text:
800 University WaySpartanburg, SC 293031-864-503-5000
Griffin EubanksTeam: Men's Cross Country
Emily Koelling - 18Team: Volleyball
2016 speaker biographies coming soon!
2015 Speaker Biographies
Robert Block, M.D., Professor Emeritus,University of Oklahoma and Past President of the American Academy of PediatricsDr. Robert Block is an emeritus professor of pediatrics
and immediate past Daniel C. Plunket Chair of the Department of Pediatrics at the
University of Oklahoma School of Community Medicine in Tulsa. He was elected by the membership of
the American Academy of Pediatrics (AAP) as
president-elect in October 2010 and served as president from October 2011
through October 2012.Dr. Block received
his doctor of medicine degree from the University of
Pennsylvania and completed his
pediatric residency at the Children's Hospital of Philadelphia.
He has been a member of the O.U.
College of Medicine
faculty since 1975. As a faculty member, Dr. Block has been nominated for the
Aesculapian teaching award six times, winning on three occasions. Dr. Block has
been awarded the prestigious Stanton L. Young Master Teacher Award, a University of Oklahoma Presidential Professorship,
the Accreditation Council for Graduate Medical Education Parker J. Palmer
"Courage to Teach" Award, the Ray Helfer Society Award in recognition of his
work in the field of Child Abuse and the Award for Outstanding Service to
Maltreated Children by the American Academy of Pediatrics. In October, 2013 he
was inducted into the Tulsa, Oklahoma Hall of Fame. He was appointed the first Chair of the newly formed sub-board on Child
Abuse Pediatrics by the American Board of Pediatrics (ABP) from 2006-2009 and
continued to serve on the sub-board through 2012. He holds Certificate #1 from the ABP in Child
Abuse Pediatrics.Dr. Block is a
diplomate of the American Board of Pediatrics, a Fellow of the American Academy of Pediatrics, a past
president of the Oklahoma AAP Chapter and a former member and chair of the
Academy's Committee on Child Abuse and Neglect. He is a former member and chair
of the United States' Advisory
Commission on Childhood Vaccines. Dr.
Block is the immediate past president and current board chair of the Academy on
Violence and Abuse (AVA), the relatively new national organization focused on
increasing health care professionals' education and academic research on the
health effects of violence and abuse.Dr. Block was
appointed Oklahoma's first chief child
abuse examiner in 1989 and served in
that capacity until October 2011. He was a past Chair and member of the
Oklahoma Child Death Review Board from 1992 through September 2011. He has
been a member of the medical team for the Tulsa Children's Justice Center and served as a past
president and member of the board of directors for the Child Abuse Network,
Inc. He is now an Emeritus
Director. Dr. Block has authored several
papers and a textbook and has delivered over 2,000 public presentations. Dr. Block is married to Sharon Block, a
retired science teacher and registered nurse. They have two married daughters, Erika Mays
and Andrea Wooldridge, and two wonderful grandchildren.
Return to top
Daniel Garrabrant, Special Agent, Federal Bureau of Investigation
In 1989 Special Agent
Daniel A. Garrabrant graduated from the University
of Delaware with a Bachelor of Science in
criminal justice, a Bachelor of Arts in psychology and an associate degree in sociology. SA
Garrabrant worked as a mental health
worker in adolescent treatment facilities from 1985 until 1990. Special Agent Garrabrant
was employed as a police officer with the New Castle County Police, New Castle
Delaware from 1990 to 1997. Special Agent Garrabrant was hired as an agent with the Federal Bureau of Investigation in
1997. In addition to Special Agent Garrabrant's
investigative duties as an agent, he also has the following duties:
Currently assigned to the Newark Division's
Atlantic City Resident Agency:
AppointmentsAppointed to the New Jersey Commission on
Human Trafficking by Gov. Chris Christie March 2014 to March 2016
Nancy Henderson, M.D. Dr. Henderson serves as the medical director of the Division of Forensic Pediatrics at Greenville Hospital System. She graduated from Bowman Gray School of Medicine and did her pediatric residency at TC Thompson Children's Hospital in Chattanooga, Tenn. She is board certified in Pediatrics and Child Abuse Pediatrics. She spends many of her days addressing one of the most difficult issues facing children: child abuse. For a decade, this pediatrician has performed child abuse medical exams at the Children's Advocacy Center. She has the skills, patience, warmth and compassion to calm an anxious child, while gathering facts and medical evidence without further traumatizing the child. Just as importantly, she serves as an expert witness in Family and Criminal Court. Her testimony is often instrumental in the prosecution of child molesters.
Anna Salter, Ph.D., Consultant, Wisconsin Department of Corrections
Anna Salter, Ph.D., received her Ph.D., in
Clinical Psychology and Public Practice from Harvard University and obtained a
masters degree in Child Study from Tufts. She was a Teaching Fellow at both
Salter has lived in Madison, Wisc., since 1996 and
consults half time to the Wisconsin Department of Corrections. In addition, she
lectures and consults on sex offenders and victims throughout the United States
and abroad. She has keynoted conferences on sexual abuse in Australia, New
Zealand, Scotland and England. In all, she has conducted trainings in 50 states
and 10 countries. Salter also evaluates sex offenders for civil commitment
proceedings and other purposes. She testifies as an expert witness in sexual
abuse civil and criminal cases.
Before moving to Madison, Salter was on the faculty of
Dartmouth Medical School in Lebanon, N.H., in the Departments of
Psychiatry and Maternal and Child Health. While there, she was director of
Psycho-social Training for the Pediatric Residency Program, director of Child
Psychiatry Consultation to the Pediatric Ward, co-director of the Parenting
Clinic, assistant director of the Children-at-Risk Program and director of the
Parents in Distress Program.
Salter is the 1997 winner of the Significant Achievement Award
from the Association for the Treatment of Sexual Abusers, and she also won
the Saul Blatman Teaching Award in the Department of Pediatrics and Maternal
and Child Health. She is the author of several nonfiction books, as well
as fiction novels.
Sergeant Jim SearsIrving
Police Department – Domestic Violence and Child Abuse Units
Jim Sears has been a law enforcement officer for over 30 years working with the
Irving Police Department. He has served
as a patrol officer, school resource officer and as a detective in the youth
services unit, domestic violence unit and child abuse unit. Sergeant Sears has worked as a detective in the
child abuse unit for 10 years before being promoted to sergeant. He has worked the past five years as the
supervisor for the domestic violence, child abuse and youth service units at
the Irving Family Advocacy Center.
dedicated advocate of children, he currently serves as a law enforcement
consultant and instructor with the Shaken Baby Alliance for the Serious
Physical Child Abuse and SIDS Program, as a partner
agency contact with the Dallas Children's Advocacy Center, as a T.C.O.L.E.
instructor specializing in domestic violence and child abuse, as an instructor at the
Crimes Against Children's Conference in Dallas, is a certified instructor for advanced child abuse investigations through Texas Municipal Police Association
(TMPA), is on the design team for the new Fox Valley / OJJDP national training
project for child abuse as one of their instructors and is an instructor for the
Gundersen National Child Protection Training Center. Sergeant Sears is the 2011 recipient of the Lieutenant Bill
Walsh Award for the Dallas Children's Advocacy Center for career achievements
in the field of child abuse investigations. Sergeant Sears frequently lectures on topics related to child abuse
investigations, interviews and interrogations and crime scene investigations for
domestic violence and child abuse. A
father of three wonderful boys, Sergeant Sears is dedicated to bringing justice to
the victims of domestic violence and child abuse.
Return to the top
Victor Vieth, J.D.
Victor Vieth, J.D., serves as the Executive Director Emeritus of the National Child Protection Training Center (NCPTC), a program of Gundersen Health system. It is a state-of-the-art training complex located on the campus of Winona State University (WSU). NCPTC includes five moot court rooms, four forensic interview rooms and a "mock house" in which to conduct simulated child abuse investigations. NCPTC staff provides intensive instruction for undergraduate students and current professionals in the field on how to better recognize, react and respond to children who are being abused. The Center trains approximately 15,000 child protection professionals each year. Mr. Vieth has trained thousands of child-protection professionals from all 50 states, two U.S. territories and 17 countries on numerous topics pertaining to child abuse investigations, prosecutions and prevention. He gained national recognition for his work in addressing child abuse in small communities as a prosecutor in rural Minnesota. He has been named to the President's Honor Roll of the American Professional Society on the Abuse of Children, and the Young Lawyers Division of the American Bar Association named him one of the "21 Young Lawyers Leading us Into the 21st Century." Mr. Vieth has been instrumental in implementing 22 state and international forensic interview training programs and dozens of undergraduate and graduate programs on child maltreatment. Vieth has published countless articles related to the investigation, prosecution and prevention of child abuse and neglect. He is author of Unto the Third Generation, a bold initiative that outlines the necessary steps we must all take to eliminate child abuse in America in three generations. Mr.Vieth graduated magna cum laude from WSU and earned his Juris Doctor from Hamline University School of Law (HUSL). While studying at HUSL, he received the American Jurisprudence award for achievement in the study of constitutional law and served as editor-in chief of the Law Review. For more information about the National Child Protection Training Center (NCPTC), visit www.ncptc.org.
Mark your calendar!
March 25, 2016
Conference LocationUniversity Readiness CenterUSC Upstate
Pre-Conference WorkshopsMarch 24, 2016
Contact InformationDr. Jennifer ParkerProgram firstname.lastname@example.com
Ms. Shawn MastoProgram firstname.lastname@example.com
The University of South Carolina Upstate is accredited by the Southern Association of Colleges and Schools Commission on Colleges to award baccalaureate and masters degrees. Contact the Commission on Colleges at 1866 Southern Lane, Decatur, Georgia, 30033 or call 404-679-4500 for questions about the accreditation of USC Upstate. Comments or Complaints?


text:
Your name:
Eddy Webb
Location: St.
Louis, MO
Age: 31
Sex: Male
Family: I
am married to a lovely woman (also a gamer) named Michelle, and we have
a roommate named David that lives with us. My mother lives in Avon, OH
with my stepfather. I have no siblings, but a half-sister and two
half-brothers that I rarely see.
party/affiliation: Independent with Democratic leanings.
Pets: We have two cats -- a gray cat named Greebo and an
orange cat named Claudius. We also have a hyperactive pug dog named
Puck (after the Shakespearean character, not the Marvel superhero).
I graduated high school from Admiral King High School (now Lorain
Admiral King) in Lorain, OH in 1993. Although I learned about gaming in
elementary, high school is when my gaming really took off (and, of
course, when I had to deal with the most confusion and conflict
regarding my hobby). I went to college at the University of Akron for
one year, before moving to Lorain County Community College and starting
the gaming group there. I am now taking the occasional class at
Washington University in St. Louis, changing my major from Television
Production to English Literature.
Reading (lots of genres, but mostly fiction), writing fiction and RPGs,
professional wrestling, working out (we have a personal trainer that
comes twice a week to our home), watching television, traveling.
service: I've worked at some animal rescues places in
Louis. I've also donated my time and efforts to a variety of charities
the Camarilla (White Wolf's official fan club), helping to raise money
charity auctions or public service when I am able.
Just to
test the stereotype - Have you ever lived, or are you currently living,
in your parents' basement? No. My parents lived in an
older house, with a dirt basement that I was only barely able to stand
up in. If I were forced to live in the basement, I'm fairly sure it
would violate some public health laws. Actually, I lived on my own as
soon as I went to college (the first time) and haven't lived with my
parents since.
Which of
your accomplishments are you the most happy with?
Originally, it was simply becoming a publisher writer, but since that
time I think my two favorite accomplishments have to be writing my own
RPG pretty much from the ground up (Midway City)
and being nominated for an industry award (Origins Award, Best RPG of
the Year 2003).
What is
your favorite time of year, and why? The fall. I
dislike the summer because it's often too hot, and I dislike the winter
because it's often too cold, but I like being able to wear a light
jacket, watching the trees change color, and enjoying all of the food
that fall brings (like pumpkin pie and roast turkey).
Did you
have any embarrassing nicknames as a kid? Given that my
last name is Webb, I got an endless supply of Spider-Man-based
nicknames as a child: Webhead, Webby, Spidey and the like. For a while
I actually hated Spider-Man as a result, but eventually I got past
that. However, those nicknames still drive me up a wall.
What did
you want to be when you grew up? It sounds cliche, but I
always wanted to be a writer. Even when I was 10 I joined a "Young
Authors" program and wrote my own book for public display. I tried to
direct my passion into other (more salable) areas over the course of my
life, but my first love has always been writing, and it's sad that it
took me over 15 years to finally just do what I love.
If you
could pick any other time period to live in, which would it be, and
why? The mid-to-late 1800s. Both in American and in
England, I am in love with that time period, and cannot read enough
fiction and non-fiction books based in or detailing that era. A close
second is the time period between Prohibition and World War II in
Tell us
about your favorite RPG character that you've ever played.
I actually
don't often have characters that I continue to talk about long after
they're gone,
but there is one that still holds fondness for me, a Brujah Anarch
Watanabe Takashi that I played in Mind's Eye Theatre:
Masquerade (2nd edition
to the end of the first WoD line). He was half-Japanese,
half-Caucasian, and
just a loud-mouthed bastard. Before then I was actually quite a shy
and uncomfortable with speaking in groups or being mean to people, but
playing Taki really helped me realize that not only did I have
something to say,
but that other people would listen to me. The character was incredibly
fun as I
played him for about four years, but as I played him I constantly
learned more
about myself as well.
What are your favorite RPGs? I primarily play the Mind's
Eye Theatre line of Live-Action games. Beyond that, I have a number of
favorite RPGs: Exalted, D&D 3rd edition,
Deadlands, Cyberpunk 220.127.116.11., Star
Wars D6, Over The Edge, FUDGE, the PDQ system, the Marvel
Super Heroes RPG, Mutants & Masterminds,
Top Secret S.I., and a variety of others.
What was
your first RPG session like? My first RPG session was
done using the "red box"
version of Dungeons & Dragons. I was the
DM. It was terrible -- we had no idea what we were doing, and
completely messed up the rules. However, the possibilities were
fantastic, and I was instantly hooked.
What was
your WORST RPG session like? Playing in an RPGA
tournament round in the late 80s. It was my first experience with
playing a pregenerated characters, and the players were so obsessed
with scoring points to progress rather than enjoying the game that I
eventually just sat there, rolling dice, until the event was over. I
haven't played a roleplaying game competitively since.
Who is
your all-time favorite person to game with? My wife,
Michelle. Partially because she's my wife and I love doing things that
involve her, but also because her gaming style is so compatible with my
own. We've been gaming together for almost eight years now, so we're
very comfortable with each other as players. We even briefly played
antagonists against each other.
Do you
have anything gaming-related to plug? I've been blessed
with the opportunity to write the Mind's Eye Theatre version of Mage:
The Awakening for White Wolf, due out next summer. That's where a lot
of my time is dedicated, and I hope that live-action players will find
the product to be a worthwhile addition to the line.
- Main
- FAQs - Blog
- Forum
- Wiki - Features
- Projects
- Resources
- Support
- Contact

subset: commoncrawl


text:
Health Industry Proves Effective, but Proper Care Still Evades Many
Watkins, Robert, THE JOURNAL RECORD
By several measurements, the answer appears to be yes, despite clear knowledge that health care still lies beyond the reach of thousands. Improving the so-called safety net to catch the unemployed and low income people whose resources exceed the eligibility requirements for Medicaid assistance is seen by some observers as a critical step toward a healthier environment.
Whether action is near on this controversial front hinges largely on the outcome of a major study here by the state's Council of Health Care Delivery as well as congressional debate on legislation intended to shore up the system. Although some members of Congress favor a move to mandate health care insurance coverage by the largest employers, and offer government-backed coverage to the unemployed, the safety net gap is likely to remain untouched until a new administration moves into the White House.
Certain recommendations are expected from the state council in the fall, and the Legislature may be asked to intervene long before the federal government gets around to dealing with the issue. It is, however, a national issue.
More than 37 million people are believed to be without health care coverage. In Oklahoma, the evidence indicates that at least a quarter of the state's population is without coverage.
Hospitals here and elsewhere accept a certain level of non-paying, or charity, patients, a practice that partially eases the burden for the uninsured.
Records show, however, that fewer and fewer people re going to Oklahoma's hospitals for treatment. Over the last several years, the number of patient days has dropped by 23 percent, and the number of occupied beds has fallen even more dramatically - from 61 percent in 1982 to 46 percent in 1986, according to state officials. The state has 130 acute care hospitals.
Through much of the same period, the supply of physicians rapidly outpaced population growth. Between 1975 and 1980, the state's population rose by 11.4 percent. At the same time, the number of doctors - MDs as well as osteopathic physicians - increased 27.3 percent.
While there are obvious benefits, health care experts say, the growth in the supply of doctors does affect spending levels. But those who measure health manpower levels now expect the rapid rise to stop and possibly decelerate in the next decade, a trend that would ensure lower inflationary pressures.
The supply of dentists, which are also part of the health care equation, has risen from 42.8 per 100,000 of population to 46.6 dentists per 100,000.
The principal problem, however, is maldistribution among both dentists and physicians - large numbers concentrated in urban areas, too few in rural counties. Moreover, the state suffers from a shortage of nursing personnel. Enrollments in baccalaureate nursing degree programs have declined in recent years.
Structural changes notwithstanding, there are signs that important public health gains are being made in Oklahoma.
Fewer births are being recorded, but the rate of infant mortality, watched carefully by health authorities around the world as a reliable barometer of society's general health, has begun to show improvement here. …


text:
The remote Livingstonia Mountains are situated in Southern Tanzania, Africa. They form part of the great African Rift Valley, home to the plains of the Serengeti and the great lakes of Tanganyika and Malawi. Amongst this natural landscape lies one of the oldest organic tea estates in the world, Luponde. At an altitude of 7,000 ft. the plants grow slowly to produce a range of full flavored, organic, Fair Trade teas. The leaves are carefully handpicked to deliver to customers the perfect cup of tea.
Number of Members:
Annual Production:
Production Unit:
United Republic of Tanzania
Geo Location:


text:
Coastal Scents 88 eyeshadow palette
357 reviews
66% would repurchase
Package Quality: 3.2
Price: $$
Package Quality: 3.2
Price: $$
INGREDIENTSTalc, Mica, Mineral Oil, Kaolin, Titanium Dioxide, Magnesium Stearate, Isopropyl Palmitate, Lanolin, Methylparaben, Propylparaben, BHT. May contain: Mica and Titanium Dioxide, Iron Oxides, Ultramarine Blue, Manganese Violet, Ferric Ammonium Ferrocyanide, Chrome Oxide Greens, Chrome Hydroxide Green, FD&C Red No.40 Al Lake, FD&C Yellow No.5 Al Lake, FD&C Blue No.1 Al Lake.
Age: 18 & Under
Skin: Combination, Medium, Not Sure
Hair: Black, Straight, Fine
Eyes: Black
Pigmentation - soft eyeshadows, but not great on my medium/tan skin
Price - they aren't actually that cheap in my opinion, considering the quality. their pigmentation is like $2 shop shadows, and several of those combined make up the quantity of one of these shadows. so it's not exactly an unheard of bargain
But sure there's a lot in quantity, it's probably an okay set for a teen or someone new to makeup, like myself (but lighter skinned) and that's willing to use eyeshadow base which I haven't used yet but will do, hoping it will improve the pigmentation?
Anyway, referring to the top few reviews and really bad reviews, perhaps they're thinking it's a rip off because everything is cheap in the US but I still don't think it's that terrible for $30 is it? I think some people may need to get off their pretentious high makeup horses. (Sorry didn't meant to offend any one) It's seriously at least 2 stars I think. And I got mine off the wholesalers on ebay :) For really cheap too, I got the like 128 colour one for like $10, and you may be wondering why I'm still rating it so low, well the MATTE colours, my god, were SO chalky and not pigmented AT ALL. EVEN with the swipe of my FINGER. They were so difficult to get out.
Age: 36-43
Skin: Combination, Fair, Cool
Hair: Brown, Wavy, Fine
Eyes: Brown
Most of the shadows/blushes, in any of type of these named/numbered finished palettes, are nicely pigmented.
Though, I find that if you don't flick off your brush and use a base, you will get more than average fallout.
So I recommend that you do your foundation last..... with any of these various named/numbered palettes.
Each one are great and have a variety of colors you can play with.
@Everyone: Please save your hard earned $ and just buy all the Coastal Scents, Bh Cosmetics, etc...etc...Palettes off of EBAY!!
They really ARE the SAME thing/colors!
Its just that they switch up the pans in different places sometimes!
I know some say that some are pigmented than other brands. But no they are not really!
Its just that some palettes are FRESHER therefore they will give you BETTER PAYOFF.
You can buy any variety for around $10.00 each on EBAY!
I actually bought the 10 Blush, Neutral, Concealer, Camouflage Palettes for under $8.00 each.... on EBAY!! Really!
Now I am a big believer for supporting American businesses. But we all now know where they get their stuff from....so I feel perfectly fine buying from overseas. ;)
Age: 19-24
Skin: Combination, Medium, Warm
Hair: Black, Straight, Fine
Eyes: Brown
Although I think this is a decent product, I don't think I'd buy this again because I don't find myself using it as much as I thought I would.
I absolutely love the colour selection, as most people do, but it can seem a bit overwhelming. This is because there are a lot of colours that I wouldn't use very often (yellow, orange, green, etc) that I tend to forget about this palette. Another reason is because sometimes the little eyeshadow pans become unglued and can shatter all over the other colours.
Overall, I think the shadows are great, but if you are someone that likes to use the same colours all the time, I think you'd be better off buying the palette that suits you best (88 warm, 88 shimmer, etc).
Age: 18 & Under
Skin: Combination, Fair-Medium, Neutral
Hair: Brunette, Straight, Fine
Eyes: Brown
I liked it, but not enough to repurchase it. Let me start out by saying that the eyeshadows DO fall out consistently, and I'd be a mess without my clear nailpolish to repair. But some of the eyeshadows (mainly the neutral ones) are very good quality and can be used on a regular basis. I personally think this is a great palette for the makeup newbie who is looking for a great way to expand their collection within a good price range. On the other hand, if you have a bigger collection (without a need for travel shadows) I would stick to the higher end products. But at the same time, I don't want to be so harsh, considering you are paying a few cents per eyeshadow.
Age: 30-35
Skin: Dry, Fair, Neutral
Hair: Brunette, Curly, Fine
Eyes: Green
I love this pallet, but let�s be honest for about 20.00 for 88 eye shadows they are not all going to be winners. Although I do feel that most of the shadows are pigmented, with little to no fall out, some are crap. But I also feel that way about a lot of pallets even the high end ones.
The only real downside is you must use a primer with this pallet but I feel like that is a give with any eye shadow high end or drug store. And the packaging is meh, not the worst but defiantly not anything great.
This is great pallet for anyone who needs/wants a lot of colors but doesn�t want spend a lot.
Edit. The more and more I wear this pallet the more shades I find are either not milled to my liking or fade badly. I am removing another lippie for this reason.
Age: 25-29
Skin: Normal, Dark, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I don't understand how this product recieves so many great reviews. For me the product was hardly visible on my lids. I tried using a variety of primers from UD, Too Faced, and MAC; however, that didn't help to intensive the colors. Yes, the colors are beautiful in the palette, but once it's applied to the lids its very subtle.
Also, it is chalky. If you read the ingredients of this product, research where it is made (China), and do a little research about the company, you should have a great idea why you should stay away from it.
Age: 19-24
Skin: Oily, Medium, Not Sure
Hair: Brunette, Other, Other
Eyes: Blue
This palette is awesome!! It's so cheap for all the colors you get but the quality is great!! All the colors are so pigmented and easy to work with. I am not a professional, but I am known by my family, friends, and community for the makeup I do. I'm always being called upon to do girls make up for pictures, dances, proms, weddings, etc. So I am in a way a make up artist and I have a lot of make up but I am no where near where I'd like to be. Make up is expensive and I don't have the funds to buy all the stuff and all the colors I want! So this palette is awesome!! It has all the colors I need and more for any type of look I want to do! I love it! Surprsingly, for how small the differnet shadows are they take a while to use up, because they are so pigmented and you don't need a ton to get the desired effect. Some colrs in the shimmer palette are more matte, but its not bad at all! I love these palettes!!
Age: 19-24
Skin: Oily, Tan, Warm
Hair: Brown, Other, Other
Eyes: Green
This Palette is Great! For a few years now I've been eyeing this, but I never got the chance to sit down in front of the computer to buy it hhaha. When I finally got it, I was surprised to see the palette wasn't too big. It was smaller than the size of a magazine. This is great for traveling since it's flat, lightweight, and has almost all the colors you would need for any occasion! This is a must have! It's pigments are great, and there are so many colors! I find myself not buying anymore eye shadows because all I need is in my cs palette. I highly recommend anyone getting this, and even if you don't find it as useful, 20 bucks isn't so bad. And as for amount of eyeshadow contained in this palette...there are so many colors to use I hardly find myself using just one, so I think it would be hard to run out.
Age: 25-29
Skin: Dry, Medium, Not Sure
Hair: Red, Other, Other
Eyes: Brown
I bought this palette in the set that has all 4 palettes together and all I have to say is this product is absolutely worth every cent. Quality is great. PIgmentation is excellent. Not a lot of fall out and best of all, there is so much colors to choose from. there are infinite possiblities to all the looks you can create with palette. I definitely recommend.
Age: 18 & Under
Skin: Other, Other, Not Sure
Hair: Other, Other, Other
Eyes: Other
(This is for the 88 Shimmer Palette). This palette is nice for the # of colors you get for the price. Some of the colors are very pigmented and smooth, and others are just a nasty, chunky glittery mess. The downside is that the pans are so tiny. If there is one color you really like and use often, it probably won't last very long because the pans are so darn small. Another problem I have is that the pans are so close together, and sometimes the eyeshadows crumble a bit when using them..then the colors all get into the other colors, and you end up with powder everywhere.
When I recieved mine in the mail from coastal scents, one of the eyeshadow pans had popped out of its place but didn't break. I figured, no big deal, I'll just glue it back. I've had it for maybe 6 months, I don't bang the palette around a lot or anything, but many of the pans have popped out of place.
Overall, its good especially if you are just starting to get into makeup, or if you want a lot of colors to experiment with but don't want to spend a ton. (If you are hesitant about buying it, there are a lot of big palettes like this on eBay for cheaper).
Popular Palettes
46 Reviews
104 Reviews
2278 Reviews
204 Reviews
34 Reviews
109 Reviews


text:
When Austin-based FÖDA Studio was approached to rename a construction company and develop its identity, it used the hands of the crew to drive the concept. The battered hands are the story; they are how jobs get done. In contrast is a custom stencil and a dapper name, Burnish&Plumb. The work-a-day identity is a contrast between two ideas that mirror the distance between the from-scratch nature of the construction process and the actual finished product. From dirty hands come fine finishes. Under damaged boots lie spotless floors. Through weathered tools come burnished fittings.
Dale Wallain/Jett Butler, design team;
Jett Butler, creative director;
Matt Williamson, developer;
FÖDA Studio, photographer.


text:
ADobe DNG Converter Growing in size
Started Oct 4, 2012 | Discussions thread
Shop cameras & lenses ▾
Senior Member • Posts: 1,318
ADobe DNG Converter Growing in size
Oct 4, 2012
I had just seen the news about the latest versions of LR4 and ACR, and went to the Adobe site to check it out, and noticed the that the Adobe DNG Converter has grown in size by 12MB since the last version. Now new cameras are being released all the time, and the data has has to be included to cater for these new cameras, but the size seems to getting quite large at over 100MB.
In 2005 the DNG Converter started out at 3.1MB. but if the number of cameras supported is directly related to the size of the program, then at one point will it get too large? And would Adobe maybe start dropping support for some camera RAW files to keep the size of the program down?
Reply to thread Reply with quote Complain
|Post ()
|Posted by
|Oct 4, 2012
|Oct 4, 2012
|Oct 5, 2012
|Oct 5, 2012
|Oct 5, 2012
|Oct 6, 2012
|Oct 6, 2012
Keyboard shortcuts:
FForum PPrevious NNext WNext unread UUpvote SSubscribe RReply QQuote BBookmark post MMy threads
Color scheme? Blue / Yellow


text:
Cathy Neal and son Cameron
- Filed Under
Each week, the Democrat features a Q&A with a local person involved in recreation sports. Today's feature is with Cathy Neal, president of Levy Park's two Advanced Baseball Leagues (ages 9-10 and 7-8). Originally from Texas, Neal attended Florida State University and returned to Tallahassee with her husband after a couple of moves. The couple has three young boys, all of whom play baseball. Here's Bryan's interview with Cathy.
Q: How did you end up as president of Levy Park?
A: "My first year at the park was with Carson, our son, when he was 9 years old. When he was 10, they asked me to sit on the ...


text:
Swamp Gas for Safer Surgery
Hydrogen sulfide gas could give surgeons a little extra time to perform rare heart surgeries.
Researchers at Massachusetts General Hospital in Boston have confirmed that hydrogen sulfide–a swamp gas that's toxic at high concentrations–can be used to temporarily lower oxygen requirements in mice without adverse effects. The researchers say it could make some of the most difficult heart surgeries safer for patients and less stressful for surgeons.
In rare surgical cases–to fix severely damaged aortas and the worst congenital heart defects–surgeons must briefly shut off all blood and oxygen flow in the body, including to the brain. And when brain cells don't get the oxygen they require, they die. To stave off a patient's death, surgeons must cool his or her body (to around 15 degrees Celsius) in order to reduce brain cells' need for oxygen and prevent damage.
But such extreme cooling has drawbacks, says Fumito Ichinose, a cardiac anesthesiologist and leader of the MGH team. It impairs blood clotting so much that patients need transfusions after surgery. And cold can only stave off brain damage for about 45 minutes–which means surgeons must rush to complete the procedure.
The MGH team believes hydrogen sulfide gas might work longer and better than cooling to reduce oxygen demand during these procedures. At a normal temperature, the researchers gave mice a low concentration (80 parts per million) of hydrogen sulfide gas. Within five minutes, the rodents' oxygen demand was halved. Then their heart rate and breathing slowed. And the mice stayed in this suspended state for six hours. Two hours after breathing regular air again, their body functions returned to normal, and a day later they were behaving normally. By all appearances, the gas reduced their oxygen demand for hours–with no adverse effects.
Earlier research at the Fred Hutchinson Cancer Research Center in Seattle, WA, had suggested that this might be the case. In 2005, scientists there combined the cooling and hydrogen sulfide gas methods, and the mice were similarly revived with air, and resumed normal behavior.
MGH's Ichinose hopes that people who require problematic heart surgery will one day be able to receive gas instead of being cooled, or get both procedures one after the other. Either way, it would allow surgeons to operate on a blood-free heart for a longer period of time.
Having extra time to operate while the flow of blood is stopped could make a difference, says Jeffrey Pearl, a pediatric cardiac surgeon at Children's Hospital in Cincinnati. Operating in just 45 minutes "takes a lot of planning," he says. "You need training. And you have to be more perfect because there's no time to hesitate."


text:
$50 iTunes Gift Card
- $ 47 88 47.88
- Shipping
- Free shipping
- Enter ZIP Code for shipping options
- Estimated arrival
About this item
Why We Love This
The perfect gift for everyone on your list! With the Apple iTunes Gift Card, the lucky recipient can download apps, games, music, movies, TV shows, books and more.
- Use on the App Store, iTunes Store, iBooks Store and toward an Apple Music membership
- Enjoy on your iPhone, iPad, iPod touch, Apple TV, Mac or PC
- Max 15 units per order
The Apple iTunes Gift Card can be redeemed at the App Store, iTunes Store and iBooks Store, or used towards the cost of an Apple Music membership.
Purchases made with an iTunes Gift Card are compatible with iPhone, iPad, iPod touch, Apple TV, Mac and PC.
Valid only on purchases made in the U.S. from the U.S. iTunes Store. Use requires an active iTunes account & prior acceptance of license & usage terms. Not redeemable for cash, for resale, for shipments outside the U.S., & no refunds or exchanges (except as required by law). Data collection and use subject to Apple's Privacy Policy; see apple.com/privacy. Neither Apple nor Issuer is responsible for any loss or damage resulting from lost or stolen codes or for use without permission. Void where prohibited. Terms apply; see apple.com/legal/itunes/us/terms.html. iTunes codes are issued and managed by Apple Value Services ("Issuer"). © 2015 Apple Inc. All rights reserved. Apple Music requires initial sign-up. At the end of the trial period, the membership will automatically renew and payment method will be charged on a monthly basis until autorenewal is turned off in account settings.
- Compatible with iTunes for Mac or Windows
- No returns or refunds on iTunes Gift Cards
- Good for the U.S. iTunes Store only
* Sam's Club Advertised Merchandise Policy – It is our firm intention to have every advertised item in stock. Occasionally, however, an advertised item may not be available for purchase due to unforeseen difficulties. We reserve the right to limit quantities to normal retail purchases or one-per-member or household, and to exclude resellers. We have done our best to ensure all information in this piece is accurate and up-to-date. Errors and omissions occasionally occur and are subject to correction. Pricing and item availability may vary by location and in Alaska, Hawaii, Oklahoma, Puerto Rico, Wisconsin and on SamsClub.com. No rain checks. Items and prices valid through November 21-November 25, 2015.
Assembled Country
Component Country


text:
"The Yelling Mule team took the time to
understand our business from the inside out..."
Jake Kalick, HarbourFood.com
We are an award winning Boston web design company that builds results-driven websites for companies of all sizes. Our services range from custom web design to responsive website development to full online marketing campaigns that drive traffic and sales for our clients.Learn More »
The goal of any website is to generate more business, whether it's through an e-commerce site, an educational site, or a lead generation site, the end goal is to convert your visitors into customers. Our results-driven approach ensures that converting visitors is a top priority, from the very first discovery meeting to the post-launch marketing campaign.Learn More »
James Shiner, President/CEO and Founder of Yelling Mule joined the Board of Directors for the Boston / New England Better Business Bureau. Read More »
I can't remember the last time a change in the web industry got this much hype. Read More »
We are proud to announce that we have recently won five web design awards. Read More »
Learn why a do-it-yourself website may not be the best fit for you. Read More »


text:
- KNIA / KRLS - http://kniakrls.com -
Mild Winter Easy On Supplies, Public Works Director Says
Posted By News On March 20, 2011 @ 6:25 am In Today's Local News | Comments Disabled
Another winter is almost in the books, and Pella Public Works Director Denny Buyert says this one was a little less intense than the last few. Buyert says his crews worked to keep streets clear after eight winter events. He says this number is down from 16 to 18 over the past few years. Buyert says a good barometer to measure the severity of the season is looking at how much salt was used. Public Works went through about 200 tons of salt, about half the amount of average years. He says the mild winter was also a littler easier on the streets, as repair crews have used about 25 tons of material to fill in winter pot holes, a significant reduction from past years.
Article printed from KNIA / KRLS: http://kniakrls.com
URL to article: http://kniakrls.com/2011/03/mild-winter-easy-on-supplies-public-works-director-says/
Click here to print.
Copyright © 2009 KNIA/KRLS. All rights reserved.


text:
Car Trip
Taking a road trip for spring break? Meet your new best friend, the Car Trip app for iPhone ($0.99). This handy app helps calculate your mileage and potential gas costs so you can plan the most advantageous route. It's also a weather predictor and will help you steer clear of nasty weather while you road trip for a fabulous spring break.


text:
- Filed Under
Central Louisiana Technical Community College is in the news in a big way these days, as it should be.
The main campus in Alexandria soon will get a new home - moving from South MacArthur Drive to one of several downtown locations still under consideration.
At the same time, the multi-campus college is enjoying increased visibility as the state invests more public funding into education programs that respond directly to private-sector employment needs and as students and families consider how to get the most bang for their college bucks. ...


text:
File APIs for Java Developers
Manipulate DOC, XLS, PPT, PDF and many others from your application.
A friendly place for programming greenhorns!
Big Moose Saloon
Java FAQ
Recent Topics
Flagged Topics
Hot Topics
Zero Replies
Register / Login
Java Forums
JSESSIONID value is not changed on invalidating session
Joao Longo
Joined: Jan 04, 2012
Posts: 14
May 15, 2014 11:29:25
Hello people!
I needed to change JSESSIONID's domain to ".something.com" in a context.xml file:
<Context path="/test" sessionCookiePath="/" sessionCookieDomain=".something.com" useHttpOnly="true" />
After that, when I perform a httpSession.invalidate() the session is reset but JSESSIONID value does not change.
I'm using
7, Spring MVC and
7. I also tried to remove the JSESSIONID cookie manually, but it seems that Tomcat or Spring are not letting I change its value.
This may difficult troubleshooting on my system. I'd like to know if it's possible to change this behavior either on Spring or in Tomcat.
Tim Holloway
Saloon Keeper
Joined: Jun 25, 2001
Posts: 17417
I like...
May 19, 2014 05:24:09
I'm not following you.
If you change the cookie domain in a Tomcat Context, you would have to restart the entire web application. In fact, Tomcat will generally sense the change and do that automatically on its next timed scan for changes.
You sound like you expect that you can change this value in the middle of running the application.
An IDE is no substitute for an Intelligent Developer.
Joao Longo
Joined: Jan 04, 2012
Posts: 14
May 19, 2014 06:17:13
I think the situation is not clear. The JSESSIONID domain was changed and Tomcat was restarted.
When a user enters on the app, he receives a JSESSIONID, e.g., "12345678". The problem is that when this user leaves the app (calling session.invalidate()), the JSESSIONID value does not change, it remains "12345678", but the session values was reset.
Tim Holloway
Saloon Keeper
Joined: Jun 25, 2001
Posts: 17417
I like...
May 19, 2014 07:14:17
It is still not clear.
The JSESSIONID cookie (or URL suffix) is a name/value pair, whose name is "jsessionid" and whose value is a "random number". That "random number" is generated to serve as a hash key used by the
server (Tomcat) to retrieve the HttpSession object for that particular user. Since it is "random", it exposes no details about the session itself to unfriendly listeners.
When you invoke session.invalidate() on the HttpSession, it detaches the session from Tomcat's hashtable. The jsessionid itself then becomes meaningless. I wouldn't expect the server to send further jsessionid cookies back to the client, although without checking, I don't know if the response to the request that destroyed the session also sends back cookie-destruction information, and if it doesn't that would leave the jsessionid cookie on the client, even though it was meaningless.
For a non-secure session, it's probably OK if a new session request would create a new session instance and bind it to the old session ID if the client continued to send down the original cookie. For https, it would be a security issue, though. Tomcat keeps the session but changes the jsessionID when it shifts from http to https transport. Which means that the jsessionid cookie it sends back via SSL has a different value.
In any event, the actual value of jsessionid on either client or server should not be used by any application code. That's a good way to end up in a lot of trouble.
Joao Longo
Joined: Jan 04, 2012
Posts: 14
May 19, 2014 11:13:29
I got your point. In fact, I need one of the two behavior below:
1. When I call session.invalidate(), JSESSIONID cookie is removed
2. When I call session.invalidate(), JSESSIONID cookie value is changed
The option #2 was happening before I change JSESSIONID's domain to ".something.com".
Now, although HTTP session gets clean, JSESSIONID remains with the same value. This means that the next time (without close the browser) user enters on my app, JSESSION will have the same value! This is disturbing troubleshooting.
I've already tried the following workarounds without success:
1. Call request.getSession(true) after I call session.invalidate() -> session is created with JSESSIONID value equals to previous one
2. Remove the JSESSIONID cookie explicitly -> it doesn't work
Tim Holloway
Saloon Keeper
Joined: Jun 25, 2001
Posts: 17417
I like...
May 19, 2014 11:38:14
I still do not comprehend.
The jsessionid and its associated cookie and/or URL suffix do not belong to you nor to the application program. They are the exclusive property of the client and the server. The server creates/updates/removes it, the client stores it and transmits it. Neither you personally nor your application code should even care if it exists or not or even if magic elves are the mechanism that associates a given client with a given server session rather than cookies or URL rewriting. If the server wishes to discard a session but not explicitly remove the cookie, it has the right to do so. According to a quick check on my client, the jsession cookie's natural lifespan extends until the client itself is destroyed. Or until an explicit clearing of cookies is done by the client's security tools, whichever comes first.
As I said before, any attempt by client or server application code to explicitly work with jsessionid is more likely to introduce problems than to solve them. It's better to devote time to more productive concerns.
Joao Longo
Joined: Jan 04, 2012
Posts: 14
May 19, 2014 13:32:52
I don't agree completely with the sentence: "It's better to devote time to more productive concerns". I had a requirement to change JSESSIONID's domain to ".something.com" for a reason X. But this has caused the issue I reported on this bug.
This may difficult troubleshooting on my system. So, my question is if there is some configuration on Tomcat to do not keep JSESSIONID value the same when invalidation session. I don't want to change JSESSIONID in app. I want Tomcat/Spring takes care of it as before I've changed its domain.
Joao Longo
Joined: Jan 04, 2012
Posts: 14
May 19, 2014 13:41:28
I found the problem in Tomcat's documentation:
Note: Once one web application using sessionCookiePath="/" obtains a session, all subsequent sessions for any other web application in the same host also configured with sessionCookiePath="/" will always use the same session ID. This holds even if the session is invalidated and a new one created. This makes session fixation protection more difficult and requires custom, Tomcat specific code to change the session ID shared by the multiple applications.
The issue is related to cookie path, and not with domain
Tim Holloway
Saloon Keeper
Joined: Jun 25, 2001
Posts: 17417
I like...
May 19, 2014 15:26:27
No I understand. I have been subject to this fault as well. You asked a question with a pre-conceived answer and you asked it in terms of your answer.
question doesn't have to do specifically with manipulating jsessionid cookies, it has to do with
how webapps share sessions.
I could review the situation in those terms, but since you apparently need to know what you need to know, I won't bother. If I read it correctly, however, this is a case where a superior context ("/", or the root context) will override inferior contexts ("/abc", "/def").
I think that there are some further tricks you can do to fine-tune what webapps share what sessions, but that would require reading the manual. I'll leave that honor to you.
With a little knowledge, a
cast iron skillet
is non-stick and lasts a lifetime.
subject: JSESSIONID value is not changed on invalidating session
Similar Threads
Problem in logging in web application
Session Fixation Attack with Tomcat 7
How tomcat keep session
How can i change the session name of a certain war
Changing the session key name in Tomcat
All times are in JavaRanch time: GMT-6 in summer, GMT-7 in winter
Contact Us
| Powered by
Copyright © 1998-2015
Paul Wheaton


text:
Darian Marshall was looking for a fresh start.
The 41-year-old owns his own refrigerator and air conditioning repair business. But he didn't become an entrepreneur out of choice. A 17-year-old arrest for possession left him with little choice, he says.
"It makes life difficult being unemployed," said Marshall. "That's why I became an entrepreneur."
But like thousands of others who filled the first floor of the Roberto Clemente Community Academy for the fourth annual "Expungement Summit" over the weekend, Marshall still aspires to something better.The summit, organized by Clerk of Courts Dorothy Brown, included representatives of the state's attorney's office, the public defender's office, Chicago Public Schools and the Chicago Police Department, among other agencies offering advice on how to clear a past criminal arrest or conviction.
By 11:35, 2,500 people had signed up, organizers said.
Brown said the summit was designed to help streamline the
process for people who in the past have been turned away.
"I wasn't pleased with the other summits I have attended," she said. "People were not being serviced properly. They were standing in line waiting to see an attorney, only to find out they were not qualified to get their record expunged."
In the past, the process of expungement could take years. According to Brown, the process has been streamlined to take only three to six months.
At the summit, volunteer attorneys provided same-day information on whether individuals were eligible to file a petition seeking expungement, which must be ruled on by a circuit court judge.
According to Julian Brevard, of the state's attorney's office, expungement seals off a criminal conviction or arrest to all except certain public employers and agencies. "Agencies such as (the Department of Children and Family Services) and the schools are allowed to view the sealed record," he said.
Brevard says the expungement process can "open doors" for people having difficulty getting a job, applying for citizenship, purchasing a home or trying to adopt a child - all of which can be out of reach for individuals with an arrest record.
"It is really important for them to come to an expungement summit like this so they can get help," he said. "They can contact an attorney to help with the process. Hopefully this can help open doors for them."
Stacey Stringer, 30, has also suffered the hardships that can follow an arrest. Her husband attended the summit hoping to clear a 15-year-old record that has made it difficult for him to support their family, she said.
"It is hard because we have two kids, 8 and 12-years-old, and then we have mortgage payments and car notes," she said.


text:
This program is the ultimate utility for developers of applications designed for the Windows CE operating system. Because it reads and writes the Windows CE CAB file format directly, it eliminates the need to learn the complicated Windows CE INF file format normally used to generate the cabinet files used to install Windows CE applications.
A2zDrugs™ is the handheld version of A To Z Drug Facts, the easy-to-use drug guide that includes latest FDA approvals, indications, dosages, side effects, and patient care considerations. This latest update is based on the 2010 print edition with additional features, enhanced functionality and ongoing updates.
1. Download the Colibri SDK from Toradex (link) and save it to the desktop.
2. Install Visual Studio (tested to work with 2005 & 2008) on Windows
3. Run cmd.exe an an administrator
4. Browse to your desktop
5. Type the following "msiexec /qb /i colibri_SDK_1_0.msi"
6. Ensure the SDK has been installed by opening Visual Studio and clicking (tools -> options -> device tools -> devices).
CmdHere adds an option to the context menus of the folders to quickly access a command window. It's a shortcut for the cmd.exe file with the additional advantage that the command window, which will be opened, will automatically set the path to the folder from which you execute cmd.exe.
IXP4xx (IXP425, 422, 421, 420) BSP for Windows CE (wince/Windows Embedded Compact) 4.2/5.0/6.0/7.0
To find out how to get your BSPs and CPUs certified, please visit the Windows
Embedded CE BSP and CPU Certification Program.
Download the program from sourceforge project page.
This application needs .Net Framework 3.5 to run (SP1 recommended) and as of 7/26/2010 this software will only work under Windows Vista or 7, Windows XP doesn't have the mklink command inside the cmd.exe app. With this utility you can use the symlink application Microsoft Windows .
BizCard Finder for Twain Flatbed scanners save you the hassle of scanning name card one by one. Using this version of BizCard Finder,8 name cards can be scanned at one time.
Moreover, you do not have to purchase additional scanner to work with BizCard Finder (TWAIN). You can just use any flatbed scanner that you currently have now.
The Moxa MXIO library supports the WinCE and Linux operating systems, as well as the C++, VB/VC, and .NET development platforms. The library makes it easy to use high-level computer languages to manage I/O devices and data transfer operations over an Ethernet or RS-485 network, thanks to a large repository of C# and Visual Basic code samples.
Download Accelerator Plus is not the standard download manager, but a comprehensive application that combines easy file downloading with Internet browsing and system maintenance tools (a trace cleaner, an anti-virus utility, a file shredder, and many other add-ons that you can download and install from DAP).
It is an application designed to update your Epson devices to the latest version. It support the next devices:
- Epson Expression Home XP-102.
- Epson Expression Home XP-103.
- Epson Expression Home XP-202.
- Epson Expression Home XP-203.
- Epson Expression Home XP-207.
Download Accelerator Manager is intended to manage and speed up Internet downloads. The program has an intuitive interface somewhat similar to those of other download managers. The download jobs are automatically categorized according to their state into All, Finished and Unfinished; and at the same time, they are further classified into the type of contents.
Super MP3 Download is easy-to-use software which enables you to search and download over 100 million MP3 files. With this app you can search songs in tags of titles, artists, albums, and editions. You can even search the live, piano, guitar or cover editions of your favorite songs.
It can be used as a method of reconstructing phylogenies but is also a framework for testing evolutionary hypotheses without conditioning on a single tree topology. BEAST uses MCMC to average over tree space, so that each tree is weighted proportional to its posterior probability.
It guarantees you the fastest possible download , as it has speeding boosting technology such as automatically looking for the fast download sources and switching to mirror sites to make downloading even faster. And if that's not fast enough, you can preview videos while they are still downloading
Good Download Manager is an application which helps you download files from torrent websites. When you start downloading, a new window appears which shows the loading level of the file. The program offers you the means to check the download and the upload speed.
Download keeper is a free browser add-on that allows you to save money and shop online completely hassle-free. The program gives you the ultimate advantage in your online shopping experience by providing you the best buying deals and coupons for various online retailers.
eMusic is an online service that allows you to find and buy your favorite music, either single songs or entire albums. eMusic Download Manager tool is the client app that you can install on your PC for managing all your eMusic pending downloads. The program allows you to pause your downloads and synchronize them with media players such as WinAmp, Windows Media Player, and iTunes.
MetaProducts Download Express is a useful free application for downloading files from the Internet Web and from FTP sites.
The application uses the maximum available speed for the downloads and multi-channels technology. The 'Express' appellative surname tryies to show the download high speed meaning that the application offers a download time as low as possible.


text:
- Filed Under
A traffic technician is in critical condition after an accident along East Nine Mile Road in Pensacola this morning.
Brian Steinbeck, 25, a technician with HSA Consulting Group was taken to a local hospital after being struck near the intersection of East Nine Mile Road and Scenic Hills Drive while at work, according to the Florida Highway Patrol.
Around 7 a.m., Steinbeck was working in the grass median of East Nine Mile Road near a parked vehicle and attempting to place a traffic counter across the eastbound lanes, according to FHP. Steinbeck was being assisted by his co-worker Robert ...


text:
An authority level is providing to support the next potential and also existing small entrepreneurs involved, which offering competitive prices with top quality products and wide ranges of handicraft products the same as big manufacturer of handicraft fields. Home furnishings crafted expertly and designed with stylish selection of Indonesian furniture and handicraft. Resource of modern style and affordable for home furniture, living room furniture and also outdoor furniture. we provide rattan furniture and We have one of the most extensivecollections of Your choice handicraft with whole marketplace. Trade Promotion Network held yearly in Jakarta, Indonesia.
Prefer a presentation of Indonesia Furniture Handicraft Wholesale Marketplace new collection related with furniture system distribution. Indonesian ethnic furniture handicraft essence. The wholesale handicraft and furniture in Indonesia have many positive factors and advantages to be offered. Delivery Manufacturer Exports Co. continuously discover our ranges of fine Mahogany and other pieces from indoor and outdoor furniture. rattan wholesale, offer thousands of items online wholesaler, exporter, and manufacturer of handcrafted wholesale, Indonesian teak furniture and wholesale home furniture, extensive selection of Antique reproduction Indonesian furniture catalogues supports the increase of furniture made from Indonesian contribute for modern living if the competitiveness carries the finest hand-crafted Indonesian furniture for the home or office collections, as well as teak furniture the center of Indonesia handicraft manufacturer, handicraft business trade directory is well designed to promote global business for many kind of Indonesia Handicrafts offer the highest quality Completely Various Handicraft Collection, We offer wholesale handicraft Bali, handicraft Jogja, Handicraft Indonesia and special Discount Export trading company sourcing service unique gift items Java Bali Lombok and exporter woven furniture Best Design and Quality of Indonesia handicraft abstract sculptures, handmade ceramic, wood carving you will find right wholesale partner. Either used furniture and contemporary are available with each wide of varieties.
As discussed in Indonesia furniture handicraft wholesale marketplace, many usage of daily aappliances, indoor and outdoor teak furniture, handcrafted decorative furn or other source such as bamboo, tropical mahogany, wicker furniture, rattan furniture upto many styles of handicraft. Antique reproduction with traditional finishing touch can also become trend in this year. Collection of garden furniture also home furniture: bedrooms, living rooms, dining rooms, and patio has been export to the world. Original Indonesia Furniture Handicraft Wholesale Marketplace can also made by custom.


text: St-Guilhem-le-Desert is regarded as the prettiest village in the whole South of France. Situated in a narrow gorge away from prying eyes, St Guilhem has long been home to religious followers seeking refuge from persecution. It is also a prominent stop-over on the old pilgramage route to Santiago de Compostella in Northern Spain. Locations du Sud has a number of properties close to St Guilhem that you can rent for a holiday vacation.


text:
Each Sunday, pick one team in every noon NFL game and any designated over/unders. If you pick them all correctly, you'll win your share of the $1,000 prize pool (plus any previous carryover)! If no one wins, the prize carries over to the next week for an even bigger pool! Do you think you can make a perfect pick?
Entry forms can be submitted from 10 AM to Noon on Sundays at the 3rd Floor Info Booth or Card Casino MVP Desk. No entries will be taken after kickoff of the first game.
Entries will be scored upon completion of the Noon football games. Prizes will be available the following Wednesday. Prize Pool divided among all perfect pickers
$1,000- Mark Vaughn
$1,000- Keith Erickson
$1,000- Ian Clausen
Prize money will be determined and available Wednesday by Noon.
Watch every NFL game with the NFL Ticket and enjoy
Food & Beverage Specials
Sundays 11 AM - 3 PM
Chili Cheese Dogs - $2.50
Nacho Grande - $2.50
Sour Cream is an additional $.50
16oz Domestic Tap - $3.00
16oz Premium Tap - $3.50
Minimum of 10 NFL outcomes per week. If there aren't 10 noon games, additional designated Over/Under sets will be added to the entry card.
Players must be enrolled in the MVP Rewards program to participate in this contest. Free to enter. One entry per person. Players submitting multiple entries or entering picks for persons not present will have all of their entries disqualified. If nobody wins, 100% of the prize pool will carry to the following week. If no one goes perfect the final Sunday of the Perfect Pick there will be a force payout via drawing.Prizes will be attached to MVP Card or at Card Casino Cage by the following Wednesday. Prize Pool divided among all perfect pickers.
Minimum play required for full prize pool payout. Minimum Play requirements: Must meet one of the following before 3 PM on Perfect Pick Sundays:Racebook:$20 Wagered • Table Games: 20 minutes played • Poker: 20 minutes played. If minimum requirements are not met payout will be $50.


text:
Historic Sites & Museums
Photo Courtesy of Historic Latta Plantation
The towns of Cornelius, Davidson, and Huntersville have preserved several historic sites, including architecture and rural farms. Some are part of The Pure Carolina Trails Guidebook and the Regional History Guide. Several locations hold periodic historical re-enactments, and living history events.The Pure Carolina Trails Guidebook covers trails in 16 North and South Carolina counties and highlight Motorsports, Adventure, Culture, and Culinary trails.
Download History & Heritage Tour Map
The Charlotte Regional History Consortium promotes cooperation among and interest in the region's history and heritage organizations and resource centers. Founded in 1994, the Consortium holds quarterly meetings at member sites, which allows organizations an opportunity to exchange ideas, arrange cooperative events, and coordinate program scheduling. Its geographic region covers Charlotte and the surrounding counties. For more information on the Charlotte Regional History Consortium, please visit their website: www.charlotteregionalhistory.org
Photo Courtesy of Visit Lake Norman of Rural Hill Homestead Actors
Search Listings
There are no listings that match your query.


text:
Thank you for reading the MtDemocrat.com digital edition. In order to continue reading this story please choose one of the following options.
Current Subscribers
If you are a current subscriber and wish to obtain access to MtDemocrat.com, please select the Subscriber Verification option below. If you already have a login, please select "Login" at the lower right corner of this box.
Special Introductory Offer
For a short time we will be offering a discount to those who call us in order to obtain access to MtDemocrat.com and start your print subscription. Our customer support team will be standing by Monday through Friday, 8am to 5pm to assist you.
If you are not a current subscriber and wish not to take advantage of our special introductory offer, please select the $12 monthly option below to obtain access to MtDemocrat.com and start your online subscription
You have to understand that the animal shelter location is being directed by the newly created Facilities Department under Russ Fackrell, an accountant "bean counter" by trade appointed by the CAO Terri Daly.
Mr. Fackrell has virtually no experience in the realm of facilities management duties that he is charged with. Mr. Fackrell makes his decisions primarily based on lowest cost. He claims to have looked at 100 different sites through the highly questionable use of a CAO-appointed 30-year-old commercial real estate office space leasing agent who has a very strange and questionable relationship with the county and no experience in this type of site acquisition.
Of course, many are wondering if kickbacks are involved in this strange relationship. If Fackrell's department had to look at 100 different sites, they obviously don't know what they are doing. Then whittling it down to six sites and holding negotiations with six different competing property owners is insanity; they should have done their due diligence first. There was a reason for this, as the decision the county is making is primarily being driven by the lowest cost it can purchase an existing building for, as this is purely an accounting driven decision of acquisition at the lowest cost. That is why they decided to hold negotiations with six different property owners and play them against each other to beat them down and obtain the lowest building price. Site constraints, environmental issues, neighbors, incompatible use were all a second thought as everything was based on "price." Otherwise the county would have picked one of the other potential sites that didn't abut residential housing.
Couple that with the county's huge conflict of interest in preparing its own environmental document (Negative Declaration) and the neighbors have a very good lawsuit challenge to the county's placement of this facility and its fabricated and biased environmental documents. Of course this is an incompatible use next to the residential. No, you will never be able to remediate and get rid of the bad smells from the animals and the incineration of animal carcasses. Neighbors need to hire an experienced real estate environmental attorney now.


text:
Mayan Iced Mocha
Adina Organic Coffee
BevNET Review
Last Updated: 8/2/2007 11:17 AM
Mayan Mocha is our favorite flavor of Adina's organic Iced Coffee lineup. Like the other varieties, it features a pleasant brew of Guatemalan coffee that has been blended with low fat milk. And, as the name suggests, they've added bittersweet chocolate as well as dash of spice to the finish. The spice part is what seals the deal for us, making this one of our all-time favorite RTD iced coffee formulations. Packaging is good, but things are a bit tight on the front of the label. Our biggest concern is that it might look a bit too much like a Starbucks Frappuccino, which would certainly be a disservice to this stellar tasting product.
Product Type
Container8.5 fl oz (252 ml) glass
Nutritional Info
Calories 110, Fat Cal. 20, Total Fat 2g, Sat. Fat 1.5g, Cholesterol 10mg, Sodium 115mg, Potassium 190g, Total Carbohydrate 20g, Sugars 19g, Protein 4g, Vitamin A (4% DV), Calcium (15% DV), Iron (6% DV)
Fair Trade Guatemalan Organic Coffee (water and coffee), Organic Reduced Fat Milk (2% Milk Fat), Fair Trade Organic Evaporated Cane Juice, Fair Trade Organic Cocoa, Fair Trade Organic Vanilla, Sodium Citrate, Carrageenan, Organic Spice Extract
Additional Images (1)Upload More Images


text:
Undergraduate Catalog 2013-2014
This course is an overview of the professions in the field of exercise science. Career opportunities within exercise science and allied health will be investigated. Various aspects of careers, determining requirements for advanced study and learning what coursework would be appropriate for the different career paths.
Credits: 1
Highlighted text indicates a change from the official version of the catalog.


text:
The receptor activator of nuclear factor-κB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer).
As discussed in previous reviews in this supplement, a specific inhibitor of receptor activator of nuclear factor-κB ligand (RANKL) could be of great therapeutic value in the treatment of patients with a variety of metabolic and inflammatory bone disorders. Numerous biologic agents have been developed, including protein ligands (calcitonin [Miacalcin™; Novartis, East Hanover, NJ, USA], parathyroid hormone [Forteo™; Eli Lilly, Indianapolis IN, USA], and bone morphogenetic protein-2 [Infuse™; Medtronic, Memphis, TN, USA]), soluble receptors (tumor necrosis factor [TNF] receptor-Fc [Enbrel™; Amgen, Thousand Oaks, CA, USA] and cytotoxic T-lymphocyte associated antigen-4 immunoglobulin [Orencia™; Bristol-Myers Squibb, New York, NY, USA]), and mAbs (anti-TNF [Remicade™; Centocor, Horsham, PA, USA and Humira™; Abbott, Abbott Park, IL, USA] and anti-CD20 [Rituxan™; Genentech, San Francisco, CA, USA]). These have emerged as drugs of choice for many conditions as they are effective and, because they target a single molecular interaction, they are relatively safe. This specificity is largely due to the hundreds of millions of years of evolution (ligands and receptors) or more than 1012 DNA recombination events (mAbs) that occur to produce a high-affinity (>10-9 M) interaction with only one other protein in the body. Methods to achieve this kind of specificity with small molecule drugs are not available. Thus, even with rational drug design approaches based on atomic structures, undesirable interactions with other proteins that cause severe side effects often occur. Furthermore, some of these side effects only occur in humans, and so the first signals may only appear in clinical trials or postmarketing reports.
Development of a specific biologic agent for the treatment of human disease requires the evaluation of several different iterations and formulations. Indeed, this was the case for denosumab. Natural antagonists to RANKL were produced first because it was relatively easy to clone the cDNAs for RANK [1] and OPG [2] into expression vectors that would produce large amounts of the encoded proteins (receptor activator of nuclear factor-κB [RANK] and osteoprotegerin [OPG], respectively) in vitro. To facilitate their use in animal models, the Fc portion of the immunoglobulin heavy chain was fused to the aminoterminus of OPG (Fc-OPG) and the carboxyl-terminus of RANK (RANK-Fc) to generate effective recombinant proteins. The Fc domain allows for the dimerization required for high affinity to trimeric RANKL; it facilitates large-scale purification via protein A or protein G column chromatography; and it dramatically increases biodistribution and pharmacokinetics of the recombinant proteins in vivo. RANK-Fc and OPG-Fc proved to be very specific and effective inhibitors, and essentially all published preclinical studies to date have used these recombinant proteins [3].
Clinical history of Fc-OPG
Amgen Inc. (Thousand Oaks, CA, USA) performed the first clinical trial to evaluate the efficacy of RANKL inhibition using recombinant Fc-OPG as a drug in postmenopausal women with osteoporosis [4]. This phase 1 study was designed to evaluate the effect of a single subcutaneous dose (placebo, 0.1, 0.3, 1.0, or 3.0 mg/kg) on bone resorption, and the primary outcome measures were biochemical markers of collagen catabolism (urinary N-telopeptide [NTX] and deoxypyridinoline). The highest dose yielded an approximate 80% decrease in NTX levels 4 days after dosing and significant effects lasted for 45 days. The study also evaluated the effects of Fc-OPG on osteoblasts by monitoring serum levels of bone-specific alkaline phosphatase (BSAP), which were largely unaffected by the drug. Because Fc-OPG was well tolerated by all patients and no serious adverse events were reported, the investigators concluded that this RANKL inhibitor is a viable candidate.
A subsequent phase 1 trial evaluated a different formulation of OPG known as AMGN-0007 in patients with multiple myeloma or breast carcinoma who exhibited radiologically confirmed lytic bone lesions [5]. Because ethical considerations prohibit the use of placebo in such cancer patients, a double dummy, active controlled study design was used, in which each patient received either a single subcutaneous injection of AMGN-0007 (0.1, 0.3, 1.0, or 3.0 mg/kg) accompanied by intravenous placebo, or intravenous pamidronate (90 mg) accompanied by subcutaneous placebo. Although the study found AMGN-0007 to be well tolerated and that its effects on bone resorption were similar to those of pamidronate, this was to be the last clinical trial with OPG. The reasons for this were described by Bekker and coworkers [6] and stem largely from the facts that AMG 162 (denosumab) is superior to Fc-OPG in that it yields greater decreases in bone turnover markers at lower doses and it has a longer duration of antiresorptive effect at equivalent doses. Those authors also cited two potential concerns with Fc-OPG therapy that do not apply to AMG 162. The first is the generation of anti-Fc-OPG antibodies, which might cross-react with endogenous Fc-OPG, neutralizing its activity. The second potential concern is binding of Fc-OPG to TNF-related apoptosis-inducing ligand [7], which could inhibit its role in tumor surveillance. Thus, it has been proposed that AMG 162 is safer and more efficacious than Fc-OPG as a therapeutic inhibitor of RANKL.
Denosumab: a fully human mAb directed against RANKL
Denosumab is a fully human mAb directed against RANKL and is currently under investigation in phase 3 clinical trials [8,9]. Denosumab was generated by immunizing the XenoMouse [10] with full-length human RANKL protein. This immunization produced a fully human IgG1 mAb, known as AMG 161, which recognized an epitope with a single amino acid difference between the mouse and human sequences (Kostenuik PJ, personal communication). Because human IgG1 can direct complement-dependent cytotoxicity or antibody-dependent cell cytotoxicity to target cells [11], there was concern that AMG 161 would have an undesirable toxic profile caused by death of RANKL-producing cells (stromal cells, osteoblasts, and T cells). Thus, it was converted to a noncytotoxic IgG2 mAb, known as AMG 162, which has an extremely high affinity (Kd approximately 10-12 M) for human RANKL. The fact that it does not recognize rodent RANKL has complicated preclinical development somewhat, in that the only relevant animal data were derived from studies conducted in cynomolgus monkeys [12].
Clinical experience with denosumab
Table 1 summarizes the 21 clinical trials to date that investigated the effects of denosumab in patients with postmenopausal osteoporosis (PMO), prostate cancer, breast cancer, multiple myeloma, solid tumors, and rheumatoid arthritis (RA). The initial phase 1 studies in PMO [6], and multiple myeloma or breast cancer [13] focused on pharmacokinetics and pharmacodynamics while monitoring adverse events. Both studies evaluated the effects of a single subcutaneous injection (0.01, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg) and monitored denosumab levels in serum and urine NTX levels. The results revealed that the drug effects had a rapid onset (within 12 hours) and were sustained in some patients for up to 6 months. In the trial conducted by Bekker and coworkers (in osteoporosis) [6] the maximum half-life was 32 days. In beast cancer and multiple myeloma the mean half-lives were 46.3 and 33.3 days, respectively [13]. No drug-related serious adverse events occurred in these phase 1 studies.
Table 1. Clinical trials investigating the effects of denosumab
A phase 2 trial conducted to identify an ideal dose and treatment regimen for denosumab in PMO was recently completed [14], with the primary end-point being bone mineral density (BMD). Similar studies were conducted in patients with metastatic cancer, but the primary outcome was urine NTX [15,16]. Four other phase 2 trials are ongoing. These include a head-to-head comparison of denosumab with alendronate in PMO using bone structure as the primary outcome measure; a trial evaluating the efficacy of denosumab in treating multiple myeloma, in which complete and partial responses will be assessed; and an evaluation of the anti-RANKL effects of denosumab (60 or 180 mg subcutaneously every 6 months) on cartilage degradation and bone erosion (assessed using plain radiographs and magnetic resonance imaging) in RA. The 6-month magnetic resonance imaging data from the RA trial were presented in November at the American College of Rheumatology annual meeting [17]. The results indicate that, compared with placebo, the 180 mg group exhibited significantly less progression of bone erosions compared with placebo (P < 0.019). Although progression in the 60 mg group was also numerically less than that with placebo, this did not reach significance (P = 0.247). These results are consistent with the finding that markers of bone resorption (serum collagen C-terminal crosslinked peptide [CTX]-I and procollagen type 1 intact N-terminal propeptide [P1NP]) and cartilage loss (urine CTX-II) were significantly decreased [18], and BMDs in the lumbar spine, total hip, and trochanter were significantly increased [19] in these RA patients on denosumab therapy.
Currently, there are 10 ongoing phase 3 clinical trials with denosumab for either PMO (60 mg subcutaneously every 6 months) or cancer (120 subcutaneously monthly). The largest is an international study in PMO in which drug effects on fracture reduction will be assessed. The other PMO trials will examine effects on BMD either as a head-to-head comparison with alendronate, after transition from bisphosphonate therapy, or as a prophylaxis in postmenopausal women. Additional pre-metastatic prostate cancer and breast cancer trials are underway that will analyze the effect of denosumab on bone loss related to androgen deprivation therapy and aromatase inhibitor therapy, respectively (Table 1). Another central question in the area of tumor metastasis is whether inhibition of bone remodeling will influence disease progression in terms of prolonging bone metastasis free survival in men with hormone refractory prostate cancer who have no bone metastases at baseline, or in terms of reducing skeletal related events (including pathologic fracture, radiation therapy to bone, surgery to bone, and spinal cord compression) in patients with bone metastases from prostate cancer, breast cancer, and solid tumors (Table 1).
Potential side effects of denosumab therapy
Three potential side effects have been identified based on information derived from the biology of RANKL, the literature on preclinical models of RANKL inhibition, and clinical experience of bisphosphonate therapy to date. Considerable effort has been invested in looking for signals related to these adverse events in the denosumab trials [20].
Frozen bone
The first potential side effect is so-called 'frozen bone', a process whereby complete inhibition of remodeling leads to accumulation of microfractures and brittle bone. In fact, concerns were raised regarding this complication in postmenopausal women receiving bisphosphonate therapy, based on findings from animal studies [21]. However, the fragility fractures that were predicted to occur in this population of patients, who have been treated with alendronate for more than 10 years, have not materialized. Frozen bone is less of an issue with denosumab in part because it is completely cleared from the body; this is in contrast to the more potent bisphosphonates, for which the half-life in bone may be 5 years or longer. The issue of decreased fracture healing has also been addressed in animal experiments [22]. These studies demonstrated that RANK-knockout mice are able to heal their fractures, and therefore osteoclasts are not required to generate a union. The studies also indicated that discontinuing RANKL inhibition at the time of fracture in wild-type mice results in normal healing.
RANK-RANKL signaling was originally identified as a co-stimulatory pathway during T-cell activation [23], and RANK [24] and RANKL [25] knockout mice have altered lymphocyte development and lack lymph nodes. These facts have led to a concern regarding potential immunosuppression. Subsequent findings, however, have revealed that the role of RANK-RANKL co-stimulation in T-cell activation is only evident in the absence of CD40-CD40 ligand signaling [26]. It has also been shown that RANKL inhibition with OPG does not alter cellular or humoral immunity, or render mice susceptible to bacterial challenge [27]. Thus, although dendritic cells and T lymphocytes express these molecules, it would appear that they play a minor or redundant role in the mammalian immune response. Of course, close attention will be given to the incidence of infection and neoplasms in the larger phase 3 trials.
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) has recently emerged as an adverse side effect of bisphosphonate therapy [28,29]. Currently, the nature of ONJ remains enigmatic, and its cause is a topic of great debate. Although it has been established that 94% of published cases occurred in cancer patients who received intravenous nitrogen-containing bisphosphonates, ONJ has also been reported in healthy women who take oral bisphosphonates for PMO. It is also known that 60% of cases are preceded by a dental surgical procedure, and so it has been proposed that the etiology of ONJ involves oversuppression of bone turnover combined with infection and possibly additional, as yet unidentified co-morbidities. Based on the serious nature of ONJ and our lack of knowledge on its etiology, the American Society for Bone and Mineral Research has commissioned a task force to investigate this problem [30]. Thus, until we have additional data, investigators should be aware of this potentially severe complication, and practice vigilant monitoring of patients who take all forms of anticatabolic therapy for bone loss.
Advantages of denosumab over bisphosphonates
Although the comparative ratios of risk to benefit for bis-phosphonates and denosumab are currently unknown, there are three potential advantages of denosumab over bisphosphonates. As mentioned above, the first is that denosumab is completely cleared over a relatively short period of time, so that the effects on bone may not be long-lasting. The second is that it could be the first anti-bone resorbing agent to halt focal erosions and osteolysis. Over the past two decades clinical trials designed to demonstrate the effectiveness of bisphosphonates on erosions in RA have repeatedly failed to show such an effect [31-33]. Interestingly, one of the more recent, well designed studies was able to demonstrate that etidronate therapy had a favorable effect on general bone metabolism (osteopenia), but it did not inhibit serum NTX levels or worsening of erosion scores in patients with RA [34]. The results from these trials are consistent with our preclinical studies, which showed that TNF protects osteoclasts from alendronate-induced apoptosis by stimulating Bcl-xL expression through Ets-2 [35], while RANKL inhibition in the same setting of inflammation leads to rapid osteoclast apoptosis [36,37]. Thus, there is great expectation that denosumab will effectively prevent erosions in inflammatory arthritis and periprosthetic osteolysis.
Another disappointment of bisphosphonate therapy is the inability to use these agents effectively and safely in combination with anabolic agents. This was formally demonstrated in the teriparitide and alendronate trial conducted in patients with PMO [38]. Mechanistically, there are two prevailing explanations for this. The first relates to uncoupling of osteoclast-mediated bone resorption and new bone formation by osteoblasts. If failure of combination regimens results from uncoupling, then similar results to those with alendronate are expected with denosumab. On the other hand, if the lack of osteogenesis is due to osteoblast toxicity, such as that observed in preclinical models [39], which does not occur with RANKL inhibition [36,40], then denosumab would be expected to work in combination with anabolic agents.
The discovery of the RANK, RANKL, and OPG pathway as the final effector of bone resorption has generated great expectations regarding the potential of a biologic antagonist for the treatment of patients with various metabolic and inflammatory bone disorders. The broad clinical trial experience to date indicates that denosumab may be a biologic agent that can effectively inhibit bone resorption with minimal side effects. The hope is that ongoing phase 3 clinical trials will demonstrate similar efficacy and safety profiles for denosumab therapy in PMO and metastatic cancer. Finally, looking to the future, it is not unreasonable to expect that other metabolic bone diseases, which have been refractory to bisphosphonates, will respond to this novel therapeutic approach.
BMD = bone mineral density; mAb = monoclonal antibody; NTX = N-telopeptide; ONJ = osteonecrosis of the jaw; OPG = osteoprotegerin; PMO = postmenopausal osteoporosis; RA = rheumatoid arthritis; RANK = receptor activator of nuclear factor-κB; RANKL = receptor activator of nuclear factor-κB ligand; TNF = tumor necrosis factor.
Competing interests
During the past five years, EMS has received reimbursements, fees, and research funding from the sponsor (Amgen Inc.). No funding was received for preparation of this manuscript. EMS holds stock or shares in Amgen Inc. CTR is a consultant to Wyeth/Amgen and is an investigator on the AMG 162 RA trial.
The authors are supported by Public Health Service grants from NIH, NIAMS (RO1s AR46545, AR48149, AR51469 AR/AG48697, and P50 AR54041).
This article is published as part of Arthritis Research & Therapy Volume 9 Supplement 1, 2007: Basic science, rationale, background and future of denosumab: a RANK ligand inhibitor. The full contents of the supplement are available online at http://arthritis-research.com/supplements/9/S1.
Publication of the supplement has been supported by an unrestricted grant from Amgen Inc.
Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function.
Nature 1997, 390:175-179. PubMed Abstract | Publisher Full Text
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, et al.: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Cell 1997, 89:309-319. PubMed Abstract | Publisher Full Text
Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation.
Nature 2003, 423:337-342. PubMed Abstract | Publisher Full Text
Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR: The effect of a single dose of osteoprotegerin in postmenopausal women.
J Bone Miner Res 2001, 16:348-360. PubMed Abstract | Publisher Full Text
Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, Harousseau JL, Lipton A, Mariette X, Williams CD, et al.: A phase I study of AMGN-0007 a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases.
Cancer 2003, 97:887-892. PubMed Abstract | Publisher Full Text
Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, Holmes GB, Dunstan CR, DePaoli AM: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.
J Bone Miner Res 2004, 19:1059-1066. PubMed Abstract | Publisher Full Text
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al.: Identification and characterization of a new member of the TNF family that induces apoptosis.
Immunity 1995, 3:673-682. PubMed Abstract | Publisher Full Text
Weiner LM: Fully human therapeutic monoclonal antibodies.
J Immunother 2006, 29:1-9. PubMed Abstract | Publisher Full Text
Lonberg N: Human antibodies from transgenic animals.
Nat Biotechnol 2005, 23:1117-1125. PubMed Abstract | Publisher Full Text
Green LL: Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies.
J Immunol Methods 1999, 231:11-23. PubMed Abstract | Publisher Full Text
Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J: Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions.
Cytokine 1995, 7:251-259. PubMed Abstract | Publisher Full Text
Kostenuik PJ: Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength.
Curr Opin Pharmacol 2005, 5:618-625. PubMed Abstract | Publisher Full Text
Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M, Holloway D, Peterson MC, Bekker PJ: A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.
Clin Cancer Res 2006, 12:1221-1228. PubMed Abstract | Publisher Full Text
McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, et al.: Denosumab in postmenopausal women with low bone mineral density.
N Engl J Med 2006, 354:821-831. PubMed Abstract | Publisher Full Text
Suarez T, Fizazi K, Rahim Y, Wilson JM, Fan M, Jun S, Lipton A: A randomized trial of denosumab (AMG 162) versus intravenous bisphosphonates in cancer patients with bone metastases on established IV BP and evidence of elevated bone resorption [abstract].
Lipton A, Alvarado C, De Boer R, Steger GG, Tonkin KD, Kinsey A, Fan M, Jun S: Randomized, active-controlled study of denosumab (AMG162) in breast cancer patients with bone metastasis previously treated with intravenous bisphosphonates [abstract].
Cohen SB, Valen P, Ritchlin CT, Schechtman J, Peterfy C, van der Heijde D, Zhou L, Newmark R, Tsuji W: RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: month 6 MRI results [abstract 2120].
Lane NE, Iannini M, Atkins C, Haraoui B, Zhou L, Tsuji W, Newmark R: RANKL inhibition with denosumab decreases markers of bone and cartilage turnover in patients with rheumatoid arthritis [abstract 451].
Arthritis Rheum 2006, 54:S225. Publisher Full Text
Dore R, Hurd E, Palmer W, Shergy W, Zhou L, Newmark R, Tsuji W: Denosumab increases bone mineral density in patients with rheumatoid arthritis [abstract 488].
Whyte MP: The long and the short of bone therapy.
N Engl J Med 2006, 354:860-863. PubMed Abstract | Publisher Full Text
Allen MR, Iwata K, Phipps R, Burr DB: Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate.
Bone 2006, 39:872-879. PubMed Abstract | Publisher Full Text
Flick LM, Weaver JM, Ulrich-Vinther M, Abuzzahab F, Zhang X, Dougall WC, Anderson D, O'Keefe RJ, Schwarz EM: Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing.
J Orthop Res 2003, 21:676-684. PubMed Abstract | Publisher Full Text
Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS III, Frankel WN, Lee SY, Choi Y: TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells.
J Biol Chem 1997, 272:25190-25194. PubMed Abstract | Publisher Full Text
Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, et al.: RANK is essential for osteoclast and lymph node development.
Genes Dev 1999, 13:2412-2424. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, et al.: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.
Nature 1999, 397:315-323. PubMed Abstract | Publisher Full Text
Bachmann MF, Wong BR, Josien R, Steinman RM, Oxenius A, Choi Y: TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation.
J Exp Med 1999, 189:1025-1031. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Stolina M, Guo J, Faggioni R, Brown H, Senaldi G: Regulatory effects of osteoprotegerin on cellular and humoral immune responses.
Clin Immunol 2003, 109:347-354. PubMed Abstract | Publisher Full Text
Woo SB, Hellstein JW, Kalmar JR: Systematic review: bisphosphonates and osteonecrosis of the jaws.
Ann Intern Med 2006, 144:753-761. PubMed Abstract | Publisher Full Text
Capsoni F, Longhi M, Weinstein R: Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist's role.
Arthritis Res Ther 2006, 8:219. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
Shane E, Goldring S, Christakos S, Drezner M, Eisman J, Silver-man S, Pendrys D: Osteonecrosis of the jaw: more research needed.
J Bone Miner Res 2006, 21:1503-1505. PubMed Abstract | Publisher Full Text
Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA: Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis.
Ann Rheum Dis 1989, 48:396-399. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Maccagno A, Di Giorgio E, Roldan EJ, Caballero LE, Perez Lloret A: Double blind radiological assessment of continuous oral pamidronic acid in patients with rheumatoid arthritis.
Scand J Rheumatol 1994, 23:211-214. PubMed Abstract | Publisher Full Text
Eggelmeijer F, Papapoulos SE, van Paassen HC, Dijkmans BA, Valkema R, Westedt ML, Landman JO, Pauwels EK, Breedveld FC: Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial.
Arthritis Rheum 1996, 39:396-402. PubMed Abstract | Publisher Full Text
Valleala H, Laasonen L, Koivula MK, Mandelin J, Friman C, Risteli J, Konttinen YT: Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease.
J Rheumatol 2003, 30:468-473. PubMed Abstract
Zhang Q, Badell IR, Schwarz EM, Boulukos KE, Yao Z, Boyce BF, Xing L: Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2.
Arthritis Rheum 2005, 52:2708-2718. PubMed Abstract | Publisher Full Text
Childs LM, Paschalis EP, Xing L, Dougall WC, Anderson D, Boskey AL, Puzas JE, Rosier RN, O'Keefe RJ, Boyce BF, et al.: In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis.
J Bone Miner Res 2002, 17:192-199. PubMed Abstract | Publisher Full Text
Li P, Schwarz EM, O'Keefe RJ, Ma L, Boyce BF, Xing L: RANK signaling is not required for TNFalpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis.
J Bone Miner Res 2004, 19:207-213. PubMed Abstract | Publisher Full Text
Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.
N Engl J Med 2003, 349:1207-1215. PubMed Abstract | Publisher Full Text
Iwata K, Li J, Follet H, Phipps RJ, Burr DB: Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia.
Bone 2006, 39:1053-1058. PubMed Abstract | Publisher Full Text
Kostenuik PJ, Capparelli C, Morony S, Adamu S, Shimamoto G, Shen V, Lacey DL, Dunstan CR: OPG and PTH-(1–34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats.
Endocrinology 2001, 142:4295-4304. PubMed Abstract | Publisher Full Text