text:
Medics are en route to Havasu Inn for a report of a female subject that is seizing and is turning blue. The RP is no longer answering dispatcher's questions.
FD en route.
Ambulance en route.
PD is also en route in case they can arrive quicker and provide medical aide.
FD reporting patient and medical staff en route to hospital.


text:
Peak District Stag and Hen Do – Activity Choices?
If you have been given the responsibility of organising a stag or hen do in the Peak District then you will be faced with the same dilemma as many others before you. Where can you stay? what activities can you do? what is the best location? where can we go on a night time and How much will it all cost?
When you call us we will talk through activity options to help you decide on an activity day which may include Abseiling, Mountain Biking, Caving, Rock Climbing, Competitive Team Challenges or Ghyll Scrambling. Most of these outdoor activities can be run across many different parts of the Peak District so some of it will come down to where you decide to stay. We can help you with this and point you in the right direction based on budget and location.
Stag and Hen parties in the Peak District offer a wide variety of choices in terms of accommodation and activities or proximity to places like Manchester / Sheffield / Derby. The Peak District has some beautiful group accommodation dotted all over the Peak District. You have a playground for adventurous activities on the doorstep with a wide range to choose from.
Dolomite Training have been running Stag and Hen parties in the Peak District for nearly 10 years now so have met plenty of people and come up with lots of ideas to make your day even better. We understand that not everyone in the group will want to Abseil off a viaduct or go Rock Climbing in the Peak District, so we tweak each course to allow for this and be as inclusive as we can. This makes for a better day for everyone and you can all have a laugh in the pub about what adventures you have had.
It is always easier to talk through what adventurous outdoor activities will work for you and come up with a plan. Even if you don't know where you are staying yet why not get in touch for an informal chat about options that might work and ideas of where would be best to get group accommodation in the Peak District
For more information why not visit our Stag and Hen page and complete an enquiry form.

subset: commoncrawl


text:
Charro Saddles
The Mexican charro saddle evolved from the Spanish saddle brought to America by the conquistador Herman Cortes.
But the Spanish saddle did not have a horn. That feature is a Mexican invention. The Aztec Indians had taught settlers to braid and throw rope from the ground. They then adapted the skill for horseback work by building the iconic charro saddle horn recognized today.
Compared to a Western saddle, the charro saddle has a wider seat and a bigger horn, and it's constructed with leather strings holding it together. The Charro saddle is well suited for riding in the Western American mountains. The region has the same terrain and climate as Spain, where the saddle originally came from.


text:
Live Your Moment is dedicated to the development of material and presentations designed to train and inspire individuals to effectively pursue their goals, dreams, and aspirations in an organized and
systematic fashion.
When NASA successfully launches a shuttle craft into orbit, the accomplishment of this goal is contingent upon dedicated people who have a clearly defined mission and are prepared to carry it out.
In no way are they flying by the seat of their pants. Neither should you. When you know what you want to do and are determined to get it done, you need, as well, to clearly define your goal and be prepared to effectively carry out your mission to make that goal a reality.
Whether your objectives are related to your profession, your business, or are more personal and domestic in nature, Live Your Moment can help you to make it happen.
Click a Category To See a List Of Seminars and Training Classes Offered by
Live Your Moment
view all training courses by title
Company Policies
(class times,
cancellations etc.)
Meals - Beverages and snack provided.
Dress - Business Casual
Class times - A.M. classes are 8:00 -12:00 AM, Afternoon classes are 1:00 - 5:00 PM
Search providers by category
Search By Alphabet
Search By Geographical Location
Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware District of Columbia Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming
Your Company
send a link to this page!
FindaSeminar.com provides
multiple ways for you to search and register for semianrs workshops and
conferences. Please read these
Seminar search tips for easy instructions about how to search training
by city and or use the links above to search seminars by category, title,
hotel. zip code, and by month.
Use our
Training calendar creator tool to create free personal training
calendars and them send them to yourself and your friends and associates.
Use the alpha links or the
other seminar search links to quickly find thousands of local training
seminars workshops and other training events held by popular training
providers like Live Your Moment
Click any title to view course details and
event dates and locations
course list
© 2002-2018 FindaSeminar.com™ All Rights Reserved.
Terms of Use |
Privacy Policy |
Training News Network


text:
Product Benefits and Features
Part of an ingenious, trendy mix-and-match system, deluxe Large Orange Gift Box Bases are designed with a pitch-perfect color and well-made quality. All Items sold separately unless noted.
- 8" L x 8" W x 5" H
- 25 box bases per case.
- Made of 350 GSM SBS paperboard with a matte finish.
- Recyclable.
- The lids and gift box bases are sold separately allowing the option to mix and match colors.
- Gift box base fits lids GBL-L-35 (Orange), GBL-L-12 (Black), GBL-L-44 (Chocolate), GBL-L-87 (Pistachio), GBL-L-1 (Red), GBL-L-7 (Silver), GBL-L-9 (White) or GBL-L-14 (Fuchsia).
- Gift box base fits lids GBL-L-15 (Gold), GBL-L-29 (Lime Green), GBL-L-30 (Robin's Egg Blue) or GBL-L-8 (Kraft).
- Gift box base fit lids with windows GBLW-L-44 (Chocolate), GBLW-L-15 (Gold), GBLW-L-7 (Silver), GBLW-L-9 (White) or GBLW-L-8 (Kraft).
- Food-safe barrier is recommended.
- Ships flat; easily assembled with a fold and tuck tab lock.
- Please allow 3 - 5 business days for processing. Product ships from a separate warehouse. Additional time might be required during peak holiday season.
- 20% restocking fee if item is returned.
- Made in China.


text:
Africa's rapid urbanization can be a driver of industrialization
By 2035, half of Africa's population will be urban, compared to just one third in 1990. This rapid urbanization creates growing challenges in terms of infrastructure and services' needs, but it can also be a driver of industrial development on the continent, under the right policy framework.
In this context, the latest Economic Report on Africa by the UN Economic Commission for Africa (ECA), "Industrialization and Urbanization for Africa's Transformation", makes concrete recommendations for harnessing the rapid urban transition.
During the launch of the report by the ECA in Eastern Africa, Ms. Giovanie Biha, ECA's Deputy Executive Secretary, stressed that "African urbanization has not been driven by improving agricultural productivity or increased industrial output, as has been the case elsewhere". "On the contrary," she added, "it has been dominated by the expansion of the informal sector – often services. To foster enhanced growth and poverty eradication, African countries should put in place industrial policies that will generate the skilled jobs and productivity gains needed for the structural transformation of their economies."
According to Edlam Yemeru, Chief of Urbanization Section at ECA, there is an urgent need to connect policies and strategies for urban and industrial development for better performing cities and industries. "Coordinating urban and industrial development is possible by linking economic and spatial policies in the context of national development planning", said Yemeru
Speaking on behalf of the government of Rwanda, Mr. Richard Mushabe, Division Manager of National Planning and Research at Ministry of Finance and Economic Planning highlighted that urbanization requires coordinated initiatives. "We need an integrated plan which ensures that our cities can improve the lives of our people and can enhance inclusive growth our economies", he said.
The launch of the 2017 Economic Report on Africa also provided an opportunity to discuss the challenges of industrialization and structural transformation on the continent and for Eastern Africa in particular. In most of the 14 countries covered by the SRO-EA, the share of the manufacturing sector has been stagnant or declining over the past ten years while the services sector has expanded rapidly.
Despite a weak structural transformation process, the long-term growth outlook remains promising in Eastern Africa. The GDP growth rate is estimated at 5.6% in 2017, the same as in 2016. This is down from the exceptional performance of the past five years, with Ethiopia achieving an average annual growth rate of 9.5% and Rwanda 7.2% between 2012 and 2016, but it remains well above the African continent average of 3.1% in 2017.
Andrew Mold, Acting Director of ECA in Eastern Africa, highlighted some of the growth catalysts such as massive investments in infrastructure or dynamism of some service sectors (such as trading, finance, and tourism). However, these increased investments have also started to stretch budgets and structural constraints remain such as weak credit to the private sector or exchange rate volatility.


text:
Series: Defy, #1
Publisher: Scholastic
Release Date: January 7, 2014
Genres: Fantasy, Romance, YA
Pages: 336
Source: Received in exchange for review
Goodreads | Purchase
A lush and gorgeously written debut, packed with action, intrigue, and a thrilling love triangle.
Alexa Hollen is a fighter. Forced to disguise herself as a boy and serve in the king's army, Alex uses her quick wit and fierce sword-fighting skills to earn a spot on the elite prince's guard. But when a powerful sorcerer sneaks into the palace in the dead of night, even Alex, who is virtually unbeatable, can't prevent him from abducting her, her fellow guard and friend Rylan, and Prince Damian, taking them through the treacherous wilds of the jungle and deep into enemy territory.
The longer Alex is held captive with both Rylan and the prince, the more she realizes that she is not the only one who has been keeping dangerous secrets. And suddenly, after her own secret is revealed, Alex finds herself confronted with two men vying for her heart: the safe and steady Rylan, who has always cared for her, and the dark, intriguing Damian. With hidden foes lurking around every corner, is Alex strong enough to save herself and the kingdom she's sworn to protect?
Despite my one star rating, I wasn't at all disappointed with Defy. Simply because I knew it was going to be bad, and I went into this novel just to see how terrible it was. However, I had not expected it to be so bad that I nearly vomited in my mouth.
Defy checks all boxes for one of the worst fantasy books I've read this year. Sure, we're only 7 days into 2014 but I can just feel like it's going to be the worst I've encountered.
1. Fail, un-kick-ass protagonist? Check. We have Alexa (Alex) Hollen, disguised as a boy to be her brother's twin in order to escape the breeding houses instead to be a member of Prince Damian's personal guard. Apparently, Alex could beat the captain of the guard in a match but I felt that Alex was so weak. I wanted an as hard as nails chick who would kick ass in her sleep. I wanted a girl with a heart of steel. But instead I got a girl who dreams of her two love interests. I got a girl who couldn't stop her goddamn emotions. There was this certain scene where the main characters are being attacked and Alex quickly jumps into the action, I was rather confused. Because her personality was whiny and girly I totally forgot that Alex was supposed to be some heroic and kick-ass boy.
2. Non-existent world building? Check. For majority of the time, I couldn't imagine anything that the author was taking about. Just insert some castle here and jungle there, viola! I need more details, more substance. And not breeding houses.
3. Illogical plotting? Check. So there's a war that's been going on for some 10-20 years and the evil, evil king decides to get all females who have reached the age where they can reproduce to go to these breeding (rape) houses so they can make soldiers. So basically, these lil' infants are going to go to war. WUT? You at least have to have them grow up as well as train them which is also gonna take another 10-20 years. How the flip does that work when your nation is already losing the war? How long is this war gonna go on for? NOTHING MAKES SENSE.
4. No history on the world the author as created? Check. Apart from the horrendous and irrelevant breeding houses, we don't have much else. There's no history of what happened to make this war begin and stuff like that. I don't want to be thrown in the middle of a book and just left there staring into the distance. I need background information. I need to know why some people have special powers and why some don't.
5. Love triangle? Check. We have a snotty and lazy and ungrateful Prince Damian and a sweet but annoying best friend Rylan. Who does she choose? Why of course, the impossible to have, Prince Damian! *rolls eyes*
What makes me want to gag more is that it just happens that both love interests knew that she was a girl ever since and loved her ever since. O___O
If you want a girl disguised as a guy, go for Eon or watch Mulan. Honestly. Don't waste your time on this.
~Thank you Scholastic for sending me this copy!~
Latest posts by Melanie (see all)
- Giveaway: The Mortal Instruments by Cassandra Clare - February 14, 2016
- Midnight Blogging 101: The Thing About ARCs - January 16, 2016
- YA Midnight Reads is looking for a new co-blogger! - January 9, 2016
- Mel's 2016 Resolutions (That Hopefully Will Last the Year) - January 7, 2016


text: The village of Afissos, amphitheatrically built, is situated on the foot of mountain Pelio, 25km. away from Volos, covered in olive groves. The wide beach consists of three sandy bays, all of which are ideal for swimming and relaxation. Along the waterfront the visitor may find several tavernas, cafeterias and bars. All houses follow the traditional architectural style. There is also a satisfactory choice of accommodation, including hotels and rooms to let.


text: I love the device but I feel a really big oversight (maybe I am wrong) if so please enlighten me. Shouldnt one of the 4 buttons be a phone button to bring you right back to the phone app as fast as possible? I feel like I get lost a little in the OS when looking for the phone app. I feel it is not intuitive to getting back to hang up a phone call etc... and doing it in a FAST WAY. Maybe its just me?


text:
Paulasi Taulava's (206-C-73, college: BYU-Hawaii) situation in the Philippines isn't getting better. The PBA commissioner said that he couldn't play in the PBA Cup despite a local court injuction, and his team lost 2-4 in the final series. The Department of Justice is looking into the possibility of filing criminal charges against him for obtaining Filipino citizenship through fraudulent means.
Taulava thought he would be cleared to play when he was able obtain a writ of preliminary injuction from the Quezon City Regional Trial Court in late January, ordering the PBA Commissioner to lift the player's suspension. He played in the Game 1 of the Cup Finals series between his team Talk'N'Text and the Barangay Ginebra. While Taulava contributed minimal points and rebounds, his presence alone was enough to contain Ginebra's big men, leading to an 89-71 victory by his team. Unfortunatly the PBA Board called this situation illegal and gave the victory to Ginebra, they decided to prevent Asi to play in the other games of the serie, his coach said that this decision was "demoralizing.". His squad lost the Game 2 105-106."I wish there's a chance I could be there right now to help my teammates defend the crown," said Taulava after his team walloped Barangay Ginebra, 102-66, in Game 3 of the finals. "But it's difficult right now" His side would also claim the Game 4 90-85 to tie the serie even at 2-2.The Quezon City Regional Trial Court denied the motion filed by PBA Commissioner Noli Eala for the court to reconsider its lifting of the suspension of Asi Taulava. But Eala, a lawyer by profession, said that although his office has yet to receive a copy of the decision, the PBA is expected to appeal, and the 6-foot-10 center remains suspended from the league. Without its best player, Talk'N'Text lost the Game 5 and 6 (85-95 after two overtime, 86-96 in front of 18000 fans.A worst news came from the Department of Justice which is looking into the possibility of filing criminal charges against Taulava for obtaining Filipino citizenship through fraudulent means. According to Justice Secretary Raul M. Gonzalez, Taulava could face charges or violation of Article 172 of the Revised Penal Code for falsification of public documents. Hoping to press its extradition case against him, the Department of Justice put the center on a list of persons to be subpoenaed in order to investigate the alleged falsification of his birth certificate and determine his citizenship. Justice Secretary Raul M. Gonzalez also said "new evidence" against Taulava will give the department the chance to lift the injunction order issued by the Manila Regional Trial Court, which prevented the deportation of the PBA star.But the future could get brighter. Taulava would have a last chance to prove his filipino roots, and after that he would be able to play for the Philippines National Team! The NT coach Chot Reyes virtually guaranteed a slot for Taulava in the 21-man training pool once the suspended center is cleared to play by the PBA. "If he is cleared by the PBA, we will reserve a slot for him the in the training pool. Without that, I guess we cannot do much," Reyes added. We hope that this situation will be set in the near future, and that Paulasi Taulava won't be ban from the league as an example.


text:
It's not over the emails we've seen, but the ones we haven't. Rosenthal admits to erasing thousands of emails after a federal judge told him to turn them over.
By now you probably know about Chuck Rosenthal's scandalous emails, but do you have any idea why he had to turn them over and even more importantly why he has to answer to a federal judge?
It all started on Houston's East Side, on a cold afternoon on January 4, 2002. Harris County Sheriff's Deputies showed up at a home with a search warrant, looking for drugs.
They arrested Niconar Gonzales' father.
"They put a shotgun on my head," he said. "Get on the floor or I'll shoot you in your head."
Niconar's grandmother took photos after she saw Niconar and other kids being kept outside without shoes or warm clothes that cold morning.
"My main concern was the kids," Madalyn Valdez said.
Next door neighbors Sean and Erik Ibarra were shocked by what cops were doing, so they too grabbed their cameras.
"What we wanted to insure happened that if it was an injustice with those kids next door, that is was documented," Erik Ibarra said.
"They wanted our film because they tore it up here," Valdez recalled. "They were laughing in front of us and tearing it up."
Officers arrested the Ibarras for evading arrest. The brothers were found not guilty and two years later filed a federal suit claiming the arrest and seizure of their film was a violation of their civil rights.
But the details of this raid six years ago and the arrest of neighbors for apparently photographing it won't even come up in court. This is all about Chuck Rosenthal. The thing is Rosenthal didn't know about the raid beforehand six years ago, he certainly wasn't there six years ago, in fact his name doesn't even come up in this lawsuit. So then why is Chuck Rosenthal going to court facing jail time in the morning?
"I think something should happen to him," said attorney Lloyd Kelley.
Lloyd Kelley is the Ibarra's lawyer. Kelley wanted Rosenthal to investigate the way sheriff's deputies behaved at the raid.
Kelley claims the DA's didn't conduct a proper investigation so he subpoenaed Rosenthal's emails to see what the DA was saying about the case.
Under court order, Rosenthal turned over hundreds of messages, but deleted 2,500 more. That's why Rosenthal has to face a federal judge.
"He destroyed evidence," Kelley said. "You can't do that in our system."
There wasn't anything in the recent emails about the Ibarras, but there sure was enough in there to cause Rosenthal a lot of trouble and help Lloyd Kelley's friend Clarence Bradford who happens to be running for DA.
Something Lloyd Kelly quickly dismisses.
"You would have to give me power of clairvoyance to know what he had," Kelley said. "I was looking for stuff about my case. What falls out is evidence of illegal activity, racism - sexism, all sorts of horrible stuff."
"I'd hate to see a political hit job ruin a guy's career, but Chuck Rosenthal has a lot to answer for here," said attorney Mark Bennett.
Houston defense lawyer Mark Bennett is the president elect of the Harris County Criminal Defense Lawyers Association.
Bennett believes Kelley had political, as well as legal motives, for exposing Rosenthal's email. In a federal contempt hearing, motive just doesn't matter.
"I don't know if he belongs there, but he's there and when you're in federal court and a federal judge tells you to do something, you do it," he said. "If I had a client who did the same thing, I would remind the client it was an exceptionally stupid thing to do. The question is was it contempt of court and was it a criminal violation?"
The hearing starts Thursday morning and is expected to last all day. Rosenthal is expected to speak in court under oath.
He refused an interview with us.


text:
Music to my ears! November 29, 2013Posted by Stella☆LunaC in Mike's Big Adventure in Liver Transplant.
Tags: liver, Nazareth, rehabilitation, Thanksgiving, transplant
4 comments
Happy Happy Thanksgiving!
We took dinner to Nazareth Health and Rehab Center; they allowed us to use one of their lovely conference rooms, and provided the flatware and dinner plates, coffee and water. The room was perfect!
Mike's sis and brother-in-law came out and spent the day with Mike; she made the most excellent cranberry apple sauce for the dinner. We had turkey breast, dressing, Brussels sprouts with bacon and cheddar jack cheese, garlic mashed potatoes, gravy and rolls. She even brought a can of cranberry jelly for Mike to put on his sandwich; he just wanted the canned kind…*snorts!
We were so busy enjoying the meal and the time together, in a lovely homelike setting, I totally forgot to take pics!
Today I got a phone call from Mike's Transplant Coordinator, Sue. She called to tell me she had just spoke with Mike; she could not believe the change in him!!! She said, while she didn't really know Mike long before his transplant, did not really know the person he was before his illness took over, she had to say his post-op mental status sure surprised her since his discharge in Sept. She said he is a study in how a person can go from being so SICK and encephalitic, to where he is today, she couldn't get over the improvement! She said she plans to use his case as a guide for others who may experience extremes of the transplant process (and help wives who are ready to pull their hair out, like I was).
it just made Mike's and my day!
HAPPY@#^$%@$)! Thanksgiving, Turkeys! Yep, Mike's back!
don't rock the Bitstrip… November 19, 2013Posted by Stella☆LunaC in Mike's Big Adventure in Liver Transplant, to liver transplant and beyond.
Tags: bitstrips, Cirrhosis, liver, PT, Trailblazer, Willows
add a comment
Just when I thought it was safe to go back in the water….
You would think an oil change wouldn't be any big deal, right? HA, you haven't been in my neck'o the woods lately. Things around here just don't work the way you'd think.
So I had this oil change coupon, with tire rotation included. $16.99 YAY! They got the TBlazer up on the lift, then I get the page…."Sandra, we have a problem…" Seems the lower ball joint is Lucy Goosey and needs to be fixed immediately-UGHS!
Then we can't find the wheel lock tool. It isn't anywhere in the truck; most likely at the last place I took the truck, a year ago. GAH!!!!! No problemo, they can unlock it, but now we're up against a time frame and it'll all have to wait until morning. SOoooo I called the neighbor and she came and got me and Igor, and brought us home. Jo saves the day!
Tomorrow, I'll break the news to Mikee, I can't make it until after the truck is fixed.
In other news, I spent much of the morning on the phone with various Skilled Nursing/Rehab facilities, trying to find out if any of them was close to accepting Mike into their PT/OT program. One promises to come through, but we are waiting for a yet to be named "Regional Entity" to call the director back. No worries, it will all work out eventually, right?
Day 74 : Colors of Days and the Marsh Ghosts of Cambridge…. November 4, 2013Posted by Stella☆LunaC in Mike's Big Adventure in Liver Transplant.
Tags: Fall, Liver Cirrhosis, LTAC, organ transplant, PSC
add a comment
I went to visit Mike yesterday, it was a beautiful ride and the best visit yet!!
I saw a strange sight, and had to get a pic this trip, because seeing IS believing. I drive past this one particular marsh just north of a lake between Fort Atkinson and Cambridge, and as you round a turn and look off to the south side of the highway, you may catch a glimpse of a strange local prank we will call the Marsh Ghosts of Cambridge.
Look closely, you will see what looks like an upside-down remote control airplane that perhaps crashed into the marsh. Or a kite that got away from it's Owner, or….
The locals say there is an old man who for years has put on his waders, trudged out into the marsh, and erects up to 7 or 8 of these "ghosts", and then moves them around every night when no one is watching. This trip, I only saw 2 of the strange apparitions.
Mike was very happy to see me and didn't fuss hardly at all while I was there. I brought treats: a mixed box of orange cranberry, banana walnut and blueberry muffins, Crunch 'n Munch and pretzels. Igor was of course, the hit of the day again, mooching Crunch 'n Munch off Dad.
Dr. Hobson came in and talked with us, engaging Mike in the conversation as well. He told us the Wound VAC is doing remarkably well, and may be taken off by the end of this week! Then we can concentrate on getting out of bed and walking again. But for now, they don't want to out any strain on the newly healing wound. Mike took Doc's meaning that he is going home this week. I wish that were true, but he's still got a long way to go… but I still believe.
The time change was the night before, so I stayed over until 4pm, pretending it was 3 pm, and yet staying longer.
I got to meet the girl Mike said reminded him of Natalie, and with her permission, snapped a quick pic to share with Nats. Cutie!
Mike is getting along a tiny bit better on his iPad I bought him last Friday. He still has issues with keeping online; the wifi connection goes off if he is inactive for so long, then someone has to re-connect him. No biggie, but he doesn't like the smallness…He will get used to it, I hope. I found out today, his PS3 is not compatible with WIN8, so no point getting him a laptop. Besides, when will he enjoy it, after he is home and on his feet again? Nice now, while he's bed-ridden, but that won't last forever….
Mike called me this morning, cheery again, until he started talking about how I was never around to see things happen. When I reminded him I was there yesterday, and it was on Sunday, he got very confused and argued that it was Monday I came, and didn't show up at all for the weekend. Nothing I said would change his mind, he got frustrated and then hung up on me when he didn't want to talk anymore. Rational Mike flew out the window again……
I don't know when this will end, the Seroquel helps a lot with the mood swings, but it seems to wear off after about 4-5 days, with peak of clarity on day 3-4. He is also sleeping more, and his days and nights are screwed up. I spoke with him at midnight last night, and he swore it was noon. I told him, "Mike, look outside your window, it's pitch black nighttime…" Nope, that didn't matter; in his head it was high noon…..OY…..
Now I wonder if or when he will manage without anti-psychotic meds…his Psych Dr sent us a letter out last week, she is quitting the practice. Lovely, they are all dropping off Mike's radar like flies…
Tomorrow has to get better. I will not be able to go in, awaiting a delivery via UPS in the afternoon. He will be disappointed, but then he doesn't remember when I am there, so I guess it really doesn't matter…
I started another Ijustwantablackhat for Mike; seems his other hat got lost in the laundry. GRRRrrrrrrrrr….


text:
Because of My Love for You
This devotional poem, or psalm, is intended to be heard as a reflection on Jesus' sacrifice and love for us, in conjunction with communion. Communion is a time to for us to recalibrate our hearts, and this thoughtful posture is a healthy practice, even in our homes and at our workplaces. May this poem encourage you today and remind you of God's great love.
Podcast: Play in new window | Download
You need to login in order to like this post: click here
You might also like


text: I myself am not a fan of the B8's, but yes... I think Sabian does make them in Light/Medium/Heavy versions. Also, how tight did you make the washers between the Top Hi-Hat and the clutching device? If it is to tight it may be choking their sound a little, which would explain their less than satisfactory sound you're getting from them. Not only that but I don't think having the nut to tight in relation to the cymbal can't be to good for the cymbal, being to taught and no freedom to move, and all. You also might want to think about putting a thicker layer of felt washers between the bottom hat and the actual stand [more freedom to move, therefore less 'chok-y' sound] and maybe even more between the top hat and the clutch [again for the freedom of movement]. Hope I Was Of Some Help.


text:
Any person who has to wear glasses or contacts in order to be able to see clearly has probably thought at some point about corrective surgery to better their vision permanently without having to wear corrective lenses every day. Refractive surgery, when performed by a professional, can correct many common vision problems, such as farsightedness, nearsightedness, and even astigmatism, allowing the patient to see without the help of contacts or glasses. If you have been thinking about having this procedure done, there are a few things to consider talking about with your eye doctor.
Consider the Benefits
When performed correctly, there are a number of benefits that the average person will enjoy from their LASIK eye surgery. When performed correctly and by a skilled doctor, this procedure is proven to correct vision in most patients and causes very little pain. Although there will be a short period of time when your vision is blurry after the procedure, it returns to normal by the next day, and since there are no stitches or bandages, recovery time is rather quick.
If there are problems with your vision in the future, a skilled eye doctor can easily make any necessary corrections to improve your vision. In addition, most patients will never again have to wear contacts or glasses after they have this procedure performed.
Are You a Good Candidate?
Unfortunately, not everyone will be able to have San Antonio LASIK and achieve the successful outcome they desire. Your doctor will be able to determine whether or not you are a good candidate for this procedure by checking your eyes and talking to you about your age and the risks that come with the surgery. Unfortunately, LASIK is not an option for people who are under 18 or over a certain age, as the eyes are changing when you are younger and can develop problems as you get older.
It's also important that your eyes are generally healthy, with no scars or problems with the cornea from infections. You need to be willing to stop wearing contacts at least two weeks before your procedure, as they actually change the shape of the cornea and can affect the results when your eye doctor checks to make sure you are a good candidate for the procedure. By allowing your eyes to return to their normal shape, you will give the doctor the best possible chance to see the quality and condition of your eyes.
If you are ready to enjoy the best vision of your life without a lot of pain, a long healing time, or with glasses or contacts, then it's time that you talk to your eye doctor about LASIK. This is a great option for a lot of people and can greatly improve vision quickly, ensuring that this improvement lasts. Glasses and contacts are not only expensive, they also can be very frustrating to keep up with and take care of. But with LASIK, you will no longer have to worry about losing your corrective lenses or keeping them clean.


text:
- Review
- Open Access
Dyslipidemia in diabetic nephropathy
- Daiji Kawanami1Email author,
- Keiichiro Matoba1 and
- Kazunori Utsunomiya1
© The Author(s) 2016
- Received: 12 January 2016
- Accepted: 15 February 2016
- Published: 2 May 2016
Diabetic nephropathy (DN) not only is a major cause of end-stage renal disease (ESRD) in developing and developed countries but also plays a critical role as a risk factor for cardiovascular disease. The pathogenesis of DN is multifactorial and remains to be elucidated. It is well known that dyslipidemia is frequently complicated with diabetes. Recently, dyslipidemia has been recognized to be involved in the progression of DN. In general, diabetic dyslipidemia is caused by impaired action of lipoprotein lipase (LPL) that is localized to the endothelial cells, resulting in increased serum levels of increased triglyceride (TG) and decreased high-density lipoprotein cholesterol (HDL-C). Smaller size and modified low-density lipoprotein (LDL), such as glycated and oxidized LDL, play important roles to induce vascular and renal cellular dysfunction. Previous studies demonstrated that dyslipidemia enhances macrophage infiltration and excessive extracellular matrix (ECM) production in the glomeruli under diabetic conditions, leading to the development of DN. Clinical studies have demonstrated that lipid-lowering therapy shows a protective effect on the renal function. It is well known that statins reduce albuminuria in patients with DN. A series of our studies indicated that this effect is mediated by Rho-kinase inhibition. Rho-kinase plays a key role in the pathogenesis of DN by activating the inflammatory pathway, including oxidative stress, NF-κB, and hypoxia inducible factor (HIF)-1. Intriguingly, Rho-kinase inhibitors have been shown to attenuate glomerulosclerosis as well as atherosclerosis. Therefore, Rho-kinase could be a promising therapeutic target for both DN and cardiovascular disease.
- Diabetic nephropathy
- Dyslipidemia
- Cardiovascular disease
- Statin
- Rho-kinase
Dyslipidemia, an important risk factor for cardiovascular disease, is frequently complicated with diabetic nephropathy (DN). Managing dyslipidemia in DN is extremely important because patients with DN are at a high risk for cardiovascular disease-associated death [1]. Furthermore, dyslipidemia has been shown to play crucial roles in the development and progression of DN [2]. Impaired lipoprotein metabolism, such as increases in very low density lipoprotein (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) and a decrease in high-density lipoprotein cholesterol (HDL-C), is observed in patients with diabetes [3]. In addition to these quantitative changes, quality changes including small dense LDL [4] and oxidized LDL (ox-LDL) make lipoproteins more proatherogenic in diabetes. This review article describes our current understanding of the role of dyslipidemia in the development of DN and the significance of lipid-lowering therapy for the prevention of cardiovascular disease and DN.
Etiology and epidemiology of diabetic dyslipidemia
Typically, patients with type 2 diabetes show increased serum levels of triglyceride (TG) and decreased HDL-C. Furthermore, modifications of LDL, such as glycation and oxidation, are enhanced under diabetic conditions. The prevalence of high LDL-C in patients with diabetes appears to be similar to that of the general population, as demonstrated by the Framingham Study and the United States National Health and Nutritional Examination Survey (NHANES) [5]. In the United Kingdom Prospective Diabetes Study (UKPDS), no differences in total cholesterol levels were reported between diabetic and non-diabetic subjects. The LDL-C levels were comparable in males but higher in females with type 2 diabetes compared to those without type 2 diabetes [6]. On the other hand, increased serum levels of TG and decreased HDL-C were reported in diabetic patients in these studies. In the Framingham Study, an elevation in serum was observed in 19 % of males and 17 % of females with type 2 diabetes, whereas it was observed in 9 % of males and 8 % of females in non-diabetic subjects [7]. In the UKPDS, 50 % of patients with type 2 diabetes had high serum levels of TG [6]. The Heart Protection Study (HPS) showed that the prevalence of low HDL-C was higher in diabetic individuals (21 % in males and 25 % in females) compared to non-diabetic individuals (12 % in males and 10 % in females) [8].
Lipid metabolism in diabetes and DN
As described above, dyslipidemia in diabetes is characterized by an increase in VLDL, LDL, and TG and a decrease in HDL [9]. Under the diabetic milieu, hormone-sensitive lipase is activated, which results in the release of free fatty acid (FFA) from the adipose tissue. The flux of FFA promotes hepatic triglyceride production, leading to excessive apoB and VLDL synthesis [9]. In addition, lipoprotein lipase (LPL) activity is suppressed under the condition of insulin resistance [10]. These changes result in an increase in the serum levels of TG and remnant particles. Apolipoprotein (apo) B48, a major component of chylomicron, is also increased in diabetes, suggesting an accumulation of chylomicron remnants [11]. It has been demonstrated that insulin resistance is aggravated along with the progression of DN, even in the early stage of microalbuminuria [12]. An elevation in the serum levels of apoC-III, an inhibitor of LPL, is also observed in subjects with DN [3].
It has been reported that the serum level of apoB100 is increased in DN [13]. ApoB100 is synthesized in the liver and transferred into VLDL or LDL particles at one molecule per particle. Therefore, a high serum level of apoB100 indicates an increment in the number of VLDL and LDL particles.
Cholesteryl ester transfer protein (CETP) mediates exchange of cholesteryl ester and TG. CETP activity is regulated by apoC-I, a physiological CETP inhibitor. Recently, Bouillet et al. demonstrated that apoC-I's ability to inhibit CETP activity is impaired in diabetic patients [14], which is explained by glycation of apoC-I [14]. Furthermore, it has been shown that the CETP levels are increased in ESRD patients, although the precise mechanism remains unknown [15, 16]. VLDL receives cholesteryl ester from HDL and transfers TG to HDL by CETP. As a consequence, the amount of cholesterol-rich VLDL remnant particles and cholesterol-depleted HDL particles are increased. TG-rich HDL can be hydrolyzed by LPL or hepatic TG lipase (HTGL), thereby becoming lipid-poor HDL which is filtered by the glomeruli and degraded in renal tubular cells [4]. Insulin has been shown to play an important role in the production of apoA-I, which is a major apolipoprotein of HDL [17, 18]. As such, reduced insulin action is potentially involved in the low HDL levels in type 2 diabetes, especially complicated with DN. Furthermore, inflammatory cytokines including tumor necrosis factor (TNF)-α have been shown to inhibit the production of apoA-I and HDL [17]. Nevertheless, the mechanism underlying low HDL in diabetes is complicated and remains unclear.
Ox-LDL is a well-known atherogenic lipoprotein that is modified by oxidation [4]. Recently, small dense LDL is recognized as another important atherogenic lipoprotein due to its potent oxidative property. The serum level of small dense LDL is increased in insulin resistance and diabetes [3]. Of note, the serum level of small dense LDL is reportedly elevated in patients with DN [3], which may be associated with an increased risk for cardiovascular disease in DN.
Impairment of the renal function by lipids
It has been recognized that lipid nephrotoxicity is involved in the development of DN since the 1970s [19]. Previous studies have shown that dyslipidemia facilitates glomerulosclerosis under diabetic conditions. Dyslipidemia complicated with diabetes has been shown to be involved in the development of DN. We have previously demonstrated that hypercholesterolemia exaggerates albuminuria in diabetic rats [20]. From a mechanistic standpoint, this was the first report to demonstrate the involvement of macrophage infiltration into the glomeruli in the progression of DN [20]. Furthermore, excessive extracellular matrix (ECM) production was found in the glomeruli of diabetic LDL receptor-deficient mice [21]. Finally, lipid-lowering therapy has been shown to improve glomerulosclerosis in the Zucker rat, a model of diabetes complicated with dyslipidemia [22]. Mesangial cells and glomerular epithelial cells (podocytes) have been shown to express receptors for TG-rich lipoproteins (TGRLs) [23–26]. TGRLs stimulate inflammatory pathways via the secretion of proinflammatory cytokines such as TNF-α, transforming growth factor (TGF)-β, and interleukin (IL)-6 [27], which results in the production of reactive oxygen species (ROS), leading to excessive ECM production. It has also been reported that ROS itself potentiates TGF-β-mediated signaling, which may cause a vicious cycle in the process of excessive ROS and ECM production [2, 28]. Ox-LDL binds to scavenger receptors in mesangial cells and podocytes [29, 30], thereby increasing ECM production as well as chemokine production, such as monocyte chemoattractant protein (MCP)-1 which induces monocyte migration toward the glomeruli and results in macrophage infiltration [31]. Macrophages become foam cells through the uptake of ox-LDL and facilitate the inflammatory pathway. Several factors, including sterol regulatory element binding protein (SREBP)-1 and Toll-like receptor (TLR) 4, have been shown to mediate lipid nephrotoxicity [32, 33]. The expression of SREBP-1, an important regulator of cellular lipid synthesis [34], is upregulated in STZ-induced diabetic rats. Interestingly, the progression of DN is inhibited in SREBP-1-deficient mice. The development of DN is also inhibited in TLR4-deficient mice fed a high-fat diet [32, 33].
Another mechanism by which TGRLs induce glomerulosclerosis is disruption of the endothelial cell glycocalyx [2]. The glycocalyx is composed of proteoglycans, glycoproteins and glycosaminoglycans and located at the interface between the lumen and endothelial surface [35]. The glycocalyx maintains the endothelial function and regulates glomerular permeability depending on the size and charge of the solute [2]. It has been reported that the volume of systemic glycocalyx was significantly lower in patients with type 1 diabetes than in age-matched control individuals [36]. More interestingly, patients with microalbuminuria showed lower volumes of systemic glycocalyx compared to those without microalbuminuria [36], suggesting that disruption of the glycocalyx may cause alterations in glomerular permeability, leading to albuminuria.
Significance of lipid-lowering therapy in DN
Statins and Rho-kinase
A significant body of evidence has shown the efficacy and usefulness of statins in the management of DN through its pleiotropic effects beyond lipid-lowering effects [39, 40]. Our previous study was the first report to demonstrate a favorable effect of statins on the reduction of albuminuria in patients with type 2 diabetes [41]. Several studies including the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) [42] and Pravastatin Pooling Project [43] demonstrated that statins may be effective for maintaining the eGFR in patients with type 2 diabetes. In the Treating to New Target (TNT) study, atorvastatin increased the eGFR in patients with chronic kidney disease (CKD) [44]. Intriguingly, the Collaborative Atorvastatin Diabetes Study (CARDS) showed that atorvastatin improved the eGFR in patients with diabetes, in particular, those with albuminuria [45]. Thus far, many groups have focused on the mechanism whereby statins exhibit the renal protective effect.
We next elucidated the role played by the Rho/Rho-kinase pathway in macrophage infiltration into the glomeruli. TNF-α, a potent inflammatory cytokine which is involved in insulin resistance, induced the activation of Rho/Rho-kinase and the expression of MCP-1 in cultured mesangial cells. Y-27632, a specific inhibitor of Rho-kinase, attenuated TNF-α-induced MCP-1 expression, indicating that TNF-α stimulates MCP-1 production via a Rho/Rho-kinase-dependent pathway. This was also confirmed by a chemotaxis assay demonstrating that monocytic migration toward mesangial cells was suppressed by a Rho-kinase inhibitor [54]. The expression of macrophage colony-stimulating factor (M-CSF), another important chemotactic cytokine, was also induced by TNF-α via activation of Rho-kinase in cultured mesangial cells [55]. Small interfering RNA-mediated knockdown of ROCK1 and ROCK2, two isoforms of Rho-kinase, indicated that both isoforms have a comparable contribution to the M-CSF expression in mesangial cells. Nuclear translocation and subsequent DNA binding of NF-κB RelA/p65 to the promotor site are critical steps for the transcriptional regulation of M-CSF. We found that TNF-α enhances nuclear translocation of RelA/p65 in cultured mesangial cells. Interestingly, Rho-kinase inhibitor suppressed nuclear translocation of RelA/p65 and accordingly reduced the promoter activity of the NF-κB binding site [55]. This study provided new insight on the role of Rho-kinase, demonstrating that Rho-kinase may regulate intracellular translocation of transcriptional factors, likely through re-organization of actin stress fibers. Finally, we have shown that Rho-kinase blockade attenuates other microvascular complications such as diabetic retinopathy [56] and neuropathy [57], as well as atherosclerosis [58]. Importantly, the effect of Rho-kinase inhibitors on diabetic complications is independent of glucose and blood pressure [51, 53]. These findings suggest that Rho-kinase could be a comprehensive therapeutic target that governs both microvascular and macrovascular complications.
A previous study showed that Rho-kinase inhibition attenuates dyslipidemia-mediated CKD [59]. The study investigated the effects of fasudil on spontaneously hypercholesterolemic (SHC) rats, an animal model of CKD. The rats developed proteinuria accompanied by Rho-kinase activation in the renal cortex. Intriguingly, fasudil significantly attenuated proteinuria in SHC rats. Furthermore, the combination of fasudil and olmesartarn exaggerated this effect [59]. A mechanistic analysis revealed that fasudil inhibited the infiltration of macrophages into the glomeruli and podocyte injury, thereby exerting protective effects against dyslipidemia-mediated CKD [59]. It will be interesting to elucidate the relationship between Rho-kinase and dyslipidemia in DN in the future.
The mechanism by which fibrates ameliorate hypertriglyceridemia remains unknown; however, PPARα agonistic property is considered to play a role in the effects of fibrates. PPARα is expressed in the kidney and reported to possess a renal protective effect in a lipid-lowering-independent manner. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study demonstrated that fenofibrate suppresses the development and progression of DN [60]. Furthermore, the FIELD study revealed that long-term administration of fenofibrate retains the eGFR decline rate [61]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study investigated the effect of combination therapy with simvastatin and fenofibrate [62]. Compared to the control group (simvastatin alone), the combination therapy group (simvastatin plus fenofibrate) significantly suppressed the development of both microalbuminuria and overt proteinuria in patients with type 2 diabetes [62]. In this study, 47.4 % of the type 2 diabetic participants showed a ≥20 % increase in serum creatinine levels from baseline after the initiation of fenofibrate therapy. However, this increase was reversible and there was no residual loss of eGFR over 5 years [63]. On the other hand, 24.6 % of the participants had no increase in serum creatinine levels [63]. Of note, the participants with no increase in serum creatinine levels after the initiation of fenofibrate therapy appeared to have a lower degree of renal function loss over 5 years of therapy in comparison to the patients who received a placebo [63]. Taken together, these results indicate that fenofibrate has protective effects against DN. However, it has been reported that serum creatine levels are increased or unchanged after fenofibrate treatment [64–66]. Although fenofibrate treatment has been reported to alter the renal hemodynamics [67] and induce the secretion of creatinine from the renal tubules [68], the precise mechanisms by which fenofibrate increases the serum creatinine levels are not fully understood.
Interestingly, bezafibrate has been shown to improve glucose metabolism in diabetic individuals [69]. In this study, dyslipidemic patients with diabetes were administered bezafibrate along with anti-diabetic agents. A 24-week administration of bezafibrate resulted in a significant reduction in the HbA1c levels [69]. In relation to enhancement of β-oxidation of fatty acid by bezafibrate, two potential mechanisms have been raised according to these observations. First, bezafibrate improves fatty acid accumulation in β cells, thereby improving insulin secretion. Second, fat accumulation in the liver and muscles are reduced by bezafibrate [69, 70]. Such effect of fibrates regarding the improvement in lipotoxicity and insulin resistance may be beneficial for DN.
Ezetimibe is an inhibitor of a cholesterol transporter in the small intestine (NPC1L1). The Study of Heart and Renal Protection (SHARP) investigated the efficacy and safety of ezetimibe in 9270 patients with CKD (including 3203 patients on dialysis) [71]. In this study, the patients were randomized into the control and simvastatin-ezetimibe combination therapy groups. A significant reduction in LDL-C was observed in the simvastatin-ezetimibe group. Simvastatin-ezetimibe combination therapy also reduced atherosclerosis-related events by 17 % in comparison to patients who received a placebo. The combination of ezetimibe and simvastatin did not worsen the renal function [71]. SHARP is the first study to demonstrate that combination of a statin and ezetimibe is effective in preventing atherosclerosis-associated vascular events without adverse effect on the kidney in patients with CKD. In SHARP, the effects of simvastatin-ezetimibe combination therapy on CKD progression in 6245 non-dialyzed CKD patients were also analyzed [72]. More than 60 % of the patients in the study had advanced CKD (eGFR of <30 ml/min/1.73 m2) and 15 % of patients had DN [72]. Simvastatin-ezetimibe combination therapy was not associated with a significant change in the incidence of ESRD, while it doubled the baseline creatinine level and led to a decline in the eGFR rate in comparison to patients who received a placebo [72]. These findings indicate that in CKD patients, therapy to lower LDL-C prevents atherosclerotic disease but not the progression of renal disease. To date, SHARP is the largest trial to examine the effects of lipid-lowering therapy in patients with advanced CKD. Further studies will be required to elucidate whether lipid-lowering therapy has preventive effects against the progression of early stage DN. SHARP provided evidence that CKD patients should be indicated for lipid-lowering therapy to prevent atherosclerotic events, regardless of their stage of CKD.
The long-chain polyunsaturated fatty acids (PUFAs) consist of omega-6 PUFAs (e.g., arachidonic acid (AA)) and omega-3 PUFAs (e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)). Omega-6 PUFAs are absorbed through the consumption of plant oils such as canola, which is rich in linoleic acid, and omega-3 PUFAs (EPA and DHA) are absorbed through fish consumption. Among them, fish-oil-derived long-chain omega-3 PUFAs have been shown to attenuate glomerulosclerosis and albuminuria in several investigations on experimental DN [73–75]. Hasegawa et al. reported that an intraperitoneal infusion of ethyl-EPA significantly decreased albuminuria along with inhibition of glomerulosclerosis in KKAy/Ta mice, a model of type 2 diabetes [73]. A mechanistic analysis showed that these observations were mediated by the anti-inflammatory and anti-oxidative stress effects of EPA [74].
A retrospective analysis from the Diabetes Control and Complications Trial (DCCT) revealed that the dietary intake of long-chain omega-3 PUFAs is inversely associated with the degree, but not with the incidence, of albuminuria in type 1 diabetes [76]. A cross-sectional analysis investigating the association between fish consumption and microalbuminuria with or without diabetes has been performed [77]. It demonstrated that no significant association was detected between fish consumption and the incidence of microalbuminuria in patients with or without diabetes, but importantly, diabetic patients that consumed more than two portions of fish a week showed a lower risk for macroalbuminuria than those who consumed less than one portion a week [77]. These epidemiologic studies suggest the potential favorable effect of long-chain omega-3 PUFAs on DN. However, clinical interventional studies investigating the effect of PUFAs on DN yielded inconsistent findings. Two studies which investigated the effect of long-chain omega-3 PUFAs supplementation on albuminuria in patients with type 1 diabetes failed to show a significant reduction in albuminuria [78, 79]. In contrast, EPA supplementation resulted in a significant reduction in albuminuria in Japanese patients with type 1 and type 2 diabetes [80, 81]. Racial disparities may be involved in these discrepancies, as it has been suggested that the response to long-chain omega-3 fatty acid or fish consumption may differ between Western and Asian populations [82]. Taken together, further clinical studies are required to determine the effect of PUFA consumption and supplementations on DN.
End-stage renal failure and lipid-lowering therapy
The effect of lipid-lowering therapy on the prevention of cardiovascular events has been established in patients with moderate CKD. A meta-analysis indicated that the effectiveness of statins is independent of moderate impairment of the eGFR [83]. In contrast, evidence is lacking regarding the usefulness of statins in ESRD. The Deutsche Diabetes Dialyse Studie (4D; the German Diabetes Dialysis Study) investigated whether atorvastatin may affect cardiovascular events in type 2 diabetic patients on hemodialysis [84]. After a 4-year follow-up, atorvastatin reduced the LDL-C level by approximately 40 % but failed to improve cardiovascular events [84]. The AURORA trial (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) obtained similar results [85]. Rosuvastatin significantly reduced the LDL-C levels, but it was not able to inhibit cardiovascular events [85]. However, a sub-analysis of the AURORA trial demonstrated that rosuvastatin reduced cardiovascular events (32 % reduction compared to control) in patients with diabetes on hemodialysis [86]. On the other hand, statin therapy failed to show secondary prevention of cardiovascular events in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) study [87]. In this study, statin therapy was initiated at discharge to patients who were hospitalized due to new-onset myocardial infarction. During a 1-year follow-up, statin use significantly inhibited cardiac death in patients with an eGFR (ml/min/1.73 m2) of 15 and over. Statin use at discharge was associated with an improved 1-year survival of patients with mild-to-severe renal insufficiency. However, this effect was attenuated in patients with ESRD [87]. Taken together, evidence has not yet been established for statin use in preventing cardiovascular disease in ESRD patients. Further studies are required to investigate whether the presence of diabetes affects the effectiveness of statin use in ESRD.
Dyslipidemia is an important therapeutic target in the treatment of diabetes. Furthermore, DN accelerates abnormal lipoprotein metabolism, which causes the progression of DN as well as cardiovascular disease. Statin use should be considered for patients with DN to prevent cardiovascular events and renal impairment. However, further evidence is required to establish the benefits of statin use in patients with ESRD.
There is growing evidence that Rho-kinase plays a key role in the development and progression of DN. Statins inhibit Rho-kinase activation, which may be responsible for the pleiotropic effects of statins. Our recent findings raise the possibility that the use of Rho-kinase inhibitors along with statins provides a more potent and specific protective effect on DN.
Lipid-lowering therapy other than statins, such as fibrate, is also important. However, it should be noted that the combination of statin and fibrate is contraindicated for patients with moderate to severe renal impairment. The clinical background of each patient should be taken into account before starting lipid-lowering therapy.
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to K.U. and D.K.), Takeda Science Foundation (to D.K.), Banyu Foundation International (to D.K.), and the Uehara Memorial Foundation (to D.K. and K.M.).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors' Affiliations
- Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225–32. doi:10.1046/j.1523-1755.2003.00712.x.View ArticlePubMedGoogle Scholar
- Rutledge JC, Ng KF, Aung HH, Wilson DW. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol. 2010;6(6):361–70. doi:10.1038/nrneph.2010.59.View ArticlePubMedGoogle Scholar
- Hirano T. Abnormal lipoprotein metabolism in diabetic nephropathy. Clin Exp Nephrol. 2014;18(2):206–9. doi:10.1007/s10157-013-0880-y.View ArticlePubMedGoogle Scholar
- Chehade JM, Gladysz M, Mooradian AD. Dyslipidemia in type 2 diabetes: prevalence, pathophysiology, and management. Drugs. 2013;73(4):327–39. doi:10.1007/s40265-013-0023-5.View ArticlePubMedGoogle Scholar
- Jacobs MJ, Kleisli T, Pio JR, Malik S, L'Italien GJ, Chen RS, et al. Prevalence and control of dyslipidemia among persons with diabetes in the United States. Diabetes Res Clin Pract. 2005;70(3):263–9. doi:10.1016/j.diabres.2005.03.032.View ArticlePubMedGoogle Scholar
- U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care. 1997;20(11):1683–7. http://care.diabetesjournals.org/content/20/11/1683.
- Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J. 1985;110(5):1100–7.View ArticlePubMedGoogle Scholar
- Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation. 2012;125(20):2469–78. doi:10.1161/CIRCULATIONAHA.111.073684.View ArticlePubMedGoogle Scholar
- Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(3):150–9. doi:10.1038/ncpendmet1066.View ArticlePubMedGoogle Scholar
- Pollare T, Vessby B, Lithell H. Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity. Arterioscler Thromb. 1991;11(5):1192–203.View ArticlePubMedGoogle Scholar
- Hayashi T, Hirano T, Taira T, Tokuno A, Mori Y, Koba S, et al. Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease. Atherosclerosis. 2008;197(1):154–8. doi:10.1016/j.atherosclerosis.2007.03.015.View ArticlePubMedGoogle Scholar
- Svensson M, Eriksson JW. Insulin resistance in diabetic nephropathy—cause or consequence? Diabetes Metab Res Rev. 2006;22(5):401–10. doi:10.1002/dmrr.648.View ArticlePubMedGoogle Scholar
- Bonnet F, Cooper ME. Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies. Diabetes Metab. 2000;26(4):254–64.PubMedGoogle Scholar
- Bouillet B, Gautier T, Blache D, Pais de Barros JP, Duvillard L, Petit JM, et al. Glycation of apolipoprotein C1 impairs its CETP inhibitory property: pathophysiological relevance in patients with type 1 and type 2 diabetes. Diabetes Care. 2014;37(4):1148–56. doi:10.2337/dc13-1467.View ArticlePubMedGoogle Scholar
- Kimura H, Miyazaki R, Imura T, Masunaga S, Suzuki S, Gejyo F, et al. Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP levels. Kidney Int. 2003;64(5):1829–37. doi:10.1046/j.1523-1755.2003.00285.x.View ArticlePubMedGoogle Scholar
- Vaziri ND. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol. 2006;290(2):F262–72. doi:10.1152/ajprenal.00099.2005.View ArticlePubMedGoogle Scholar
- Mooradian AD, Haas MJ, Wehmeier KR, Wong NC. Obesity-related changes in high-density lipoprotein metabolism. Obesity. 2008;16(6):1152–60. doi:10.1038/oby.2008.202.View ArticlePubMedGoogle Scholar
- Mooradian AD, Haas MJ, Wong NC. Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes. 2004;53(3):513–20.View ArticlePubMedGoogle Scholar
- Wellmann KF, Volk BW. Renal changes in experimental hypercholesterolemia in normal and in subdiabetic rabbits. II. Long term studies. Lab Invest. 1971;24(2):144–55.PubMedGoogle Scholar
- Utsunomiya K, Ohta H, Kurata H, Tajima N, Isogai Y. The effect of macrophage colony-stimulating factor (M-CSF) on the progression of lipid-induced nephrotoxicity in diabetic nephropathy. J Diabetes Complicat. 1995;9(4):292–5.View ArticlePubMedGoogle Scholar
- Hammad SM, Hazen-Martin DJ, Sohn M, Eldridge L, Powell-Braxton L, Won W, et al. Nephropathy in a hypercholesterolemic mouse model with streptozotocin-induced diabetes. Kidney Blood Press Res. 2003;26(5-6):351–61. doi:10.1159/000073942.View ArticlePubMedGoogle Scholar
- Kasiske BL, O'Donnell MP, Cleary MP, Keane WF. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney Int. 1988;33(3):667–72.View ArticlePubMedGoogle Scholar
- Wheeler DC, Fernando RL, Gillett MP, Zaruba J, Persaud J, Kingstone D, et al. Characterisation of the binding of low-density lipoproteins to cultured rat mesangial cells. Nephrol Dial Transplant. 1991;6(10):701–8.View ArticlePubMedGoogle Scholar
- Grone HJ, Walli AK, Grone E, Kramer A, Clemens MR, Seidel D. Receptor mediated uptake of apo B and apo E rich lipoproteins by human glomerular epithelial cells. Kidney Int. 1990;37(6):1449–59.View ArticlePubMedGoogle Scholar
- Quaschning T, Koniger M, Kramer-Guth A, Greiber S, Pavenstadt H, Nauck M, et al. Receptor-mediated lipoprotein uptake by human glomerular cells: comparison with skin fibroblasts and HepG2 cells. Nephrol Dial Transplant. 1997;12(12):2528–36.View ArticlePubMedGoogle Scholar
- Kramer A, Nauck M, Pavenstadt H, Schwedler S, Wieland H, Schollmeyer P, et al. Receptor-mediated uptake of IDL and LDL from nephrotic patients by glomerular epithelial cells. Kidney Int. 1993;44(6):1341–51.View ArticlePubMedGoogle Scholar
- Nishida Y, Oda H, Yorioka N. Effect of lipoproteins on mesangial cell proliferation. Kidney Int Suppl. 1999;71:S51–3.View ArticlePubMedGoogle Scholar
- Eiselein L, Wilson DW, Lame MW, Rutledge JC. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. Am J Physiol Heart Circ Physiol. 2007;292(6):H2745–53. doi:10.1152/ajpheart.00686.2006.View ArticlePubMedGoogle Scholar
- Schlondorff D. Cellular mechanisms of lipid injury in the glomerulus. Am J Kidney Dis. 1993;22(1):72–82.View ArticlePubMedGoogle Scholar
- Nosadini R, Tonolo G. Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes. Nutr Metab Cardiovasc Dis. 2011;21(2):79–85. doi:10.1016/j.numecd.2010.10.002.View ArticlePubMedGoogle Scholar
- Kamanna VS, Pai R, Roh DD, Kirschenbaum MA. Oxidative modification of low-density lipoprotein enhances the murine mesangial cell cytokines associated with monocyte migration, differentiation, and proliferation. Lab Invest. 1996;74(6):1067–79.PubMedGoogle Scholar
- Ishigaki N, Yamamoto T, Shimizu Y, Kobayashi K, Yatoh S, Sone H, et al. Involvement of glomerular SREBP-1c in diabetic nephropathy. Biochem Biophys Res Commun. 2007;364(3):502–8. doi:10.1016/j.bbrc.2007.10.038.View ArticlePubMedGoogle Scholar
- Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, et al. Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice. Diabetologia. 2012;55(8):2256–66. doi:10.1007/s00125-012-2578-1.View ArticlePubMedGoogle Scholar
- Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89(3):331–40.View ArticlePubMedGoogle Scholar
- Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJ, Stroes ES. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16(5):507–11.View ArticlePubMedGoogle Scholar
- Nieuwdorp M, Meuwese MC, Mooij HL, Ince C, Broekhuizen LN, Kastelein JJ, et al. Measuring endothelial glycocalyx dimensions in humans: a potential novel tool to monitor vascular vulnerability. J Appl Physiol. 2008;104(3):845–52. doi:10.1152/japplphysiol.00440.2007.View ArticlePubMedGoogle Scholar
- Ramasamy R, Yan SF, Herold K, Clynes R, Schmidt AM. Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis. Ann N Y Acad Sci. 2008;1126:7–13. doi:10.1196/annals.1433.056.PubMed CentralView ArticlePubMedGoogle Scholar
- Iacobini C, Menini S, Ricci C, Scipioni A, Sansoni V, Mazzitelli G, et al. Advanced lipoxidation end-products mediate lipid-induced glomerular injury: role of receptor-mediated mechanisms. J Pathol. 2009;218(3):360–9. doi:10.1002/path.2536.View ArticlePubMedGoogle Scholar
- Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med. 2006;145(2):117–24.View ArticlePubMedGoogle Scholar
- Koya D, Campese VM. Statin use in patients with diabetes and kidney disease: the Japanese experience. J Atheroscler Thromb. 2013;20(5):407–24.View ArticlePubMedGoogle Scholar
- Sasaki T, Kurata H, Nomura K, Utsunomiya K, Ikeda Y. Amelioration of proteinuria with pravastatin in hypercholesterolemic patients with diabetes mellitus. Jpn J Med. 1990;29(2):156–63.View ArticlePubMedGoogle Scholar
- Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis. 2004;43(4):589–99.View ArticlePubMedGoogle Scholar
- Tonelli M, Keech A, Shepherd J, Sacks F, Tonkin A, Packard C, et al. Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol. 2005;16(12):3748–54. doi:10.1681/ASN.2005070779.View ArticlePubMedGoogle Scholar
- Shepherd J, Kastelein JJ, Bittner V, Deedwania P, Breazna A, Dobson S, et al. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study. Clin J Am Soc Nephrol. 2007;2(6):1131–9. doi:10.2215/CJN.04371206.View ArticlePubMedGoogle Scholar
- Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54(5):810–9. doi:10.1053/j.ajkd.2009.03.022.View ArticlePubMedGoogle Scholar
- Zhou Q, Gensch C, Liao JK. Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease. Trends Pharmacol Sci. 2011;32(3):167–73. doi:10.1016/j.tips.2010.12.006.PubMed CentralView ArticlePubMedGoogle Scholar
- Fujisawa K, Fujita A, Ishizaki T, Saito Y, Narumiya S. Identification of the Rho-binding domain of p160ROCK, a Rho-associated coiled-coil containing protein kinase. J Biol Chem. 1996;271(38):23022–8.View ArticlePubMedGoogle Scholar
- Adiels M, Boren J, Caslake MJ, Stewart P, Soro A, Westerbacka J, et al. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol. 2005;25(8):1697–703. doi:10.1161/01.ATV.0000172689.53992.25.View ArticlePubMedGoogle Scholar
- Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 2002;16(13):1587–609. doi:10.1101/gad.1003302.View ArticlePubMedGoogle Scholar
- Budzyn K, Marley PD, Sobey CG. Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol Sci. 2006;27(2):97–104. doi:10.1016/j.tips.2005.12.002.View ArticlePubMedGoogle Scholar
- Gojo A, Utsunomiya K, Taniguchi K, Yokota T, Ishizawa S, Kanazawa Y, et al. The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2007;568(1-3):242–7. doi:10.1016/j.ejphar.2007.04.011.View ArticlePubMedGoogle Scholar
- Isoe T, Makino Y, Mizumoto K, Sakagami H, Fujita Y, Honjo J, et al. High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int. 2010;78(1):48–59. doi:10.1038/ki.2010.99.View ArticlePubMedGoogle Scholar
- Matoba K, Kawanami D, Okada R, Tsukamoto M, Kinoshita J, Ito T, et al. Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1alpha. Kidney Int. 2013;84(3):545–54. doi:10.1038/ki.2013.130.View ArticlePubMedGoogle Scholar
- Matoba K, Kawanami D, Ishizawa S, Kanazawa Y, Yokota T, Utsunomiya K. Rho-kinase mediates TNF-alpha-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells. Biochem Biophys Res Commun. 2010;402(4):725–30. doi:10.1016/j.bbrc.2010.10.093.View ArticlePubMedGoogle Scholar
- Matoba K, Kawanami D, Tsukamoto M, Kinoshita J, Ito T, Ishizawa S, et al. Rho-kinase regulation of TNF-alpha-induced nuclear translocation of NF-kappaB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells. Am J Physiol Renal Physiol. 2014;307(5):F571–80. doi:10.1152/ajprenal.00113.2014.View ArticlePubMedGoogle Scholar
- Yokota T, Utsunomiya K, Taniguchi K, Gojo A, Kurata H, Tajima N. Involvement of the Rho/Rho kinase signaling pathway in platelet-derived growth factor BB-induced vascular endothelial growth factor expression in diabetic rat retina. Jpn J Ophthalmol. 2007;51(6):424–30. doi:10.1007/s10384-007-0471-0.View ArticlePubMedGoogle Scholar
- Kanazawa Y, Takahashi-Fujigasaki J, Ishizawa S, Takabayashi N, Ishibashi K, Matoba K, et al. The Rho-kinase inhibitor fasudil restores normal motor nerve conduction velocity in diabetic rats by assuring the proper localization of adhesion-related molecules in myelinating Schwann cells. Exp Neurol. 2013;247:438–46. doi:10.1016/j.expneurol.2013.01.012.View ArticlePubMedGoogle Scholar
- Kawanami D, Matoba K, Kanazawa Y, Ishizawa S, Yokota T, Utsunomiya K. Thrombin induces MCP-1 expression through Rho-kinase and subsequent p38MAPK/NF-kappaB signaling pathway activation in vascular endothelial cells. Biochem Biophys Res Commun. 2011;411(4):798–803. doi:10.1016/j.bbrc.2011.07.031.View ArticlePubMedGoogle Scholar
- Kushiyama T, Oda T, Yamamoto K, Higashi K, Watanabe A, Takechi H, et al. Protective effects of Rho kinase inhibitor fasudil on rats with chronic kidney disease. Am J Physiol Renal Physiol. 2013;304(11):F1325–34. doi:10.1152/ajprenal.00447.2012.View ArticlePubMedGoogle Scholar
- Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61. doi:10.1016/S0140-6736(05)67667-2.View ArticlePubMedGoogle Scholar
- Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia. 2011;54(2):280–90. doi:10.1007/s00125-010-1951-1.View ArticlePubMedGoogle Scholar
- Ginsberg HN, Elam MB, Lovato LC, Crouse 3rd JR, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74. doi:10.1056/NEJMoa1001282.View ArticlePubMedGoogle Scholar
- Mychaleckyj JC, Craven T, Nayak U, Buse J, Crouse JR, Elam M, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35(5):1008–14. doi:10.2337/dc11-1811.PubMed CentralView ArticlePubMedGoogle Scholar
- Ansquer JC, Dalton RN, Causse E, Crimet D, Le Malicot K, Foucher C. Effect of fenofibrate on kidney function: a 6-week randomized crossover trial in healthy people. Am J Kidney Dis. 2008;51(6):904–13. doi:10.1053/j.ajkd.2008.01.014.View ArticlePubMedGoogle Scholar
- Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet. 2001;358(9275):39–40. doi:10.1016/S0140-6736(00)05271-5.View ArticlePubMedGoogle Scholar
- Forsblom C, Hiukka A, Leinonen ES, Sundvall J, Groop PH, Taskinen MR. Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes: the FIELD Helsinki substudy. Diabetes Care. 2010;33(2):215–20. doi:10.2337/dc09-0621.PubMed CentralView ArticlePubMedGoogle Scholar
- Lipscombe J, Lewis GF, Cattran D, Bargman JM. Deterioration in renal function associated with fibrate therapy. Clin Nephrol. 2001;55(1):39–44.PubMedGoogle Scholar
- Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron. 2002;92(3):536–41.View ArticlePubMedGoogle Scholar
- Teramoto T, Shirai K, Daida H, Yamada N. Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients with diabetes: the J-BENEFIT study. Cardiovasc Diabetol. 2012;11:29. doi:10.1186/1475-2840-11-29.PubMed CentralView ArticlePubMedGoogle Scholar
- Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab. 2004;89(2):463–78. doi:10.1210/jc.2003-030723.View ArticlePubMedGoogle Scholar
- Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92. doi:10.1016/S0140-6736(11)60739-3.PubMed CentralView ArticlePubMedGoogle Scholar
- Haynes R, Lewis D, Emberson J, Reith C, Agodoa L, Cass A, et al. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol. 2014;25(8):1825–33. doi:10.1681/ASN.2013090965.PubMed CentralView ArticlePubMedGoogle Scholar
- Hagiwara S, Makita Y, Gu L, Tanimoto M, Zhang M, Nakamura S, et al. Eicosapentaenoic acid ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice: involvement of MCP-1 suppression and decreased ERK1/2 and p38 phosphorylation. Nephrol Dial Transplant. 2006;21(3):605–15. doi:10.1093/ndt/gfi208.View ArticlePubMedGoogle Scholar
- Zhang M, Hagiwara S, Matsumoto M, Gu L, Tanimoto M, Nakamura S, et al. Effects of eicosapentaenoic acid on the early stage of type 2 diabetic nephropathy in KKA(y)/Ta mice: involvement of anti-inflammation and antioxidative stress. Metabolism. 2006;55(12):1590–8. doi:10.1016/j.metabol.2006.07.019.View ArticlePubMedGoogle Scholar
- Shapiro H, Theilla M, Attal-Singer J, Singer P. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat Rev Nephrol. 2011;7(2):110–21. doi:10.1038/nrneph.2010.156.View ArticlePubMedGoogle Scholar
- Lee CC, Sharp SJ, Wexler DJ, Adler AI. Dietary intake of eicosapentaenoic and docosahexaenoic acid and diabetic nephropathy: cohort analysis of the diabetes control and complications trial. Diabetes Care. 2010;33(7):1454–6. doi:10.2337/dc09-2245.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee CT, Adler AI, Forouhi NG, Luben R, Welch A, Khaw KT, et al. Cross-sectional association between fish consumption and albuminuria: the European Prospective Investigation of Cancer-Norfolk study. Am J Kidney Dis. 2008;52(5):876–86. doi:10.1053/j.ajkd.2008.02.307.View ArticlePubMedGoogle Scholar
- Haines AP, Sanders TA, Imeson JD, Mahler RF, Martin J, Mistry M, et al. Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin-dependent diabetics. Thromb Res. 1986;43(6):643–55.View ArticlePubMedGoogle Scholar
- Jensen T, Stender S, Goldstein K, Holmer G, Deckert T. Partial normalization by dietary cod-liver oil of increased microvascular albumin leakage in patients with insulin-dependent diabetes and albuminuria. N Engl J Med. 1989;321(23):1572–7. doi:10.1056/NEJM198912073212304.View ArticlePubMedGoogle Scholar
- Hamazaki T, Takazakura E, Osawa K, Urakaze M, Yano S. Reduction in microalbuminuria in diabetics by eicosapentaenoic acid ethyl ester. Lipids. 1990;25(9):541–5.View ArticlePubMedGoogle Scholar
- Shimizu H, Ohtani K, Tanaka Y, Sato N, Mori M, Shimomura Y. Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients. Diabetes Res Clin Pract. 1995;28(1):35–40.View ArticlePubMedGoogle Scholar
- Wallin A, Di Giuseppe D, Orsini N, Patel PS, Forouhi NG, Wolk A. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care. 2012;35(4):918–29. doi:10.2337/dc11-1631.PubMed CentralView ArticlePubMedGoogle Scholar
- Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini F, Nicolucci A, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008;336(7645):645–51. doi:10.1136/bmj.39472.580984.AE.PubMed CentralView ArticlePubMedGoogle Scholar
- Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238–48.View ArticlePubMedGoogle Scholar
- Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395–407. doi:10.1056/NEJMoa0810177.View ArticlePubMedGoogle Scholar
- Holdaas H, Holme I, Schmieder RE, Jardine AG, Zannad F, Norby GE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol. 2011;22(7):1335–41. doi:10.1681/ASN.2010090987.PubMed CentralView ArticlePubMedGoogle Scholar
- Szummer K, Lundman P, Jacobson SH, Schon S, Lindback J, Stenestrand U, et al. Association between statin treatment and outcome in relation to renal function in survivors of myocardial infarction. Kidney Int. 2011;79(9):997–1004. doi:10.1038/ki.2010.524.View ArticlePubMedGoogle Scholar


text:
You'd never plan your wedding at work (cough, cough) — but your lunch break is a whole other story! For your #WeddingWednesday lunchtime, we rounded up gorgeous real weddings, pretty style details, and helpful tips from across the web. Our favorite recent wedding blogs feature some of the best ideas for seasonal weddings in rain, snow, and shine!
Think about it: You budget in everything you need to have for your wedding, except a weather contingency plan! Doesn't that sound like a nightmare? Avoid that anxiety by checking out this handy list of unexpected wedding costs. — POPSUGAR
This classic Connecticut wedding would have been pretty on a sunny day, but the unexpected rain that fell made the whole thing even more romantic. You have to see how the couple avoided blaming it on the unexpected weather. — BRIDES
This fall-themed inspiration shoot shows how to incorporate the vibrant colors and chilly temperatures of the season into a warm, cozy event. Dripping candles and rich emerald hues? Yes, please! — *100 Layer Cake
An outdoor wedding in Barcelona was a dream for this couple, until rain got in the way. Somehow, when they moved the whole event inside, it got even more beautiful! — Ruffled
Sometimes, the only weather you have during your wedding is sunshine! This stunning winery wedding is dappled with sunlight, and the photos are simply dreamy. — Green Wedding Shoes


text:
1. Introduction
1.1. Archaic texts in the collections of the Oriental Institute
The Oriental Institute of the University of Chicago houses a small collection of archaic cuneiform documents. Copies of five of them (A 2513-2516 + one missing) were first published by V. Scheil (1929: 15-17), where they are said to come from clandestine excavations at Jemdet Nasr before 1915. These tablets are among the first Mesopotamian known documents dating to the Uruk III / Jemdet Nasr period (for a history of the first purchases and acquisitions, see Englund 1998: 23ff.). Transliterations and new copies of these texts were offered later by R. K. Englund (MSVO 1: nos. 10, 25, 68 and 222), who reports that one of the tablets, namely Scheil 1929 no. 3, "seems however to have been lost in Chicago, although a fifth tablet was never assigned an OI number" (MSVO 1: 7, fn. 3). After a brief stay in Paris, these five tablets were accessioned in Chicago on October 6th 1920 together with an Ur III administrative text from Drehem (A 2517, OIP 115: no. 482) and some Hellenistic legal documents from Warka (A 2518-2527, BiMes 24: nos. 1, 13, 14, 19-23, 28, 35). For more details on the history of the archaic documents of this lot, see MSVO 1, p. 7.
One more text in the collections of the Oriental Institute (A 12259) comes from regular excavations conducted by H. Frankfort at Tell Asmar in 1933-1934 and was first published as a photo by P. Delougaz (OIP 63: 77, pl. 64 no. 68). As in the case of the Jemdet Nasr tablets, a transliteration and a copy were later provided by Englund (MSVO 4 no. 79).
The fragment here presented, A 2564, is the last archaic text in the collections of the Oriental Institute and until now has never caught the attention of scholars. It was purchased in Cairo in 1919 in a lot of Ur III tablets mostly from Drehem and Jokha, with a few perhaps from Muqayyar (W. Farber, personal communication, November 18th 2014), being itself part of the small bunch of archaic texts known before the regular excavation of the archaic levels of the most important southern Mesopotamian cities. It is the upper-left corner (32 × 25 × 14 mm) of a tablet of ca. 80 × 60 mm or slightly smaller (fig. 1), probably not a lot thicker than the fragment itself. It constitutes alone the first entry of an administrative account, running the lower break on the ruling. For more complete tablets of the same format see among others MSVO 1: 26 (80 × 50 × 18 mm), MSVO 1: 126 (90 × 56 × 18 mm), MSVO 3: 3 (84 × 59 × 17 mm), CUSAS 1: 77 (81 × 58 × 15 mm).
The ductus of the few readable signs does not leave any doubt about the archaic dating (see infra). The format and the physical features of the fragment may provide some first hints about its provenance: the obverse is slightly convex and the reverse rather flat, unlike most of the tablets from archaic Ur and more similarly to the Jemdet Nasr ones (UET 2: 4), while the scope of the corner and the limited thickness point to Jemdet Nasr or Uruk. The date of acquisition restricts the choice, since not many excavated archaeological sites would have offered accessible archaic levels for plunders in these years. As for Uruk, one should consider the possibility of the renewed interest of looters after the first campaign of J. Jordan in 1912. This excavation left the site exposed to plunder until 1928, the date in which field-work resumed after the forced interruption caused by World War I. Nevertheless, no archaic text until now is known to have found its way to the market during these years. A noteworthy exception is constituted by a gypsum numerical tablet (BM 1851-1-1, 217) collected in the late 40s of the 19th century by the explorer W. K. Loftus (Reade 1992: 177-178). On comparative grounds it is likely to have been found in the White Temple, and leaves open the possibility of the exposure of further archaic material from Uruk before 1928. Nonetheless, a provenance other than Jemdet Nasr in the case of our fragment is still improbable.
2. Transliteration
O0101 1N46; LAGABb? ⌜TE?⌝ BA ⌜GIŠ3b⌝ DUBa ⌜SANGAa⌝
3. Commentary
N46: This numerical sign is exclusively associated with the Š'' system, which traditionally qualifies capacity measures of cereals and specifically emmer. Like here, both in Uruk and in Jemdet Nasr the sign form is a deeper rounded impression crossed by two shallow wedges, whereas in archaic Ur they are almost always three wedges crossing a rounded or squared impression. The diameter of the impression measures 6 mm, almost twice the usual form of N19, of which it represents a multiple. Traces of an erased sign, maybe a DA, are visible directly above the numeral.
LAGABb TE: also transliterated as GIŠ TE. Attested some thirty times in many different archaic corpora. This wording occurs in administrative documents only, mostly associated to the Š'' system and more rarely with the Š system (i.e. emmer and barley accounts). The physical format of these documents is often the same of the fragment under study with the noteworthy exception of an ancient kudurru (OIP 104: no. 1). LAGABb TE occurs a few times in sheep accounts (e.g., in CUSAS 1: no. 59 and Green 1980: nos. 7 and 26). It seems to refer to a total (see among others CUSAS 1: no. 98, where it follows a large amount of emmer, in the final part of the account). In my knowledge, it occurs four times as LAGABb TE A (Green 1980: nos. 7 and 26, W 20511,1 and W 20274,1), suggesting the use of this wording as a participle. Nevertheless, the meaning remains unclear. LAGABb was partially pressed down on the fresh clay and probably written over an erasure; TE is broken and barely recognizable. Hence, this should be considered a tentative reading.
BA: as in the case of LAGABb, the sign was partially pressed down on the fresh clay. This action might have also slightly curved the first vertical to the left, making the sign less recognizable. The high frequency of this sign in the archaic corpora and its position right after the counted item leave little doubt about its meaning, "distribution".
GIŠ3b: maybe (part of?) a PN. It occurs in the archaic lists of fish and birds (Fish 16 and Birds 2) and in another unidentified fragment of lexical nature (ATU 3: pl. 94, W 21019,5). Mostly attested in administrative documents from Jemdet Nasr and Umma, where it occurs more often than the sign form GIŠ3a, preferred in Uruk. Englund (2009: appendix) lists GIŠ3b URa among the PNs occurring in the archaic slave accounts. Nonetheless, the presence of another broken sign in this line is not very probable. This PN might be connected to the name of an ED ensi of Umma, conventionally read UŠ (RIME 18.104.22.168). It is relatively well-attested at ED Umma and is probably to be read as nita, male. GIŠ3b SANGAa is twice attested (CUSAS 1: no. 160; BaM 22: 117).
DUBa SANGAa: well attested in the archaic list of professions Lu2 A (Lu2 48 and 70). Probably a cultic officiant. S. F. Monaco suggested that SANGAa alone might designate an official responsible for accounting and its registration, not necessarily responsible for cults (personal communication, November 20th 2014). For later readings pisan2/3 and umbisaĝ, see Selz 1997: 172 and 192, fn. 99 with former literature.
4. Further remarksEvidently the fragment A 2564 does not offer many wedges for an in-depth palaeographical study. The wedges are thin and mostly quite shallow. The last vertical of DUBa is the most deeply impressed and leaves some space for technical analysis withal. A different view of the wedge (fig. 2, a) let us clearly see the traces left by the head of the stylus, i.e., the three inner edges in form of a "Y" (fig. 2, b). This pattern suggests that only the tip of the stylus to have come into contact with the clay was tetrahedral, and cannot, in any case, on its own provide a certain reconstruction of the whole tool (for a methodological and terminological insight, see Cammarosano et al. 2014). The apertural angle between the left and the right inner edges is approximately equal to 40° (fig. 2, c) and constitutes the maximum aperture of one of the angles of the section of the tool. This datum is obviously subjected to a certain extent to the "lateral tilt" which the scribe himself could have issued with a rotation of the wrist, increasing the angle. The curvilinear trace of one of the inner edges is a marker of the usage of a reed stylus, which in the reconstructions of Messerschmidt (1906: 305, Abb. 6) and Falkenstein (ATU 1: 6, Abb. 1) features a right triangular section. An angle ≥40° is always the narrowest angle of an approximately right triangle: this suggests how the scribe might have had at his disposal three different writing tips, choosing in this case the narrowest of them (fig. 2, d). Nevertheless, scribes did not necessarily make the same choice during the course of the centuries and in different regions. The meticulous analysis of features like the (eventual) disposition of the curvilinear inner edge and of the fibrous reed impressions and the width of the angle of aperture might be crucial in order to trace the history of the usage of an everyday object like the writing stylus, which cannot be ignored anymore in the scope of future palaeographic research. A forthcoming article of M. Cammarosano provides, for instance, the state of the arts of iconographic and archaeological sources regarding the writing stylus, then focusing on 2nd millennium Mesopotamian and Anatolian primary sources. Analogous research is in the case of earlier times still a big desideratum.
5. Conclusions
The fragment A 2564 is the first entry of an administrative account, yielded almost certainly in unofficial excavations at Jemdet Nasr before 1919, not very differently from the other archaic texts which reached the market before the first official excavations at Jemdet Nasr, Uqair, Warka etc. Just a few dozens of archaic texts were known at the time in which the Oriental Institute accessioned this fragment, all of them coming virtually from Jemdet Nasr. This (and obviously its dimensions and the scarce amount of explicit data) might explain why it did not gain the attention of the scholars until now. Both the general ductus of the signs and the other general features of the fragment point to the period generally referred as Uruk III / Jemdet Nasr (3100-3000 BCE) in which proto-cuneiform developed in the direction of a full writing system capable of timekeeping, administration and tradition of knowledge. The administrative account of which this fragment constitutes the incipit deals with distributions of emmer, the second most frequently attested Mesopotamian type of grain after barley. The person involved in the distribution is most probably a high-ranking official, as suggested by the presence of a big numeral (N46) sixty times multiple of the basic unity of the Š'' system (N4) (Englund 1998: 111-120 with former literature). The wording LAGABb TE might convey the meaning of total, but it is unfortunately impossible to know whether it referred to a total of previous accounts or to a sum of other entries of the same tablets, now broken.
Despite providing some interesting information, this fragment – as many analogous ones – is destined to long remain a small piece of the big jigsaw puzzle of the archaic Mesopotamian administration.
* I thank Prof. W. Farber, curator of the Tablet Collection of the Oriental Institute, and Andrew Dix, M.A., assistant curator of the same collection, for putting this fragment at my disposal. Richard J. L. Essam revised the English form of this contribution, but I bear the full responsibility for any mistakes or inaccuracies.
ISSN 1546-6566 © Cuneiform Digital Library Initiative | Archival: 2015-04-15