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Need BMW E46 lighting? This page lists our E46 lighting products. Each E46 lighting option will change your style. To stick out, get E46 lights for yourself. E46 light is for both exterior and interior E46 lighting on your BMW. Lighting for E46 is a popular mod because it makes stock E46 lights look boring. Lighting of BMW E46 can accent your unique BMW. Our lighting at Modbargains for your interior changes what your passengers experience. Our E46 lighting parts are important to being one-of-a-kind. E46 BMW lighting will make you what people notice. E46 head lights will make things more visible to you and others. E46 lighting - light up the sky. Ready to upgrade your lights of E46? Call our sales at (714) 582-3330 for assistance!


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FRESNO, Calif. (KFSN) -- Families in Fresno County struggling to pay rent can now get help.
The Fresno Housing Authority will soon start accepting online pre-applications for the Section 8 program.
The program offers rental assistance or affordable housing to low-income families.
The Fresno Housing Authority expects between 65,000 to 70,000 applications during the two-week application process.
When funding becomes available pre-applicants will be randomly selected through a lottery system and will receive assistance through Fresno County.
The pre-application period begins May 1st.
LINK: Pre-application for Section 8 Housing
Applicants must have a valid email account set up prior to completing the pre-application.
Applicants that do not have access to a computer or mobile device can apply at any Fresno County Library or at a computer lab at some Fresno Housing properties.
Pre-applications accepted soon for 'Section 8' program
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Geography isn't always exciting and fun to learn, but you can change this by supplementing geographical studies with a hands-on craft project, such as making a crumpled paper mountain. Create crumpled paper mountains from wadded up paper, glue, and decorate them with paint. When possible, collect printer or other paper that has already been used. This will not only teach children about the geography of the planet, but about protecting the environment as well.
Crumple up pieces of scrap paper. Some pieces can be smaller than others. Wrap masking tape around some of the wads of paper to make them more solid and firm. Place four larger wads of paper on to a piece of 30 by 30 cm (12 by 12 inch) cardboard, and tape them on to the cardboard with masking tape.
Squeeze 30 ml (2 tbsp) of craft glue into a small dish, and add 15 ml (1 tbsp) of water. Dip a heavy-duty paintbrush into the diluted glue, and brush the mixture over the larger wads of paper. Place the smaller wads of paper on top of the larger wads of paper to fill in the gaps, and brush glue over the entire paper mountain. Allow the glue to dry completely.
Paint the mountain to make it appear more realistic. Use only non-toxic watercolour or acrylic paint. The base of the mountain can be grey or green, depending on where the mountain is located on the planet, and the top of the mountain can be painted white if there is snow. Allow the paint to dry completely before displaying the model.
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There is certainly nothing wrong with the other types of window treatments, but there are plenty of reasons why so many people are going with one or more types of the wide variety of blinds for windows.
On average, blinds last longer and are easier to maintain than curtains and draperies. There is often a lot of sewing and hemming that needs to be done with window coverings made of fabric. Some people simply do not have the time (or expertise) to do it themselves nor the budget to get custom-made curtains or drapes.
By the way, for the folks that want to make their own window coverings, information on that very topic will be included on the pages of this site.
One of the things people like about window blinds is that the blinds can easily be adjusted to different positions depending on the angle of the natural sunlight and how much light you want coming into the room.
Being able to block or minimize the sun's ultraviolet rays can help to prolong the life and beauty of your furniture, carpets (and/or rugs), as well as your upholstery.
Let's take a look at different types of blinds:
Venetian Blinds:
It is generally thought that this type of blind was introduced in Venice, Italy around 1770, hence the name. However, some people claim this style was in use in France long before then. I am not an expert on the actual history of this item, so we'll just move on, okay?
Venetian blinds have horizontal slats positioned one above the other with a bit of space in between. They are held in place by cloth strips, called tapes, or by thin cords. The slats can be rotated in unison to control the amount of light and glare. When the blind is raised, the slats are stacked against each other.
Venetian blinds can be made of metal, plastic, vinyl, wood or a composite that consists of wood and man-made materials.
A mini-blind is simply a Venetian blind that is not nearly as wide as the original design.
Vertical Blinds:
Sometimes called track blinds, they look like very wide Venetian blinds that hang down vertically and move along a track. Vertical blinds can be opened completely to allow for an unobstructed view out the window or rotated to various angles when closed.
Solid Blinds:
These are commonly called window shades. These cannot be rotated like a Venetian blind. They are rolled up or folded partially or completely to allow light to enter.
There are different types of solid blinds, including Holland blinds (also know as roller shades), woven wood or bamboo blinds, pleated shades, honeycomb shades (also known as cellular shades) and Roman shades.
Roman shades have a cord that is woven into the fabric that enables you to raise or lower the shade in an accordion-like pattern.


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Calf Warmers from Barn World
To provide the best care in the critical after-birth hours of your calf's life, be sure to enlist the help of a calf warmer.
Calf warmers should be a livestock supply staple when raising livestock
Calf warmers create an excellent shelter and warm nurturing environment for new born calves. Usually constructed out of a durable, long-lasting and rust proof medium density poly, this animal shelter is a must for newborns and should be in every livestock supply arsenal.
New born calves require a warm enclosed space during the critical hours right after birth. They are vulnerable to the cold and need a safe place to recover from the birthing process. Barn World calf warmers have top of the line heaters located in the rear of the warmer in a separate enclosure that provides a steady warm, circulating flow of air. The area is large enough so the calf can stand up or lie down while remaining in the interior warmth of the heater. Being contained allows the identity scent to remain intact so the mothers will instinctively reclaim their rejuvenated infant once they're ready to be released.
Calf Warmer Features
Barn World carries the Sioux Steel calf warmer with the following top-of-the-line features including a fully controllable an automated heater.
The Sioux Steel Warmers come with:
- • An adjustable 1500 watt electric heater with a fan with automatic shutoff and built in thermostat for controlling temperature and air flow speed
• The top hinged section is completely removable for ease of cleaning and for providing the largest allowable access area for calves to enter and leave the enclosure
• The bottom of the warmer is reinforced for easy towing and durability. It comes compete with a tow rope already installed so you're ready to remove the calf from the delivery area
• The floor is raised and grated to provide warm air circulation throughout the entire warmer. It has a two panel system and is removable for easy cleaning
• The top eve vent allows for ventilation and circulation control as well as provides sighting access so you may keep an eye on the calf without raising the lid and disturbing it
• A popular feature is the 12v adapter
• The warmer measures 45" high, 25" wide and is 48" long to allow for maximum comfort inside.
Livestock Supplies are necessary for newborns
To keep your young, newborn livestock healthy and to give them a great start at a long and healthy live, a calf warmer is a must during the crucial hours after birth. Providing a safe and comfortable environment for your animal is a must to ensure a great beginning in a stress-free setting. To take advantage of all the calf warmer has to offer, call (720) 238-2190 or visit BarnWorld.com today for all your livestock supply needs and remember, they carry everything from cattle guards to saddle pads!


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What does Cookies, Cache and Internet temporary files mean? Every time you open a webpage using a browser to read your email or to purchase something online, viewing the weather online, reading the latest news or reading the sports, that information is stored on your computer and Windows operating system for later use. All the information described above is what we call cache files or Temporary Internet files. Many websites stores special files on your computer called cookies which includes information you've used in some websites like application forms or…Read More
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Landlords in New York City are taking unprecedented steps to get leases signed.
In January, concessions like a month of free rent and brand-new appliances rose to a record high in both Manhattan and Brooklyn, according to the real-estate appraiser Douglas Elliman. Concessions hit new highs for a fourth straight month, and the share of new leases with such giveaways was above 30% for the first time.
Concessions climbed to a record 18.1% of all leases in Brooklyn, more than triple the amount of a year ago.
"It's one thing to give concessions because it's a new building and amenities aren't working yet or the building's not fully completed," Andrew Barrocas, the CEO of the brokerage MNS, recently told Business Insider.
"And then there's concessions because you can't rent at that price."
It appears to be the latter case in New York, as landlords adjust prices to be more in line with what prospective tenants are willing to pay. The heaviest concessions were in the market for two-bedroom apartments, according to Douglas Elliman's monthly report.
The median net effective rent in Manhattan — which factors in concessions — slipped year-over-year by 0.1% to $3,369, while the number of new leases signed dropped by 5% to about 3,200. Both the number of days on the market and the listing inventory were higher, suggesting that landlords had a harder time filling up vacant apartments.
"Overall there's definitely signs of the rental market weakening," Barrocas said. The market slowed down, he added, amid disagreement over New York state's 421-a tax exemption for developers that would normally encourage the construction of affordable housing.


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"so many brains. I feel like a kid in a candy store"
A quote from the film with Steve Martin form the mid 1980's.
By the end of today that was just how I was feeling except maybe I needed more than two.
Confused yet....
Read on!
Today I discovered something about my brain. First I only ACTUALLY have one. As we don't consciously use even the one we have to its full potential, what on earth would I do with two!
However it finds it difficult to change track. Let me explain -and this is why this is a BFO for me today - I'd been two a couple of sales meetings today in the morning and by the time I came back into the office, I couldn't focus on routine things - like opening the mail, reviewing and finalising accounts and tax returns. It sounds awful when I write that but honestly, my mind was in sales mode and NOT accounting mode.
The brain behaves totally differently for these two opposite tasks. Accounting, Tax etc requires a logical, calm and almost cold approach. The numbers themselves have no emotion, no warmth, no feeling.
Sales on the other hand requires a care for people, a listening and open mind, it needs to be able to see the gaps in thinking. Sales generates extremely high levels of adrenalin - certainly in my case - and extra energy. I don't know why that happens; I just know it does.
So no matter how long the drive back, it takes some hours to "come down" from Sales so maybe the best thing is NOT to try to do things that sales brains can't do, but perhaps to stay in the marketing zone. The marketing zone is a creative place, and good fun to be in.
Not that accounting isn't fun or creative at times. So take my experience to heart and on a sales day don't try to do logical cold tasks, stay in the heat of sales and use up your adrenalin responsibly.
I'm quite sure that Dr Hfuhruhurr would approve.


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Painted Wooden Bird Brooch - Pink
Simple painted wooden bird brooch, laser cut from 4mm thick Baltic birch plywood. It has a crisp caramelised edge from the laser-cutting process and is painted with two coats of acrylic paint and then lightly varnished to seal it.
Comes with a silver plated brooch back.
This brooch measures 17mm high by 40mm wide.
Comes pinned to a card backing and wrapped in bubble wrap to protect it during transit.
Perfect for livening up your cardigan!
This design is also available in electric blue, cerise, mustard, green, gold and bronze colourways.
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Capsula Mundi aims to help you turn into a tree after you die
Not literally, but pretty darn close.
A few years ago, we brought you a story about the Capsula Mundi concept, which is an egg-shaped burial pod made from biodegradable materials, inside which a person's mortal remains would be placed. A tree would then be planted over the pod, which would eventually fully decompose, essentially turning the deceased's body into a tree. Sort of.
Based on the comments on that piece, it seemed to resonate with the treehugging green burial crowd, so I'm happy to announce that Anna Citelli and Raoul Bretzel, the designers behind Capsula Mundi, are moving forward with this project, with the aim of developing a viable full-sized industrial prototype of the 'egg' and producing molds for the eco-coffin by sometime next year.
"We have designed an egg-shaped pod - an ancient and perfect form - made of biodegradable material, where the departed's body will be laid down in a fetal position. The pod will then be buried as a seed in the earth. A tree, chosen in life by the deceased, will be planted on top of it, as a legacy for future generations and the future of the planet. Family and friends will take care of it."
In addition to the burial pod, Capsula Mundi envisions cemeteries becoming memorial forests, full of life and natural beauty instead of perfectly manicured lawns punctuated by headstones and gravesites that essentially serve to keep those plots from being used for any other purpose than as a (seldom visited) memorial site. The project creators also aim to integrate a GPS system to create a map full of virtual memorials:
A GPS system will map the trees' location. Using a recognition system, every tree will be linked with data storage which can keep all the virtual memories of the deceased: pictures, videos, audios and anything the person wanted leave to family and friends.
Here's a great short talk by the designers, which sheds some light on the thinking behind this project, which also seeks to change our perception of death:
"Could our perception of death be changed by simply redesigning one object, the coffin? Anna and Raoul, two designers who are part of the Capsula Mundi project, believe so. Their goal is to change the perception of death, not as the end of life but as the beginning of a return path in the biological cycle of life."
Capsula Mundi is currently in a crowdfunding phase, with the intent of raising funds to finish a viable prototype and create the molds for future production of these burial eggs, as well as to continue the designers' research on potential materials for the pods and to address the "biological matters and legal considerations concerning the project." Rewards for backers range from a small version of the pods, the Capsula for ashes, which allows for the slow dispersal of the deceased's ashes into the soil, to a flip book about the project (and about the natural cycle of life), as well as Capsula Mundi t-shirts and cloth shopping bags.


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From Bullyland's Disney range of miniature figurines comes Merida! All of Bullyland's figures are made from PVC-free, recylable, TVC plastic, and colourfully painted with non-toxic paints.
Brand: BullylandSize: Approx 9 cm tallAge: 3 years +
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You would think that if your body was constantly attacking itself, it would be pretty obvious and a simple doctor visit would be all it takes to uncover this nasty problem. Turns out it's usually quite mysterious. I called what was happening to me "Zombie-ism." I would have episodes of extreme fatigue, foggy brain, dry burning eyes, blurred vision, dry skin and hair and painful joints. These and other issues seemed unrelated until we discovered I have antibodies for Hashimoto's, or hypothyroidism. What this means is that my body is eating at my thyroid as if it were a foreign body. It is an autoimmune disorder not unlike multiple sclerosis, type 1 diabetes, psoriasis, rheumatoid arthritis, Grave's disease, and many others. I learned that if you have one autoimmune disorder, your weakened immune system makes you more likely to a host of many other sicknesses. So, not surprising that I also have Epstein Barr.
I have known that I have Hashimoto's for about four months (though the symptoms have been there for a few years at least). Despite the clear episodes of Zombie-ism and declining ability to exercise, I still considered myself a very healthy person. I really wanted to believe that because I have stuff to do; I have ambition, I have ideas, I have things to make, I have people to love. Hashimoto's is an inconvenience I really don't want to have. But I also don't want the inevitable medications and hormone replacement my doctor says I'm going to need. So I have a choice: deny it or embrace it?
I am participating in Jeffrey Davis' (of Tracking Wonder) #daretoexcel challenge this month. I had all kinds of ideas of what kind of art and creativity related projects I might do. Then I had a harsh and immediate episode of Zombie-ism over the weekend that left me completely deflated, without creativity, energy and hope. I realized that I needed to take on Hashimoto's above any creative project in order to ensure that I could take on many more creative projects in the future. To be completely honest, I'm not happy about this at all. I would rather focus my attention on other things. But as it so happens, my prerequisite to "other things" is my wellness. So be it. I will go with it. Head on, 100%. I want my wellness, dammit; I want it bad.
Dare #1: My Burning Question
So my burning question is: How might I take this lifestyle change and do something others could also benefit from while cementing it as a new way of life for myself? How might I cure myself of Hashimoto's (without meds) and make that cure available to others with autoimmune disorders so that they could know thriving once again? How would I do it so that it's rigorous and complete, but not so daunting that it feels impossible? How could I make it accessible? How could I make it sustainable? How could I do it so that the choice to embrace it head-on feels less painful than denying it? I believe all of this is possible. I feel like it's bigger than me and it's going to be really hard. But I also think that it will be worth it – more than money could buy.
Dare #2: Project Brief
How will I do this? What project could I create with this endeavor? "Curing Zombie-ism" will be a book that helps people choose non-medicated wellness and relief from autoimmune disorders.
Dare #3: Bringing My Young Genius To Work
As Jeffrey reminds us, genius comes from the Greek idea that there is a force each of us uniquely has that helps us find our way in the world. As young people, that force is how we make our way and what we choose to do when we make our world. So the question is: what was I like when I was 8, 9, or 10 years old that factors into how I will tackle this project?
When I was 8, 9 or 10 years old, I stood on the front steps of our home with my older sister. She had issued a challenge: a race to the blue pole barn. After beating me, she told me that there was no limit to how fast I could move my legs. I believed her and set about in earnest to see if I could prove it. After a few more races I beat her. In my mind that was proof enough. What that experience did for me was to look at myself and my world differently – that limits were movable and even somewhat arbitrary.
The adjectives I would use to describe myself would be: pliable, curious (about what's possible) and dedicated. Dare #3 is to take these qualities and bring them to my project. I will be testing what is possible (how will I push limits? how will I adapt myself to achieve unexpected expectations?). I will need to continue to show up to this challenge over and over again to move my perceived limits. I need these qualities to explore the limits of disease, adapt those limits and move beyond them to create a new condition for myself.
Double Dog Dare
#DareToExcel is designed to get people to step up to do the things they already want to do, to be their better selves. The challenge is to have courage to be yourself, beyond what you'd imagined in day to day life. I love these dares; they're very hard, but very fulfilling on many levels. But this isn't the kind of dare I'm meant to take this time around.
This dare is the double dog dare for me: the dare you issue to someone who is entirely NOT motivated to take the dare. It's the kind of dare meant to challenge your capacity to accomplish something you don't want to do. It also raises the stakes; if I can manage to do this tough thing, others will take on the dare as well. "Curing Zombie-ism" is a double dog dare for me. I don't really want to do it (I'd rather take on a number of creative projects), but I can't not do this. We can't not do this.


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Pavitra Royal Palms
Pavitra Royal Palms is one of the popular residential developments in Malleshpalya, neighborhood of Bangalore. It is among the completed projects of its Builder. It has lavish yet thoughtfully designed residences.
Pavithra Builders and Developers offer a comprehensive portfolio of villas and apartments in Bangalore's finest locations. Known for its speedy quality construction, Pavithra homes are fast altering the cityscape.Pavithra has grown steadily since its inception. The company's intention is to have a sustained and managed growth by maintaining a low debt-to-equity ratio. The company's success lies in its ability to attract and retain experienced personnel with its good HR policies and thus keeping the attrition of employees to the lowest level.


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Joe Chiccarelli
Why less is more, but talent is everything
Chiccarelli with singer/songwriter Keaton Henson
at Sunset Sound in Los Angeles.It's hard to imagine anyone with a more diverse collection of successful major album and singles credits than Joe Chiccarelli. Having jumped at the chance to engineer with Frank Zappa in his just-getting-started days, he hit the ground running and has been moving along at a great clip ever since. The list of recordings bearing this multiple Grammy winning producer/ engineer's soulful touch is as long as it is broad. From Etta James to Alanis Morissette, from U2 to The White Stripes, Chiccarelli's devotion to building creative mixes, showcasing stellar voices, and crafting enticing aural atmospheres points to the diversity of his own outstanding talents as an engineer, musician, and producer.
Chiccarelli has just finished up a number of projects, and iTunes and radio airwaves are buzzing with his signature production sound and creative influence. On some of these albums he's the sole producer, and on others he's sharing the role. Producing the new Alanis Morissette album along with composer and producer Guy Sigsworth (Madonna, Seal, Bjork), has given him new insight on collaborating in the studio, and his efforts are currently riding high on the charts with Morissette's "Guardian" and Jason Mraz's new single "I Won't Give Up." Electronic Musician caught up with him while he was on a break from the action in Los Angeles. Always talkative and eager to share, he was happy to discuss his personal recording philosophy and the technical and performance particulars of albums you've heard or will be hearing soon.
You've been credited by many with having a great propensity to showcase amazing vocal performances in your work. There is a real up-close and personal connection that seems to be going on from the singer to the listener on many songs.
A song is only as great as the singer. I'm really old school about that. A great singer makes your job really easy. In a sense that's the first and foremost thing that you hear. Maybe you hear a great guitar hook in the intro of the song, but if the vocal and the story don't carry it through the three-and-a-half minutes or whatever it is, you're not interested. It's still all about that, and recently I've been very lucky to have worked with such great singers such as Alanis Morissette and Jason Mraz, but also with others like Elton John, Beck, and Bono. These are people who are just masters of pumping big emotions through a microphone. I think it's the key, getting it so that you're committed and connected for that entire vocal. Sometimes it's a simple thing, just one magical take. Jack White can be the master of that; when he's on, it's really simple. Other times, it's about crafting a vocal performance. Jim James from My Morning Jacket is great at knowing how to layer his voice and use echo and effects to deliver a beautiful emotional blanket. Alanis is such a pro after so many albums; I mean, she just gets up to the microphone, and two or three takes and you're done. She's got a beautiful tone, and it's pretty easy that way.
What do you do to as far as your preproduction process before tracking sessions?
It's something I definitely take a lot of time with. I make sure that songs are in the right key for the singer. However, sometimes it's a matter of doing the opposite—putting the song in a key that may not be the most comfortable but provides them with a different tone. They may have a big, strong voice that's really full, and if you put them on the lower edge of their range, it can make them sound maybe softer or more vulnerable. From there, it's choosing the arrangement and instrumentation so that it doesn't fight the vocal, choosing a guitar sound that doesn't swallow the singer. It's easy to get a big guitar or a big drum sound, but I'm always keeping the singer in mind. When I'm working in rehearsal for preproduction the singer is there and singing along; same thing goes for when I'm tracking live, and if the singer isn't there, I like to have a guide vocal that I can build things around. It's really important to me that the singer be the focus, no matter what the band is about, soundwise.
On Alanis Morissette's new album, Havoc and Bright Lights, it must have been an unusual way to work, with Guy Sigsworth programming the songs first and then you working backward with the live tracking…
It was a challenge, indeed; it was almost like the "remix" album was done first, having sort of reverse engineering going on. It was actually kind of fun; she was great, in that she gave me a lot of freedom. I used several members of her band but coincidentally a lot of them were people that I've worked with before on other projects as session musicians. The tracking sessions included Victor Indrizzo, the L.A.studio drummer who also plays in her band; Sean Hurley did most of the bass playing along with Paul Bushnell; Dave Levita, who is her live guitarist, played almost all of the guitars on the album. Lyle Workman, an L.A. session guitar player and film composer , did a lot of the big rock guitars as well. These are people that both Alanis and I have great relationships with. They understand her and what she likes, and that kind of made it easier for me.
You seem to have a relaxed way of getting involved in the songs, of inserting your influence into the arrangements and production values—almost like you are a member of the band.
Most artists come in with an idea of what they want; it's rare when someone doesn't. No matter what the credit reads it's always an equal collaboration with the artist. Truly, It's almost always the songwriting that determines where an album is going to go. Sometimes we'll do a number of very different versions, just trying to find the most honest place for the song. On [Jason Mraz's] "I Won't Give Up," we did a very simple acoustic version, which ended up being the current single version out now, but also we did a blue-eyed soul, Memphissort- of-feeling version; and we did a much more uplifting pop ballad version of the song, as well. You certainly want to serve the song, but at times you also want to serve the audience and the record company and a lot different people, so you'll try different things to see what will have the most honesty and impact.
There usually seems to be a very prominent percussion sound going on up front with the vocalist in your mixes that works very well. Can you elaborate on that?
Groove is really important, no matter what the music is; it's the vehicle in which the vocal rides. It's like the train or the automobile underneath it, so I really to make sure the groove kicks the vocal in the butt, that it percolates it, keeps it alive. Whether it's the syncopation with the kick drum, or if it's something more intricate, I definitely pay attention to that.
You learned your craft in an era when commercial studios were more vibrant, and you gained knowledge in that community atmosphere. What can you tell people who are working in more isolated personal setups; how do they avoid "cabin fever"?
You know, that's really a good question! That's easy to get caught up in, even if you're working in a commercial studio. The home thing…for me, it's tricky. It's nice having the "no pressure" environment where you can experiment and try things that you might not if you knew that you only had a certain amount of days or budget restrictions. It's easy to get locked in routine, though. When I was doing the album with The Shins, Wincing The Night Away, James Mercer had worked on his own on the album for a while before I came in. He needed someone to bring in some objective opinions. I spent probably three months working on that record to bring an outside perspective. I just kind of showed him some possibilities and options that he couldn't see himself, because he was working in a very isolated environment on his own.
It doesn't always work with other art forms, but certainly some of the best music can come from great collaborations. You look back and whether it's George Martin and The Beatles, or Gus Dudgeon and Elton John, or Lanois and Eno with U2, those are great collaborations. Having somebody there to help you see something that you missed is a great asset. I even find that myself. I'll be working on something for months and somebody will all of a sudden come into the room and hear a track for the first time. A great A&R person can be a major asset to me; someone who can remain objective throughout the whole process. He or she may say something like, "I know you guys are really loving this track, but the groove in the verse isn't as great as the groove in the choruses." Or maybe, "Do you think this one section you have as a breakdown, maybe it's too long or it doesn't need it at all." It's amazing to have someone come in and give new perspective on something you may have been working on for months and you can't see it clearly. Objectivity is really a wonderful gift.
Having stepped right into working with Frank Zappa early in your career, what ideas did you learn from him that you find you are still using today?
The best thing that he taught me is that there are no rules. He tried to break every rule wherever possible. [laughs] The minute you box yourself into a certain way of working, you're dead. I try to embrace change and challenge.
What do you look for in demos when you are starting a project?
It's different for different kinds of music; obviously, from somebody who is doing something that is beats driven, I would want something that has a major sense of what the groove is. For a singer/songwriter project, I want demos that are very basic. I'm happy with a very lo-fi iPhone recording of something that's just guitar and voice or piano and voice. That way, it leaves me room to imagine all of the possibilities. Occasionally, people come in with fully formed demos that sound great, and you think, look, don't change anything, except here in the bridge where you kept the same color going for the rest of the song; maybe it could take a left turn, maybe be more dramatic. I'll just be tweaking them up a little bit. Certainly, the home-recording thing is great; you can make demos that are record quality.
Can you give us some advice on producing a home/personal-studio recording?
On a recording level, I think about space. People are so keen to try all of their tricks and layer things to such a large degree so that there's no space in the recording whatsoever; it's just inundated with overdub after overdub. I get many recordings where there's like a hundred tracks of things on there. You know, you can get by very well with just two great guitar tracks rather than forty of them layered in the same range and same sound; as a result, it just sounds small. Sometimes two well-recorded, wellorchestrated guitar parts sound way bigger than forty tracks all layered in the same range, same tonality, same guitar; they all kind of cancel each other out.
That's certainly a technique that has served the Rolling Stones well.
There's a lot to be said for that, and Keith is the master of really coming up with one part that slowly evolves over the song, and it kind of incorporates those five guitar parts you are thinking of, but those parts happen at different moments, helping build the song and taking it to another place.
How do you go about tracking in the studio? Do you like to have a live feel?
Tracking-wise, I definitely enjoy when everybody is in the same room at the same time, feeding off each other; there is that sort of "X factor" that happens when you get a lot of great players in a room. If I'm doing bands, I don't like to layer the records; I like to build it as a band. All great bands kind of fill in all the extra pieces by playing together. That's the magic of a band like U2. Sometimes it may seem that the parts are very simple, but when you put it all together, it's like this chemical explosion. Getting people in the same room is important. The Café Tacuba record I'm working on is being done in studios and clubs and even restaurants. We're inviting guests, 60 to 150 people to sit in the room with them while they're playing. It's still a recording session, the band is wearing headphones and things are miked up the same way as in a studio, but there's a select audience for emotional support and feel. It's a challenge, of course, with a P.A. system in the room and there may be other distractions, but there is something about having that extra energy that's inspiring.
What's coming up with you?
Well, I just finished an album for this really great U.K. based artist named Keaton Henson; he's a singer/songwriter. The songs are very intimate, stripped back, very vulnerable, and personal; he sings very quietly. Emotionally, the songs are very strong. I mixed the recordings up at 25th Street Studios, Dave Lichtenstein's studio in Oakland. He's got a great-sounding room and console. I'm tracking another band up there this fall—Long Beach based Hellogoodbye, who had a huge hit a few years ago on Drive Thru Records..
Later in the year I'm working with Bernard Fanning, the former singer of the huge Australian band Powderfinger. As well as being in the midst of co-producing this record for Café Tacuba, a really amazing Latin band that's been successful for 20 years.
Can you tell our readers something they may not know about you?
Like everybody's career, it's up and down. You have good years and not-so-good years. I'm always pushing myself to see what's next and what's new. It's important to me to be fresh; I hate getting into routines and not feeling creative or like I'm repeating myself. I'm also challenging myself designing a couple of pro audio products, and I'm working on a music TV show. I always think of those actors that do Broadway plays for years, and their ability to make it fresh every night is amazing to me. Fortunately, making new records with new artists every few months brings a new approach, but I certainly still want to bring new challenge and perspective to everything I do.
Craig Dalton is a regular contributor to Electronic Musician.


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Freaking News
Chicken Robot on the Road - pictures
Why did the chicken cross the road?
3933 days ago
18 comments
high resolution picture
very nice,,and i love his helmet...
Fantastic work. In my opinion, the only weak part of the image is the lettering at the top. It's not bad, but I think the image would have more " factor" if it was metallic or somethin'.
That is one badazz man-meaty goodness ... Bet he pecks like a Jackhammer hahahahahaahah Nicely done.
Congrats again Rain. Great factor. I really like the cyborg chicken. Kinda reminds me of your sumo wrestler entry. The transformer legs is a great idea.
congrats rainnn this is fantastic,,
I figured this was yours as well Amazing work. Got a double header.
Bronze trophy for bronze chicken. Top job putting him in armor. Congratulations.
Congrats on the silver AZ, another beauty..
Congrats once more...what a crazy looking chicken.
Love all the details in the movie credits at the bottom.
to comment and participate in contests.
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- August 18, 1924 - March 28, 2015
- Saugus, Massachusetts
of Dorothy's Passing
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Dorothy was born on August 18, 1924 and passed away on Saturday, March 28, 2015.
Dorothy was a resident of Saugus, Massachusetts at the time of passing.
Dorothy was married to Harry sr.
Visiting hours will be held in the Bisbee-Porcella Funeral Home, 549 Lincoln Ave., SAUGUS, on Thursday 4-8 p.m. Relatives & friends invited. A funeral service will be held in the funeral home on Friday at 10 a.m. Interment Riverside Cemetery, Saugus.
In lieu of flowers donations in her memory may be made to the Hallmark Health Visiting Nurse Association & Hospice, 178 Savin St., Suite 300, Malden, MA 02148.


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Other Disorder
Disorder Name: Congenital Adrenal Hyperplasia
Acronym: CAH
- What is CAH?
- What causes CAH?
- If CAH is not treated, what problems occur?
- What is the treatment for CAH
- What happens when CAH is treated?
- What causes the 21-hydroxylase enzyme to be absent or not working correctly?
- How is CAH deficiency inherited?
- Is there genetic testing available?
- What other testing is available?
- Can you test during pregnancy?
- Can other members of the family have CAH or be carriers?
- Can other family members be tested?
- How many people have CAH?
- Does CAH happen more often in a certain ethnic group?
- Does CAH go by any other names?
- Where can I find more information?
This fact sheet contains general information about congenital adrenal hyperplasia (CAH). Every child is different and some of these facts may not apply to your child specifically. Certain treatments may be advised for some children but not others.
There are a number of different inherited causes of CAH. This fact sheet describes 21-hydroxylase deficiency (21-OHD) which accounts for about 95% of all cases of CAH. The other causes of CAH are not covered in this fact sheet but are listed at the end.
What is CAH?
CAH stands for "congenital adrenal hyperplasia". CAH is an inherited condition that affects the adrenal glands and causes a number of specific health issues.
'Congenital' means the condition is present at birth. The adrenal glands are cone-shaped organs that sit on top of each kidney. They make a number of hormones necessary for healthy body function. Hyperplasia means 'overly large.' In people with CAH, the adrenal glands cannot make enough of a hormone called cortisol. As they start working harder in attempts to make more cortisol they increase in size, resulting in hyperplasia.
Babies with CAH are born with a number of physical changes. Their adrenal glands are often larger than normal, even at birth. Girls with CAH may be born with external sex organs that appear more masculine than they should. If not treated, both boys and girls will develop early sexual characteristics, well before normal puberty should begin.
What causes CAH?
Normally, the adrenal glands make a number of different hormones, including cortisol, aldosterone and androgens. Hormones are chemicals that send messages to other organs or tissues of the body, telling them to do specific things.
CAH occurs when a particular enzyme called 21-hydroxylase (21-OH) is missing or not working correctly. The job of this enzyme is to help make cortisol and aldosterone in the adrenal glands so they can be released when the body needs them.
One of the main jobs of cortisol is to keep the amount of glucose, the sugar used for energy by the body's cells, at a normal level. Cortisol also helps protect the body during times of physical or emotional stress such as surgery, injury or illness. It helps to regulate the immune response and inflammation so our bodies can deal with infection or illness.
Another hormone made by the adrenal glands is aldosterone. This hormone is released into the blood when the blood pressure drops too low. It tells the kidneys to pull salt and water out of urine and put it back into the blood. This raises blood pressure back to normal and prevents the body from losing too much fluid. Babies with a form of CAH called "salt-wasting" do not make enough aldosterone and they lose too much salt and water in their urine. They become dehydrated and their blood pressure drops too low. This can be life-threatening if not treated quickly.
The other hormones made by the adrenal glands are called androgens. These are male-like sex hormones. The adrenal glands also make a small amount of female hormones.
Most people with CAH make too much of the androgen hormones and not enough cortisol or aldosterone. Having too much of the androgen hormones in the blood causes female babies to develop masculine changes to their genitals. And, high levels of androgens lead to early sexual development, well before the normal age of puberty, in both boys and girls.
If CAH is not treated, what problems occur?
The effects of CAH can vary greatly from person to person. There are a number of different forms of CAH which are described below.
Most babies found to have CAH during newborn screening have 'classic CAH.' One type of classic CAH is called 'salt-wasting' which is a serious condition needing immediate treatment. The other type of classic CAH is called 'simple virilizing.' Children with this type do not have immediate risks to their health but still need treatment.
A small number of children are found through newborn screening to have milder or 'nonclassic CAH' which often causes fewer health problems. The symptoms of nonclassic CAH are quite variable from person to person.
Classic CAH – "Salt-wasting form"
About 75% of babies with classic CAH have the 'salt-wasting' form. Salt-wasting CAH occurs when the adrenal glands make lower amounts of both cortisol and aldosterone and too much androgen. Babies who do not make enough aldosterone will start losing too much water and salt in their urine. This can quickly cause dehydration and very low blood pressure. This can be life-threatening if not treated right away.
Infants with salt-wasting CAH usually show some of the following features within the first few weeks of life:
- Poor feeding
- Listlessness and drowsiness
- Vomiting
- Diarrhea
- Dehydration
- Weight loss
- Low blood pressure
- Low blood salt (low blood sodium level)
- Too much acid in the blood, called metabolic acidosis
If not treated, severe dehydration leads to shock, a serious situation in which not enough blood is getting to the brain and other organs. In babies with salt-wasting CAH, this is also called an "adrenal crisis". The signs of an adrenal crisis include:
- Confusion
- Irritability
- Rapid heart rate
- Coma
Periods of adrenal crisis due to too little aldosterone can occur as early as one week to one month of age. If a child in shock is not treated, there is a risk of death.
Even when carefully treated, children with salt-wasting CAH are still at risk for adrenal crises when they become ill or are under stress. The body needs more than the usual amount of adrenal hormones during illness, injury or stress. This means a child with CAH must be given more medication during these times to prevent an adrenal crisis.
All babies with salt-wasting CAH have the other features of classic CAH listed below. Girls with salt-wasting CAH usually have more male-like changes to their genitals than girls with simple virilizing CAH.
Classic CAH – Simple virilizing form
About 25% of babies with CAH have the simple virilizing form. The adrenal glands make enough aldosterone but not enough cortisol; they also make too much androgen.
Classic CAH starts its effects before birth. Excess androgen hormones are made by the fetus. This causes the genitals of female fetuses to develop male-like features. Baby girls born with classic CAH often have an enlarged clitoris. In some girls this is not very noticeable, but in others it may look like a small penis. Baby girls may also have labia which are fused together, may be wrinkled and may look more like a male scrotum. Some baby girls have fewer genital changes than others. The high level of androgen hormones does not affect the uterus and ovaries, which develop normally.
Girls who are not treated may develop other male-like traits and behaviors as they grow. Some of these changes may include:
- Deep, husky voice
- Excess hair on the face and body
- Lack of menstrual periods or scanty or irregular periods
- Early puberty changes such as hair in the armpits and pubic area
- Severe acne
- Male-pattern baldness (loss of hair near the temples)
Boys who are not treated may have some of the following traits:
- Muscle growth at an early age
- Pubic hair and underarm hair during childhood
- Enlargement of the penis during childhood
- Early deepening of the voice
- Early beard
- Smaller than normal testicles
- Severe acne
Sometimes the changes of early puberty happen in boys and girls as young as two to four years old. Both boys and girls may have rapid growth during childhood but end up being short as adults. Excess androgen hormones in childhood cause the rapid growth. The androgens also cause shorter adult height by closing the growth plates too soon.
Some untreated adults also have problems with infertility and may have difficulty achieving pregnancy.
Children with simple virilizing CAH are at risk for adrenal crises, though typically less severe than seen in children with the salt-wasting form. Acute illness or stress increases the body's need for cortisol. If children with CAH do not receive increased amounts of medication during illness or stress, they are at risk for health problems.
Nonclassic CAH / Late-onset CAH
Nonclassic CAH, also called 'late-onset', usually causes milder effects than classic CAH. However, symptoms can be quite variable from person to person. Many people with nonclassic CAH often start showing signs during childhood, adolescence, or early adulthood. Some people never develop symptoms. Newborn screening can detect some, though not all, babies with the nonclassic form of CAH.
Babies with nonclassic CAH are usually healthy at birth and their genitals are normal in appearance. They do not have salt-wasting and are not at risk for adrenal crises.
Children and adults with nonclassic CAH have adrenal glands that make near-normal amounts of cortisol and normal amounts of aldosterone. However, they have too much 17-OH progesterone (17-OHP), a chemical used to make cortisol, in their blood. They also may make too much of the androgen hormones.
Some of the traits that are sometimes seen in both males and females with nonclassic CAH include:
- Rapid growth in childhood and early teens with short adult height
- Severe acne
- Early puberty with development of pubic hair, underarm hair and body odor during childhood
- Excess hair on the face and other parts of the body
- Male-pattern baldness (hair loss near the temples)
Girls and women may have:
- Male-like changes in physical appearance and behavior
- Irregular menstrual periods or early-onset of periods
- Infertility
- Polycystic ovary syndrome
Boys may have:
- Early beard growth
- Enlarged penis
- Small testicles
What is the treatment for CAH?
Your baby's primary doctor may work with a pediatric endocrinologist to provide medical care to your child. It is important for babies with classic CAH to be diagnosed as quickly as possible. This allows treatment to begin soon after birth which helps reduce the effects of CAH.
The main treatment for classic CAH is a drug called 'hydrocortisone' (also called 'cortisone'), taken in pill form. This medication replaces the cortisol that your baby cannot make on his or her own. It must be taken daily throughout life to prevent effects of CAH. Cortisone is sometimes given in other drug form, such as prednisone or dexamethasone
Treatment for Classic CAH – both simple virilizing and salt-wasting forms:
Cortisone medication
The main treatment is to replace the amount of cortisol not being made by the adrenal glands. Hydrocortisone, a synthetic form of cortisol, is given by mouth in pill form. This treatment lessens the amount of androgens, prevents early puberty, and allows for more typical growth and development. Your doctor will follow your child's growth, pubertal development, blood pressure, and hormone levels throughout childhood. The level of medication needed to control symptoms will be adjusted as needed throughout your child's life.
It is important to always follow your doctor's orders on how much cortisone to give your child. Too much cortisone can cause temporary symptoms of Cushing syndrome so the dose must be carefully balanced to your child's height, weight and activity level. Signs of Cushing syndrome include: stretch marks on the skin, rounded face, weight gain, high blood pressure, and bone loss.
In addition, your doctor will give you instructions for increasing the dose of hydrocortisone during an acute illness. If you have questions about dosing, call your doctor. The body needs more cortisol during illness, injury or times of stress. Therefore, the cortisone dosage must be increased by your doctor when your child is ill, injured, or requires surgery. If your child is ill and cannot take the pills, cortisone injections may be necessary.
Your doctor may advise you to carry an emergency treatment letter with steps for your child's care during stress or illness. Children with CAH should also consider wearing a Medic-Alert bracelet.
Hydrocortisone must be taken throughout life to prevent CAH effects. If the medication is stopped, symptoms will develop.
Surgery for girls with classic CAH
Girls who are born with an enlarged clitoris or changes to the labia have the option of surgery to change their outer genitals to a more female appearance. Some women who have CAH have not had surgery and are happy they did not. Others are glad their parents decided to give them the surgery. This is a complex decision made by the parents with guidance from their doctors. Parents who are not sure about surgery may want to talk with other families who have faced similar decisions.
If you choose corrective surgery, it can be done as early as age one to three. Surgery on the clitoris usually hides the excess tissue but leaves the clitoris itself intact. Surgery to separate the labia and to create a normal vagina is often delayed until the teenage years. Ask your doctor about the risks and benefits of surgery for these changes and the best time to do these surgeries.
Treatment to prevent short stature
Your doctor may take periodic X-rays to check your child's 'bone age.' This allows your doctor to tell whether your child is growing at too rapid a rate. It also shows whether the growth plates are still open or whether they are closing too early.
Specific medications may help increase height in children and teens that show signs of early growth failure. Certain medications lower androgen levels. If you have questions about your child's growth, talk to your doctor about the costs and benefits of these treatments.
Treatment for early puberty
Children who show changes of puberty at a young age are sometimes treated with medications that lower the amount of androgen hormones. Your doctor will talk to you about these medications should your child start showing signs of puberty during childhood.
Additional treatment for classic CAH – salt-wasting form
Children with salt-wasting CAH need to take an additional medication called Florinef. Florinef (9a-fludrohydrocortisone) is a 'salt-retaining' drug that replaces the aldosterone absent in children with salt-wasting CAH. It is given by mouth in pill form.
Some children with salt-wasting CAH need to follow a food plan that contains more salt than usual. In addition, your doctor may recommend salt tablets to prevent dehydration. It is important to follow your doctor's instructions on how much salt to feed your child. Most children on medication do not need to add extra salt to their diets.
Treatment for nonclassic CAH
Some people with nonclassic CAH do not need treatment and may go through life without symptoms. Others begin having symptoms in childhood, adolescence or young adulthood and may need medication in the form of cortisone pills. Symptoms that may signal the need for treatment include:
- Severe acne
- Excess body hair
- Irregular menstrual periods
- Lumps in the testicles
- Infertility
Children and adults with nonclassic CAH usually need less medication than children with classic CAH.
What happens when CAH is treated?
Children with CAH who start treatment soon after birth usually have normal growth and development. In most treated children, puberty occurs at the normal age, although some still have early changes. Even when treated, some adults are shorter than average.
Girls on medication usually have normal menstrual periods. Pregnancy is possible, although fertility may be lessened in some women.
Children with salt-wasting CAH who remain on treatment usually do not have further salt-wasting adrenal crises or other associated health problems.
Pregnant women with classic salt-wasting CAH should be followed carefully by an endocrinologist during pregnancy. Medications may need to be increased during pregnancy to prevent problems with fetal growth.
What causes the21-hydroxylase enzyme to be absent or not working correctly?
Genes tell the body to make various enzymes. People with CAH have a pair of genes that do not work correctly. Because of the changes in this pair of genes, the 21-OH enzyme either does not work properly or is not made at all.
How is CAH deficiency inherited?
CAH is inherited in an autosomal recessive manner. It affects both boys and girls equally.
Everyone has a pair of genes that make the 21-OH enzyme. In children with CAH, neither of these genes works correctly. These children inherit one non-working gene for the condition from each parent.
Parents of children with CAH rarely have the condition themselves. Instead, each parent has a single non-working gene for CAH. They are called carriers. Carriers do not have CAH because the other gene of this pair is working correctly.
When both parents are carriers, there is a 25% chance in each pregnancy for the child to have CAH. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.
Genetic counseling is available to families who have children with CAH. Genetic counselors can answer your questions about how CAH is inherited, choices during future pregnancies, and how to test other family members. Ask your doctor about a referral to a genetic counselor.
Is genetic testing available?
Genetic testing for CAH can be done on a blood sample. Genetic testing, also called DNA testing, looks for changes in the pair of genes that causes CAH.
DNA testing is not always necessary to diagnose your child but it can sometimes be helpful in determining whether your child has classic or nonclassic CAH. It can also be helpful for carrier or prenatal testing, discussed below.
What other testing is available?
CAH is confirmed by testing the level of 17-OHP and other substances in the blood. Other blood and urine tests may also be necessary to determine whether your child has the salt-wasting form of CAH. Talk to your doctor or your genetic counselor if you have questions about testing for CAH.
Nonclassic CAH is confirmed through testing a blood sample for the levels of 17-OHP and other adrenal hormones.
Can you test during pregnancy?
If both gene changes have been found in your child with CAH, DNA testing can be done during future pregnancies. The sample needed for this test is obtained by either CVS or amniocentesis.
Parents may choose to have testing during pregnancy or wait until birth to have the baby tested. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.
Treatment during pregnancy
If you have had a child with CAH and become pregnant again, ask your doctor whether prenatal treatment would be helpful. Female fetuses with CAH are sometimes treated with a medication taken by the mother during pregnancy. This medication, called dexamethasone, may prevent some of the genital changes caused by CAH, although some doctors do not recommend this treatment because of other potential risks to the fetus.
Can other members of the family have CAH or be carriers?
Having CAH
If they are healthy and developing normally, older brothers and sisters of a baby with classic CAH are unlikely to have CAH. Talk to your doctor or genetic counselor if you have questions about your other children.
CAH carriers
Brothers and sisters who do not have CAH still have a 2/3rds chance to be carriers like their parents. Except in special cases, carrier testing should only be done in people over 18 years of age.
Each of the parents' brothers and sisters has a 50% chance to be a carrier. It is important for other family members to be told that they could be carriers. There is a small chance they are also at risk to have children with CAH.
All states offer newborn screening for CAH. However, when both parents are carriers, newborn screening results are not sufficient to rule out the condition in a newborn baby. In this case, special diagnostic testing should be done at birth in addition to newborn screening
Can other family members be tested?
Diagnostic testing
If there is concern about whether they have the condition, your other children can be tested. Talk to your doctor or genetic counselor if you have questions about testing for CAH.
Carrier testing
If both gene changes have been found in your child, other family members can have DNA testing to see if they are carriers.
How many people have CAH?
About one in every 15,000 babies in the United States is born with classic CAH.
Does CAH happen more frequently in a certain ethnic group?
CAH occurs in people of all ethnic groups around the world. It is more common in the Yupik Eskimos; about 1 in 300 babies in this population is born with CAH. It is less common in African-American and Asian people.
Nonclassic CAH may occur in up to 1 in every 100 people. It appears to happen more often in people of Ashkenazi Jewish, Hispanic, Slavic and Italian background.
Does CAH go by any other names?
CAH is sometimes also called:
- 21-hydroxylase deficiency
- 21-OH deficiency
- Adrenogenital syndrome (AG syndrome)
- C-21-hydroxylase deficiency
- Congenital adrenocortical hyperplasia
- Salt-losing CAH
The nonclassic form of CAH is sometimes also called:
- Attenuated CAH
- Late-Onset CAH
Some less common causes of CAH not discussed in this fact sheet are:
- Steroidogenic acute regulatory protein deficiency (STAR)
- 3-beta-hydroxysteroid dehydrogenase deficiency (3B-HSD)
- 17-alpha-hydroxylase deficiency
- 11-beta-hydroxylase deficiency
- Cytochrome P450 oxidoreductase deficiency
Where can I find more information?
Being told your child has CAH can be a very stressful experience for the whole family. Your health care practitioners can help you deal with some of the feelings, concerns and questions that naturally come up when a baby is diagnosed with CAH. There are also national support groups and other organizations that provide written information about CAH. Many of these groups have volunteers who can talk with you by phone or by email about your feelings and concerns and may be able to connect you with other parents who have children with CAH. Some of these support networks and organizations are listed below.
CARES (Congenital Adrenal Hyperplasia Research, Education and Support) Foundation, Inc.
The CAH Support Group
National Adrenal Diseases Foundation
MAGIC Foundation (Major Aspects of Growth in Children)
Congenital Adrenal Hyperplasia Education and Support Network
Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: A guide for patients and their families
National Library of Medicine Genetics Home Reference (CAH)
Genetic Alliance
DISCLAIMER:THIS INFORMATION DOES NOT PROVIDE MEDICAL ADVICE. All content ("Content"), including text, graphics, images and information are for general informational purposes only. You are encouraged to confer with your doctor or other health care professional with regard to information contained on this information sheet. After reading this information sheet, you are encouraged to review the information carefully with your doctor or other healthcare provider. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. NEVER DISREGARD PROFESSIONAL MEDICAL ADVICE, OR DELAY IN SEEKING IT, BECAUSE OF SOMETHING YOU HAVE READ ON THIS INFORMATION SHEET. This project is supported by a grant from the Maternal and Child Health Bureau, Health Resources and Service Administration, Genetic Services Branch, MCH Project #:H46MC24091 http://mchb.hrsa.gov
Fact Sheet was last updated on: 12/12/12


text:
Antioxidant Nutrient Supplementation Reduces the Susceptibility of Low Density Lipoprotein to Oxidation in Patients With Coronary Artery Disease
Author + information
- Received December 1, 1996
- Revision received April 14, 1997
- Accepted April 24, 1997
- Published online August 1, 1997.
Author Information
- Lori Mosca, MD, MPH, PhDA,*,
- Melvyn Rubenfire, MD, FACCA,
- Caroline Mandel, MS, RDA,
- Cheryl Rock, PhD, RDB,
- Tom Tarshis, MPHA,
- Alan Tsai, PhDC and
- Thomas Pearson, MD, MPH, PhD, FACCD
- ↵*Dr. Lori Mosca, Preventive Cardiology Program, The University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 363, Ann Arbor, Michigan 48106-0363.
Objectives. This study sought to determine the effect of antioxidant supplementation on the susceptibility of low density lipoprotein (LDL) to oxidation in patients with established cardiovascular disease (CVD).
Background. Data are inconsistent regarding the role of antioxidant nutrients in the prevention of CVD.
Methods. The study design was a 12-week, double-blind, placebo-controlled clinical trial. Patients with CVD (n = 45) were randomized to 1) placebo control; 2) 400 IU of vitamin E, 500 mg of vitamin C, 12 mg of beta-carotene (mid-dose); or 3) 800 IU of vitamin E, 1,000 mg of vitamin C, 24 mg of beta-carotene (high dose) daily. Reduced susceptibility of LDL to oxidation was estimated by an increase in lag phase (minutes). Baseline and 6- and 12-week measurements of lipoproteins and lag phase were obtained. Plasma levels of antioxidants were measured at baseline and 12 weeks.
Results. Concentrations of alpha-tocopherol, vitamin C and beta-carotene significantly increased in the mid- and high dose groups during the trial. Lag phase significantly increased from baseline (190.1 ± 63.8 min [mean ± SD]) to 12 weeks (391.1 ± 153.0 min) in the high dose group (p < 0.01). A nonsignificant increase in lag phase in the mid-dose group was observed during the same time interval. A dose response was found for mean percent change from baseline to 12 weeks for lag phase for the placebo, mid- and high dose groups (p = 0.004 for trend).
Conclusions. A high dose combination of antioxidant nutrients reduces the susceptibility of LDL to oxidation in patients with CVD and may be useful in secondary prevention.
Despite significant reductions in risk factor levels and advances in medical and surgical intervention, cardiovascular disease (CVD) remains the leading cause of death in the United States [1]. The risk of future cardiovascular events is substantially increased in subjects with established CVD compared with those without previous manifestations of clinical disease [2]. Therefore, it is important to identify effective strategies for the secondary prevention of coronary artery disease (CAD).
Recent data suggest that antioxidant nutrients may play a role in the prevention of CAD. The protective effect of antioxidant nutrients may be mediated through inhibition of the oxidative modification of low density lipoprotein cholesterol (LDL), which is believed to be a key step in the pathogenesis of atherosclerosis [3, 4]. In addition, antioxidants may reduce platelet adhesiveness [5], preserve endothelial function [6]and stabilize plaque [7]. These mechanisms lend support for a role of antioxidants in the prevention of atherosclerosis and thrombosis and in the regulation of vasomotor tone.
Epidemiologic data have shown associations between antioxidant intake and reduced CVD in several prospective studies [8–15]. Data from randomized clinical trials have not supported the findings from observational studies. A Finnish trial [16], designed to test the effect of low dose alpha-tocopherol (50 mg) or beta-carotene (20 mg/day), or both, on the incidence of lung cancer in 29,133 male smokers, failed to show a protective effect of antioxidants on death from CVD. Recent results from large, randomized clinical trials showed no effect of beta-carotene alone (Physician's Health Study [17], Skin Cancer Prevention Study [18]) or in combination with retinol (Carotene and Retinol Efficacy Trial [19]) in the primary prevention of CVD.
Few data are available to evaluate the role of antioxidant nutrients in secondary prevention. A subgroup analysis of the Cholesterol Lowering Atherosclerosis Study (CLAS) study [11]demonstrated an association between supplemental vitamin E intake and a reduction in coronary lesion progression by angiography. The Cambridge Heart Antioxidant Study (CHAOS) [20], a secondary prevention trial of 2,002 patients with CAD followed up for a median of 510 days demonstrated a 77% reduction in nonfatal myocardial infarction in patients randomized to receive either 400 or 800 IU of vitamin E versus those receiving placebo.
Experimental evidence [21–30]demonstrating favorable alterations in indexes of oxidized LDL in subjects treated with antioxidant supplements provides biologic plausibility for a role of dietary micronutrients in CVD prevention. These data are limited to patients free of disease, and the generalizability of results to patients with CVD remains unclear. Patients with CVD have unfavorable indexes of oxidized LDL compared with healthy control subjects, and it may not be appropriate to extrapolate doses of antioxidant vitamins to be used in secondary prevention trials on the basis of data obtained from subjects without CVD [31–33].
This purpose of the present study was to test the effect of two doses of a combination of vitamin E, vitamin C and beta-carotene on lag phase, a surrogate measure of the susceptibility of LDL to oxidation, compared with placebo in a randomized clinical trial in subjects with established CVD.
1 Methods
1.1 Subjects.
Forty-five nonsmoking, nondiabetic subjects (39 men, 6 women; 39 to 80 years old) with established CAD were recruited from the cardiac catheterization laboratory and the preventive cardiology program at the University of Michigan Medical Center between January 1994 and May 1995. CAD was determined by angiography (at least one lesion >70% lumen stenosis), previous angioplasty, coronary artery bypass graft surgery, myocardial infarction by history validated by electrocardiographic changes or classic angina with an ischemic response on a treadmill test. Subjects had to have been on a stable diet and exercise program for 6 months and have normal hepatic and renal function, no evidence of malabsorption, pancreatic or biliary disease and no acute medical condition for at least 3 months before study entry. Patients currently receiving resin therapy or using vitamin supplements above the recommended dietary allowance (RDA) levels within the previous 6 months were excluded from the study. There were no exclusion criteria based on serum lipid status. All subjects gave informed consent. The study was approved by the Institutional Review Board of The University of Michigan Medical Center.
1.2 Experimental protocol.
After baseline measurements, subjects were entered into a 12-week double-blind, placebo-controlled clinical trial. Each subject was randomly assigned to receive 1) placebo (control group, n = 15); 2) 400 IU of vitamin E, 500 mg of vitamin C, and 12 mg of beta-carotene daily in two divided doses (mid-dose group, n = 15); or 3) 800 IU of vitamin E, 1,000 mg of vitamin C and 24 mg of beta-carotene daily in two divided doses (high dose group, n = 15). Supplements were given in the form of a capsule (vitamin E [200 IU] as dl-alpha-tocopheryl acetate, vitamin C [250 mg] and beta-carotene [6 mg]) obtained as a gift from Hoffmann-La Roche Inc. Each subject took two capsules (supplement or placebo, or both) twice a day to maintain blinding. Pill counts were done at 6 and 12 weeks to assess adherence to study protocol. Four subjects did not complete the trial (one assigned to the placebo group who had an adverse effect of headache within 2 weeks of the trial; one assigned to the high dose group who had an adverse effect of stomach discomfort after 1 week of therapy; two who did not return after the baseline visits because of scheduling difficulties). All 41 subjects who completed the trial were 100% compliant with the study medication.
1.3 Laboratory protocol.
Two lipid, lipoprotein and lag phase measurements were obtained 1 week apart immediately before study entry and were averaged to obtain baseline values. One laboratory measurement was done at study midpoint (6 weeks). Two ending measurements were done at 11 and 12 weeks and were averaged to obtain the 3-month follow-up laboratory values. Plasma tocopherol, carotenoid and vitamin C levels were measured once at baseline and again at 12 weeks in subdued light at the time of other laboratory measurements.
After a 12-h fast and a 15-min supine rest period, one 20-ml tube without anticoagulant and two 12-ml heparinized tubes of blood were obtained with the tourniquet deflated. Whole blood without anticoagulant was centrifuged at 2,000 rpm for 30 min to separate serum. Aliquots of serum samples were frozen at −15°C for up to 4 weeks for serum lipid and lipoprotein lipid analysis, and fresh serum was used for LDL lag phase assay.
Heparinized blood was separated by refrigerated centrifugation at 2,300 × gfor 10 min. Plasma aliquots designated for tocopherol and carotenoid quantification were preserved in sodium ascorbate and stored at −70°C in cryogenic tubes for up to 6 months. One-milliliter aliquots designated for vitamin C analysis were processed with 10% trichloroacetic acid before freezing to enhance stability during short-term storage.
1.4 Measurement of lipids, lipoproteins and lag phase.
For measurement of lag phase, LDL was isolated immediately from fresh serum according to the method of Weiland and Seidel [34]. This method highly correlates (r = 0.9) with results obtained from ultracentrifugation to isolate LDL.
The oxidation of polyunsaturated fatty acids in a buffer system was continuously monitored at 234 nm with a Beckman DU-6 spectrophotometer up to 10 h according to the method of Esterbauer et al. [35]. Lag phaseis expressed in minutes and is the time interval from addition of Cu2+ions to the onset of the propagation phase of LDL oxidation, which is the maximal rate of conjugated diene production. Lag phase is determined by extrapolating a tangent drawn from the slope of the most rapid rise in the absorbance curve to the horizontal time axis. Lag phase is indicative of the resistance of LDL to oxidation; the greater the resistance of LDL to oxidation, the longer the lag phase.
Cholesterol and triglyceride concentrations were determined enzymatically with commercially available reagents (Sigma) by the methods of Allain et al. [36]for total cholesterol (TC), LDL cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and McGowan et al. [37]for TC, LDL-triglycerides. The isolation of LDL-C was according to the method of Weiland and Seidel [34]. HDL-C was isolated by precipitation with phosphotungstic/MgCl2according to the method of Assmann et al. [38].
1.5 Plasma antioxidant measurements.
Plasma carotenoids were separated and quantified according to the high performance liquid chromatographic (HPLC) method of Bieri et al. [39], as modified by Craft et al. [40]and Craft [41]with further modifications to reduce oxidative loss and improve recovery of compounds during analysis. This analytic method measures 90% of the total plasma carotenoids present and permits quantification of the predominant serum carotenoids, including beta-carotene.
Plasma tocopherols were separated and quantified according to the HPLC method of Bieri et al. [42]. This analytic method permits separation and quantification of alpha- and gamma-tocopherol, using tocopherol acetate (Sigma) as an internal standard. Plasma vitamin C was measured by the derivative spectrophotometric method of Omaye et al. [43].
1.6 Measurement of covariates.
Demographic variables, lifestyle habits and medication usage were assessed by standardized questionnaire. Anthropometric and physiologic variables were evaluated based on a standard examination. Body fat was calculated from three gender-specific skinfold measurements using the generalized equations of Jackson and Pollock [44]and Jackson et al. [45]for predicting body density.
Detailed dietary histories based on 3-day food records were obtained by a nutritionist 1 week before study entry and during the final week of the study. Diet records were analyzed using Nutritionist IV software (version 2.1 1995 N-Squared computing). Average daily total energy intake, percent energy from fat, percent energy from saturated fat, percent energy from carbohydrate, percent energy from protein and grams of alcohol/day and intake of antioxidants were determined at the beginning and end of the study.
1.7 Statistical analysis.
Statistical analysis was performed based on intention to treat. Continuous variables are expressed as mean value ± SD. Normal probability plots of all continuous variables were examined, and the Shapiro-Wilk statistic was used to test for normal distribution. Data that were not normally distributed, including lag phase, was log transformed when appropriate. Within-group change for lipids, plasma antioxidants and lag phase during the treatment period were evaluated using paired ttests. Between-group differences at baseline and 6 and 12 weeks for lipids, plasma antioxidants and lag phase were evaluated by analysis of variance (ANOVA) with a Tukey test to control for multiple pairwise comparisons. The relations between continuous variables were evaluated using Pearson correlation coefficients or Spearman correlations when data were not normally distributed. Differences in mean values for dichotomous variables were examined by Student ttests or Wilcoxon rank sum for nonnormally distributed variables. Significant independent predictors of lag phase were incorporated into a multiple linear regression model to assess the independence of antioxidant supplementation on resistance of LDL-C to oxidation. All tests were two-tailed, and statistical significance was set at p < 0.05. All data were double entered, discrepancies were corrected, and analysis was performed using SAS for Windows version 6.08 (1992 SAS Institute, Inc.). Blinding was maintained until the analysis was complete. The study was designed to detect a 10% difference in LDL oxidation with 80% power at p = 0.05.
2 Results
2.1 Patients.
Descriptive information for the 45 subjects with CAD is shown in Table 1. The only statistically significant difference between groups for any of the variables was the use of beta-adrenergic blocking agents. In the placebo group, seven subjects reported current use of beta-blockers use compared with four in the mid-dose group and one in the high dose group.
2.2 Lipid profiles.
Mean baseline and 6- and 12-week lipid profiles, according to group assignment, are presented in Table 2. There were no significant differences in baseline TC, LDL-C, HDL-C or triglyceride levels between groups. In the placebo group, HDL-C increased from 0.90 mmol/liter at baseline to 1.02 mmol/liter (p < 0.05) from baseline to 6 weeks. In the high dose group, TC and LDL-C significantly increased between 6 and 12 weeks, from 5.64 to 6.08 mmol/liter and from 4.09 to 4.56 mmol/liter, respectively. HDL-C increased between 6 and 12 weeks, from 0.99 to 1.08 mmol/liter (p < 0.05) in the high dose group. LDL-C and triglycerides increased significantly from baseline to 12 weeks in the high dose group, from 3.86 to 4.56 mmol/liter and from 1.75 to 2.07 mmol/liter, respectively.
2.3 Plasma antioxidants.
2.3.1 Within-group changes.
Plasma concentrations of alpha-tocopherol, vitamin C and beta-carotene were 24.43 ± 7.06, 71.94 ± 36.34 and 0.29 ± 0.17 μmol/liter, respectively, at baseline and did not significantly change at 12 weeks in the placebo group (Fig. 1). Results were unchanged when plasma alpha-tocopherol was lipid standardized. Alpha-tocopherol levels increased twofold during the trial in the mid-dose group, from 28.63 ± 7.7 to 60.57 ± 17.4 μmol/liter (p < 0.01), and threefold in the high dose group, from 27.39 ± 10.10 to 88.72 ± 47.85 μmol/liter (p < 0.01). Vitamin C levels increased 1.5 fold in the mid-dose group, from 73.13 ± 36.34 to 107.31 ± 28.95 μmol/liter (p < 0.05), and nearly twofold in the high dose group, from 61.95 ± 22.14 to 118.67 ± 35.77 μmol/liter (p < 0.01). Beta-carotene levels also significantly increased with supplementation in the mid- and high dose groups, from 0.34 ± 2.01 to 1.99 ± 1.17 μmol/liter (p < 0.01) and from 0.29 ± 0.1 to 3.01 ± 1.5 μmol/liter (p < 0.05), nearly six- and tenfold, respectively.
2.3.2 Between-group changes.
A significant between-group difference at 12 weeks for plasma concentrations of alpha-tocopherol was observed (p = 0.0001, ANOVA), with significant pairwise comparisons between mid-dose versus placebo, high dose versus placebo and high versus mid-dose. Beta-carotene levels were significantly different between groups at 12 weeks (p = 0.0001, ANOVA), with significant pairwise comparisons between placebo versus mid-dose and placebo versus high dose. No statistically significant between-group differences were noted for vitamin C at 12 weeks (p = 0.057). However, the between-group differences for change from baseline to 12 weeks were significant for vitamin C (p = 0.0001), which was attributable to a significant pairwise comparison for high dose versus placebo. Both alpha-tocopherol and beta-carotene plasma levels showed significant between-group changes over time for high dose versus placebo and mid dose versus placebo (p < 0.05).
2.4 Lag phase.
2.4.1 Within-group changes.
Table 2also describes the change in lag phase after treatment at 6 and 12 weeks according to group assignment. In the placebo group, there is a significant increase in lag phase between baseline and 6 weeks, from 219.5 ± 69.4 to 258.2 ± 77.0 min (p < 0.01), with no significant increase at 12 weeks (256.8 ± 73.8 min) compared with that at baseline or 6 weeks. The mid-dose group experienced an increase in lag phase between baseline and 6 weeks, from 182.0 ± 100.6 to 267.1 ± 76.3 min (p < 0.01) and between 6 and 12 weeks, from 267.1 ± 76.3 to 311.8 ± 112.5 min (p < 0.01). The high dose group had a significant increase in lag phase at 12 weeks (391.1 ± 153.0 min) compared with that at 6 weeks (239.1 ± 97.3, p < 0.01) and baseline (190.1 ± 63.8 min, p < 0.01). There was no statistically significant increase in lag phase between baseline and 6 weeks.
2.4.2 Between-group changes.
Lag phase did not differ significantly between treatment groups or placebo at baseline or at 6 weeks. At 12 weeks there was a significant between-group difference in mean lag phase (p = 0.02, ANOVA). The change in lag phase from baseline to 6 weeks did not differ between groups, but the change from baseline to 12 weeks did differ (p = 0.04, ANOVA).
Fig. 2illustrates a significant dose response for mean percent change in lag phase between the treatment groups from baseline to 12 weeks (p = 0.004 for trend). The mean percent increase in lag phase from baseline to 12 weeks in the mid-dose group was 71% compared with a doubling of lag phase in the high dose group. The mean percent change in lag phase from baseline to 12 weeks was highly correlated with mean percent change in plasma alpha-tocopherol (r = 0.48, p = 0.002) and beta-carotene (r = 0.49, p = 0.002).
No significant within or between-group differences at baseline or at 12 week follow-up were noted for dietary intake of antioxidant nutrients, total calories, percent energy from fat, saturated fat, carbohydrate, protein or grams of alcohol/day.
2.5 Predictors of lag phase.
No statistically significant dichotomous predictors of lag phase were identified. Continuous predictors of lag phase are shown in Table 3. The only significant lipid predictor of lag phase was LDL-C (r = −0.39, p = 0.01). Significant inverse correlations existed for body mass index (r = −0.33, p < 0.05), heart rate (r = −0.34, p < 0.05) and percent body fat (r = −0.41, p < 0.01). Only heart rate retained significance when univariate predictors were examined in multiple regression models controlling for age, gender and LDL-C at 12 weeks and LDL-triglycerides. Heart rate was significantly associated with beta-blocker use (p = 0.02); however, heart rate still was a significant predictor of lag phase when beta-blocker use was controlled for in a multiple regression model (p = 0.02).
Supplementation with a combination of vitamin E (800 IU), vitamin C (1,000 mg) and beta-carotene (24 mg) was a significant predictor of lag phase in multiple regression models controlling for age and gender (p = 0.008, model R2= 0.21). When heart rate and beta-blocker use were added to the model, high dose group assignment still remained a significant predictor of lag phase (p = 0.02, model R2= 0.23).
3 Discussion
The major finding of our studywas a significant reduction in the susceptibility of LDL-C to oxidation in patients with CVD supplemented daily for 12 weeks with a combination of 800 IU of vitamin E, 1,000 mg of vitamin C, and 24 mg of beta-carotene 24 daily compared with placebo. In addition, we observed a significant dose response for this high dose combination compared with a combination of 400 IU of vitamin E, 500 mg of vitamin C and 12 mg of beta-carotene and a placebo control.
This finding is consistent with data from a study by Jialal and Grundy [25]who observed a reduction in the rate of LDL oxidation in 24 healthy men given 800 IU of dl-alpha-tocopherol in the form of soy bean capsules compared with placebo. In their study, indexes of oxidized LDL, time course curves of thiobarbituric acid-reacting substances (TBARS) activity or conjugated diene formation were significantly lower among treated subjects at 6 and 12 weeks than at baseline. We did not detect significant between-group differences until 12 weeks. This finding suggests that a longer exposure to antioxidant nutrients may be necessary to protect LDL against oxidation in patients with CVD compared with healthy subjects and may be important in the design of future studies of antioxidant supplementation in patients with CVD or those with cardiovascular risk factors because these groups may have significant biologic variability in response to antioxidant supplementation. An alternative explanation for the lack of a significant treatment effect at 6 weeks may be the significant increase in lag phase that was observed in our control group at 6 weeks.
We chose lag phase to evaluate the effect of antioxidant supplementation on LDL oxidation as opposed to measurement of the products of peroxidation or the maximal rate of oxidation. Lipophilic antioxidants, such as vitamin E and beta-carotene, are carried in LDL and may protect polyunsaturated fatty acids against oxidation by competing with them for free radicals. Once antioxidants are depleted from LDL, the propagating chain reaction of lipid peroxidation ensues, so an increase in the amount of antioxidants in LDL would be expected to delay the onset of this process. Change in lag phase is most likely the most appropriate measure of the effect of antioxidant vitamin supplementation on LDL oxidation because it reflects altered susceptibility of the LDL particle to oxidation.
In a more recent dose–response study by Jialal et al. [22], a minimal dose of alpha-tocopherol (400 IU) was necessary to prolong lag phase in 48 healthy men after 8 weeks of vitamin E supplementation ranging from 60 to 1,200 IU daily. Our mid-dose group, which included 400 IU of alpha-tocopherol supplementation, did not show a significant prolongation of lag phase compared with placebo at 12 weeks. This difference may reflect an increased dose of antioxidant vitamins required to alter LDL-C oxidizability in patients with CVD or may be due to a lack of power to detect a difference at that level of supplementation in our study.
Abbey et al. [29]showed a significant increase in lag time after 3 months in 45 nonsmoking subjects supplemented with a daily dose of 18 mg of beta-carotene, 900 mg of vitamin C, 250 mg of d-alpha-tocoheryl succinate (equivalent to 50 mg of vitamin E) and 12 mg of elemental zinc. Plasma concentrations of beta-carotene, alpha-tocopherol and ascorbic acid increased fivefold: 55% and 27%, respectively. We observed similar or greater changes in plasma antioxidants in our mid-dose group but did not detect a significant increase in lag phase in that group compared with the placebo group. This result raises the possibility that patients with CAD may require more significant changes in plasma antioxidants to protect the LDL particle from susceptibility to oxidation relative to that in healthy subjects. However, this finding should be interpreted with caution because our power to detect a statistically significant increase in lag phase in the mid-dose group compared with the placebo group was low because of the small sample size. Substantial individual variability in the ability of antioxidants to protect LDL from oxidation may also exist in patients with CAD.
Our study was also consistent with a crossover study of eight healthy, mildly hyperlipidemic volunteers by Reaven et al. [28], who used in vitro assays of oxidation to show that long-term supplementation with large doses of vitamin E conferred increased protection to LDL. A linear increase in LDL alpha-tocopherol levels up to an intake of 800 IU/day in 20 healthy nonsmoking volunteers was demonstrated by Princen et al. [24]. Simultaneously, the resistance of LDL to oxidation was increased in a dose-dependent manner and differed significantly from baseline even after ingestion of only 25 IU/day.
The finding of a significant increase in lag phase at 6 weeks in our placebo control group may have been due to chance. It is interesting that the trend was similar for all groups and raises the possibility that altered lifestyle habits, such as diet, in the initial phase of the study may have been associated with an improvement in lag phase in all groups, making it difficult to detect between-group differences at the 6 week time point. Beard et al. [46]recently demonstrated an increase in lag phase in subjects participating in a 3-week residential program with access to high complex carbohydrate/low fat foods and formal exercise classes. The significant increase in plasma levels for all antioxidants at 12 weeks may have been able to overcome nonpharmacologic effects on lag phase at that point. Furthermore, we documented no significant within- or between-group differences in dietary variables at 12 weeks, so any alterations in dietary habits may have returned to baseline levels by the conclusion of the study.
An alternative explanation for the significant increase in lag phase at 6 weeks in the placebo group is the corresponding significant increase in HDL-C in the placebo group at 6 weeks. HDL-C is protective for LDL oxidation, and the increase in lag phase that was observed in the placebo group at 6 weeks may have been a reflection of the increase in HDL-C that occurred in the placebo group in that time frame. We were surprised by the finding that LDL-C and triglycerides were significantly increased from baseline in the high dose group. Tsai et al. [47]has reported a significant reduction of serum thyroid hormone levels and an elevation of serum triglyceride levels in women receiving supplemental megadoses of vitamin E (600 IU). A recent review of the safety of vitamin E supplementation [48]suggests inconsistent effects on serum lipid and lipoprotein levels. It is unclear whether the lipid alterations that we observed are adverse or simply reflect conformational changes in LDL, which we did not evaluate in the present study. The increase in LDL-C that was observed in the high dose group is not likely to explain the effect of treatment on lag phase. LDL-C was inversely related to lag phase, and therefore an increase in LDL-C would tend to attenuate the effect of treatment in the high dose group.
The prolongation in lag phase with high dose supplementation of antioxidant nutrients in our study is consistent with the results of the Cambridge Heart Antioxidant Study (CHAOS) [20]. In that randomized, clinical trial of 2,002 patients with angiographically proven CVD, a nearly 50% reduction in the combined end point of CVD death and nonfatal events was demonstrated with supplementation of vitamin E (400 to 800 IU daily), attributable to a significant reduction in nonfatal myocardial infarction.
3.1 Study limitations.
Our study is limited because we used a combination of antioxidant vitamins, and therefore we cannot define the relative contribution of each individual component of the supplement we utilized to the inhibition of LDL oxidation. Because vitamin E is contained in the LDL particle at substantially higher concentrations than other antioxidant nutrients, we speculate that the alpha-tocopherol component would have a major impact on reducing the susceptibility of LDL to oxidation. Future studies should address the effects of vitamin E with and without other antioxidant supplements on LDL oxidation and other cardiovascular risk factors.
It is unlikely that the powerful effect of antioxidant supplementation on LDL oxidation that we observed can be explained by selection bias or confounding because this was a randomized clinical trial, and groups were well matched at baseline. Although beta-blocker use did differ between groups, there were no significant differences in baseline lag phase between groups, and drug usage did not change throughout the trial. If beta-blockers do confer a protective effect on LDL to oxidation, our results would be strengthened because the placebo control group had increased usage of beta-blockers. Our data suggest that it is heart rate and not beta-blocker use that is a significant multivariate predictor of lag phase. We questioned whether this finding may be explained by improved levels of fitness and attempted to evaluate exercise level as a predictor of lag phase. We were unable to detect significant effects of exercise on lag phase, which may be due to our small sample size and the small range of variation in exercise levels in our subjects. Future studies should address the role of exercise and fitness levels in predicting changes in the oxidizability of LDL.
3.2 Conclusions.
We demonstrated a significant reduction in the susceptibility of LDL to oxidation, as evidenced by a doubling of mean lag phase, in patients with CAD supplemented with a combination of vitamin E (800 IU), vitamin C (1,000 mg) and beta-carotene (24 mg). These data lend support for a role of antioxidants in secondary prevention; however, the potential adverse effects of high dose vitamin supplementation deserves further investigation.
We are indebted to Terri Johnson, Elizabeth Maimon and Leslie Bluman for assistance with data collection. We are grateful to Jackie Toms for technical assistance in the preparation of the manuscript, and we sincerely appreciate the helpful comments and critical review of the manuscript by Kim Eagle, MD.
☆ This study was supported by a gift from Kay and Z. Harold Peplau.
- Abbreviations
- analysis of variance
- body mass index
- coronary artery disease
- cardiovascular disease
- high density lipoprotein
- high density lipoprotein cholesterol
- high performance liquid chromatography
- low density lipoprotein
- low density lipoprotein cholesterol
- total cholesterol
- Received December 1, 1996.
- Revision received April 14, 1997.
- Accepted April 24, 1997.
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