Toward An Objective Correlate Of Pain

While taking a hot water bag to find relief for a severe spondylosis pain, I wondered why pain could not be expressed in a way different from the generally used Visual analog scale. The patient is asked to look at a chart (shown in the figure) and told to rate his sensation, that tallies most well with his pain. If that hot bag were to be applied to a person not having any pain, he would jump almost instantly. The fact that I tolerated it so well (and benefited from it), only shows its countering (counter irritant property) property, which should be somewhat proportional to the severity of one's pain. The relationship of a counter-irritant to pain severity, whether linear, logarithmic or exponential, needs to be established and quantified.

A patient's own account of pain may be subjectively modified according to the personality of the patient and many other factors. As such, this type of quantification is liable to be erroneous. Pain should better be measured in an objective manner, free of bias. In this instance cited above, one could use the formula: Q(heat)=m(mass) x s(specific heat of the substance) x t(temperature), to know the amount of heat energy transferred to the patient. I am assuming that the pain relieving techniques will, kind of, obey Newton's Third law. Amount (intensity) of counterirritant that just suffices pain relief will be equal to the degree of pain. But it is not actually so, as we will see later.

By noting the difference in local temperatures before and after the procedure, one could get "t".
Mass or "m" could be measured by estimating the volume of the body tissue that was actually heated by infrared mapping, for example; and the expected density of that area. Specific heat for the tissue in question could be easily known and standardized using some cross-sectional studies. A suitable nomogram may later be drawn by plotting values obtained from such observations, for quick estimates. It seems logical that pain so measured, will have its units in British Thermal Units (btu), calories or their work (mechanical) equivalents like ergs, Joules, foot-pounds etc..

In pain therapies using mechanical energies (Ultrasound), electromagnetic devices (laser, short wave diathermy, high frequency photons such as X rays) , a similar formula may be used to obtain the pain equivalent. For example, in laser or short wave therapy, we may design a device that will measure the amount of energy in Watt.seconds/Joules the given area of tissue is supposed to absorb, over a given period of time. The chemical analgesics (pharmaceuticals e.g. Non Steroidal Anti Inflammatory Drugs or steroids; counter irritants such as capsaicin) may be quantified using Scoville scale or by evaluation on the degree of relief from algesia.

Calculating pain may be quite painful in itself. Pain sensation does not tally linearly with noxious stimulus. Rather, a logarithmic relationship was proposed in the Weber Fechner law, which held that the magnitude of pain (or a sensation) felt, was proportional to the log of the intensity of a stimulus. In other words, to feel twice as much pain, you needed to hurt 10 times! To complicate matters further, our present knowledge suggests that the magnitude of a sensation is related by a power factor to the intensity of that sensation. R=KS^A; where R is the sensation felt, S the intensity of stimulus, K and A are constants for that particular tissue. The brighter side is, we get a preformulated relationship for pain calculation.

Pain (musculo skeletal/ visceral, exogenous/endogenous) is generally of two types: fast pain and slow pain. Fast pains such as sharp pain of pricks, stabs are usually carried by Ad (A delta) nerve fibres, while slow aching pains are carried by type C nerve fibers. Ad fibres can carry impulses rapidly as these fibers are myelinated and are of large caliber. C fibers, on the other hand, are unmyelinated and narrow. A-delta fibres release glutamate and C fibers secrete substance-P. A way to measure these chemicals could be a step closer to quantifying pain.

The signals from these fibers travel to the thalamus, a part of the lower brain, on their way to the cerebrum for the localization of pain. Measuring the metabolic activity in thalamus, arising out of increased neural discharges there, by fMRI or PET scan may also shed some light on the intensity of pain stimuli (the stimulus at this level is unmodified by the higher brain) that reaches thalamus. We can also measure the blood levels of endogenous opioids (enkephalins, endorphins) which are secreted in body's response to the pain and adrenaline, secreted in response to increased sympathetic discharge, which is an usual accompaniment of pain. Their blood/plasma levels may correspond with pain severity. Other pain markers like bradykinin, histamine, potassium ions and proteolytic enzymes could be probed too.

True, that the patient may or may not feel as much pain as has been measured this way, because pain perception may not be proportional to the physical/chemical parameters thus described and it is not uniform in all subjects. The brain sees pain in its own mathematical terms, and everyones' brain is different in this regard. A soldier may overlook his gushing wounds, whereas pampered girls of rich persons may feel a lot of pain from an apparently trivial injury. But, quantification of pain in this way (by measuring the physical/chemical yardsticks) may correctly establish the severity of pain in silent myocardial infarction of neuropathy (pain sensation is dulled here due to neural malfunction), decubitus ulcers, trophic ulcers, malingering and in similar situations. In this way we may be able to find a better and objective correlate of pain in clinical practice and develop more efficient analgesics.

P.S. In a recent development, some objective physiological correlates of pain has been tracked. These include measurements from the nonlinear composite of heart rate, heart rate variability, amplitude of the photoplethysmogram, skin conductance, fluctuations in skin conductance, and their time derivatives.  Algorithms can then convert the data into a real-time, continuous index on a bedside monitor. This has resulted in the fabrication of a wearable sensing device can be mounted on a finger.

Last modified: Nov 28, 2015
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What's Food Got To Do With It

I don't know who names these words, but whoever does it, seems to do it with a sense of perversion. Medical professionals are notorious in naming medical symptoms or signs or investigations in such a way that they are apt in describing the condition itself, but they make some delicious foods seem rather repugnant in the process.

Lets start with appetizers: Port wine stain (naevus flammeus) is a birthmark due to hemangioma, a conglomeration of dilated blood capillaries, which are often treated by laser.
If the word pea-soup makes you fell yummy, wait, for pea soup has traditionally been used to describe the stool of typhoid patients, while 'rice water' refer to the stool of cholera! If you want to find solace in coffee, coffee ground vomiting of hematemesis, in which the blood has been altered by its reaction with gastric acid (hydrochloric acid), won't let you, while teaspoon nails refer to koilonychia of iron deficiency anemia and nothing related to tea. Red currant jelly is not some salivating stuff rather it is something found in intussusception, a situation when the intestinal coils get entangled.

Lets discuss fruits (desserts) instead. Perhaps they wouldn't let you down. But they have left no stone unturned here too. Strawberry angioma- is a birth mark, cherry red spot- another birthmark, peau d' orange refer to carcinoma of the breast, and lot more. No rest for the wicked!

Your appetite for Swiss roll by may be dampened when you know the fact that these are sheetlike membrane-coverings by Schwann cells, in the Peripheral Nervous System. Italian dish Spaghetti and meatball have not been spared too. They are found in Tinea versicolor, a skin condition characterized by both hyper and hypopigmentation, caused by Malassezia furfur. In endometrial hyperplasia (=Uterus) you will get Swiss cheese; if you want chocolate, don't ever try the chocolate cyst of ovary for they are endometriosis/endometrioma of the ovary.

If you wanted onion you better not confuse it with the onion peel appearance of Ewing's sarcoma. Be ware of: Popcorn calcification in Hodgkin's disease, melon seed bodies of tuberculous knee joint and the bunch of grapes of sarcoma botryoides: a tumour of skeletal muscles. Apple jelly (=lupus vulgaris) nodules, Maple syrup urine disease (MSUD): a branched chain ketoaciduria; are other decoys lurking in the dark. Fried egg appeareance is deceptive as it refers to Mycoplasma pneumonii of lung. The list is endless.

Perhaps, these nomenclatures reflect the attitude of the male dominated pathologists of that time towards the kitchen. With the advent of female pathologists in the arena the situation will probably change.

Check out for more at 'food for thought'! You will get a good poetry here.
Caption: The above heading has been intentionally rhymed with "What's Love Got To Do With It", by Tina Turner.

Height of Compression: Look at this DNA Video

...and you thought that data compression softwares like win zip, 7-zip or win-rar were great! Well, they are; but when you are talking about hardware compression, you just simply can't beat nature at it.

Here, we can see, the DNA molecules, comprising of 4 nitrogenous bases (Adenine, Guanine, Thymine and Cytosine), deoxyribose sugars and phosphoric acid, are packed so compactly, so as to fit into the nucleus. They wrap around the histone proteins, to form nucleosomes, coil upon themselves to ultimately form chromosomes. The reverse of this is to occur, when a cell needs to multiply. To begin with, the heavily folded DNA molecules will need to be unwound first. This is done by enzymes called helicases. When this enzyme is defective (due to a mutation in the helicase gene), the DNA molecule can no longer be unwound. They can no longer be "read and copied" and even 'repaired' as the DNA needs to unfold, to show its faulty codes. Hence, in helicase deficiency, errors accumulate within the DNA molecule and replication is inefficient. This leads to accelerated aging, diseases called segmental progerias. Werner's syndrome (adult onset progerias, seen mostly in the Japanese; often presents with cancer) and Hutchinson-Gilford progeria (childhood onset progerias) are two common examples. In these diseases the persons age very fast; the skin wrinkles faster and there is rapid overall decline in health. There may also be a component of free radical injury or telomere shortening in these diseases. In fact, cells with much shorter telomeres have been observed in these diseases. 

Onto the video now. Its showtime folks!

Aging: Lifestyle Modification and Drugs

So far, only caloric restriction with adequate nutrition (CRAN) has been shown to retard aging in animals and possibly humans. How many obese elderly people do we see on the street? Only a few and this possibly gives credence to CRAN. In nearly all religions, periodic fasting is recommended and it seems that our wise ancestors were aware of this fact. It is also equally important to remain active by doing regular physical (and mental) exercises. Smoking should be discouraged and 'challenges', such as trauma and infection are to be tackled at the earliest; since the elderly are 'homeostenosed'. The importance of good eating habits can not be overemphasized. We must ensure adequate intake of vitamins by ingesting adequate fruits and vegetables. They not only supply us with vitamins but also the dietary fibers in them ensure regular bowel habits as well as in fighting cancers, such as cancer of the colon. They also contain antioxidants in them, such as lycopene (in tomatoes); apart from vitamins A,C,E and various others. Water intake should be adequate to flush out the toxins of metabolism.

Retarding aging by giving drugs seems fascinating. It has indeed been suggested that the following be taken in a supervised way, in order to live a healthy and long life. Vitamins C, E, B5 (pantothenic acid), carnitine, alpha lipoic acid, coenzyme Q10, deprenyl (eldepryl), flavonoids such as carotene, folic acid, selenium etc has been proposed in this regard. These substances act by scavenging free radicals, fighting oxidation, altering glycation and metabolism and by other factors.

To conclude, it must be remembered that, our motto should be adding lives to years and not merely adding years to lives. Hence the elderly (in fact all of us) should make lifestyle changes and it is our duty to make our senior citizens comfortable, in our society.

Tobacco Trouble ?

For centuries this substance, obtained from the plant Nicotiana tabacum has entertained (or rather haunted) the human race. After Colombus's introduction of this habit into the new world, a tobacco epidemic has gripped the entire world. The addictive ingredient in tobacco is mostly nicotine, while its adverse effects on human bodies are largely attributable to its tar content. When smoked, about 4,000 different molecules are released and this includes the radioactive substance Polonium 210.

Not only the active smoker inhales it but also the 'sidestream smoke' it generates, makes passive smoking a reality. Nicotine is then rapidly absorbed from the lungs. The vast capillary networks surrounding the pulmonary alveoli aid its absorption directly into the blood stream. The onset of its action is very quick, since it takes only a few seconds to pass across the blood brain barrier. The blood-brain barrier acts as a frontier of defense in the brain, against many molecules thus protecting the brain.

Nicotine then liberates a long list of neurotransmitters including, noradrenaline, adrenaline (they make the heart race, pump more blood into the circulation, makes you alert, increases the blood glucose level and many related actions responsible for 'fight or flight reaction'), beta endorphin (a pleasure chemical in the brain, which binds to the opioid/morphine receptors), dopamine (a substance released from the 'reward center' of the brain ) and many others. These substances make smokers feel alert, cool and all the effects a smoker feels. These are the same chemicals that cause the serious cravings when one tries to kick the habit.

Nicotine, in addition, stimulates nicotinic cholinergic receptors in small doses, but depresses them in larger amounts. Tobacco causes a plethora of diseases. Cardiovascular diseases including peripheral arterial diseases; pulmonary diseases like emphysema, chronic bronchitis and cancers are just a few of them. It also decreases the sperm count, and even causes impotency (due to its vasoconstricting action).

But not all of us know that it guards against some diseases too. The frequency of ulcerative colitis, Alzheimer's disease, Parkinson's disease, and even breast cancers (in women harboring the BRCA gene =BReast CAncer) are statistically less in smokers than in non smokers. But the risks far outweigh the benefits it offers. Hence, kicking the habit is a more sensible option than to carry on smoking.

Quitting Tobacco: An Easy Way For The Blind To Go!

Its really hard to quit smoking. So much so, that its quitting has been compared to that of cocaine or even heroin. First and foremost, a resolute and firm mental preparation is required. Once a decision has been made, it can be set forth into action. However, there are certain drugs which make quitting easier. For example, nicotine may be supplemented as a gum, nasal spray or as a dermal patch, so that a small amount of it will be released and weaning off may be easier (guess you remember, fight fire with fire).

Apart from that, clonidine, bupropion, varenicline (Chantix) and many other drugs have been tried. Bupropion (Wellbutrin, Zyban) is a dopamine and norepinephrine reuptake inhibitor (DNRI). Dopamine, the reward chemical, and norepinephrine are secreted by nerve terminals in the brain. They then exert their effects, till they are metabolized or they are recalled back (reuptake) to the originating cells. Thus, actions cease once they are uptaken by the secreting cells themselves. Bupropion, by preventing their (dopamine and nor-epinephrine) reuptake, lets them remain in the synapse for alonger time, thereby making the person feel the high, even while they are not on tobacco. Varenicline, on the other hand, acts as a partial agonist at nACh (nicotinic acetyl cholinergic) receptors. A partial agonist is one substance (ligand) that can bind with a receptor and can elicit an action, though milder. Thus when varenicline is given, it stimulates the same nACh receptor that nicotine of tobacco smoke used to bind and stimulate. Thus, the craze for the crazy puff is gone. But, no matter what therapy you are on, as long as you are resolute, you can win, and nothing else matters!!

Recently, a vaccine is being developed that would bind nicotine and thus will not allow nicotine to bind to the nicotinic receptors. This is expected to wean away smokers since they will no longer be able to get the 'kick'. Normally a vaccine is given to boost immunity to pathogens. Here however its properties will be exploited for another noble purpose.

N.B. Recently (July 1, 2009) the US Food and Drug Administration (FDA) has announced that bupropion and varenicline manufacturers must carry a 'boxed warning' in their labels, that use of these drugs has been associated with serious neuropsychiatric events. They can cause symptoms ranging from mood changes to suicidal tendencies, hostilities and agitation. Whether they were the effects of nicotine withdrwal or the effects of the drugs themselves were not clear.

However, the site concluded with the following advice: "Any adverse events associated with varenicline or bupropion should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787."

Last updated: 2nd July 2009

Lithium: The Lightweight Champion

Lithium is an important drug for the treatment of bipolar illnesses, so named because, the patients have both manic (elated/grandiose/euphoric) and depressive (sad/depressed) features during the course of illnesses. As manic and depressive are at two extremes (poles), manic depressive psychosis is also known as bipolar illness. The discovery of lithium for medical purposes was a serendipity, not only that, a good deal of luck was there in choosing the right dose, as an excess would have been disastrous due to its low therapeutic index.

It is not exactly known as to how it acts. There was speculation that lithium, being a monovalent cation, like sodium ions (Na+), replaced Na+, thereby stopped or inhibited nerve conduction in the brain. Lithium decreases noradrenaline level in the CNS (central nervous system=brain) while increasing the serotonin level. There is a strong correlation between the levels of these neurotransmitters and mood. Lithium could also act by altering the level of glutamate, which acts as an excitatory neurotransmitter in the brain. It might also act by altering gene expression, and this might explain the delay of its onset of action for about a week. Lithium also hinders the regeneration of inositol (a substance necessary for the formation of IP3, an important molecule of the IP3- DAG second messenger system). Presently, the role of lithium in deactivating Glycogen Synthase Kinase enzyme (GSK enzyme, a member of serine/threonine protein kinase family) is implicated as its possible method of action. We all have a 'master clock' in our body, the circadian clock (circa=around, dian =day). A protein named Bmal1 resets this clock. But activated GSK 3B enzyme doesn't let Bmal1 to reset it. Li+, by deactivating GSK3B, brings this clock back into action. But the way it actually acts remains elusive till date. The therapy is not without its attendant risks. Sodium depletion, dehydration, diuretic therapy may augment the risks.

Lithium is also used in batteries (for their high charge density and lightweight: in cell phones, computers), in ceramics (it has a high specific heat capacity), space technology, and was even used in nuclear weapons. No wonder why Kurt Cobain of Nirvana sang his song of praise 'Lithium'.

Protein Folding And Disease: Nature's Own Origami

Human body is like a very complicated computer. It's code (genetic) is written in 4 letters: Adenine, Cytosine, Guanine and Thymine, compared to 2 letters (0,1) in computers. But in our cases, this code is again translated into another language using 20 letters, the 20 amino acids, genes produce by the way of transcription and translation. This language of the proteins that forms, as a result of combinations (and permutations) of these amino acids, is not a word for word (verbatim) dictation by the human genome. Genes only tell the order in which one protein would arrange itself like the beads in a string, where the beads are individual amino acids.

Proteins then fold themselves (much like origami: the ancient Japanese art of paper folding), adding another dimension to this language. This folding is dictated by numerous factors like charge, hydrophilicity, hydrophobicity, van der Waals forces, hydrogen bonding etc. Once they fold upon themselves, they are accompanied by chaperone proteins, so that this configuration is preserved (like write protecting in computers). Any misfolding, due to aging or some other defect, is severely dealt with by a peptide consisting of 74 amino acids, called ubiquitin. It tags the defectively folded proteins to be destroyed, for removal, in a multi unit intracellular factory called proteasome, in much the same way a Windows computer would tag a file to be deleted to the recycle bin. Many diseases occur from misfolded proteins, Alzheimer's disease, Prion diseases like bovine spongiform encephalopathy or mad cow disease etc. In Alzheimer's for example, a protein named beta amyloid accumulates in the brain. We normally produce beta amyloid in our brains, but this amyloid is in soluble form. Proteins consist of both water dissolving (hydrophilic) and water non dissolving (hydrophobic) amino acids. In normal beta amyloid, the hydrophilic domains lie outward while the hydrophobic domains are kept in the interior. Thus, it remains soluble in the interstitial body fluids. But when this protein is misfolded, the hydrophobic domains are exposed, making it immiscible in water, allowing it to aggregate in clumps, called neurofibrillary tangles. This tangle presumably strangles the neurones and causes AD. Thus it is necessary that we understand the property of the tertiary structures (foldings) of proteins, in order to deal with such diseases.

Recently, scientists have developed a unique way to explore this. They are using atomic force microscopes (AFM) to have an understanding of this. They tied one terminal (end) of a protein to a substrate (serving as an anchor) and stretched the other end, which were tied to a very tiny cantilever, a part of the AFM itself. Then they released this (cantilever end) and measured the intermediate energy it released, as it went back to the equilibrium point (previous state), reminding us of the way we measured the energy stored in a spring (isn't it?). This 3D shaping as a function of energy, a measurable and objective quantity, would definitely help us decipher the enigmatic coils of proteins, thus help us tackle these deadly and disabling ailments effectively.

Eutectic Mixture : Electronics and Medicine

Anyone who has done some soldering in electronics, will know how fast the soldering wire melts. The soldering wire comprises of tin 63% (stannum) and lead 37% (plumbum). This alloy melts at a specific temperature of 183 degree centigrade. Also this is the proportion of the two metals, at which the lowest melting point is achieved. The resulting alloy is termed an eutectic mixture, as this has the lowest melting point (not just a range of temperature).

In medicine too, we use eutectic mixtures. For example, when lignocaine (also known as lidocaine) and prilocaine (both are local anesthetics, i.e they anesthetize without producing unconsciousness) are mixed together, they form a liquid like stuff, although individually, both are crystalline in nature. This mixture of local anesthetics is called EMLA (Eutectic Mixture of Local Anesthetics). EMLA has the ability of producing surface anesthesia; which means the application of this mixture on intact skin has the ability to anesthetize that part. Individually, prilocaine or lignocaine does not have the property.

EMLA is used in small surgical procedures. It is used in circumcision, vasectomy (male sterilization), lumber puncture (puncturing the back, to analyze the cerebrospinal fluid) and many other applications including ear surgery and cathterization.

Diagnosing Diabetes Mellitus

You may wonder, why I am putting so much stress on diabetes. It is because it is a major cause of morbidity (ill health) and mortality (death), in present society. Also our stressful lifestyles, eating habits, sedentary lives (lack of exercise) and many others have pushed ourselves to the brink of a major health disaster. Diabetes is a major contender among them. Adding to this, there are complications like cardiovascular diseases, renal, neural and retinal diseases; apart from obesity, which also reinforces diabetes (in addition to it being reinforced by diabetes).

To put it succinctly, diabetes can be diagnosed on the following criteria; a person meeting any of the three criteria described below, is said to have diabetes.

1. A random plasma glucose test result of 200mg/dL (11.1 mmol/L) or more in a patient who already has symptom of diabetes (such as polydipsia or excessive thirst, polyuria or excessive urination or progressive unexplained weight loss).

2. A fasting (=at least 8 hours of no caloric intake, i.e. no carbohydrates, proteins or fats: water may be allowed) plasma glucose level of 126mg/dL (7.0mmol/L) or more

3. A oral glucose tolerance test value of 200mg/dL (11.1 mmol/L) or more. This test is carried out by giving the patient 75 grams of glucose orally, and then taking the plasma glucose values of the patient.

When the person satisfies any of the above criteria, he is automatically considered a patient of the disease. However, in presence of any doubts the test/s may have to be repeated, on a separate occasion.

Thus, it behooves upon us to get ourselves checked at regular intervals. Better forewarning is better forearming.

Related topics: insulin, type2DM, water water..