BSE, Cervical Cancer and Toxoplasmosis

14 May 2006
Presented by Chris Smith, Helen Scales.


As the ten-year ban on British beef is lifted, Tony Minson joins us to discuss what causes BSE, how it is spread and why it is such a problem, and with another example of how animal diseases pass to humans is Joanne Webster, who describes the life cycle of Toxoplasma gondii and its possible link to schizophrenia. Margaret Stanley provides some happier news and reveals the astounding success of a cervical cancer vaccine in clinical trials, and Derek Thorne has fun with food colouring in Kitchen Science.

In this episode

Sea Pores Over New Defences

German manufacturing giant BASF have developed a new way to protect sea walls from the incessant crashing of the sea - by giving them a holey coating which behaves like a trampoline. The spray-on treatment, which is currently being tested against the ravages of the North Sea on the Island of Sylt, is administered by mixing two chemicals, isocyanate and a polyol. The mixture cures (hardens) in twenty minutes, making it perfect for use between tides. A high pressure spray can then be used to apply the mixture to stone surfaces, or it can be mixed with loose stones and sprayed in layers upto 30cm thick. But it's not a solid layer. The surface is punctuated with large pores a few centimetres across. When a wave slams into the surface some of the energy is dissipated by the natural elasticity of the material. But even more is mopped up by the pores as sea water tries to force its way through, turning destructive wave energy into heat and noise. According to project leader Marcus Leberfinger a wall reinforced with the coating has "reliably withstood the huge impact of the waves during this past storm season". Apparently the porous plastic is also proving popular with wildlife, with the holes making ideal homes for crabs, limpets and plants.

Phone Masts help Meteorologists

If you are going to predict the weather the first thing you need to know is what the weather is like now, the second thing you have to know is whether your prediction was right so you can improve your model.

One of the hardest things to measure is rainfall, rainfall radar covers large areas but isn't very accurate, and rain guages whilst being very accurate only give you a few points of data. Israeli Researchers from Tel-Aviv University have come up with a new source of data - mobile phone masts. When your phone shows a weak signal both your phone and the mast will crank up their power. Rain gets in the way of mobile signals, so by looking at the power mobile masts need to use, you can find out about the rain in the area. Hagit Messer-Yaron, an electrical engineer found that the data from the mobile masts was much closer to the rain guages than the weather radar, and using this resource wouldn't require any investment in equipment as it is already there.

- Pedal Powered Computing

Microsoft are investigating foot-pedals for computer control...

Pedal Powered Computing

In a step that will see computers become even closer to being an extension of the body, Microsoft Research are now looking into ways to implement foot pedals to help you control your desktop.

At the moment they're looking at which aspects of the mouse and keyboard control of their Microsoft Office package could be best translated to pedal power.

However, whilst this is likely to be welcomed by sufferers of repetitive strain injury affecting the wrist, are we about to see the first cases of ankle RSI caused by over-enthusiastic word-processing?


- Brownian motion in hot and cold water

This week we demonstrate the science of Brownian motion...

Brownian motion in hot and cold water

This week Sheena Elliot and Derek Thorne demonstrate the science of Brownian motion...

Derek - Welcome to Downham Market High School, we have a very easy experiment for you to do at home. With us we have Sheena who has the experiment set up for us. What do we have today?

Sheena - We are just looking at how food colouring looks, and changes in hot and cold water.

Derek - So it sounds easy and indeed it is, and with us today we have a volunteer who is going to be doing the experiment. So could you introduce yourself?

Tom - I'm Tom and I'm in year 10

Derek - So do you like science?

Tom - Yeah it's ok.

Derek - That doesn't sound enthusiastic enough for the Naked Scientists, so we are going to try and turn you onto science. We have a very simple experiment for you to do and if you want to do it at home these are the things that you will need: two bowls which are able to hold, say, a litre each; a boiled kettle; and some food colouring. Now Sheena is going to tell us what we do with all these things

Sheena - First fill one bowl with cold water, and another with our boiled hot water. Then we just need to let them settle, so put a cover on the hot one to retain the heat and leave them to settle for 5-10 minutes.

Derek - A bowl of water may look like it is still but you are saying there is still some sort of movement in there?

Sheena - Yeah there will probably be some movement for quite some time, but if we leave it to settle for 5 - 10 minutes it should be fine

Derek - So we need to wait until the water is nice and still for 5-10 minutes.

Sheena - Then we add just a little food colouring in each bowl in a nice controlled way. So I would suggest dipping maybe a handle of a teaspoon into the food colouring and then just touch the surface of each bowl of water with it.

Derek - So you are not putting anywhere near a teaspoon full in there.

Sheena - Yeah just a tiny amount.

Derek - So Tom what do you think will happen?

Tom - No idea at all.

Derek - But we have one that is hot and one that is cold. When you put food colouring in the water what would you expect to see?

Tom - In one the food colouring is going to spread more than the other?

Derek - So if you at home are wondering what is going to happen you can do the experiment yourselves. It is very easy and you can tell us the result. So get those bowls filled with water and see what happens. We'll come back to you later with the results. Until then, back to the studio. LATER….

Derek - Hello there and welcome back to Downham Market High School. We've been waiting here to do this experiment with hot and cold bowls of water. Tom is here from Downham Market High School and Sheena set up the experiment too. So Sheena, would you care to instruct Tom over what to do right now.

Sheena - Ok so Tom, if you take the bottle of food colouring and then dip in the handle end of your spoon. Then put it into your bowl of cold water and just repeat for the hot water.

Derek - Tell us what you see.

Tom - It's moving a lot quicker in the hot water the cold water.

Derek - And in what way is it moving in the hot water when you look at that?

Tom - It's spreading far and then dropping down to the bottom, whereas in the cold water it's not spreading quite as far and then it's dropping down to the bottom.

Derek - Yeah and I suppose we've got a really definite shape in the cold water one. We've got this weird structure of food dye that's suspended in the water and it doesn't appear to be movign anywhere does it?

Tom - No, it's diffusing more in the hot water.

Derek - And we've been waiting here for a minute. Now, what does that hot water one look like?

Tom - It's all red, or a light pink.

Derek - So what do you think is going on here?

Tom - I thin it could be because of the heat in the hot water making the particles more energised, meaning the food colouring can diffuse more easily through it.

Derek - Sounds reasonable to me. What do you say Sheena?

Tom - That sounds like a perfectly good explanation. I think there are actually two things that might be happening here. First of all, in the hot water the molecules will be moving much faster and have much more kinetic energy. When we talk of heat, what we're actually talking about is kinetic energy and all these molecules are moving very fast. That's what we perceive as being hot.

Derek - If we were to look down an amazingly massive microscope at these particles, would they be moving around a lot?

Sheena - Yeah, they'd be moving around like crazy in there. So that's what I originally thought would be causing the food dye to be bashed around. It's Brownian motion: they're all being hit by the hot molecules around them. In the cold water you still have these molecules moving but they won't be moving as fast. However I think there might be another explanation that's actually the one we're seeing so quickly here. I think that's convection currents. The hot water at the top of the surface where it's next to the cold air will evaporate and cool down and it will no longer be the hottest water in the bowl. Hot water from below will then rise and take its place because hot liquids rise. You then set up these currents where hot water from below keeps rising and the cold water gets pushed down. All these currents cause the mixture to mix up very quickly.

Derek - Ok, so do convection currents just happen continuously in something with warm water in it?

Sheena - Yes. As long as the vessel is a different temperature to the surrounding air, then it will continue to evaporate and you'll get this cooling effect at the surface.

Derek - So you've talked about two different effects. I suppose it's quite reasonable that they might both be happening.

Sheena - Yes I think they will both be happening to some extent but we can't really conclude which is the dominant one.

Derek - So Tom, your guess about diffusion was to do with one of those, but do you understand the whole thing a bit more now?

Tom - Yeah it's clear.

Derek - Well thanks. Did you enjoy it?

Tom - Yeah it was fun.

Derek - Thanks you for doing the experiment with us and we'll be back next week for some more science from somewhere in the East of England. Until then, it's goodbye!

- Science Update - Monopoly and Lung Cancer

The Naked Scientists spoke to Chelsea Wald and Bob Hirshon From Aaas

Science Update - Monopoly and Lung Cancer
with Chelsea Wald and Bob Hirshon From Aaas

Chelsea - When you are playing monopoly having a get out of jail free card makes landing in jail much less of a worry, and some scientists want to know if there is a similar effect in real life.

Bob - Exactly if there were a cure for lung cancer, would you start smoking? A recent study by University of Florida Professor of Marketing Joel Cohen and his colleagues offers some insight. They found that for people predisposed to risky behaviours like smoking and gambling learning about potential remedies to the problem made them more likely to downplay the risk and indulge, but for people with no such vices the information had the opposite effect.

Joel - The availability of a remedy would only convince non - users that, boy there were serious risks here and convince them of the correctness of their behaviour.

Bob - So remarkably marketing remedies can sometimes hurt the people who are most in need of help.

Chelsea - So it is with a little trepidation that we present to you the next story, which is that there may soon be a get out of jail free card for people putting on a few extra pounds.

Bob - Yes and this features the same dermatologist mentioned on the Naked Scientists recently: Fox Anderson from Harvard Medical School who found a new way to erase tattoos. Well now he is saying lasers can erase fat cells. Anderson noticed that certain wavelengths of light are absorbed by fat cells better than other cells of the body. So he worked with laser physicist Fred Dylla of the Department of Energy's Jefferson Lab in Virginia who tuned a powerful laser to that wavelength. Anderson then used the laser to zap away fat; first in pieces of pork then, Dylla explains, in samples of human tissue.

Fred - And that is the experiment he did down here using our free electron laser and he found he could selectively kill and damage fat tissue about one centimetre below the skin without affecting the skin.

Bob - In the future he says the technique could potentially clear up cellulite, melt down excess body fat, or even scour away unhealthy fat from arteries

Chelsea - Next week we will be talking about that most loved and reviled of all hormones, testosterone. Until then I'm Chelsea Wald.

Bob - And I'm Bob Hirshon for AAAS, the science society.

- What Is Bse And How Is it Spread?

The Naked Scientists spoke to Professor Tony Minson, University of Cambridge

What Is Bse And How Is it Spread?
with Professor Tony Minson, University of Cambridge

Chris - Can you just tell us, what actually is BSE?

Tony - The disease is a disease that causes paralysis, coma and then death: it's a central nervous system disease. It's one of a group of diseases of this kind, but BSE is special because it appeared out of the blue in cows in the late 1980s. From almost nowhere it got to about 40 000 cases per year by around 1990. What was really horrible was that it proved to be transmissible to people but extremely inefficiently. So it turns out that there have been about 100 cases all told in the last ten years in people but there have been hundreds of thousands of cases in cattle.

Chris - If you zoom in with a very powerful microscope on the brains of cows and people that have been affected, what is the nature of the infectious agent?

Tony - It's really unusual and it's taken the last fifteen years to show that it's this totally new kind of disease not caused by a bacteria or a virus but by on eof our own proteins folding abnormally. It extremely rarely folds abnormally and then forms aggregates of that abnormally folded protein. It's strange because it seems that this abnormally folded protein that attracts other normal protein and recruits it. If you look at it with a really powerful microscope, what you see is rod - like aggregates of this material and they're the things that are called prions. You hear the term prion diseases, and prion diseases are this group of diseases caused by abnormal proteins.

Chris - It's not just BSE though: there are a whole clutch of these that occur naturally in people and animals and in different forms in people.

Tony - There are many different diseases of this kind. In sheep it's called scrapie; in man we've known for many years about a disease called ordinary-CJD which occurs spontaneously in every population in the world. About one person in a million every year gets CJD where the formation of the abnormal protein occurs spontaneously. Where it gets risky is when you start recycling into the same species. One of the famous example of that is Kuru. In the highlands of New Guinea in a particularly isolated area, they practise cannibalism as part of a funeral rite. When people died, they used to take the brain material and eat it as part of the funeral rites.

Chris - When they were doing that, how was the protein that was in that brain tissue getting into the person's brain?

Tony - When you eat a bit of the brain it goes into your stomach and it passes across the stomach wall into the lymph system. It's thought that in the lymphoid tissue and in the spleen it expands and begins to recruit more of the same protein. Then it appears to go along the nervous system into the brain, all the time recruiting more protein and converting more of the normal protein like a chain reaction. The dangerous thing jis obviously the cannibalism and recycling food back into the same species.

Chris - Is it just unlucky that it happened here in Britain?

Tony - I think that's probably right. I think we were just extremely unlucky because virtually every western country was certainly taking the remains of beef carcasses and then rendering that down into a high-protein supplement to feed back to more cows. So I think it could have happened anywhere.

Chris - So if anything, British beef is now safer than it's ever been, and perhaps we should be suspicious of beef from other countries.

Tony - Well I wouldn't like to say anything about other countries because we will end up getting sued, but I think you're right. We now take extra-ordinary precautions. First of all we don't recycle any bovine material back into the bovines and we don't make meat in bonemeal anymore. Secondly, we don't eat any animal that was born before 1996 when we stopped recycling food completely back into bovines. Thirdly, we remove all the dangerous tissue, such as the lymph and the brain tissue from the carcass before it's butchered and then finally animals are tested for the presence of prions when they go tot the abattoir. So it's an extra-ordinary range of tests that's done. Because we no longer recycle bovine meat into cows, the number of BSE cases in this country is now reducing. It's now a thousand-fold lower than it was ten years ago.

- When Rats Chase The Cats

The Naked Scientists spoke to Dr Joanne Webster, Imperial College London

When Rats Chase The Cats
with Dr Joanne Webster, Imperial College London

Chris - Your research looks at the parasite Toxoplasma gondii, which most people have probably never heard of. What actually is it?

Joanne - It's a very very common parasite that humans sometimes hear about when they're pregnant. It's a parasite we're told to avoid cleaning out the cat litter for to avoid catching toxoplasmosis.

Chris - But tell us about it's life cycle. What does it do?

Joanne - It's an indirectly transmitted parasite, which means it's got two stages to its life cycle. We've got the cat as the final host for the parasite, and it will have an intermediate host such as a rat or a mouse. What the parasite wants to do is make sure it's transmitted from this rat or mouse into the cat, and that's what it does. It changes the behaviour of its intermediate host to enhance this transmission rate and complete its life cycle.

Chris - How does it change the behaviour of the mouse or the rat?

Joanne - The parasite prefers to exist within the brain of its host and that puts it in a very privileged position in which to achieve manipulation. What it does is to specifically alter those behaviours which are more likely to make it predated by the cat. Cats are immediately attracted to fast moving objects, so the parasite increases the activity of rats and mice. It also makes them less fearful. One of the interesting things is it not only overrides their innate fear of cats but it actually seems to make them attracted to them. So it manipulates the behaviour so that they will actually approach signs of cat presence.

Chris - And is there anything specific about the cat they don't like normally?

Joanne - Normally it seems to be an odour within cat urine. It seems to evoke a very specific physiological response in rats and mice. This is why many scientists use this response when they're developing anxiety reducing drugs. The parasite seems to be interfering with that response.

Chris - How is it doing that and what is the outcome?

Joanne - The mechanism is very much a black box at the moment. It's nothing so crude as having lots of these cysts in the brain. What it seems to be is that it seems to be interacting with dopamine within the brain of these rodents. This is one possibility. Of course the implications are that this is a very common parasite, and about 35% of us in Britain are infected. The parasite infects all warm-blooded animals so the implications are that we'll be seeing these behavioural changes, albeit subtle, in other hosts such as humans.

Chris - And we can get this parasite because it's set up this tissue cystic form in the muscle of all other animals that are infected. So if we eat a piece of meat that's not cooked properly, it can get into us.

Joanne - Absolutely, and that seems to be the most common way that people are infected nowadays. Traditionally it would be coming from cat faeces, but most commonly we're getting it through undercooked meat.

Chris - And the population of France who thrive on cooking their meat at room temperature: how many of them are infected?

Joanne - Yes, it goes up in particular parts of France to 84%. There has been a study finding 92% in Paris, but it's certainly a lot higher in Britain.

Chris - And if there are people picking up this parasite, is there any evidence that it might be leading to behavioural changes or even mental illness?

Joanne - Certainly there are a number of studies by a group in the Czech Republic, and they're doing the same sorts of studies that we do in the rats to see if humans are increase their activity and decrease their reaction times. Indeed they are finding this. In terms of clinical implications there was a study finding that showed you are 2.5 times more likely to be involved in a road accident. What has particularly interested me is that because we've got this parasite within the brain, and if it is indeed altering neurotransmitter levels, then that may have implications in a very few people. A convincing body of evidence is gathering that some mental illness, particularly schizophrenia, may be associated with an infectious origin and toxoplasma seems a prime candidate for this.

Chris - Thanks for joining us and telling us about your research. One of the other points that Joanne made to me on the phone yesterday is that the drugs that can be used to treat diseases like schizophrenia do seem to be toxic to this particular parasite, which suggests that it may have a role to play in diseases like schizophrenia.

- Human Papilloma Virus And a Cervical Cancer Vaccine

The Naked Scientists spoke to Professor Margaret Stanley, University of Cambridge

Human Papilloma Virus And a Cervical Cancer Vaccine
with Professor Margaret Stanley, University of Cambridge

Chris - Margaret Stanley is someone from the Department of Pathology at Cambridge University and she's spent a lot of her life working on Human Papilloma Viruses, the viruses that cause warts and verrucas, but they also cause cervical cancer. Tell us about your research.

Margaret - My research has always been asking how does this virus change cells, and more importantly, how can we intervene early in the virus infection to prevent either infection or to prevent the consequences of it.

Chris - How does a virus trigger cancer, because for many people that will be a pretty unusual thing to have said?

Margaret - It's rare. Viruses exist to make more viruses but as part of their life cycle they turn cells on to divide and make DNA. If there is an accident during the virus's replication, when the virus is making its own DNA, and the virus proteins are expressed at the wrong time or in the wrong amount, then they can change the behaviour of the cell. That's basically how this virus causes cancer. It's a rare accident.

Chris - How was it first picked up that this was linked to cervical cancer?

Margaret - That all starts in the 1970s. Everyone's heard of the Pap smear. Well there was a smart cytologist in Canada who realised that some of the cells you saw in the Pap smears were the same types of cells you saw in warts. We'd always assumed from the epidemiology of cervical cancer that it was a disease that had an infectious basis, and so as soon as this was found there was a big effort to find out whether these viruses were involved. The next big step was a German scientist that isolated virus DNA from a cervix cancer, identified what it was and it turned out to be a papilloma virus.

Chris - Was there some anecdotal evidence that nuns were very rare among the bunch of people that got cervical cancer and Jews and Muslims were also very rarely implicated?

Margaret - In essence, you're right. It's an apocryphal story. About 15 000 Belgian nuns were surveyed and only one of these ladies had cervical cancer. Her behaviour before taking the veil was rather extreme.

Chris - So that was a weak link for the nuns. But how did you go about making a vaccine to stop this virus?

Margaret - Again, that was tricky. What you need to do is present the body with the protein that the body first sees with the natural virus infection. In other words, the protein against which you make antibodies. This is actually very difficult for papilloma viruses for all sorts of reasons. Microbiology, recombinant DNA technology, came to the rescue. You isolate the gene that makes the protein of the virus coat. A virus is like and egg: it's got a coat and it's got an interior. So you isolate the gene that makes the protein of the coat and then you express this gene in something like a yeast that grows extraordinarily quickly. As the yeast grows, it expresses the gene and makes the protein, so you make huge amounts of the virus protein. When you make the virus that way, the protein forms its natural shape. In other words, it forms what we call 'the native shape'. It looks like a ball of wool with a set of railway lines. It's the ball of wool that you need for an immune response to be made.

Chris - And at what age is this effective? At what age would you need to challenge someone with this vaccine to guarantee that they're going to be protected?

Margaret - When you immunise someone with a prophylactic or a preventative vaccine, you must give it before they're infected. This is a virus that you acquire as a consequence of sexual activity. I have to say that everybody gets this. This is not a rare virus infection. The only other thing you get as much of with sex is pregnancy so this is very common. So obviously you've got to immunise people before they start having sex. The best age at which to immunise is at childhood. The reason for that is that children make much better antibody responses than adults. I have bad news: as soon as you hit puberty, then immune system goes downhill, so that's why you immunise children. So the optimal age is probably nine or ten.

Chris - Where is it in clinical trials now? It's in humans isn't it?

Margaret - Yes, it's in the large trials called phase three trails and at the moment we've got five year data on about 8000women. I can tell you that it's 100% effective in the women who've been vaccinated.

Chris - So internationally what are the implications?

Margaret - This is the biggest killer from cancer in the Third World. This is a vaccine that prevents infection.

Chris - And I guess, sensitive subject as it is, that this couldn't have been developed with out the use of an animal research model?

Margaret - Absolutely. This has depended on rabbits and dogs because rabbits and dogs were the animals with natural warts and we showed the virus worked there before we went to people.

Chris - So you can actually cure animals and dogs from their own infections if they actually had it?

Margaret - You can indeed.

- Do TV and radio signals travel vertically as well as horizontally?

Do TV and radio signals travel vertically, and if they do, do they disappear or travel off into space forever? If so, does that mean that...

Do TV and radio signals travel vertically as well as horizontally?

Yes the signals we create are creating a sort of bubble around the earth which is expanding at the speed of light. That means that the bubble is roughly 100 light years across now and spreading away from the earth. But when you think that the Milky Way is easily about 100 000 light years across, it's going to take a long while for many of the stars just in our own galaxy to hear us. When you consider that there are 10 000 000 000 000 000 000 000 stars out there, it is going to take a long while before the messages get to anyone else. So it is not surprising we haven't heard anyone replying yet.

- Why did switching on my desk lamp produce interference on my radio?

I was listening to my radio one night and I noticed that when I turned on my desk light there was a little blip of noise on the radio. I ...

Why did switching on my desk lamp produce interference on my radio?

When your light switch is just on the border of making a circuit, you are creating a switch which is almost closed. At some point the switch will create a spark. When you create a spark you will create a little surge of current in the wire. The spark will then finish and break the circuit again. You will keep getting sparks, each creating it's own surge of current. Your light bulb is flickering because you have a changing current, and a changing current will produce a changing magnetic field. A changing magnetic field produces a changing electric current. So when we create a radio wave, what you've got is a transmitter which is applying a changing electric field to a piece of metal (the aerial). The changing current going up and down that piece of metal then induces a changing magnetic field around the metal and the changing magnetic field then creates a change in electrical current in the fabric of space around it. That electrical current in space time produce a wiggle of magnetic field, and so you get this wave that propagates as an alternating magnetic field and electrical field. This propagates through space at roughly the speed of light. That's a radio wave. So why did your interfere with your radio? Well when you're just on the verge of completing a circuit with your light, it's creating enormous amounts of changing current in the wire. This creates lots of funny frequencies of radio waves at a fairly low power. These then come out around the wire, spread out into the room and are picked up by the aerial of your radio. They interfere destructively. In other words they cancel out the radio waves of the station you were listening to. That's why you get the interference.

- Why don't mammals use blue or green colouration?

As far as I know, mammals do not use the colours blue or green, but most other animals and plants do. Is there a reason for this?

Why don't mammals use blue or green colouration?

Animals are the colour they are to blend in with their environment. The key thing that drives survival is not being preyed upon or eaten. If you're not eaten then you get to have babies and you pass your genes on to the next generation. If you're a polar bear and your genes make you white, then you're less likely to be caught and eaten. As a result, you're more likely to have babies and those babies will have babies. So animals will change their colour so that they're the same as the surroundings and blend in. That either makes their hunting easier or they don't get eaten by other things. It might be that the colours you're referring to have not been adopted because they're not very good colours in nature. A snake is a greeny-brown colour because it wants to blend into the background. Other animals use the converse. They don't want to blend in because they want to mark out that they're toxic. That's why they use colour. The other reason they use colour, especially in things like fish, is for part of the mating game. It can be used for recognition and communication. Actually, I think baboons have big blue noses and I think there is a mammal that is green, although it's for a slightly different reason. It's called a three-toed sloth. The reason it's green is because moss grows on its fur as it moves so slowly.

- Have we got a time bomb in the population with mad cow disease?

Have we got a time bomb in the population with mad cow disease?

Have we got a time bomb in the population with mad cow disease?

I don't think so. The number of cases of this new form of CJD rose to a peak of 28 cases in the year 2000. Last year there were five. It looks very much that far from being a time bomb, numbers are dropping and the disease is under control. That's what I would say. When the first cases appeared in the end of 1995 and the beginning of 1996, nobody knew what the incubation period was. We knew that the maximum exposure of people to contaminated beef was around 1990 and so some people said that if there's a 20 year incubation period, then these first cases in 1996 might expand to hundreds of thousands of cases in 20 years time. Nobody could be sure that that wasn't right. It turned out that the incubation period is about ten years, BSE transmits very inefficiently to people and the maximum of 28 people in 2000 was the maximum. Now it's going steadily down.


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