text:
The Malayalam cinema has truly arrived with Lal Jose who employs a unique method to narrate stories in each of his movies. In Diamond Necklace again, the director brings a 'not so common' topic to fore and does complete justice to the plot.
Lal Jose and actor Fahad Fazil have shown in the past that they are new age director and actor, respectively. The two have once again proved that with this film. The Diamond Necklace more than makes up for the lack of big names with its strong theme and brilliant direction.
Diamond Necklace like all of Lal Jose' previous venture is a youthful and romantic film with some melodious songs and enriching moments. Script by Iqbal Kuttipuram is excellent as he has made sure not to give away the 'flavour' of Lal Jose' movies.
Dr Arjun (Fahad Fazil) is a young oncologist who lives in a posh apartment in the world's biggest and expensive building in Dubai, Burg Khalifa. Because of his lavish lifestyle and spendthrift attitude, Dr Arjun gets into a huge debt with credit card companies. Over the period that he lives in Dubai and in Kerala, Dr Arjun's life gets completely intertwined by the three women who enter his life. Somehow, a very expensive diamond necklace makes him realise the finer aspects of his life.
Fahad Fazil is outstanding as usual. He has done similar roles before and this is just another feather in his cap! Samvrutha Sunil and Gowthami Nair are fine actresses and they have proved that once again with the Diamond Necklace. Anushree, in her debut film seems very promising. All other actors have given a decent performance.
Diamond Necklace is definitely worth a watch.
Cast: Fahad Fazil, Samvritha Sunil, Gowthami Nair, Anushree
Director: Lal Jose


text:
Separation of Powers
The Separation of powers is a vital part of the Constitution. Governmental powers are distributed equally among three distinct and independent branches of the government. These branches are the Legislative, Executive, and Judicial branch.
By separating the three branches of American government, it gives each branch separate but equal powers. The separation of powers also allows for each branch to act as a check and balance system for the other branches.
Click here, here, or here for more information on Separation of Powers
Examples of Separation of Powers:
In the American Government, the Legislative branch is given the power to make laws with Congress at the head. The Executive branch is given the power to enforce laws with the power given to the President. The Judicial branch, such as the United States Supreme Court, is given the power to interpret the laws outlined in the Constitution.
To test your knowledge on the Separation of Powers, click here

subset: commoncrawl


text:
This product is no longer available.
You can try these similar gifts instead.
Peridot Sterling Silver and Gold Fill Earrings
Peridot is among the most beautiful of all gemstones, said to have the look, and feel of "sunshine on a warm spring day". Peridot loop earrings, as well as matching peridot pendants, are also available.


text:
Congenital heart disease (CHD) is a relatively common childhood disorder. While new transcatheter and surgical treatments have improved patient outcomes, many challenges remain. The Hybrid approach strives to further enhance clinical results by combining surgical and interventional management strategies, with the goal of diminishing the risks associated with the individual procedures. Additionally, it reduces the cumulative risks associated with multiple interventions.
ISHAC remains a unique forum where a 2-day Symposium is coupled with a special 1-day Skills Workshop. Attendees will learn the latest clinical and research developments in Hybrid therapies from our prestigious international faculty. Over the years, we have had faculty and participants from over 34 states, 50 countries, and 6 continents; we expect this year to be no exception. ISHAC truly has something for everyone - surgeons, cardiologists, anesthesiologists, nurses and nurse practitioners, perfusionists, allied health professionals, and research scientists. There will be didactic lectures, moderated discussions, live case demonstrations, special noon presentations with box lunches, tours of the Hybrid Suites at Nationwide Children's Hospital, and direct access to our faculty for questions and answers. This year, procedures will be performed from Hybrid Suites at Rush Medical Center in Chicago, Miami Children's Hospital, and Nationwide Children's Hospital... with special Hybrid procedures broadcast from out University Laboratory Animal Resources Experimental Surgical Suites (ULAR).
We are especially proud of the 1-day Skills Workshop at ULAR to be held on Tuesday, August 31st, which requires a separate registration and has limited attendance. Registrants will work directly with our faculty and have hands-on experience with many forms of Hybrid therapies in our specially designed animal models. The Workshop is truly unique and allows the attendees to return to their own institutions to initiate, expand, and improve Hybrid therapies.
ISHAC should enable participants to:
Thanks again for marvelous stay at Nationwide Childrens Hospital, Columbus, Ohio. We were really impressed observing your cathlab and OR activities, especially Hybrid procedures and transcatheter valve implantation. Since the visit we started our first hybrid procedures in our institutio, we performed two infant periventricular muscular-VSD closure with pretty good results. Our first patient was 9-months old girl with a history of coarctation repair and PA-banding due to multiple VSDs, that were finally closed periventricularly with 8 mm Amplatzer Muscular VSD Occluder via sternotomy. The second is an intact baby girl who received VSD Occluder implantation because of multi-VSDs, 6 kg 5 months, who is really the youngest and smallest child who underwent Hybrid procedure in Poland. We take the program really seriously while building our new center, and we expect to develop Hybrid team in the institution. The next 3 babies are listed as candidates to Hybrid VSD occlusion. We reached the license to Hybrid program from the Polish Ministry of Health.
We are sure that this all would have not be possible without your contribution, so we highly appreciate your help.
Department of Pediatric Cardiac Surgery Province Hospital of Gdansk, Poland


text:
teaching about sperm and ovaries UPDATE
should I tie it together and just teach her about sperm, eggs and ovaries?
update: so DD actually came home and the perfect opportunity to talk about all this opened up. She was telling me earlier in the week J was transferring to a new school but her brother wasn't. She was upset. That was her BFF. Ok so today I tell her were going to the library to find books about her body and she can pick out what she wants to learn. She immediately said "BABIES" I said you mean ovaries, and how sperm and eggs create the baby? She said "yeah. I guess. J says she thinks she's pregnant (guess this was discussed before her transfer" she even felt it kicking her! I think maybe that's why she doesn't go to my school anymore. She has to go to a special pregnant mom school"
I couldn't stop laughing. But after correcting her and reassuring her it was HIGHLY unlikely that her 6 year old friend was expecting...i now know we HAVE to cover these things. Like...NOW! on one hand in laughing at her innocence but on the other I'm smh at whatever silliness brought that up. Lol
Quoting Jinx-Troublex3: The Americqn Girl book,"Care and Keeping of you" is great for the young girl/preteen age. They have a boy version as well.
I didn't know this. Everyone only talks about the girl version.
This has happened to me before. Sometimes, it's just not the right time. lol
Quoting twyliatepeka:
My 6 yr old dd asked me the other day. I changed the subject simply because I didn't know how to get into all that with a child. She probably would not have asked if I were not about to have a baby. She knows how babies are born just not how they get in there so now she is curious as to how they get there in the 1st place.
I started with each child at 4. They know the appropriate names for all of the anatomy and how babies are actually made. And they know that there are many myths and stories other parents might tell their children because they are uncomfortable with the subject so they all know that they are not to discuss this with other children. They also know that they can come to me with any question about anything and they will get an honest answer. :-) I feel like in order for them to comfortable with their own bodies and their own sense of self, we, as parents, have to get comfortable talking to them about it. I don't want them guessing, making assumptions, listening to other kids ideas, etc. I want to know that they have been given accurate info from day 1. :-)
We use the series of books from Robie Harris. It starts with "It's Not the Stork" for the 4 to 7 year old set and has 2 more that work with the age groups as they get older. There can be controversial info in them so be prepared to discuss your views on that - in particular the one for the oldest group, 10 and up, called "It's Perfectly Normal". They have a liberal slant that does not jive with our conservative Christian beliefs (we are pro-life, pro-traditional marriage, pro-abstinence, etc.) but I used it as a great jumping off point to discuss these difficult subjects with my son (he is the only kiddo I have old enough to have used it).
My 5yo saw her sister be born and we have touched on the subject but she still doesnt know how the baby got there.


text:
Product Code: 2204Claddagh
Product Code: 2204Claddagh
Titanium ring with laser engraved Celtic Claddagh symbols.
The width of ring is 4mm to 8mm and this ring can also be engraved on the inside.
Don't Forget every item we sell carries a 30 day Moneyback Guarantee if you are not completely satisfied and delivery in the UK is FREE.
We also send a special ring sizer to everyone who orders a ring to make sure, so you can order with confidence.
This item is made from scratch to your specification. Delivery is in 10 to 14 days. If you need it by a specific date please tell us in the special instructions box you will see when checking out. If a return is required please send by Royal Mail Special Delivery.


text: When you stop to ponder how many times Billy Blanks gets his ass kicked over the course of T.J. Scott's dorky science fiction actioner "TC 2000", you seriously start to question his status as an action hero. I'm not saying that he has to coast through the entire picture without getting a few scratches on his angular puss, but it would be nice to see him completely overwhelm his decidedly outclassed opponents without getting his posterior handed to him in the process. Of course, if you shortened the action sequences, you'd realize that there's not much of a story to speak of, no intricate plotting supporting the picture's countless corridor-centric set pieces. The film's only saving grace — besides watching Bobbie Phillips obliterate her enemies while wearing a ridiculously cheesy albeit realistically futuristic S&M costume — is the presence of martial arts veteran Bolo Yeung, who is featured prominently towards the second half of the feature. Although his dialogue is extremely limited, his penchant for beating a severe amount of ass makes up for the guy's lack of verbal correspondence. Those of us who like our dodgy martial arts flicks laced with generic sci-fi overtones will openly embrace "TC 2000" for all the wrong reasons. God bless the 90's. And isn't Billy Blanks due for a big-screen cinematic revival? Given the state of the American box office, "TC 3000" honestly doesn't sound that far fetched. Call me if you need a script.


text:
Assault charges filed in workplace fight
A 20-year-old from Wadena was charged with a felony-level assault crime in Wadena County District Court for punching a coworker in the parking lot of their place of employment.
According to court documents, Evan Michael Roggenkamp was waiting outside and repeatedly punched another man in the face. The victim said he was punched in the eye five times, and was treated in the emergency room for a one-inch gash above his eye.
Roggenkamp was charged Oct. 11 with third-degree assault for the Oct. 8 incident. He was scheduled for his first appearance on Oct. 19.


text:
bracelet woman jewellery Roberto Giannotti Angeli
Code: NKT187N
€ 91.89 € 118.00 You save € 26.11
This article is no longer produced by parent company and so the purchase does not guarantee the necessary spare parts and technical assistance.
Product Info
Product: bracelet woman jewellery Roberto Giannotti Angeli NKT187N
Jewel Roberto Giannotti, Collection Of Angels. Black Bracelet With Gold Elements. Gold 375, Leather A Double Tour. News in March 2015, Reference: Nkt187N
this bracelet will be shipped with the original box Giannotti
30 days to return the product
this bracelet is shipped worldwide with UPS
Features bracelet NKT187N Giannotti
brand: Giannotti
package: original box Giannotti
Product Guarantee: International Warranty Giannotti
kind: woman
category: jewellery
Subcategory: bracelets
style: casual
producer code: NKT187N
collection: Chiama Angeli
Bracelet type: Leather
Clasp type: Hook
Jewel Material: Yellow gold
Jewel Material: Leather
Metal Carats: Gold 375
Stone type: No Stone
You might also like
Other products Giannotti


text:
Top RANKING B-School
Source: 14th "Business Today - MDRA" Best Business School Survey-2013
The 14th 'BT-MDRA Best Business Schools Survey-2013' has been released and it has ranked ASIA-Pacific Institute of Management, New Delhi at 10TH POSITION amongst top B-Schools of the country.
A total of 213 B-Schools all over the country participated in the ranking process this year. The list includes IIM's and other eminent B-Schools. Amongst the North based B-Schools, we have been ranked alongside MDI, IMI, IMT, etc.
The ranking is based on the objective data, experiential and perception survey. Business Today Survey is an "objective survey" that ranks B-Schools based on the data that they submit, combined with a "perception survey" which ranks B-Schools based on opinions of key stakeholders such as teachers, students, recruiters and others. This year's survey has introduced the "experiential survey" which brings in the views and experiences of alumni too.
Thus it can be seen that the B-Schools have been ranked in the most comprehensive and complete manner.
The parameters on which Asia-Pacific Institute of Management has scored well are as follows:


text:
Basic Allowance for Housing for Military Families
The Department of Defense's Basic Allowance for Housing (BAH) is designed to help those in the military handle the extra expenses of living off base.
Intended to provide service members compensation based on local civilian housing costs, the BAH is available to most pay grades at most locations. Payment rates are passed on geographic location, pay grade, and dependency status. BAH is also tax free.
Before you purchase off-base real estate, consult a military tax advisor for details on tax benefits and restrictions of the BAH. For more details, visit the Department of Defense website's Defense Finance and Account Service page.


text:
Health Centers
Health Forums
Ask a Doctor
Sign Up
Email or Display Name
Remember Me
Forgot your password?
Medical Questions
Mental Health
Depression Forum
Having troubles
Must Read
Clinical Depression
Do you know how doctors define clinical depression? Learn more about this brain disorder and types of depression that doctors diagnose here....
Read more >>
Depression Causes and Risk Factors
Can depression run in families? Can hormones really make you depressed? Yes! Learn more about causes and conditions of clinical depression here....
Read more >>
Depression Symptoms
People with depressive illnesses do not all experience the same symptoms. Do you know the signs and symptoms of depression? Read on to learn more....
Read more >>
Mental Health
Having panic attacks ?
Constantly feeling guilty and having neg...
Having panic attacks ?
Having suicidal thoughts
having a melt down
having someone who loves you helps
Related Topics
Having a colonoscopy
Major pain after hysterectomy
Having trouble conceiving
May 11th, 2010
hey. i''m 12 and i''m having troubles, family and friends. i constantly think i''m a loser. i still watch kiddy programs and people laugh at me. my friends are smoking and i rlly want them to stop, but they won''t. i never get invited anywhere, i''ve only ever been shopping witha friend once, and everyone around me is constantly talking about when they went shopping. i like this guy and he asked me out so i said yes, but then things went wrong. he wanted to snog and make out all the time and i just wasn''t ready. i dumped him, because i didn''t rlly like him anymore, but now i like him again and i dont know what to do. i want to be a singer, but whenever i tell anyone they snort and laugh. my "friends" are always making fun of me, and my school grades are starting to go down. my parents are getting rlly annoyed with me. my dad sometimes hits me. i get scared when he comes home drunk nearly every weekend. last week he came home bleeding. he said he fell into some brambles. i don''t know what to do i sometimes just lock myself up in my room and cry and cry. pls help
Did you find this post helpful?
You marked this post as helpful!
I changed my mind
about depression
about smoking
stop smoking
all about depression
Quick Reply
Sign up for FREE weekly health tips!
Do you live in Canada?
Sign up here.
Ask a doctor
Type your medical question here
Featured Experts
Dr. Abhijeet Deshmukh
Psychiatry, Psychotherapy (Rational Emot ...
eHealthPedia Articles
Depression Causes and Risk Factors
Clinical Depression
Depression Diagnosis
Depression Symptoms
Depression Treatment
Search eHealthForum for
Learn About Us
Contact Us
About Us
Advertise With Us
Privacy Policy
Cookie Policy
Terms of Use
Get Help
Ask a Doctor
Getting Started
Join In
Sign Up
Find People
Free Medical Forms
Community Guidelines
Do More
Become an Expert
Become a Partner
RSS Feeds
Thank you so much for you time. Its a wonderful thing what you do for all of these people. - Alwaysyours
The site is not a replacement for professional medical opinion, examination, diagnosis or treatment. Always seek the advice of your medical doctor or other qualified health professional before starting any new treatment or making any changes to existing treatment. Do not delay seeking or disregard medical advice based on information written by any author on this site. No
health questions
and information on eHealth Forum is regulated or evaluated by the Food and Drug Administration and therefore the information should not be used to diagnose, treat, cure or prevent any disease without the supervision of a medical doctor. Posts made to these forums express the views and opinions of the author, and not the administrators, moderators, or editorial staff and hence eHealth Forum and its principals will accept no liabilities or responsibilities for the statements made.
Health Disclaimer
This page was last updated on Nov 18, 2017.
© 2017 eHealthForum.com


text:
WARREN, Maine (NEWS CENTER) -- The family of Debra Dill has lived in fear since the 18 year old was brutally murdered back in 1973.
"The day Debra's grisly murder was discovered, the world as my family knew it was gone," Kim Dill, Debra's sister, explained to the Maine Parole Board.
Debra Dill had been driving alone when a man, later identified as Michael Boucher, rammed her car with his own in order to get her to pull over, then sexually assaulted her and beat her to death with a hammer.
"Days turned to weeks, to months, to years, to decades," Kim Dill told the board about the search for her sister's killer. It wasn't until Boucher was arrested for assaulting another woman that police found evidence connecting him to Debra Dill's murder. He was convicted of murdering her in 1991.
Because the crime occurred when the state still allowed murderers to seek parole, Boucher is eligible to request his parole every five years. So every five years members of Dill's family are forced to relive the past and fight to keep him behind bars.
"Every time a parole hearing happens, all the emotional turmoil of those wretched days after the murder are relived," Kim Dill explained. "The nightmare of brutality and cruelty, which no one should have to live through, are experienced by anybody and everybody who's life was impacted by Debra's death."
"If he is paroled, would you allow this man in your neighborhood, in your house, with your wives, daughters or sisters knowing his past history?" asked Cindy Dill-DiRusso, another of Debra's sisters.
"We implore you to keep Michael Boucher behind bars for the rest of his natural life," she begged the Parole Board.
The family delivered more than just emotional testimony, they also handed over more than 1400 petitions signed by members of the community asking the board deny Boucher's attempt at parole.
After hearing from Dill's family and supporters, the board met to consider his case. In the end, the board voted to deny his parole. Boucher will be eligible for parole again in 2019.


text:
This Week: After Rich starts off with a delicious gummy worm and most of Ben's cream soda, Ben kicks off a discussion about the games, books and music that CaPC is looking forward to in 2009. Plus, the Top 5 is Back with our Top 5 Things that Lived Up To the Hype!
Every week, Richard Clark and Ben Bartlett sit back and discuss the posts of the previous week on Christ and Pop Culture, acknowledge and respond to the big issues in popular culture, and give a sneak peak at the week ahead. We love feedback! If you'd like to respond you can comment on the website, send an email to firstname.lastname@example.com, or go to our contact page. We would love to respond to feedback on the show, so do it now! Subscribe to us in iTunes by clicking here. While you're at it, give us some good iTunes feedback! We'll love you forever!


text: Product: Geotube® Dewatering Technology Application: Aquaculture Location: Bay of Fundy, East Coast, North America Installation: 2003 The Challenge: An aquaculture cage site located in Passamaquoddy Bay (of the Bay of Fundy region) needed to clean the waste generated by the fish farming operation. The Solution: This aquaculture site's cages were equipped with the Lift-Up® mortality retrieval system. This allowed the operator to collect the waste produced by fish feces and unconverted feed. Once a day, a pump was used to extract the collected waste and load it to a tank aside the farming cages [photo 2]. Once the tank in the boat was filled, the boat approached the shore where the waste was pumped to a Geotube® unit. The chemical conditioning and polymer flocculation was achieved within the line between the boat and the Geotube® unit. The waste was pumped at 1.5% solids [photo 3]. The Results: Approximately 5,000 gallons of fish feces and unconverted food were collected and processed using Geotube® dewatering technology. The results were excellent in terms of water quality and nutrients removal: Removed 95% of solids. Removed nutrients (more than 90% phosphorous and more than 70% nitrogen). Produced a clean, clear effluent water -- ready to be returned back to the ocean environment [photo 4].


text:
San Francisco, California - The latest outrageous claim from San Francisco Zoo officials where a tiger attack killed a 17-old-boy and mauled two other young men came today when they alleged that the reason why the tiger that leaped from its sub-standard enclosure was because one, if not all three victims, provoked the attack, using a catapult, blowgun and boomerang.
Hand sketched artist illustrations just released by zoo officials clearly show all three young men dressed in full native regatta with their stone aged catapults, blowguns, and boomerangs sneaking right pass zoo security.
Surprisingly, said zoo officials, the three made their way through the park grounds while drawing little attention from other zoo patrons as well, even as the moved into position in front of the tiger enclosure.
Novelty lottery ticket sized posters of artist renderings showing all three men donned in their native ceremonial garb and wearing facial war paint poised before the tiger enclave filled the zoo's press conference stage.
"As you can clearly see," said the zoo official into a handless microphone suspended under his chin, attached to a silvery metallic harness that hung from his shoulders, dressed in a matching kaki safari hat, shirt and shorts and using a Nepal walking stick as a pointing aide. "The three natives…I mean young men encircled the helpless tigers that cowered in the corner of their enclave. Until one tiger reluctantly leaped to the defense of the others."
Although zoo officials could not produce any videotaped footage from the security cameras rolling at the time of the young men actually assaulting the tiger enclave with their stone aged weaponry, zoo officials denied any foul play on their behalf, citing security personnel was merely following zoo policy to destroy any incriminating evidence indiscriminately.
The final panel was the most controversial as it depicted the victims apparently injuring themselves with their stone aged weapons as they attempted to sacrifice each other to the attacking tiger.
"We believe this final panel proves the young men were engaged in some male bonding ritual in which the one who dies receives immortality in the afterlife of the great hunting grounds in the sky," said the zoo official, struggling to speak above the sound feedback on his microphone.


text:
Besides having really great album art and a frustratingly hip name, Dale Earnhardt Jr. Jr. have talent. They can write a damn good pop song. "Vocal Chords" is one of three examples off their Horse Power EP, which also includes a cover of the Beach Boys' "God Only Knows".
Have a listen:


text:
The first acts have been revealed for Hideout 2013. Tickets are now on sale!
Jayne Robinson
Date published: 15th Nov 2012
Europe's premier dance music festival returns to Croatia's beautiful Isle of Pag from June 30th to July 5th 2013, where it will set up home for a week of sun soaked boat parties, outdoor clubbing and late night raving on the white sands of Zcre Beach.
Loco Dice, Chase and Status, Jamie Jones, Modeselektor and Pendulum are amongst the first headliners to be revealed for the festival.
More acts announced today include Andy C, Ben UFO, Camo & Krooked, Cassy, Claude Von Stroke, Damian Lazarus, David Rodigan, Dyed Soundorum, Eats Everything, Scuba, Joy Orbison, Jackmaster, Mosca, Pearson Sound, Erol Alkan, Justin Martin and Heidi.
Pre-parties, pool parties, and boat parties will be hosted throughout the festival by label partners such as 20:20 Vision, One Records, and Hessle Audio, as well as club partners Circo Loco, Zutekh, and Mono_Cult.
See the full Hideout 2013 line-up so far
More acts are set to be revealed over the coming weeks and months, but already it's clear that once again, Hideout Festival have pulled it out of the bag.
Tickets for Hideout Festival 2013 are now available, priced at £109 or £114 with a programme. The festival has sold out well in advance for the past two years running - so we're expecting these to fly out.
Deposit scheme - only through Skiddle
If you want to secure your place at Hideout 2013 but can't afford to stump up the entire ticket cost just yet, then a £59 deposit will reserve your ticket, with the remaining balance payable by 30th April. This deposit scheme is exclusive to Skiddle and not available through any other ticket outlets.
Find out more about Hideout 2013 and get your tickets now!
Tickets are no longer available for this event
Read more news
Here are the next 4 upcoming events At Zrce Beach, Isle Of Pag


text:
{ad}Today Apple unveiled what they're dubbing "Exchange for the rest of us": MobileMe. The MobileMe service features the ability to keep applications on your Mac, PC, iPhone and iPod touch all in sync. With support for Microsoft Outlook on PC, Mail, Address Book, and iCal on the Mac, accessing and managing your email, contacts, calendar, photos and files is now easy and supported by Apple.
The MobileMe service will be available at Me.com and will sell for $99 a year, with a 60 day free trial, when it becomes available in early July. If you're wondering what happens to .Mac, current customers can migrate at will, but .Mac will be replaced completely by MobileMe eventually.
There's a guided tour available but you can get a pretty good idea of how it works by checking out the live blogs. Another benefit to the service is that the web-based component looks and feels like a real application. So, you could conceivably just play on the web version and enjoy mobility with the iPhone or iPod Touch.
For $99 for the year, if it really does perform all of that cross platform syncing, this seems like a logical step for anyone who runs multiple platforms and/or multiple devices. I'm currently a hosted Exchange customer and if Apple suddenly decides to roll Windows Mobile into the equation, I'm hooked. I should also mention that I previously wrote up a feature on getting iCal, Entourage, Exchange, and more to play nicely together, and it's no easy task. For $99 it can apparently be pretty easy.
Read more about MobileMe at Apple.com.


text:
FAIRFAX, Va., Oct. 15 (UPI) -- The lawyer for convicted Washington sniper John Allen Muhammad says he'll ask for clemency for his client, scheduled for execution next month.
Jonathan Sheldon plans to file the clemency request with Virginia Gov. Timothy Kaine next Thursday, his Web site says. He also plans to file an appeal with the U.S. Supreme Court.
Kaine told WTOP-AM, Washington, last month he knew "of no reason why clemency would be granted in this case," but said he would review Muhammad's request. The Supreme Court had no comment.
Muhammad was sentenced to death for the Oct. 9, 2002, death of Dean Harold Meyers, 53, killed while pumping gasoline at a Sunoco gas station near Manassas, Va., during a string of shootings that left 10 people dead and three wounded in Virginia, Washington, D.C., and Maryland.
His execution is scheduled for Nov. 10.
Muhammad's teenage co-defendant, Lee Boyd Malvo, is serving a life sentence without parole for six murders in Maryland.


text:
Objective: Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice. Methods: Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling. Results: LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids. Conclusions: Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.
- leptin
- cardiac metabolism
- lipotoxicity
- glycerolipid/free fatty acid metabolism
- peroxisome proliferator-activated receptor
- peroxisome proliferator-activated receptor γ coactivator
obesity is associated with hypertension, atherosclerosis, cardiomyopathy and decreased longevity. Obesity-induced heart disease, including nonischemic cardiomyopathy characterized by intramyocellular lipid excess, has become an important public health problem as the number of overweight children and adults has surged worldwide.
The role of leptin, an adipocyte-derived hormone that regulates appetite and metabolism, remains incompletely understood in obesity-induced cardiovascular disease. Leptin resistance and, more rarely, deficiency have been implicated in cardiovascular disease. Hyperleptinemia and leptin resistance are highly correlated with fat mass in diet-induced obesity and have been linked to adverse cardiovascular outcomes. However, hyperleptinemia appears to be adaptive during caloric excess, protecting the heart and other organs from lipotoxicity by reducing intracellular lipid accumulation. (20, 21). In support of this antilipotoxic hypothesis, obese leptin-deficient (ob/ob) and leptin-resistant (db/db) mice develop left ventricular (LV) hypertrophy, increased intramyocardial triglyceride accumulation, and accelerated cardiomyocyte apoptosis, abnormalities associated with reduced longevity (2, 3). In the ob/ob murine model, leptin administration suppresses caloric intake resulting in weight loss, regression of LV hypertrophy and normalization of myocardial steatosis and apoptosis (2, 3).
Similar to caloric excess, fasting has been linked to steatosis in nonadipose tissues as triglycerides are mobilized from fat depots and metabolism switches from the utilization of glucose to free fatty acids. Steatosis in the heart and liver has been demonstrated in both animal models and humans subjected to fasting and lesser degrees of caloric restriction (17, 19, 38). Fasting upregulates cardiac peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of myocardial energetics and mitochondrial function in normal animals. Mice lacking PPARα (−/−) develop massive lipid accumulation in nonadipose tissues in response to either high fat diets or fasting, indicating the importance of PPAR signaling pathways in protecting organs from excess steatosis (19). Leptin, which induces PPARα (41) and protects the heart from high-fat diets, has not been similarly investigated during caloric deprivation in the setting of clinically relevant obesity.
Here, the cardioprotective effects of leptin were examined during calorie restriction (CR) using electron microscopy, quantitative measures of myocardial lipid content, mitochondrial coupling studies, and global myocardial expression profiling. CR consisted of pair feeding with leptin-repleted animals, a milder form of lipotoxic stress than true fasting. We hypothesized that despite restoration of normal weight, CR in the absence of leptin would fail to reverse the cardiac steatosis of the ob/ob mouse phenotype. (3). In contrast to leptin repletion (LR), which restored the hearts of ob/ob mice to the wild-type (WT) state, CR with equivalent weight loss did not normalize cardiac steatosis and further dysregulated gene expression with induction of some PPARα target genes despite suppression of PPARα. Gene set enrichment analysis (GSEA) identified glycerolipid/free fatty acid (GL/FFA) cycling, a so-called futile metabolic pathway involved in thermogenesis, as a leptin-regulated, antisteatotic network in the heart.
We studied 6-mo-old ob/ob mice with C57BL/6J background, as previously described (2) and age-matched C57BL/6J WT controls. Weight loss was induced in ob/ob mice for 4 wk by either LR or CR and compared with WT and ob/ob controls fed ad libitum. Echocardiography was performed at 4 wk (see Supplemental Methods for details).1 The Institutional Animal Care and Use Committee of The Johns Hopkins University School of Medicine approved all protocols and experimental procedures.
Electron Microscopy, Lipid Quantitation, Mitochondrial Copy Number, and Respiration
Fixed sections of three hearts from each group were examined with electron microscopy. Unfixed ventricular tissue was used to measure myocardial triglycerides (TG) and perform oil red O staining (see Supplementary Methods for details). Mitochondrial copy number was assessed by quantitative PCR of mitochondrial genes ND1 and cytochrome b. Mitochondria were isolated from fresh LV tissue, and respiration was measured by oximetry (see Supplemental Methods for details).
Myocardial RNA Isolation and Oligonucleotide Microarrays
Mice were killed and hearts quickly removed, weighed, minced, and placed in RNALater solution (Qiagen). Total RNA was isolated and cDNA synthesized. Biotin-labeled cRNA was prepared from 1 μg of cDNA, fragmented and hybridized (10 μg) to Affymetrix (Santa Clara, CA) mouse 430_2 oligonucleotide probe arrays for 16 h at 45°C. Signal intensities were measured using Agilent GeneArray Scanner (Affymetrix) (see Supplemental Methods for details).
Gene Expression Validation with Quantitative Real-Time PCR
Total RNA from three samples of each of the four groups was aliquoted, treated with DNase1, and reverse transcribed to cDNA. Quantitative real-time PCR (RT-PCR) was performed on target genes to validate results generated by microarrays (see Supplemental Methods for details).
Statistical Analysis
Phenotypic data.
Data are presented as means ± SE. Statistical significance (P < 0.05) was determined by ANOVA or Student's t-test where appropriate. A Dunnett's test or Student Newman-Keuls test was used for post hoc analysis.
Microarray data.
Signal intensity values (Affymetrix Microarray Suite 5.0) for the oligonucleotide arrays were standardized and transformed using the Symmetric Adaptive Transform (http://abs.cit.nih.gov/MSCLtoolbox/). Principal components analysis was performed on this restricted transformed data matrix to allow for detection of outliers or other relevant patterns. Differentially expressed probe sets were selected based on a 5% false discovery rate (FDR) ≥ 50% fold-change between any group, and ≥ 50% present call in at least one group. Functional themes among differentially regulated genes were explored using Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, California; http://www.ingenuity.com/). To further identify metabolic gene sets enriched with leptin or caloric restriction without imposing arbitrary cutoffs, we utilized GSEA (Broad Institute, MIT; http://www.broad.mit.edu/gsea/index.jsp) (35) (see Supplemental Methods for details). The entire data set of the above investigation has been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO; http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=xbglneqscuqcenk&acc=GSE16790), accession number GSE16790.
Characteristics of the Murine Phenotypes
Supplemental Table S1 summarizes anatomic and echocardiographic measurements from the four groups at 7 mo of age. Body weight was increased in ob/ob mice compared with WT mice. Increased wet heart weight was attributable to concentric hypertrophy, as previously reported, (2) with a relative 50% increase in wall thickness in ad libitum ob/ob mice and a decrease in fractional shortening compared with WT. CR and LR both resulted in significant weight loss, reduction in concentric hypertrophy, and restoration of fractional shortening after 4 wk of intervention. At the time of death, no significant difference was identified between the CR and LR ob/ob groups in heart weight, end-diastolic interventricular septal and posterior wall thickness, relative wall thickness, or fractional shortening.
Effects of CR and LR on Cardiac Steatosis
Electron microscopy was performed to identify ultrastructural and mitochondrial changes. As shown by others, (10) ob/ob mice fed ad libitum were found to have increased accumulation of lipid droplets in cardiac myocytes compared with the WT control hearts (Fig. 1). LR restored the heart to a nonsteatotic phenotype, consistent with myocardial tissue TG levels returning to WT (3). However, equivalent weight loss after CR in ob/ob mice did not result in a significant decrease in lipid accumulation (Fig. 1, C and D). Measurement of myocardial triacylglycerol (TAG) confirmed severe cardiac steatosis with leptin deficiency and no significant reduction with CR, while LR normalized intramyocardial lipid to WT levels (Fig. 2). Further electron microscopy analysis revealed the increased lipid deposition within the mitochondrial zones in between the myofibers without evidence of ultrastructural damage (Supplemental Fig. S1). We also observed within the mitochondrial zones the presence of focal lamellar inclusions, suggestive of lipid storage in the CR-ob/ob mice. There were no significant ultrastructural changes observed in mitochondria in any of the ob/ob groups relative to WT, but a qualitative increase in the number of mitochondria was noted in both the ad libitum and CR-ob/ob groups. We also noted enlarged nucleoli and an increase in myocyte width relative to the nucleus in both the ad libitum and CR-ob/ob groups compared with LR and WT, ultrastructural features that are suggestive of myocyte hypertrophy.
Effects of CR and LR on Mitochondrial Function and Biogenesis
We performed cardiac mitochondrial respiration studies to confirm previous observations of mitochondrial dysfunction in the hearts of ob/ob mice, (5) and to investigate whether excess cardiac steatosis in CR-ob/ob mice leads to a further increase in mitochondrial uncoupling. We identified increased mitochondrial uncoupling in the hearts of ad libitum fed ob/ob mice compared with WT based on a decreased ratio of oxygen consumption in the presence and absence of ADP [respiratory control ratio (RCR), Fig. 3]. LR improved coupling of oxygen consumption and ATP production, restoring the RCR to WT levels. Surprisingly, the CR-ob/ob group also restored mitochondrial coupling back to WT levels, despite the presence of severe myocardial steatosis. Mitochondrial copy number, measured by the ratio of mitochondrial genes (ND1 and cytochrome b) to the nuclear gene H19, was found to be significantly increased in the hearts of the ad libitum and CR-ob/ob groups relative to WT (Supplemental Fig. S2). Only LR restored mitochondrial numbers back to WT levels.
Effects of CR and LR on the ob/ob Mouse Cardiac Transcriptome
Microarray analysis identified 794 differentially regulated probe sets across the four groups (5% FDR, ≥1.5-fold change with any other group and 50% present-absent call). Figure 4 depicts differentially expressed genes comparing the effects of LR (y-axis) versus CR (x-axis) relative to ob/ob mice fed ad libitum (no intervention). From the 794 probe sets that originally met criteria for differential expression between any group-wise comparison, 790 were divided into one of eight areas reflecting all major patterns of gene expression between experimental groups (see Supplemental Methods). Notably, LR consistently corrected ob/ob ad libitum expression profiles toward those of WT animals (Fig. 4, patterns I–III and VI–VIII) and left unaltered genes that were not affected by leptin deficiency (patterns IV and V). Conversely, CR corrected ob/ob ad libitum gene expression for only a small minority of regulated transcripts (Fig. 4; patterns III and VI, representing 139/790 probe sets). For all other probe sets and patterns, CR failed to directionally alter gene expression toward levels of normal WT animals. In two patterns (I and VIII) containing the largest number of probe sets (271 and 139, respectively), LR corrected, while CR further displaced gene expression away from WT controls. For a complete list of genes falling within each expression pattern, please refer to Supplemental Table S2.
An analysis of overrepresented functional themes among differentially regulated genes using Ingenuity Pathways Analysis found significant alterations in lipid metabolism, inflammatory response pathways, and cell death-associated genes (P < 0.00001 for all). Within each of these functional categories, CR-ob/ob animals displayed the greatest deviations in gene expression compared with WT (Fig. 5). For lipid metabolism (Fig. 5A, pattern I), CR further suppressed PPARα and two proteins involved in lipid trafficking, caveolin, and phospholipid transfer protein, compared with ob/ob animals fed ad libitum. Pattern VIII (Fig. 5A), capturing genes downregulated by LR toward WT, but further increased by CR, identified several aspects of disordered lipid metabolism, including alterations in transport and processing (fatty acid transporter 1, acyl-CoA synthetase long-chain family member 6), beta-oxidation of fatty acids (acetyl-coenzyme A acyltransferase 2, mitochondrial 2, 4-dienoyl CoA reductase 1), and modification of lipids (CYP1BI, epoxide hydrolase 2). The predominant impact of CR on inflammatory response genes (Fig. 5B) was to exacerbate leptin-induced suppression (P < 0.00001, patterns I and IV), particularly affecting canonical pathways associated with antigen presentation, the complement system, and cytokine signaling (P < 0.0001 for all). Like lipid metabolism and inflammation, cell death pathway genes were overrepresented among differential regulated transcripts (P < 0.006) and displayed all eight of the major expression patterns seen across our four groups (Fig. 5C). However, leptin deficiency primarily downregulated antiapoptotic genes (i.e., hypoxia upregulated 1, heat shock proteins 1 and 90 alpha, E26 avian leukemia oncogenes 1 and 2, disabled homolog 2, and CD53 antigen; Fig. 5C, all in pattern I) and upregulated proapoptotic genes (i.e., DNA damage-inducible transcript 4, plectrin homology domain containing-family F, member 1 and TP53 apoptosis effector; Fig. 5C, patterns VI, VII, and VIII, respectively), a response that may be consistent with lipotoxic stress. Importantly, CR worsened or failed to reverse these abnormalities (patterns I, II, and IV for downregulation of primarily antiapoptotic genes; patterns V, VII, VIII for upregulation of primarily proapoptotic genes). Likewise, oxidative stress-related, free radical scavenging genes, overrepresented among transcripts that were upregulated in the leptin-deficient state, were further aggravated by CR.
GSEA of Pathways Affected by CR and Leptin
To detect significant coordinated changes (without a fold-change restriction) in the cardiac gene expression of ob/ob mice subjected to CR versus LR, we performed GSEA (Broad Institute, MIT) with a priori defined gene sets of lipid metabolism and cardiac failure (see Table 1 for summary of significantly enriched gene sets and supplemental methods for list of a priori defined gene sets). In the CR compared with ad libitum ob/ob hearts, we identified significantly upregulated pathways of fatty acid biosynthesis, mitochondrial fatty acid beta oxidation and glutathione metabolism.
In the hearts of LR compared with ad libitum ob/ob mice, we identified significant upregulation of the GL/FFA cycle, an exergonic process implicated in thermogenesis and energy homeostasis. (26, 27) This pathway of glycerolipid metabolism was also demonstrated to be significantly downregulated in the ad libitum ob/ob group relative to WT. CR failed to restore the glycerolipid metabolism pathway back to WT levels.
We also identified a significant upregulation of a gene set in LR-ob/ob that is downregulated in the ventricular myocardium of end-stage failing human hearts. This is consistent with the echocardiographic finding that LR restored myocardial function as measured by the return of fractional shortening to WT levels.
Effects of Leptin on Cardiac Expression of Peroxisome Proliferator-Activated Receptor γ Coactivator-1α/PPARα and Glycerolipid Cycling
Given the importance of the peroxisome proliferator-activated receptor γ coactivator (PGC)-1α/PPARα regulatory pathway on fatty acid metabolism and lipid homeostasis in models of obesity (39, 40) and fasting, (19, 23) quantitative RT-PCR was performed to verify changes in PPARα and PGC-1α gene expression. These studies confirmed that transcriptional PGC-1α is downregulated in the heart of ob/ob mice (Fig. 6A). With equivalent weight loss, LR but not CR significantly increased cardiac mRNA levels of PGC-1α back to WT. Despite the known increase in intramyocellular fat in the hearts of ob/ob mice (3, 11, 18, 19) cardiac PPARα gene expression is decreased in leptin-deficient states (see Fig. 6B). LR increased, whereas CR further decreased cardiac PPARα mRNA levels.
Next, we investigated expression changes in key regulators of lipid metabolism and mitochondrial function that are transcriptionally induced by PPARα. In Fig. 7, we demonstrate by RT-PCR reductions in the cardiac expression of pyruvate dehydrogenase kinase 4 (PDK4), uncoupling protein 3 (UCP3), and fasting induced adipose factor (FIAF or angiopoietin-like 4) in ob/ob mice. Cardiac mRNA levels of PDK4, UCP3, ACOT2, SLC27a1 (fatty acid transporter) and Angptl-4 are induced several-fold in the CR-ob/ob group, despite a significant decrease in PPARα mRNA. In the case of malonyl-CoA decarboxylase (Mlycd, Fig. 7), a key regulator of fatty acid oxidation, both ob/ob ad libitum and CR mice show increased expression relative to WT animals, despite robust downregulation of PPARα in both groups. In contrast, cardiac gene expression of acyl-coenzyme A dehydrogenase (Acadvl) and carnitine palmitoyl transferase 1b (cpt1b) is not increased in the leptin-deficient ob/ob ad libitum and CR groups, but induction of gene expression is observed with LR, suggesting maintenance of PPARα-dependence with respect to these two genes involved in fatty acid oxidation. These observations suggest either: 1) the presence of a variable degree of PPARα responsiveness among key regulatory and metabolic genes associated with lipid homeostasis in leptin-deficient hearts challenged by states of overnutrition and CR; or 2) the presence of other factors controlling the activity of PPARα such as unmeasured posttranslational modifications or increased PPARα ligand availability. We identified increased myocardial FFA in the CR group relative to the ob/ob ad libitum group (Supplemental Fig. S3), which may explain some of the significant differences in PPARα target gene expression between these groups (SLC27a, AngptL4, UCP3, ACOT2, PDK4) We also measured by RT-PCR the expression of other nuclear receptors, PPARβ/δ and ERRα, to understand the changes in the PPAR-regulated genes and found no significant differences across the four groups (Supplemental Fig. S4, d and f).
To validate the findings from GSEA which identified the Glycerolipid/FFA pathway as a potential leptin-regulated mechanism to relieve myocardial steatosis, we performed RT-PCR on additional genes involved in glycerolipid cycling (Fig. 8). Stearoyl CoA desaturase 1 (Scd1, Fig. 8A), which had been shown to be significantly upregulated in the liver of ob/ob mice, (9) is also induced in the myocardium of leptin-deficient animals and suppressed even below WT levels with LR (P = 0.045 for post hoc comparison of LR-ob/ob vs. WT). In contrast, CR failed to normalize Scd1, which catalyzes the conversion of fully saturated to monounsaturated fatty acids and is an important committed step in the synthesis of TAG. In leptin-deficient groups, we identified increased expression (Fig. 8) of gene products involved in the partitioning of FFA toward TAG [long-chain acyl-CoA synthetase (Acsl1)], esterification (Agpat2, Dgat1), and stabilization of lipid droplets storing TAG [Plin2, adipocyte different ion-related protein (ADRP)]. We identified induction of hormone-sensitive lipase (Fig. 8B: Lipe, HSL) with LR, which plays an important role in the hydrolysis of TAG to glycerol and FFA, both TAG → diacylglycerols (DAG) and DAG → monoacylglycerols (MAG).
One of the major peripheral roles of leptin may be to regulate intracellular lipid homeostasis in nonadipocytes such as liver, skeletal muscle, and cardiac muscle. Thus, leptin may prevent TG overload while allowing for a sufficient supply of fatty acids for cellular energy substrate utilization during periods of overnutrition. Here we have demonstrated a pivotal role of leptin in preventing cardiac steatosis during periods of weight loss due to CR. The following observations have been made that emphasize the importance of leptin on cardiac liporegulation: 1) Despite equivalent weight loss in CR-ob/ob and LR-ob/ob mice, we demonstrated that the hearts of CR-ob/ob mice had persistent severe cardiac steatosis; 2) Lack of leptin during CR was associated with dysregulation of genes involved in cardiac lipid homeostasis marked by significantly increased expression of some PPAR-target genes despite a decrease in cardiac expression of PPARα and no significant change in PPARβ/δ or ERRα; 3) Core genes of the GL/FFA cycle implicated in lipid detoxification and energy homeostasis, including Scd1 and Dgat1, are differentially regulated in leptin deficiency; and 4) That CR, in the absence of leptin, restored mitochondrial coupling to WT levels despite the oxidative stress and lipoapoptotic risk associated with severe intramyocellular lipid accumulation. In contrast, LR restored mitochondrial coupling in parallel with the resolution of cardiac steatosis in ob/ob mice.
The protective role of leptin in nonadipose tissue, including the myocardium, has been supported by multiple studies (5, 40). Leptin increases myocardial fatty acid oxidation in nonadipose tissue and thereby may prevent lipotoxicity by attenuating TG accumulation. In the heart, this leptin-induced increase in FAO is independent of AMPK/ACC activity or malonyl-CoA levels. (1) However, despite the absence of leptin, ob/ob mice and db/db mice have demonstrated increased levels of fatty acid oxidation in the heart (5, 6, 24). It has also been demonstrated that despite improvement in body weight, diabetes, and serum TG, CR does not decrease the levels of myocardial fatty acid oxidation in ob/ob mice. (33) With enrichment analysis using a priori defined gene sets, we have identified an alternative mechanism of cardiac lipoprotection linked to leptin with significant upregulation of the GL/FFA cycle in the hearts of LR but not CR-ob/ob mice (Table 1). This "futile" cellular process continuously cycling between esterification of fatty acids to a glycerol backbone and hydrolysis has an essential and established role in energy homeostasis and thermogenesis. (26, 27) RT-PCR of core genes implicated in glycerolipid cycling (Fig. 8) identified a pattern of differential gene expression consistent with lipid storage in both ad libitum and CR leptin-deficient groups, while leptin repletion led to the hydrolysis of glycerolipids. Functional studies are necessary to confirm this and investigate whether myocardial utilization and synthesis of TAG through GL cycling is altered in leptin deficiency. Nevertheless, our observation suggests a mechanistic link between leptin signaling and GL/FFA cycling in the heart that could explain the increase in myocardial lipid (Figs. 1 and 2) that persists despite CR as well other findings that have been identified in models of impaired leptin signaling.
The reduced cold tolerance of ob/ob mice and Zucker fatty rats may be related to a compromised thermogenic response due to decreased GL/FFA cycling. A recent study demonstrated that increased cardiac apoptosis in ob/ob mice may be mediated by decreased catalytic activity of phosphoinositide-3 kinase (PI3K) (p110a), which was reversed by LR (37). Given the link between the GL/FFA cycle and cell survival/proliferation, possibly through lysophosphatidic acid-mediated (a GL/FFA intermediate) activation of the PI3K/mTOR/p70S6K pathway, (13) leptin repletion could reduce cardiomyocyte apoptosis and hypertrophy through an increase in Akt and PI3K signaling. Furthermore, there is mounting evidence that altered GL/FFA cycling contributes to insulin resistance (4, 31), which is present in leptin-deficient mice despite CR (32). Our gene set enrichment analysis may thus provide the initial evidence linking leptin deficiency to myocardial insulin resistance mediated by decreased GL/FFA cycling in the heart. Finally, leptin deficiency-induced decreases in GL/FFA cycling may provide an explanation for cardiac and other end-organ lipotoxicity that exists in murine models of obesity (including the ob/ob mouse model), despite the presence of increased fatty acid oxidation in the heart. The protective effects of hyperleptinemia observed in several murine models of obesity and lipotoxicity (1, 8, 20, 21, 30, 34, 41) may thus be explained by increased cycling of GL and FFA with the release of heat.
Myocardial Steatosis in Leptin Deficiency and PPARα Expression
PPARα has been shown to increase the expression of genes invoked in every step of cardiac fatty acid utilization. Cardiac specific overexpression of PPARα results in increased FA uptake, increased FA oxidation and lipotoxic cardiomyopathy similar to the cardiac metabolic profile of the diabetic heart (14, 15). PPARα-null mice have decreased cardiac expression of genes involved in the cellular uptake, mitochondrial transport, and oxidation of fatty acids. This knockout model has provided ample evidence for the central role played by PPARα in cardiac lipid homeostasis, especially with the development of massive cardiac steatosis in PPARα−/− mice subjected to fasting. (19, 23) This and other studies suggesting that PPARα is induced in response to fasting would predict that PPARα should be robustly upregulated in response to CR. In our model, PPARα gene expression was further suppressed with CR again implicating leptin, even in low or falling levels, as necessary for the normal physiological response of PPARα to caloric deprivation and fasting. We cannot exclude the possibility that the decreased expression of PPARα is compensatory in response to the increased rate of fatty acid oxidation that has been identified in leptin deficiency (5, 6, 24, 33). More recent evidence in a model of recurring ischemia/reperfusion injury suggests the possibility that reactive oxygen species (ROS) suppress PPARα as a compensatory phenomenon that prevents further cardiac injury from secondary lipotoxicity (10). Oxidant stress resulting from increased FAO in ob/ob mice might similarly suppress PPARα. Although measures of oxidant stress were not performed in this 6 mo old murine model, serum malondialdehyde (MDA) was increased in 2 mo old ob/ob mice, and CR failed to decrease this marker of oxidant stress (Supplemental Fig. S5). Future studies with double knockout (ob/ob//PPARα −/−) and transgenic (ob/ob//cardiac-specific PPARα overexpression) models should clarify the role of PPARα in mediating or protecting against lipotoxicity in the leptin-deficient heart.
Leptin Deficiency Dissociates PPARα From the Regulation Of Target Genes
Previous models of obesity implicating impaired leptin signaling, including the obese Zucker diabetic fatty (ZDF) rat resulting from a loss of function (fa/fa) mutation in the leptin receptor, have demonstrated a dissociation between PPARα expression and PPARα target gene regulation. In the ZDF rodent heart marked by lipotoxic cardiomyopathy and other models of leptin resistance (db/db), no change in PPARα transcript levels were observed but significant increases were noted in myocardial MCAD, CPT1, and other PPARα-target genes (6, 7, 29). Although our model suggests that decreased PPARα expression in the heart may be a causal determinant of cardiac steatosis by inhibiting fatty acid oxidation, it is now well accepted that cardiac fatty acid oxidation is increased in ob/ob and db/db mice (5, 7). Furthermore, our study cannot exclude the possibility of increased PPARα activation with leptin deficiency, which could be present in the setting of increased PPARα ligand availability. Although we did not measure activation of lipoprotein lipase (Lpl), which has been recently shown to be an important determinant of PPARα ligand activation (12), we did observe an increase in myocardial FFA with CR (Supplemental Fig. S3), which may explain increased expression of some PPARα target genes in this group (Fig. 7).
Mitochondrial Biogenesis and Uncoupling in Leptin Deficiency
The results of the mitochondrial respiration study can also be interpreted in light of our finding that PGC-1α/PPARα gene expression was suppressed in ad libitum and CR ob/ob mice. Ob/ob mice demonstrated increased mitochondrial uncoupling of oxygen consumption and ATP production relative to WT, consistent with the observation by Boudina et al. (5). Notably, this increase in fatty acid-induced mitochondrial uncoupling was not dependent on the expression of UCP3. In fact, we identified a significant decrease in the expression of UCP3 (Fig. 7) and no significant change in UCP2 in the hearts of ob/ob mice fed ad libitum, implicating other potential mechanisms behind the observed increase in mitochondrial uncoupling of obese hearts. We cannot exclude the possibility that increased activation of uncoupling proteins despite decreased expression in ob/ob mice could account for the increased mitochondrial uncoupling that was observed in our study, a mechanism identified in a study of db/db mice. (6) That study demonstrated an increase in ROS and lipid and protein peroxidation in db/db hearts, which is hypothesized to drive the increase in mitochondrial uncoupling by the activation of UCPs. Although we did not directly measure myocardial ROS or peroxidation products, our study did demonstrate in the hearts of both CR and ad libitum ob/ob mice an increase in the expression of genes involved in oxidative stress and glutathione metabolism (Table 1).
Interestingly, despite increased steatosis, CR restored mitochondrial coupling in the ob/ob mice. In CR-ob/ob mice, gene expression of both UCP3 and UCP2 was significantly increased despite suppression of cardiac PPARα. These data also support that mitochondrial uncoupling is not strictly dependent upon UCP3/UCP2 gene expression. (25) CR ob/ob mice had normal mitochondrial coupling despite increased expression of both UCP3 and UCP2, while ob/ob mice fed ad libitum demonstrated increased mitochondrial uncoupling, but decreased UCP3 and unchanged UCP2 expression.
We identified in our model a disruption of the tight link that has been demonstrated between PGC-1α and mitochondrial biogenesis (22). Our study identified an increase in mitochondrial copy number in both ob/ob ad libitum and ob/ob CR groups compared with WT (Supplemental Fig. S2), despite a decrease in PGC-1α expression. Although this concept was not directly explored, this observation might in part be attributed to CR-mediated induction of SIRT1, which would deacetylate PGC-1α and thereby enhance its activity (16, 28). Another explanation may be temporal, as PGC1α has been demonstrated to be initially induced in both ob/ob and db/db mice, leading to mitochondrial biogenesis and then suppressed with time (7). LR alone in ob/ob mice achieved equivalent weight loss without cardiac steatosis and restored mitochondrial copy number and function to WT levels.
In conclusion, we have found that the regulatory effects of leptin in the heart may be mediated by increased PPARα expression and changes in the control of GL/FFA cycling. Our study shows that the disruption in leptin signaling in ob/ob mouse hearts is associated with downregulation of genes encoding for GL metabolism and concomitant dysregulation of the PGC-1α/PPARα pathway. PGC-1α/PPARα gene expression was decreased in ob/ob mice, while PPARα target genes were nonetheless upregulated, consistent with the known increase in fatty acid oxidation rates (5, 24). Further evidence to support this hypothesis is found in the CR ob/ob model, in which suppression of PGC-1α/PPARα gene expression is highly suggestive of a mechanistic link between leptin signaling and PGC-1α/PPARα-mediated control of cardiac lipid homeostasis. Since diet-induced obesity in humans is associated with leptin resistance and myocardial steatosis (36), this study raises the possibility that the PGC-1α/PPARα axis and glycerolipid/FFA cycling are impaired in obese patients and that restoration of these pathways may be cardioprotective by reducing myocardial steatosis.
This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) Cardiovascular Medicine Fellowship (J. E. Rame), the American Heart Association National Scientist Development Grant 0730375N (J. E. Rame), NHLBI Division of Intramural Research (M. N. Sack), National Institutes of Health Clinical Center (R. L. Danner), and NHLBI Grants R01-HL-077785 and K08-HL-076220 (L. A. Barouch).
No conflicts of interest, financial or otherwise, are declared by the author(s).
The authors thank Dr. Roger Unger for advice and review of the manuscript. Carolea Logun provided invaluable experience in expression profiling and Kelly Byrne formatted and edited the manuscript. Maeva Nyandjo is acknowledged for assistance in the lipid protocols.
↵1 The online version of this article contains supplemental material.
- Copyright © 2011 the American Physiological Society


text:
Pulitzer Prize-winning author speaks in ER/S lecture series
Samantha Power makes presentation at the Cintas Center on American foreign policy and the problem of genocide | March 3, 2005
Power's presentation, titled, "American Foreign Policy and the Problem of Genocide," was part of Xavier University's 2004-2005 Ethics, Religion and Society lecture series.
"In her book, Power reveals a pattern of failures by the American government to recognize and respond to genocide across the globe dating back to World War I," says Sara Melcher, co-director for the department of Ethics, Religion and Society. "She has opened a lot of Americans' eyes to situations of genocide that need to be addressed by our government because we are a nation fortunate enough to have an impact."
Power's book, A Problem from Hell: America and the Age of Genocide, was awarded the 2003 Pulitzer Prize for general nonfiction and the 2003 National Book Critics Circle Award for general nonfiction. Power was the founding executive director of the Carr Center for Human Rights Policy (1998-2002). From 1993-1996, she covered the wars in the former Yugoslavia as a reporter for U.S. News and World Report, the Boston Globe, and the Economist. She is the editor, with Graham Allison, of Realizing Human Rights: Moving from Inspiration to Impact. A graduate of Yale University and Harvard Law School, she moved to the United States from Ireland at age nine. She has written a new introduction to Hannah Arendt's Origins of Totalitarianism and has begun work on a book on the causes and consequences of historical amnesia in American foreign policy.
This theme for this year's lecture series was "Ethics and U.S. Foreign Policy." Speakers addressed leadership issues on this topic. The program format led to informal discussion after the presentation.


text:
Day 1-Trip to Menards. Decide to buy sink for kitchen. Eat out to celebrate.
Day 2 - Spend 2 days looking, find sink, a special order. Decide we need new faucets. Look for faucets. Eat out.
Day 4 - Find faucets! special order.
Day 8 - Faucets come in. Pick up.
Day 13 - Sink comes in. Pick up. Also buy putty, grout, strainer, caulk, sawblade, flange, adhesive, etc. Husband goes nuts.
Day 14 - Friend who is a tileman comes over to release and lift old cast iron sink. We need him so we don't break the special order ceramic tiles around it. He scores sink, breaks a tile. We don't kill friend. Husband goes nuts after friend leaves. Have replacement tiles in basement from former owner. Husband says he can cut them and repair. Uses maybe a chain saw. Tiles destroyed. Sawblade destroyed. Decide to check out tile cutters.
Day 15 - Other friend comes over, helps lift out old sink because plumber buddy coming tomorrow to help put in new sink. Old sink now out. Eat out. Plumber buddy calls and can't come for 3 days. Eat out for 2 days.
Day 16 - Back to Menards to return grout. Wrong color. Go to Home Depot. Buy tile cutter that is really cool. Husband goes nuts because he only needs diamond blades for his chainsaw or whatever he used. Buy diamond blades but also tile cutter. Husband tries tile cutter and loves it. Problems solved. Eat out. Measure - realize old hole for sink is too small for new hill dollar sink. Husband goes nuts. Recut support for sink and pull out tiles. (I would have attached this if I knew how.)


text:
|Número de publicación
|Tipo de publicación
|Número de solicitud
|Fecha de publicación
|10 Ago 2010
|Fecha de presentación
|10 Ene 2008
|Fecha de prioridad
|10 Ene 2008
|También publicado como
|Número de publicación
|Brady Aller
|Cesionario original
|Hill Laboratories Company
|Exportar cita
|BiBTeX, EndNote, RefMan
|Citas de patentes (43), Clasificaciones (17), Eventos legales (2)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
The present invention relates to the therapeutic application of electrotherapy and the therapeutic application of phototherapy to a patient, and more particularly, the present invention relates to a medical electrode assembly for use in applying these therapies and a method in which the therapies can be applied to a patient simultaneously.
Phototherapy and electrotherapy are two very different therapies. Phototherapy is a process where light and/or laser photons are directed onto the skin of the patient and enter the tissue of the skin of the patient for therapeutic purposes. The phototherapy light source is typically provided by a pad with a cluster of LEDs or a probe with LEDs and/or lasers or other light source. U.S. Patent Application Publication No. 2004/0166146 A1 of Holloway et al. provides an example of the use of phototherapy.
In contrast, electrotherapy is the therapeutic application of electricity to the body. Stimulation wires have one end electrically connected to an electrical stimulation machine and the other end electrically connected to the skin of the body. Single or multiple channels with various frequencies can be utilized. Medical electrodes assemblies are used to connect the stimulation wires to the skin of the patient's body and are typically made of at least three separate layers. The three layers include an adhesive layer used to attach the medical electrode assembly to the body, a black rubber layer secured over the adhesive layer, and a foam or cloth backing layer attached to the rubber layer. Such medical electrode assemblies are not transparent with respect to visible, ultraviolet or infrared light, and one cannot visually see the skin of the patient through the electrode assembly.
U.S. Pat. Nos. 5,450,845 and 5,785,040 issued to Axelgaard provide examples of the construction of a typical medical electrode assembly. Also see U.S. Patent Application Publication No. 2005/0010161 A1 of Sun et al. for applying electricity or light to the skin of a patient. Further, see U.S. Patent Application Publication No. 2002/0068861 A1 of Yang and U.S. Pat. No. 4,539,995 issued to Segawa, U.S. Pat. Nos. 4,674,511 and 4,838,273 issued to Cartrnell, U.S. Pat. No. 4,685,467 issued to Cartnell et al., U.S. Pat. No. 4,800,887 issued to Shigeta et al., U.S. Pat. Nos. 5,265,579 and 5,571,165 issued to Ferrari, U.S. Pat. No. 5,356,428 issued to Way, U.S. Pat. No. 5,499,628 issued to Wright, and U.S. Pat. No. 6,600,957 B2 issued to Gadsby for medical electrode assemblies that are radiolucent or transparent with respect to x-rays. U.S. Pat. No. 4,300,575 issued to Wilson, U.S. Pat. No. 6,907,299 B2 issued to Han, U.S. Pat. No. 6,999,822 B2 issued to Koike, U.S. Pat. No. 4,391,278 issued to Cahalan et al., U.S. Pat. No. 4,694,835 issued to Strand, U.S. Pat. Nos. 5,133,356 and 5,226,225 issued to Bryan et al., and U.S. Pat. No. 5,215,087 issued to Anderson et al. and U.S. Patent Application Publication No. 2006/0183989 A1 of Healy disclose other medical electrode assemblies.
While the medical electrode assemblies and/or methods of use disclosed in the above referenced patents and published applications may function in a satisfactory manner for their intended purposes, there remains a need for a method of treatment and medical electrode assembly enabling the simultaneous therapeutic applications of electrotherapy and phototherapy to a patient.
The present invention provides a method for combining the two above referenced very effective modalities of electrotherapy and phototherapy. It is submitted that the combination of electrotherapy and phototherapy will have advanced synergistic effects since these therapies have proven therapeutic effectiveness when used alone. The present invention also provides a medical electrode assembly. Substantially the entire medical electrode assembly is transparent or translucent so that the radiation or light rays emitted by a phototherapy device shines and passes through the medical electrode assembly and is applied to the skin of the patient, including skin located directly underneath the medical electrode assembly, to achieve the combination therapy.
Preferably, the medical electrode assembly according to the present invention comprises or consists of an upper flexible gel layer secured over a lower flexible gel layer with an exposed end of an electrically-conductive lead wire sandwiched therebetween. The lower flexible gel layer is electrically conductive for electrically coupling the assembly to the skin of the patient and is self-adhesive for adhering the assembly to the skin of the patient. Both the upper and lower flexible gel layers are transparent or translucent relative to visible, ultraviolet and/or infrared light to permit passage or transmission of visible, ultraviolet and/or infrared light rays through the assembly.
Preferably, the method of therapy using the medical electrode assembly of the present invention comprises the steps of adhering the medical electrode assembly to the skin of patient and applying electrotherapy to a patient via the medical electrode assembly while simultaneously applying phototherapy to the skin of the patient with a light source. The step of applying phototherapy preferably includes directing visible, ultraviolet and/or infrared light emitted by the phototherapy light source through the medical electrode assembly and onto the skin of the patient including the skin of the patient located directly underneath the medical electrode assembly.
In one contemplated embodiment, the light source emits electromagnetic radiation within a wavelength range of 280 nm to 50,000 nm, and the medical electrode assembly includes upper and lower flexible transparent layers that are transparent or translucent to, and permit passage of, electromagnetic radiation of a wavelength of 280 nm to 50,000 nm. In another contemplated embodiment, the light source emits electromagnetic radiation within a wavelength range of 400 nm to 1,000 nm, and the upper and lower flexible transparent layers are transparent or translucent to, and permit passage of, electromagnetic radiation of a wavelength of 400 nm to 1,000 nm.
The features and advantages of the present invention should become apparent from the following description when taken in conjunction with the accompanying drawings, in which:
Both of the dual layers, 12 and 14, are transparent or translucent to visible light, ultraviolet light, and/or infrared light. For example, with respect to the preferred embodiment, the dual layers, 12 and 14, are substantially clear and a person can visual see directly through the dual layers, 12 and 14, to objects located on the other side of the dual layers, 12 and 14. Preferably, each of the dual layers, 12 and 14, are continuously transparent or translucent throughout their entire body so as not to block, absorb, reflect, or prevent substantially any transmission of light through any part of the assembly 10 and therefore, enable maximum passage of light to the patient's skin 20 lying directly underneath the assembly 10. The only exception is the relatively small and thin lead wire 18 which may not be transparent and may absorb and/or reflect rays of light. Otherwise, the entire assembly 10 is transparent or translucent to light and permits light rays "R" emitted by a phototherapy device, or light source, 22 to shine through the layers, 12 and 14, onto the skin 20 of the patient. See
Preferably, the dual layers, 12 and 14, include a lower flexible layer 12 intended to engage the skin 20 of the patient and an upper flexible layer 14 that faces outward of the skin 20 toward the phototherapy, or light source, device 22. The flexibility of the layers 12 and 14 enable the assembly 10 to conform to the contour of the skin 20 on which it is attached. Flexibility is particularly important for relatively large assemblies having a relatively large surface area. Alternatively, the layers, 12 and 14, can be substantially rigid if the assembly is relatively small and has only a small surface area.
As an example, the lower layer 12 can be a sticky, tacky, or self-adhesive gel-like substance. Such a gel layer 12 can be electrically-conductive such that it electrically couples the lead wire 18 to the skin 20. In addition, the gel layer 12 can have an exterior relative-tacky surface enabling the gel layer 12 to be removably self-adhered directly to the skin 22 of the patient. The upper face 24 of the gel layer 12 can also be tacky for purposes of self-adhering the lead wire 18 thereto and for adhering the upper layer 14 thereto. Alternatively, separate adhesive layers can be used.
The upper flexible layer 14 can be made of the same gel material as the lower flexible layer 12. If desired, the upper gel layer 14 can made of a conductive gel material, or more preferably, a non-conductive gel material. Its surfaces can be tacky to enable it to form a strong bond with the lower gel layer 12 and lead wire 18. Its upper face 26 can also be tacky to enable the separate phototherapy, or light source, device 22 to be removably adhered thereto. See
Preferably, the assembly 10 is provided as a disposable medical electrode assembly. For instance, as best illustrated in
A method of treatment according to the present invention includes adhering lower layer 12 to the skin 20 of the patient. The proximal end of the lead wire 18 can be electrically connected to the electrical stimulation device 32 for electrically stimulating the patient via the medical electrode assembly 10. As an example, electrotherapy is typically given for about a period of 8 to 12 minutes depending upon the purpose of the application.
Simultaneously with the electrotherapy treatment, a phototherapy light source 22 can be used to provide phototherapy to the skin 22 of the patient, including the skin located directly underneath the medical electrode assembly. Phototherapy treatment typically is longer in duration then electrotherapy treatment. Thus, there may be periods of time where only phototherapy treatment or only electrotherapy treatment is applied. However, the use of the medical electrode assembly 10 enables the treatments to be applied simultaneously or sequentially without any disconnection or re-connection of the electrode assembly to the patient.
According to one contemplated embodiment, the phototherapy light source 22 comprises a small lightweight light emitting diode (LED) cluster that can be adhered directly to the upper tacky face 26 of the upper layer 14 of the assembly 10. Thus a phototherapy treatment and an electrotherapy treatment can be given simultaneously to substantially the same region of the body. Alternatively, the light source can be a large bank of lights not supported on the assembly or connected to the assembly.
The type of light rays used during phototherapy depends upon the purpose of the application. Visible or optical light having a wavelength of about 400 nm to 700 nm could be used, and the assembly 10 could permit such electromagnetic radiation to pass through the layers, 12 and 14, of the assembly. Alternatively, ultraviolet rays could be used, including UV-A, UV-B, or UV-C rays. This would correspond to electromagnetic radiation of a wavelength within the range of about 10 to 400 nm. Still further, infrared rays could be used, including near or far infrared. This would correspond to electromagnetic radiation of a wavelength within the range of about 700 nm to 1,000,000 nm. According to one contemplated embodiment the medical electrode assembly would permit passage of light rays having a wavelength of between 280 nm to 50,000 nm, or alternatively, between 400 nm and 1000 nm.
While preferred electrodes and methods of treatment have been described in detail, various modifications, alterations, and changes may be made without departing from the spirit and scope of the electrode assembly and method according to the present invention as defined in the appended claims.
|Patente citada
|Fecha de presentación
|Fecha de publicación
|25 Jun 1979
|17 Nov 1981
|Staodynamics, Inc.
|Air-permeable disposable electrode
|14 Feb 1980
|5 Jul 1983
|Medtronic, Inc.
|Tape electrode
|30 Dic 1983
|10 Sep 1985
|Fukuda Denshi Kabushiki Kaisha
|X-Ray transmissive electrode-shielded wire assembly
|9 May 1984
|23 Jun 1987
|American Hospital Supply Corporation
|Medical electrode
|10 Jul 1985
|11 Ago 1987
|American Hospital Supply Corporation
|X-ray transparent medical electrodes and lead wires and assemblies thereof
|21 May 1986
|22 Sep 1987
|Minnesota Mining And Manufacturing Company
|Biomedical electrode
|26 Ago 1986
|31 Ene 1989
|Kureha Kagaku Kogyo Kabushiki Kaisha
|X ray-transparent electrode for a living body
|22 Jun 1987
|13 Jun 1989
|Baxter International Inc.
|Medical electrode
|16 Abr 1991
|28 Jul 1992
|Minnesota Mining And Manufacturing Company
|Biomedical electrode having centrally-positioned tab construction
|26 Jul 1991
|30 Mar 1993
|Graphic Controls Corporation
|Disposable leg plate electrode assembly
|16 Abr 1991
|1 Jun 1993
|Minnesota Mining And Manufacturing Company
|Biomedical electrode construction
|16 Jul 1992
|13 Jul 1993
|Minnesota Mining And Manufacturing Company
|Method of making a biomedical electrode
|21 Sep 1992
|30 Nov 1993
|Ferrari R Keith
|X-ray transparent monitoring electrode and method for making
|13 Ago 1992
|18 Oct 1994
|Cardiotronics, Inc.
|Non-invasive, radiolucent electrode
|11 Ene 1993
|19 Sep 1995
|Axelgaard; Jens
|Medical electrode system
|21 Mar 1994
|12 Dic 1995
|Dusa Pharmaceuticals, Inc.
|Combination controller and patch for the photodynamic therapy of dermal lesion
|27 Ago 1993
|19 Mar 1996
|Micron Medical Products, Inc.
|Medical electrode
|21 Mar 1994
|9 Abr 1996
|Dusa Pharmaceuticals, Inc.
|Article of manufacture for the photodynamic therapy of dermal lesion
|8 Dic 1995
|5 Nov 1996
|Ferrari; R. Keith
|X-ray transmissive transcutaneous stimulating electrode
|19 Sep 1995
|28 Jul 1998
|Axelgaard; Jens
|Medical electrode system
|28 Jun 2001
|29 Jul 2003
|The Ludlow Company Lp
|High-energy disposable medical stimulation electrode
|24 May 2002
|14 Jun 2005
|Shu-Chang Han
|Electrodes for a transcutaneous electrical nerve stimulator
|5 May 2004
|14 Feb 2006
|Nihon Kohden Corporation
|Medical electrode
|13 Sep 2002
|28 Feb 2006
|Neothermia Corporation
|Electrosurgery with infiltration anesthesia
|8 Abr 2003
|18 Sep 2007
|Commissariat A L'energie Atomique
|Photodetectors array with isolated pixels and storage grid, hybridized on a readout circuit
|10 Dic 2003
|4 Dic 2007
|University Of Florida Research Foundation, Inc.
|Phototherapy bandage
|1 Dic 2000
|6 Jun 2002
|Wen Yang
|Structure of an electrode plate penetrable by X-rays
|10 Jun 2002
|26 Dic 2002
|Casio Computer Co., Ltd.
|Reading apparatus
|31 Oct 2002
|6 May 2004
|Gilbert Bruce R.
|Device for surface stimulation of acupuncture points
|31 Jul 2003
|15 Jul 2004
|Lucent Technologies
|Electro-optic devices having flattened frequency response with reduced drive voltage
|10 Dic 2003
|26 Ago 2004
|University Of Florida
|Phototherapy bandage
|19 Jun 2003
|23 Dic 2004
|Craige David N.
|Skin-applied electrode pads
|23 Jun 2004
|13 Ene 2005
|Ying Sun
|Methods of treating acne and rosacea with galvanic generated electricity
|14 Oct 2005
|16 Feb 2006
|Fujitsu Limited
|Information processing device
|30 Nov 2005
|20 Abr 2006
|Genetronics, Inc.
|Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation
|3 Dic 2004
|8 Jun 2006
|3M Innovative Properties Company
|Process for making pressure sensitive adhesive hydrogels
|12 Dic 2005
|20 Jul 2006
|Palomar Medical Technologies, Inc.
|Light energy delivery head
|13 Ene 2006
|17 Ago 2006
|Healy James W
|Biomedical electrodes and biomedical electrodes for electrostimulation
|4 Ago 2005
|8 Feb 2007
|3M Innovative Properties Company
|Conductive adhesives and biomedical articles including same
|26 Feb 2007
|4 Oct 2007
|Jona Zumeris
|System and method for surface acoustic wave treatment of skin
|28 Mar 2006
|4 Oct 2007
|Eastman Kodak Company
|Light therapy bandage with imbedded emitters
|11 Jun 2007
|20 Dic 2007
|Johnson Scot L
|System and method for simultaneously applying a plurality of therapeutic modalities to treat carpal tunnel syndrome
|18 Abr 2005
|14 Ago 2008
|Sydney West Area Health Service
|Biomedical Return Electrode Having Thermochromic Layer
|Clasificación de EE.UU.
|607/115, 607/117, 607/88, 606/2, 607/89
|Clasificación internacional
|Clasificación cooperativa
|Clasificación europea
|18 Ene 2008
Owner name: HILL LABORATORIES COMPANY, PENNSYLVANIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALLER, BRADY;REEL/FRAME:020423/0720
Effective date: 20080115
|10 Feb 2014
|Fee payment
Year of fee payment: 4


text:
Undying love | The Sun |News
Moving ... couple in embrace. REX
DEATH did not part this couple — they were still holding hands when their tomb was uncovered 1,500 years after their burial.
Archaeologists found the couple in Modena, northern Italy.
Excavation director Donato Labate, said: "We believe the couple were originally buried with their eyes facing each other's. I have been involved in many digs but I've never felt so moved."
Romantic ... pair's love has stood test of time. REX


text:
Forgot your password? Enter the email address you signed up with and we will send you a link to create a new password.
Your password reset has been submitted to the address provided.
Design plus words, letters, and/or numbers
promoting the use of mortgage loan programs through a loyalty reward program directed to mortgage brokers, correspondent lenders, and clients
Business in Coral Gables, FL


text:
Brown leather coin purse, handmade. Brown and blue leather. Closes with a snap. Sewn with red thread.
Just the perfect size for your cards and money. It is completely handmade, unique. Very soft and durable. Very colorful.
Size: 4,52 x 3,3 inches.
Perfect for your pocket. Simple and beautiful.
More models here:
3-5 business days
I'll do my best to meet these shipping estimates, but can't guarantee them. Actual delivery time will depend on the shipping method you choose.
Buyers are responsible for any customs and import taxes that may apply. I'm not responsible for delays due to customs.
Just contact me within: 7 days of delivery
Ship items back to me within: 14 days of delivery
Request a cancellation within: 24 hours of purchase
But please contact me if you have any problems with your order.
Because of the nature of these items, unless they arrive damaged or defective, I can't accept returns for:
Buyers are responsible for return shipping costs. If the item is not returned in its original condition, the buyer is responsible for any loss in value.
I will only use your shipping and billing address, and contact information
The standard items are shipped via standard shipping (Correos, Spanish National mail service). They have an available update to add a tracking number. It must be selected during checkout. If registered mail is not selected, the shipping won't have tracking number.
The items with weight lower than 100gr are shipped with Registered mail via Correos.
The items with weight over 100gr are shipped with Express Shipping with DHL company. In this case, it will take less than one week to arrive.


text:
your browser is out of date
To get the best experience please upgrade to a new browser
Giselle came to pay us a visit and boy are we glad she came. This girl is one of the definitions of Round and Brown! She has one of the biggest and nicest asses Ive seen in some time. We had to let her strut her stuff around the pool before we got started, so we set up a slip and slide in the lawn and turned the hose on an had some fun outside first. Before you knew it Jmac was banging her doggie style in the kiddie pool and she was loving it. From there we took it inside and wrapped things up with a nice load all over the Round and Brown booty. Enjoy!


text:
Release Date: Feb 08, 2011
Total Songs: 14
Genre: Urban > Smooth R&B
(aka) Mr. JackHamma *A Spoken Word Aphrodisiac* Is the "HOTTEST" collection of music out this year! This is a must have album!
The MP3 album is ready for download after your purchase. The album will contain all songs listed below.
©1997-2017 SoundClick Inc. All rights reserved!


text:
BATTLE CREEK, Mich. — Kellogg's is honoring the U.S. women's gymnastics team by debuting limited-edition boxes of Corn Flakes this fall.
The box will feature team members Gabby Douglas, McKayla Maroney, Aly Raisman, Kyla Ross and Jordyn Wieber, who collectively won the gold medal in the women's team competition at the 2012 Olympic Games in London. Kellogg's, an official sponsor of the United States Olympic Committee and USA Gymnastics, said the limited-edition boxes will hit retail shelves this fall.
Kellogg's announced last week that a limited-edition box featuring team member Gabby Douglas also will be rolled out this fall.


text:
This procedure reduces the stomach's volume and also eliminates the part of the stomach that produces the hormone that stimulates hunger. Approximately 85 percent of the stomach is removed, with the remaining stomach volume measuring around 2 to 5 ounces. Other than the reduction in volume, the stomach tends to function normally, so most foods can be consumed, but in small amounts.
Because this procedure doesn't involve intestinal bypass, it's a good option for people with existing conditions such as anemia or Crohn's disease. It can be performed laparoscopically on most patients, even those with a high BMI. After the initial weight loss, patients on the higher end of the BMI scale may need a second-stage procedure to lose the remaining weight.
Attend our support group session.


text:
Buy an Axon, Axon II, or Axon Mote and build a great robot, while helping to support SoR.
0 Members and 1 Guest are viewing this topic.
(1) What rating would the resistors on the Tapered Charger Circuit need to be, assuming a maximum charge rate?
(2) What would be the optimum charge rate? A two hour charge time would be great but I imagine this comes at the cost of overheating & reduced battery life.
I'd prefer to use DC input for safety. Is it just a matter of chopping out the rectifiier and connecting the DC input to the top (+) and bottom (-) rail? What would be the relevant input voltages / resistor values for DC input?


text:
Kalpana Chawla
News about Kalpana Chawla, including commentary and archival articles published in The New York Times.
Shuttle Roars Back to Space After 2 1/2-Year Absence
With a stuttering roar that shook the air for miles around, the shuttle Discovery lifted off on Tuesday morning.
July 27, 2005, Wednesday
As NASA prepares to return the space shuttle to orbit this spring, a debate over whether the fleet is as safe as it should be has been building inside and outside the space agency. There is widespread agreement that the National Aeronautics an...
February 7, 2005, Monday
NASA Delays Plans to Fly Shuttle Soon
NASA has abandoned plans to resume flying the space shuttle next March because of the impact of four hurricanes on space agency centers and work schedules.
October 2, 2004, Saturday
Mayor's Sentiments Were Right, if the Astronaut Wasn't
As mayor, Michael R. Bloomberg attends many memorial ceremonies for strangers. But yesterday, when he visited Queens to honor an Indian-American astronaut killed in the explosion of the space shuttle Columbia, Mr. Bloomberg made a point of noting ...
July 12, 2004, Monday
NASA May Need to Consider Alternative Plans on Shuttle
The difficulty of developing an in-flight inspection and repair system may force NASA to consider alternative approaches if it wants to resume flying the space shuttle next spring, an oversight group said Wednesday. The return-to-flight task fo...
May 20, 2004, Thursday
Photos of Soldiers' Coffins Spark a Debate Over Access
A White House spokesman, Trent Duffy, said on Friday that President Bush had seen photographs of the coffins of service members killed in Iraq arriving at Dover Air Force Base that were made public on Thursday and agreed with the Pentagon that rel...
April 24, 2004, Saturday
Shuttle Flew for Decades With Potentially Fatal Flaw
Some of the nation's space shuttles may have flown for 25 years with a potentially fatal problem in the rudders of their tail sections, a NASA official said Monday. The official, William W. Parsons, the shuttle program manager, said some gears ...
March 23, 2004, Tuesday
Adventure or Inquiry? Two Visions of Cosmic Destiny
''The best marriage of human spaceflight and science.'' That is how Dr. John M. Grunsfeld, astronomer, astronaut and chief scientist of NASA, described the Hubble Space Telescope when he announced last month that the agency was canceling maintenan...
February 3, 2004, Tuesday
Astronauts Remembered on Anniversary of Columbia Loss
One year after the shuttle Columbia broke apart over Texas, NASA workers held a quiet memorial on Sunday at the moment of destruction. ''One year ago, at this very hour, the unthinkable occurred,'' the Kennedy Space Center's director, Jim Kenne...
February 2, 2004, Monday
Resting Place for Columbia's Debris: A Springboard for Memories
The first piece of wreckage lifted from the first trailer to arrive here from the fields of Texas and Louisiana was a window frame. Just 10 days before, on the morning of Feb. 1, 2003, astronauts had still been looking through that frame at the gl...
January 31, 2004, Saturday
Rss Feeds On Kalpana Chawla
Subscribe to an RSS feed on this topic. What is RSS?
Get Alerts On Kalpana Chawla
Receive My Alerts e-mails on topics covered on this page.More Alerts >>


text:
What does a 300-pound high school football player with appendicitis have in common with a tiny newborn with the birth defect gastroschisis? Children's General and Thoracic Surgery providers can give both the care they need.
If your child really needs surgery, are you sure the surgeon is experienced enough to be able to handle any contingency? Even straightforward operations can turn out to have variances that only an experienced team of pediatric surgeons can handle. That's why you should come to Children's.
Dr. John Waldhausen, chief, General and Thoracic Surgery
In 2006, our doctors performed more than 2,000 general and thoracic surgeries on children at all ages and developmental stages — from infants through teens — to treat a range of conditions, including those that affect the chest, abdomen and pelvis.
We use the most advanced diagnostic and surgical techniques and state-of-the-art equipment, and all our surgeons are board certified in pediatric surgery, which means they have special training in operating on children. This matters because children have different needs for surgery, anesthesia and recovery than adults do.
You might be surprised to know that more than 40% of the children and teens seen in General and Thoracic Surgery go home without needing an operation. We've found that some conditions commonly treated with surgery are actually better treated using other therapies. So even though we're a surgical team, we often use nonoperative methods to help our patients.
If an operation is the best method for your child's condition, we offer expertise in a broad range of approaches, including minimally invasive procedure. This means a smaller scar, less pain during recovery and a shorter hospital stay. We do more minimally invasive surgeries on children for a broader range of conditions than any institution in the region.
Looking at all types of surgery that we do, Children's also has the lowest complication rates and fewest repeat operations of any institution in the region doing pediatric surgery. Our surgeons, nurses and other care team members have the breadth and depth of knowledge to manage any condition, along with the unexpected issues that can arise during treatment. You can feel assured your child is in good hands, before, during and after their operation.
11.17.17 — GeekWire
With cutting-edge immunotherapy treatments opening doors to fight cancer, the outlook for patients today is much better than...
11.16.17 — Xconomy
The researchers and doctors at Seattle Children's are embarking upon a complicated quest, involving multiple clinical...
11.16.17 — ABC News
Russel and Magda Newman's son, Nathaniel, was diagnosed with Treacher Collins, an extremely rare congenital craniofacial...