If you live in (most places in) the United States as well as many other countries, you have reset your clocks back by one hour last night (or last week). How will that affect you and other people?
One possibility is that you are less likely to suffer a heart attack tomorrow morning than on any other Monday of the year. Why? Let me try to explain in as simple way as possible (hoping that oversimplification will not lead to intolerable degrees of inaccuracy).
Almost all biochemical, physiological and behavioral parameters in almost all (at least multicellular) organisms display diurnal (daily) rhythms and most of those are directly driven by the circadian clock (or, more properly, by the circadian system). Here is an old and famous chart displaying some of the peaks (acrophases) of various physiological functions in the human:
It may be a little fuzzy, but you can see that most of the peaks associated with the cardiovascular function are located in the afternoon. The acrophases you see late at night are for things like "duration of systole" and "duration of diastole" which means that the Heart Rate is slow during the night. Likewise, blood pressure is low during the night while we are asleep.
Around dawn, heart rate and blood pressure gradually rise. This is a direct result of the circadian clock driving the gradual rise in plasma epinephrine and cortisol. All four of those parameters (HR, BP, Epinephrine and Cortisol) rise roughly simultaneously at dawn and reach a mini-peak in the morning, at the time when we spontaneously wake up:
This rise prepares the body for awakening. After waking up, the heart parameters level off somewhat and then very slowly rise throughout the day until reaching their peak in the late afternoon.
Since the four curves tend to be similar and simultaneus in most cases in healthy humans, let's make it easier and clearer to observe changes by focusing only on the Cortisol curve in the morning, with the understanding that the heart will respond to this with the simultaneous rise in heart rate and blood pressure. . This is how it looks on a day when we allow ourselves to wake up spontaneously:
But many of us do not have the luxury of waking up spontaneously every day. We use alarm clocks instead. If we set the alarm clock every day to exactly the same time (even on weekends), our circadian system will, in most cases (more likely in urban than rural areas, though), entrain to the daily Zeitgeber - the ring of the alarm-clock - with a particular phase-relationship. This usually means that the rise in cardiovascular parameters will start before the alarm, but will not quite yet reach the peak as in spontaneous awakening:
The problem is, many of us do not set the alarm clocks during the weekend. We let ourselves awake spontaneously on Saturday and Sunday, which allows our circadian clock to start drifting - slowly phase-delaying (because for most of us the freerunning period is somewhat longer than 24 hours). Thus, on Monday, when the alarm clock rings, the gradual rise of cortisol, heart rate and blood pressure will not yet be as far along as the previous week. The ring of the alarm clock will start the process of resetting of the circadian clock - but that is the long-term effect (may take a couple of days to complete, or longer.).
The short term effect is more dramatic - the ring of the alarm clock is an environmental stressor. As a result, epinephrine and cortisol (the two stress hormones) will immediately and dramatically shoot up, resulting in an instantenuous sharp rise in blood pressure and heart rate. And this sharp rise in cardiovascular parameters, if the heart is already damaged, can lead to a heart attack. This explains two facts: 1) that heart attacks happen more often on Mondays than other days of the week, and 2) that heart attacks happen more often in the morning, at the time of waking up, than at other times of day:
Now let's see what happens tomorrow, the day after the time-change. Over the weekend, while you were sleeping in, your circadian system drifted a little, phase delaying by about 20 minutes on average (keep in mind that this is an average - there is a vast variation in the numerical value of the human freerunning circadian period). Thus, your cardiovascular parameters start rising about 20 minutes later tomorrow morning than last week. But, your alarm clock will ring an entire hour later than last week - giving you an average of a 40-minute advantage. Your heart will be better prepared for the stress of hearing the ringing than on any other Monday during the year:
Now let's fast-forward another six month to the Spring Forward weekend some time in March or April of next year. Your circadian system delays about 20 minutes during the weekend. On top of that, your alarm clock will ring an hour earlier on that Monday than the week before. Thus, your cardiovascular system is even further behind (80 minutes) than usual. The effect of the stress of the alarm will be thus greater - the rise in BP and HR will be even faster and larger than usual. Thus, if your heart is already damaged in some way, your chances of suffering an infarct are greater on that Monday than on any other day of the year:
This is what circadian theory sugests - the greater number of heart attacks on Mondays than other days of the week (lowest during the weekend), the greatest number of heart attacks on the Monday following the Spring Forward time-change compared to other Mondays, and the lowest incidence of heart attacks on the Monday following the Fall Back time-change compared to other Mondays.
A couple of days ago, a short paper appeared that tested that theoretical prediction and found it exactly correct (Imre Janszky and Rickard Ljung, October 30, 2008, Shifts to and from Daylight Saving Time and Incidence of Myocardial Infarction, The New England Journal of Medicine, Volume 359:1966-1968, Number 18.). The authors looked at a large dataset of heart attacks in Sweden over a large period of time and saw that (if you look at the numbers) the greatest number of heart attacks happens on Mondays compared to other days of the week (and yes, the numbers are lowest during the weekend), the greatest number of heart attacks occur on the Monday following the Spring Forward time-change compared to Mondays two weeks before and after, and the lowest incidence of heart attacks happens on the Monday following the Fall Back time-change compared to Mondays two weeks before and after:
Thus, the predictions from the circadian theory were completely and clearly correct. But I was jarred by the conclusions that the authors drew from the data. They write:
The most plausible explanation for our findings is the adverse effect of sleep deprivation on cardiovascular health. According to experimental studies, this adverse effect includes the predominance of sympathetic activity and an increase in proinflammatory cytokine levels.3,4 Our data suggest that vulnerable people might benefit from avoiding sudden changes in their biologic rhythms.
It has been postulated that people in Western societies are chronically sleep deprived, since the average sleep duration decreased from 9.0 to 7.5 hours during the 20th century.4 Therefore, it is important to examine whether we can achieve beneficial effects with prolonged sleep. The finding that the possibility of additional sleep seems to be protective on the first workday after the autumn shift is intriguing. Monday is the day of the week associated with the highest risk of acute myocardial infarction, with the mental stress of starting a new workweek and the increase in activity suggested as an explanation.5 Our results raise the possibility that there is another, sleep-related component in the excess incidence of acute myocardial infarction on Monday. Sleep-diary studies suggest that bedtimes and wake-up times are usually later on weekend days than on weekdays; the earlier wake-up times on the first workday of the week and the consequent minor sleep deprivation can be hypothesized to have an adverse cardiovascular effect in some people. This effect would be less pronounced with the transition out of daylight saving time, since it allows for additional sleep. Studies are warranted to examine the possibility that a more stable weekly pattern of waking up in the morning and going to sleep at night or a somewhat later wake-up time on Monday might prevent some acute myocardial infarctions.
And in the quotes in the press release they say the same thing, so it is not a coincidence:
"It's always been thought that it's mainly due to an increase in stress ahead of the new working week," says Dr Janszky. "But perhaps it's also got something to do with the sleep disruption caused by the change in diurnal rhythm at the weekend."
Dr.Isis has already noted this and drew the correct conclusion. She then goes on to say something that is right on the mark:
And, of course, my first thought is, what about all the other times we are sleep deprived by, you know, one hour. Is waking up in the middle of the night to feed Baby Isis potentially going to cause Dr. Isis to meet her maker early? In that case Baby Isis can freakin' starve. But, this is the New England Journal of Medicine and Dr. Isis appreciates the innate need that authors who publish here have to include some clinical applicability in their work.
The authors responded to Dr.Isis in the comments on her blog and said, among else:
We wonder whether you have ever tried to publish a research letter somewhere. The number of citations (maximum 5!) and the number of words are strictly limited. Of course we are familiar with studies on circadian rhythms and cardiovascular physiology. There was simply no space to talk more about biological rhythms than we actually did.
But what they wrote betrays that even if they are familiar with the circadian literature, they do not really understand it. Nobody with any circadian background ever speculates about people's conscious expectations of a stressful week as a cause of heart attacks on Monday mornings. Let me try to explain why I disagree with them on two points they raise (one of which I disagree with more strongly than the other).
1) Sleep Deprivation. It is important to clearly distinguish between the acute and the chronic sleep deprivation. Sleepiness at any given time of day is determined by two processes: a homeostatic drive that depends on the amount of sleep one had over a previous time period, and a circadian gating of sleepiness, i.e., at which time of day is one most likely to fall asleep. Sleep deprivation affects only the homeostatic drive and has nothing to do with circadian timing.
Humans, like most other animals, are tremendously flexible and resilient concerning acute sleep deprivation. Most of us had done all-nighters studying for exams, or partying all night with non ill effects - you just sleep off the sleep debt the next day or the next weekend and you are fine. Dr.Isis is not going to die because her baby wakes her up several times during the night. This is all part of a normal human ecology, and human physiology had adapted to such day-to-day variations in opportunities for sleep.
The Chronic sleep deprivation is a different animal altogether. This means that you are getting less sleep than you need day after day, week after week, month after month, year after year, with rarely or never sleeping off your sleep debt ("catching up on sleep"). As a result, your cognitive functions suffer. If you are a student, you will have difficulties understanding and retaining the material. If you are a part of the "creative class", you will be less creative. If you are a scientist, you may be less able to clearly think through all your experiments, your data, and your conclusions. No matter what job you do, you will make more errors. You may suffer microsleep episodes while driving and die in a car wreck. Your immune system will be compromised so you will constantly have sniffles and colds, and may be more susceptible to other diseases.
And yes, a long term chronic sleep deprivation may eventually damage your heart to the extent that you are more susceptible to a heart attack. This means that you are more likely to suffer a heart attack, but has no influence on the timing of the heart attack - it is the misalignment between the natural circadian rhythms of your body and the social rhythms imposed via a very harsh stressor - the alarm clock - that determines the timing. Being sleep deprived over many years means you are more likely to have a heart attack, but cannot determine when. Losing just one hour of sleep will certainly have no effect at all.
Thus, the data presented in the paper have nothing to say about sleep deprivation.
2) Cytokines. These are small molecules involved in intercellular signaling in the immune system. Like everything else, they are synthesized in a diurnal manner. But they act slowly. Maybe they play some small part in the gradual damage of the heart in certain conditions (prolonged inflammation, for instance), thus they may, perhaps, have a role in increasing risk of a heart attack. But they play no role in timing of it. Thus they cannot be a causal factor in the data presented in the paper which are ONLY about timing, not the underlying causes. The data say nothing as to who will suffer a heart attack and why, only when you will suffer one if you do.
If I was commissioned to write a comprehensive review of sleep deprivation, I may have to force myself to wade through the frustratingly complicated and ambiguous literature on cytokines in order to write a short paragraphs under a subheading somewhere on the 27th page of the review.
If I had a severe word-limit and needed to present the data they showed in this paper, I would not waste the space by mentioning the word "cytokine" at all (frankly, that would not even cross my mind to do) as it is way down the list of potential causes of heart attack in general and has nothing to do with the timing of heart attacks at all, thus irrelevant to this paper.
So, it is nice they did the study. It confirms and puts clear numbers on what "everybody already knew for decades" in the circadian community. But their interpretation of the data was incorrect. This was a purely chronobiological study, yet they chose to present it as a part of their own pet project instead and tried mightily to make some kind of a connection to their favourite molecules, the cytokines, although nothing warranted that connection. Nails: meet hammer.
The fake-insulted, haughty and inappropriate way/tone they responded to Dr.Isis is something that is important to me professionally, as is there misunderstanding of both the role and the tone of science blogs, so I will revisit that issue in a separate post later. I promise. It is important.
But back to Daylight Saving Time. First, let me ask you (again) to see Larry's post from last year, where you will find a lot of useful information and links about it. What is important to keep in mind is that DST itself is not the problem - it is the time-changes twice a year that are really troubling.
Another important thing to keep in mind is that DST was instituted in the past at the time when the world looked very different. At the time when a tiny sliver of the population is still involved in (quite automated and mechanized) agriculture, when electricity is used much more for other things than illumination (not to mention that even the simple incandescent light bulbs today are much more energy efficient than they used to be in the past, not to mention all the newfangled super-efficient light-bulbs available today), when many more people are working second and third shifts than before, when many more people work according to their own schedules - the whole idea of DST makes no sense any more.
Even if initially DST saved the economy some energy (and that is questionable), it certainly does not do so any more. And the social cost of traffic accidents and heart attacks is now much greater than any energy savings that theoretically we may save.
Furthermore, it now seems that circadian clocks are harder to shift than we thought in the past. Even that one-hour change may take some weeks to adjust to, as it is not just a singular clock but a system - the main pacemaker in the SCN may shift in a couple of days, but the entire system will be un-synchronized for some time as it may take several weeks for the peripheral clocks in the liver and intestine to catch up - leading to greater potential for other disorders, e.g., stomach ulcers.
The social clues (including the alarm clocks) may not be as good entraining agents as we thought before either, especially in rural areas where the natural lighting still has a profound effect.
Finally, the two time-change days of the year hit especially hard people with Bipolar Disorder and with Seasonal Affective Disorder - not such a small minority put together, and certainly not worth whatever positives one may find in the concept of DST. We should pick one time and stick with it. It is the shifts that cost the society much more than any potential benefits of DST.
Related reading:
Daylight Saving Time
Daylight Savings Time worse than previously thought
Time
Sun Time is the Real Time
Seasonal Affective Disorder - The Basics
Lesson of the Day: Circadian Clocks are HARD to shift!
Lithium, Circadian Clocks and Bipolar Disorder
Everything You Always Wanted To Know About Sleep (But Were Too Afraid To Ask)
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Thanks for the excellent explanation. My gut reaction to the study was that they had found an interesting correlation, but that the explanation for the correlation didn't appear to be based little except speculation - and of course it's that explanation that is reported as the "result" of the study by the main stream media. I don't really know much about circadian clocks or the causes heart attacks, so I figured I might have been missing something obvious.
I find it a bit dismaying that the study's authors are so adamant that any discussion of the paper should be held within the confines of the NEJM letters page (or perhaps private correspondance). This paper has been given a lot of play in the main stream media, and I think it's important that it is discussed in media available to the interested public, such as blogs with open comment sections.
Interesting point about the alarm clock as environmental stressor. I've heard that individuals with familial long QT syndrome, in which ventricular arrhythmias can lead to sudden death, should not use alarm clocks, and should not have phones that might ring loudly during normal sleeping times. Adrenergic stimulation during excitement or fear exacerbates the already-impaired repolarization phase in the heart. Of course the implantable cardioverter-defibrillation units are a better solution for individuals with LQTS, but I'm not sure how widely available the units are. Also, not all individuals with LQTS have been diagnosed as such.
Bora, this is a very carefully reasoned and well-presented review of the relevant literature. I truly hope that people interested in this topic review this. I intend to crosspost it over on my humble little site. I think we interpret this article in exactly the same way -- the only difference is that what you crafted so elegantly, I abbreviated with a bear sitting on a toilet.
My top's off to you, Bora (I don't wear a hat).
It's way cool to see such a circadian-rhythym focused treatment of this paper.
I'm also in total agreement with you on eliminating DST.
However, I'm here to speak for the cytokines...for the cytokines have no tounges, and I'm asking you, sir, at the top of my lungs... WHAT ARE YOU TALKING ABOUT, CYTOKINES ARE TOO SLOW?! Tell that to someone dying of septic shock. Ok, so maybe they are slow compared to heart attacks, but why should we take your word that they are irrelevant for explaining why heart attacks happen unless you show pretty graphs of cytokine peak levels over the course of the day?
Also, the idea that cytokines are "way down the list of potential causes of heart attack in general" I suspect is dead wrong. There's some really interesting stuff out there about TLR2 and it's expression in particular areas of the heart where nasty lipids reside if you are put on a high fat diet. If you think high fat diets are high up on the list of causes of heart attacks, but proinflammatory cytokines are low on that list... you may be missing something very big. Cytokines would only be a proximate cause mediating the effects of nasty lipids, but that's no reason to ignore them.
That said, I agree with you that these data speak to when one is going to get a heart attack, but not who. Except, presumably, that living in a place with DST may increase your odds. (and the bit about the effect being greater in the under 65 and female crowd- which wouldn't really be explained by proinflammatory cytokines or circadian rhythyms, so far as I can see).
Peggy- I think the authors got too snarky. However, I think they weren't at all "adament" their work only be discussed in the pages of the NEJM. I think they were only adament that cute bears on toilets not be associated with their names. Which is silly enough (were it my work being targeted, I hope I would be wise enough to laugh at the whole thing).
Becca, I agree that cytokines are cool and I should brush up on them. But even if they act faster than I thought, and even if they do more than just increase predilection for HAs but also play a role in the HA event itself, they are still downstream of the main axis: clock -> epinephrine/cortisol -> HR/BP. The experimental design does not in any way study the mechanism of the heart attack, ONLY its timing, so the discussion on 'how' the HA happens need not be included in this paper given the severe length restrictions.
In an earlier post, burried deep inside, is this thought of mine:
What happened on Dr.Isis' blog is very similar - a clash of two cultures. I think that the picture of the Teddy Bear on the potty was a clever and funny shorthand for your point. If you did it about something I published, I'd laugh my ass off. But I can see how the uptight strain of the scientists would balk at it. It is them, though, who need to get up to speed on the changed rhetoric of science. The straight-laced, uber-formal way of writing in science is on its way out.
The rhetoric, even after it completely modernizes, will still have four concentric circles: the paper itself will always be more formal, especially the Materials/Methods and Results sections due to the need for precision; the letters to the editor will remain pretty formal, but not as formal as they are now; the comments on the paper itself will be still less formal but still polite; the commentary on the trackbacked blogs will be freewheeling, funny and to-the-point, just like yours was, not mealy-mouthing with politeness on the surface and destructive hatred underneath, but honest and straightforward. So, if it is crap, what better way to say it than with a picture of a Teddy Bear on a potty - much more lighthearted and polite than saying it politely, and less devastating for the paper's authors as it takes their mistake lightly instead of trying to destroy their reputation forever.
The point that both Dr.Isis and I made is that the paper is neat, experimental method sound, data are good, but the interpretation is crap. Now, having a couple of crappy paragraphs in an otherwise good paper is not the end of the world. A paper is not some kind of granite monument with The Truth writ in stone. It is becoming a living document (with comments on the paper and tracbacked blogs), and it has always been a part of a greater living document - the complete literature of a field. That is how science works.
It is hard to know which paper will persist and which one will perish in the future, what sentence will turn out to be a gem of prophetic wisdom, and which one is crap. People publish a lot of stuff, some better than other.
Making a mistake in one paper is not the end of one's career. But many people perceive criticism as if they are just about to be sent out to join a leper colony. This is, in part, due to the formal rhetoric of science: outwardly polite, but underneath it is an attempt to destroy the person. In comparison, a light-hearted joke with a Teddy Bear acknowledges the failability of humans, allows for everyone to make a mistake and move on (we all shit, don't we?). It is actually much more normal, and much less dangerous for one's career to receive such a funny form of criticism than a formal-looking destruction of all our work and our personna.
Yeah, because they are whiny-ass titty-babies!!
Speaking of which, I wonder why they aren't here yet, defending their young children from the scurrilous association of their names with a cute bear taking a poop!
Excellent explanation, Coturnix! I learned a lot today. I look forward to your follow-up on the conversation.
It reminds me of a conference I was at least. My advisor was arguing with someone who she really didn't agree with. They actually attracted a crowd, and he was practically screaming at her, and called her data "idiotic". I wonder what he would think if she's held up a picture of a teddy bear on a toilet?
Hi,
I am the first author of the study on DST and incidence of heart attacks.
Thank you very much for presenting your interesting opinion about our study. In some points I respectfully disagree.
First, I would like to comment a little bit about the overall style. I think you should be a little bit more careful in your statements. It is OK that you are definitely sure that your suggestion is THE explanation and that?s it. But it is an epidemiological finding, it needs confirmation, further evaluation etc. If you communicate it to the general audience (as you definitely do here), you have to emphasize more the uncertainty around this issue. There are many potential explanations, many involves no chronobiology or sleep at all. Yours is simply what you think is the most plausible at this point.
At least that's what I try to do with my explanation when the general audience is concerned. The journalists asks: So what do you think what the explanation is? I am telling them what I think as the most plausible explanation, and in the second sentence I am telling them that it is the very first study, needs confirmation and further evaluation. The second sentence does not appear always in the mass media coverages, but that is not my (or our) mistake. As a journalist told me they do not like too careful statements because those are not helping their publicity (previous experience, not now with DST...). We cannot and shall not avoid journalists (after all we leave on public money) and we cannot change the way of mass media operates but blogs should written smarter!
(Off topic: Could you give me a reference where it was predicted that DST slightly increases the risk for heart attacks after the spring shift and decreased even more slightly in the autumn? I mean when you write "Thus, the predictions from the circadian theory were completely and clearly correct.")
Now lets examine what happens with DST changes:
As we wrote "transitions can disrupt chronobiologic rhythms and influence the duration and quality of sleep, and the effect lasts for several days after the shifts" and "The most plausible explanation for our findings is the adverse effect of sleep deprivation on cardiovascular health. According to experimental studies, this adverse effect includes the predominance of sympathetic activity and an increase in proinflammatory cytokine levels. Our data suggest that vulnerable people might benefit from avoiding sudden changes in their biologic rhythms."
We claim disruption of chronobiologic rhythms and influence of duration and quality of sleep based on the following references:
Monk TH, Folkard S. Adjusting to the changes to and from Daylight Saving Time. Nature. 1976;261(5562):688-689.
Kantermann T, Juda M, Merrow M, Roenneberg T. The human circadian clock's seasonal adjustment is disrupted by daylight saving time. Curr Biol. 2007;17(22):1996-2000.
Lahti TA, Leppamaki S, Lonnqvist J, Partonen T. Transition to daylight saving time reduces sleep duration plus sleep efficiency of the deprived sleep. Neuroscience letters. 2006;406(3):174-177.
Lahti TA, Leppamaki S, Lonnqvist J, Partonen T. Transitions into and out of daylight saving time compromise sleep and the rest-activity cycles. BMC physiology. 2008;8:3.
You seemed to have a strong disagreement on sleep deprivation.
You say that we are "tremendously flexible and resilient concerning acute sleep deprivation. Most of us had done all-nighters studying for exams, or partying all night with non ill effects - you just sleep off the sleep debt the next day or the next weekend and you are fine."
The trick with dealing with triggers that any trigger represent an extremely little risk increase per se. Let's look at anger or physical activity for example. They are well known triggering factors. Still the chance with an actual anger episode or physical exercise to get a heart attack is extremely low in general.
If acute sleep deprivation is really a trigger that's a different issue.
Let's see why we claim it might be:
Mechanistic studies on sleep deprivation show a big bunch of potentially dangerous mechanisms which could play role in triggering heart attacks.
Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435-1439.
Irwin MR, Ziegler M. Sleep deprivation potentiates activation of cardiovascular and catecholamine responses in abstinent alcoholics. Hypertension. 2005;45(2):252-257.
Lusardi P, Zoppi A, Preti P, Pesce RM, Piazza E, Fogari R. Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study. Am J Hypertens. 1999;12(1 Pt 1):63-68.
Zhong X, Hilton HJ, Gates GJ, Jelic S, Stern Y, Bartels MN, Demeersman RE, Basner RC. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol. 2005;98(6):2024-2032.
Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, Mullington JM. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. Journal of the American College of Cardiology. 2004;43(4):678-683.
Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, Chrousos GP. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. The Journal of clinical endocrinology and metabolism. 2004;89(5):2119-2126.
Many of these mechanisms can play in triggering. Yes, that includes proinflammatory cytokines. With your views on proinflammatory cytokines I sincerely disagree. You say "Maybe they play some small part in the gradual damage of the heart in certain conditions (prolonged inflammation, for instance), thus they may, perhaps, have a role in increasing risk of a heart attack. But they play no role in timing of it." I strongly disagree with it. Please see the HUGE literature on plaque rupture and inflammation, proinflammatory cytokines. (My improvised very short laymen summary about plaque rupture: people might have huge narrowings at their arteries and nothing happens to them and but even small stenotic parts may rupture which leads to thrombus formation and consequently to occlusion which evolves to a myocardial infarction. So my answer is definitely yes, cytokines can potentially play part in triggering cardiovascular events.)
And there are of course many other papers on the topic and other potentially dangerous mechanisms. (Here of course I have to be very careful: these papers usually deal with more serious sleep deprivation than those with the DST changes. So I have to assume some "graduality" here.) I think it is a little bit outdated view that acute sleep deprivation has no harmful effects at al. Personally I would not communicate that to the public, really, especially not to those who are at high risk. We do not know very exactly to what extent and for whom acute sleep deprivation is dangerous but its better to be careful than the opposite. Primum nil nocere, i.e. "first, do not harm" was the principal when I got my medical education.
But there is also at least some epidemiological support for acute sleep deprivation as a trigger:
Tofler GH, Stone PH, Maclure M, Edelman E, Davis VG, Robertson T, Antman EM, Muller JE. Analysis of possible triggers of acute myocardial infarction (the MILIS study). The American journal of cardiology. 1990;66(1):22-27.
Singh RB, Pella D, Neki NS, Chandel JP, Rastogi S, Mori H, Otsuka K, Gupta P. Mechanisms of acute myocardial infarction study (MAMIS). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2004;58 Suppl 1:S111-115.
I am sorry to say that though your offer for an explanation is interesting and might also play a role, it clearly did not make me to regret offering our original "most plausible explanation" at all (sleep deprivation and disruption of chronobiologic rhythms). To base everyting ("completely and clearly") on our hearts possibility to prepare or not to prepare in the morning for the stress of the alarm as an explanation for our findings is even more speculative for me than these above. With that I do not say that there is no doubt: the morning is more dangerous than other parts of the days and the morning stress also plays a causative role. But it is clearly not only the morning stress of the alarm what triggers AMIs. You said "But what they wrote betrays that even if they are familiar with the circadian literature, they do not really understand it." Well, you do not have to believe us, that we are aware of the circadian literature (at least some of it) and used to understand - in general - what we read. Actually, during my PhD studies, just a few years ago, I planned to study change in heart rate variability in coronary heart disease patients around the getting up time in the morning, I had to delay it as other studies necessary for my thesis were much easier. This is information was completely "off topic" of course.
You wrote: "And in the quotes in the press release they say the same thing, so it is not a coincidence: "It's always been thought that it's mainly due to an increase in stress ahead of the new working week," says Dr Janszky."
"Nobody with any circadian background ever speculates about people's conscious expectations of a stressful week as a cause of heart attacks on Monday mornings."
But there are other people with other backgrounds, and they might speculate on "mental stress of starting a new workweek and the increase in activity" as an explanation for the increased risk on Mondays (not Monday mornings just Mondays) compared to weekdays. We only CITED one of them.
By the way, we might have some possibility in the near future to look into the timing issue (the start of symptoms during the day) of heart attacks in relation to DST changes that could answer some questions. Unfortunately the statistical power is much lower than for the Swedish Myocardial Infarction Register.
And finally and unfortunately I have to turn back to the "Dr.Isis" question. Given the correct tone of your blog may I say that I am a little bit surprised about your following sentence: "The fake-insulted, haughty and inappropriate way/tone they responded to Dr.Isis is something that is important to me professionally, as is there misunderstanding of both the role and the tone of science blogs, so I will revisit that issue in a separate post later. I promise. It is important."
Well, you can open of course another "lets defend the blogshpere against Janszky and Ljung" post. But there are two already (or may be more, I just do not know?). It is more and more a "Josef K." feeling for me I can tell you.
Dear Bora, you really wanted to write "fake-insulted, haughty and inappropriate way/tone"
An anonymous blogger, with her background not clear for us, neither her real thoughts apart from being very negative on our paper, mocked us in a very sarcastic style. Now, instead of completely ignoring her - I can assure you the very vast majority of the authors would do so -we stood up with our real names, with everything what it implies and answered.
What was so wrong with our answer? I can imagine that you may have disliked two things:
1. We somewhat sarcastically invited her to an epidemiology class. Do you think that questioning the background of an anonymous blogger is more offensive, "haughty" or "inappropriate way/tone" than what you just did in this post concerning persons with real names?
"But what they wrote betrays that even if they are familiar with the circadian literature, they do not really understand it."
I think we had full right for sarcasm as much as she had full right to write anything she wished in her blog.
2. We encouraged her to write a comment letter on our work. I think comments to journals and blogs can be equally important forums (am I not proving my interest to blogs communicating with you right now or with the fact that we reacted on the very first blog?). Was that so wrong that we invited her to that forum as well? Yes, we called a comment letter as "a" (but NOT the "only" as the ) normal way. A blog can be normal, too. Like yours. Her original post simply did not qualify. It was a mixture of mocking, jokes and some scientifically sound arguments. It was impossible to disentangle her real opinion as well her background and level of knowledge. Again, no one questioned her rights to do it for a moment. But do you really want science blogging in the style of Dr.Isis used concerning our study? I can assure you that the vast majority of authors will just run away from these blogs and never ever return or ever consider them as a forum where they want to discuss their findings. Do you have statistics on how many authors do actually enter to blogs concerning their work? (I mean with real identity). I would guess extremely few for blogs like that of Dr. Isis. If so, what do you think what is the reason? Do you think it is a smart way to promote open science and real discussions?
Sincerely,
Imre
Dude, quit your whining!!!! HAHAHAHAH!!!!
Hi Imre, welcome to my blog and thank you for your thoughtful response.
As you note, most of the studies you cite concern chronic, long-term sleep deprivation. I shall check that one you cite as evidence for the effects of acute deprivation, though, as I may learn something new.
I should, though, respectfully disagree with you, and now I think I know why: you are deeply embedded in your research on cytokines and cardiovascular events. In your mind, this paper is a small part of a bigger research program on those topics. Thus, you did not notice that this particular study actually has no connection to heart attacks or cytokines. It does not, in any way, address the question of the causal factors of heart-attacks. It is ONLY, as I noted in the comment above, dealing with timing.
Mind you, the study is excellent, as I noted in my comment above: the experimental design is as perfect as any chronobiologist could design, the data are clean and beautiful and a tour-de-force proof that circadian theory was correct about this all along. So I commend you for this - I expect to see this study cited a lot in the future despite my misgivings about your unneccessary tie-in to cytokines and causal factors of heart attacks, and sloppiness about the use of the term "sleep deprivation".
I explained, in this post, in simplest possible terms for my lay audience, the most basic, 'skeletal' causes of heart attacks at wake-up time. But actually, the data you present could have been explained with ZERO reference to any physiology whatsoever. The circadian theory made a prediction, you tested it correctly, and got good data that support the theory. The entire paper could have been written theoretically, explaining everything in terms of theory of circadian entrainment and Phase-Response Curves. Your analysis explores the phase relationship between optimal wake-up time and environmental Zeitgeber. Both the "optimal wake-up time" (for what? - avoding heart-attacks) and "Zeitgeber" (alarm clock) could have been entirely left out and dealt with in the abstract and you would still have come to the same conclusion.
Now, as your interest is in heart-attacks and cytokines, I am sure your future research will follow up on this in that domain. And that is excellent. But this study is only tangentially related to the rest of your work - the common thread are heart-attacks, but this paper does not deal with the underlying physiology, only timing. Your interest is elswehere, so you see this study in the context of your greater research program, but there is really no physiology in this particular study.
As my interests are different, I would likely go in another direction. I am intrigued by the sex and age differences you mention in your study and would likely follow up on that finding. Was there an interaction between sex and age in your statistics? We know that a) there is a difference in freerunning period between human males and females, b) the clocks with longer periods (thus "owls") tend to be easier/faster to phase-shift than shorter periods ("larks"), and c) there is a large phase-delay and period-lengthening starting in early puberty and lasting until as late as 30 years of age (I have written a lot about this, e.g., here, here, here, here, here, here, here, here and here). Going forward in this direction, just as with going forward in your direction, would lead to the study of actual underlying physiology, e.g., effects of hormones and such. But this particular study is purely mathematical. Nothing wrong with this - so was much of my own old work as well: using experiments in animal models to test mathematical models. Physiology came later.
Now, back to rhetoric of scientific communication and your view of blogs in that ecosystem.
In the comments on this post on Dr.Isis' blog, I wrote:
I followed that up in my comment here - see above.
Then I turned to the other topic - authority online - and asked Dr.Isis:
And the answer is: false deferrence to "real identity". The question of online pseudonymity has been discussed over and over again. But you may want to check out the latest flurry of posts on this topic: here, here, here, here, here, here, here, here, here, here, here and here.
Briefly: pseudonymity is not anonymity. Pseudonym, JUST LIKE THE REAL NAME, is just a string of letters. Online, just like offline, one builds reputation through one's words and deeds. I've been a science blogger for more than four years (in Internet dog years that is about two centuries) and I have learned to trust many pseudonymous bloggers years before I learned their true identities: SciCurious, Sciencewoman, Dr.Isis, DrugMonkey, Physioprof, Abel PharmBoy, Orac, Revere and others earned their reputation by being smart, honest, well-informed and yes, witty. They demonstrated both their expertise on the topics they write about AND their understanding of the medium. There are some excellent reasons to be Pseudonymous online and this does not detract one bit from the earned authority.
As time went by and I discovered true identities of some of these bloggers, I realized that their real names mean nothing to me. None of them turned out to be Craig Venter or Jim Watson. Their real names were completely new to me - just a few out of thousands of scientists out there. Learning their real names did nothing to enhance or detract their reputation - they earned it under their Pseudonyms. Pseudonym is a name, just like the real name: a string of letters, the former given to oneself, the latter received from parents. It makes no difference whatsoever.
But it is interesting that people who diss pseudonyms tend to all be male. Insensitivity? Total lack of perception of what is going on in the hallways of academia? Male privilege? Reverence for the formal academic hierarchy regardless of merit? Yes, all of the above.
So, I am insulted that you are in any way differentiating between Dr.Isis and myself. Why is it? We are both scientists (heck, she is more of a scientist - I have not done an experiment in 5-6 years now), we are both obviously well informed about biology related to your paper as demonstrated by our almost identical criticisms. We both can be and often are snarky and witty (look around my blog, especially the older archives - there is plenty of snark and straight-out nastiness in some of the posts). And that is a Good Thing. We are both equally ahead of the curve in the ongoing change in scientific communications and we should be treated equally as well. I think you need to go there and apologize to Dr.Isis for treating her as if she was not your (or my) equal.
It was impossible to disentangle her real opinion as well her background and level of knowledge.
It always comes back to this, doesn't it? "...her background and level of knowledge." That's the real shame of it. In a time in science where we are desperately in need an injection of new, creative talent, we are interested in keeping the status quo and verifying the number of letters after one's name before we will validate an opinion. Let me tell you, Dr. Isis has enough letters to play with the big boys but some of the people who contribute the most to her work, the people whose input she values the most, are letterless. I have said before and I will say again, you respond to criticism with data and additional explanation and then be open to clarify if need be. Dumbing down science is exactly what pisses the public off and leads to the propagation of overly simple interpretations (*cough* like the ones in the paper *cough*).
Again, no one questioned her rights to do it for a moment. But do you really want science blogging in the style of Dr.Isis used concerning our study?
You know, we can all spend our time crafting falsely pretentious letter to NEJM or we can just say what we're thinking and have a discussion. Dr. Ljung said on my own blog, "I urge you to write a comment on our paper in NEJM, if you are an experienced researcher in the field you will have no problem with getting it accepted." No, no, no, no! Science cannot continue to happen this way -- through communications of one or two letters in a journal. Sure, this is a valid way of communicating, but it cannot, cannot, cannot be the only way. It is apparent to Dr. Isis that the current cultural state of science is exclusionary and that our intellectual capital is suffering as a result. Research is isolated within sub-disciplines -- some of the best ideas in science come from cross-discipline collaborations. You might be pissed off by the bear (but really, the bear was cute), but I guarantee that people are talking about your work. Some agree with Bora and I and some don't. I give you the two posts by two bloggers here on ScienceBlogs as evidence of that. Either way, I would argue that this "style" of blogging has encouraged people to think outside of the confines of their own narrow world
But, if you all think the status quo is working just fine....
In fairness Bora, there is a number 5) for that list of reasons that Imre may have been more respectful here- your tone does come across as more respectful than that of Dr. Isis (less hilarious, but I think that's the price you pay).
Now, we can get into a fine discussion about whether women, in science and elsewhere, are judged more harshly for being "impolite" than men, and whether it's a form of male priviledge that men can be rude, or whether it's a form of female priviledge that they can expect people (at large, definitely not in science) to be sweeter to them. I think it's a tremendously facinating topic, actually. But it might be a touch tangential.
I also don't share your opinion that suggesting one take an epidemiology course is nasty. A smidge snarky, yes. But (as my comment on the very original thread indicated) I suspect most basic scientists could benefit from an epi course. And vice versa (and in fairness, Imre did at least seem to grasp this).
We all have to understand that we tend to have a vested interest in viewing the data in certain ways... whether that be through the lens of a vascular physiologist, a circadian biologist, or an immunologist. Bottom line- Drs. Janszky and Ljung inadvertantly triggered Dr. Isis's idea of "epidemiologists who aren't paying attention to physiology", and she responded acordingly. Dr. Isis appears to be sick to death of proinflammatory cytokines being invoked as explainations for everything. Fair enough. I'm sick to death of the term "junk DNA". We all have our pet peeves.
But pet peeves aside, the idea that proinflammatory cytokines (and associated cell damage response pathways) have no role in the etiology of myocardial infarctions is ludicrous. (fortunately, no one has made this argument!)
But Bora, I must ask you, how does cortisol lead to a change in heart rate?
Isn't it possible that (aside from whatever else cortisol is known to do) cortisol alters tristetraprolin [J Immunol. 2008 Jun 15;180(12)"Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation." Ishmael FT, Fang X, Galdiero MR, Atasoy U, Rigby WF, Gorospe M, Cheadle C, Stellato C.]
, causing massive global post-transcriptional regulatory responses (especially in cytokines like TNF-alpha!), but in particular affecting genes such as Ier3 which are implicated in the physiological control of blood pressure[Mol Cell Biol. 2006 Dec;26(24):9196-208 "Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts."Lai WS, Parker JS, Grissom SF, Stumpo DJ, Blackshear PJ.]?
And this is just one little hypothesis a student can come up with from a little spare Pubmed searching on her CFM (current favorite molecule = tristetraprolin). Imagine what somebody who actually knows the field and all the key molecular players downstream of cortisol and epinephrine could do...
I'm not saying the authors weren't too speculative in their writing- but ultimately, that's a critique about scientific norms of communication, not about the logic of their thinking. The idea that known proinflammatory cytokine signaling pathways will be involved in this phenomenon is quite reasonable.
Anyway, if we truly want to open up scientific dialog (not just form a younger and hipper elitist scientific squad), scientific speculation should be rigorously analyzed... but not abandoned at that point. It's not enough to just tear an argument down. You have to explain why your hypothesis is better. For a lot of us, that means proposing a molecular mechanism. Personally, I think a speculative mechanism is better than no mechanism at all (provided it's not stated as "this is the only explaination for these data"- which was never an argument Drs. Janszky and Ljung made).
I think speculation is better than no speculation because I don't think any of us see a huge amount of value in this study as an end point... but I think we are all excited about it as a good place to start with designing new studies. Some of those studies should be circadian rhythym studies. Some should be cytokine studies. But most should probably look at both.
Hi again,
I will answer the research part soon. Unfortunately I have not time for that now as I have many other duties.
But now for the very last time I am turning to the question of Dr Isis and her blog. You can write and manipulate my words (I do not accuse you literary to do that but with the meaning) as you like in the future. I simply cannot take the whole debate seriously.
"So, I am insulted that you are in any way differentiating between Dr.Isis and myself.We are both scientists (heck, she is more of a scientist - I have not done an experiment in 5-6 years now), we are both obviously well informed about biology related to your paper as demonstrated by our almost identical criticisms."
1. Can you tell me how should I know that when first seeing her blog?? And what's wrong to question someone's knowledge (again you did the same with us right now in this blog, although you had some idea about who we are)? If you do it is OK. If we do it it is "fake-insulted, haughty and inappropriate way/tone".
2. I am not questioning the right of being anonymous. Never did. I am not questioning the right to put anything on your blog. Never did. But do I have a right to have an opinion at all? Can I have my preferences over blogs tones and styles?
3. I am not against blogs. If that was not clear so far, it seems it will never be clear for you.
4. Again, I think the approach of Dr. Isis will lead a blog shpere without authors. That would be really pity for the blogsphere. And I guess that's not how you, Bora, a big promoter of open science, imagine open science. I asked you to present statistics on involvement of authors. Let me make it very simple now: Dr. Isis, how many times you criticized papers in a similar tone and how many times the author answered you among those cases?
5. Are you insulted that I prefer the tone of your critique and blog over that of Dr. Isis? And Dr. Isis was offended by an offer of an epidemiology class? Oh, my poor ones. You seemed to be really sensitive. Perhaps you should have taken the whole issue with a little more humor.
Best regards,
Imre
Sorry I forgot from my previous post:
"I think you need to go there and apologize to Dr.Isis for treating her as if she was not your (or my) equal."
Actually, I did aplogize for that as you can see on her blog. By the way is it only me who has to apologize?
Imre
Becca: Yes, it is possible that cytokines are downstream from cortisol and are a part of, as I alluded above, of the HA event. But even cortisol is not necessary for the explanation. Questions and answers need to be at the same level. It is not appropriate to answer molecular questions with organism- or population-level answers. It is not appropriate to answer organism- or organ-system level questions with molecular answers. Molecules are just one of many levels of biological organization and the thinking that a final answer to every question will eventually be molecular is so-called "philosophical reductionism" (Rose 1998), "strong reductionism" (Brandon 1996, Ch.11), or "vulgar reductionism" (hallway vernacular, perhaps I heard Lewontin use that one), which is philosophically just plain wrong. See this for a very old (outdated on science, but still philosophically sound) view on the question. The 'need' to go molecular underlies frequent references to chemicals in discussions of experiments that do not deal with a molecular level at all.
Remember that biological organization displays 'nested hierarchy' (as in Russian dolls) in which the identity of parts cannot predict the behavior of the whole. But manipulation of the whole can give insights into relationships between the parts (not identities, but types of interactions between the parts, often possible to describe mathematically or with conceptual models). This is the principle of "Downward Causation" - we can learn about the parts from the behavior of the whole, but we cannot learn about the whole from the behavior of the parts.
As the study of biology is the study of organisms, study of molecules is only one of the many tools in the toolkit we use to understand the whole - the organism as it develops, survives and reproduces in its environment.
There is another excellent commentary on this here.
"Can you tell me how should I know that when first seeing her blog??" This is an excellent question. Can you tell me how should I know about a scientist when first seeing a paper?? It is the same process. You enter a field or community not knowing anyone from Adam. You can read everything by the person and make your own opinions, of course. But, especially if you are new, you may need more - the opinion of others who have been in that community longer. Just because someone has a PhD and a nice long list of publications, does not mean s/he has a good reputation. And reputation does not come overnight and cannot be sustained on a single publication (or blog post). We all know, from our own scientific community lore, whose papers not to trust - those people's work could not be replicated, nobody cites it, nobody sends invitations to give a seminar.
It is the same on blogs. You can spend some time reading many posts by the blogger and, over time, develop trust (or not). Or you can look at stats: what is the traffic, who links there, Technorati/Google rankings, etc. Or you can see how the rest of the community treats the person. The way some very prominent members of the science blogging community jumped to Dr.Isis' defense is a good indication that she has over time earned our trust.
"I am not against blogs. If that was not clear so far, it seems it will never be clear for you."
No, I never suggested that and do not think that at all. I am very happy that you are participating in all of our blogs, posting comments, challenging us, even developing your own sense of snark. That is very good and commendable. Welcome to the blogosphere - I hope you stick around longer, after this whole brouhaha is over, as you clearly have insights and expertise, as well as the penchant for online discussion, that is valuable.
"Can I have my preferences over blogs tones and styles?"
Yes. But this is a landmine territory on science blogs since the beginning of blogging. We constantly bicker over the "proper tone" - the oldest debate in our world. You just stepped into it unprepared. But you are taking it with good humor - and so am I.
Perhaps think of this as induction into a secret society or fraternity - you just survived the hazing in order to become a member. I think you should start your own blog.
Perhaps think of this as induction into a secret society or fraternity - you just survived the hazing in order to become a member.
So this makes PP what, Bluto?
I think you should start your own blog.
Speaking of the whole world being a nail!
Perhaps my name as a blogger should be teddy bear.
LOL! ;-)
See, Imre!?! That is the spirit!
And I think your first post should include a picture of a horses rear that you can liken to Dr. Isis. I totally won't even make a stink about it.
Welcome to the fraternity.
Dear bloggers. (seems the tone has been a bit friendlier the last hour when I have been writing this - bu twhat th eheck - thi sis what I felt an hour ago)
I am the second author. I actually liked the scientific discussion here. But why cant we hold it on the scientific level.
Though me comment here will only be on the way we have been addressed and treated.
Why do we respond politely to Coturnix (and not to DrIsis? - we responded politely to her(?) there too)
according to Coturnix these could be some reasons:
1) I am writing under my real name, or
2) I am a man, or
3) I am an expert in the field, or
4) I work for PLoS so they don't want to rub me the wrong way in case they are interested in publishing with us.
Dear Coturnix:
A: 1) I have not looked up your name, and I have not searched you on pubmed , I just felt that your tone and scientific reasoning appealed more to me than dr isis crap-jokes. ( for me you two could be the same person - what do I care? Just that the tone and scientific level seams more mature here)
A:2) ? You have totally no clue about my thoughts on gender-rolls, etcetra - I actually live in, I would guess, the most gender-egalitarian country in the world! (off topic: it will be interesting if you in the US tomorrow will vote for another old trigger-happy cowboy asking God for advice)
A:3) That actually helps, then I (hopefully) can be more assure that you are familiar with epidemiological research. It sets the level of the discussion - you cannot deny that.
A:4) to be honest - it actually scares me if you as a potential editor/reviewer of PloS actually do not take your hand of scientific comments as those of DrIsis. You even support it!? Could I quote you in my next cover letter to PloS, if I refer to some other authors work?
Coturnix said: I think that the picture of the Teddy Bear on the potty was a clever and funny shorthand for your point
>i<
I think they were only adament that cute bears on toilets not be associated with their names.
Yeah, because they are whiny-ass titty-babies!!
Speaking of which, I wonder why they aren't here yet, defending their young children from the scurrilous association of their names with a cute bear taking a poop!
by comrade physioprof
>i<
Another clever remark from a chronobiology professor?
Imre had a brilliant idea, we analysed and wrote a nice letter in NEJM.
Looking forward to reading an editorial in PloS or comments in NEJM. (smiley)
Rickard Ljung, MD PhD
(dont confuse me with prof R Ljung (hematology research) if you search for me on pubmed)
( and luckily my kids dont have teddy bears - they have a rabbit and a dog)
No way! Comrade PhysioProf's the romantic dude with the mood lighting and stuff!!!
Oh, I have nothing to do with the editorial side of PLoS. I am their online rabble-rouser community manager and blogger.
And look around the blog under the category 'Politics' ;-)
And the best summer of my life was in 1990 in Stockholm.
(off topic: it will be interesting if you in the US tomorrow will vote for another old trigger-happy cowboy asking God for advice)
Professor Ljung - I can absolutely guarantee you that the people who frequent this blog and comment threads are vehemently opposed to any such thing (and were vehemently opposed to the outcome of the 2000 and 2004 elections). In fact, a great many of us already cast our ballot in the early voting for the Democratic ticket. A great many of us have done our best to be sure that the rest of the world does not continue to laugh at us because of our president. But, of course, we have been sadly surprised in the past.
"So this makes PP what, Bluto?"
Sorry, Animal House is not my favorite movie (I have never seen it - just know kiefer(?) Sutherland turned down a percentage on the movie for a fixed salary- missing 30 mil dollars - so I actually do not understand the oneliner? (English is not my native language)
Politics- sorry didnt want to change the subject - just couldnt resist. But I am actually just watching a documentary on how american presidents have been portrayed in the movies (Air Force One, Independence Day etc)...
I will search your and DrIsis cites for Roosevelts on toilets (I think this was a pretty clever joke - or have I misunderstood the president's nickname ?)
Yes, Teddy Bear was named after Theodore Roosevelt. But still, it sounds so funny: "Roosevelts on toilets" ;-)
I think you'd be surprised what you'll find, KingClown. The pictures Dr. Isis has posted about the bear that is supposed to be our president are downright pornographic in comparison to the potty.
;-) I'll look. and come back to the other categories than science to see if I find something else of interest to comment on. (but regarding our previous discussion, the W guy is an official person I am not)
closing on midnight here in Stockholm - so sleep tight with your teddies...
"It is not appropriate to answer molecular questions with organism- or population-level answers." With the utmost respect Bora, that is a load of codswhallop. What are studies comparing incidents of a trait in identical twins vs. siblings other than organismal level analysis? How many fewer genetic diseases would we understand if we didn't start at that level?
"It is not appropriate to answer organism- or organ-system level questions with molecular answers."
Even if that were true (and see above) who defines what is an "organism- or organ-system level question"? Why is myocardiac infarction necessarily about an organism (not that I'm claiming it's necessarily about cells, or ion channels, or anything else)?
Of course a Final Answer to all biological questions need not involve molecules. However, I didn't say molecular speculation was better than organismal speculation; I just said some (reasonable, hypothesis-generating) molecular speculation was better than not having any molecular speculation.
Yes, emergent properties are ultra-cool. No, I'm not a believer in fetishizing molecular explainations as many molecular geneticists are. However, the idea that molecular analysis should never be linked to organism analysis is patently absurd.
As a total aside, who says the study of biology is the study of organisms? I know perfectly respectable biologists who think the study of biology is the study of energy-gradients-across-membranes, or of cells, or of ecosystems. Organismal-biologist-chauvinsim much?
*grumble grumble grumble*!
Molecular Medicine represent!
Energy-gradients-across-membranes, cells, and ecosystems are studied so we could understand organisms. There is one explanation in biology - evolution. Everything else is description.
"However, the idea that molecular analysis should never be linked to organism analysis is patently absurd." I agree 100% with this statement, which is what I said - you can manipulate the organism (or organ or tissue) and infer something about molecules from it. Then you ID the molecules in order to get a 'handle' (those ATCG codes make it so easy) in order to track the molecules in order to understand what is happening at higher levels. You can manipulate molecules in an organism and by observing how the organism's behavior changes, infer something about the way the organism is working. Yet, in the end, the answer to all biological questions is: evolution.
"Please see the HUGE literature on plaque rupture and inflammation, proinflammatory cytokines. (My improvised very short laymen summary about plaque rupture: people might have huge narrowings at their arteries and nothing happens to them and but even small stenotic parts may rupture which leads to thrombus formation and consequently to occlusion which evolves to a myocardial infarction. So my answer is definitely yes, cytokines can potentially play part in triggering cardiovascular events.)"
Ehhhh...I suppose the question you haven't stated explicitly here is, "what are the potential sources of plaques." There's some literature that suggests chronic intracellular infections (C. pneumoniae, specifically) initiate plaque formation, which would then logically induce inflammation. Or, do you think that the inflammation is a sort of low-grade autoimmunity brought on by dyslipidemia or hyperlipidemia? There are a couple of papers suggesting that dyslipidemia only causes mild coronary artery disease with not-very-large and fairly stable plaques, while chronic infection produces large and unstable plaques. I am a bit doubtful about the autoimmune idea, and I know some researchers have discontinued this line of thinking as unprofitable (literally, I work in drug discovery). So I am inclined to agree with Coturnix here that the cytokine association merits no more than a brief mention at best. It's not been truly demonstrated whether inflammation is a cause or a consequence.
And you will never know me from Jane Doe on the street, as my employer doesn't approve of blogging ;-)
I have a feeling that I am about to learn much more about cytokines than I ever expected or wanted ;-) Ah, the beauty of blogs!
Anyway, there is more discussion going on here and here.
But Lora, that's why you have a pseudonym!! And blog on your own time. Join us on the Dork Side...we have cookies.
And even more discussion here.
"The fake-insulted, haughty and inappropriate way/tone they responded to Dr.Isis is something that is important to me professionally, as is there misunderstanding of both the role and the tone of science blogs, so I will revisit that issue in a separate post later. I promise. It is important."
Amen, Bora!
I must say, I'm delighted at the turn this discussion has taken! Instead of devolving into a flamewar, the participants seem to have reached something of an understanding, and that warms my perky heart.
One of the things the authors (being Swedish) may be unaware of is that "take a class in X" is an oft-used line in America by male scientists to belittle the criticism of female scientists-- this is why their original response to Dr. Isis comes across to American eyes as offensive. That said, however, I happen to believe that all scientists ought to take an epidemiology class, as it is a way cool subject! :D
Thx Perky for the explanation why everybody seemed so focused on gender-roles and us being gender rasists?! We had no clue about the expression.
And when that is made clear -Bioephemera- who over-reacted?! All of you - who used your own predjudies in your mind and put the thoughts on us! - or us who had our "picture" taking a shit?
If not before, I will come back next time I have a paper in NEJM.
Hi,
The promised answer:
"As you note, most of the studies you cite concern chronic, long-term sleep deprivation."
?? That's not correct. Why would I bother you with citations on studies on chronic, long-term sleep deprivation at all? These all present data on acute sleep deprivation.
Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435-1439.
"11 young men after time in bed had been restricted to 4 h per night for 6 nights"
Irwin MR, Ziegler M. Sleep deprivation potentiates activation of cardiovascular and catecholamine responses in abstinent alcoholics. Hypertension. 2005;45(2):252-257.
"36 abstinent alcohol-dependent men and 36 age-, gender-, and ethnicity-matched controls after a baseline night of sleep, in the morning after early night partial sleep deprivation, and again after a full night of recovery sleep"
Lusardi P, Zoppi A, Preti P, Pesce RM, Piazza E, Fogari R. Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study. Am J Hypertens. 1999;12(1 Pt 1):63-68.
"The influence of acute sleep deprivation during the first part of the night on 24-h blood pressure monitoring (ABPM) was studied in 36 never-treated mild to moderate hypertensive patients."
Zhong X, Hilton HJ, Gates GJ, Jelic S, Stern Y, Bartels MN, Demeersman RE, Basner RC. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol. 2005;98(6):2024-2032.
Here it is clear already from the title that it is about acute sleep deprivation.
Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, Mullington JM. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. Journal of the American College of Cardiology. 2004;43(4):678-683.
"In Experiment 1, 10 healthy adult subjects stayed awake for 88 continuous hours."
"In Experiment 2, 10 subjects were randomly assigned to either 8.2 h (control) or 4.2 h (partial sleep deprivation) of nighttime sleep for 10 consecutive days." Even 10 days is not chronic, long-term sleep deprivation
Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, Chrousos GP. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. The Journal of clinical endocrinology and metabolism. 2004;89(5):2119-2126.
"To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory." One week is also not "chronic, long-term sleep deprivation".
You say about our study as "this paper does not deal with the underlying physiology, only timing" and "It does not, in any way, address the question of the causal factors of
heart-attacks. It is ONLY, as I noted in the comment above, dealing with
timing." Yes, I (we) ALWAYS, STRICTLY and ONLY referred to triggering of heart attacks. Triggering is the term for timing in epidemiology. But, you are right that in a blog we shall use a more generally understandable term: timing.
"You are deeply embedded in your research on cytokines and cardiovascular
events. In your mind, this paper is a small part of a bigger research
program on those topics."
No. This is simply not true. What makes you think so? I do not work completely outside of the inflammation and infarction world but I am not very much into it. As a matter of fact it is not very easy nowadays in cardiology and cardiovascular epidemiology research to avoid them as they are so very hot. The only thing I might admit that as several landmark studies on the topic were conducted by Goran Hansson's group from our institution we here might like the topic of "inflammation and heart attack" more than at other institutions. You might get the feeling that I am defending the proinflammatory cytokines. But that's simply because you were so negative about them. It is acute sleep deprivation and cytokines where you had strong statements and disagreements: you state that acute sleep deprivation has no dangers what so ever (at least that's how I read it) and cytokines are slow and "they play no role in timing" of heart attacks. I do not say at all that they are certainly THE mechanism, I thought it is was clear. But what you say about them is outdated. The are a lot of studies suggesting the opposite. But as you wrote to Becca you need to refresh your knowledge on cytokines. I suggest that you take into this refreshment the considerable literature on timing of myocardial infarction and proinflammatory cytokines.
Still about cytokines. LORA wrote: "that the cytokine association merits no more than a brief mention at best. It's not been truly demonstrated whether inflammation is a cause or a consequence" I absolutely agree. I know that several papers question whether they are causal or marker (but then what they are marking for could be a mechanism). But as you see it was just a brief mention.
Back to Bora: "Mind you, the study is excellent, as I noted in my comment above: the experimental design is as perfect as any chronobiologist could design,"
Thank you but perhaps we do not deserve your nice words. We have not invented here anything. There are many studies with similar designs to study heart attack triggers. It was simply quite a standard design to examine the triggering (timing) effect of DST transitions keeping in mind chronobiology (variations in incidence). The principles are similar to case-crossover design.
"The data are clean and beautiful and a tour-de-force proof that circadian theory was correct about this all along" (Off topic: could you provide me with a citation on ""Thus, the predictions from the circadian theory were completely and clearly correct.")
If a result is predicted by a theory it does not prove the theory. The acute sleep deprivation as trigger hypothesis could have as well predicted it. Now I am still finding your interesting idea about our hearts possibility to prepare or not to prepare in the morning for the stress of the alarm as an explanation for our findings far too speculative. But I could be convinced. For example: The majority of heart attacks are evolving from plaque ruptures. Now, do you have support for "preparation/lack of preparation" as being protective against/ facilitating plaque rupture? That could give some credibility to this hypothesis. (I made a little lay summary about plaque rupture in my original answer)
Thank you very much for your ideas on how you would have written the paper. I partly agree. We ourselves revisited our thoughts about it after the big media coverage which really took us by surprise (it was NEJM informing all the international media, we had not contacted anyone, NEJM just asked whether they can give our emails and phones to the media in case they are interested). I do not think at all about our study as something "groundbreaking". It clearly needs further evaluation. The fact that it was published around the autumn DST switch was a big determining factor in triggering media .
But I disagree in the point on not offering physiological explanation. I fully share Becca's view here. And actually as you are seemingly much more confident with your explanation ("complete and clear") then we are with ours, it makes me feel that perhaps you would have also included a proposed mechanism if being in our shoes.
Let me tell you the story of our paper. We have sent it to NEJM in a full-length paper format. They looked at it and rejected in that format but came up with an offer that we can write it in this letter format instead (with very strict limitations, although they allowed us somewhat more space than typically for non-comment letters) and if we are ready to cut it then we can answer to the external and internal reviewers and they might reevaluate their decision. Our first reactions was feeling very frustrated over cutting so many interesting things from our work. But when we asked our more experienced colleagues they all suggested that we shall not miss this opportunity to get a peer review paper presenting original data - however short it is - accepted in NEJM (which happened eventually). But we definitely plan to write in a follow up paper on the material we had to cut from our original version (together with some data outside of the Swedish Myocardial Infraction Register) . I would not write about the interactions in your blog because that is the topic of this planned follow up paper. I guess it is not very likely but we may run into problems with getting it accepted as original if we show here anything.
I had very little time to look for other comments, but the one right before my current one was an excellent one:
"One of the things the authors (being Swedish) may be unaware of is that "take a class in X" is an oft-used line in America by male scientists to belittle the criticism of female scientists-- this is why their original response to Dr. Isis comes across to American eyes as offensive. That said, however, I happen to believe that all scientists ought to take an epidemiology class, as it is a way cool subject! :D"
I think it is a very important point. I was completely not aware of that. I visited US only once in my life for 10 days and my English originates from school. A lot of words and expressions in blogs were not in my "school"/ "literature English from books"/"polite formal English" vocabulary so I spent some time finding them at dictionaries. Good way to improve my English! As a matter of fact I do not understand (though I might have a good guess for it) and could not find in my dictionary the expression "whiny-ass titty-babies", Though that his "Ceterum censeo" for PhysioProf so obviously he wanted to express with it something very important :-). I am absolutely sure that my colleague, Rickard, was not aware of the American meaning of ""take a class in X" " either. It now explains a lot for me. I think we had a lot of cultural difference/language barrier problem in our discussion for far. Can I ask someone who visits other blogs on the "Janszky and Ljung case" to cross-reference it (I do not know how to do it). So those not visiting this blog will understand much more. Thank you very much in advance! By the way, completely off topic: I am not Swedish I am a Hungarian living in Sweden.
Imre
NB. I won't be able to comment for almost three weeks from now, just to know if you do not get a reply from me.
Dr. Janszky, you wrote, "I can assure you that the vast majority of authors will just run away from these blogs and never ever return or ever consider them as a forum where they want to discuss their findings. Do you have statistics on how many authors do actually enter to blogs concerning their work?"
Dr. Janszky, I think responsible researchers will always seek to defend and explain their work in whatever medium it is responsibly challenged. The simple choice of venue does not determine whether a response will be made.
For reference, I would refer you to the discussion surrounding the "Great Helena Heart Miracle" study in the BMJ. The study was heavily criticized in the BMJ's own Rapid Response section at:
http://www.bmj.com/cgi/eletters/bmj.38055.715683.55v1
The validity of these criticisms can be judged by the fact that the editors of the BMJ themselves felt that it was completely unnecessary to formally publish a study countering the Helena results since the study had "been pretty roundly criticised already"
http://www.acsh.org/factsfears/newsID.990/news_detail.asp
Yet, despite the criticisms, challenges, and open questions in a very high profile and professionally important medium, the three authors, at least two of whom continue to tour the country and speak glowingly of the results of that study, failed almost utterly to rise in defense of their work.
In such instances less formal and more distinctly harsh criticisms in the free-wheeling blogger world are not only reasonable, but fully deserved.
{Please note: I am not in any way referring to your own work as deserving criticism here... merely pointing out the validity and importance of taking scientific criticism beyond the pages of formal journals where it is sometimes quite irresponsibly ignored.)
Michael J. McFadden
Author of "Dissecting Antismokers' Brains"
Hi,
Just to make a point. I am an author and an editor, albeit in a different field of science. What I see from this discussion boils down to two things and an ancillary point: The author of a blog post felt insulted because the targets of her critique suggested she might not have enough knowledge on a specific area. The author of a blog post portrayed two scientists as teddy-bears thinking of their conclusions on a potty and the authors of target work felt insulted by this. A further relevant detail is that while the blog author is pseudonymous, the authors of the paper were not. As scientists, you all purpose to be champions of rigorous thinking, who always take the logical discussion path. If you have a look at what is summarized above, you would see:
1) Every point of discussion related to sex is moot - there is no discrimination here. So, this is just a red herring
2) Snarky calls on the comments suggesting that the authors are complaining too much and should lump it up, as it were, are irrelevant to the discussion at hand. Nevertheless, they are revealing of the nature of thought processes underpinning most of the contributions.
3) In the position of these authors, I would feel that one thing is discussing the scientific points of an open conclusion: that is the whole point of science; another is requiring depreciatory images to underscore our contempt for another reasoning process.
4) Feel free to discuss what would you do if a reviewer of one of your papers would send over a bear crapping as a summary? Do you feel that possibility is part of logical reasoning?
5) Based on the above, I do not feel compelled to follow any of these blogs any more - they are just childish vociferations of partisan minds. And those, I gather, are the ones you all so deride elsewhere...one always has to think of looking glass mirrors
So long, and thanks for all the fish.
Oak
Oak, "childish vociferations of partisan minds" is a fantastic phrase, and perhaps even applicable here.
If the snark upsets you, you're probably better off avoiding the blogs in question. If it doesn't emotionally bother you, but you instead want to debate the science, just put a substantitive comment out there, ignore the whackaloonery, and see what happens.
"There is one explanation in biology - evolution. Everything else is description."
If by "description" you mean "stamp collecting" you're all set to be a fizzycyst! Did you have a specific hypothesis generated through thinking about what evolution implies in the case of heart attacks and DST? That'd be awesome- please share.
However, the importance of evolution says nothing about whether we study molecules to understand organisms. My beloved molecules (including the dear, sweet cytokines) are illuminated by evolution every bit as much as your fluffy fauna. I don't think you'll ever convince me that the organismal layer of biology is the most fundamental/important. It is certainly one interesting layer, but so are my molecules.
As far as what Imre said- I think there are two (not-mutually exlcusive) possibilities for what is going on here. 1) Because Imre knows a spiffy researcher doing work on inflammatory cytokines and heart attacks, he is ahead of the curve and there will be an explosion of literature on connections between these two well-studied fields. 2) Because Imre knows a spiffy researcher doing work on inflammatory cytokines and heart attacks, he is decieved into thinking it's a much more well-studied field than it really is.
Personally, I think that 1) is likely enough, that it's worth speculating about mechanistic connections.
Both 'explanation' and 'description' have pretty firm definitions in philosophy of science. Description is good and useful and should NOT be treated as if lesser than explanation. It is just in a different form - answers How questions and not Why. Stamp-collecting, which is also not to be ridiculed as it is useful, is answering the What questions. In Biology the only Why questions are evolutionary questions. What, How and Why questions can be answered in various ways, some of them including hypothesis-testing. Hypothesis-testing is just one (though greatly hyped these days) element of the "scientific method".
Bora
Im very late to this discussion but I wanted to stop and think first.
I agree that circadian effects could completely explain the Swedish MI pattern. But I disagree with you statement that "Losing just one hour of sleep will certainly have no effect at all". I don't think that you have the data to back this up. Of course I certainly don't have the data to confirm that it does. But as we both know one cannot disentangle the effects of sleep and circadian effects in the real world- hence forced dysynchrony in chronobiology labs.
There is certainly a mismatch in the knowledge bases of the discussants as Janskzy (perhaps indelicately- due to language differences) pointed out. I've done a little bit of thinking about what I call chronoepidemiology- studying the effects of circadian pertubations of the health of populations.
The short form is this- I think that the Daylight savings time effect on MIs could be due to both circadian and sleep deprivation effects working in tandem.
Circadian effects you have carefully outlined and I completely accept as a potential cause. The circadian shift is a highly likely cause of a small amount of sleep restriction across the whole population.
Acute Sleep deprivation- even as little as 45mins-1 hour could also play a role. You and Dr Isis dismiss this out of hand. There are some epidemiological considerations, however.
There a number of experiments of the effects of short term sleep restriction in humans indicating effects that are possibly biologically consistent with triggering MIs as Janskzy helpfully provided everybody. The caveats are that these:
1. They involve fairly heavy sleep restriction (i.e. not 45 mins-1hour depth and more like 4 hours per night)
2. the participants are very few, super healthy and heavily selected and also usually males only. (i.e. they do not represent the sorts of people who actually have heart attacks)
3. They clearly don't cause actual MIs in these studies and thus rely on very intermediate markers.
However, in public health if factor A (sleep restriction) has effects on important outcome B (heart attack triggering) even very small changes in factor A can have very important effects when multiplied across millions of people on outcome B. So we could hypothesise that acute sleep restriction can trigger MI and that there is no threshold effect (i.e. a linear effect where every minute causes a miniscule increase in risk) then what one ought to see in conjunction with daylight savings is a small increase in heart attack risk after losing 1 hour sleep and a small decrease when gaining 1 hour sleep.
The data presented by Janszky and Ljung are consistent with this hypothesis as they have indicated (a small effect which is significant across millions of people). They are also consistent with a circadian effect as you and others have indicated.
The public health decision that arises does not require us to understand the mechanisms be they circadian sleep restriction or anything else merely that daylight savings is the underlying cause.
So I congratulate Janszky and Ljung in getting Chronoepidemiology into the NEJM.
Tangential? Maybe -- but I observe that tangents only happen with curves, and being male I highly approve of curves.
As for the topic and discussion, I will be utterly fascinated to see it -- please drop a hint in one of the too-many places I frequent if you get the chance. For that matter the name and e-mail are easy to put together.
I'm interested in the subject, but I'll drag along DarlingDaughter, and that happens to be her research subject. Should be a blast.
You're making this waaaaay too complicated. She posted a fistful of citations which were material to your thesis, and you ignored them. Had you addressed her citations and taken the substance of her post seriously instead of taking umbrage at its form, you might well have launched an enlightening discussion on the intersection of physiology and timing of heart attacks.
What's wrong is that it's totally beside the point and distracts from discussing what really matters: science.
Maybe it's cultural. I've chaired conferences where the absolute best material came from someone we'd never seen before, never heard of, with no particular personal credentials. I don't even remember their faces or names now, but their presentations! Boy, Howdy! Rich, luscious, filled with meaty data-goodness and solid crunchy experimental methods. Ummmmmm, nomnomnom!
On the Internet, nobody knows you're a dogan Egyptian mythwith the head of a jackal.
"The rest is commentary; go and study the commentary [1]."
My perspective is that the ultimate answer is string theory, and the rest is just the result of complexity piled on top of the fundamentals. Unfortunately, this isn't a very useful abstraction level for discussing macrobiology.
Barring that (impossible) level of descent to detail, we're forced to use simplifying assumptions. There are objections to Russell's "levels of abstraction" model, but it's useful if not rigorous. As long as we recognize that they're necessarily incomplete, the abstractions mostly serve us well. Molecular models mostly work, cellular models mostly work, etc. Then we find an organism which depends on Van der Waals forces for climbing and are reminded that it's all a cheat sheet.
NB: I am an engineer who has recent bruises from being reminded that system-level behavior sometimes requires descending to quantum physics before we can deal economically with the consequences.
[1] The preface to this punchline is actually quite topical. I commend it to all of the participants in this affair.
There is a whole slew of posts following this one - I have collected them here.
Also see this new study and also this new study.
Dear Bora and all visitors of this blog,
I have not been here for a long time I had simply no possibility even to read the comments. The most interesting for me was Dr. Marshall's comment. I have found very interesting and useful! Thank you for it and thank you also for your nice and encouraging words.
I absolutely agree with every point you raised! Just a very small thing I would like to make it clear for everybody reading this blog:
"Even as little as 45mins-1 hour could also play a role" Actually, for some people DST changes are much more than that, and DST shifts not only affects sleep duration but quality as well. Of course we do not know whether they are the ones who are more at risk for triggering heart attack by DST shifts.
Thank you for the other comments too! Some of them were very informative for me. And of course thank you, Bora, for your thoughtful post and later on for your discussion. [Bora, as I wrote before, it would be very helpful for my future research if you could provide me with a citation (even if it is "only" a conference abstract or alike) for where it was predicted that DST slightly increases the risk for heart attacks after the spring shift and decreased even more slightly in the autumn. I mean when you write "Thus, the predictions from the circadian theory were completely and clearly correct." Again, this would be extremely useful for me.] I have really learnt a lot. This actually strengthens my opinion that blogs with authors are certainly more meaningful than without. Thanks for your thoughtful opinion on that Dr. McFadden :"Dr. Janszky, I think responsible researchers will always seek to defend and explain their work in whatever medium it is responsibly challenged." For instance, if Bora and the bloggers can provide us with some statistics on the presence of authors that would be very insightful. Both descriptive statistics would be interesting both if we would be able to get some independent (necessarily subjective) rating on the blog style (level of "less formal and more distinctly harsh criticisms" and level of "responsibility of the challange") and relate that to the tendency of authors to enter and post any reaction.
The debate you cite is professionally interesting for me as well (smoking ban and AMI). I will look at those carefully as soon as my time allows!
By the way, thank you for the offer, Bora, to start my own blog! My time is extremely limited so I will certainly not do it in the close future. But I might criticize papers in the future on other blogs meanwhile. My favorite topic is interpretation of statistics in medicine. I plan to be certainly formal to some degree and treat authors how I would like to be treated (I have first hand experience on that after all!). And I think it is never wrong to be polite, one can very seriously disagree meanwhile being polite. So if you see someone challenging authors with poor "formal English" on interpretation of statistics under the name "janszimre", "teddy bear", "DrOsiris" (other names, who knows?), that might be me...
All the best until then!
Imre
Osiris was wife to Isis. She ressurected him from the dead.
I knew Dr. Janszky loved me after all. I look forward to seeing him in the blogosphere.
The post about rhetoric that I promised in this thread appeared a couple of months later - you should read it here.