Physiologia .blog

Bitter taste receptors in the human airways: possible target for therapy and functional riddle

2010-10-25T08:09:00.008+01:00

TAS2Rs (bitter taste receptors) in the airways (red bands)

Researchers at the University of Maryland School of Medicine in Baltimore have discovered that bitter taste receptors are not just located in the mouth but also in human lungs.

This discovery could have an impact on the treatment of asthma and other obstructive lung diseases.

The detection of functioning taste receptors on smooth muscle of the bronchus in the lungs was so unexpected that we were at first quite skeptical ourselves.
Stephen B. Liggett, M.D., senior author

According to Dr. Liggett, the taste receptors were found by accident, during an earlier, unrelated study of human lung muscle receptors that regulate airway contraction and relaxation.

The taste receptors in the lungs (TAS2) are the same as those on the tongue. However, in the airways, they are not clustered in buds and apparently are not connected to any sensory pathways.

For the current study, Dr. Liggett's team exposed bitter-tasting compounds to human and mouse airways, individual airway smooth muscle cells, and to mice with induced asthma.

I initially thought the bitter-taste receptors in the lungs would prompt a 'fight or flight' response to a noxious inhalant, causing chest tightness and coughing so you would leave the toxic environment, but that's not what we found.
Dr. Liggett.

But, the interesting thing about these TAS2Rs, besides the fact that they induce bronchodilatation, is the way they do it:

TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²⁺]_i) in ASM (airway smooth muscle) in a Gβγ–, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP₃) receptor–dependent manner, which would be expected to evoke contraction.
Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca2+]i response at the cell membrane, which opens large-conductance Ca²⁺-activated K⁺ (BKCa) channels, leading to ASM membrane hyperpolarization.
Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

This find will (very probably) lead to some effective new approaches in the treatment of obstructive respiratory diseases, but it also rises an interesting question about the physiological purpose of these receptors being there.

Ontogenetically, the respiratory and the digestive tracts are related, so the fact that some proteins (which we are used to consider very specific to a certain place) are expressed across these two is not hard to grasp. But the particular reason for the existence of bitter taste receptors in the airways, that when activated generate bronchodilatation will most certainly remain unclear for years, unless some endogenous agonists are identified.

Follow-up: A clue in an article published last year, about the same sort of receptors on motile cilia from human airway epithelial cells that when activated "increased the intracellular calcium ion concentration and stimulated ciliary beat frequency" (see references).

References

Deshpande DA, Wang WCH, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JSK, Liggett SB.
Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction.
Nature Medicine.
doi:10.1038/nm.2237

Wolfgang Meyerhof et al.
Human Bitter Taste Perception
Chem. Senses (2005) 30 (suppl 1)
doi:10.1093/chemse/bjh089

Shah et al.
Motile Cilia of Human Airway Epithelia Are Chemosensory
Science Express; Science 28 August 2009
doi:10.1126/science.1173869

Story via EurekAlert!
Image: University of Maryland School of Medicine

Heribert Watzke on 'The brain in your gut'

2010-10-23T14:57:00.002+01:00

Heribert Watzke (food scientist, Nestlé) talks about how the "big brain" and the "gut brain" operate together and what can be done to prevent conflicts between the two, pointing to cooking as one crucial characteristic of humans.

"Heribert Watzke is irrepressible. In the midst of explaining some scientific point, he can't restrain himself from springing over to his computer to show a graphic animation of molecular structures in cappuccino foam."

Why the obvious: women sweat less than men

2010-10-22T08:42:00.004+01:00

Everybody is blogging about this:

Tomoko Ichinose-Kuwahara et al.
Sex differences in the effects of physical training on sweat gland responses during a graded exercise
Experimental Physiology doi:10.1113/expphysiol.2010.053710

The tested hypothesis was "that an enhanced sweat gland response by physical training would be smaller in the TF group than in the TM group."

The results:

The mean local sweating rate (SR) on the forehead, chest, back, forearm and thigh was significantly greater in the trained subjects than in the untrained subjects of both sexes. The degree of the increase in SR with physical training was greater in males than in females at higher levels of exercise intensity. This increase in SR depended primarily on an increase in the sweat output per gland (SGO) in both sexes. However, control of the SR increase with increasing exercise intensity was altered by training in females, i.e. the increase in SR from exercise at 50 to 65% V_O2max. depended only on an increase in SGO in trained females and males and untrained males, but it depended on increases in activated sweat glands and the SGO in untrained females. It was concluded that training improved the sweating response, and a sex difference was observed in the degree of improvement in the sweating response due to physical training. This sex difference became more pronounced with increasing exercise intensity. A sex difference was observed in the control of sweating rate to an increase in exercise intensity, i.e. the maximal activated sweat gland responses of untrained females required a higher body temperature or work intensity than the other groups.

With fewer words:

[...]a sex difference in the effects of physical training on the sweating response, and the degree of improvement with physical training is smaller in females than in males. This sex difference increases with increasing exercise intensity[...]

What I find odd is that although they mention testosterone in the article, citing various results about how it contributes to sex differences in sweating regulation, they only measured plasma oestrone, oestradiol and progesterone. In regard of hormones, the science stops with the use of these measurements to confirm that the females were in the mid-follicular phase of the menstrual cycle.

The authors themselves mention this limitation:

In the present study, we did not measure testosterone levels, hence the effects of testosterone on the sex difference in the effects of training are unclear. However, based on our findings and previous reports, it is conceivable that testosterone levels affect the sweat gland response. Further studies are necessary to clarify this point.

It is conceivable indeed :)

Well, this got in the media as some kind of breakthrough.

The beautiful picture is Sweat V by Jeffrey Montes

Open courses @ Yale: Frontiers of Biomedical Engineering

2010-10-22T01:41:00.000+01:00

If you're the "always-want-to-learn-about-stuff" type, go to Open Yale Courses and watch prof. Saltzman lecturing about "basic concepts of biomedical engineering and their connection with the spectrum of human activity".
It's a good way of filling long coffee breakes.

Answers about capillary fluid exchange

2010-10-22T00:29:00.005+01:00

I came across this; I decided to answer the questions - it feels good to write about these things:)
These are some simple questions about capillary fluid exchange:

How would decreased blood volume affect exchange between capillaries and the interstitial fluid?
How would increased blood pressure affect exchange between capillaries and the interstitial fluid?
How would higher amount of plasma proteins affect exchange between capillaries and the interstitial fluid?
Would these make more or less fluid go from the capillaries to the interstitial fluid?

First, let's recall the forces that drive the dynamics of fluid through the capillary wall:

Plasma colloid osmotic pressure - inward: about 28 mmHg
Capillary hydrostatic pressure - outward: approximately 30 mmHg at the arterial end, approximately 10 mmHg at the venous end, with a mean value of 17.3 mmHg
Interstitial fluid colloid osmotic pressure - outward: about 8 mmHg
Interstitial free fluid (hydrostatic) pressure - outward: about -3 mmHg (negative value)

So, the inward pressure is 28 mmHg at both ends, determined solely by the colloid osmotic presure of the plasma.
The outward pressure however is different. At the arterial end: 30 + 8 + 3 = 41 mmHg. At the venous end it is 10 + 8 + 3 = 21 mmHg.

It is now easy to see what the water does: at the arterial end, the sum of the pressures is 28 - 41 = -13 mmHg (the negative value means that the water moves out of the capillary into the interstitium); at the venous end, 28 - 21 = 7 mmHg (positive pressure that drives water into the capillary).

If we use the mean value of the capillary pressure (17.3 mmHg - this a functional average, calculated based on measurements for the entire length of a capillary) we come to an average outward pressure of 17.3 + 8 + 3 = 28.3 mmHg. This is 0.3 mmHg higher than the "constant" 28 mmHg inward pressure. These values best reflect the reality of what is happening under normal conditions: a small amount of fluid escapes into the interstitium - this the reason we need the lymphatic system.

After all that textbook theory, let's answer the questions.

1. How would decreased blood volume affect exchange between capillaries and the interstitial fluid?
If we assume that the decrease of the blood volume leads to a decrease in blood pressure and this in turn decreases the capillary pressure, the logic is simple: since the capillary pressure pushes a certain volume of fluid into the interstitium, we would expect a decrease of this volume; if the decrease in capillary pressure is large enough, the normal flow can be reversed i.e. water passing into the capillary from the interstitium. The body tends to maintain a convenient blood volume at the expense of the interstitial fluid.

2. How would increased blood pressure affect exchange between capillaries and the interstitial fluid?

This is the reverse of the previous question. Increased blood pressure leads to increased capillary pressure (though not always) and so on.

3. How would higher amount of plasma proteins affect exchange between capillaries and the interstitial fluid?

The plasma proteins (albumin in particular) are responsible for the colloid osmotic pressure. High albumin content of the plasma leads to an increased osmotic pressure of the plasma, that generates flow into the capillary.

4. Would these make more or less fluid go from the capillaries to the interstitial fluid?

See above.

Notes:
This and this could help.
Anaesthesiamcq.com has a promising Fluid Physiology online textbook

I used values from Guyton's textbook of Medical Physiology, 11th ed. The numbers vary depending on the book, but the phenomena they describe are the same.

Analysing web popularity

2010-10-20T23:45:00.001+01:00

When properly investigated, the WWW can offer some interesting results to wise researchers, as this piece of information confirms it: a team at Indiana University looked at traffic data for 9 million web pages gathered in 10 years, in order to find out why and how web pages grow in popularity. Their results show that usually, the increase popularity some websites experience is not sustained, but rather it comes and goes.

"Network models that only assume “the more you have, the more you’ll get” fail to capture the distribution of bursts. The reason: these models don’t take into account external influences on people’s choices, such as new interest in an actress’ website after she wins a major award. Instead, Ratkiewicz et al. propose a “rank shift model” where, at each time interval, a web page randomly receives a new rank in overall popularity that is somewhere between where it currently is and the top (most viewed) position." (Synopsis)

The team is the same one that developed Truthy, the system that shows how memes spread on Twitter and exposes "political smears, astroturfing, misinformation, and other social pollution".

Story via Physorg

Ratkiewicz, Fortunato, Flammini, Menczer, Vespignani - “Characterizing and Modeling the Dynamics of Online Popularity.” Physical Review Letters 105, 158701 (2010). DOI: 10.1103/PhysRevLett.105.158701

Alternative Therapy Flowchart :)

2010-10-19T18:56:00.001+01:00

Source: Science, Reason and Critical Thinking: A Handy Alternative Therapy Flowchart. There also is a Periodic Table of Irrational Nonsense

Physiology Understanding Week, November 1-6

2010-10-19T02:14:00.001+01:00

In the US: 1-6 November is Physiology Understanding Week (PhUn Week).

Phizzy the Physiology Bear :)

The event is designed to increase student understanding of physiology in students’ daily lives, introduce them to possible physiological careers, and to help teachers integrate physiology into their curricula.

Physiology Understanding Week is sponsored by the American Physiological Society.
Website here

ECG simulation for teaching, learning or just playing

2010-10-18T21:58:00.008+01:00

In physiology, simulation with proper tools can be a powerful resource in teaching and research. Most of the processes in the human body are both complicated and not fully described by research, so running accurate simulations is not so easy. This is not the case for the electrical phenomena in the heart. We now know enough about them to engineer electronic devices that generate all kinds of rhythms (I'm sure almost all medical students have used such contraptions in the lab).

For those who want to play with ECG in the serenity of their home there's this:

ECGSIM

ECGSIM screen

ECGSIM is a free software developed at Radboud University in the Netherlands, that enables the study of the relationship between the electric activity of the heart and the resulting potentials on the thorax: PQRST wave forms and body surface potential maps. ECGSIM is distributed under the Creative Commons GNU general public license and can be run under Windows and Mac OS X.

I have used it a few years ago and I must say it is a wonderful tool for learning ECG. Before you start, I advise reading the program's manual carefully; also revisit your physiology textbook for the basic theory on cardiac electrical phenomena and principles of ECG. Keep in mind that this tool is not meant to explain the basics, but to provide some additional insight. The more you already know about ECG, the more you will get from ECGSIM.

Click here to go to ECGSIM's homepage.

I will come back with some updates on how to use ECGSIM soon (or at least I hope to).

ECG simulation using Matlab, WFDB or Octave

It is also possible to run ECG simulations using Matlab or its free counterpart - Octave.

I have almost no experience with these, but I can tell you that they are most suited for research than for learning. For those who want to know more, PhysioNet is the place to go; when you're there, be sure to check out the resources in PhysioBank and PhysioToolkit (there you will find the WFDB Software Package) areas - you never know when you might need them.

For Matlab, a good start may be this.

ECG on-line resources

There are numerous sites providing ECG tutorials, guides or quizzes. My advice is: know your textbook before going to the web. Always be careful about the information these resources provide, as it may not be completely accurate. Anyway, when learning to interpret ECG is useful to see and scratch your mind with as many strips as possible. Here are a few sites:

The Alan Lindsay ECG Learning Center @ Utah

http://library.med.utah.edu/kw/ecg/

The Whole ECG Primer @ anaesthetist.com

http://www.anaesthetist.com/icu/organs/heart/ecg/

Ekginterpretation.com

http://www.ekginterpretation.com/

Electrocardiogram Tutorial @ cvphysiology.com

http://www.cvphysiology.com/Tutorials/Tutorial%20-%20ECG.htm

ECG tutorial @ emedu.org

http://www.emedu.org/ecg/

Six Second ECG Simulator @ SkillStat Learning

http://www.skillstat.com/Flash/ECGSim531.html

The basics of reading an ECG wiki @ OzEMedicine.com

http://www.ozemedicine.com/wiki/doku.php?id=ecg_easy

ECG Wave-Maven

http://ecg.bidmc.harvard.edu

Dr. Smith's ECG Blog

http://hqmeded-ecg.blogspot.com/

ECG Library @ Lifeinthefastlane.com

http://lifeinthefastlane.com/ecg-library/

They finally nailed it: ABC becomes CAB

2010-10-18T07:24:00.007+01:00

The American Heart Association is re-arranging the ABCs of cardiopulmonary resuscitation (CPR) in its 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, published in Circulation: Journal of the American Heart Association.

Recommending that chest compressions be the first step for lay and professional rescuers to revive victims of sudden cardiac arrest, the association said the A-B-Cs (Airway-Breathing-Compressions) of CPR should now be changed to C-A-B (Compressions-Airway-Breathing).

"For more than 40 years, CPR training has emphasized the ABCs of CPR, which instructed people to open a victim's airway by tilting their head back, pinching the nose and breathing into the victim's mouth, and only then giving chest compressions," said Michael Sayre, M.D., co-author of the guidelines and chairman of the American Heart Association's Emergency Cardiovascular Care (ECC) Committee. "This approach was causing significant delays in starting chest compressions, which are essential for keeping oxygen-rich blood circulating through the body. Changing the sequence from A-B-C to C-A-B for adults and children allows all rescuers to begin chest compressions right away."

In previous guidelines, the association recommended looking, listening and feeling for normal breathing before starting CPR. Now, compressions should be started immediately on anyone who is unresponsive and not breathing normally.

All victims in cardiac arrest need chest compressions. In the first few minutes of a cardiac arrest, victims will have oxygen remaining in their lungs and bloodstream, so starting CPR with chest compressions can pump that blood to the victim's brain and heart sooner. Research shows that rescuers who started CPR with opening the airway took 30 critical seconds longer to begin chest compressions than rescuers who began CPR with chest compressions.

The change in the CPR sequence applies to adults, children and infants, but excludes newborns.
Other recommendations, based mainly on research published since the last AHA resuscitation guidelines in 2005:

During CPR, rescuers should give chest compressions a little faster, at a rate of at least 100 times a minute.
Rescuers should push deeper on the chest, compressing at least two inches in adults and children and 1.5 inches in infants.
Between each compression, rescuers should avoid leaning on the chest to allow it to return to its starting position.
Rescuers should avoid stopping chest compressions and avoid excessive ventilation.
All 9-1-1 centers should assertively provide instructions over the telephone to get chest compressions started when cardiac arrest is suspected.

All of the above via EurekAlert
Photo credit: Flickr

Needless to say: it was time! I was always intrigued by the apparent emphasis on airways and breathing/not breathing in basic life support for the nonprofessionals. From what I know, it almost always led to lost time with checking, tilting and bending.

Another mnemonic bytes the dust...

To read and watch

2010-10-17T21:25:00.002+01:00

If you are not yet tired of reading about how every progress imaginable is sooo close, throw a look at New Scientist's artificial life special.

Also, watch Juan Enriquez talking about a major "reboot" on TED. He points to three trends in technology that might open doors in the near future: cell engineering, tissue engineering and robotics.

What is Crosstalk and what can we learn from it

2010-10-16T09:21:00.006+01:00

In physiology, crosstalk is a phenomenon that occurs when signals are shared between two or more signaling pathways. When this happens (and it is not rare) one signaling event may lead to different effects on every system that responds.

Some examples of crosstalk:

TNF (tumor necrosis factor) alpha: this is a cytokine involved in inflammatory response and cell death, produced by the macrophages and other cells. It can bind to many receptors, but two of these
are the most important: CD120a (aka TNF-R1)and CD120b (aka TNF-R2). Although we are tempted to consider TNF as a death sentence for the cell (its name, maybe?), it is actually a so-called "Janus-faced" molecule because of the crosstalk between the pro- and the anti-apoptotic pathways.

Activation of NF-κB promotes protein synthesis and actually interferes with apoptosis by messing with the caspases
The MKK-JNK and FADD-caspases pathways promote cell death.

In the case of TNF alpha, crosstalk occurs at more than one point:

The receptors themselves activate both the pro- and anti-apoptotis pathways
NF-κB pathway leads to an incresed production of apoptosis-regulator proteins (for example FLIP/CFLAR) that inhibit the pro-apoptotic pathways


Image credit: cellsignal.com. Click on the image see the original Apoptosis Signaling schematic.

Leptin: Leptin is a hormone produced by adipocytes at a rate that is proportional to the body fat. Its main purpose appears to be the control of the amount of food intake. It achieves that by inhibiting the response of hypothalamic neurons to neuropeptide Y, by increasing production of alpha-MSH and by interfering with the actions of anandamide. Besides these actions and other tweaks of the metabolism, it "allows" ovulation (more in mice than in humans, it seems) by crosstalk that takes place in the hypothalamus.

Besides these two examples there are countless other instances of interconnected pathways. In fact, very few molecules have a single effect, in addition to that, many receptors, when activated, trigger more than a single chain of events in the cell and there are a many types of different receptors for a given entity, situated on different cells that know and do different things.

So, crosstalk is essential for integration. When we can imagine a connection between two regulatory pathways, most probably it is there, preventing chaos from taking over. What if TNF would lead ONLY to apoptosis and what if a starving female could ovulate as usual?

Integrative physiology is harder to grasp and harder to teach but the real beauty of it reveals itself in the multitude of interconnections that complicate the classic approach.

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Modelling along the paths of Guyton's diagram

2010-10-08T06:43:00.004+01:00

In 1972, Guyton, Coleman and Grander draw and published a diagram:

This representation of the numerous regulatory pathways of circulation was the result of a brilliant idea and thousands of hours of work.
Originally intended to aid(?!) in teaching physiology to medical students, it is now used for the development of models for research in developing simulation software.

There is still some debate along some of the blocks that comprise the diagram but, interestingly, with some tweaks over time, Guyton's work seems beautifully valid.

The article that got my attention (the reason I write this post) describes a few SIMULINK runs of the Guyton-Coleman diagram and explains how and why some errors got corrected.
Thanks to these guys, we are one step closer to a reliable way of simulating real clinical scenarios. But we are still far from that. Anyway, seeing the above diagram and becoming aware of the debates around it makes me feel sad for patients in shock.