Big Brains Make Big Demands.

Brains are demanding organs; big brains dominate the biology of life-forms that develop them.

Like computers, brains must have an uninterrupted power supply, and a constant environment.

Unlike computers, brains cannot be switched off and rebooted.

Glucose is the energy source of the human brain. Our brains must have an uninterrupted supply of glucose, and lots of it. The brain is permanently damaged within a few minutes if the flow of glucose fails. This why hypoglycaemia - blood glucose below 3 mMolar - is dangerous, and below 1 mMolar, an emergency.

But hyperglycaemia - too much glucose in the blood - is also damaging to the brain, but in a different way, over a much longer time, and to kidneys, retinae, heart and other organs as well. 

Glucose is an aldehyde, it is chemically active, it has toxicity. In particular its aldehyde reacts with amine groups, forming Schiff bases, a process called glycosylation. Proteins have amine groups, and are vulnerable.

Blood glucose values persistently above 10 mMolar increase the glycosylation of basement membrane proteins, so damaging capillaries, especially in the retina and kidney.

In clinical practice the percentage glycosylation of haemoglobin is a useful guide to the severity of a patient's diabetes, and the degree of control achieved.

In normal human blood the glucose concentration is between 3.5 and 10 mMolar for at least 95% of the time. Values sustained above 10 mean diabetes mellitus. That normal range is presumably a biological trade between glucose concentrations needed to fuel the brain, and keeping glycosylation within safe limits.

Glucose concentrations are important, but glucose flow into brain and other organs is what matters, and that is much more difficult to evaluate.

On a conventional British diet most blood glucose comes from starch. Regulation of blood glucose is a function of the liver in particular, controlled by insulin secreted by the islet cells in the pancreas. Other hormones affect the blood glucose, notably glucagon, adrenaline and corticosteroids, but insulin is the most powerful.

Increasing blood glucose stimulates insulin secretion into the portal vein, to go straight to the liver. The liver extracts maybe a third of all insulin secreted.

Insulin directs the liver to take up glucose from the blood, for storing in liver cells as glycogen, 'animal starch', a polymer of low solubility. In a well-nourished person liver glycogen may be as much as 10% of liver weight.

Insulin secretion ceases if blood glucose concentrations fall. Without insulin the liver breaks down glycogen, to release glucose into the blood and prevent hypoglycaemia. As liver glycogen is depleted the liver begins to make glucose from protein, a process called gluconeogenesis. If glycogen is exhausted then gluconeogenesis is vital to maintain glucose flow to the brain.

The brain does not need insulin. It takes glucose from the blood as it requires, and presumably under its own control. It cannot store glucose in any quantity - it lives in an enclosed space.

Muscle needs insulin to take up glucose, and can store limited amounts as glycogen in muscle cells. Muscle glycogen is for muscle only: it cannot be excreted from muscle to support blood glucose in times of need. In starvation muscle is an important source of protein for liver gluconeogenesis.

Reduced muscle sensitivity to insulin is an important factor in type 2 diabetes mellitus.

Fat also needs insulin to take up glucose, but metabolizes it to fat components. As with muscle, glucose uptake by fat is irreversible.

The distribution of glucose between liver, brain, muscle and fat varies with diet, exercise and other factors, but the brain has priority in glucose disposal.

Carnivores must depend on gluconeogenesis to supply their brains with energy. Food protein is limited, so thrifty animals will be at a selective advantage. Maybe that is why cats sleep a lot, conserving resources for intense brain work during hunting, or defending territory.

Dolphins have large brains, and depend on fish protein for gluconeogenesis. It is interesting that they develop a transient diabetic state while fasting, with increased blood glucose. It may be they can adjust muscle insulin sensitivity in response to feeding. Well fed their livers  deliver glucose enough for the big hungry brain and muscle; while fasting the brain has priority, glucose uptake in muscle is regulated down.

It would be interesting to know if other carnivores can do this, if indeed humans might do it under special circumstances. Could failure to regulate such a facultative state become type 2 diabetes?

Women and Tobacco.

My posting on this topic is here.

Good News for Buruli Ulcer

I first saw cases of Buruli Ulcer in Agogo Hospital, in Ashanti Region, in Ghana. I was shaken by what I saw.

Buruli Ulcer is a serious skin disease afflicting poor, rural people, notably children and teenagers. It occurs in wet tropical regions; in West Africa, Uganda, East Africa, South-East Asia, New Guinea, Australia, and Central and South America. Its prevalence seems to be increasing in most areas.

Pictures of the disease can be found here - beware, they are distressing.

Death from Buruli Ulcer is uncommon. Ulcers may become huge, but are usually painless and not smelly. Most cases eventually heal, but after months of activity, and leaving extensive scarring with deformity, contractions, and disability. Buruli Ulcer on the face may threaten eyes, mouth or ears; on the lower trunk the genitals are at risk; and an ulcer crossing a joint may leave a limb or hand useless.

Buruli Ulcer is caused by infection by Mycobacterium ulcerans. This is a bacterium related to the Mycobacteria causing tuberculosis and leprosy.

It is likely that M. ulcerans comes from stagnant water or mud. Skin is contaminated, and the bacteria are inoculated by thorn stabs, insect bites or other trauma. This may explain a curious excess of right-sided disease - inoculation occurring while people are working or pushing forward through vegetation.

But the mode of transmission is not established.

Inoculated M. ulcerans multiply in the panniculus adiposus - the layer of fat which underlies the skin. Destruction of fat cells undermines the skin, which breaks down to expose the fascia - the fibrous sheath covering the underlying muscle, bone and other tissues.

The initial lesion is an itchy lump under the skin. In many cases this heals without ulcerating. As in other mycobacterial diseases, most infected people mount a successful immune defence and contain the disease.

But immunity fails in a minority, for reasons not well understood, and serious progressive disease may ensue. The lump becomes a plaque, the plaque becomes an ulcer, and the ulcer grows. At any point immunity may pick up, and healing begin, but great damage can be done before this happens.

For many years the only treatment was dressings and surgery: excision of smaller ulcers, otherwise removal of as much diseased tissue as possible, and maybe skin grafting. A need for skin grafting is always bad news; in a rural hospital in hot, humid areas it is difficult at best, and often impossible.

Now there is good news, published in The Lancet. Buruli Ulcer responds to treatment with rifampicin and streptomycin, and rifampicin and clarithromycin. Streptomycin has to be given by injection; rifampicin and clarithromycin are given orally.

The new work is a controlled trial, completed with commendable thoroughness in difficult circumstances. It shows that an effective protocol is streptomycin and rifampicin for one month, then rifampicin and clarithromycin for a second month. This reduces the need for injections.

Healing occurred in more than 90% of patients, but still needed months of observation and dressing after the drug course was completed.

Obviously best results come with early diagnosis, prompt prescription, and persistent follow-up.

And big neglected ulcers will still need surgery, if possible.

But at last there is progress in management of this dreadful disease, and hope for the thousands of poor people afflicted by it every year. Let the message be spread through the villages: if you get an ulcer, don't delay; come to the hospital for treatment.

And I hope WHO, governments or charities will fund drug provision without question.

Willemien Nienhuis, her colleagues, and the project leader, Tjip van der Werf merit congratulation and recognition for their important achievement.

My small contribution is to award them the Kataphusin Prize for the most important contribution to the management of neglected diseases in the past year.

Measles and the Papacy

So, Pope Benedict will visit Britain later this year (DV).

Pope John Paul II visited in May 1982. He celebrated an open-air mass on Coventry airfield. It was planned to be a huge event, with hundreds of thousands expected to attend.

A local military unit set up a field hospital. An RC colleague organised medical cover, and asked me to volunteer to be there in case of emergency. I accepted, and spent the day in the field hospital.

An anaesthetist colleague was tasked to follow the Pope at a discrete distance, carrying an emergency bag of resuscitation equipment.

It was a hot day, but the numbers attending were much less than anticipated, in tens, not hundreds, of thousands. I had only a distant view of the occasion; the hospital was away to one side of the airfield. I spent much of the day admiring the tents, equipment and vehicles of the hospital.

There was a slow flow of people needing some medical attention: faints, sickness, sunburn. One middle aged man was suspected of acute myocardial infarction, and was sent on to hospital without delay.

Then, about mid-afternoon, I was asked to see a boy of maybe 7. I heard him cough before I saw him. His mother was anxious. He had been hot and off-colour when he got up, but the family had decided to come. During the day he had got worse, complaining of shivering, headache, and coughing.

He was flushed and hot, with pink conjunctivae. He sneezed several times. His chest sounded a little musical. Otherwise general examination showed little of note

But, looking in his mouth, I found small pink spots on the inside of the cheeks. Each spot had a tiny white centre, like a grain of salt.

Koplik's Spots: this was measles, in its early stage. The rash would appear the next day.

Take him home to bed, lots to drink, maybe a junior aspirin if he became too hot. Call the general practitioner tomorrow for a home visit.

Two other children in the family, younger, neither had had measles. More trouble ahead: expected incubation about 10 days.

Measles is very infectious: all other children to stay away.

I think that was the last time I saw measles in Britain; for sure it was the last time I saw Koplik's spots.

I may be in the last generation of doctors familiar with measles.

Measles vaccination has stopped the biennial epidemics; only sporadic cases occur now, in unimmunised children and young adults.

Measles is a nasty illness, causing much discomfort and distress. It is not a mild passing infection of young children. It has a significant risk of complications, notably otitis media and bronchitis; and encephalitis, rare maybe, but always serious, often fatal.

In the tropics it has been a major killer of children. Europeans brought measles to America, with devastating consequences for some indigenous peoples.

Measles vaccination is a wonderful advance in childrens' health. It is safe and effective. Measles is not extinct, and may never be. All children should be protected.

No-one familiar with measles will question the benefits of immunisation.

Let us petition the Pope. Maybe he could conduct a service of thanksgiving for the blessing of immunisation, and for the medical science which created it.

It would surely reflect well on the papacy if he did.