Monday, 30 May 2011

Nocturnal asthma

went down with a cold last week, the first day I was up at 2am all bunged up, coughing, and struggling to breathe. As I was sleepily sipping on my hot lemon and honey I remembered that I'm not alone - a lot of people have breathing difficulties at night.  In fact, I'm really lucky that I do not have asthma, as most asthmatics have a lot of difficulties breathing during the night. A survey of 7729 asthmatics in the 1980s showed that 94% had woken up in the night at least once in that month with difficulty breathing [1].
Many asthmatics have to take preventative medication before bedtime 
(c) Luke Morgan 2011

What causes this nocturnal asthma? Is it caused by our sleeping environment, or is there something innate about our body clock that intensifies breathing difficulties at night?

Our sleeping environment can make things worse. Allergens on our pillows (or teddy bears) can cause asthma attacks, even up to four days after contact. Then there's our position when we're sleeping, lying flat compresses our airways making it harder to breathe. Even cold bedroom temperatures have been known to trigger asthma attacks.

However, asthma is a textbook example of how the time of day affects our physiology. There are daily changes in many body rhythms that make breathing between the hours of midnight and 8am much harder. Two important hormones involved in healthy airway maintenance are cortisol and adrenaline. 

During the day adrenaline relaxes the muscles around the airway and cortisol reduces swelling, making breathing easier. At night, our body releases lower levels of both of these hormones, causing airway muscles to constrict and swell. This makes breathing at night harder. 

Daily changes in cortisol and adrenaline in healthy individuals at rest, adapted from Sheer, 2010 [2]

The implications of this hormone change in normal people causes a detectable, but low, amplitude change in the day/night variation of airway function. However, in asthmatics the the rhythm in airway function has a greater amplitude, making them more vulnerable to breathing difficulties at night [3].

One way to measure our lung capacity is to record peak flow. The higher a person’s peak flow the better their lungs are. One study in 1980 looked at the peak flow of normal and asthmatic sufferers throughout the day and night [4]. In the afternoon and early evening the peak flow was the highest in both normal and asthmatics. However, the asthmatic sufferers had far lower peak flow measurements during the night: a 50% difference in their best and lowest peak flow compared to only 8% in a non-asthmatic.

Asthma does not occur randomly over a 24 hour period, it is much more likely to attack during the night in most sufferers. There is still a lot to be investigated about the causes and types of asthma attacks that occur during the night. However, if you are constantly bothered by nocturnal asthma attacks, speak with your GP. By ensuring your asthma medication protects you during the night, you can avoid attacks and get a better night’s sleep.

References

[1]    M. Turner-Warwick, “Epidemiology of nocturnal asthma,” The American Journal of Medicine, vol. 85, 1988, pp. 6-8.
[2]    F. a J.L. Scheer, K. Hu, H. Evoniuk, E.E. Kelly, A. Malhotra, M.F. Hilton, and S. a Shea, “Impact of the human circadian system, exercise, and their interaction on cardiovascular function.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, Nov. 2010, pp. 20541-20546.
[3]    M. Smolensky and L. Lamberg, The body clock guide to better health, Holt Paperback, 2000
[4]    M.R. Hetzel and T.J. Clark, “Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate.,” Thorax, vol. 35, Oct. 1980, pp. 732-8. 

Tuesday, 10 May 2011

Pimm’s all around the clock. Alcohol and Body Clocks Part 2


Chatting to a scientist at a party

When at a party and asked about body clocks alcohol is a great example to explain how our bodies respond to drugs differently at different times of the day (and no-one wants to be stuck talking to a scientist who doesn't have fun facts about their research). In Part 1 I've explained how our body clock can change how we respond to alcohol, but the same also works in reverse: alcohol affects our body clock with both short-term and long-term consequences.

Alcoholics often suffer from mood and sleeping disorders, and this could be exacerbated by how their own body clocks are damaged by chronic alcohol abuse.

Scientists look at the hormone melatonin to monitor body clocks. Melatonin is normally released only at night, and can be measured from urine samples, so it is a good and reliable indicator of an individual's clock time. In chronic alcoholics, their melatonin secretion is completely reversed: they produce it during the day! [1]

Melatonin rhythms are not affected in non-alcoholic healthy adults that drink alcohol [2], however, alcohol can still have a short-term disruption on body temperature rhythms. Normally, there is a 24-hour change in our core body temperature, dipping to its lowest of 36°C at 4am, and peaking during the day at around 37°C. Our body tries to keep to these temperatures by sweating when it's hot and shivering when it's cold etc.

Alcohol is thought of as a hypothermic agent, it makes your body cold, and hypothermia is an indicator of alcohol toxicity. Oddly however, taking alcohol at night time (when you should be asleep) raises body temperature. Drinking alcohol can change your body temperature's 24-hour profile.

A study was done on 9 healthy, non-alcoholic males, who had the arduous job of lying in bed all day and hourly either taking fruit juice or fruit juice and ethanol (to try and make it so they wouldn't know which they were taking). Their core body temperature was measured every 20 minutes (the old-fashioned rectal way), and it clearly shows that alcohol during the day lowers body temperature, but at night alcohol raises body temperature [3].


Alcohol changes the body clock's 24 hour temperature profile. Adapted from Danel, 2001

This is an excellent example of why a drug should be tested for its effects on the body with a complete 24 hour profile, not just seeing what its effect is during the day. For users, it warns us to be careful when drinking during the early hours, or even when our body thinks it's the early hours of the morning, such as shortly after a transmeridian flight. The effects of alcohol are not the same during the day and the night.

To sum up: body clocks can alter how we can tolerate alcohol, but alcohol in turn can alter our body clock.

[1]    G. Murialdo, U. Filippi, P. Costelli, S. Fonzi, P. Bo, A. Polleri, and F. Savoldi, "Urine melatonin in alcoholic patients: a marker of alcohol abuse?," Journal of endocrinological investigation, vol. 14, Jun. 1991, pp. 503-7.
[2]    T. Danel and Y. Touitou, "Alcohol consumption does not affect melatonin circadian synchronization in healthy men.," Alcohol and alcoholism (Oxford, Oxfordshire), vol. 41, 2006, pp. 386-90.
[3]    T. Danel and C. Libersa, "The effect of alcohol consumption on the circadian control of human core body temperature is time dependent," Am J Physiol Regul Integr Comp Physiol, 2001, p. R52-R55.

 

Tuesday, 3 May 2011

Pimm’s o’clock: Alcohol and the body clock Part I



Lunchtime drinking

Our bodies can tolerate alcohol better in the early evening. A pint at lunchtime will make you feel drunk faster than the same pint taken later in the day.

In 1941 the first link to alcohol was reported in the scientific literature, this paper showed that alcohol was removed slower from the body during sleep. [1]

Then in 1956 results showed that the metabolism of alcohol, how it is broken down, was affected by the body clock [2]. 5 lucky test subjects drank whiskey hourly for 2 days whilst the amount of alcohol in their blood and saliva was tested. There was a clear change in how fast their bodies were breaking down the alcohol so it could be removed from the body.

Many further experiments were carried out in the 1960's to 80's confirming these results, one can only imagine they had plenty of undergraduate students signing up as trial subjects.

Alcohol drunk in the morning is metabolised by your liver faster, and reaches your blood earlier, making you feel drunk faster, than if you had the same amount to drink in the early evening [3].


Blood alcohol levels are higher when drinking during the day. Adapted from Yap, 1993.

So how does the liver change its way that it breaks down alcohol? We think this is due to changing the concentration of an enzyme that metabolises alcohol, alcohol dehydrogenase. Experiments in rodents show that this enzyme is affected by the body clock [4]. It seems that our bodies have evolved to produce less of this enzyme later in the day, so we are able to tolerate alcohol better later in the day.

So bear in mind the next time you have a pint down the pub at lunchtime, you'll probably only need a half.

References:

[1]    T. Danel and Y. Touitou, "Chronobiology of Alcohol : From Chronokinetics to Alcohol-related Alterations of the Circadian System," Chronobiology International, vol. 21, 2004, pp. 923-935.
[2]    R.H.L. Wilson, E.J. Newman, and H.W. Newman, "Diurnal variation in rate of alcohol metabolism," Journal of Applied Physiology, vol. 8, 1956, p. 556.
[3]    M. Yap, D.J. Mascord, G. a Starmer, and J.B. Whitfield, "Studies on the chronopharmacology of ethanol.," Alcohol and alcoholism, vol. 28, Jan. 1993, pp. 17-24.
[4]    F. Salsano, I.P. Maly, and D. Sasse, "The circadian rhythm of intra-acinar profiles of alcohol dehydrogenase activity in rat liver: a microquantitative study," The Histochemical Journal, vol. 22, Aug. 1990, pp. 395-400.

 

Sunday, 1 May 2011

The Sleepless Days Blog

I first became passionate about body clocks and circadian biology when I was an undergraduate at University of Surrey, studying Biochemistry & Pharmacology. For 3 years I had been studying at length the effects of drugs and how they interact with the body, learning all the tiny details about their composition and the intricate ways they act on other molecules (let alone something as large as an organ). 

Then, in my final year I was introduced to a simple and yet profound concept: the time of day a drug is taken matters. 

During 24 hours our body temperature, blood pressure, alertness, metabolism, and many other bodily functions, changes from the very high to the very low. For example, our livers can tolerate alcohol better in the evening than the morning.

What?! So here we are trialling many drugs, testing them on patients that come into clinics during the day between 9-5. Trial results might deem a drug completely useless or harmful, but if it was given at night it might be the next cure for cancer! 

The really great thing about timing drug delivery is that a drug will usually be most effective at a time that it will produce least side effects. Wouldn’t it be great if all drugs tested were also analysed for the effect of time of day on their actions.

Circadian biology also makes sense. Our bodies need to be able to respond differently at different times of day, to anticipate changes in our environment. Ideally, we are sleepy at night time, alert during the day, and hungry at meal times. 

We are increasingly becoming aware of the effect of disrupting our body clocks such as the effects of night shift working, jet lag, and general living in a 24 hour society. There is still a lot to learn and be investigated by scientists.

So after finishing my undergraduate studies, I started a PhD at UCL to study and learn more about body clocks. I thought I would start this blog to share my growing knowledge (or increasing ignorance) about the body clock field. We all notice when we have sleepless nights, but do we appreciate why we have sleepless days?

The 24 hour clock at the Greenwich Observatory, London