Thursday, October 28, 2010

BPA - is it a threat to health?

A recent article in Dr Gupta's CNN blog, carries the frightening headline "BPA may reduce sperm count". It goes on to detail a study in China of workers in plastics factories who had lower sperm counts (and high blood levels of BPA). The problem with this study is those workers are exposed to the chemical in a way that we will never be, from drinking from plastic bottles.

And yet, one wonders - how much chemical does leech into the substance in the plastic bottle? Do all plastic bottles leech BPA into your drink or food?

BPA is short for bisphenol-A, a chemical used in clear plastic. It has lately been loosely linked with numerous problems including obesity, cancer, brain damage and early puberty.

It is true that girls are exhibiting earlier puberty these days but that also could be attributed to other factors - pharmaceutical estrogen which is widely used for birth control and HRT, has been found in drinking water (it is thought to be excreted in the urine), and pollution in the atmosphere has also been suspected as a factor. So how much of the earlier development can be linked to BPA? No one knows.

As for obesity, here the links are very vague and much more likely factors can be named such as labor saving devices (our grandparents burned a whooping 800 calories more daily than we do, just in executing housework etc), and foods which are delicious but extremely high calorie while not being particularly filling. Lending fuel to those reasons is the lack of obesity found in environments which do not have easy access to fancy and fast foods and do not have labor saving devices like cars and automatic washers (for example, the PIMAs of Mexico who still live the same way they lived 1000 years ago).

Cancer? Well, here again, there are many factors have been strongly linked to it, including heredity, use of tobacco and alcohol, pollution in the air, synthetic estrogen and even some medications like those medications taken to lower cholesterol (statins).

So again, we are left with questions about BPA.

Even more concerning, is the fact that there is no way around plastic bottles - everything comes in it, from milk to water. So if plastic is really leeching into our food and causing health problems, where would we turn?

It seems in our modern society, rather than curing all the ills, we are often doing trade-offs like the vaccines which have been linked to the high incidence of autoimmune disorder in exchange for infectious disease. And I also wonder why some chemicals which happen to be popular or hot sellers are never mentioned in our many health warnings. Chemicals like aspartame which has been linked to brain cancer in 100 worldwide studies and is actually banned in some countries, or the preservative in vaccines which is a form of mercury, known to be extremely toxic, even in trace amounts. Or coffee, which contains caffeine, a stimulant which can, over a lifetime especially in larger quantities, disarray the dopamine in the brain, possibly leading to the development of Parkinson's disease (REF: PROZAC BACKLASH by J. Glenmullen, MD, NY,2005).

I would tend to think, if BPA is a player, it's a minor player in causing disease. But I guess it's more of a "stay tuned". Studies like the Chinese study of workers in plastics factories are not really telling us anything about the general public and BPA.

Friday, October 22, 2010

New Study finds high cancer risk with low dose birth control/hormone replacement

Low Dose Birth Control Hormones are given for birth control and also for hormone replacement therapy (HRT). And the cancer risk with pharmaceutical estrogen first popped up in the 1930's when rats given the drug, all came down with breast cancer, both males and females. In the 1960's this study was repeated with the same results, but funded by Planned Parenthood which saw a gold mine in selling a medication for contraception, research pushed on and in the mid 1960's, the "birth control pill" became available, touted as safe and effective.

Epidemiological studies which are notoriously inaccurate but because of the large numbers involved, convincing to the public (and medical providers also) suggested that giving menopausal women estrogen (and later on, low dose birth control including estrogen and progestin) would relieve their hot flashes and other symptoms associated with menopause and even protect them from heart attacks.

But even after these studies, nursing magazines referred to the "estrogen - breast cancer risk". The Merck Manual also listed these medications as significantly raising the risk for heart attack, stroke and thrombosis (40% higher risk in those taking the hormones). But the general public never heard about these risks and the large epidemiological studies which suggested that this medication was "heart protective" were convincing.

In the year, 2000, 9 million women were on premarin for menopause.

Meanwhile, the incidence of breast cancer went from a low percentage in the 1950's to occurring in 1 in 8 women by 2000 (80,000 women die yearly in the USA, from breast cancer).

In the early 2000's, 2 NIH double blind studies had to be stopped mid-term because those on estrogen alone or low dose birth control - estrogen and progestin, were getting too many heart attacks, strokes and cancer. And pharmaceutical estrogen was put on the FDA list of cancer causing chemicals in 2005.

Recently a new study, an 11 year point analysis of the Women's Initiative Study Data, suggested that low dose birth control given for Menopause and Hormone Replacement significantly raises the risk of cancer.

The women taking both estrogen and progestin were found to have a much greater chance of dying from lung cancer or breast cancer (for example, women on HRT had a 70 percent greater chance of dying of lung cancer than those who never took the hormones).

The study was reported on in the AMA's Journal. Rowan Chlebowski, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, who led the analysis,told the press:

"Women taking estrogen plus progestin are at greater risk from dying from the two leading causes of cancer death in women."

In 2002, there were 110 million prescriptions filed for low dose birth control. By 2005 after both NIH studies had to be halted, prescriptions "plummeted" to 40 million. And the incidence of breast cancer also dropped somewhat.

However, today, millions of women still take the hormones as birth control and hormone replacement therapy. In my acquaintance, I've seen a 17 year old have a stroke (she was on hormones for birth control - it paralyzed her partially) and recently, a woman in her 50's with no other risk factors, had a major stroke paralyzing her totally on one side. This woman was likely on hormone replacement therapy.

It is hoped that with the new analysis, the public will finally consider not taking these hormones.

When my husband and I got married in 1966, the "pill" was a new thing. Everyone asked me enthusiastically if I was planning to take the pill. "No," I told them, "That's a system which is too sensitive and I have a hunch that dumping amounts of pharmaceutical hormones into my body would not be a healthy thing!" I never did take birth control medication - but had no idea how unhealthy and risky those hormones would turn out to be.

NOTE: Natural Progesterone Cream (like "Progesta-Care") is a nice alternative for menopause which cuts the symptoms but does not put the woman at risk. See "WHAT YOUR DOCTOR MIGHT NOT TELL YOU ABOUT MENOPAUSE" by Dr John Lee, MD. (No, I do not sell this but this is what I used to get me smoothly through menopause and also, to avoid a hysterectomy.)

Friday, September 3, 2010

Are the medications we use a factor in Alzheimers and Parkinsons?

A few years ago, some very poorly publicized studies suggested that long term use of drugs and medications which alter the amounts of dopamine and serotonin in the brain, can injure the dopamine and serontonin receptors. This includes the use of medications in the often used SSRI group (selective serotonin re-uptake inhibitors) which prevent the brain from absorbing the feel good chemical serotonin. These are used to combat depression and other uses including losing weight.

A book called "PROZAC BACKLASH" by Dr Joseph Glenmullen brought out another little known but possibly noteworthy, complication of these meds - the brain, like other places in the body is a finely balanced system - flooding it with serotonin causes it to produce greater amounts of dopamine to counteract what it detects as a "problem" and in the long run, said Glenmullen, this can cause Parkinsonism.

He pointed out that any stimulant has a similar effect and thus can raise the risk for Parkinson's disease and this causes me to wonder about even those well accepted stimulants like the caffeine in coffee.

Parkinsons is very common these days - could something so mild as our coffee drinking habits be contributing?

The fact is, medications have side effects - so do drugs and caffeine is a drug albeit people don't think of it as that because it's so commonly consumed.

In the NY Times recently a study was reported on which suggests that party drugs which give a "high" like meth and cocaine can damage dopamine receptors.

The article naturally, in the media fashion, emphasized the ill effects of meth and cocaine - drugs which most readings of that periodical won't be using but I have not seen much in the media about the real dangers of the SSRI's - the so-called Prozac group of medications which are widely in use.

Perhaps the legal drugs won't bring folks to the "edge of personal ruin" like the extreme case the NY times talked about... unless a case of Parkinson's would be considered somewhat ruining - I would consider it so.

Today I heard about two people I know - one formerly scholarly, talented university professor and the other, a talented string player who had chaired a section in a symphony orchestra - both downed with Alzheimers.

Everyone has heard of the nuns study on Alzheimers which was supposed to give us the exact cause of the disease (nuns allowed their brains to be dissected after death). It was a long carefully run study according to the book by the head researcher and midway into the study, they had a theory... nuns with alzheimers seemed to have smaller brains than those who retained their mental prowess.

But then came a 94 year old who was extremely mentally sharp, up to her death, teaching others, caring for nuns in the elderly home etc. When they dissected her brain, they found it was much smaller than another nun who'd had Alzheimers for several years.

"Now we are back to first base again," wrote lead researcher, David Snowdon, in his book published in 2007, "Aging with Grace"

Although the study revealed a lot about how to stay healthier and more mentally alert in one's Autumn years, it apparently left researchers with more questions than answers about Alzheimer's.

I continue to wonder though, could the chemicals we consume be a factor in some of these brain disorders? I would bet it's a good possibility.

Wednesday, August 18, 2010

Health shorts...

Click the links to read the stories...

1 Unrestrained dogs in the car can endanger them and you by falling on you in an accident or distracting you from driving. If you want to travel with your dog, seat it in the back seat with a seat belt.

2. Is Cymbalta, originally sold as an anti depressant, safe and effective for pain? Lilly which manufactures it is seeking FDA approval for more uses than depression, fibromyalgia and diabetic nerve pain. Lilly would like approval for general pain. Cymbalta, besides a host of side effects including nausea, nightmares, insomnia, can also cause liver damage with long term usage. There are 14.6 million taking Cymbalta. Since Lilly stock dropped in value after a trial for a new Alzheimer's drug in which those not taking the drug did better than those taking it, perhaps, Lilly wants to make up the loss.

3. A new study found 3000 children from 12-18 with hearing loss. Loud music and blaring Ipods are a suspected factor.

4. Acai berries do not help you lose weight, say experts - but only work as a laxative. The FTC is going after a couple of internet places making claims for the product which the FTC expert says are false. Additionally, taking these herbs can cause damage on a longer term basis. Just because it's a herb doesn't mean it's safe.

Thursday, July 15, 2010

Pillz pillz pillz - do they really offer hope for easy weight loss

A headline in the AZCentral website boasts that "Experimental diet pill has promise, little risk".

Apparently a large study in the New England Journal of Medicine stated that this medication,

Lorcaserin caused more people to lose at least 5 percent of their body weight over one year, more than twice the rate achieved by those on dummy pills.

So what is this wonder drug? Yet another flavor of an SSRI i.e. like Prozac etc. And in fact, according to the newsletter, Heartwire, Lorcasin isn't that much different from fenfluramine - one of the medications in Phen-Fen:

Lorcaserin is a selective serotonin 2C receptor agonist, and previous studies have shown that drugs targeting serotonin are beneficial in weight loss. The nonselective serotonin agonist fenfluramine, which, along with phentermine, made up the antiobesity medication fen-phen, for example, was approved by the Food and Drug Administration (FDA) in the early 1970s as an adjunct for the treatment of obesity. It was pulled from the market after reports it caused valve disease and pulmonary hypertension.

And what was this amazing weight loss the drug caused? Well, the average weight loss among the people in the study, was 12 lbs over a year which they apparently kept off mostly during the second year of the study. This compared to a weight loss of 4.8 lbs in those taking sugar pills (Placebos).

Adverse events according to the researchers on the study ( abstract is available,) were 'only' headache, nausea and dizziness.

Fact remains, to lose 12 lbs in a year, is easy even without their drug. For example something as small as a walk a day will do it. (That's about 1 lbs a month)In fact, a 2003 study (reported on in the JAMA) by Stanley Heshka found that people on Weight Watchers who attended most meetings, lost an average of 11 lbs in a year - without any drugs. (JAMA. 2003 Apr 9;289(14):1792-8.)

This isn't the only "wonder drug" coming out - there is another I recently read about called Qnexa which is really a combination of two already available medications, Phentermine (yes, the stimulant and part of Phen-Fen, the combination which caused Pulmonary hypertension in some people) and Topamax, the anti seizure drug. Vivus called the combination Phen/TPM in the FDA documents but obviously since that's uncomfortably close to the unsafe Phen-Fen, I'm sure it won't be marketed under that name.

According to the releases on this medication, the weight loss was better than the serotonin agonist above:

Qnexa showed the best weight loss results in clinical trials, with patients losing between 13 percent and 15 percent of their body weight. But the drug also had the highest rate of patient dropouts due to side effects, which include memory and concentration problems. Qnexa is a combination of two older drugs: the amphetamine phentermine and topiramate, an anticonvulsant drug sold by Johnson & Johnson as Topamax. According to the company, phentermine helps suppress appetite, while topiramate makes patients feel more satiated.

In other words, the Phentermine makes your heart beat faster (which can't be good for the heart) and the Topamax causes you to forget how hungry you are?

Kidding aside, there seems to be conflicting reports how much weight the cohort lost as well as what those side effects are. (Vivus, the manufacturer has not yet published their two 56 week long studies on the drug combo yet)

UPI reported a weight loss of 3-11 percent which is considerably less than reported in the Dallas news media:

Included in the review [for the FDA] are two randomized, double-blind, placebo-controlled 56-week trials conducted by Vivus and presented at medical meetings, but not yet published in peer-reviewed journals. Under the low dose, body weight losses were 3 percent or more, while the higher dose (including 100 mg of Topamax - enough to cause the adverse side effects) resulted in a body weight loss of about 11 percent.

I have a friend who was put on Topamax for seizures - she didn't lose any weight and she complained bitterly about the side effects of the drug. What she described which seems to have been missed in the news but was described in an FDA memo document was as follows:

When used at doses of 100 mg to 400 mg per day for migraine prophylaxis and the treatment of seizures, topiramate is associated, in a dose-related manner, with an increased incidence of cognitive-associated adverse events including confusion, psychomotor slowing, difficulty with concentration/attention, and difficulty with memory, speech or language problems, particularly word-finding difficulties.

Another adverse side effect reported on in the FDA memo was Metabolic acidosis in a percentage of the cohort on Qnexa - this could cause kidney stones as well as osteopenia:

A mild, sustained metabolic acidosis increases the probability of developing nephrolithiasis [kidney stones] and adversely affects bone structure and function. In the one-year clinical trials, there were twenty-two reported cases of nephrolithiasis [kidney stones] in the PHEN/TPM group compared with five in the placebo group.

(Having gotten a kidney stone once in my life, I would add- you so don't want to suffer that one - yes, it is true what people say, that the pain is exquisite and intense!)

Finally the FDA memo stated that although cardiac arrythmias and other cardiovascular events were of low incidence, there was no information available about the repercussions of using it for the long term treatment of obesity.

And according to the FDA Briefing document from the manufacturer, most of the year, those on in studies were told to change their lifestyles to one of regular exercise and calorie restriction, which will, of course, cause a weight loss without the drug.

One blog stated that the FDA had concerns about the drug combo:

FDA reports show that Qnexa has potentially bad side effects on the heart. Increased heart rate, depression, adverse effects on pregnant women and memory and language problems were noted during testing. Attention span also seems to decrease with usage.

Unfortunately, I could not find the affore mentioned FDA reports and the blogger did not give the cite however, since Phen-Fen caused serious heart problems, I would not be surprised if Phen-TPM did also. They will only find that out in the aftermarket studies after thousands of people have been the guinea pigs for the new drugs.

There is a dark side of stimulants also, (and the serotonin agonists also work as stimulants which is why they are often used to treat depression) according to "PROZAC BACKLASH" by Joseph Glenmullen, MD, is that on the long term, they can significantly raise the risk for Parkinson's disease, something which people are seldom warned about despite a body of research suggesting this. Serotonin agonists tend to cause a flood of the brain chemical serotonin, which causes the brain to react by producing more dopamine - this imbalance of an overage of dopamine is what is thought to raise the risk for Parkinsonism.

Additionally some "whole life" animal studies have suggested that longer term use of the serotonin agonists can also damage the serotonin receptors in the brain.

The only wonder about these two drugs in my book is that I would bet people will buy them, still looking for the elusive "easy way out" of counting calories and exercising to achieve and maintain weight loss.

Truth being that people do not have to lose weight to get healthy - they only have to make mostly healthy food choices and try to exercise (cardio) 4-5 times a week - this is called HAES and is well proven by clinical studies including the 2 year study at USC - researchers on this clinical study were Linda Bacon and Judith Stern and since Stern is a member of the Weight Watchers International Medical advisory committee, she would have undoubtedly, preferred a different finding than the finding of the HAES study i.e. that healthy lifestyle without a focus on weight loss trumped dieting as far as reducing health risks.

Take a look: Link for the HAES study

For more info, also see Dr Bacon's website.

Monday, April 19, 2010

Music - are we body and mind alone?

A friend who is a music teacher and I (another music teacher) were chatting this morning. He said that he believed we are mind, body and soul. And our schools do pretty well with the mind (academics) and the body (sports and phys ed). But the soul is often ignored and yet, might be one of the most important parts.

Specifically, when a financial crunch happens within the school system, what is it that is usually first deleted? The music program which apparently many feel is unnecessary.

In my some 50 years of being a violinist and teacher, I have met hundreds of folks who tell me that they studied a bit of violin or organ or piano or trumpet in their youth but gave it up and now are sorry that they didn't pursue the music because they so wished they could play now.

I have never met anyone who continued music and can play now who is sorry they continued music.

But music programs also enrich the mind - thus found several studies over the years. Typically children and adolescents involved in music tend to do better at not only academics but also at sports.

For example in a study reported in 2009, Laurel Trainor, director of the Institute for Music and the Mind at McMaster University in West Hamilton, Ontario, compared pre schoolers who had studied music with those who had not. She found the kids who had studied music had better responses on a test of brain development, suggesting music actually enhances the brain functions. She further noted:

Even a year or two of music training leads to enhanced levels of memory and attention when measured by the same type of tests that monitor electrical and magnetic impulses in the brain.


We therefore hypothesize that musical training (but not necessarily passive listening to music) affects attention and memory, which provides a mechanism whereby musical training might lead to better learning across a number of domains

Trainor said the reason for this might be:

"that the motor and listening skills needed to play an instrument in concert with other people appears to heavily involve attention, memory and the ability to inhibit actions. "

Harvard University researcher Gottfried Schlaug has also studied the cognitive effects of musical training. Schlaug and his colleagues found a correlation between early-childhood training in music and enhanced motor and auditory skills as well as improvements in verbal ability and nonverbal reasoning.

A study published in the magazine, "The New Scientist" suggested that music training can actually boast the IQ scores of children and adolescents!

Read the bios of the valedictorians of the High School classes and you will find that the overwhelming majority of them play a musical instrument.

So even if the happiness music brings us is not considered important, perhaps the powers that be will consider that encouraging music training will likely cause the participating students to get higher scores on the AIMS and/or Iowa tests also!

My friend and I talked about the recent Allstate festival in our state. This is where selected musicians and singers from all the schools are put together into a large chorus, band and orchestra and they practice and give a concert (or two). The result is simply amazing. My friend described it as "hearing the Chicago Symphony couldn't be better than this".

I totally agree with him because the thing I remember most vividly from High School in Chicago was the conference festivals (we had so many music schools and programs in the area that an "Allstate" orchestra might have been too large).

We rode on a bus to another school in our conference, we practiced in the afternoon, and then, the next evening went back to give the concert.

One has never lived until one has listened to (or better yet, participated in) these large orchestras, bands and choruses. A chorus of over 500 High Schoolers singing "The Seven Last Words of David"? I can still hear it, over 40 years later.

Or how about 25 trumpets playing on "The March from Ben Hur". After hearing this rendition, the movie version pales by comparison.

Not withstanding the rich experience of playing under famous conductors and meeting so many other High Schoolers and much more. We all looked forward to these festivals as the high point of the year!

Most people I've talked to, feel the music program in school gave them some of the best times in their lives, studies suggest that participation in music helps people for life and just talk to anyone you meet - everyone loved the music program and no one is sorry for having participated but many feel cheated that they gave up music too early in life!

So why are we always considering cutting the music program. Just consider this - the IPOD's are even more precious to the average teen than their cell phones (or they use their cell phones to listen to music).

We seem to have an inborn desire for music and all evidence suggests it not makes us happier and better adjusted people but actually makes us smarter too. Seems a win-win to me.

So let's consider cutting something OTHER than the music programs! Please! Trust me, your children will thank you for making sure these programs continue!

Tuesday, April 6, 2010

Tysabri for MS - re-visit

I received a comment from "Enjolez" who is listed as having a blog but when you click on the link, it's non existent. The comment used explictives and suggested I didn't know what I was talking about when I wrote about the Multiple Sclerosis "disease modifying" medications, particularly a cancer chemo therapy drug named Tysabri which can cross the blood-brain barrier and cause a deadly type of brain infection called "progressive multifocal leukoencepelopathy" which according to the manufacturer of the medication, causes death or "severe disability".

Enjolez didn't mince words - he or she called me a f-king idiot but didn't bring up any facts to refute my claims. Despite the type of comment, I want to answer his or her issues because it's important that he or she (probably having infusions of this medication) has informed consent.

At a recent MS meeting, I was given a colorful brochure produced by Biogen. Biogen didn't mince words about the possible risks however or the fact that Tysabri hasn't been studied for "use longer than 2 years" (that's on the first page of the booklet). Interestingly enough, the gentleman I talked to, representing the company, really believed in the medication - he told me his wife was on it.

However, when the risk of a medication appears greater than the risks of the disease it is used to treat, it may be a smart thing to consider another type of treatment. Treatment with a medication which even the lax FDA approved with difficulty for MS, a disease which if treated properly is mild in most folks for years, sounds a bit to me, like playing "Russian Roulette".

From the "Safety information" tab in the same brochure from biogen we are informed that

Tysabri is not recommended if you have a medical condition that can weaken your immune system.

MS is a condition that can weaken your immune system all by itself because it's an autoimmune disorder and/or autoimmune/lymphocyte B disorder (the jury is still out on this). In other words, by having this drug infused into you, you could be dealing yourself a double whammy so to speak!

Biogen also warns that Tysabri can cause liver damage.

What many people do not know is that the nature of studying the MS disease modifying medications is such that they are typically studied in people who display "white spots" on an MRI of their brains but have not been formally diagnosed with MS yet i.e. they have no symptoms of the disease. Some of those in the studies cohorts never come down with MS!

Also, the white spots on the brain appear long before serious symptoms appear - progressive or intermittent MS is a mild disorder which takes many years to disable.

Back in the old days, people were not diagnosed until they had the clinical symptoms but now with MRI's, we have many cases of folks being diagnosed with some fleeting mild symptoms (one lady I'm thinking of, had some "weakness in the legs" but not enough to stop her from being in college athletics) and the MRI "white spots" and they are told that the sooner they get "on the medications", the better and because they had no real symptoms in the first place, and they "believe in" the medications, they naturally attribute this good feeling to the medications or the fact that they have virtually no symptoms but perhaps this is only because if they DO have MS, it's an early enough case that they would not have symptoms anyway. (We won't even discuss here, the possible ramifications of a "too early" diagnosis, psychologically which by itself is questionable since the person may never come down with active disease!)

In contrast, those who have a lot of clinical symptoms often do not experience the "help" that the early cases experience. One lady I talked to who was on Tysabri because she'd tried the other medications with no help, said she was disgusted with her neurologist because she'd been on Tysabri a year and no change. However, when I told her it was a risky medication, she shrugged her shoulders and said "Who cares?"

This attitude of doom and lack of knowledge of the nature of MS is, I think, what causes many folks with MS to take unnecessary risks.

I'm back from the 1970's before all the new treatments. Back then, the MS society told us that 10 years after diagnosis (from clinical symptoms), most folks with MS were still walking and many were still working. They advocated a healthy lifestyle with moderate exercise and range of motion moves, healthy eating and "some walking, some sitting, some standing and some lying down".

In my own research, I noticed that folks with MS who did the highly experimental medical treatments even like large doses of steroids, tended to have more disability in the long run. In fact, there were even a couple of studies which suggested that!

With today's "disease modifying medications" for MS, they don't promise patients anything as far as less disability but only (perhaps) less MS flare-ups. In the studies of these medications, "flare ups" are decided totally upon "new white spots" showing up on an MRI since those in the cohort have not formally come down with MS yet.

Our son, the medical provider, tells me that the disease modifiers for rheumatoid arthritis work well. These are also, medications which are not without risks, however, none of them have the risk (however rare) of causing a deadly brain infection like Tysabri.

Perhaps the problem with the MS disease modifiers is that they really don't know that much about the cause of MS i.e. they may know more about rheumatoid arthritis than they do about MS.

A favorite internist told me "neurology really don't understand a lot of these things". Well said.

Informed choice is the only way but that includes looking at the research behind the medication or at least just reading the caveats from the manufacturer. I wonder if the person who called me an "idiot" ever did the latter.

If "Enjolez" will write me privately and give me an email address to write him/her at, I will furnish more information about myself.