Salt really does get under your skin

Salt. It — or rather its sodium ions — are essential for animal life. The Romans used salt to pay their solders, salarium argentums. Ants and termites in tropical forests in the Amazon >100 km inland from the sea have smaller populations than those nearer the coast because they get less wind carried sea salt. Adding salt and sodium can increase their numbers seven-fold. Evolution has given us a taste for sodium ions. Cooks flavor our diet  with salt and we add our own.

But salt is also toxic in excess–ask any bacteria or fungi that seeks to grow and multiple on salt persevered meat or pickle. Brine is usually fatal to life unless cells can find away to protect themselves from its osmotic pressure that "drinks" water out of them. The average diet gives us a massive overdose–15 grams rather the 6 grams we need. How do we get rid of the unnecessary and dangerous sodium ions?

Urine and sweat was the traditional answer. Sweat can remove large amounts. In hot climates hard work can cause the body to bucket out sweat–up to 12 liters a day (though 8 to 10 litres are more normal). With that goes salt –  estimated depending on researchers to be 12–15 grams or even 25 grams (nearly an ounce). But this salt and with it sodium removal by sweat is a byproduct. Traditionally the answer was that the real heavy removal work was done by the kidneys and that was then flushed down the drain.

Now that story has changed. Our bodies also have a previously hidden way of removing excess sodium ions; storing them under our skin. Or rather into our subcutaneous lymphatic system its interstitium fluid (extracellular fluid between tissues).

The lymphatic system is where our body collects the fluid that bathe our tissues so it can be put back into circulation. The lymphatic system also works as the eyes and ears of the immune system. And now it turns out it is the body's salt salter. Excess sodium ions get temporarily stored by being bound to proteins called proteoglycans and glycosaminoglycans. This makes them osmotically inactive.

Not that hiding salt away is what this biosalt salter was evolved to do. Our ancestors faced the opposite problem to us of excess salt–deficiency. Animal bodies that could create a backup buffer had an advantage over those that could not store sodium ions. Animals face the same problem with energy–we are advantaged if we can store it from the times when it is available for when it cannot get it. The answer for energy storage is expanding adipose fat cells. With salt the body faced a similar storage problem and evolved salt salter proteoglycans in the subcutaneous lymphatic system.

Benvenuto Cellini's Saliera (saliera is Italian for salt cellar). This is sometimes called the "Mona Lisa of Sculpture". It shows masses of skin thus suggesting that Benvenuto "appreciated" 470 years before modern science the key link between skin and salt.

That we can biologically squirrel away sodium in this way is no small discovery. The kidney's regulation of sodium links to its regulation of blood volume and through this blood pressure. We are diet aliens to early humans. They eat  with  no salt on the table or in the kitchen a sodium-poor but potassium-rich diet of wild not factory processed meat and veg. (Potassium is an element next down in the periodic chemistry table and in some ways very like sodium–the chemist Dalton gave them very similar symbols as shown left and right to reflect this fact. However in the body they have very different roles its biochemistry). Our kidneys evolved to keep sodium and remove potassium ions. They now face the problem that we eat lots of hidden and not so hidden sodium. How does the system of balance sodium and potassium ions work in us with our evolution alien diet that is sodium rich and potassium poor? It seems that a physiological "bug" is exposed that results in our body's getting rid of too many potassium ions. This causes increased contraction of vascular smooth muscles and changes to the cerebral control of blood volume that ups blood pressure.

Knowing that sodium gets buffered under our skin presents us with a more complex story. For a start it suggests that our kidneys do not face the fall impact of our salt rich food–our skin helps us stop poisoning ourselves with the stuff. The storing of excess sodium is also odd. If experimental animals eat a high salt diet the lymphatic capillaries expand (see the green thicker lines on the right) due to the activation of macrophages (a type of immune cell). Stop those cells getting active and with that this lymphatic capillary expansion and blood pressure goes through the roof.

So the newly discovered salt salter under our skin really matters to us modern people. Thanks to our salt buffering subcutaneous lymphatic system, salt is changed from being a toxic substance that would kill us by dramatically raising blood pressure into a moderately toxic one with which we can live. 

References

Marvar PJ, Gordon FJ, Harrison DG 2009 .Blood pressure control: salt gets under your skin. Nat Med. May;15(5):487-8.

Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J. 2009 Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. May;15(5):545-52.

Rabelink TJ, Rotmans JI. 2009 Salt is getting under our skin. Nephrol Dial Transplant. Nov;24(11):3282-3.

Kaspari M, Yanoviak SP, Dudley R, Yuan M, Clay NA. 2009. Sodium shortage as a constraint on the carbon cycle in an inland tropical rainforest. Proc Natl Acad Sci U S A. 106(46):19405-9.

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A cup of strychnine can be nice

Caffeine is a molecularly similar to strychnine and acts upon the same neural receptors, which cause the latter's lethality. Oddly this makes them both in low doses stimulates.

Strychnine was taken to revise for exams, aid endurance in Olympic Marathons and prescribed by doctor as a tonic. It was the Victorian caffeine and high-energy tonic. 

That is not odd: strychnine and caffeine are similar molecules. They both block glycine receptors. The difference apart from strength–caffeine is much weaker is that caffeine also blocks another group of receptors – those for adenosine. But similarity of its stimulant effects with strychnine suggests that its stimulant actions might also be due to its actions upon glycine receptors.

Strychnine was an ingrediant of tonics such as Easton's tablets, Wampole's Preparation and Fellows’s Syrup of Hypophosphites. As recently as 1981 Brent Smith found that 41 commerical products in the US were available for human consumption including proprietary analgesics, digestive aids, cold remedies, cathartics, tonics, vitamins, stimulants, and sedatives. One of the tonics taken by Hitler contained strychnine. As Ronald McGarry and Pamela McGarry note

Another commonly prescribed medication, nux vomica (essence of bachelor button), contained strychnine, a highly toxic central nervous system stimulant. Given that “the bitters”was prescribed for a multitude of ailments, one wonders how many cases of strychnine poisoning there were.

Research by the famous psychologist Karl Lashley in 1917 found it enhanced the training done by rats in mazes. Medical students used it as a pick me up while revising with occasional problems as one Leondard Sandall, recalled in 1896 in a letter to the The Lancet.

Three years ago I was reading for an examination, and feeling " run down" I took 10 minims of strychnia solution (B.P.) with the same quantity of dilute phosphoric acid well diluted twice a day. On the second day of taking it, towards the evening, I felt a tightness in the "facial muscles " and a peculiar metallic taste in the mouth. There was great uneasiness and restlessness, and I felt a desire to walk about and do something rather than sit still and read. I lay on the bed and the calf muscles began to stiffen and’ jerk. My toes drew up under my feet, and as I moved or turned my head flashes of light kept darting across my eyes.. I then knew something serious was developing, so I crawled off the bed and scrambled to a case in my room and got out (fortunately) the bromide of potassium and the chloral. I had no confidence or courage to weigh them, so I guessed the quantity-about 30 gr. bromide of potassium and 10 gr. chloral-put them in a tumbler with some water, and drank it off. My whole body was in a cold sweat, with anginous attacks in the precordial region, and a feeling of "going off." I did not call for medical aid, as I thought the symptoms declining. I felt better, but my lower limbs. were as cold as ice and the calf muscles kept tense and, jerking. There was no opisthotonos, only a slight stiffness at the back of the neck. Half an hour later, as I could judge, I took the same quantity of bromide of potassium and chloral, and a little time after I lost consciousness and fell into a " profound sleep," awaking in the morning with no unpleasant symptoms, no headache, &c., but a desire " to be on the move " and a slight feeling of stiffness in the jaw. These worked off during the day. 28 March 1896. "AN OVERDOSE OF STRYCHNINE." The Lancet, 147(3787):887.

The mention of bromide is interesting because in Agatha Christie's first novel, The Mysterious Affair at Styles, the poisoning happens by the addition of bromide to a normally safe strychnine containing medicine to precipitate  to the bottom of a bottle where they get taken in a single, lethal dose.The medical student presumably took it to precipitate in the strychnine in his gut to stop further absorption.

It was one of the original performance enhancing sport’s drugs. At the 1904 Olympic Marathon, the US runner Thomas Hicks after 30 kilometer his manager following in a car administered 1/60th grain (approximately 1 mg) of sulphate of strychnine and repeated this a few kilometers later when Hicks tried to lie down. He finished the race in first place and then collapsed.

Caffeine and strychine molecules
caffeine strychnine

Duan L, Yang J, Slaughter MM. Caffeine inhibition of ionotropic glycine receptors. J Physiol. 2009 Aug 15;587(Pt 16):4063-75.

Doyle D. Adolf Hitler's medical care. J R Coll Physicians Edinb. 2005 Feb;35(1):75-82.

McGarry RC, McGarry P. Please pass the strychnine: the art of Victorian pharmacy. CMAJ. 1999 Dec 14;161(12):1556-8.

Pain S. Marathon madness. New Scientist. 7 August 2004. 46–7.

Lashley KS (1917) The effect of strychnine and caffeine upon rate of learning. Psychobiology 1:141–170

Smith BA. Strychnine poisoning. J Emerg Med. 1990 May-Jun;8(3):321-5. Jackson G, Diggle G. Strychnine-containing tonics. Br Med J. 1973 Apr 21;2(5859):176-7. 

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Not all your bones are needed

The entire clavicle or any portion of it can be excised without causing any disabilityThis remarkable statement comes from a piece, "Expandable Bone" by George Curry and Sydney Lyttle in the American Journal of Surgery published back in 1955 when editors allowed quirky interesting papers. Only one person has cited it so it worth rescuing its observations from obscurity–unfortunately nothing like it has been published since.

It identifies 10 expendable bones or bits of that can be removedat least in adults.

1. CLAVICLE (COLLAR BONE).

Clavicula  means "little key" in Latin which just about describes this doubly curved long bone. It is the part of the shoulder girdle above the first rib that connects the arm to the body. It seems to act as a strut to support the scapula but in cases of its congenital absence no apparent limitation of shoulder according Curry and Lytte exists. One delivery man without it lifted in his work "heavy packages weighing up to 110 pounds or more".

clavicle minus the end that attaches to the acromion part of the shoulder bladeFor those (such as myself) that have an acromioclavicular joint dislocation the tops of this bone sticks up above a lowered scapula (shoulder blade). This due to the pull of its muscles–the ligaments that are broken not exit to hold it down to the acromion part of the shoulder blade. (They note in passing the acromion process itself can be removed without disability.)

Curry and Lyttle note that for people like me "Excision of the distal end of the clavicle … [may] lessen the period of disability and obviate the late complication of acromioclavicular arthritis ." (See the adjacent X-ray.) The main problem with it seems to them that it "result in a high-riding clavicle which may preclude the wearing of a strapless evening gown". The orthopedic consultant did not offer this and I am not sure the NHS would pay. Indeed, I rather suspect it is no longer done.  But it is oddly reassuring–my shoulder has a "step" deformity and I would worry if I thought the bone sticking up had a function. It does not–it is vestigial just like my appendix.

2. HEAD OF THE HUMERUS

humerus head removedCurry and Lyttle admit "The head of the humerus is essential for normal shoulder function. Its absence is a severe disability". But they also note people without it can still use their arm: "although they have an unstable shoulder joint, they are able to place their hands in their hip pockets, and wash their forehead." They report that one person that could "hang up clothes" –see the X-ray of the arm joining the shoulder minus its humerus head.

3. ELBOW JOINT

Again Curry and Lyttle also describe that living without your elbow joint leaves you disabled. But again they note that a  much surprising amount of function is left. As they point out: "Full flexion and extension can be obtained but lateral stability is lost. These patients can comb their hair, put their hands in their hip pockets and perform almost any function of the elbow not requiring stability."

4. OLECRANON

Your olecranon is the l curved bony bit of the forearm that sticks out behind the elbow at the end of your ulna (in your lower arm). Curry and Lyttle note that along with the third of ulna that articulates the elbow it can be removed "with little or no residual disability" .

5. HEAD OF THE RADIUS
The head of the second bone–the radius–in your lower arm can be removed also at its elbow end. As Curry and Lyttle note "That the head of the radius is expendable has been recognized over many years."

6. ULNA

Not only is much your your ulna bone at your elbow is unneeded but so is it at the other end at the wrist. As Curry and Lyttle note:  the end "fifth of the ulna is expendable. Its distal articulation is small and contributes little, if anything, to the stability of the wrist. The ligaments on the ulnar aspect of the wrist are strong and furnish the needed support in the absence of the distal ulna. Its absence causes no disability." The below X-ray shows this (the black is the surgical metal repair bits put in the wrist). In the colored figure below the ulna is bone 2 and the radius bone 1.

7. CARPAL LUNATE

In the wrist, one of its bones, the lunate (B in the figure) can be removed. As Curry and Lyttle put it that "Its absence causes little, if any, demonstrable disability of the wrist.". They note also in the introduction that the scaphoid (A) is also surplus.

8. PATELLA

The patella is your knee cap. It is "completely expendable" according to Curry and Lyttle. Due to this perhaps when paramilitaries knee-cap a victim to punish them they do not aim to injure the knee cap (which would cause only a minor injury) but its surrounding nerves and arteries. Another part mentioned that is surplus is the meniscus (a crescent-shaped fibrocartilaginous structure) of the knee,

9. HEAD OF THE FIBULA

Curry and Lyttle observe that the knee joining part of the fibula (also called shin- or shankbone) can be removed without effecting the normal function of the lower leg and knee. They also note that much of its shaft can be removed–as often happens for use in bone grafts. Indeed that "Cases are on record in which the entire fibula, including the lateral malleolus, has been excised for osteomyelitis with little resulting disability."

10. MEDIAL MALLEOLUS

The medial malleolus is the inner end part of the tibia at the ankle. A large amount of it–25%-50% can be removed without making the ankle unstable. 

Curry and Lytte note there are more expendable bones that they do not discuss such as the ribs and their cartilage and the coccyx. Though my search may be incomplete I cannot find that a similar paper has ever been written.

Curry and Lyttle make one qualification: they above noted bits "are not expendable in children".

They end their paper with this statement.

It is not the intent or purpose of this presentation to recommend the indiscriminate excisions of portions of the skeleton. An attempt has been made, however, to evaluate the usefulness of excision in certain selected cases rather than reconstruction. In many instances the length of disability can be decreased and the late complications of reconstruction reduced or eliminated with no residual loss of function.

Their paper was published in 1955, I wonder if modern orthopedic consultants would still agree with its conclusions.

From my viewpoint as an evolutionary biologist I think it ignores how radically "soft" our modern lives are compared to those in which our bodies evolved. Maybe if modern humans more vigorously used their bodies, there might be more obvious dysfunction. Without disability means different things given the vigor with which tasks need to be done for survival. Modern humans in the West have very soft lives–things might have been very different on the savannah where our bodies evolved.

On the other hand, evolution selected our bodies when there were no orthopedic consultants. Perhaps the musculoskeletal system involved to be able to compensate through its ligaments and muscles much more than we realize for fractures and injuries. We are after all primates–members of an order of mammals that specialized in climbing in trees. It is reasonable to suppose that our primate bodies evolved also to be robust against tree falls?

Then again it could be that our usual use of our primate bodies have left them with redundancies. I was rather shocked to find when researching my acromioclavicular dislocation that this joint is extremely variable in modern people see the 1949 paper by Marshall R. Urist. In some acromioclavicular joints they are separated by a meniscus attached to the superior acromioclavicular ligament. This meniscus may be a blade of fibrocartilage that extends nearly halfway into the joint or it may form a complete disc that divides the joint into two parts. In other acromioclavicular joints no synovial joint is present with the joint being made by a pad of fibrous tissue attached to the outer end of time clavicle, and no articular cavity. In 49% articular surface of the clavicle overrides the articular surface of the acromion and in 29% of time acromion and clavicle are nearly vertical and lie in same plane. In 6% the two surfaces do not even touch! Clearly this joint is evolutionarily redundant otherwise such variability would not have been allowed to arise. Was my shoulder one without out the proper synovial joint and was this why it came apart?

References

Urist, M. R. (1946). COMPLETE DISLOCATIONS OF THE ACROMIOCLAVICULAR JOINT: The Nature of the Traumatic Lesion and Effective Methods of Treatment with an Analysis of Forty-One Cases. J. Bone Joint Surg. Am.28: 813 – 837.

Curry GJ, Lyttle SN. (1955). Expendable bone. Am J Surg. 1955 Apr;89(4):819-33. abstract

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