http://www.winterparkresort.com (970) 726-5514
A ski resort's overall star rating displayed here is not calculated based on a simple average but takes several factors, including the age of a review, into account.
150 Total Reviews:
Helpful Highlights:
My family and I have been season pass holders here since 2005 and still look forward to coming up to the mountain. However, the towns of Winter Park and Fr...
Displaying 61 - 66 of 149 Resort Reviews
Friendly staff is everywhere, answering questions and pointing out tips; lifts easy and well operated; so many long cruising runs for intermediate and even ...
The first experience I had in the first 5 minutes of being here was not good. We were the only people in the rental shop and three people stood around talki...
My first trip to Winter Park and it is an immediate favorite... it probably helped that I got 9" fresh day one, 4" fresh day two and 7" fresh day three... s...
The website promised discounts that were not available. It was not simply ambiguous sales talk- it was simply wrong. When I called the 800 number they said...
loved this resort! my dad took me here for my 25th birthday. Everything was great from the weather to the food! we had 2 feet of fresh snow friday morning...
Winter Park is a ski area with so much to offer for families and ski hounds too. With Mary Jane attached at the hip, you can experience top expert terrain ...
NOTE: We will not publish posts containing:
See our Posting Policy for more information about our posting criteria.
By clicking on the "Preview" button below, you agree to follow the guidelines in our Posting Policy.
* Required
NOTE: If you represent the management of this property and would like to respond to a review, please use the management response form.
View All
Full Article
Trail Map
Get snow reports, weather, forecasts, news and ski conditions for your favorite ski resorts.
Mobile | Newsletter | Facebook | Twitter | Google+


text:
Dear People Who Think It's Okay to Ask If We're "Trying"
Thursday, February 17, 2011Ever.
9 boats moored
What an awesome picture--so expressive and perfectly illustrative of the reaction most sane people have upon being asked that question! And it's you (not a random Internet picture of a stranger), how fun!
I love when people ask if we're trying for a baby (married 7 months)... it allows me to stare blankly at them, blink once or twice, and politely say, "I'm sorry?" until they realise that what they've said is actually rather inappropriate. I can only hope that maybe that way they'll think before saying it to the next person!people don't ask so much as demand: my grand father, my mother, my in laws, my husband's work buddies. When it's family, they see a baby, look at me, and say "see that? I want one of those." When it's friends/co-workers it's not "have you started" but "you should start"
(I think it's 'cause I just turned 30)Kahlia - Thanks! My bridesmaids scanned a whole load of baby/child/awkward teenager pictures of my for my hen party, so I have a ready supply of hilarious pictures for any topic. I love your suggested response - so far my approach has been to laugh awkwardly, immediately change the subject, and then write passive aggressive blog posts about it.
Kristy - you are so right. Don't get me wrong, I love awkward moments, when they're happening to other people.
Peonies - truly, words fail me.
Marie - Next time you're home you should put a cushion up your jumper when you get off the plane. That would teach them.
Lauren - well, I mean, no wonder, if you're as OLD as THIRTY, in the words of my 5-year-old cousin, "you're almost dead". ("How funny", I said through gritted teeth...)


text:
The largest Australian-owned holiday rental site - AURA®Holiday houses, apartments and self-contained short-term rentals
2 properties found.
view mode
2 27 3
Villa - Whitsundays & Mackay - 11km from Glen Isla (Palm Grove)
Pamper yourself in the contemporary splendour of a Seclude Villa and enjoy all that the resort and local area has to offer. Bring your own food or if you would prefer, add items from our Dining Menu and we will have them ready for your arrival.
from A$228.00
10 12 3
Guest house - Whitsundays & Mackay - 12km from Glen Isla (Cannon Valley)
Clean, spacious, totally private and one of the best value per head per night accommodation in the Whitsundays. Kookaburra Lodge is perched high among the trees and surrounded by Conway National Park. Your stay here will be a truly memorable one.
from A$310.00


text:
NHCO Trixerone 100 Capsules
NHCO Trixerone 100 Capsules on sale in our pharmacy bio: Normal Lipid metabolism
Expedié Available in 1-2 days
Preview the Shipping Fees - Free Shipping from 99€*NHCO TRIXERONE POWER AND FORCE 100 CAPSULES
Description NHCO Trixerone Power and Vigour 100 Capsules
NHCO Trixerone Power and Vigour 100 Capsules: Specialists aminosience, scientific teams NHCO nutrition laboratories have developed trixerone, dietary supplement for male performance based on three innovative complex:
- pro-Gh peptide, dosed at 1320 mg per hydrochloride day of L-arginine and L-lysine
- testo T3 matrix, concentrated vitamin B5 which maintains the normal production of steroid hormones and Tribulus and zinc that contribute more spécifiqument to support normal levels of testosterone in the body. Tribulus is recognized as well for stiumuler sexual performance in men.
- D-cort 50-23-7, made from extracts of ginseng and rhodiola that contribute to physical and mental energy, boosting resistance to physical effort. Magnesium and vitamin B6 complex also help reduce fatigue.
Directions for use of NHCO Trixerone
First 10 days: 4 capsules (2 morning and 2 at lunchtime)
30 days: 2 capsules.
Composition capsules NHCO Trixerone
Ingredients: hydrochloride of L-arginine; magnesium bisglycinate extract of Tribulus terretris fruit; hydrochloride L-lysine; extract of Siberian ginseng roots; root extract of Rhodiola rosea; anti caking agent: magnesium stearate; zinc L-aspartate; Testofen (from braked fenugreek); vitamin B5, vitamin B6.
Capsule shell: hydroxypropyl methylcellulose
Colorant: titanium dioxide.
This product is suitable for vegetarians
This dietary supplement is not a drug. For adults, except pregnant or lactating women.
Do not exceed the recommended daily dose, consume as part of a varied and balanced diet and a healthy lifestyle.
Keep out of reach of young children.
Reseal after opening, store in cool, dry conditions.
Presentation NHCO Trixerone
Box of 100 capsules
Save time by using the quick order form. With a few clicks , you can easily order your favorite references.
Be fan of our Facebook page and get 5 % discount!
If you are not logged in to Facebook, please first log in and then refresh this page before clicking the Like button. Otherwise, you will not get your voucher.


text:
Clarksville Lawyer, Maryland
Jac E. Knust
✓ VERIFIEDCredentials and Bar Status verified by Lawyer.com on January 17, 2014 Click here for more details
Jac E. Knust has extensive experience in divorce and family law, collaborative law, mediation, Elder law,... (more)
CONTACTSarah Novak-Nesbitt
✓ VERIFIEDCredentials and Bar Status verified by Lawyer.com on March 24, 2014 Click here for more details
The Family Legal Advocacy Groupâs (FLAG) mission is to provide advocacy and education for our clients in... (more)
Jonathan Scott Smith
Jonathan Scott Smith is an experienced, successful problem solver with over 30 years of courtoom... (more)
Stephen C. Thienel
Stephen Thienel is the founder and managing member of Thienel Law Firm, LLC. His practice focuses on... (more)
Michael J Silverman
Michael J. Silverman, Esq. has a reputation for successfully dealing insurance adjusters to maximize the... (more)
Cynthia Lifson
Cynthia M. Lifson graduated from Smith College, majoring in government, and from the Johns Hopkins School... (more)
Elizabeth Jane Case


text:
Comments from terry
Showing 1 - 25 of 328 comments
Some years ago I pointed out (on Flickr.com) that this is the ABC Regal and NOT the Majestic.
After 16 years of working in Management for ABC/EMI I was appointed Manager there, my previous theatre in Newcastle being one of the many casualties of debt ridden new owners, Cannon……..
Some years ago I pointed out (on Flickr.com) that this is the ABC Regal and NOT the Majestic.
After 16 years of working in Management for ABC/EMI I was appointed Manager there, my previous theatre in Newcastle being one of the many casualties of debt ridden new owners, Cannon……..
Was this the show with 'The Bachelors' or Roy Castle? Either way, it would be interesting to see it and I wish I had known it was still at ABC South Shields when I was there, Dave! Would it be very expensive to have the 35mm filmlet you mention transferred to DVD and uploaded to YouTube?
Thorn-EMI made a mess of Blackpool ABC when, in the tripling process, they isolated the stage (which had a revolve), dressing room block and front stalls all those years ago. It was all reversible, however, just in case the need for large capacities and stage spectaculars should ever return. The acquisition and closure by Odeon and subsequent conversion to 'The Syndicate' put paid to that, however.
I have to agree about the screens in older cinemas often being rather on the small side in relation to the auditorium size. Where I worked with ABC (too numerous to list here) the screens were either very large or vice versa with no happy medium.
However, below are links to surviving footage of venues which had very large screens. In the case of Blackpool (ABC as opposed to the Princess where we also had 70mm) the screen is not seen but there are some distance shots of the 60 + feet wide pros which provide an indication of how large the screen was.
ABC Sheffield:–
Coliseum Cinerama Glasgow:–
ABC New Centre Bristol:–
ABC Blackpool (at 05:24):–
ABC Blackpool (First ever public performance of 'Yesterday' – watch out for star line up at the very end):–
My apologies for posting the above on a page devoted to an Odeon but a great deal of cross referencing does occur on the CT site……..
Photo uploaded of The Beatles on stage 22 November 1963.
Needless to say, I have very happy memories of Sunderland Odeon which was one of the most impressive and best equipped venues in the country. It was the favourite cinema of both my Mum and Dad and they remembered going there (Blacks' Regal) in the 1930's when, as part of the programme, there were stage presentations and recitals at the Compton Organ. I think my Dad said the Musical Director was Arnold Eagle.
For the record, my Dad had been a Chief Projectionist at one time and he was trained by a Gaumont man by the name of Tommy Bell who later worked for Blacks as Co-Chief at the Regal before transferring to the Royal on Bedford Street as the Chief where he was very much at home.
When I used to ask my Dad how the ABC Ritz compared with Blacks Regal he would reply that he would have liked the Ritz more if , at the 11th hour, ABC had not cancelled the Compton organ which it was designed to house (the chambers were above the proscenium).
I always got the impression that, large as the Ritz was at just over 1900 seats, the original project had been scaled down by the time the final plans were drawn up and building work commenced. I mention this as, in towns of similar size with cinemas like the Regal already established, ABC invariably provided a theatre with well in excess of 2000 seats, a fully equipped stage, a restaurant – and an organ! I wonder what went wrong in Sunderland?
I have happy memories of your Dad, John, by the way and our 'after work pints' in the likes of 'The Park Inn' and 'The Beehive'……
This is home cinema as it should be:–
Apparently, many items from the ABC are incorporated within.
Article re closure:–
Very interesting to read the comments of the CTA's Richard Gray when comparing the original ABC and Odeon circuits………
World Premiere of 'Happy Go Lovely'in 1951 :–
Photo uploaded. I made a rare excursion into Newcastle today and fully expected to see the scaffolding already up. So far, however, nothing seems to have taken place – at least on the outside. I guess that inside the usual asbestos stripping etc must be in progress.
What a pity that the Paramount/Odeon was not considered worthy of restoration as it would have made a fine multi purpose auditorium (there is sufficient space at the rear to deepen the stage). It would have been far superior to the barren looking City Hall and the 'slugs on the riverbank' known as The Sage…..
There were indeed live shows at the Odeon and two names which come to mind are Adam faith and Dusty Springfield. The Hippodrome, Dovecote Street also had 'one night stands' but the main venue in the town was the ABC Globe and the likes of The Beatles and The Rolling Stones used to play there.
Joseph Seal, the famous Resident Organist of the Regal Kingston upon Thames became ABC's Controller of Live Entertainment and his signature can be seen at the foot of a memo, a scanned image of which I have uploaded to the photos section, from early 1969 relating to a forthcoming live show week at the ABC (Ritz) Huddersfield.
Re Vic Mancini: We 'lent' ABC Derby a projectionist (from base ABC Huddersfield) when it tripled. Obviously, he was going to be working overtime, and I asked this particular operator to ring me weekly for details of his shifts at Derby. Prior to his secondment I said that I would , to be going on with, include an extra two shifts in week 1 until we got up to speed (at this time the payroll system was geared to the convenience of London and not those out in the field).
Mr Mancini rang me, and in his usual obnoxious, gruff, belligerent manner, asked "What are you doing about *******'s overtime, mate?" and, before I could explain that what I had arranged for week 1 was just an interim measure, he retorted" Two shifts – what the hell bloody use is two ruddy shifts, mate? Get stuffed!" to which I replied "Mr Mancini, you may be the Zone Engineer, but do NOT speak to me like that!" and the old so and so climbed down…….
As I said this the Huddersfield Chief knocked at the office door and could not help but overhear my irate tone and said "You just did right speaking to Mancini as you did as he'll walk all over you if you let him!"
Although, as I recall, the Dick Emery Show in 1976 was presented at ABC Great Yarmouth the previous year ie 1975.
Did you , as a young man, once take a number of interior shots of the Haymarket, Newcastle whilst I was there? If so, it would have been on a Sunday afternoon.
If I am correct, then they will be the only ones of a professional standard taken in full houselights and with the tabs closed. Would it be possible to obtain copies, please?
Better still, perhaps you could upload them to the Haymarket's photo section as the existing shots do not give people a true indication of how nice an auditorium (albeit rather old fashioned) it really was.
My apologies if I have mistaken you for someone else.
3 more images uploaded.
Uploaded to the photos section are the following:–
3 Roadshow shots. ABC 1 (former Stalls) with tabs open. Entrance foyer. ABC 2 (former Rear Circle: 3 shots).
Four photos uploaded of the auditorium in the houselights taken a few days before closure.
Unfortunately, the cable for the tabs had just 'given up the ghost'. Steve Veasey, ABC Furnishing Manager, had ordered new curtains and a pelmet for the Haymarket in 1980 but the latter failed to materialise for some unknown reason.
The fountains were only partially illuminated latterly and many of the elaborate light fittings had been removed during a 1976 re-dec. Furthermore, most of the trough lighting had also been disconnected.
By and large, though, the photos give a hint of what the place had looked like in its heyday.


text:
The weather has been beautiful here in Leuven, and it's making our walks around town a thousand percent better. However, although I know I should be floating in the delirium of spring, I am plodding around in a fog of fatigue and weightiness. I wake up exhausted after sleeping poorly, I take naps prior to 10 am, and only guilt about the Mister doing so much of the housework and child-wrangling on top of his busy job and dissertation-writing provokes me to get the laundry done, make and clean up dinner, and pick up toys (squatting or on all fours, because--oof--the bending over thing is just not good).
My belly is, I am convinced, as big as it was with Gabriel shortly before he was born. And we have ten weeks to go. It's sticking out like a giant torpedo, probably because all of my muscles have given way entirely. Wherever I go--church, book club, daycare, Dutch class--people assume that I am on the verge of giving birth. Yet: ten weeks to go. At thirty weeks with Gabriel, I was still only just starting to feel *really* pregnant. Hah!
In comparison with my first pregnancy, I am doing very little by way of body-strengthening and stretching, and I imagine this is in part to blame for the aches and pains. I took yoga and birth movement classes with Gabriel, but here I haven't been able to find a prenatal yoga class that's accessible to me. I know I should just do some yoga at home and figure it out on my own or via podcasts/youtube videos, but somehow a nap always sounds better. At least I am walking at least four miles a day, no matter what, so there's that. But I do want to start working on stretching and yoga practice, so I hope registering that desire here will spur me to do so.
The best part about this pregnancy with Junebug is how much he is in motion. He is continuously stretching and rolling, more than I remember with Gabriel. It's not a pummeling or a kicking feeling as much as a sensation of smooth but seriously pushy-outy gestures. I'm constantly grinning in wonder as I watch a little fist or foot make a visible path across my skin, sometimes strong enough that I feel like I need to press back with my hand lest he bust out of there! (Even if I'm not stretching enough, *he* certainly is!) It's very easy to feel his little head or rump, probably due to the aforementioned stretched-out and separated abdominal muscles, and I love poking at him (although he probably doesn't appreciate it as much). I'm convinced he moves in response to Gabriel's voice or cry, and he always wakes up and starts moving in the morning when Gabriel comes to our bed asking for a banana.
Gabriel still doesn't have much of a clue what is in store, even though we've gotten a few books about a new baby and try to read them regularly, in addition to talking about (and praying for) his new brother. He knows that my belly is "baby," but I don't think he realizes that the baby will come out and be one of the babies in his books, or the babies we see of our friends and family. I'm very curious to see how he reacts to a new sibling, and find it hard to predict what response he'll have. A friend suggested that we let him pick out a gift *from* him to his brother, an idea I like a lot--helping him feel big brotherly. We shall see!
I have a lot more to say about Mr. Gabriel, who is such a delight and a handful these days. We got him a new bed at Ikea, and he transitioned perfectly well from sleeping on a mattress on the floor to sleeping in his bed, which we are very relieved about. "New bed!" he says. He's busting out with new words and phrases all the time, in all three of his languages, and it's pretty adorable. Our favorite is "Extra yum!", which comes from an adorable book called Little Pea, about a pea who hates the candy his parents give him for dinner but loves spinach for dessert: "yum, yum, extra yum!" Gabriel gobbles up most of the food we give him, in portion sizes about equivalent to ours, so the phrase is apropos. Anyway, now I'm rambling on about Gabriel and I will try to write a separate post soon.
We leave for Barcelona again shortly...there is a general transportation strike on Thursday, the day we are scheduled to leave, and our flight is cancelled, so we are currently trying to reschedule and don't know yet when that will be. Could be as soon as tomorrow night. We'll be gone for 10 days, much of that time without internet when we head up the coast. I'm looking forward to a longer, quieter break from our regular routine, and the weather forecast is looking good. So I don't know how much I'll post during that time. By the time we get back it will be well into April, which...wow! Ten weeks is going to fly by.
27 March 2012
Subscribe to:
Post Comments (Atom)


text:
Thu Mar 9, 2017, 10:50 PM
TheMastersNemesis (7,361 posts)
Extreme Left Made Up. A Myth. It Is A Scare Tactic To Inflame The GOP Base.
Extreme left would be communist really. And the Democratic party has no ties to what exist.
The progressive wing of the Democratic party which believes in civil rights and economic and social justice has been tagged with this meme. What progressives want most American workers and Americans want. And what progressives and liberal want are in line with FDR's 2nd Bill Of Economic Rights. The RW and GOP are viciously apposed to ANYTHING that benefits middle and lower class workers and constituents. They are against government helping ANYONE except the royalist upper class. And it is classic class warfare.
7 replies, 421 views
Always highlight: 10 newest replies | Replies posted after I mark a forum
Replies to this discussion thread
7 replies | Author | Time | Post |
Extreme Left Made Up. A Myth. It Is A Scare Tactic To Inflame The GOP Base. (Original post) |
TheMastersNemesis | Mar 9 | OP |
emulatorloo | Mar 9 | #1 | |
CitizenZero | Mar 9 | #2 | |
bluedye33139 | Mar 9 | #3 | |
Vilis Veritas | Mar 9 | #4 | |
CitizenZero | Mar 9 | #5 | |
BainsBane | Mar 11 | #6 | |
milestogo | Mar 12 | #7 |
Response to TheMastersNemesis (Original post)
Thu Mar 9, 2017, 10:56 PM
emulatorloo (30,749 posts)
1. Center right, center left, and liberal Dems believe in civil rights and economic and social justice
Just a reminder that all Democrats believe in those goals and principles.
Response to TheMastersNemesis (Original post)
Thu Mar 9, 2017, 11:04 PM
CitizenZero (130 posts)
2. Anti-Communist
Mainstream Dems are both anti-communist and anti-fascist. Both of those ideologies (communism and fascism) are extreme and are rejected by Democrats. Communism is totalitarianism from the Left, and Fascism is totalitarianism from the Right. Americans and Democrats are mainstream and in the center. They reject both of these extremes, right and left.
As Democrats, we are in favor of Free Enterprise as long as working people and the middle class get their fair share of the economic pie. Republicans only seem to support the Rich at the expense of the rest of the People. Radical Capitalism is economic hegemony by the ultra-rich and an oligarchy of large corporations. It is not true capitalism. It is broken capitalism. Free enterprise is about allowing room for small and medium businesses to thrive, and for workers/employees at all levels to be treated fairly. I have no problem with the rich and the corporations as long as they pay their fair share of tax and take care of their employees and customers. If they meet these basic requirements of fairness, they deserve to thrive and have profits. The more, the better. The extreme Left is a phantom in the minds of old school Republicans and People who can't reason. |
Response to CitizenZero (Reply #2)
Thu Mar 9, 2017, 11:09 PM
Vilis Veritas (2,287 posts)
4. Thank you for articulating what I could not.
Response to Vilis Veritas (Reply #4)
Thu Mar 9, 2017, 11:22 PM
CitizenZero (130 posts)
5. Glad To Help
This topic needs to be talked about.
Response to TheMastersNemesis (Original post)
Sat Mar 11, 2017, 05:47 AM
BainsBane (40,479 posts)
6. I don't think that term is used to refer to Democrats
But rather third party and Trump voters who claim to be on the left. But of course they aren't. You're quite right that radical leftism is based on collectivism, like communism. These are people focused entirely on self.
Response to TheMastersNemesis (Original post)
Sun Mar 12, 2017, 08:00 PM
milestogo (2,618 posts)


text:
Play Video
Random Drug Test
Posted by Skittsburgh on May. 29, 2008
Ah yes, nothing better than a good Disney conspiracy theory to brighten up ...
Learn everything you need to know about how to become royalty!
Hey Break fans! Check out our latest compilation - Crazy People in Public!
Posted by Skittsburgh on May. 29, 2008


text:
Wisport PenCott Snowdrift
Discover a wide range of Wisport survival backpacks and padded rifle cases in PenCott Snowdrift camouflage at Military 1st online store.
Made of top quality Cordura Nylon and developed with Polish Armed Forces, Wisport bags and rucksacks are extremely durable and versatile, perfect for both civilian and tactical use.
Find out more at http://mil1.st/WisportPenCottSnowdrift
Free UK delive...
- Views: 156
- Likes: 0
- Category: News & Announcements
New Wisport SilverFox Rucksack at Militar...
Wisport SilverFox Rucksack in PenCott Snowdrift camo is available now at Military 1st online store.
Built of robust Cordura Nylon with DuPont Teflon fabric protector, Wisport SilverFox Rucksack is a sturdy survival backpack featuring spacious main compartment with a snow collar, removable lid and innovative OpenBack carrying system, three outer pockets, and MOLLE loops, elastic bands and D-Rin...
- Views: 132
- Likes: 0
- Category: News & Announcements
Helikon CPU Hats now at Military 1st
Helikon CPU Hat comes with a narrow and adjustable brim, elastic band sewn around the crown, mesh tunnels for improved air circulation, soft inner sweatband for comfort and adjustable chin strap for secure fit.
Durable and lightweight Helikon CPU Hat offers effective protection against sun and rain and is ideal for various outdoor activities, including Airsoft, hunting, shooting and fishing.
- Views: 348
- Likes: 0
- Category: News & Announcements
PenCott Uniforms Available Now at 0241Tac...
SixKa's Combat shirts have a large collar that can be worn up or down. Quarter length zipper front closure for comfort while wearing body armor or load bearing equipment. Matching moisture whicking chest, back, and under arm material used to provide breathability while wearing body armor or gear.Velcro faced shoulder pockets for patches with hook and loop closure. Seamless underarm construction wi...
- Views: 210
- Likes: 0
- Category: News & Announcements
First Pencott Viper Hoods!
SCG company is still developing new camouflage systems. We introduced into our offer two new ghillie lines.
-Hybrid Series
-Shadow Series
Check our website & Make nature work for you!
- Views: 550
- Likes: 1
- Category: New Products
PenCott GreenZone Rainwear and Pullovers
0241Tactical - Tactical Pullover Garments ready soon. Two versions available Rain Pullover and Ripstop Operator's Jacket. Simple in design and affordable for everyone from airsofters to real-steal operator's. 0241Tactical will be the sole seller (product sold from producer directly to customer). No distributors means no mark-up prices! Built using genuine Mil-Spec materials with quality American ...
- Views: 694
- Likes: 0
- Category: News & Announcements
PenCott Neck Gaiters (GreenZone, BadLands...
Our Premium PenCott Neck Gaiters are produced using a Brushed Polyester material coupled with a high strength, bonded, nylon thread to increase the strength and lengthen the life of your Neck Gaiter. This is an excellent material with excellent color retainability and incredible stretch. These neck gaiters will keep your head, face, and neck camouflaged. Use our Neck Gaiters to keep yourself prote...
- Views: 654
- Likes: 0
- Category: News & Announcements
SnowDrift Backpack Covers
HydeDefenition Camouflage Backpack Cover available in GREENZONE, BADLANDS, and SANDSTORM. Made of official Pencott (HydeDefinition) Nylon/Cotton Ripstopm material that will fit a large backpacks or a pack of similar size. Make your existing backpack blend with your HydeDefinition uniform while protecting your contents from dust. Backpack Covers keep your gear free of dust and sand and provides you...
- Views: 397
- Likes: 0
- Category: News & Announcements
PenCott Shemaghs
0241Tactical PenCott Shemaghs are made from 100% 50 Denier Tafetta officially licensed PenCott material produced in the USA. Our Shemaghs are 44 X 44 inches square with a rolled hem along the edge to prevent fraying and rips. Our Shemagh will provide protection from direct sun exposure, as well to protect the mouth and eyes from blown dust and sand. Additionally (and unlike typical checkered Shema...
- Views: 524
- Likes: 0
- Category: News & Announcements
Wisport Whistler Rucksacks in PenCott cam...
Wisport Whistler Rucksacks in genuine PenCott camouflages are available now at Military 1st!
Made of extremely durable Cordura Nylon, Wisport Whistler Rucksacks come with 35L capacity, numerous pockets, enhanced SAS Plus Military carrying system, MOLLE webbing and multiple attachments points. Allow the use of hydration systems. Great for hiking and EDC.
Find details at Military 1st online stor...
- Views: 564
- Likes: 0
- Category: News & Announcements


text:
Sun, 30 October 2011
After a short Batman break we are back, and boy to we have some catching up to do. We go over the Batman...I mean NY comiccon news, all the hot roumors around TF4 and whats going on in the world of custom ronots. Oh and I think somewhere in here we talk about Batman. So join the dynamic duo for the latest round of TF glory...and Batman. |
Thu, 27 October 2011
Matt and Aimee cover a press conference and 2012 Solicits! Then we bring you our final Auto Assembly 2012 interview with Simon Furman and Andrew Wildman. Then to finish off the podcast we answer a listener question! Thanks for listening! * Intro & Press Conference Talk [@3 mins] * Jan Solicits & Comic Highlight [@30 mins] * Interview with Simon Furman and Andrew Wildman from AA2011 [@41 mins] * Underbase answers a question [@1 hr 12 mins] |
Thu, 20 October 2011
Matt, Aimee, and Andy back once again hunting robots in 28. Have a listen and kick back as we have some stupid fun with our review! No spoilers in our news section this week! * Intro & News * Comic Highlight [@21 mins] * The Review of Ongoing 28 [@31 mins] |
Thu, 13 October 2011
Aimee, Matt, and our special guest reflect on Classic UK issue 45 and 46 of Icarus theory, the build up to Dinobot Hunt! We talk Exiles in the News section, with spoilers, so skip to 10 minutes in if you'd like to avoid those reveals! Thanks for joining us! * Intro & News: Exiles talk w/spoilers, 10 mins in the rest of the news non spoiler * Comic Highlight [@17 mins] * The Review of Icarus Theory [@25 mins] |
Mon, 10 October 2011
Thanks for listening |
Wed, 5 October 2011
Matt, Aimee, and Andy back once again second week in a row with another Ongoing review. Have a listen to what we thought about this issue and where it might end? (Sign Aimee's Petition to High Moon @ http://www.PetitionOnline.com/TFwfcABP/ ) * Intro & News * Comic Highlight [@12 mins] * The Review of Ongoing 27 [@23 mins] |
Sun, 2 October 2011
Thats for listening. |


text:
Changes of activity and isoforms of alkaline sphingomyelinase (nucleotide pyrophosphatase phosphodiesterase 7) in bile from patients undergoing endoscopic retrograde cholangiopancreatography
© Duan et al.; licensee BioMed Central Ltd. 2014
Received: 6 February 2014
Accepted: 24 July 2014
Published: 7 August 2014
Alkaline sphingomyelinase (NPP7) is an ecto-enzyme expressed in intestinal mucosa, which hydrolyses sphingomyelin (SM) to ceramide and inactivates platelet activating factor. It is also expressed in human liver and released in the bile. The enzyme may have anti-tumour and anti-inflammatory effects in colon and its levels are decreased in patients with colon cancer and ulcerative colitis. Active NPP7 is translated from a transcript of 1.4 kb, whereas an inactive form from a 1.2 kb mRNA was found in colon and liver cancer cell lines. While the roles of NPP7 in colon cancer have been intensively studied, less is known about the function and implications of NPP7 in the bile. The present study examines the changes of NPP7 in bile of patients with various hepatobiliary diseases.
Bile samples were obtained at endoscopic retrograde cholangiopancreatography (ERCP) in 59 patients with gallstone, other benign disease, tumour, and primary sclerosing cholangitis (PSC). The NPP7 activity was determined. The appearance of the 1.4 and 1.2 kb products in the bile was examined by Western blot. The results were correlated to the diseases and also plasma bilirubin and alkaline phosphatase.
NPP7 activity in the tumour group was significantly lower than in the gallstone group (p < 0.05). The activity in the tumour plus PSC group was also lower than in gallstone plus other benign disease group (p < 0.05). Within the tumour group NPP7 activity was lowest in cholangiocarcinoma patients, being only 19% of that in gallstone patients. Bilirubin correlated inversely to NPP7 and was higher in the tumour than in the gallstone group. Western blot identified both the 1.4 kb and the 1.2 kb products in most bile samples. The density ratio for the 1.4/1.2 kb products correlated to NPP7 activity significantly. Two patients (one PSC and one cholangiocarcinoma) lacking NPP7 activity had only the 1.2 kb form in bile.
NPP7 activity and the ratio of 1.4/1.2 kb products in bile are significantly decreased in malignancy, particularly in cholangiocarcinoma. The implications of the finding in diagnosis of cholangiocarcinoma and 1.2 kb product in hepatobiliary diseases require further investigation.
NPP7 Alk-SMase Bile Patients Cholangiocarcinoma Liver diseasesBackground
Alkaline sphingomyelinase is an intestinal brush border enzyme highly expressed in jejunum and ileum [1, 2] and released into the lumen by bile salts and trypsin [3, 4]. It is resistant to pancreatic and faecal proteases [3] and high activity can be detected in the faeces [5]. Purification and cloning showed that the enzyme is a novel member of nucleotide pyrophosphatase phosphodiesterase (NPP) family and is now called NPP7 [6, 7]. NPP7 cleaves phosphocholine moiety from both exogenous and endogenous sphingomyelin (SM) in the gut and turns SM to ceramide. Ceramide is a lipid messenger that inhibits cell proliferation and induces apoptosis and may counteract cancer development [8]. Via its phospholipase C activity NPP7 also hydrolyses and inactivates platelet activating factor (PAF) [9], an important molecule with proinflammatory properties [10]. NPP7 has thus important roles in generation of sphingolipid signals, regulation of PAF functions and in the absorption and reutilization of choline in the gut [11]. Our recent study in NPP7 -/- mice has confirmed the key role of the enzyme in SM digestion and ceramide generation in the intestinal tract [12].
NPP7 activity was also identified in human bile but not in bile of other species including rat, mice, pig, rabbit and baboon [1, 13, 14]. Since in humans the activity was not detected in the mucosa of gallbladder, bile NPP7 was indicated to be derived from liver. This was confirmed later by identification of NPP7 mRNA in HepG2 cells [15]. Physiologically, bile NPP7 may contribute to a more efficient digestion of SM in humans, since in patients with ileostomy, most of fed SM is hydrolysed and absorbed [16], whereas in rodents, SM digestion is relatively slow, extended and incomplete [17]. We previously showed that dietary SM inhibited cholesterol absorption and this inhibition was also more obvious in rodents than in humans [16, 18].
Several pieces of evidence suggest anti-inflammatory and anti-tumour roles of NPP7 [11]. NPP7 activities decrease in patients with colon cancer [19], longstanding colitis [20] and familial adenomatous polyposis [21]. Incubation of the enzyme with colon carcinoma HT 29 cells inhibits cell proliferation [22]. In dextran sulphate induced experimental colitis in rats, rectal installation of the enzyme alleviates colitis [23]. Hypotheses behind these effects have been linked to the generation of ceramide and to the inactivation of PAF [11, 24]. The impact of NPP7 in liver cancer is a field that has not been extensively explored, although preliminary assay in human liver biopsies showed that the NPP7 level tended to be lowered in liver diseases predisposing to liver tumours [15].
Due to the alternative splicing, two isoforms of NPP7 have been identified in both colon cancer HT29 and liver cancer HepG2 cell lines [25, 15]. The active full length NPP7 is a protein translated from 1.4 kb transcript consisting of 5 exons. The aberrant splicing form lacks exon 4 and the protein translated from it has no activity against SM [25]. Considering the intensive studies on NPP7 in the intestine, relatively little is known about the enzyme expressed in the liver. Liver is an important organ in terms of synthesis and secretion of SM [26] and probably PAF [27, 28], two major substrates of NPP7. We therefore asked how the NPP7 activity in bile varies with different hepatobiliary diseases and whether the changed NPP7 activity or appearance of the 1.2 kb form in bile could be linked to these diseases, and thus be a potential disease marker. In the present study, we analysed NPP7 activity and the occurrence of two isoforms in bile from 59 patients undergoing diagnostic and/or therapeutic endoscopic retrograde cholangiopancreatography (ERCP).
Age, sex and diseases of patients in groups
Group | Gallstone | Tumour | PSC | Others | Total |
Number | 29 | 13 | 10 | 7 | 59 |
Female | 19 | 7 | 6 | 3 | 35 |
Male | 10 | 6 | 4 | 4 | 24 |
Age range | 33–85 | 60–79 | 20–82 | 53–83 | 20–85 |
Median age | 67 | 66 | 48 | 67 | 66 |
Mean age | 68.5 | 66.0 | 50.2 | 68.4 | 65.2 |
Sample preparation
The bile samples were centrifuged at 14000 rpm for 10 min at 4°C to remove the undissolved materials. A small aliquot of the supernatant was saved as original bile for NPP7 activity assay and protein determination. The rest of the samples were subjected to protein precipitation by ammonium sulphate which was added step by step up to 40% saturation with stirring. The samples were kept stirring at 4°C for 1 h followed by centrifugation at 14000 rpm for 10 min. The precipitated protein pellet was dissolved in PBS buffer and stored at -20°C for Western blot analysis.
NPP7 and bile alkaline phosphatase activity assays
The activity of NPP7 in the bile against SM was determined as described previously, using 14C- choline labelled SM as substrate [29]. Briefly, 5 μl of the original bile was incubated in 95 μl 50 mM Tris–HCl buffer containing 0.15 M NaCl, 80 pmole 14C-SM, 4 μg unlabelled SM, 10 mM taurocholate, 2 mM EDTA, pH 9.0 at 37°C for 30 min. After phase partitioning, an aliquot of the upper phase containing the cleaved 14C-phosphocholine was taken for liquid scintillation counting. The activity of NPP7 was expressed as the formation of phosphocholine in 1 h by per ml of bile and by per mg protein in the bile samples. Alkaline phosphatase (ALP) activity in the bile was determined using β-nitrophenylphosphate as substrate in 10 mM Tris buffer pH 10.0 as described previously [30]. Protein in the bile was assayed using a kit from Bio-Rad using albumin as a standard.
Western blot for NPP7
Western blot was performed as described previously [23]. Normally 50 μg of the precipitated bile proteins were subjected to 10% SDS-PAGE and transferred to a nitrocellulose membrane. The membrane was probed with anti-NPP7 antibody (1:5000) obtained from R&D System (Abingdon, UK). After washing, the membranes were reacted with second antibody against rabbit IgG conjugated with horseradish peroxidase. The NPP7 bands were identified by ECL advance reagents and the remitted light was recorded on Fuji Image. A standard purified NPP7 from human bile was routinely loaded as a positive marker of the product of 1.4 kb transcript. The densities of the NPP7 bands and the ratio of the densities of the products from 1.4 kb/1.2 kb transcripts were analyzed by MyImage Analysis Software from Thermo Scientific.
Clinical biochemical analysis of the serum
Bilirubin, alkaline phosphatase and γ-glutamyltranspeptidase (γ-GT) in plasma were analysed the day before or in the morning the same day as the ERCP were available in 58 patients and C-reactive protein taken at these times in 38 patients. The levels of bilirubin, ALP and γ-GT were determined at the Clinical Chemistry Laboratory, Skåne University Hospital, Lund Sweden on a Cobas 701 instrument using reagents from Roche (Roche Diagnostics, Mannheim, Germany). Reference values are 5–25 μmole/L for bilirubin, 0.60–1.8 μkat/L for ALP and 0.15–1.2 μkat/L for women and 1.2–1.9 μkat/L for men >40 years old.
Statistical analysis
Statistical analysis was performed by soft program Graphpad Prism 5. Since the groups in comparison were independent of each other, and the values showed non-normal distribution, the significance of the differences between different groups were evaluated by Mann–Whitney test, whereas the correlation was analysed by linear regression test. P < 0.05 was considered to be statistically significant.
Age and sex distribution in disease groups are shown in Table 1. The gallstone group comprises 29 patients. Common bile duct stones (CBDS) were removed at ERCP in 22 patients with gallstone disease, after a sphincterotomy had been performed. The remaining 7 patients all had a history of gallstone disease and 5 of them had previously undergone cholecystectomy. The clinical suspicion of CBDS was strong, but at ERCP no stones or only sludge was found. It was, however, considered likely that the stones had passed recently.
In the tumour group of 13 patients, 5 had cholangiocarcinoma, 1 had gallbladder cancer, 5 had pancreatic cancer, 1 had a hepatocellular carcinoma superimposed on an advanced PSC, and 1 had colon cancer with liver metastases.
The group designated "Others" consists of 7 patients, of which 1 was severely icteric and appeared to have severe alcohol related liver disease with cholestatic features, and 1 had severe icterus and a cholestatic profile for unknown reasons, combined with renal insufficiency. The other 5 were less severely ill. They underwent ERCP because of abdominal pain, moderately pathologic liver tests and in two cases widened common bile duct on ultrasonography. At ERCP 1 was considered to have a benign stricture of the common bile duct, and 1 had an irregular common bile duct for unknown reasons. Brush cytology was normal and no sign of malignancy appeared during a two year follow up.
NPP7 activity
NPP7 activity in the bile and the results of other clinical chemical analysis in patients in different groups
Group | NPP7 nmol/h/ml | NPP7 nmol/h/mg | Bilirubin | ALP | GT | n |
Gallstone | 311.6 ± 290.1 | 58.21 ± 69.93 | 54.59 ± 63.19 | 2.91 ± 1.60 | 6.69 ± 5.74 | 29 |
Tumor | 164.9 ± 147.1* | 25.16 ± 14.49* | 161.2 ± 135.3** | 12.2 ± 11.2** | 14.15 ± 9.87* | 13 |
Others | 312.6 ± 236.1 | 50.95 ± 31.09 | 124.9 ± 197.8 | 4.08 ± 3.52 | 4.75 ± 4.12 | 7 |
Two patients, a 73 year old woman with PSC and a 67 year old man with cholangiocarcinoma had extremely low levels of NPP7, 1.2 and 0.1 nmole/h/mg protein respectively. These patients had bilirubin levels of 22 and 156 μmole/L and ALP levels of 4.9 and 1.9 μkat/L respectively. ALP values in bile varied considerably between individuals but did not correlate to plasma bilirubin or γ-GT.
Western blot for NPP7 isoforms
The present study for the first time examines the activity and isoforms of NPP7 in the bile in humans with different diseases. The major findings are that although almost all bile samples contained considerable NPP7 activity, the activities were significantly decreased in the bile of patients with cholangiocarcinoma.
NPP7 is expressed in the intestinal tract and additionally in human liver [11]. NPP7 from human liver is released in bile, probably by bile salt action on the canalicular membrane, analogous to the release from intestinal segments by luminal bile salt perfusion [4]. Due to the generation of ceramide and inactivation of PAF, the enzyme has been considered to have anticancer properties [11]. Reduction of NPP7 level has been reported in colorectal cancer [19] and longstanding colitis [20], and an inactive isoform of NPP7 was identified in both colon cancer HT29 and liver cancer Hep G2 cell lines [15, 25]. In the present study, the lowered NPP7 activity in bile of patients with cancers comparing with those with gallstones is in agreement with previous studies in human colon cancer samples [19]. The finding that most obvious reduction of NPP7 was found in cholangiocarcinoma patients is of particular interest. Cholangiocarcinoma is a cancer with increasing incidence, and the disease is considered incurable except for the few cases where surgical removal is possible. Due to the lack of an early marker, most cholangiocarcinomas are diagnosed at a stage when surgical cure is impossible, and the 5 year survival rate for the patients is almost zero [31, 32]. The possibility that the great reduction of NPP7 in bile can be a marker in prediction of cholangiocarcinoma at early stage is attractive. It may be noteworthy that reduced NPP7 activity was also found in the patients with the chronic bile duct inflammation PSC, which has strong links to ulcerative colitis and risk for cholangiocarcinoma [33, 34].
The occurrence of the aberrant NPP7 from the 1.2 kb mRNA in the majority of the bile samples is not a finding we expected, but interesting. It may indicate that appearance of the aberrant isoform cannot simply be used as a marker for malign hepatobiliary disease. The strong correlation between the ratio of 1.4/1.2 kb products and NPP7 activity supports our previous finding that the 1.4 kb product is active whereas the 1.2 kb form is not [25]. It also suggests that the secretion of the 1.2 kb product in bile was actually less affected than the secretion of the 1.4 kb product in the tumour and tumour plus PSC group. The result also argues against a nonspecific effect of cholestasis as explanation of the lower NPP7 activity in these groups. Interestingly two patients, a 73 year old woman with PSC and a 68 year old man with cholangiocarcinoma (Klatskin tumour) had almost immeasurable NPP7 activity but strong bands corresponding to the 1.2 kb and no band matching the 1.4 kb transcript. Although the aberrant 1.2 kb form has no activity against SM, this protein may have other functions that have not been identified. It is well known that alternative splicing is an important mechanism to produce isoforms with different, or opposite functions compared to the normal product [35, 36].
NPP7 has 5N-glycosylation sites and defect glycosylation reduces the enzyme activity [37]. Since the identification of the 1.4 and 1.2 kb products in the present study was based on Western blot, one might ask whether the product with smaller molecular weight is derived from abnormally glycosylation. We consider this an unlikely explanation of the molecular mass difference. The 1.2 kb mRNA for the isoform has been shown to be expressed in liver cells and transfection of Cos7 cells with the 1.2 kb cDNA produces a protein band on Western blot similar as the one found in this study [15]. In addition, Dr. Yang LP in Nantong Cancer Research Institute, Jiangsu Province, China, also found the two bands on Western blot in human colon cancer tissues. In their experiment, pretreating colon cancer samples with glycosidase did not affect the size differences between the two bands on Western blot (personal communication). However, further studies to characterize sugar moiety of the two products in human bile is still necessary, as abnormal glycosylation has great impact on carcinogenesis [38].
In the present study, we also found a week positive correlation between bile NPP7 and plasma ALP within the gallstone group, suggesting that cholestatic stress may increase NPP7 secretion in bile. There was, however, no such correlation in whole patient population or within the tumour group which had higher ALP level than the gallstone patients. In the whole patient population there was rather a week inverse correlation between NPP7 and bilirubin levels, and NPP7 was lower but bilirubin higher in cholangiocarcinoma than in pancreas cancer patients. If cholestasis itself stimulates secretion of NPP7 into bile, other factors thus may act in tumour group to counteract this phenomenon. Although we earlier found a trend towards low NPP7 levels in liver biopsies from humans with liver disease [15], only one of the tumour patients in this study had known liver disease (hepatocellular cancer in a PSC liver). Pre-existing liver disease therefore does not explain the lower NPP7 values in the tumour group.
In conclusion NPP activity was decreased with malign hepatobiliary diseases and lowest activity was associated with cholangiocarcinoma. Although the occurrence of both the normal 1.4 kb and the aberrant inactive 1.2 kb form of NPP7 in human bile is a general phenomenon, the NPP7 activity is derived from the 1.4 kb form. However, what determines the partitioning between the two forms, and the identity and function of the 1.2 kb form require further study.
Limitations of the study
Although the results of the study are potentially important, a few limitations need to be noted. Since cholangiocarcinoma is not a common cancer disease, the number of the patients with cholangiocarcinoma in the present study is small. Further study in a large scale is required. In addition, as an ectoenzyme, bile NPP7 is expected to be expressed in the canalicular membrane of the hepatic cells, but the precise location of NPP7 in liver cells has not been clearly demonstrated. This is partly due to the fact that NPP7 has not been found in the liver of animals so far, and its levels are down regulated in cancer tissues. Immunohistochemistry study on normal and diseased human liver should be performed when possible. Finally we also lack the genetic analysis on the two patients in the study who lack NPP7.
Alkaline phosphatase
Common bile duct stone
Endoscopic retrograde cholangiopancreatography
- γ-GT:
Gamma glutamyl transpeptidase
Nucleotide pyrophosphatase phosphodiesterase
Primary sclerosing cholangitis
The work was supported by Swedish Research Council, the Albert Påhlssion Foundation, Swedish Cancer Society, Anslag för läkares forskning (ALF) grant for clinical research, Region Skåne.
Authors' Affiliations
- Duan RD, Hertervig E, Nyberg L, Hauge T, Sternby B, Lillienau J, Farooqi A, Nilsson A: Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences. Dig Dis Sci. 1996, 41 (9): 1801-1806.View ArticlePubMedGoogle Scholar
- Nilsson Å: The presence of sphingomyelin- and ceramide-cleaving enzymes in the small intestinal tract. Biochim Biophys Acta. 1969, 176: 339-347.View ArticlePubMedGoogle Scholar
- Wu J, Liu F, Nilsson A, Duan RD: Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity. Am J Physiol Gastrointest Liver Physiol. 2004, 287 (5): G967-G973.View ArticlePubMedGoogle Scholar
- Duan RD, Cheng Y, Tauschel HD, Nilsson A: Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis. Dig Dis Sci. 1998, 43 (1): 26-32.View ArticlePubMedGoogle Scholar
- Di Marzio L, Di Leo A, Cinque B, Fanini D, Agnifili A, Berloco P, Linsalata M, Lorusso D, Barone M, De Simone C, Cifone MG: Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2005, 14 (4): 856-862.View ArticlePubMedGoogle Scholar
- Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J, Nelander S, Palmberg C, Nilsson A: Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family. J Biol Chem. 2003, 278 (40): 38528-38536.View ArticlePubMedGoogle Scholar
- Stefan C, Jansen S, Bollen M: NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci. 2005, 30 (10): 542-550.View ArticlePubMedGoogle Scholar
- Hannun YA, Obeid LM: Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008, 9 (2): 139-150.View ArticlePubMedGoogle Scholar
- Wu J, Nilsson A, Jonsson BA, Stenstad H, Agace W, Cheng Y, Duan RD: Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. Biochem J. 2006, 394 (Pt 1): 299-308.View ArticlePubMedPubMed CentralGoogle Scholar
- Yost CC, Weyrich AS, Zimmerman GA: The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie. 2010, 92 (6): 692-697.View ArticlePubMedPubMed CentralGoogle Scholar
- Duan RD: Alkaline sphingomyelinase: an old enzyme with novel implications. Biochim Biophys Acta. 2006, 1761 (3): 281-291.View ArticlePubMedGoogle Scholar
- Zhang Y, Cheng Y, Hansen GH, Niels-Christiansen LL, Koentgen F, Ohlsson L, Nilsson A, Duan RD: Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice. J Lipid Res. 2011, 52 (4): 771-781.View ArticlePubMedPubMed CentralGoogle Scholar
- Nyberg L, Duan RD, Axelsson J, Nilsson Å: Identification of an alkaline sphingomyelinase activity in human bile. Biochim Biophys Acta. 1996, 1300: 42-48.View ArticlePubMedGoogle Scholar
- Duan RD, Nilsson Å: Purification of a newly identified alkaline sphingomyelinase in human bile and effects of bile salts and phosphatidylcholine on enzyme activity. Hepatology. 1997, 26: 823-830.View ArticlePubMedGoogle Scholar
- Cheng Y, Wu J, Hertervig E, Lindgren S, Duan D, Nilsson A, Duan RD: Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis. Br J Cancer. 2007, 97 (10): 1441-1448.View ArticlePubMedPubMed CentralGoogle Scholar
- Ohlsson L, Hertervig E, Jonsson BA, Duan RD, Nyberg L, Svernlov R, Nilsson A: Sphingolipids in human ileostomy content after meals containing milk sphingomyelin. Am J Clin Nutr. 2010, 91 (3): 672-678.View ArticlePubMedGoogle Scholar
- Nyberg L, Nilsson Å, Lundgren P, Duan RD: Localization and capacity of sphingomyelin digestion in the rat intestinal tract. J Nutr Biochem. 1997, 8: 112-118.View ArticleGoogle Scholar
- Nyberg L, Duan RD, Nilsson A: A mutual inhibitory effect on absorption of sphingomyelin and cholesterol. J Nutr Biochem. 2000, 11 (5): 244-249.View ArticlePubMedGoogle Scholar
- Hertervig E, Nilsson A, Nyberg L, Duan RD: Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma. Cancer. 1997, 79 (3): 448-453.View ArticlePubMedGoogle Scholar
- Sjöqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Lofberg R: Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity. Inflamm Bowel Dis. 2002, 8 (4): 258-263.View ArticlePubMedGoogle Scholar
- Hertervig E, Nilsson A, Bjork J, Hultkrantz R, Duan RD: Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?. Br J Cancer. 1999, 81 (2): 232-236.View ArticlePubMedPubMed CentralGoogle Scholar
- Hertervig E, Nilsson A, Cheng Y, Duan RD: Purified intestinal alkaline sphingomyelinase inhibits proliferation without inducing apoptosis in HT-29 colon carcinoma cells. J Cancer Res Clin Oncol. 2003, 129: 577-582.View ArticlePubMedGoogle Scholar
- Andersson D, Kotarsky K, Wu J, Agace W, Duan RD: Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model. Dig Dis Sci. 2009, 54 (7): 1440-1448.View ArticlePubMedGoogle Scholar
- Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, McCrea PD, Park JI: PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol Cell. 2013, 52 (2): 193-205.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu J, Cheng Y, Nilsson A, Duan RD: Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells. Carcinogenesis. 2004, 25 (8): 1327-1333.View ArticlePubMedGoogle Scholar
- Nilsson A, Duan RD: Absorption and lipoprotein transport of sphingomyelin. J Lipid Res. 2006, 47 (1): 154-171.View ArticlePubMedGoogle Scholar
- Svetlov SI, Howard KM, Debuysere MS, Olson MS: Secretory PAF-acetylhydrolase of the rat hepatobiliary system: characterization and partial purification. Am J Physiol. 1998, 274 (5 Pt 1): G891-G900.PubMedGoogle Scholar
- Zhou W, Chao W, Levine BA, Olson MS: Role of platelet-activating factor in hepatic responses after bile duct ligation in rats. Am J Physiol. 1992, 263 (5 Pt 1): G587-G592.PubMedGoogle Scholar
- Duan RD, Nilsson A: Sphingolipid hydrolyzing enzymes in the gastrointestinal tract. Methods Enzymol. 2000, 311: 276-286.View ArticlePubMedGoogle Scholar
- Duan RD, Nyberg L, Nilsson A: Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. Biochim Biophys Acta. 1995, 1259 (1): 49-55.View ArticlePubMedGoogle Scholar
- Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD: Cholangiocarcinoma. Lancet. 2005, 366 (9493): 1303-1314.View ArticlePubMedGoogle Scholar
- Reddy SB, Patel T: Current approaches to the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep. 2006, 8 (1): 30-37.View ArticlePubMedGoogle Scholar
- Boberg KM, Lind GE: Primary sclerosing cholangitis and malignancy. Best Pract Res Clin Gastroenterol. 2011, 25 (6): 753-764.View ArticlePubMedGoogle Scholar
- Kummen M, Schrumpf E, Boberg KM: Liver abnormalities in bowel diseases. Best Pract Res Clin Gastroenterol. 2013, 27 (4): 531-542.View ArticlePubMedGoogle Scholar
- Modrek B, Lee C: A genomic view of alternative splicing. Nat Genet. 2002, 30 (1): 13-19.View ArticlePubMedGoogle Scholar
- Venables JP: Aberrant and alternative splicing in cancer. Cancer Res. 2004, 64 (21): 7647-7654.View ArticlePubMedGoogle Scholar
- Wu J, Hansen GH, Nilsson A, Duan RD: Functional studies of human intestinal alkaline sphingomyelinase by deglycosylation and mutagenesis. Biochem J. 2005, 386 (Pt 1): 153-160.View ArticlePubMedPubMed CentralGoogle Scholar
- Hakomori S: Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci U S A. 2002, 99 (16): 10231-10233.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/14/138/prepub
Pre-publication history
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


text:
Biography History Documentary IRA Irish Americans Irish Immigrants Irish Mob Irish Folklore The Old Country Modern Ireland Boxing Bibliography
Irish Fail
his site was designed specifically for people outside of Ireland to find Irish themed films they can view now. Films made in Ireland and England can take years to 'cross the pond' and are only listed here when they become available. With a few exceptions, all the films listed here are available either on media or on demand.
A Little Bit O'Irish in Film
Copyright © 2001-2017 Boston Arts, Sciences & Technologies All rights reserved.Page by BAST


text:
EeePCLinuxOS: Custom PCLinuxOS build for Eee PC
I've never spent much time playing with PCLinuxOS, as it doesn't work very well on my primary computer. But EeePCLinuxOS looks pretty interesting. It's a custom version of EeePCLinuxOS designed for the Eee PC with a couple of tweaks that will improve its performance on the tiny laptop.
First off, EeePCLinuxOS is easy to install even if you don't have a CD/DVD drive plugged into your Eee PC. You install it by downloading a disc image to any computer, burning it to a disc and restarting that computer to boot into a LiveCD. Then you can quickly create a LiveUSB install by plugging in a USB flash drive. This should all be very familiar to anyone who's tired installing eeeXubuntu.
EeePCLinuxOS also helps keep the install size down through file compression.
- Login or register to post comments
- Printer-friendly version
- PDF version
More in Tux Machines
- Highlights
- Front Page
- Latest Headlines
- Archive
- Recent comments
- All-Time Popular Stories
- Hot Topics
- New Members
6 Reasons Your Favorite Linux OS Is Plagued by Bugs
| today's howtos
Linux and Linux Foundation
| Red Hat and Fedora


text:
Capreomycin is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of active tuberculosis (TB). TB is an opportunistic infection. An opportunistic infection is an infection that occurs more frequently or is more severe in people with weakened immune systems—such as those infected with HIV—than in people with healthy immune systems.
The Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA-HIVMA), include recommendations on the HIV-related use of capreomycin to treat active TB disease.
The above may not include all of the HIV-related uses of capreomycin recommended in the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Some recommended uses, such as uses in certain rare circumstances, may have been omitted.
Before taking capreomycin, tell your health care provider:
Ask your health care provider about possible side effects from capreomycin. Your health care provider will tell you what to do if you have side effects.
Take capreomycin according to your health care provider's instructions. Your health care provider will tell you how much capreomycin to take and when to take it. Before you start capreomycin and each time you get a refill, read any printed information that comes with your medicine.
More information about capreomycin is available:
Last Reviewed: September 14, 2015


text:
Note: This is a seattlepi.com reader blog. It is not written or edited by the P-I. The authors are solely responsible for content. E-mail us at firstname.lastname@example.com if you consider a post inappropriate.
Posts filtered on Tag
Tag: Dolph Lundgren
5 Reasons To See The Expendables 2
By Tim Hall on August 19, 2012 at 7:55 PM
The Expendables aka Action AARP aka The Medicare Mob aka The Elderly Assassins are back at the box office. After 2010's The Expendables earned a whopping $274 million worldwide, it was only a matter …


text:
- Subscribe to RSS Feed
- Mark Question as New
- Mark Question as Read
- Bookmark
- Follow this Q&A
- Email to a Friend
- Printer Friendly Page
- Report Inappropriate Content
- Mark as New
- Bookmark
- Subscribe
- Subscribe to RSS Feed
- Email to a Friend
- Report Inappropriate Content
Best products to control and hide oily skin, i am getting married next summer!
I have extremely oily skin, what are the best product to control and hide my oily skin? I am getting married next summer, i want to look perfect!!!!
- Mark as New
- Bookmark
- Subscribe
- Subscribe to RSS Feed
- Email to a Friend
- Report Inappropriate Content
[ Edited ]Sonya® is the essence of more than just beauty: it is an expression of rejuvenation, admiration and love. Our collection's formulation of ingredients including aloe vera, fruit extracts, white tea and superior moisturizers give back to your skin. They help to rejuvenate and moisturize your skin like never before.
The Sonya® Skin Care Collection contains five fundamental elements for cleansing, moisturizing, and maintaining overall skin condition and appearance. Aloe Purifying Cleanser, Aloe Refreshing Toner, Aloe Nourishing Serum, Aloe Balancing Cream, and Aloe Deep-Cleansing Exfoliator work together to leave your skin looking fresh and radiant. Indulge in this five-step process, and treat your skin to the luxury it deserves!
- Cleanse twice daily with Aloe Purifying Cleanser.
- Tone and freshen twice daily with Aloe Refreshing Toner.
- Apply Aloe Nourishing Serum twice daily.
- Apply Aloe Balancing Cream twice daily.
- Exfoliate approximately 2 times weekly with Aloe Deep-Cleansing Exfoliator.
The Sonya® Aloe Skin Care Kit includes:
- Aloe Purifying Cleanser
- Aloe Refreshing Toner
- Aloe Nourishing Serum
- Aloe Balancing Cream
- Aloe Deep-Cleansing Exfoliator
- (Products also sold separately.)


text:
Invalid e-mail address. Invalid Password.
Here you will find sample augmentative-alternative communication evaluation reports / funding requests. These reports may provide assistance for your own report writing. However, it is strongly advised that you check the guide lines for funding with each insurance company you are submitting funding requests to. The device manufacturer's funding department is the best resource for ensuring your report and funding packet will contain the most up to date requirements. Speech Generating Device (SGD) funding requests must be submitted by a qualified speech-language pathologist (who is licensed and certified by the American Speech and Hearing Association) and must be accompanied by a complete funding packet including but not limited to: a physician's prescription for the SGD, copies of ALL the client's insurance cards (front and back), a current list of medications, client information form, assignment of medical benefits form, client bill of rights, written concurrence from school if client is a student in the public schools, statement of non-conflict of interest. All of these forms can be obtained through the funding department of the device manufacturer (check the manufacturer's website). Funding packets must be submitted to the funding department of the device manufacturer and it will be submitted to the insurance company via the device manufacturer.
Here you will find a sample adult AAC evaluation report/funding request for a client with a diagnosis of Cerebral Palsy. This report is based on an actual report that resulted in Medicaid funding for the purchase of the recommended voice output devic... read full details
Here you will find a sample adult AAC evaluation report/funding request for a client with a diagnosis of Amyotrophic lateral sclerosis (ALS), for the purchase of the recommended voice output device. This report may provide assistance for your own rep... read full details


text:
« Local Home |
Bonin Boarding & Dog Training
Get Driving Directions
Save to Your Address Book
Nearby Listings:
- A Pampered Pet
1.5 miles - Pet Stop
1.8 miles - William C Mayer Dvm
4.5 miles - Willow Oaks Farm
1.9 miles
Do you go to this place?
» Save listing» Add a review
Sniffing for more?
See other:» Groomers & Spas» See all Duson listings
» See all LA listings
Attributes [ add attributes ]
Description [ add a description ]
No reviews yet. Be the first to review this listing!


text:
Standard & Poor's reported on April 29 that LandSource Communities Development is expected to file for bankruptcy protection within the next two to three weeks.
The ratings agency was told of the impending filing by the group's lenders following a private call, said analysts Abby Latour and Kerry Kantin in their report.
"A depletion of cash will likely prompt the filing next month," Latour and Kantin wrote. "The company's cash pile has dwindled to roughly $25 million, from about $115 million in early February."
By filing for protection from creditors in bankruptcy court, the company could preserve its remaining cash and start arranging to sell assets, sources told S&P.
LandSource's spokesperson could not immediately be reached for comment.
Last week, LandSource, a California-based land development company owned by MW Housing Partners, Lennar Corp., and LNR Properties, received a notice of default on its loan agreements.
Just over a year ago, LandSource took out $1.3 billion in loans arranged by Barclays to buy 68% of the company from Lennar and LNR, which each retained 16% interest. The first lien on the company for $1 billion is in default.
The notice came after LandSource missed a deadline to re-margin the deal made necessary because the land had lost value in the plummeting home building market.
Despite the notice, discussions on how to restructure the total of $1.3 billion in debt so the company can make the payments in the current market continued, Tamara Taylor, a LandSource spokesperson, said at the time.
S&P reported that there has been little communication between the company's sponsors and lenders recently, "raising the ire of lenders, who delivered a default notice after the most recent forbearance agreement expired on April 16."
The California Public Employees Retirement System (CalPERS), which is part of MW Partners, said it was not willing to move forward with a credit-enhancement package for LandSource that included a $550 million commitment over three years, according to S&P.
"Lenders heard in an April 15 call that CalPERS's view is that the terms are no longer tenable," Latour and Kantin wrote.
Just last year, Lennar was lauded as masterful for finding a way pull cash out of land while still retaining rights to use it later when it sold off the lion's share of LandSource. Lennar and LNR Property each received about $700 million for selling off 68% of LandSource to MW Housing Partners, an entity co-managed by McFarlane Partners on behalf of CalPERS, and Weyerhaeuser.
MW Housing got 50% of the voting rights, while Lennar and LNR retained 16% ownership each and a combined 50% of the voting rights. Lennar also maintained access to the land for future construction and, in the meantime, would be paid "significant" management fees.
The deal was heralded as a perfect partnership. CalPERS is a long-term investor, valued for its patience in receiving returns. And it fit with Lennar's ongoing strategy to move more land--and its costs and risks--off its home building books.
At the time of the deal, LandSource's properties had a book value of about $1.3 billion. To fund the sale, $1.55 billion in debt was taken on the assumption that the land had more than doubled in value during the three years since LandSource's biggest asset, Newhall Land And Farming Co.'s 15,000 acres of mixed-use property 30 miles north of Los Angeles County, was bought.
LandSource's debt is labeled non-recourse, which is said to insulate Lennar and LNR from repercussions; but if the land ends up for sale in bankruptcy court, Lennar could lose access to the lots--one of the advantages it touted when announcing the sale last year.
Pali Capital analyst Stephen East suggested in a research note there is a possibility that the LandSource partners could be sued under "Bad Boy" clauses, claiming misrepresentations were made, since the deal deteriorated so rapidly.
"The bigger question for LEN is what remains for all the other JV's sitting out there," East wrote. "LandSource is one of the largest and most visible, but it could well be a harbinger of things to come. The cash burn so readily apparent in this JV is likely not unique."
If the bankruptcy occurs and the banks come out as well or better than they would have by renegotiating the loan, "We believe it would encourage a stiffer spine at the banks in future negotiations--signaling tougher times ahead for LEN and all other aggressive users of JV's," East wrote.
Learn more about markets featured in this article: Los Angeles, CA.


text:
Hmm, witch one to get?
Archive for the 'Uncategorized' Category
Rumor: Apple will launch 4.7-inch iPhone 6 in Sep, but 5.5-inch model later in the year
Wednesday, April 9th, 2014The top 10 high quality, low-cost used cars through mechanics' eyes | Motoramic – Yahoo Autos
Sunday, March 30th, 2014The top 10 high quality, low-cost used cars through mechanics' eyes | Motoramic – Yahoo Autos.
I'm glad that my favorite sports car is in the list, also its the only sports car. So does that say something about the car.
Hmm, Microsoft port Office to Apple's iOS iPad!
Saturday, March 29th, 2014Why did Microsoft port Office to Apple's iOS iPad before Android?.
Got to read to see why Microsoft changed direction with Apple.
This is the room where the iPhone was born
Wednesday, March 26th, 2014This is so cool to see!
Opinion: Why the upgrade cycle means the 'Apple tax' is lower than it seems
Friday, March 21st, 2014This is why I switched 3 years ago and haven't looked back!
Who would have guessed? Apple reportedly the most valuable Silicon Valley brand
Thursday, March 20th, 2014This is interesting when it's said that Apple is no longer innovative.
Eddy Cue throws a pen at Haunted Empire/Yukari Kane's accuracy, says story isn't true
Thursday, March 20th, 2014Glad it wasn't true.
iOS 8: Apple works to further push iCloud as the future of the file system
Thursday, March 20th, 2014I'm looking forward to this happening when it does.


text:
Hotel Best Western City Centre
- Terms and facilities
- Useful information
- Location
- Opinions
With a stay at Best Western Plus City Centre/Centre-Ville, you'll be centrally located in Quebec, steps from Church of St. Roch and minutes from Le Lieu. This eco-friendly hotel is close to Citadelle of Quebec and Place Royale. Don't miss out on the many recreational opportunities, including a health club, an indoor pool, and a spa tub. Additional amenities include complimentary wireless Internet access, concierge services, and complimentary use of a nearby fitness facility. Featured amenities include a computer station, express check-out, and complimentary newspapers in the lobby. Make yourself at home in one of the 177 air-conditioned rooms featuring refrigerators and iPod docking stations. Your room comes with a memory foam bed. 40-inch flat-screen televisions with cable programming provide entertainment, while complimentary wireless Internet access keeps you connected. Bathrooms have complimentary toiletries and hair dryers.
Choose your room
Share it
Score based on 1 reviews
Average price per night for this hotel for the following weeks
29/03/2017 - 2/04/2017 | 3/04/2017 - 9/04/2017 | 10/04/2017 - 16/04/2017 | 17/04/2017 - 23/04/2017 |
$61 |
Services and terms: Hotel Best Western City Centre
Standard Room Services
- Air Conditioning
- Safe
- Hairdryer
- Television
Accommodation facilities
- Lift
- Bar/Café
- Business Centre
- Meetings Room
- Laundry
- People with reduced mobility access
- Non-smoker Rooms
- Parking
- Restaurant
- 24 hr Room Service
Leisure facilities
- Gym
- Massage
- Swimming Pool
Useful information: Hotel Best Western City Centre
Other names for Hotel Best Western City Centre:
Best Western City Centre Quebec Quebec City Qc Best Western Plus Centre Ville Quebec
Bw Plus Centreville