Monthly Archives: September 2013

asbestos and black pudding

Some cancers are better than others. Mesothelioma is one of the worst. Alfred was admitted to our ward earlier this week. He is a 78 year old retired shipbuilder. He has mesothelioma in his lung. He spent most of his life in the Naval shipyards welding large plates of steel together to make warships. When he was young, a huge amount of asbestos was used in naval ships. It was packed in thick layers between the compartments of the vessel as it was being constructed. Alfred and his mates played snowballs with lumps of the stuff (of course, no masks were worn then).  Asbestos was used in naval construction because it is a refractory material. That means that it will not burn or melt even at high temperatures, so that it will prevent fire spreading from one part of the ship to another. It is also very cheap – a mineral that needs no further processing once it has been dug out of the ground.

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chrysotile asbestos
from Ra’ike – wikimedia commons

The reason Alfred came into hospital was because he had suddenly become more breathless and had bad chest pain when he breathed deeply. When we examined him it was clear that he had a large amount of fluid between his lung and chest cavity – a pleural effusion. We were also worried that he may have a pulmonary embolus. Patients with cancer commonly develop blood clots in their veins that travel to the lungs and block up the circulation causing shortness of breath, chest pain and even death if the clots are big enough.

His wife was with him. She knew he had cancer. She did not say it, but clearly she thought he was about to die.

We gave Alfred oxygen, an injection of low-molecular-weight heparin to prevent further blood clot formation and arranged a CT pulmonary angiogram.

Why is asbestos so dangerous?

The common form of asbestos is chrysotile. This is white asbestos. There is also brown, and the even more deadly blue asbestos. Chrysotile is a fairly simple chemical compound – magnesium silicate. Talcum powder is also magnesium silicate, but asbestos has a different crystal structure to talc. The crystals which asbestos is made of are very long, and very thin and break up into tiny, sharp needles. These needles get stuck into the lung and cannot be removed.

Ordinary dust commonly contains silicates. Sand is pure silicate. Silicon and oxygen are by far the two most common elements in the earths crust. Lots of stuff we use every day is made of silicates, including glass, ceramics (the cup you are drinking coffee out of right now), the bricks your house is made of, the cement mortar holding the bricks together, the surface of the paper you put in your printer, toothpaste etc. etc. The reason silicates are so useful is that the silicon-oxygen bond is very strong. This means when you put strong acids, alkalis or solvents in a glass vessel it does not dissolve. It also means that when it is in the wrong place in your body it can cause a problem because it cannot be broken down.

the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.
the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.

Ordinary dust, in reasonable amounts we can cope with. If it gets down into our lungs, it is trapped by the mucus layer on the surface of the tubes, or bronchi. This mucus is continually produced by goblet cells – called that because they have a goblet shape.

Mucus is a very wonderful substance. It is mainly water, but clearly not only water because it is very sticky. It is designed to be sticky to trap dust particles and bacteria. Bacteria don’t like to be trapped in mucus because they find it hard to move around – like us trying to swim in a swimming pool full of treacle.

treacle

Once the bacteria and dust particles are trapped, tiny, beating cilia on the surface of the bronchial epithelial cells move the mucus layer along. These cilia, which look like miniscule hairs, push the mucus, with its cargo of dust and germs, in one direction – upwards. Eventually, it reaches the larynx and then goes down the tunnel of death – the oesophagus – to end up in the acid of the stomach. No germs can survive this apart from helicobacter pylori – the subject of a future blog no doubt. The cilia are easily damaged. One reason smokers cough is because their damaged or absent respiratory cilia do not move mucus up the escalator, so it collects and needs to be coughed up.

Mucus is a wonderful substance made mainly of sugars. Sugars are essentially sticky substances. Lollipops are sticky, honey is very sticky. In earlier times wallpaper was stuck to walls with flour and water paste – wheat flour is composed mainly of starch –  a long polymer of the sugar, glucose.

wallpaper paste

Modern wallpaper paste is made of methylcellulose – a form of cellulose that dissolves in cold water to make something that looks quite like mucus. We use a lot of K-Y jelly in our work. It is also made from methylcellulose. I have read that many litres of K-Y jelly were used to simulate mucus in the Alien films.

The sugars in real mucus are quite special – they are in the form of long sugar chains known as mucopolysaccharides or glycosaminoglycans. I prefer the word mucopolysaccharide. It just means polysaccharide – a sugar chain – derived from mucus. They are special because unlike the common sugar glucose, many of the sugars in mucopolysaccharide chains have an amino group (NH2) and many have sulphate (SO4) groups attached. The sulphate groups make mucus even stickier.

The mucus produced by goblet cells is not just a solution of mucopolysaccharides. It is a complex structure. The goblet cell extrudes a long protein molecule called mucin. The sugar chains are attached to the mucin like bristles on a bottle brush.

Slide1
structure of mucus
the central red shaft is a protein to which many long sugary mucopolysaccharide chains are attached (blue)

So, on average, mucus has more than twice as much sugar as  protein in a large amount of water – rather like wallpaper paste.

Our bodies use mucopolysaccharides for a lot of things apart from making mucus. They are important in lubricating joints and are found in the jelly-like vitreous humor in our eyes. Some bacteria produce these sugars as a slime-coating or capsule which makes them more difficult for phagocytic cells to ingest. (See phlegm and horseradish previously).

Back to the asbestos particles. Being very thin and sharp, they manage to penetrate the mucus layer and get into the lung substance. They would not cause too much of a problem if it were not for the police in the form of macrophages. These officers of the law are very intolerant of foreign invaders and try to destroy them. (I’m not suggesting police are racist by the way). If the foreign invader is a bacterium then fair cop. If it is an organic substance like wood fibre, engulfing it and breaking it down is also a good idea. The problem with asbestos is that it is a silicate, and even though macrophages can make some pretty nasty chemicals, they cannot break down asbestos. It is like glass or ceramic. That does not stop the macrophage trying.

There is a great picture of a macrophage trying to eat an asbestos particle at the end of this imgur gallery:

http://imgur.com/gallery/nBJb6

When trying to dissolve foreign bodies, the nasty chemicals such as hypochlorite can damage DNA. This may be why asbestos exposure causes cancer, although the details are not clear at present.

There is one place in the body where foreign bodies do not cause inflammation – the anterior chamber of the eye. This is because the damage caused by cells such as macrophages would endanger our sight. The eye is known as an immunologically privileged site It means that we can put new plastic lenses in the eyes of patients with cataracts and graft a new cornea from donors without needing immunosuppressive therapy.

And now back to Alfred. He was found to have several large blood clots in his lungs. They had formed in his legs or large veins in the abdomen and travelled upwards and got stuck, reducing the flow of blood in his pulmonary arteries. We treated him with enoxaparin – a low molecular weight heparin. He got better quite quickly and went home with his wife a few days later. She looked much happier than when they arrived. We taught her how to inject her husband with heparin every day.

Heparin is a mucopolysaccharide, made from cow lungs or pig intestines. It is made from the slimy stuff on the surface of the tubes – the mucus. It is separated from the protein it is stuck to using enzymes and chemicals, and purified – the bristles are removed from the brush. We used to use this unfractionated heparin to prevent and treat blood clots.

heparin is a chain of sugars with amino groups and sulphate groups low molecular weight heparin has short chains of five sugars
heparin is a chain of sugars with amino groups and sulphate groups
low molecular weight heparin has short chains of five sugars

Now the long sugar chains are chopped up into five-sugar lengths – low molecular weight heparin. This is easier to give by an injection under the skin rather than into a vein. It is also more reliable in treating and preventing blood clots.

cartoon of fibrin breakdown - from Jfdwolff wikimedia commons
cartoon of fibrin synthesis and  breakdown – from Jfdwolff wikimedia commons

Heparin interferes with the horribly complicated cascade of events that leads to an insoluble protein – fibrin, being formed from the soluble clotting factors circulating in our bloodstream. The system is so complicated because it is vitally important. Stopping blood leaking out of holes in our blood vessels is pretty high up the list of things we have to get right if we are to survive as a species. The clotting cascade is designed to produce large amounts of fibrin clots very quickly when we need it – whether you are being savaged by a wild beast or crushed by a bus, clotting can save your life.  But blood clots in vessels without holes to repair can also be fatal. Alfred could well have died if he had not been treated with heparin.

Fibrin formation is responsible for forming clots in veins. It also strengthens the clots formed by platelets in arteries. The problem is that patients with cancer, or people who have been ill and immobile (or even after a long-haul airplane flight) can develop clots in their veins even when there is not a hole in them.

We suspected Alfred may have a blood clot problem because we found a high concentration of D-dimer in his blood. When a clot forms, say in the wall of an artery which has been damaged, it is remodelled by an enzyme called plasmin which dissolves fibrin. This shaves away the unwanted bits of clot to make them neat and fit for purpose. The fibrin turns into, among other things, D-dimer. Whenever there is a lot of fibrin clot around, the D-dimer level in the blood increases.

Now the food link. I’m particularly pleased with this one – black pudding.

black pudding
black pudding

I went to the butchers yesterday to buy some. I fried it with tomatoes, bacon and sausage for a late breakfast. Black pudding is made in the UK from pigs’ blood. It is cooked, which makes it clot, and mixed with oatmeal and herbs and stuffed into a pig’s intestine from which the inner surface or mucosa has been removed. Drug manufacturers use the mucosa to make heparin. So, black pudding is a large blood clot made in the very organ that gives us a drug for preventing blood clots!

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Chest pain and horsemeat lasagna

A heart attack, or myocardial infarction to give it the proper name, is still a very common cause of death in the UK. Those unfortunate patients with severe heart attacks don’t even touch the ground, going straight to the cardiology department to have the offending blood clot removed from their coronary artery. In the medical admissions unit we also see a lot of patients with chest pain who have less severe heart attacks.

Today we admitted Toby, age 57, who had bad episode of chest pain which woke him up at 4am. The pain was so bad it made him vomit. It was a like a heavy pressure on the front of his chest. His wife woke up and noticed that he looked really pale and ghastly and realised there was something seriously wrong,

“No, its just a bit of indigestion dear, you go back to sleep, I’ll be OK”,

he said, at the same time also knowing that this was not the case. Of course she did the sensible thing and called the ambulance. When the ambulance men arrived they gave him morphine, oxygen, nitroglycerine and some aspirin tablets to chew. They did an EGC and sent the result to our ED department – not normal but not a major heart attack.

When he arrived we measured the level of troponin (a substance that indicates heart muscle damage) in his blood – it was increased to over 200 – the normal upper limit in our hospital is less than 14. He had an NSTEMI, that is a non-ST elevation myocardial infarction. That meant the damage was probably caused by a partial rather than complete blockage of his coronary artery.

What causes the pain with heart attacks? When a coronary artery is blocked, or partially blocked, the bit of heart muscle it normally supplies gets starved of oxygen. It needs oxygen to make energy in the form of ATP to keep on beating. In the hope that oxygen will be soon restored, the cardiac cells take out a pay-day loan.

The cells that have spent all their oxygen convert glucose into lactic acid to produce four ATP molecules. Normally, when oxygen is available a glucose molecule produces about 30 molecules of ATP. Lactic acid produced in the abscence of oxygen lowers the pH (more acid) and stimulates sensory nerve cells – this is perceived as pain.

Bad pain. Visceral pain. The sort that makes you vomit and makes think you are going to die. Payday loans are always costly. About half of the patients with full-thickness STEMIs who die, do so before they get to hospital. This is mainly because the lack of oxygen and metabolic upset caused by the blocked coronary artery causes ventricular fibrillation – a fast and totally chaotic electrical activity which results in no useful heart function and death in a few minutes if not terminated by an electric shock.

So why did Toby get a blocked coronary artery? Sorry, I now realise this is going to be a longer blog than usual.

I think it is useful to know that traditionally, the Japanese suffer from far less coronary artery disease than those in the US or northern Europe. By far less I mean about 30%. This is a huge difference. If we were like the Japanese we could dramatically reduce the number of patients admitted with coronary artery disease and probably reduce our cardiac department costs by over a half.

There is plenty of evidence that it is what the Japanese eat which protects them from coronary heart disease. The traditional Japanese diet has a lot of fish and vegetables. When they move to the US and eat hamburgers, fries, cookies, and donuts their rate of coronary heart disease soon matches the rest of the US population.

Slide1

What is also interesting is that those in Southern Europe eating a “Mediterranean diet” tend to have much lower rates of heart disease than in Northern Europe (although not as low as Japan). Their diet also has quite a bit of fish, but also has a lot of olive oil, pasta, and bread.

I think what we do know is that saturated fats are quite bad, trans- fats are very bad, and fish is good. What follows is an attempt to explain why, with a mix of accepted orthodoxy and some speculation. If you think my speculation is way out of line I hope you will tell me.

The traditional Northern European diet relies heavily on wheat, with supplementation by milk and dairy products, particularly in the winter. Northern Europeans have a mutation which means that they can drink large amounts of milk as adults. Infants, of course, can drink milk, but to be able to absorb the milk sugar lactose they need the enzyme lactase to break the disaccharide into glucose and galactose. This enzyme is conveniently situated in babies on the surface of intestinal cells. For most of the world’s population, the lactase enzyme disappears at age 2 or 3, meaning that if they drink more than a cup full of fresh milk they will get diarrhoea. The lactose is not absorbed but goes to feed bacteria in  the colon who have a party. Normally these bacteria see only the leftovers from our diet such as cellulose fibre. The result of the celebrations is a lot of gas, abdominal cramps and diarrhoea, otherwise known as lactose intolerance (not to be confused with milk allergy). The ability to drink milk without these problems as an adult is known as lactase persistence. This mutation has allowed humans to colonise Northern Europe and survive in the Winter by drinking milk, and more recently eating dairy products. This is a link to a fascinating blog post all about lactase persistence and a map showing which adults in the world can drink milk, and those who can’t.

http://sci.waikato.ac.nz/bioblog/2010/06/the-genetics-of-lactase-persis.shtml

The wheat we traditionally grow in Northern Europe is not good for making bread. It does not have enough of the springy gluten protein to allow large bubbles to form in the rising dough. The bread turns out heavy and unappetising. Having said that, it was the staple food of most  people in the UK until relatively recently. What English flour is really good for is making pastry and biscuits (cookies). For that you need low gluten (weak) flour and hard fat, such as butter or lard – or indeed, suet. Butter has always been plentiful in England because of the huge dairy industry – turning milk into butter preserves most of the calories and stops it spoiling so quickly.

Pastry cooks know that it is important to keep your hands cold when making pastry – the fat must stay hard when it is mixed with the flour to give the pastry that wonderful crumbly, delicate, tasty and satisfying feel in your mouth. Try to make pastry with olive oil or sunflower oil and you will get a tough, chewy and very disappointing result. I presume it is because the liquid oil seeps into the starch grains of flour, making them stick together, rather than coating them and keeping them apart during cooking (any food scientists out there?)

cakes

cakes made by my family today – from butter, not margarine

The problem is that butter contains mostly saturated fat. You can generally tell how saturated a fat is by how hard it is at room temperature. Butter is slightly more saturated than lard, but less saturated than suet, the fat surrounding kidneys. Olive oil is monounsaturated – it is normally liquid but will solidify in the refrigerator. Sunflower oil is polyunsaturated – it will stay liquid even when quite cold.

Saturation depends on how many double bonds there are in the long fat chains which make up triglyceride. Triglyceride is the way fat is stored in nature – in plants, insects, fish and mammals, including humans. Here is picture of a typical triglyceride in butter:

Slide1
green dots are carbon atoms, blue are oxygen

You will see that it is made of three long chains of carbon molecules, joined onto a backbone of glycerol – a 3 carbon molecule. Why is all fat in nature stored with this arrangement? Why not a backbone of 2 carbons, or 4 or 20? I don’t know.  Answers please.

The reason why saturated fat is solid at room temperatures is because the long fat chains are straight.  Unsaturated fats have a double bond C=C somewhere in them which makes the chain bent.

Slide6

Bent chains don’t line up next to each other so well, and are more reluctant therefore to solidify and stay liquid at lower temperatures than saturated fats with the same length of carbon chains.

Saturated fats come mainly from mammals. Unsaturated fats come from plants and fish. There is a reason for this. Plants have to endure cold temperatures. Fish live in cold water and are poikilothermic – their bodies are a similar temperature to the water. Mammals stay warm, with a core temperature of 37 degrees. If you take a lump of butter and hold it in the palm of your hand it will melt.

Slide2

So, in the cow the fat is liquid. If you buy a fish and put it in the fridge, it will stay bendy, whereas a pork chop will go stiff. We all need to have liquid fat so we can easily move it around. Have a feel of that fat under your abdominal skin – it is liquid. That’s because it is 37 degrees Celcius. If it was at room temperature it would be at least semi-solid.

One of the reasons that butter, or cow fat, is so saturated is because of the strange digestion system in cows. All the grass they eat goes first into an enormous biodigestor called the rumen. The rumen is huge. Over 200 litres – bigger than a person. Here cellulose is broken down by bacteria to simpler sugars. This fermented grass is then regurgitated back into the cow’s mouth, chewed some more, then sent down a different tube to other stomachs, ending up in the abomasum, which is similar to the human stomach when all the goodies in the grass are in a form which can be absorbed. The problem is that any unsaturated fat in the grass will be chemically reduced in the rumen to saturated fat. This fat goes to make milk and butter.

The rumen of a cow is huge - it fills up much of the inside of the animal
The rumen of a cow is huge – it fills up much of the inside of the animal. Unsaturated vegetable fats are reduced to saturated fats in the rumen.

I must mention trans-fat here. Butter is relatively plentiful in Northern Europe, but has always been a quite expensive luxury. Napoleon offered a prize to anyone who could invent a cheaper substitute for butter. Margarine was originally made from beef fat, but it later developed as a way to make cheaper oils solid by reducing the C=C double bonds into simple C-C bonds by reaction with hydrogen and nickel catalyst. Hydrogenation of unsaturated vegetable fat to make it saturated will make it hard and good for making cakes and pastry. Unfortunately it  can also cause the formation of C=C bonds in the trans- formation rather than the normal cis- formation. Trans- double bonds do not cause the lipid chain to be so bent. The straight chains are the reason that margarine is solid at room temperature.

Napoleon never invaded England, he instead invented a fiendish foodstuff which over the years has probably killed a very large number of them. Trans fats are now banned in the US and most European countries. Margarine manufacturers have now devised other ways to make liquid fat solid without the formation of trans- fats.

So why is saturated fat, and even more, trans- fat bad for us? Why does it cause coronary arteries to block up? The reason is that it increases the amount of cholesterol in our bodies, in particular the low density lipoprotein cholesterol – LDL.  You might think that the reason why saturated and trans-fats increase LDL cholesterol is well known. Well, I read the book below and could not find the answer. Not online either. The following is my best guess.

This book tells you almost all you need to know about fats.
This book tells you almost all you need to know about fats.

We have to take another aside here to talk about cholesterol. This is completely different from triglycerides. Cholesterol is an amazing molecule. It is only made by animals – vegans get no cholesterol in their diet, but luckily they can make it. I say luckily, because it is a totally vital substance which has many very important uses in our bodies. The one we are going to talk about here is its function as a constituent of cell membranes. All the cells in our bodies are surrounded by a membrane made of phospholipids – these molecules are similar to triglycerides but have just two fat chains attached to a phosphate group.

structure of cholesterol
structure of cholesterol – not at all like triglycerides

Membranes made of just phospholipids do not do all the things we need a membrane to do. It will not be strong enough, rigid enough, and will be too leaky. Small molecules like sodium ions, water and glucose would be able to leak through and cells could not work at all.

Cholesterol is incorporated into the phospholipid membrane to make it stiffer and less leaky
Cholesterol is incorporated into the phospholipid membrane to make it stiffer and less leaky

So cholesterol is used in large amounts to make the membrane stiffer and less leaky. In many membranes there is as much cholesterol as phospholipid. All cells can make cholesterol, but it is a real pain. There are over 30 enzymatic steps needed to make cholesterol from glucose. An analogy might be clothes. We could all make our own clothes if we needed to – buy the cloth, cut it up and sew all the pieces together. But we’d rather buy them from a shop – much easier. Similarly for the average cell – it needs cholesterol to incorporate into its membranes – it could make it,  but there is a ready supply in the bloodstream in the form of LDL cholesterol particles made by the liver – you don’t even have to order it – it is on tap all the time. The liver is good at a whole range of things, making cholesterol is one of them. It sends the cholesterol in little gift-wrapped packages, covered with a special protein coat, continually into the bloodstream to be picked up by cells around the body. Cells which need cholesterol make a special “docking port” on their surface to trap the LDL particle, take it inside the cell and use the cholesterol to beef up and stiffen up its membranes. These docking ports are called LDL receptors. Seems like a good system.

Gift-wrapped LDL particles are taken up by cells to provide cholesterol for cell membranes
Gift-wrapped LDL particles are taken up by cells to provide cholesterol for cell membranes

The problem is that when we eat too much saturated, hard fat, or trans- fat, these straight lipid chains get incorporated into the cell membranes. Because the chains are straight, the membranes are more rigid and less leaky. The cells therefore don’t need so much cholesterol to make the cell membranes nice and stiff and work properly. So the liver is pumping out LDL cholesterol, and the cells don’t want it.

It seems that the liver does not have a good system of knowing how much LDL is needed. It keeps making LDL cholesterol and it hangs around, like an unemployed teenager. Then it inevitably gets mixed up with the wrong company – oxidising agents. Oxidation (from enzymes such as myeloperoxidase – see previous post on phlegm and horseradish) changes the LDL particle in a bad way, and it inevitably gets picked up by the police (see previous blog on asthma). Here the police are macrophages. They, for some unknown reason take the delinquent LDL particles and imprison them in blood vessels, just below the lining cells or endothelium. With time (Toby has been eating pies and cookies with enthusiasm for more than 50 years) these bad cholesterol prisons become fill up with inmates. They make a lump on the inside of the artery. The lump slowly gets bigger and bigger, making the hole down the middle of the artery smaller and smaller. When Toby woke up at 4am with chest pain, the surface of the lump, or atheromatous plaque to give its proper name, ruptured. Blood flow to part of his heart was cut off by platelets trying to mend a hole which was not really there.

When a blood vessel is damaged, it is normally vital to plug up the hole. The first defence against bleeding to death from a hole in your blood vessel are platelets. These are tiny little bags made from bits of cells in the bone marrow called megakaryocyes. Platelets continually bud off from megakaryocytes and are packed with all the technology needed to find and mend holes in blood vessels. They have no nuclei, so are really not cells, more like pre-programmed drones which cruise round the bloodstream looking for holes.

“Your mission, should you choose to accept it*, is to go out and look for holes in blood vessels. You will know there is a hole because you will come into contact with collagen – that is sure-fire evidence of a hole. When you find the hole you will go into activate mode. You will change from smooth pebble shape to crazy octopus-with-lots-of-legs shape and you will stick onto the collagen with your sticky tentacles. You will immediately summon your platelet colleagues by making thromboxane and ADP. They will come and stick to you to help staunch the flow. If you detect thromboxane or ADP made by your fellow platelets you will go into activation mode at once and join your brave colleages until the hole is repaired. Good luck, and remember it is your mission to Save The Human Race”

When platelets encounter collagen they activate and change shape. They stick together with the sticky glycoprotein IIb/IIIa. Activated platelets release thromboxane and ADP to tell nearby unactivated platelets to come and join the party.
When platelets encounter collagen they activate and change shape. They stick together with the sticky glycoprotein IIb/IIIa. Activated platelets release thromboxane and ADP to tell nearby unactivated platelets to come and join the party.

Thromboxane is made from the cell membrane phospholipids of platelets, from a very unsaturated fat called arachadonic acid. The enzyme which makes thromboxane from arachadonic acid is called cyclo-oxygenase. The reason why the ambulance crew asked Toby to chew two aspirins is because this drug very effectively inhibits cyclooxygenase enzyme and prevents platelet activation by preventing thromboxane production. He was given clopidogrel when he arrived in ED. This prevents platelets from responding to ADP released from their colleagues by blocking the ADP receptor.

So the problem was that the atheromatous plaque, or fatty lump in his coronary artery had ruptured. This activated the platelet drones which were zooming by. Collagen is found in the wall of blood vessels, but is covered by endothelial cells, the cells lining blood vessels. When the plaque ruptures, as well as a soup of cholesterol and macrophages, there is a lot of collagen. The platelets go crazy – a feeding frenzy fuelled by massive release of thromboxane and ADP. Before long the whole coronary artery is full of activated platelets. If this happens in a large coronary artery the result is a STEMI: full thickness cardiac damage. Toby was lucky, his clot only caused partial thickness damage, but was still very painful and will mean that his heart will not work quite as well as it did.

Why are trans-fats worse than ordinary saturated fats? I don’t think there is a definite cause known, but it may be simply that once the straight trans- fat is incorporated into cell membranes it is more difficult for the normal metabolic process to add further cis- double bonds and elongate the lipid chain into a bent and more liquid form. This means that cells need even less cholesterol to make their membranes stiffer, and LDL cholesterol is even more redundant and superfluous to requirements.

We have understood about unstable atheromatous plaques only relatively recently. A really important contribution to our understanding was made by Michael Davies who died in 2003. There is a short and very understandable youtube video showing him dissecting a coronary artery from a patient who died from a STEMI.

See:

http://www.youtube.com/watch?v=F0Y5hss1tZQ

The clot in the coronary artery in the video is made of white thrombus – basically activated platelets sticking together, with a mission to save lives but causing death. Drones can be problematic. Michael Davies discovered why about 15% of people in the US and UK die. He has not even got a Wikipaedia page and there are no photos of him on Google images– can someone sort this?

I mentioned that fish is good to prevent heart disease. The Japanese eat lots of it. I have started to eat more fish. Fish oil has an extra double bond near the end of the lipid chain – 3 bonds from the end – omega 3. (Omega is the letter at the end of the Greek alphabet, so if we are counting bonds from the end of the lipid chain the omega notation is used). Now if we eat fish, the lipid chains in our membranes have an extra cis- double bond near the end. When our platelets use these lipids to make thromboxane, a slightly defective form is produced with the extra double bond. This is known as TXA3  rather than the normal TXA2. TXA3 does not work as well as TXA2 and platelets cannot stick together so fast. This is a good thing if you have a ruptured atheromatous plaque in your coronary artery.

Now the food link – dodgy lasagne. Horses do not have a rumen. They eat and digest vegetable matter in a different way from ruminants like cows and sheep. They first take out the goodness they can in a normal stomach, then ferment the residue in a huge caecum, which breaks down the cellulose into simpler, digestible molecules. They are known as hindgut fermenters. This means that the vegetable lipids are absorbed in the stomach and stay unsaturated and horse meat contains fat which is much healthier than cow or sheep fat. Ironically (given the recent scandal about horsemeat in lasagne), horsemeat is therefore better for us than beef.

*They don’t really have a choice.

Asthma and pineapple

Asthma can be a horrible disease. I don’t have asthma but a lot of people I know do. I can only imagine what it must be like to not be able to breathe. Patients I see often say that during a bad attack it feels like they are drowning. We admitted a lot of patients with asthma this week – it is one of the common reasons why young people need to come into hospital.

Yesterday we saw Christine, age 26. She has been asthmatic since she was young. Her mother said that it started when she was less than 2 years old. She also had bad eczema – but that is not a problem now. Both Christine’s sisters and her father have asthma, but not bad enough to bring them into hospital. Her 2 year old daughter, Zoe has just started nursery and is getting a new cold every few weeks (normal 2 year olds get, on average, about 8 colds per year) and she is worried that Zoe is getting more wheezy with every one. Christine also caught a cold and just as her runny nose and sore throat were getting better, her breathing started to get worse and she could hardly speak as she was so breathless. At 4 in the morning her husband was really worried about her and called the ambulance.

We’re not very close to understanding why some people get bad asthma. Genes are obviously important as it runs so strongly in families. Everyone thought that with rapid DNA sequencers we would have the answer long before now – surely we just have to look how the genetic code of those who suffer from asthma differs from those who do not and find the gene responsible?

Of course, lots of scientists have been doing just that, but like many other inherited diseases such as hypertension and schizophrenia, we have found that it is not that easy. At least 100 different gene differences have been shown to be associated with asthma, not the two or three originally hoped for. Although I’m not an expert in this area, I don’t think we can say right now that the main genetic cause of asthma is x, y or z.

And then there’s the environment. There seems to be something about living in a modern, industrialised society which makes asthma more likely. Certainly it is much more common in the UK than 50 years ago. Is it television:

A Sherriff et al: Association of Duration of Television Viewing in Early Childhood with the Subsequent Development of Asthma. Thorax 2009;64:321-325.

Or perhaps Simon Cowell, or Barbie dolls? – probably not. The “hygiene hypothesis” is at least superficially attractive. Lack of exposure to nasty germs early in life means that when we are adult we respond to environmental allergens in a different way, provided we have a certain mix of genes.

The fact that eosinophils (closely related to neutrophils I talked about two posts ago*) are found in large numbers in asthmatic lungs, and these cells are thought to be important in protecting us from worm infestation makes the idea that exposure to worms might protect us from asthma. There is some evidence that  that hookworm infection is protective.

Hookworms are small and extremely ugly creatures which are common in some parts of the world – thankfully (?) not in the UK or US – although asthma is more common here than in third world countries.

hookworm

Hookworm from istockphoto (with permission)

Wikipaedia says that 600million people worldwide are infected with this parasite. The way to get hookworm is to tread with bare feet on infected faecal matter.

The hookworm larvae burrow through the skin of your foot and find a vein. They swim up the vein all the way to the heart – they are going with the current so it doesn’t take too much effort. They pass through the right side of the heart into the lungs, and get trapped in the lung capillaries. Then they start burrowing again – this time into the airways of the lung, get coughed up and swallowed into the stomach. Presumably when they are tunnelling through the lung is the point when the immune system is modified by hookworm infection. The worms are tough enough to survive stomach acid, but when they get to the small intestine they use their two pairs of sharp teeth to latch on to the inside of the gut wall. There they live happily, sucking blood from the host, and when mature, lay eggs to be eliminated mixed in with faeces from where their babies hatch, hoping upon hope that another unsuspecting barefoot person will step on them. If you want to know where in the world you need to make sure to have shoes on, and see some even more upsetting pictures of hookworms and this nasty nematode’s questionable lifestyle see:

http://www.infectionlandscapes.org/2012/02/hookworm.html

Whatever the underlying cause of susceptibility to asthma, it is clear that asthmatics respond to certain inhaled particles differently, and in a way that is not helpful to anyone (except pharmaceutical companies). These allergens include

1. house dust mite faeces

2. pollen

3. cat hair

All medical articles about asthma mention these three things, which seem to keep the disease going in those who suffer from asthma. What links them?

House dust mites are everywhere in houses. They are very small, again not particularly attractive creatures.

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They eat human skin flakes, of which there are plenty in house dust (we each produce and shed ¾ kilo of skin cells every year). Skin is made of keratin, a tough protein polymer which also makes nails and hair. House dust mites love it. The problem is that they have only very tiny intestines and have problems breaking down the tough keratin. So what they do is soak the chewed-up skin flakes in digestive enzymes (one is called Der F 1), pack it into little balls, cover it in a thin membrane and then poo it out in a small (25 micron) faecal particle – about 20 each day. They then wander on their way and wait for the enzyme to do its work. When the faecal particle bag is nice and gooey, with the keratin dissolved, it will come back and eat it. Yum. This coprophagia (eating poo) is also seen in a surprising number of other creatures such as rabbits. Do not read the Wiki article on coprophagia.

Slide2sem of house dust mite

Because house dust mite faecal particles are so small, they stay airborne for a long time when sucked up by a vacuum cleaner and blown out into the room are easily inhaled deep into the lungs. Imagine now that you are one of the cells lining the surface of the lung – a bronchial epithelial cell. This poo-bag, the size of a large bacterium and heavily armed, lands on you. Fully tooled up with digestive enzymes threatening to dissolve you. I’m not surprised that you panic and call the police. The police come in the form of eosinophils, macrophages, basophils and lymphocytes when the alarm (interleukin 8 release, for example) is sounded. They arrive then throw their weight around, releasing all sorts of munitions like hypobromite, leukotrienes, histamine and a range of inflammatory cytokines. There is collateral damage. The effect of this activity is that the smooth muscle surrounding bronchi reacts to these chemicals by constricting. I don’t think anyone knows why bronchial smooth muscle does this – it hardly seems sensible or helpful. It certainly causes a lot of problems. At the same time there is swelling of the small airways because the inflammation caused by infiltration of these cells causes fluid to accumulate in the wall of the small bronchi, and on top of that there is more secretion of mucus than normal. All these things go together to reduce the size of the hole down the middle of the airways and make breathing difficult – asthma.

As well as constricting in response to these inflammatory chemical signals, the bronchial smooth muscle becomes much more “twitchy” – constricting more than usual in response to cold air, exercise, smoke and other triggers such as viral infections. All these cause an imperceptible increase in constriction of airways in non-asthmatics. For people like Christine a simple head cold can mean several days in hospital, a stressed-out husband, a worried daughter, and two weeks off work for both parents.

What about pollen? This is made by the male part of flowering plants – the stamens. When pollen lands on its lady partner (the stigma) that’s just like holding hands – it still has a lot of work to do before it can make babies. It has to burrow down into the gynaecium, using digestive enzymes, so that its male DNA can combine with female DNA. Again imagine the poor bronchial epithelial cell confronted with a randy pollen particle landing on top of it wanting to penetrate with its digestive enzymes – call the cops!

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Cat hair is also made of keratin. It is finer than dog’s hair and more likely to break up into small particles that can be inhaled. The story I’d like to tell you is that because cats lick themselves their hair is covered with saliva which contains digestive enzymes and therefore provoke a similar reaction from lung cells.

Slide1

I don’t think its quite so simple as that, for it seems that the allergen in cat hair is also produced from sebaceous glands as well as saliva– a protein known as Fel D 4.  Nobody knows what this protein does. Clearly the bronchial epithelial cells of asthmatics are very frightened by it. Maybe it looks like Michael Gove.

So how can we prevent asthma? Can asthmatics avoid inhaling allergens? The problem is that the offending particles are very small and get everywhere. There were some really interesting experiments in the 1980s when asthmatics were kept in special hospital rooms for 2 months or more with fine filters to keep out airborne allergens. Most of them had a remarkable improvement in their asthma, only to get worse again when they returned home. If you want to read more about it see:

Platts-Mills T et al. Reduction of bronchial hyperreactivity during prolonged asthma avoidance. Lancet 1982(2) pp 675-678.

Nobody has yet come up with a way to prevent asthmatics breathing in airborne allergens at the same time as living a normal life.

So, although we give advice about allergen avoidance to our patients, the main effort is in reducing the amount of lung inflammation. Christine is on a course of steroids (prednisolone), which is quite effective, but it takes a few days to work and concerns her, because of its long-term side effects.

Christine also takes salbutamol inhalers. Salbutamol is a drug which is designed to mimic adrenaline (epinephrine), causing relaxation of bronchial smooth muscle and therefore opening up the airways. It is quite effective when inhaled in the lungs but many patients are bothered by tremor with this drug, as some inevitably gets into the rest of the body. Christine says that sometimes she can’t hold a cup of tea without spilling it when she has had a lot of salbutamol nebulizers.  Voluntary muscles – the muscles which moves our arms and legs – respond to salbutamol and epinephrine by becoming unstable and twitchy. Imagine you are being chased by an axe-wielding psychopath. You need to run fast. You need to be strong. In amongst the normal muscle fibres are special devices called muscle spindles. These spindles control the speed and force of contraction. Adrenaline and salbutamol, acting on beta 2 receptors in the muscle spindle, turn up the amplification. This causes instability and loss of precision and results in the tremor caused by fear and salbutamol. Speed and strength are good for getting away from the psychopath, but not good for drinking cups of tea. You can’t have rapid response and fine control. For more info read:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1400891/pdf/brjclinpharm00139-0063.pdf

The food link this week is pineapple. Pineapple contains a digestive enzyme called bromelain, a cysteine protease with the same function to break down protein as the digestive enzyme in house dust mite intestine.

pineapple

Uncooked figs and papaya also have a similar proteolytic enzyme. This means if you try to make jelly (Jell-O in the US) with pineapple it will not set because it breaks down the gelatin protein and stops it working. You can use fresh (not canned) pineapple juice as a marinade to make meat more tender – be careful, or the meat will end up as a sloppy mush.

*eosinophils also have a peroxidase like neutrophils, but eosinophil peroxidase preferentially combines hydrogen peroxide with bromide, to produce hypobromite, which is presumably more effective in killing worms than hypochlorite.

Vodka and sweetbreads

Drinking too much is becoming a big problem in our admissions unit. We used to see alcohol problems occasionally, now we see them a lot. Today we admitted Kevin, age 44. He had been drinking at least a bottle of vodka every day for the past year or more.

vodka and tonic

His friend called the ambulance because Kevin had terrible upper abdominal pains and vomiting. He didn’t want to come into hospital because he knew he would not get his vital vodka, but relented when he realised that he could not drink anything without throwing up. The problem was that he had acute pancreatitis caused by his drinking.

As soon as he arrived in the emergency department an intravenous cannula was put in and he was given Pabrinex, intravenous fluids and morphine.

pabrinex

Pabrinex is the trade name for a combination of vitamins, mostly  B vitamins, and importantly it contains lots of vitamin B1 or thiamine. It is bright yellow because it contains vitamin B2, also known as riboflavin which is widely used to colour food and drinks such as orange juice (E number 101). If you take too many B vitamin supplements the riboflavin can make your urine a fluorescent bright yellow.  But thiamine is the important one.

We are really keen to make sure that alcoholics get thiamine as soon as they arrive in hospital. Without it they can suffer permanent brain damage.

Kevin is addicted to, and dependent on alcohol. That means he feels very unwell if his blood alcohol levels fall to near zero, so he must keep his intake enough to make sure that does not happen.

Alcohol is removed from the body in a different way from most other substances. Usually the rate at which a chemical such as a drug is removed from the body is dependent on the amount of drug present. To put it another way, the rate of elimination depends on the concentration in the blood. High concentrations mean that every hour a lot is removed, low concentrations much less is removed.

Bucket hole 2

The normal way things work with drug elimination is the bucket-with-a-hole-in-the-bottom method.  When the bucket is full, water gushes out of the hole quickly, but when nearly empty comes out in a trickle – this is called first order metabolism. But alcohol is not handled in this way – if it was it would be a disaster. Alcohol, or ethanol to give its proper chemical name is first turned into ethanal (also known as acetaldehyde) and then ethanoic acid (aka acetic acid). Both ethanal and ethanoic acid are pretty toxic.

Bucket ladle

Ethanol is not metabolised by first-order metabolism, but by zero-order metabolism. The bucket analogy now is to think of someone with a ladle who scoops out a measure of water from the bucket every 10 seconds. The rate at which the bucket empties now is not dependent on the amount in the bucket, but on the size of the ladle. This is a safe way to metabolise ethanol because it limits the amount of ethanal and ethanoic acid which can accumulate – not enough to do serious damage.

Ethanol-2

Have you ever noticed the guy asleep on the floor at the end of the party who has drunk so much that he can’t get himself home? Next time look at his breathing pattern – he will have slightly rapid, deep, and sighing respiration. This is known as Kussmaul breathing and is due to the large amounts of acetic acid being produced from the alcohol he has inadvisedly drunk. (Although I note that the person who has written the Wikipedia article on Kussmaul’s respiration says that this term only applies to those patients about to die from acidosis – not how it is used in most medical wards – perhaps a bit of a pedant?). If the alcohol was being metabolised by a first-order hole-in-the-bucket process he would not survive.

How big is the ladle? – various authorities suggest this is between 10-15 mls of alcohol per hour. If we take the lower figure this equates to 1 unit of alcohol per hour. That means Kevin has to drink 240mls of ethanol every day to keep enough on board to keep his brain happy.  Most vodka in the UK is 40% alcohol by volume. So an average 750ml bottle contains 300mls alcohol – that will do nicely!

The problem is that this 300mls of alcohol has a lot of calories. 300mls is 240 grammes (the specific gravity of ethanol is about 0.8). Each gramme of alcohol provides about 7Kcal so the bottle of vodka has about 1600Kcal of energy. Given that Kevin drinks his vodka with tonic water, which provides 150Kcal/day, and that his requirement to maintain normal weight is 1800Kcal/day suggests that he does not eat many other calories. He admits this.

It reminds me of the Glasgow vegetarian diet – 15 pints of heavy and 2 packets of crisps.

The serious point is that if someone is truly dependent on alcohol, they will be seriously malnourished. Vodka and tonic is not a balanced diet (no, it really isn’t). There are all sorts of nutritional problems that alcoholics encounter, but one really important one is irreversible brain damage due to thiamine deficiency.

What is thiamine, and why does deficiency cause brain damage? Thiamine is vitamin B1, present in many foods, and if you have a varied diet you will not become thiamine deficient. It is important as a co-factor in a number of enzyme reactions, particularly those of the Kreb’s cycle which produce energy from carbohydrates, protein and fats (and alcohol). The brain and heart use more energy than other organs and are therefore more susceptible to thiamine deficiency, causing cerebral beri-beri (Wernicke’s encephalopathy) and wet beri-beri (congestive heart failure).

There is a wonderful, if somewhat disturbing, paper from 1947 by Hugh de Wardener which helped convince the world that thiamine deficiency causes brain damage.

Dr de Wardener was sent to Singapore in 1942, just before the Japanese completely overran the peninsula and captured 80,000 allied troops. They were marched to the notorious Changi POW camp – see

http://www.historylearningsite.co.uk/changi_pow_camp.htm

and

http://www.abc.net.au/changi/life/default.htm

He became a medical officer at Changi, when large numbers of British servicemen were only given small amounts of white rice (with weevils) instead of their usual rations. This, combined with dysentery meant that large numbers succumbed to thiamine deficiency.

thiamine oil

Thiamine keeps the Kreb’s cycle going – you can think of it like a lubricant to keep the wheel turning. When it runs out the Kreb’s cycle comes to a juddering halt. We need about 1mg/day to do this – not much but we absolutely need it. Our bodies can store about 50mg of thiamine, so after about 6 weeks the prisoners of war became ill. They developed the classical signs of Wernicke’s encephalopathy – confusion, nystagmus (wobbly eyeballs), diplopia (double vision) and ataxia (unsteadiness and incoordination). A large number died

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Professor Hugh De Wardener MBE

Dr de Wardener realised that this was an unparallelled opportunity to study the effects of thiamine deficiency – not something you could ethically do in humans now. He and his colleagues carefully described the clinical features of soldiers suffering from thiamine deficiency, or beri-beri, and when they died, pickled parts of their brains in the small amount of formalin they had available.

Slide0001

The mammilliary bodies are particularly prone to damage by thiamine deficiency. 

When it was clear that the Japanese were in danger of losing the war, the enemy were determined that all records of what had happened at Changi should be destroyed. Hugh de Wardener realised that his precious medical notes were at risk, and he buried them 2-3 feet deep in a recent grave, along with the post-mortem brain specimens, in a 4 gallon tin which was sealed and soldered shut. The tin was later recovered, taken back to England and the paper was written. Pictures of the brain specimens are in the paper. I could not find a free fulltext version on the internet, but suggest you get your library to order it if you can – it is a fascinating read:

De Wardener, H. E. and Lennox, B. (1947) Cerebral beriberi (Wernicke’s Encephalopathy): review of 52 cases in a Singapore prisoner-of-war hospital. Lancet 1, 11 – 17.

I can’t talk about thiamine deficiency and brain damage without mentioning Korsakoff’s psychosis. This is a truly debilitating long-term loss of memory which is vividly described in Oliver Sack’s book “The man who mistook his wife for a hat”. If you have not read this book you need to buy or borrow it, but would warn that you should not plan to do anything important for the following day or two because you will not be able to put it down.

Kevin’s pancreas was damaged by too much alcohol, because ethanol is metabolized to ethanal which damages protein – much the same way that formalin (properly known as methanal) was used by Hugh de Wardener to preserve his brain specimens.

I regularly eat lamb pancreas. It is sold by my butcher as sweetbreads.

Seared lamb sweetbread in a skillet.

Salivary glands, thymus and testicles are also called sweetbreads and taste very much the same as pancreas, and they all look quite similar when viewed under the microscope. Perhaps its not surprising that the three glands which are attacked by the mumps virus are salivary glands, pancreas and testicles. Mumps virus likes them all raw. I’ve never tried testicles but  I like pancreas gently fried in butter on toast with a dribble of balsamic vinegar.

Phlegm and Horseradish

This week I’m carrying on with the theme of colours in medicine. Today we saw Janet. She is a 55 year old enthusiastic smoker who had been sent up to the emergency department because she was short of breath and had bad pain in the right side of her chest when she coughed or breathed in deeply.

“I’m coughing up some really nasty green phlegm” she told us.

I love the word phlegm.  So much better than the usual word usually used by doctors – sputum, because it is understood by patients and means much the same.  So many of the words we use in medicine are Latin or Greek, presumably designed to suggest we know more than we really do.  I tried an experiment of banning Latin and Greek words on the ward round when there is an English equivalent. It didn’t last long. Abdomen was replaced by “belly”, sternum became “breastbone”, tumour was “lump”, but many terms like myocardial infarction became too cumbersome and imprecise – “death of heart muscle due to lack of blood supply”. Also, phlegm means something else – there is a wonderful quote by one of my heroes in medicine, William Osler, at  the end of this blog about why doctors need it.

Anyway, back to Janet. We looked in the sputum pot Janet had been using and indeed there was a big, greenish-gray glob of phlegm. Slightly to the consternation of the young doctor with me, I turned the pot upside down – the glob remained stuck to the bottom .

At this point I normally ask one of two really interesting questions:

“Why is infected sputum green?”

“Why does it stick to the bottom of the pot?”

We will only have time for the first one today. The most common answer I get is that the bacteria are green. That is not the case. It is white cells (polymorphonuclear leukocyes, polymorphs or neutrophis) in the phlegm which turn green when they get angry (much like the Incredible Hulk).

neutrophi 2

Neutrophils cruising around the circulation looking for action

If you look at infected sputum under the microscope, it is stuffed full of neutrophil leukocytes. They are truly professional at killing bacteria and get very angry when they find them. How do they know they are there? When the lung cells are attacked by germs they send out chemical signals called cytokines (such as interleukin 8). Neutrophils respond to this “help! I’m being attacked!” signal by following the cytokine scent. They normally cruise around in the circulation but when they “smell” the cytokine they follow where it has come from. This gets them quite excited. What gets them more excited is when they “smell” bacteria. They hunt them down and engulf them. There is a wonderful youtube video of neutrophils chasing and eating bacteria to a Benny Hill theme tune:

http://www.youtube.com/watch?v=KxTYyNEbVU4

When they have caught and trapped enough bacteria they get really angry. In fact suicidally angry. They undergo what is known as “respiratory burst”. This involves the activation of three enzymes; NADPH oxidase, superoxide dismutase (SOD) and myeloperoxidase (MPO). Ordinary, harmless oxygen is made into the slightly nastier superoxide by NADPH oxidase, and this is then turned into the more nasty hydrogen peroxide by superoxide dismutase. Whereas hydrogen peroxide is not pleasant for bacteria, their tiny evil forms will quake when around them everything turns green. The Incredible Hulk in the form of the lurid green MPO is after them.

Neutrophil 3

MPO is an enzyme which is green because it contains haem, a complex but common iron-containing chemical arrangement that is used in a whole range of useful and colourful biological molecules, such as haemoglobin and liver enzymes which inactivate drugs (p450s). The purpose of MPO is to convert hydrogen peroxide into hypochlorite by combining with a chloride anion. Hypochlorite is a really nasty chemical which is intended to deal the final blow.

Most homes have a bottle of hypochlorite under the kitchen sink or in the bathroom cupboard – Domestos in the UK or Chlorox in the US. And as the adverts say – it kills 99% of all household germs….Dead!

domestos

Now give a thought for the poor neutrophil. In all that excitement it produced enough hypochlorite to kill not only 99% of germs but also to kill itself. But just when you thought that it had completely disintegrated with its own toxic, green chemical soup, the neutrophil comes up with a new trick, Terminator fashion. It forms a net around the debris to stop the remaining 1% of germs from getting away. The net is made from dead neutrophil DNA and other stringy compounds, and is thought to be important in both stopping the evil germs that have survived escaping and protecting surrounding host tissue from the damage. Understanding this has given me a renewed respect for neutrophils – determined, courageous and willing to give up their lives to save the world, even using their dead bodies to inflict more damage on the enemy and protect their gene-identical brother and sister cells.

You can learn more about neutrophil nets from the paper which first described them:

http://www.sciencemag.org/content/303/5663/1532.abstract

You will have to register but it is worth it.

In the title I promised horseradish. All horseradishes contain several haem–containing peroxidases, and it seems that when the plant is attacked by insects (or people) this enzyme is activated and will generate bleach-like molecules which contribute to its famous hot and burning taste. So next time you eat wasabe (a particularly potent type of Japanese horseradish), give a thought to how those bacteria feel when being attacked by neutrophils.

wasabe

These are wasabe peas. I would suggest you don’t eat more than two or three at once. Is wasabe  green because it contains loads of haem containing peroxidase? I’d like to think so but maybe you could let me know.

The quote from William Osler:

“Imperturbability means coolness and presence of mind under all circumstances, calmness amid storm, clearness of judgment in moments of grave peril, immobility, impassiveness, or, to use an old and expressive word, phlegm. It is the quality which is most appreciated by the laity though often misunderstood by them; and the physician who has the misfortune to be without it, who betrays indecision and worry, and who shows that he is flustered and flurried in ordinary emergencies, loses rapidly the confidence of his patients” From Aequanimitus, William Osler 1889. See full text at:

http://www.medicalarchives.jhmi.edu/osler/aequessay.htm