Epilepsy

                                                                 Epilepsy

                                                  PKGhatak, MD

Epilepsy is abnormal electrical activity of the brain producing alteration of muscle tone or convulsions, and changes in behavior and consciousness of an individual. Any one of these symptoms or various combinations of symptoms are the features of epilepsy. Convulsions are commonly known as seizures. Seizures and epilepsy are often used interchangeably, but strictly speaking, when two or more seizures occur at least 24 hours apart, then it is called epilepsy.

Previously seizures were classified by various names and at one time 30 to 40 different names were used. At present, there are two main groups of seizures

1. Primary generalized seizures. 2. Partial or limited seizures.

1. Primary generalized seizures.  Previously this was called Grand Mal seizures. In primary generalized seizures, abnormal electrical activities originate from both sides of the brain.

 2. Partial limited seizures originate from one limited area of the brain and remain localized to one half of the brain.

Commonly used terms for seizures are:

1. Simple focal. 2. Complex focal. 3. Absence of seizures. 4. Atonic seizures. 5. Tonic-Clonic seizures. 6. Myoclonic seizures.

This classification is not hard and fast because one type of seizure may change to another, for example, a simple focal seizure may turn into a complex focal, or a tonic seizure turns into a tonic-clonic seizure.

A list of medical conditions that may cause seizures.

1. Alcohol withdrawal.

2. Hypoglycemia (very low blood sugar)

3. Cerebral anoxia

4. Strokes

5. Certain medications

6. Encephalitis and meningitis

7. Sleep deprivation

8. Sustained exposure to flashing bright light

9. High fever and teething in children

10. Drug abuse, usually cocaine and amphetamine.

11. A-V malformation of the brain

12. Eclampsia of pregnancy

13. Hypothyroidism

14. Electrolyte imbalance.

15. Brain tumors.

Common causes of seizures according to the age of patients.

In young children. Brain injury during birth, Congenital abnormalities of the brain, Fever.

Young adults. Traumatic brain injury. Surgical scar of the brain, Drug abuse.

Adults. Brain injury and tumors.

Elderly. Strokes, Alzheimer's disease, Hypoglycemia, electrolyte imbalance.

CNS infection is an additional cause for all groups.

Clinical Presentation.

1. Absence or Petit Mal seizure.

It is commonly seen in children between 4 and 14 years of age. Sudden onset of a blank look in the middle of a conversation, smacking of lips and chewing motion. The seizures generally last only 10 to 15 seconds. The cortico-thalamic tract propagates abnormal impulses. Inheritance of GABRG2, GABRG3 and CACN gene mutations produces malfunction of energy dependent T calcium channels, which produce hyperexcitable brain cells and initiate seizures. This condition generally resolves at puberty.

2. Atonic seizure or Drop Attack. Sudden loss of muscle tone or strength causes the patient to fall on the ground, attacks lasting 15 to 30 seconds. The patients retain consciousness during the attack. The cause of the origin of this seizure is unknown.

3. Simple Local and Complex Seizures.

In a simple local seizure, it is also called an Aura. The seizures are either a movement abnormality, sensory or autonomic or psychological abnormal experiences. Muscle tightening, rolling eyeballs head movements are some of the common movement abnormalities. Numbness or crawling of insects under the skin is often mentioned by the patients. Hallucination involving hearing or vision is common. The patients may experience unfounded fear or anxiety. The patients are fully cognizant of abnormal muscle movements or sensory experiences and can fully recall incidents.

Complex seizures are like Simple Local seizures but the patients are not aware of the seizures during the attack or do not remember anything after the seizures stop. This seizure is also known as Temporal lobe epilepsy.

    4. Tonic-Clonic seizures.

Violent muscle contractions and fall on the ground and complete loss of consciousness, often a shrill cry is heard due to laryngeal muscle contractions, air entry to trachea may be prevented producing cyanosis, foaming of the mouth, chattering of teeth or forceful mouth closure, involuntary urination, arching backward due to back muscle contractions are some of the features of grand mal seizures. This seizure, the general public understands to be epilepsy. The seizures last several minutes and when exceeding 5 minutes, this becomes an emergency known as Status Epilepticus.

   5. Myoclonic seizure.

The muscle contractions are tonic-clonic but limited to a small number of muscles. Convulsions last only 2 to 3 seconds and the patient remains conscious.

Diagnosis of seizures.

An eyewitness account of a tonic-clonic attack is as good as a diagnosis that can be made on clinical grounds only to be confirmed by an Electroencephalogram (EEG; see footnote) and MRI. In many cases, photic stimulation is used for additional EEG recording. Other provocation tests may be required for localizing.

EEG in a normal person shows wave patterns classified on the frequency of waves per second. Normal waves are Alpha - 8 to 13 waves per second, Beta -13 per second, Theta - 4 to 7 per second, Delta -up to 4 per second, Gamma - 25 to 100 per second. The waves are not synchronized.

EEG in epilepsy shows synchronized spikes waves, each wave lasting 1/12 second, followed by delta waves.

MRI in epilepsy.  MRI shows structural abnormalities of the brain. In epilepsy, the MRI should be normal unless the epilepsy is due to other medical conditions deforming the brain. Other forms of MRI, like functional MRI, are useful for research purposes. 

In suspected CNS infection, spinal fluid examination and proper cultures and immunological studies are needed.

Treatment.

Status Epilepticus is an emergency. After securing the patient on a stable surface, the airway is protected and supplemental oxygen is administered.

IV Lorazepam 2 mg is given slowly, repeated after 1 minute in steps till the seizure stops or the maximum dose of 0.1 mg/Kg is given. If after 30 minutes the seizure continues, then Levetiracetam 20 mg IV is given. Alternatively, Valproic acid 40 mg IV may be used. If seizures continue then the Anesthesiology team is called and general anesthesia is induced to control convulsions.

Oral medication.

There are several effective oral medications available. The choice depends on the type of seizure, age and sex of the patients. In pregnancy and breastfeeding, special attention is required.

Commonly used oral drugs are Levetiracetam, Phenytoin, Valproic acid, Lamotrigine, Topiramate, Phenobarbital, Zonisamide,  Carbamazepine and Gabapentin.

In most cases one drug is not enough to control seizures, two or more drugs are required. Levetiracetam is well tolerated and has few side effects. It works differently from other anticonvulsant drugs. Levetiracetam combines with SV2 protein and prevents the release of neurotransmitter that is responsible for the epileptic electric discharge.

Duration of therapy.

Oral medications are continuously used for months and unless patients have no seizures for two consecutive years, the drugs are not stopped. In most patients, drugs are required for life. Therapeutic blood levels of many drugs are available and should be utilized to adjust the dosage. Phenytoin therapeutic level is 10 to 20 mcg/ml. Care should be taken in adding an additional dose of phenytoin at the higher range of therapeutic level because a small addition may push blood levels well past the normal range.

Surgery.

Removal of a single scar of the brain provides the best surgical outcome in uncontrollable seizures. The use of Laser ablation has increased safety. In recent years increasing numbers of drug resistant patients are opting for surgery. Many additional images, provocation tests and on the operating table brain mapping provide a more detailed location of the origin of the seizure and spare the functional areas of the brain.

Footnote:

Brain cells generate tiny electrical charges from various metabolic processes. These electrical activities can be recorded by placing electrodes on the head attached to a recording machine, unlike an EKG machine. Up to 64 electrodes and several hours of recording may be necessary to detect epileptic spikes. Each electrode records the activities of the cells directly underneath it and graphs are inscribed on a moving paper and all the leads record at the same time and each lead is identified by its position on the head.

In normal conditions, the brain cells are at different levels of activity and their activities are not synchronized. EEG of an epileptic discharge stands out as large waves and many adjoining leads record the same waveform synchronously.

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Regulation of the Body Temperature.

                                              Regulation of Body Temperature.

                                               PKGhatak, MD

Humans are warm-blooded and maintain a constant level of body temperature. The core or internal temperature is near constant and environmental factors do not change the core temperature. The shell or skin temperature is much lower and varies with the prevailing weather condition.

The core temperature is defined as the temperature recorded inside the body, recorded by inserting a temperature sensitive detector in the central vasculature. Oral and rectal temperatures also record the same. In normal conditions, the core temperature of humans is 37C (+/- 2C) or 98.7F. The skin temperature is lower and usually around 21C. and different in the exposed skin and covered skin areas.

Cellular functions are mostly derived from enzymes. The enzymes function at their maximum efficiency at core temperature. Certain immunocytes, however, can increase efficiency at a higher temperature. Maintaining a normal core temperature requires a steady state balance between heat generation and dissipation of heat from the body.

Sets of temperature sensors, a center for incoming information, sub-centers for coordination, and a center for outgoing instructions exist in the body just like a well designed environment control center.

Source of body heat:

Involuntary metabolic processes and physical work are the principal sources but warm food and drink also contribute to body heat.

Heat dissipation follows the Laws of Physics- evaporation, radiation, conduction and convection.

The distribution and equilibrium of heat in different compartments of the body are achieved by blood circulation and help maintain a constant core temperature.

Mechanism of heat generation.

Mitochondria are the metabolic factory of the body. As food is undergoing oxidative phosphorylation, the synthetic or secretory functions of cells are paired with it. This coupled action minimizes the loss of energy as heat.

The body has two distinct pathways to generate heat – (a) shivering and (b) uncoupled respiration and thermogenesis by brown fat.

(a) Shivering.

In exposure to cold, stress, fear, and in the face of danger, the body releases Adrenaline and Thyroxine. The effects of these hormones are many. The voluntary muscle mass responds to these inputs by muscle contractions and using up stored energy Glycogen as heat, CO2, and water.

(b) Uncoupled respiration.

The site of uncoupled respiration and heat generation takes place in the Brown fat. In fact, the brown color is due to the presence of large numbers of mitochondria in the fat cells. The oxidative phosphorylation is coupled with ATP (adenosine triple phosphate) generation. ATP is a high energy packet and the mitochondria use them for other functions requiring energy.

A protein, Thermogenine, regulates the rate of Proton (H+) transfer across the mitochondria and cell wall membranes. ATP generation depends on the availability of H+. Thermogenine keeps these two processes linked together. H+(proton) combines O-(- = electron) is the essence of cellular respiration. A H+ pump situated on the inner side of the mitochondrial membrane maintains the H+ gradient. In the situation when extra heat is required, the Thermogeneine uncouples the two processes and the H+ pump allows H+ to cross to the outside mitochondria membrane. This action stops ATP generation and increases heat production. Catecholamines, stress hormones, and sympathetic nerve impulses accelerate the rate of heat generation by recruiting additional mitochondria.

Minimizing heat loss.

Goosebumps or Piloerection. A tiny bunch of smooth muscle by contracting lifts the skin hair upright. Standing hairs in a close group, trap air in between providing a barrier to heat loss. The sympathetic nerve supplies the motor impulse for muscle contraction and adrenaline is the neurotransmitter of piloerection.

Dissipation of body heat.

In addition to the law of physics of the flow of heat from a higher temperature to a lower temperature, there are additional measures the body can utilize to lower body temperature.

Sweating. In summer we know how sweat cools the body. Sweat glands are adrenergic. And stress, anxiety, and fever also increase sweating.

Skin vasodilation.

In the non-hair region of the skin – the blood vessels of the palms, soles, and lips are supplied by only vasoconstrictor nerve fibers. There are special channels that connect skin arterioles to capillary loops in the top layer of the skin. At a higher temperature, the sympathetic tones of blood vessels are withdrawn, thereby increasing the skin blood flow. Cooling takes place by radiation.

Temperature sensors.

Skin sensors:

The entire skin is covered by sensors -touch, pain, pressure, position sensation, and cold and hot temperatures. The skin has separate cold and heat sensors. These are discussed elsewhere. The spinal nerves carry temperature sensation via the lateral spinothalamic tract of the spinal cord. The second order neurons of temperature are located in the lateral horn of the spinal cord, from there the information reaches the lateral parabrachial nucleus located in the dorsolateral pons. From there the sensation goes to the Median Preoptic Hypothalamic Nuclei. The second order neurons also carry the sensation by another tract to the ventromedial nucleus of the thalamus via the medial lemniscus.

A similar layout is seen in the sensory division of the 5^th cranial nerve carrying temperature sensation from the face. And the sensory division of the 9^th nerve from the structures of the mouth and throat. They carry the sensations to the ventromedial thalamic nuclei via the medial lemniscus.

Thalamus relays the sensations to (a). Preoptic Hypothalamus nuclei from there to the pituitary gland, (b). sensory cerebral cortex, (c). other midbrain nuclei.

Visceral censors:

The temperature sensors of the internal organs and central blood vessels are carried by the Vagus nerve. And then the sensations are relayed to the preoptic nuclei of the thalamus and from the Thalamus to the Hypothalamus – to the sensory cerebral cortex.

The diagram is taken from the Journal of Physiology, the authors are E.A. Tausey & C.D. Johnson. 

Regulating Center of Temperature.

The sensory input comes to the Median Preoptic nuclei of the Hypothalamus, and by another tract to the Ventromedial nuclei of the Thalamus.

The outgoing instructions are generated by the Medial Preoptic nuclei of the hypothalamus. These two sections of the hypothalamus are interconnected.

From the medial preoptic nuclei, the outgoing instruction is carried to the midbrain dorso-median nuclei of the thalamus. From there the outflow impulses are relayed to the Rostral Raphe Nucleus of the Globus Pallidum of the basal ganglia. Then the final instruction travels down the spinal cord to 1. Brown fat tissue. 2. Blood vessels of the skin. 3. The skeletal muscles.

The basic physiology of temperature regulation is known for nearly a century and additional information is regularly added. Biochemistry and biophysics of recent days added and refined the old information greatly and more is to come shortly. Infection, injury and state of shock change core temperature and contribute to the adverse outcome. The goal is to identify the molecular switches and then modify their actions to the benefit of the patients.

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Oxygen Radical

 

                                                        Oxygen Radical

                                                 PKGhatak, MD

The radicals are molecules containing an unpaired electron, and that makes them very reactive. Free radicals are highly reactive and unstable molecules containing unpaired electron., Radicals can damage the RNA and DNA and eventually can kill a cell.

 Oxygen.

 In the air, the oxygen is present in three different forms -

1. Oxygen molecule( O2,) 

2. Oxygen atom( O1)

 3. Ozone (O3).

Oxygen is a primary reactant, and the reaction gives out heat and it is called exothermic. 

Mitochondria are the main metabolic center of the cells; the more active the cell is, the greater the chance of generating radicals. The next order of cellular active sites is the endoplasmic reticulum, the cytosol, and the cell membrane.

Source of Oxygen Radical:

 Radicals are generated: Two sources - cellular and extracellular. The Non-cellular.  Air pollution, cigarette smoke, alcohol, Ozone, heavy metals, radiation, drugs, industrial solvents, pesticides, and herbicides are the main sources.

Oxygen Radicals and Non-Radical Oxidants.

Radical	Symbol	Oxidants	Symbol
Superoxide	O*-	Hydrogen peroxide	H2O2
Hydroxyl	*OH	Single Oxygen	1O2
Peroxyl	R00*	Ozone	O3
		Organic peroxide	ROOH
		Hypocaloric acid	HOCl
		Hypo bromic acid	HOBm

Nitrogenous Radicals and Oxidants.

Radical	Symbol	Oxidants	Symbol
Nitric acid	NO*	Peroxyl nitrogen	ONOO
Nitrogen dioxide	NO*2	Nitrosyl anions	NO
		Dinitro tetraoxide	N2O4
		Peroxyl nitrous acid	OHOOH
		Nitryl chloride	NO2Cl

The body's defense against radicals:

Mechanism of countermeasures against radical :

1.Superoxide dismutases (SOD) remove O2 by greatly accelerating its conversion to H2O2.

2. Catalases in peroxisomes convert H2O2 into water and O2 and help to dispose of H2O2 generated by the action of the oxidase enzymes that are located in these organelles.

3. Other important H2O2-removing enzymes in human cells are the glutathione peroxidases.

The human body employs Enzymes and Non-Enzymes to neutralize free radicals and oxidants.

A list of enzymes act as antiradicals and antioxidants - Superoxide dismutase, Catalase, Glutathione peroxidase,  and Glutathione reductase.

The Non-enzyme antioxidants are Vitamin E, Vitamin C, Carotenoids,  Trace metals Selenium and Zinc, Flavonoids, Omega 3 and Omega 6 fatty acids, L-arginine, Coenzyme Q10, and Melatonin.

Diseases caused by radicals in humans:

Age-related conditions- 

Loss of skin elasticity, wrinkles, cataracts, graying hair, and loss of hair.

Neurodegenerative diseases-

Parkinson's disease and Huntington's disease.

Autoimmune diseases-

Rheumatoid arthritis and various cancers.

Cardiovascular -

Coronary artery diseases.

edited May 2025

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A Look at the Diabetic Kidney.

                                              A look at the Diabetic Kidney

                                              PKGhatak, MD

Diabetes mellitus type II is a chronic illness and about 30 % of the patients show abnormal kidney function and the incidence is increasing; whereas diabetes mellitus type I is an acute illness and still about 20 % in 10 years, will develop renal involvement. This secondary renal disease is known as Diabetic Nephropathy. Diabetic nephropathy is a progressive disease and advances in stages. Drs. Kimmelstiel and Wilson described the pathological features and clinical aspects in great detail. They described the final stage of diabetic nephropathy as glomerular sclerosis, characterized by PSA positive modules replacing the glomeruli. The patients present with massive urinary protein leaks, generalized edema, hypertension and renal failure. The illness is known as Kimmelstiel Wilson Syndrome (KW syndrome) and KW nodules are pathognomic of the disease.

A glomerulus is the filtering unit of the kidney, consisting of a tuft of capillary, encased in a thin walled capsule- Bowman's capsule. The capsule continues as a tubule and ends in the pelvis of the kidney. Each glomerulus is supplied by an afferent arteriole – a tiny branch of the renal artery, and the blood exits from the glomerulus via the efferent arteriole. Each kidney contains about 1 million of these units.

Filter:

Renal filters are made up of three layers - Capillary walls are lined with fenestrated endothelial cells, lying on a basement membrane. The capillary tuft sits on a cushion of mesangial cells, accounting for 30 % of all the cells of a capsule. Mesangial cells originate separately from the kidney, then migrate to the developing kidney, some mesangial cells enter the Bowman's capsule, and others remain outside the capsule and are located in the space between the afferent and efferent arterioles. Mesangial cells have contractile protein, actin, and by selectively contracting and relaxing, can control blood flow and filtration pressure. In addition, these cells maintain the normal function of the basement membrane. They remove any tangled protein molecule in the basement membrane. The Mesangial cells can multiply when needed.

The capsular side of the endothelial cells is lined by Podocytes. The foot processes of the podocyte interdigitate with the foot process of the adjacent podocytes forming a fine network of filtering pores of about 50 nanometers in size overlying the fenestration of endothelial cells. Podocytes once damaged cannot repair or replace themselves.

Effect of high blood sugar on the filters.

High blood sugar induces metabolic stress in the renal cells. Glucose combines with amino acids forming glycosylate molecules and oxygen radicals. These molecules also add stress to the mesangial cells. Under stress, the mesangial cells multiply and secrete excess collagen, fibronectins and proteoglycans. These compounds change the filtering property of the basement membrane.

Effect on Macula densa.

Excess delivery of sugar to macula densa creates a relatively lower concentration of sodium chloride at this site. Macula densa cells signal renin secretion and activation of the renin-angiotensin-aldosterone pathway. This contributes to high BP.

Effect on Podocytes.

Higher afferent arterial pressure induces a shearing force damaging the delicate foot processes of podocytes and resulting in bigger filtration apertures. Serum albumin began to leak out of the blood in the filtrate. If this state is not reversed the protein loss will produce low blood albumin, low oncotic pressure and dependent edema.

In long standing diabetes, the above process gradually cuts off blood flow to individual small loops of glomerular capillaries. Initially, the closed capillaries appear as small isolated KW nodules. The small nodules coalesce together to form larger nodules.

Filtration:

In addition to the structural characteristic of the filter, the negative charges on the inner surface of the endothelial cells repel negatively charged protein molecules. Molecules of fat, cholesterol, hormones, and globulins are too large to pass through the filtering pores. The inorganic molecules dissolved in blood appear in the filtrate, however, 80 to 100 % are reabsorbed into the blood. Further modification of the filtrate continues along the tubule.

Cause of high BP.

Activation of renin-angiotensin-aldosterone is one main cause of hypertension. Constriction of the afferent arteriole and dilatation of efferent vessels increases filtration pressure and hyper-filtration takes place. This results in volume contraction and renin secretion, and intra-renal hypertension. Later, as the disease progress, produces systemic hypertension.

Cause of renal failure:

Disruption of renal arterial flow and changes in infiltration properties lead to the accumulation of creatinine and other waste products. In the very end, glomerulosclerosis ends in fibrosis of renal cortical tissue and the kidneys become atrophic.

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Kidney and Blood Pressure

                                                     Kidneys  and   Blood Pressure

                                                   PKGhatak, MD

A Blood Pressure (BP) of 120 mm Hg systolic and 80 mmHg diastolic, expressed as 120/80 mm Hg, is considered a normal BP in adults. When BP is over 140/80, it is called hypertension. In about 80% of cases, no definite cause of high BP will be detected. This is called Essential or Primary Hypertension. About 5 to 20 % of cases of high BP are due to kidney diseases.

Role of Kidney in maintaining a normal BP.

There are two systems that are operative. One is the Sympathetic nervous system and the other is the Angiotensin-Renin-Aldosterone system. These two systems are interconnected and act in a coordinated manner.

A. Sympathetic systems.

The BP sensors are located in the baroreceptors of the Carotid bodies and the Aortic bodies in the Aortic Arch. Any change in BP, high or low, initiates an impulse in the carotid stretch receptors in the carotid bodies and is carried by the Glossopharyngeal nerve and then relayed to the Hypothalamus. The pressure receptors of the aortic arch are sensitive only to falling BP. The Vagus nerve carries the sensation to the center and then relays it to the hypothalamus. From the hypothalamus, the outgoing impulse goes to the Celiac Ganglia. The postganglionic alpha fibers innervate all the systemic arteries and the beta fibers supply the heart.

The Hypothalamus also sends impulses to the adrenal glands and to the Juxtaglomerular cells of the kidneys.

Venous BP monitors: These are low-pressure monitors.

These monitors exist within large veins, pulmonary vessels, and within the walls of the right atrium and ventricle. Changes in volume influence the baroreceptors in the venous system and lead to the secretion of antidiuretic hormone and renin.

Effect of sympathetic alpha stimulation.

Arterial walls respond to alpha stimulation by increasing the tone of the muscular wall and the BP is raised. When the BP is high, the carotid body receptors produce a negative response in the hypothalamus, it prevents the further rise in BP. When BP falls, the aortic body sends positive impulses to the hypothalamus and BP is raised.

Effect of sympathetic Beta stimulation. Beta fibers mainly supply the heart. Stimulation of the beta fibers increases heart rate and force of ventricular contraction and elevation of BP.

Effect of sympathetic stimulation of the Adrenal glands. It increases the production and release of Aldosterone.

Effect of sympathetic stimulation of juxtaglomerular cells. It causes the secretion of Renin.

The action of the sympathetic system

Agent	Substrate	Response	Final effect
Alpha stimulation	Arterial wall	Vasoconstriction	BP elevation
Beta stimulation	Heart muscles	Rate and force of contraction	BP elevation
	Adrenal Glands	Aldosterone release	Increased Na+ absorption in exchange for K+
	Juxtaglomerular cells	Renin release	Angiotensin I formation
	Posterior Pituitary	ADH release	Blood volume increase

B. Angiotensin-Renin-Aldosterone system.

BP sensors.

The outer wall of the afferent arteriole of the kidney contains BP sensors. When blood flow/ pressure is low, these cells secrete Paracrine molecules (paracrine are chemicals, have actions like hormones but these chemicals are locally released and locally active). These molecules stimulate Juxtaglomerular cells to produce and release Renin.

Electrolyte sensors.

The Macula Densa cells of the distal convoluted tubules are specialized endothelial cells. They continuously monitor Sodium and Chloride concentrations of the glomerular fluid. Any fall in sodium chloride concentration triggers the paracrine release. Paracrine increases the rate of excretion of Potassium+ ion and H+ion production and release in exchange for Sodium+ ion from the filtrate.

Angiotensinogen is an alpha2 globulin produced by the liver and renal endothelial cells and circulates in the blood and is a non-active molecule. Renin converts angiotensinogen to angiotensin I. Angiotensin I is carried by the renal veins to the inferior vena cava to the right side of the heart and then to the lungs. In the pulmonary capillaries, the endothelial cells secrete Angiotensin Converting Enzyme (ACE). ACE converts angiotensin I to angiotensin II. In the blood, angiotensin lasts about 30 seconds and in the tissues for about 15 minutes, then it is degraded by ACE to Angiotensin III and Angiotensin IV. Both angiotensin III & IV have variable effects but are in the same line as angiotensin II.

Angiotensinogen is also produced by the fat cells, testicles, ovaries, brain, heart and blood vessels. In these secondary locations, its functions are limited at the local tissue levels.

Effect of Angiotensin II:

Angiotensin II has a multitude of functions. 1. It increases the tone of all systemic arteries and veins. 2. Constricts afferent and efferent arterioles of the glomerulus. and thereby increases filtration pressure and the GFR (glomerular filtration rate) is increased. 3. Angiotensin II increases the rate of Na+ ion reabsorption in the proximal tubules. 4. It accelerates Na+/K+ H+ exchange in distal convoluted tubules. 5. Angiotensin II causes the secretion of aldosterone by the adrenal cortex. 6. It releases an Antidiuretic hormone from the Posterior pituitary gland.

Na+/K+H+ ion exchange and water reabsorption produce an increase in total body Sodium and a decrease in potassium. The total body intravascular volume expansion takes place. The serum becomes alkalotic due to execs HCO3- ions. This condition is called Hypokalemia alkalosis.

Effect of Anti Diuretic Hormone (ADH).

ADH increases water absorption in the collecting tubules from the filtrate, thereby increasing blood volume. However, expansion of blood volume takes place only when both kidneys are ischemic. If only one kidney remains normal, then increased glomerular filtrate and loss of Sodium and water by the normal kidney in the urine keep the blood volume normal, but BP remains high.

Role of Kidneys in producing High BP:

Any condition producing a decrease in blood flow in the Kidneys (ischemic) produces high BP.

Renal causes of hypertension are discussed under

1. Renal- vascular

2. Renal parenchymal causes.

Of all the causes of Hypertension, renovascular hypertension has the most potential to be cured by corrective surgery and usually, the patients are not required to take BP medications. It is essential to find the cause of high BP before much damage takes place.

 1. Common causes of Renovascular hypertension.

In children:

Common causes are coarctation of the aorta, Moyamoya disease. Kawasaki disease, Takayasu arteritis, renal artery trauma, congenital renal artery hypoplasia or renal artery stenosis and renal graft stenosis following renal transplantation.

Moyamoya disease is more prevalent in Japan and is probably inherited by autosomal dominant inheritance. Cerebral arteries are deformed and various degrees of neurological symptoms develop at a very early age. Kawasaki disease is a multisystem inflammatory disease that usually follows a viral infection and produces signs and symptoms involving the skin, mucous membrane and lymph nodes and internal organs. It is more prevalent in China. Takayasu arteritis is an inflammatory disease of the aorta and its main branches,  producing narrowing of blood vessels and aneurysms,  producing severe ischemia to the involved areas like arms, neck, brain and kidneys. There is no known cause and treatment is not effective. It is often seen in Japan, Mexico, and India.

In adults:

The common pathology is renal artery stenosis due to atheromatous plaques.

The narrowing may be in one or both renal arteries. The plaques may be only segmental or in multiple areas, commonly involve the proximal third of the artery. The plaques develop the same way as in the coronary arteries. The risk factors are diabetes, high BP, high cholesterol, obesity, cigarette smoking, a sedentary lifestyle, and runs in a family.

Other causes of renal artery diseases are Congenital stenosis, Renal artery thrombosis, emboli, aortic dissection, A-V malformation, and aneurysm of the abdominal aorta.

In young females:

Fibromuscular dysplasia. This condition is largely confined to females of childbearing age. The condition may run in families. The medium size arteries are involved. Common sites are renal, intracranial, face and abdominal. The distal 2/3rd of the renal artery shows dysplasia. The changes may be confined in one or all three layers of the arterial wall. Bead-sized aneurysms are seen in cerebral branches of carotid arteries.

Risk factors are female hormones, the higher incidence of methysergide use in migraine, cigarette smoking, alpha 1 antitrypsin deficiency, cystic medial necrosis, neurofibromatosis, coarctation of the aorta and Ehler-Danlos syndrome.

The patients with fibromuscular hypoplasia are mostly symptoms free. A cerebrovascular episode like TIA, (transient ischemic attack) or subarachnoid hemorrhagic may lead to a diagnosis of fibromuscular dysplasia of the renal artery.

2. Renal parenchymal diseases cause hypertension.

Almost all inflammatory diseases of the kidneys raise BP.  A few common conditions are: -

Polycystic disease of the kidney. Glomerulonephritis.

Polycystic disease of the kidney is the most common hereditary kidney disease in adults causing hypertension and other complications. It is inherited as a dominant mode, and the expression of the defective gene penetration is variable. In children, the disease is much less aggressive and provides a better prognosis.

Glomerulonephritis is generally due to post-streptococcal pharyngitis, also seen in secondary to Bacterial endocarditis, Hepatitis B, hepatitis C, HIV infection and now COVID-19. Other less common causes are autoimmune glomerulonephritis. Lupus, Goodpasture syndrome, IgA nephropathy, Diabetic microvascular disease,

Investigation and Diagnosis:

The renal parenchymal disease is evident by the presence of protein, RBC, red cell casts and granular casts in the urine. If active infection is present, an increased number of WBCs and WBC casts are detected in urine. Further tests, including IgG, IgA and other serological tests are generally required for the determination of the etiology in individual cases. In most cases, needle biopsy of the kidney and special immunological staining is required to properly direct medical therapy and evaluate prognosis.

Renovascular disease is detected by an Ultrasonography of the abdomen. It is a noninvasive test and can easily detect abdominal aortic aneurysm, dissection of the aorta, atheromatous changes and fibromuscular dysplasia. The new generation Doppler ultrasound study gives flow and degree of stenosis. In case the presence of gas in the bowel interferes with the ultrasound study, MRI is an excellent alternative. The functional status of kidneys is determined by serum creatinine, urinary creatinine and GFR, electrolytes. Radio-opaque dye administration is held off till a definite surgery is planned. In a situation that is likely to be associated with vascular abnormalities of the brain and other vital organs, then a whole body angiogram may be completed before surgery.

Treatment:

Renal artery stenosis is treated by angioplasty and stent placement. This is the preferred treatment for fibromuscular dysplasia and a stent often is not needed.

Resection, repair and Dacron graft are used based on the nature of the pathology. In unilateral and atrophic kidney nephrectomy is indicated. Post-surgery prognosis is very good for children and young individuals.

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Kidney Stone

                                                                 Kidney Stone

                                                     PKGhatak, MD

Kidneys filter blood and eliminate harmful waste products from the body. The amount of work the kidneys perform is staggering. In a day, the kidneys filter 325 liters of the blood and produce 180 liters of glomerular filtrate. The reabsorption of most of the water, sodium, calcium and phosphate and the entire glucose load take place in the renal tubules. In the end, 1 to 1.5 liters of urine is produced in a day and the urine contains 1 to 2 meq of sodium out of 2,400 meq filtered, 100 % of sugar (about 162 gm), 95 % of calcium and 75 to 85 % of phosphates are reabsorbed. The waste products are urea, uric acids, creatinine, creatine, nitrate and sulfates. The amount of organic compounds in the urine of an adult on a regular western diet is as follows: urea 30 gm, creatinine 1.4 gm, ammonia 1 gm, uric acid 0.5 gm, protein less than 200 mg, and creatine 100 mg.

The worldwide incidence of kidney stones is increasing. Turkey reports that 14 % of its population experienced at least one attack of renal colic from real stone. In the USA the incidence is 11 % in males and 7 % in females. In the USA North Carolina has the highest reported kidney stones. The peak incidence of kidney stones is between 40 and 45 years of age. 

Mechanism of renal stone formation.

Two things have to happen for stone formation in the kidney. The supersaturation of any of these chemicals must take place - calcium, oxalate, uric acid and urea must take place. The second requirement is the presence of some foreign material or denuded cells in the glomerular filtrate around which the crystallization takes place and that grows into a stone.

Conditions favor stone formation.

Limited water intake, high sugar, and high salt intake are the important causes in otherwise healthy individuals. A diet containing an excess amount of calcium. phosphate, oxalate, protein and less citrate. Magnesium, uromodulin and pyrophosphate in the filtrate produce an imbalance promoting the precipitation of crystals. Obesity, excessive physical exertion in hot humid conditions, certain medications and heredity are also risk factors. Distal tubular acidosis, hereditary oxaluria and cystinosis are examples of autosomal recessive inheritance. Mendelian dominant inheritance is due to the mutation of 30 genes, but much work remains to be completed to define their importance.

Incidence of kidney stones

Type	Children %	Adult %	note
Calcium oxalate	50-60	60 - 80	Most common
CaPO4 Apatite	25	15	pH 6.8 to 7.4
hydroxyapatite		2	Very hard stone
Struvite	10	4	Infection and pH >7.8
Uric acid	3	10	Acid urine
Cystine	5	1
Other		2

Types of Renal Stones:

Kidney stones are classified as Calcium stones, Struvite stones, Uric acid stones, and Cystine stones. Calcium stones are calcium oxalate stones, calcium phosphates, Apatite and Struvite stones.

Formation of calcium oxalate stone.

In the basement membrane of the thin loop of Henle, calcium oxalate is deposited. It erodes through the basement membrane and accumulates in the subepithelial space renal papilla. This is known as Randell's plaque. Randell's plaque breaks down the cell layer and falls into the lumen. This provides the site for crystallization and stone formation.

Oxalate is present in leafy vegetables, rhubarb, root vegetables - potato, aram (taro), beets and almonds and cashew. Patients with Crohn's disease and colostomy develop fat malabsorption of fat leaving oxalate free in the small intestine for absorption resulting in high serum oxalate and kidney stones. In genetic disorders, primary oxaluria and cystinosis are characterized by repeated stone formation.

Calcium phosphate stone.

Apatite and Struvite.

Triple calcium stone is called Apatite. When one or more calcium molecules are replaced by Magnesium and rarely by iron molecules, the stone is called Struvite.

Calcium phosphate stones account for 15 % of all renal stones.

Calcium and phosphates are essential elements of the body and are present in every living cell. Metabolic processes generate serum calcium and phosphate in addition to food intake. Vitamin and calcium fortification of food also add to it. The current trend to take calcium and vitamin D supplements favors a further increase of these elements. High salt intake and diabetes are risk factors. If water intake lags behind then calcium reaches saturation points and calcium crystal forms.

Struvite stones.

Calcium phosphate stones in the renal pelvis occasionally become infected by the Proteus, Pseudomonas, Klebsiella group of bacteria. These bacteria generate ammonium from urea. Urea is the final product of amino acid metabolism. In alkaline urine, ammonia combines with urea. Ammonia urates stones grow rapidly in the pelvis of the kidney and the stone takes the shape of branched calyxes and these stones are known as Staghorn calculus. Patients with urinary retention require an indwelling catheter, infection by these bacteria produces calcium deposits around the catheter and multiple bladder stones.

Uric Acid Stone.

Purine and pyrimidine are nitrogen bases for the nucleotides which form nucleic acids. The end product of purine metabolism is uric acid in humans, in lower animals, the end product is Allantoin. High serum uric acid leads to gout and gouty arthritis. Uric acid is prone to form crystals in the urine when the pH of urine is acidic. Increased breakdown of the nucleus of cancer cells during the treatment of leukemia and lymphoma is a risk factor for uric acid stones.

Cystine stone.

Cystine stones are large stones and stones recur rapidly. This condition is inherited as an autosomal recessive mode. The patients have high blood amino acid cystine. It is filtered in the urine and forms stones. High sodium in the diet accelerates stone formation.

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Chronic Pancreatitis.

                                                     Chronic Pancreatitis

                                               PKGhatak, MD

Chronic pancreatitis is a devastating disease. Episodic severe unrelenting abdominal pain is the chief symptom. Progressive loss of weight and diarrhea of foul smelling stool are chronic symptoms. Alcoholism is the prime cause of this illness and cigarette smoking is an additive factor to alcoholism.

 Hereditary causes:

Hereditary predisposition to chronic pancreatitis is an important factor but the incidence of hereditary pancreatitis is low. The CFTR (cystic fibrosis transmembrane conductance regulator) gene mutation causes abnormal ductal secretion. CFTR is inherited as an autosomal recessive mode, and primarily affects bronchial glands producing thick sticky mucus but CFTR also affects the pancreas and other glands. SPINK 1 protein (serine protease inhibitor Kazal1) is a potent trypsin inhibitor. Mutation of the SPINK 1 protein gene prolongs the action of trypsin and damages the pancreas. Mutation of the PRSS I gene causes premature activation of Trypsinogen to Trypsin - a potent protein digestive enzyme of the pancreas. SPINK 1 gene is inherited as an autosomal dominant mode with 80 % penetration. Autodigestion of pancreatic tissue produces pancreatic insufficiency and the inflammation of the peritoneum causes pain. Progressive damage of Beta cells of the pancreas causes insulin deficiency and hyperglycemia.

Chronic pancreatitis, unlike pyelonephritis and bronchitis, is not due to an infection by viruses or bacteria. It is due to alcohol. A combination of pancreatic duct obstruction by stones or carcinoma of the head of the pancreas, sarcoma, lymphoma, etc. and alcohol abuse is the next important cause. About 40 % of chronic pancreatitis is due to alcohol, of the rest another 30 % are from a combination of pancreatic duct obstruction and alcohol, and in 10% no cause can be found.

How alcohol causes chronic pancreatitis.

Alcohol increases the protein content of the pancreatic secretion and decreases bicarbonate concentration resulting in the coagulation of protein. The coagulated protein globes block the pancreatic ducts. Alcohol increases the permeability of the cells lying in the ducts, and the pancreatic secretion spills into the pancreatic glands. Trypsin neutralizing enzyme production is decreased and trypsin action is prolonged. These result in chronic pancreatitis.

When this damage is repeated over 5 to 10 years, the damage to the pancreas becomes overwhelming and recovery becomes rare or impossible.

Other risk factors:

Increased incidence of chronic pancreatitis is seen in hypertriglyceridemia (usually 1000 mg +), hypercalcemia, abdominal surgery and trauma, and a Cardio-Pulmonary bypass procedure. ERCP (endoscopic retrograde cholangiopancreatography) and use of certain drugs. Rare incidences of autoimmune pancreatitis and systemic vasculitis are known.

Incidence:

About 50 in 100,000 people suffer from chronic pancreatitis and the rate has been going up since 1990. Men are more susceptible; the peak incidence is 40 to 45 years. The risk is proportional to the cumulative amount of alcohol consumed over the years.

Clinical Presentation. The First attack of pancreatitis.

The first incidence is acute pancreatitis. An attack starts after an episode of heavy drinking. Nausea and vomiting were soon followed by the onset of severe burning abdominal pain in the epigastrium and below the left ribcage. The pain is deep inside towards the back of the torso. At times the pain is felt on the left flank. The pain is so severe that the patient arrives at the ER immediately.

All the main signs of an acute abdomen are present on examination. The board like rigidity of the anterior abdominal wall indicates peritonitis. Depending on the severity and duration of the attack, cardiovascular compromise may be present.

Laboratory and imaging:

Indication of acute inflammation is evident by the presence of leukocytosis with a left shift, hemoconcentration, increased levels of liver enzymes, bilirubin, and alkaline phosphatase, which are indications of common bile duct obstruction. Proteinuria and the presence of sugar in the urine are usual findings. The severity of inflammation is judged by LDH over 350 units, AST over 250 units, CPK to 1000 + units, Creatinine over 1.8 mg, C-R protein to 1,500 mg/l. Low serum calcium of less than 8 mg indicates the binding of calcium with fatty acid produced by the digestion of body fat. A high Lactic acid, high LDH, high AST, and PaO2 less than 50 mmHg are bad prognostic signs.

Specific tests for acute pancreatitis are elevated serum Lipase and Amylase.  Amylase begins to rise in 3 hrs. and may reach 250 units and persist for 72 hrs., the Lipase increases in 50% of cases and may remain high for 14 days. High blood sugar is usually present.

Imaging: Ultrasound of the abdomen may not be the best test because the gas filled colon and small intestine interfere with image quality. MRI is more accurate and safer. MRI shows edematous pancreas and pancreatic duct dilatation. The dilated duct is due to obstruction of the duct by pancreatic stones or stones impacted at the sphincter of Oddi or a tumor of the head of the pancreas. Atelectasis of the lower lobes of the left lung and left sided pleural effusion may be present.

Clinical Presentation of Repeated attacks.

This first episode may not be the last in the majority of chronic pancreatic cases. Episodes of acute attacks, several times a year, are not uncommon. Repeated attacks damage the pancreatic exocrine (digestive) and endocrine (insulin production) functions to various degrees depending on the duration and frequency of acute attacks.

Acute abdominal pain may last several hours to 2 -3 days at a time. Marked weight loss and diarrhea of fatty stool are common symptoms. Signs of protein malnutrition are evident in the presence of hollowed out temples, sunken cheeks, skinny legs and arms.

Laboratory findings:

Laboratory findings in chronic pancreatitis are variable depending on the remaining functioning pancreatic tissue. Blood sugar levels are generally high, increased fecal fat points to malabsorption of fat and fat soluble vitamins A, D, E, and K.

Imaging;

MRI or CT of the abdomen is the initial test. 30% show various degrees of pancreatic calcification, and stones. The pancreas is generally atrophic and the pancreatic ducts are dilated. Secretin enhanced MRCP (a special MRI) to evaluate the hepatobiliary pancreatic system) maybe performed in difficult cases. Stones, stricture of the sphincter of Oddi and tumors are better detected by ERCP. Ultrasound study during ERCP increases visual evidence when cancer of the pancreas is suspected. Skinny needle biopsy done through ERCP scope provides a definitive diagnosis of malignancy. In chronic pancreatitis, the pancreatic tissues are in various degrees of degeneration, atrophic and replaced with fibrous tissue, the Beta cell islands are much reduced in numbers. The main pancreatic duct is dilated.

Management of Chronic pancreatitis:

The goals are pain control, prevention of future attacks, pancreatic enzyme replacement, and control of blood sugar by insulin. Pain control is crucial, success and failure depend on it.

Medical therapy:

The multidisciplinary team is better at managing pain and exocrine and endocrine deficiency brought on by chronic pancreatitis. Pancreatic enzyme replacement and insulin administration are effective in some patients but not universally. To control pain, non-opioid medications are tried to begin with but in the end, the majority of patients require opioids to control the intractable pain. Opioid addiction is a usual occurrence and becomes a major problem.

 Non-conventional treatments:

Mind-body therapy, acupuncture, chiropractic manipulation of the spine, touch therapy, dietary manipulation, supplements and antioxidant administration, etc. are tried and failed to show any improvement in pain and are disappointing.

Surgery for Pain control:

The sympathetic nerve fibers carry the pain sensation from the pancreas and the fibers originate from the T5 to the T12 segment of the spinal cord. The preganglionic fibers make a synaptic connection in the Celiac ganglion. The postganglionic fibers innervate the Pancreas, Liver- biliary system, vasculature of the small intestine and adrenal glands.

The head of the pancreas is considered the Pacemaker of Pain in chronic pancreatitis.

To assess the effect of sympathetic denervation, celiac ganglion block is performed. If effective then surgery is performed. The procedure is done by minimum invasive Laparoscopic method and is known as Bilateral thoracoscopic splanchnicectomy (BTS). The outcome of BTS is effective but the improvement may not last long. The main adverse effect of BTS is postural hypotension.

Drainage of Pancreas.

During ERCP, the dilated main pancreatic duct may be seen. If a stone is a cause, then the removal of the stone can be accomplished at the same time. If the stone is large or impacted, Extracorporeal Shockwave Lithotripsy is indicated. If dilatation of the sphincter of Oddi is performed, a stent is placed in the main pancreatic duct and drained for 6 to 8 weeks. In some cases, the drainage produces a significant decrease in pain. In those cases, an appropriate surgical procedure can result in a long term improvement.

Whipple Operation:

 In 1935 Whipple was the first surgeon to remove the head of the pancreas along with the duodenum. If the patients were able to abstain from alcohol and smoking for at least one year, they had significant relief from pain. However, the Whipple operation produced significant morbidity and mortality. Development of type 1 Diabetes mellitus, nutritional, iron, calcium and vitamin B12 deficiency followed the operation. The antrum and duodenum are not just conduits but both have exocrine and endocrine functions.

 The diagram above shows the Postoperative picture of a Whipple operation.

Modifications of the Whipple operation were undertaken by many groups in order to preserve as much duodenum as possible and save the tail of the pancreas and islets cells at the same time. To ensure adequate drainage of pancreatic secretion pancreatojejunostomy was performed.

Puestow modification 1958.

Puestow did not remove the head of the pancreas, instead opened the main pancreatic duct from the head to the tail followed by a side to side anastomosis of the main pancreatic duct and jejunum.

Berger modification of Puestow operation.

The above is a diagram of Berger's modification of the Puestow operation.

Burger modification preserved the duodenum and removed as much of the pancreatic head as possible by blunt dissection.

In 1960 Partington and Rochelle modified Puestow's operation by not including distal pancreatectomy.

Most recent modification.

In this operation, a total pancreatectomy followed by Islet cell autologous transplantation was performed to retain autonomous insulin production.

Various comparative studies were completed in order to find an operation that would control pain and produce minimum morbidity and mortality. Overall, all surgical procedures show some good control of pain but relapse in a year is common if patients go back to drinking and smoking.

Pain is the main reason the patient seeks medical attention for chronic pancreatitis. Medical and surgical treatment modalities are difficult to impose on patients because of significant morbidity. Patients with surgically correctable conditions like pancreatic stones, stricture of the sphincter of Oddi, and biliary obstruction have the best prognosis. Medically treatable conditions - hypertriglyceridemia and hypercalcemia also have a better prognosis. Overall pain control is achieved in 30-35 % of cases provided the patients abstained from drinking alcohol and stopped smoking. Opioid addiction is very difficult to avoid because of constant and unrelenting pain, and when other methods are ineffective. About 4 % of patients with chronic pancreatitis develop cancer of the pancreas but in the hereditary condition, the cancer rate increases to 20%. Increased incidence of venous thromboembolism, increased risk of CAD and other acute vascular events are known because of changes in coagulation factors and platelet function.

Written in memoriam of Sanjay Banerjee. 1965 - 2012.

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Genes Controlling Human Hair Color.

                                        Genes controlling human hair color

                                             PKGhatak, MD

The hair colors of humans are black, brown, blond, grey/white and red. And then there are many shades in each of the colors and in-between colors. It is not usual to see children born to the same couple have different hair colors. This is the magic of genes in the chromosomes.

The MC1R gene is the primary gene for human hair color. The gene MC1R is carried by chromosome 16 on the long arm q at 24.3 location (16q24.3). The deeper layer of the skin contains melanin forming cells, melanocytes. MC1R gene in a dominant and active stage produces a good amount of black pigment melanin known as Eumelanin. In MC1R mutation and in the inactive stage, produces a yellow-red pigment called Pheomelanin.

In lower mammals, another gene ASIP (agouti suppressor protein) contributes red color. In humans ASIP gene is absent but its role is exhibited in the inactive MC1R gene. Genome wide association study (GWAS) discovered Single Nucleotide Polymorphism (SNP) and its effects on the genes. The SNP in a particular locus modifies the function of the gene in an individual. About 200 SNPs are identified in the European population with blonde to light brown hair color.

In Mendelian inheritance, an individual is either in dominant or recessive mode. In dominant inheritance, there are variations of expression of gene function due to co-dominance. In addition, multiple genes may influence the same characteristic. Varieties of gene interactions are the reasons for so many shades of hair colors and the same parents having different hair colors for their babies.

Hair:

Hair has two parts, the root and the shaft. The root of the hair lies deep in the basal layer of the epidermis of the skin. The root of hairs is supplied with branches of blood vessels and nerve fibers. This is the living part of the hair.

The shaft that lies above the skin is dead tissue. The center of the shaft is called the medulla and it is surrounded by several layers of densely packed cells forming the cortex. In the cortex, the keratinocytes containing the melamine pigment lie. The outer layer is the cuticle, made up of a single layer of cells containing a protein called keratin. Several genes express the texture, length, waves, curls and luster of hair. All these genes, including the MC1R gene, are responsible for the way hair looks.

Melanin.

The melanocytes produce melanin from the amino acid tyrosine. Tyrosine is converted in stages to DOPA then to L-dopaquinone then to eumelanin or phaeomelanin pigment. The long arm of the melanocyte deposits the pigment in the keratinocytes in rows like a string of pearls.

Chemically, 5 types of melanin are present, but eumelanin and pheomelanin, the two organic melanins, are present in human skin, hair, eyes, and adrenal glands. The third one, Neurological, is present in the substantia naira of the midbrain, the decreased melamine production is responsible for Parkinson's disease.

Grey / White hair.

As hair grows at the hair root the hair is colorless, and the pigment cells melanocytes surround it. In old age, and in certain diseases and genetic conditions, melanin stops forming. The new hair that emerges looks grey or white. Australia has the most grey haired people in the world due to the effects of bright sunlight on their heads.

Red hair.

Red hair is the least prevalent when the entire world population is considered. Red hair is principally seen in Irish and Scandinavian people and their descendants in other countries.

Blond and different shades of brown hair.

The European population and their descendants carry these genes. As discussed before, multiple genes including NSP polymorphism are responsible for varieties of shades.

Black hair.

African, South Asian, and Chinese people have black hair. Chinese people by a long tradition used to headcovers and they retain black hair color longer in old age than any other race. It is said that stress can change hair to white or grey overnight. That is an exaggeration, however, stress and stress hormones depress melanin formation.

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