Showing posts with label cough. Show all posts
Showing posts with label cough. Show all posts

06 November 2025

Wisdom and Age

                             Wisdom and Age
        Long after I had resigned my Fellowship at Clare College and taken a lecturship at Newcastle University, I was enjoying the privileges of an ex-fellow and lunching again with the fellows at college.  (Ex-fellows are surprisingly rare; fellows tend to 'stay on' if they possibly can.) Remembering college protocol, I took the next available seat at the common board, and found myself sitting next to the Master, Professor Robin Matthews.

How he had aged! I remembered the occasion of his appointment 12 year previously, under the  chairmanship of the elderly Professor Godwin (though with the acute and generous mind of Charles Feinstein at his elbow). There was none of the back-stabbing and shadowy machinations described in C. P. Snow's "The Masters".  We first laid down the principle that the new master should be aged 50 years or over, to avoid the burden of having a 'dud' chairing the governing body for too long a spell. Nevertheless, the name of Robin Matthews drifted to the top of the list of 'possibles', even though he was only 49. Here he was, now 12 years on, looking 70. I wondered briefly if he was suffering some curious condition that caused accelerated aging. 

Demonstrating his mastery of college table-talk, he turned to me, perhaps to show that he recognised me and remembered that I was a biologist, and he asked: "You are a biologist. I have been wondering if Homo sapiens is the only species that lives so long after ceasing to be reproductively active." I was simultaneously grateful and taken aback. Was he also aware that he was aging? I tried to reassure him, by suggesting that, if indeed 'Man' was unusual in that regard, it might point to the evolutionary advantage of wisdom; that we were a species that benefited from, and cherished, our grandfathers and grandmothers.  

Is there a Wisdom of Age? A special brand of wisdom. Perhaps like a collection of prized pebbles that a traveller picks up along the way, increased as much by the miles travelled as by the vigilance and curiosity of the traveller. 

I have recently acquired a few tricks that are peculiarly relevant to an aging mind, like writing things down, and paying special attention when I handle small but crucial objects like keys and mobile-phones. I have also evolved a new way of finding lost objects as an adaptation to weakening eyesight. For seventy years I enjoyed the role of family-finder. I could enter a room and sweep visually from two or three vantages, and spot the missing object before anyone else. Now the visual sweep yields nothing. I have to sit down and think where it was last used, think where it would be hard to see if it were in fact present, (Perhaps under something, or camouflaged; as a white pill on a pale carpet). But these are hardly 'special powers'; they are mere 'sticking-plasters' to make good my deficits.

On the other hand, I have evolved quite recently my own way of suppressing a cough. (You must, yourself, at some time have experienced the agony of struggling with a cough during a concert?) A lozenge offers some relief, as also a sip of water. But my new method require no equipment. The cough in question is the 'dry cough', the unproductive cough that seems to do nothing for the 'cougher', but to be solely to the benefit of the virus and its progeny. I was intrigued during the COVID pandemic by the idea that the virus had found out how to trigger the cough reflex for its own purposes, and I think I found a possible (even probable) mechanism. (See my post) However, my discovery of a way to thwart the virus owed nothing to that research. It was discovered by pure serendipity.  I put my hand loosely over my nose and mouth, perhaps with the idea of containing the cloud of virions, and then breathed partly through my mouth. I was surprised to find that the compulsion to cough faded to nothing in 30 seconds. I suppose in the space confined by my hand the air became enriched in CO2 and water vapour, and a little depleted of O2; the CO2, in turn, may have affected the pH of the surface layers in the throat but, as long as it works, the mechanism does not matter, except for the curious among us. 

I have tried to interest others in this trick, purely from a love of mankind, but do not think I have made many converts; to date. That does not worry me (unduly); I am able to enjoy the benefits in my own small way.  This, I think, qualifies as 'wisdom of age', one of the benefits of living beyond the period of reproductive activity. 

Another recent discovery which I am inclined to regard as a further example of the 'wisdom of age' is my new method of drinking wine. This, also, as a life-long educator and philanthropist, I am keen to share. It is not important that you know how I came by this new method, but I am inclined to tell you that it was as much to do with my health as my pocket book. Ever since my brief experience of 'exercise-induced angina pectoris' at the age of 75 (see my post), the doctors have been asking me annually to declare the average number of units of alcohol drunk per week. As I had a small German 'tasting glass' marked '100ml' just below the rim, I resolved to limit my intake of alcohol to 100 ml of red-wine at lunch and the same again with my evening dinner. Essentially 2 bottles a week. That discipline brought its own rewards (smugness, largely) but that is not my present point. For I discovered that, by taking tiny sips, I got just as much gustatory pleasure as I had found with decent gulps of wine. I can now sip away at 100ml of wine for the best part of an hour. 

We had a young man and his mother round for a glass of wine and a chat the other day. I was astonished how quickly his glass required topping up. So much so that I found it more convenient to park the bottle his side of the table. As they were leaving, I shared my new tip; "small sips are as rewarding as large gulps." Another example of an old man's wisdom. 

        A further tip I would like to pass on is my unique 'neck-scarf'. I often used to wear a tie, but found that I was becoming a rare species in that regard. Furthermore, I noticed that my shirt-collars frayed rather quickly from rubbing against the short hairs on my neck (and perhaps also from the scrubbing required to clean the neckband). I tried tying a silk handkerchief round my neck but could not find one sufficiently large. So I bought a metre off a bolt of polyester(**) lining material; indeed one metre in green and one in blue. This is a slippery, shiny, hard-wearing, rather hydrophobic material that can be washed and drip-dried inside 2 hours. I cut strips 25 cms x 100 cms, then turned, and hemmed, the edges. Tie under the chin with a half-hitch, before or after putting on the shirt, but before buttoning the penultimate button. (Leave the highest button undone.) So simple! It is pleasing and comfortable to wear, beside closing the gap between shirt and neck. These days I am seldom dressed any other way. 


(**Beware: this material requires a very cool iron.)

29 November 2021

The Cough Reflex and its Rôle in Virus Transmission.


The Cough Reflex and its Rôle in Virus Transmission.

(“Coughs and sneezes spread diseases.” Old folk-saying: )

Introduction

The cough reflex involves (a) triggering, or activation of a nociceptor, (b) an afferent signal in C-fibres of the vagus nerve to the brain, (c) efferent signals to the diaphragm and other muscles, and (d) a rapid muscular contraction [1]. 

We can all distinguish between a “dry” cough (when there seems nothing in the trachea or larynx to cough up), and a “wet” or “productive” cough (when phlegm or mucus is moved up by the blast of air travelling, we are told, at ≤ 600 mph.) It is the former that I am interested in. The brain has some (but limited) ability to suppress a cough, as also do placebo drugs [1]. But those who have struggled to suppress a cough during a concert, or when sharing a bed, know that it is extremely difficult. 

It has probably occurred to many others, as it has often occurred to me, that virus-infected mucous membranes generate a cough-trigger "in order to spread the virus itself" [2]. A virus that is able to trick its host into a cough (or a sneeze) could spread infectious virions widely, and thus increase enormously its chance of finding a new host. But the possibility that the corona viruses target only ACE2 precisely because ACE2 is crucial to the cough-trigger is an hypothesis too good to pass over. Is there a link between ACE2 and the cough reflex? Of all the cell-surface proteins to which the virus could bind, why does it  choose to bind to the ACE2? And does such binding trigger a cough? If so, how.

This led me to wonder what is the cough-trigger, and what part is played by an active viral infection. Dipping into the medical and scientific literature brought up three important areas for further study: Bradykinins, Angiotensins, and ACEs.

Bradykinins, Angiotensins, and ACEs

Bradykinin is a nona-peptide (which can be referred to as Bk(1-9)), but it can come with an additional N-terminal Lys residue (here called Bk(0-9)), or lose the C-terminal Arg becoming the more active Bk(1-8) (also called des-Arg9 Bk). Active bradykinins work via two G-protein-coupled receptors called B1 (especially linked to Bk(1-8) and strongly induced during inflammation), and B2 (activated by Bk(1-9) and constitutive, hence the ‘normal’ receptor).[3]

Angiotensins [4] are another small family of peptides, unrelated to the bradykinin sequences other than in size, charge, and having amino acid residues P and F in positions 7 and 8; see Table 1 below.) Angiotensin I is an inactive decapeptide (Ang(1-10)). It is converted to active (vasoconstrictive) angiotensin II (Ang(1-8)) by the removal of the c-terminal dipeptide. [It is probably irrelevant to this story, but angiotensin II raises blood pressure, while bradykinin(1-8) lowers it.]

ACEs, Angiotensin-Converting enzymes [5], are integral-membrane-bound proteolytic enzymes capable of cutting peptide chains. There are two related proteins; ACE1 and ACE2. The former converts inactive angiotensin I (the deca-peptide) to active angiotensin II (the octa-peptide), by cutting off the C-terminal dipeptide. [It also converts angiotensin(1-9) to angiotensin(1-7).]

ACE2 has become famous since January 2020 as the unique and highly specific binding site of the SARS-CoV-2 virus. It is present in a wide range of tissue surfaces, but especially in kidney, the endothelium of the gut and blood vessels, the lungs, and in the heart. It converts angiotensin(1-10) to angiotensin(1-9) by cutting off the C-terminal Lys. But it also degrades active Bk(1-8) to inactive Bk(1-7) and other peptides [6]. [It is a quaint irony of history that ACE1 cuts off a dipeptide while ACE2 cuts off a single amino acid residue.]



Table 1 Peptide Sequences (in one-letter code, showing net charge).

Bradykinins 

Bk(1-9)   RPPGFSPFR         ++ Active, vasodilator, B2

(Bk(0-9) LRPPGFSPFR         +++ ?B2)

Bk(1-8)   RPPGFSPF + Active, pain, B1

(Bk(0-8) LRPPGFSPF ++ ?B1)

Bk(1-7)   RPPGFSP         + Inactive,


Angiotensins

AngI(1-10) NRVYIHPFHL +++ Inactive

AngII(1-8) NRVYIHPF         ++ Active vasoconstrictor

Ang(1-9)       NRVYIHPFH +++ ?

Ang(1-7)       NRVYIHP         ++ Less active, competes AngII(1-8)


Is Bk(1-8) the Cough-Trigger?

There are three bits of evidence in favour of the hypothesis that the binding of virus to ACE2 might directly trigger cough by allowing the build up of Bk(1-8). 

    (1) A distinct and well documented type of “dry cough” is observed in 15-20% of patients taking ACE inhibitors to counter their high blood pressure [1]. These block the generation of active AngII(1-8), but also block the inactivation of active Bk1-8, which consequently builds up.Though not rigorously confirmed, it is widely assumed that this raised bradykinin level causes the cough. 

    (2) Raised bradykinin levels are found in virally infected mucosae [3]. 

    (3) Cough-Hypersensitivity-Syndrome, especially common in women [1,9] and in patients from south-east Asia [1], can be induced in animal models by local application of bradykinin. 

This hypothesis requires that virus binding (and subsequent inversion into the cell) blocks the action of ACE2 in deactivating Bk(1-8) to inactive Bk(1-7). The raised levels of Bk(1-8) after infection suggests that virus does have that effect.


References

[1]  https://www.sciencedirect.com/topics/medicine-and-dentistry/cough-reflex

[2]  Morice, A.H. Chronic cough hypersensitivity syndrome. Cough 9, 14 (2013). https://doi.org/10.1186/1745-9974-9-14

[3]  https://www.sciencedirect.com/topics/neuroscience/bradykinin

[4]  https://www.sciencedirect.com/topics/neuroscience/angiotensin

[5]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321295/; https://www.frontiersin.org/articles/10.3389/fmed.2019.00136/full

[6]  https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30282-6/fulltext; https://www.frontiersin.org/articles/10.3389/fmed.2019.00136/full

[7]  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340691/

[8]  https://www.sciencedirect.com/topics/neuroscience/bradykinin

[9]  https://erj.ersjournals.com/content/9/8/1624


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