Human heart| structure, functions and blood flow path through heart|

Table of content

• Human Heart
• Overall size, shape, and location
• Layers of heart
• Heart walls
• Heart chamber
• Valves of heart
• Blood supply to heart 
• Heart beat
• Control of heart function
• Blood flow path through heart 
• Sources

HUMAN HEART

Human heart is a four-chambered, powerful muscular pumping organ, pumping function is coordinated by the nervous system. It is the main organ of the circulation system. 

Overall size, shape, and location

Human heart about the size of a clenched fist and varies with body size. It is cone-shaped and has a broad apex and a pointed posterior end.  It is located in the median position of the chest cavity, between the lungs and behind the sternum. It lies on the left side of the cheat cavity. 

Layers of heart

It is a very sensitive organ. Thus, it is protected in various ways: 

• Rib cage: Heart is protected by the rib cage.
• Pericardium: Heart is enclosed in a membrane called the pericardial membrane. Pericardium is inelastic, thus it protects the heart and prevents it from overextension in extreme conditions. 
• Pericardial fluid: Pericardium encloses a cavity called the pericardial cavity, which contains a lymph like fluid called pericardial fluid it act as lubricant, thus facilitating heart movement by reducing friction to a minimum during heart beats. 

Figure 1: location of human heart in thoracic cavity

Heart walls

Heart walls are composed of special types of muscles known as cardiac muscles. These muscles have the ability of rhythmic contraction and relaxation under the control of autonomic nervous system. 

The layer of muscular tissue called the septum. Which  divides the heart walls into the left and right sides. It includes:

• Interracial septum: it separated two upper chambers.
• Interventricular septum: it separate two lower chambers
• Atrioventricular septum: separate  articles from ventricles.

Heart walls have three layers:

• Endocardium: Inner layer.
• Myocardium: Muscular middle layer.
• Epicardium: Protective outer layer.

The epicardium is one layer of pericardium. 

Heart chambers 

The human heart is made up of four chambers: two atria or auricles and two ventricles.

Auricles 

Auricles are thin-walled, smaller, and weaker chambers. They act as receiving chambers. They have to pump blood into the ventricles. Both auricles are separated from one another by an inter-auricular septum. 

The left auricle receives oxygenated blood from the lungs by the pulmonary vein. The right auricle receives deoxygenated blood from the anterior part (head region) of the body by the superior vena cava and from the posterior part of the body by the inferior vena cava. 

Ventricles

Ventricles are thick-walled, larger, stronger, and more muscular because they have to pump blood to the whole body. Right ventricle receives deoxygenated blood from right atrium and then pumps it to the lungs via a pulmonary artery for oxygenation. The left ventricle receives oxygenated blood from the left auricle and pumps it into the aorta. This aorta then divides into many arteries which supply blood to all parts of the body. 

Figure 2: dorsal ventral view of human heart.

Valves of heart

• Tricudpid: the right auricle opens into the right ventricle by an aperture called right auricloventricular apertures. This aperture is guarded by a tricuspid valve. The tricuspid valve is composed of three flaps of connective tissue. The tricuspid valve allows the flow of blood from the right auricle into the right ventricle but not in the opposite direction. 
• Bicuspid: the left auricle opens into the left ventricle via a left auricloventricular aperture. This aperture is guarded is guarded by a bicuspid valve. Bicuspid valve is made up of two flaps of connective tissue. Bicuspids allow blood to enter from the left auricle into the left ventricle in one way only. 

      Both tricuspid and bicuspid valves are connected to the muscles on the inner surfaces of ventricles by a thread-like structure called chordae tendineae. Chordae tendineae support and prevent the inverting of valves. 

• Mitral valve: it acts as a door between the left atrium and the left ventricle, preventing the backward flow of blood. 
• Semilunar valve: the opening of the right ventricle into the pulmonary artery and the left ventricle into the aorta is also guarded by the semilunar valve. It includes an aortic semilunar valve between the aorta and the left ventricle and the pulmonary or Pulmonic valve lies between the right ventricle and the pulmonary artery. 

These valves are shaped like half moons. Semilunar valves allow one-way blood flow from ventricles into vessels. 

Blood supply to heart 

Blood is supplied to the heart wall myocardium by coronary arteries. The right and left coronary arteries are branches of the ascending aorta. The coronary arteries divide and re-divide and form a network of capillaries in the myocardium. After blood supply to the heart wall, the capillaries collect into cardiac (coronary) veins. The majority of cardiac veins drain into the coronary sinus, which opens into the right atrium. 

Heart beat 

Contractions of the heart chambers are called systole, and relaxation is known as diastole. The two auricles contract together for about 0.1 second, and the ventricles contract for about 0.3 seconds. Heart chambers relax for about 0.4 seconds. Thus, the heart cycle takes about 0.8 seconds. For the rest of its life, the heart beats continuously at a rate of 72 to 75 beats per minute. Each contraction of the heart pumps out about 75 ml of blood. In severe exercise, the rate may increase to over 120 beats per minute. 

Control of heart function 

The main function of the heart is to transport blood to all parts of the body with a supply of oxygen and nutrients. 

This function (heart beat) is controlled by the nervous system. 

• Nervous control: the nervous system sends signals to the heart to beat. The rate of heart beat varies during rest, work, and stress. It is also under the control of the nervous system. 
• Endocrine control: hormones in the blood vessels control the constriction or relaxation of blood vessels, which affects your blood pressure. 

Figure 3: inside view of human heart.

Blood flow path through heart

oxygenated blood enters the left side of the heart through the pulmonary veins, emptying directly into the left atrium. From the left atrium, blood flows down into the left ventricle. Most of this flow occurs before a contraction starts. When the heart starts to contract, the atrium contracts first, pushing its remaining blood into the ventricle. 

After a slight delay that permits the atrium to empty fully, the ventricle contracts. The walls of the ventricle are far more muscular than those of the atrium, so the ventricle’s contraction is much more forceful than that of the atrium. As the left ventricle contracts, the blood is prevented from going back into the left atrium by a one-way valve called the mitral valve. All four valves in the heart are one-way valves. Each acts as a flap door that opens in only one direction, ensuring that the blood that passes through them will not flow back. The blood within the contracting left ventricle enters the largest artery of the body, the aorta. Once inside the aorta, the blood is prevented from reentering the left ventricle by the aortic valve. Many major arteries branch from the aorta and carry oxygen-rich blood to all parts of the body. 

The first arteries to branch from the aorta are the coronary arteries, which carry freshly oxygenated blood to the heart muscle itself. Many other arteries also branch from the aorta. For example, two renal arteries leave the aorta and carry blood to the kidneys, where nitrogen wastes are filtered from the blood. 

After supplying oxygen to the cells of the body, the blood makes its way back to the heart through the body's many veins. Two large veins collect all the deoxygenated blood from the systemic circulatory system. The superior vena cava collects blood from the upper body, while the inferior vena cava collects blood from the lower body. These two veins empty directly into the right atrium of the heart. Blood passes from the right atrium into the right ventricle through the tricuspid valve. As the right ventricle contracts, it sends the blood through the pulmonary valve and into the pulmonary arteries, which carry the blood to the lungs. The oxygenated blood then returns from the lungs to the left atrium and the cycle continues.

Figure 4: representation of blood flow path.

Sources

Weinhaus, A. J., & Roberts, K. P. (2005). Anatomy of the human heart. In Handbook of cardiac anatomy, physiology, and devices (pp. 51-79). Humana Press.

Mahadevan, V. (2018). Anatomy of the heart. Surgery (Oxford), 36(2), 43-47.

Digestive System of Human | structure and function |

HUMAN DIGESTIVE SYSTEM

The digestive system of human beings consists of gastrointestinal track accessory organs and gastric secretion. The long coiled tube of the gastrointestinal track is called the alimentary canal, and it extends from the mouth to the anus and associated digestive gland. The alimentary canal is 7.5 to 9 m in length in an adult and consists of the buccal cavity, the pharynx, esophagus, stomach, small intestine, large intestine, and anus. 

The buccal Cavity or Oral Cavity 

The oral cavity is the site of the entrance of food into the digestive system. It consists of the tongue, teeth, and palate, and the opening of salivary glands. 

Function of oral cavity

It performs the following functions:

• Food Selection 

The oral cavity helps in the selection of food by the senses of taste, smell, and sight. If the digested food has a bad taste or smells unpleasant, it is rejected. The tongue plays an important role in food selection via taste buds. The tongue also helps in food swallowing.

• Food Grinding and Lubrication 

After selection, the food is subjected to grinding by means of moral teeth into smaller pieces. The grinding of food is important because small pieces of food can pass easily through the esophagus. Small pieces have more surface area for the action of the enzymes. Saliva contains mucus and water, which lubricates and moisturizes food immediately to make it easy for grinding, digestion, and swallowing.

Tongue and test bud

The tongue is the first organ of the gastrointestinal track. It is a fleshy, strong muscular sense organ and receives sensory information via the taste buds in the papillae present on its upper surface. The sense of test is mainly due to the presence of test buds. These buds send the signal to the brain via cranial nerves. The brain then distinguishes between the chemical properties of food and can recognize the test as bitter, sour, and sweet both mechanical and chemical digestion occur in the oral cavity by the teeth and enzymes of the saliva respectively.

Fig 1: Labeled diagram of oral cavity. 

Secretion of saliva

Saliva is secreted by three pairs of salivary glands. The Parotid gland: it is present in front of the ears. Sublingual glands: situated below the tongue. Sub maxillary gland present in the angle of lower jaw.

Saliva Volume 

1500 ml of salvia are secreted daily. Saliva is colorless. Its three main ingredients are: Water and mucus combine to form a slimy liquid that serves to moisten and lubricate foods, allowing them to be chewed and swallowed more easily. Sodium bicarbonate and other salts are also present in saliva. These salts are highly antiseptic, but their main function is to stabilize the pH of the food. Amylase, or ptyalin, is also an ingredient of saliva. It is a carbohydrate digesting enzyme that digests starch and glycogen to disaccharide (maltose). Saliva also contains lysozyme, which hydrolyses the cell walls of many species of bacteria. It also keeps the mouth clean. As a result of this mechanical and chemical digestion, food is converted into a partially digested, slimy food mass called a bolus. 

Pharynx

The bolus is pushed into the back of the mouth by the action of the tongue and muscles of the pharynx. During swallowing, the tongue moves upwards and backward against the roof of the mouth, forcing the bolus to the back of the mouth cavity. The background of the tongue pushes the soft palate up and closes the nasal opening at the back. At the same time, the tongue forces the epiglottis into a more or less horizontal position, thus closing the opening of the windpipe. The cartilage of the larynx at the top of the windpipe moves upwards under the back of the tongue. The glottis is partially closed by the construction of four rings of muscle. The food does not enter the partially open glottis because the epiglottis diverts the food mass to one side of the opening and safely down the esophagus. The beginning of the swallowing is voluntary, but once the food reaches the back of the mouth, swallowing becomes automatic. The food is then forced down the esophagus by a wave of muscular contraction called peristalsis.

Esophagus 

An esophagus is a food pipe is a muscular tube extending from the pharynx to the stomach, passing through the diaphragm. The length of the esophagus is about 18 inches or 25 centimeters. It runs through the neck and thorax between the trachea and the vertebral column. It lies above the trachea and below the vertebral column. 

Digestion 

There is no digestive juice secreted in the esophagus. The amylase of saliva keeps on digesting food in the pharynx and esophagus. The food passes through the esophagus by a process called peristalsis.

Fig 2: Labeled diagram of human digestive system.

Peristalsis

It is a series of rhythmical involuntary waves like contractions of the muscular wall of the elementary canal. Food moves through the whole alimentary canal by means of peristalsis. It starts just behind the mass of the food from the buccal cavity along the esophagus to the stomach and then along the whole of the elementary canal. A hunger contraction is a peristaltic contraction that increases as blood sugar levels fall and is strong enough to cause an unpleasant sensation known as a hunger pang. 

Antiperistalsis 

Sometimes the wave of peristalsis is reversed, which causes the food to pass from the intestine back into the stomach and even into the mouth. This reverse peristalsis is called antiperistalsis, and leads to vomiting.

Stomach

Stomach is an elastic muscular thick walled J-shaped bag. It is widest part of the digestive system. The length of stomach is about 10 to 12 inches. It is situated below the diaphragm on left side of the abdominal cavity. 

Cardiac region: The upper broad region of the stomach near the heart called the cardiac region. Where ring like muscle called the cardiac sphincter, which when relax allow the food to enter into the stomach and when contract closes the opening of the stomach from esophagus. Cardiac region contain mucus secreting gland called the cardiac gland. Fundus: It is the largest and middle part of the stomach, that hold food and gases. This portion of stomach lies below the cardiac notch. Fundus contain the gastric or fundic glands. Pylorus end: The narrow part near the small intestine is called pylorus region at the junction of pylorus region and duodenum lies a muscular ring called pylorus sphincter, which allow the food to passes from stomach into the duodenum. It contains pyloric gland which secretes number of hormones and mucus.

Composition of stomach wall

Stomach wall is composed of 4 layers. Serosa: it is an outer layer of connective tissue. Muscularis: the middle layer of muscles consist of an outer longitudinal and inner circular muscles, it lies next to serosa. Submucosa: a middle layer of connective tissue laying next to mucosa and have many glands, blood vessels, and nerve cells. Mucosa: an inner most layer of smooth muscle.   These muscular layers helps in churning and mixing of the food with the gastric secretion. The mucosa of stomach possess many tubular gastric glands. Gastric glands are composed of three kind of cells producing different secretion.

Mucoid cell or pylorus cell : secrete gastric mucous which form the inner coating and prevent the stomach wall from digestion by enzymes. Parietal or oxyntic cells: secret hydrochloric acid HCL, HCL provides an acidic medium for pepsinogen, it act as an antiseptic to kill microorganism, and also soften the food. 

zymogenic cells: secrete pepsinogen, which is an inactive form of pepsin, pepsinogen is than converted to pepsin when expose to the acidic medium.  Pepsin is the protein digesting enzyme which hydrolysis protein into smaller peptones and smaller polypeptides. 

All the three secretion are collectively called as gastric juices, the volume of the gastric juices is about 2500ml per day. The gastric juices of an infants contain an enzyme called rennin which convert milk into curd thus increasing the stay time of food in stomach. The curd is than digested by pepsin.  As a result of mechanical and chemical digestion food is converted into a homogeneous semifluid called chyme.

Fig 3: Labeled diagram of layers of stomach.

Small intestine 

The stomach open into small intestine. The small intestine is named for its small diameter. Small intestine is an elongated narrow and coiled tube. It is longest and most important part of digestive system.

Part of small intestine 

Small intestine is divided into three parts:

1:Duodenum 2: Jejunum 3: Ileum 

Digestion in Duodenum 

The duodenum is the first part of small intestine and it is about 12 inches in length. Duodenum receives chyme from the stomach. As acidic chyme enter into the duodenum, it stimulates duodenum wall to secrete hormone called secretin, which stimulates pancreas to secretes its secretion into the duodenum.

Both liver and pancreas play an important role in the digestion of food in the duodenum.

Role of liver in digestion 

Liver is the largest gland of the body and is greatest chemical factory. It is reddish brown in colour and lies under the diaphragm. Liver consists of two lobes each one is further divided into many smaller lobes. Liver secretes bile which is stored in the gall bladder and is released into the duodenum through the bile duct.

Bile

Bile is, alkaline watery fluid and contains no enzymes. Its greenish color is due to the bile pigment, which are formed from the breakdown of hemoglobin in the liver. 

Composition of bile

Bile contains water, sodium bicarbonate, excess of calcium and the breakdown product of haemoglobin. Bile contains salts which emulsified the fats,  it is antiseptic and kill germs, it is alkaline and neutralize the acidic chyme.

Pancreas 

The pancreas is a long, many-lobed gland that lies below the stomach. The exocrine tissue of the pancreas secretes pancreatic juices that flow through the pancreatic duct into the duodenum.

The nature and composition of pancreatic juice

The pancreatic juices are alkaline, thus neutralizing acidic chyme. It contains sodium bicarbonate and water, as well as enzymes that digest all of the food's major components, namely carbohydrates, fats, and protein. These enzymes are: Amylase: it is the carbohydrate digesting enzyme which digests starch into maltose. It is also known as an amylopsin. Lipase: is a fat digesting enzyme that hydrolyzes a small percentage of the fats into fatty acids and glycerol. Trypsin: it is secreted in the inactive form trypsinogen. Trypsinogen: is activated into trypsin by an enzyme of the duodenum known as enterokinse. It digests proteins into small polypeptides and peptones. 

Digestion in Jejunum and Ileum

The jejunum is the middle part of small intestine. It is about 2.4 m in length, comprising about 2/5 of the small intestine. The ileum is about 2.60m in length, which makes up about 3/5 of the small intestine. The food that escapes undigested from the duodenum is completely digested in the jejunum and ileum by a group of enzymes contained in the intestinal juices. These enzymes are: 

Aminopeptidase: it converts peptones and other smaller peptides into dipeptides. Erepsin: It is a dipeptisase, which converts dipeptides into amino acids. Lipase: it converts fats into fatty acids and glycerol. Maltase: it acts on maltose and converts it into glucose. Lactase: it converts lactose into glucose and galactose. Sucrase: it converts sucrose into glucose and fructose. 

Absorption of Food 

Absorption is the passage of glucose, fatty acids, glycerol, amino acids, vitamins, minerals, and water into the circulatory system. Absorption occurs chiefly in the small intestine, particularly in the ileum. The internal surface of Ileum has many folds. It exhibits a velvety appearance due to the presence of numerous finger-like projections called villi. Villi increases the surface area of absorption. 

Structure and Function of Villi

Each villi consists of three parts. 

1: The outer layer of epithelial cells 2: Blood Capillaries 3: A small lymphatic or lacteal vessel:

Each villa consists of thousands of small microscopic projections called micro villi. Different parts of the villi absorb the secretion selectively, e.g. simple sugar, amino acids, vitamins, minerals, and water enter the blood capillaries in the villi. These capillaries join up to form hepatic portal veins, which carry nutrients to the liver. Smaller fatty acids and glycerol are absorbed into blood capillaries while large fatty acids and glycerol are absorbed into the lymph vessels or lacteal. The ileum absorbs the digestive food efficiently, and the absorption occurs by diffusion and active transport. 

Fig 4: typical structure of villi. 

Large Intestine 

The large intestine is about 6 feet long and consists of the three regions.Cecum he cecum is about 5 to 8 cm in length and lies between the small intestine and the ascending portion of the colon. The cecum has a small finger-like projection called the appendix. It is a vestigial organ in man but has a minor role in immunity.

Colon

The colon is the largest part of the large intestine and it consists of four parts.

The ascending part: it goes up on the right side of the body to the level of the lever. 

The transverse part: it rosses the abdominal cavity just below the liver and stomach. 

The descending part: it passes down on the left side of the body. 

The sigmoid part: it enters the rectum. 

Function 

The large intestine performs the following function:

Reabsorption of water and salt 

The chyme reaches the large intestine, which contains a lot of water, salt, and undigested material. The water is reabsorbed into the blood while undigested material is expelled out of the body as feces. 

Synthesis of vitamin K

The large intestine contains a bacterial population which can synthesize some vitamins, especially vitamin K which is absorbed into the blood.

Feces 

Feces material contains a high concentration of bacteria, plant fiber, sloughed mucosal cells, mucus, cholesterol, bile pigment, and other substances. 

Rectum

It is the largest part of the large intestine. It is about 21–23 cm long. It stores feces temporarily and ejects them through an anus at intervals. When the rectum is filled with feces, it stimulates the wall of the rectum to give rise to the defecation reflex. This reflex can be consciously inhibited in individuals, but not in infants. The undigested residue may spend from 12 to 24 hours in the large intestine. 

Anus

The anus is the opening through which feces are expelled out of the body. It is guarded by a sphincter muscle. The brown color of the feces is due to the bacterial breakdown of the bilirubin. The bad smell of feces is due to the decomposition of bacteria, their byproducts, and the choice of the food you eat. Putrefaction sets up in the last portion of the large intestine of a microorganism. Putrefaction also produces various gases.

Sleep paralysis| sleep disorder| causes, prevention and treatments.

Sleep paralysis

Sleep paralysis is a worldwide phenomenon that was once thought to be caused by evil creatures such as demons, witches, or vampires appearing at night to frighten humans. Different cultures have different ideas and beliefs about it. It is known as a "night mare" in English, which means "evil sleep riding on people's chests while sleeping." In Chinese it is called "govei nulim" means being pressed down by a ghost. In Japanese traditions, it is believed that it is a vengeful sprite who sits on the person's chest while sleeping for revenge. According to new research, it is called "old hag syndrome," which is another name for sleep paralysis. "Old hag" means an evil creature who leaves her body at night and sits on the chests of victims. 

Figure 1 depicts a creature ride on someone's chest at night in order to suffocate them.

What is Sleep Paralysis? 

Definition 

Sleep paralysis a frightening phenomenon where a person suddenly finds himself unable to move, speak, or react for a few seconds or minutes between the stage of wakefulness and sleep. It usually occurs upon falling asleep or just upon waking. 

Symptoms 

The main symptoms of sleep paralysis include the following: 

While sleeping  a person is unable to move their legs and arms, nor can they speak or react a bit. It seems like a bit of a paralysis of his body. 

The experience is quite terrifying and lasts from  few seconds to minutes. 

Some people may also experience hallucinations. 

The patient may also have frightening experiences, such as the sensation of floating, hearing or seeing things that do not exist. 

Some may also feel pressure on the chest, as if someone is pressing and suffocating the chest.

 

Prevalence 

Sleep paralysis affects both genders equally. The average age when it first occurs is early teen age, at age 14-17 years. It affects people of all ages, but it is most prevalent in adolescents (14-17) and the elderly (60+). It is also common in students and psychiatric patients. The average number of individuals who experience sleep paralysis is 4 out of every 100 individuals.

Cause or reason behind it. 

Sleep paralysis occurs during REM sleep. REM is a sleep cycle during which a person’s brain is fully active and frequently dreams, but the muscles of the body are fully relaxed or turned off. The brain releases two chemicals, i.e., GABA and glycine, which turn off some specialised brain cells that perform voluntary movement in the body in order to prevent the body from physical damage during sleep. This condition is called atonia. When a person wakes up quickly during REM, they might experience mild paralysis.

REM Sleep

REM sleep (rapid eye movement) is the stage of the sleep cycle during which the body is fully relaxed but the brain is more active and continuously dreaming. At this stage, a person’s eyes are rapidly moving, the breathing rate is high, intense dreaming occurs at this stage, and a body is fully relaxed.

 

Types of sleep paralysis 

Sleep paralysis occurs in two ways.:

Predormital sleep paralysis: If it occurs while you are falling asleep, it is called predormital sleep paralysis or hypnogogic sleep paralysis. 

Post-dormital sleep paralysis: If it occurs when you are waking up, it’s called post-dormital sleep paralysis (PDSP), or hypnopompic sleep paralysis.

Classification of sleep paralysis 

It is mainly classified into two. 

1. Isolated sleep paralysis (ISP): It is more common, infrequent, and lasts for a short duration. Approximately one minute or less. In some cases, it might occur once in an individual's life. 

2. Recurrent Isolated Sleep Paralysis (RISP): It is a more chronic condition, and individuals may experience regular episodes throughout their lives, and they may last for hours or longer. 

Problems arise from sleep paralysis 

Sleep paralysis is not life-threatening but it can cause depression, anxiety, loss of sleep, terror experiences etc. 

Causes of sleep paralysis 

Lack of sleep can disturb the sleep cycle, which can cause sleep paralysis. 

Sleeping on your back or on your stomach, it can occur at any position. 

Keeping electronic devices near your head while sleeping may also cause it, because electrical devices have their own frequency and radiation which may harm you while sleeping. 

Changes in sleep schedule and time can disrupt the body's natural biological cycles, known as circadian rhythms.

Use of sleep-inducing drugs such as caffeine or alcohol. 

Mental stress or disorder, eating large meals at night, which may cause bloating and disrupt sleep. 

Inheritance may also be the cause of sleep paralysis. 

Sleep paralysis risk factors

People who have sleep disorders like narcolepsy, sleep apnea, and restless leg syndrome are all at risk for sleep paralysis. 

Mental illnesses like anxiety, depression, terror, stress, or bipolar disorder are risk factors for sleep paralysis.

 Disrupted circadian rhythms i-e 24 hours sleep wake cycle due to heavy work, lack of sleep, drugs are great  risk factor causes Sleep paralysis 

Sleep paralysis can also be inherited and can run in families.

Genetics role in sleep paralysis 

Sleep paralysis is inherited and can run in families. 

According to the new research, the variation in PER2 gene is associated with sleep paralysis. Which is located on the long arm of chromosome 2. The PER2 gene is responsible for controlling circadian rhythms  the 24 biological cycles that help to govern the sleep wake cycles.

Prevention 

Clear your mind before going to sleep. 

Avoid taking alcoholic drinks and heavy meals before bed. 

Don’t sleep on your back and stomach. 

Relaxation of the mind and body before sleep is helpful.

Relieve the stress, so sleeping becomes easier and the effect is minimized. 

Avoid watching horror movies before bed. 

Treatment 

Improving sleep habits—such as making sure you get six to eight hours of sleep each night.

Taking antidepressants as prescribed to help regulate sleep cycles

Treating any mental health problems that may contribute to sleep paralysis 

Treating any other sleep disorders, such as narcolepsy or leg cramps. 

Wiggling finger or toes of the victim so they can be able to realise the condition and be able to move.

 

Beta-catenin (CTNNB1)| Gene Protein structure| Functions and Mutation.

Beta-catenin (CTNNB1) location and structure

Beta-catenin (CTNNB1) also known as catenin beta-1, is located on the short arm of chromosome 3 at position 3p22.1. The size of the complete gene was determined to be 23.2 kb. CTNNB1 has 16 exons according sequence analysis, the exon size ranged from 61 to 790 bp, half of the introns were smaller than 550 bp, with the smallest being 84 bp and the longest being 6700 bp.  Alternative splicing within exon 16 produced a splice variant that is 159-bp shorter in the 3-prime untranslated region. The promoter region was shown to be GC-rich and to contain a TATA box.

Protein structure

The primary structure of β-catenin consists of three domains: central domain known as armadillo repeat domain, an N-terminal domain, and a C-terminal.

• Armadillo repeat domain constitute of 550-amino-acid repeats occupy between N- terminus and C-terminus. The central armadillo domain composed 12 repeats of three helices, which is known as armadillo repeats, each of which contains approximately 42 amino acid residues. This structure forms a super helix for the binding of many factors, including the Tcf transcription factor, the cell adhesion protein cadherin, APC, Axin and other.
• N-terminal domain is composed of 150-amino-acid, the N-terminal domain is the phosphorylation site for GSK-3β and casein kinase-1. The N-terminus of b-catenin is phosphorylated when b-catenin is bound to the destruction complex.
• C-terminal domain is composed of approximately 100-amino-acid residues. The C-terminal segment of β-catenin can mimic the effects of the entire Wnt pathway.

       The N- and C-terminal regions are much smaller, and form flexible regions that interact with transcriptional activating factors. Both of terminal domain combine with the armadillo repeat domain and may regulate the partner-binding properties of the armadillo repeats.

Figure 1: represet the gene protein structure of catenin beta_1 along with its protein interacting domain.

The basic biological function of β-catenin

β-catenin is crucial for two important developmental processes:

  1: Establishment and maintenance of cell-type-specific through cell-to-cell adhesion and

  2: Regulation of target gene expression via the Wnt signaling pathway.

1: Role in cell-to-cell adhesion   

In most cases, β-catenin perform its functions in combination with several other proteins to. β-catenin is normally present in the cell membrane and can play a role in cell to cell adhesion by forming a complex, β-catenin associates with the cytoplasmic domain of E-cadherin (also known as uvomorulin that expressed by epithelial cells) and also with α-catenin, which in turn binds to F-actin protein. β-Catenin, therefore, provides the physical linkage between transmembrane adhesion proteins and the cytoskeleton proteins in the cells. This linkage to the cytoskeleton play an important role to the cell adhesion function. In summary, β-catenin provides obvious connections among extracellular signals, cell-cycle management, and gene transcription.

2: Role in Wnt signaling pathway

β-catenin-dependent Wnt signaling path way is also called the ‘canonical’ Wnt signaling pathway. The canonical Wnt/β-catenin pathway is more complex because high number of ligands and receptors involved in signaling that involve in variety of intracellular responses. Activity of β-catenin is mediated by the destruction complex, consisting of APC, AXIN-1, AXIN-2, casein kinase-1α (CK-1), protein phosphatase 2A (PP2A), and glycogen synthase kinase (GSK)-3β in the cytoplasm.

This pathway has two states dependent upon the presence or absence of Wnt ligands

1: In the absence of Wnt ligands

In normal inactivated cells GSK3-β kinases bind to and phosphorylates β-catenin in the APC/Axin destruction complex, leading to subsequent degradation of β-catenin in the proteasome.

 2: In the presence of Wnt ligands

However, upon Wnt stimulation, the GSK3-β kinase activity is inhibited, so the stable and nonphosphorylated β-catenin accumulates in the cytoplasm and then translocates into the nucleus. Nuclear localized β-catenin binds to the T Cell-Factor/Lymphoid-Enhancer Factor (TCF/LEF) DNA-binding proteins and regulates the transcription of many target genes, depending on its developmental stages and context.

      

Figure 2: represents β-catenin Wnt signaling pathway, in A the absence of wnt ligant and B presence of wnt ligant.

Mutation in β-catenin

Exon 3 of CTNNB1 is a key exon encoding serine-threonine phosphorylation sites for GSK-3β (Glycogen synthase kinase 3 beta) that activates degradation of β-catenin. The CTNNB1 mutations are frequently missense mutations, mostly localized in the hot-spot exon 3, and most of them have affect the phosphorylation sites for GSK-3β; S45 is the phosphorylation site for casein kinase-1; and D32 and G34 are essential for the interaction of β-catenin with Fbw1.

Gene mutations lead to activate the Wnt/β-catenin signaling pathway, which play a role in the development of some cancer cases. Moreover, a high level of β-catenin activity is required for cancer initiation. Initial characterization of mutations of CTNNB1 and deregulation of the canonical Wnt pathway were in colorectal cancer cases.  Similarly, another mutation of β-catenin (S37F) activates Wnt signaling in several melanoma cell lines. Such mutations have been shown to result in the accumulation of nuclear β-catenin and stabilization of the protein and tumorigenesis. These mutations stabilize β-catenin, as they cease the phosphorylation-dependent interaction of β-catenin with Fbw 1 (is a type of F-box protein), involve in degradation of β-catenin in association with casein kinase-1α and GSK-3β. In addition, other relatively benign tumors, such as desmoid-type fibromatosis, also have CTNNB1 mutations and abnormal nuclear β-catenin expression.

 

Gap Junction Protein Beta-2 (Gjb2)| Gene, Protein Structure of (Gjb2) and mutation.

Gap Junction Protein Beta-2 (Gjb2)

Gj2 gene is located on DFNB1 loci and is mapped to 13q12 of the chromosome, encode a gap junction beta-2 protein known as connexins 26 which express in cochlea and epidermis of the skin. Some of the alternative names for Gjb2, are DFNB1, DFNA3, DFNB1A, DFNA3A, CX26, NSRD1, KID, HID, PPK, (gap junction protein, beta 2, 26kDa), (gap junction protein, beta 2, 26kD (connexin 26)) [http://atlasgeneticsoncology.org/gene/40716/gjb2-(gap-junction-protein-beta-2)].

Gjb2 gene structure

Gjb2 comprising the simple structure, it consists of about 26kDa molecular weight, the size of the gene comprising 5500bp or 5.5 kb, that located on chromosome no 13 at short arm of locus 13q12.11. The size of the translated m RNA consists of 4.2Kb, which encode the protein having 226 amino acid residue. Flanked between GJA3 which encode connexin-46 present at centromeric side and GJB6 which encode connexibbbn-30 present at telomeric side. The gene comprising on two exons, the untranslated exon 1 is separated from exon 2 by an intron which is 3179 bp in length, exon 2 is only the coding region consisting the uninterrupted coding region and 3’ UTR (untranslated region).  

Figure 1: Present the location of Gjb2 on the 13 chromosome and typical structure of Gjb2 gene consist of exon 1 exon 2 and an intron 3’UTR, stop codon.

Connexin-26 

Connexin-26 is transmembrane protein which is encoded by gap junction beta-2 gene, mutation in which causes most common congenital, sensorineural deafness, it is member of connexin family. The naming is based upon the molecular weight of the particular connexin protein (CX-26, CX-43, CX-30, etc. To date up to 21 connexin gene have been identified for human.  That are classified into five group (alpha, beta, gamma, delta and epsilon) connexin-26 belongs to beta groups.  Connexin family consist of hemi-channel known as connexon, which contain the six subunit of connexin protein that arrange in such a way to form water filled channel in it, two connexon in the plasma membrane of adjacent cells adjoins by head to head docking to form gap junction channel in it. A typical CX-26 consists of four transmembrane domain segment (TM1_TM4) which are consider to be anti-parallel in conformation T1 and T2 predicated to be interior hydrophilic, whereas T3 and T4 predicated to be exterior hydrophobic environment. Two extra cellular loop EL1 between T1 and T2, EL2 which is present between T3 and T4. N terminus, the interior cytosolic C terminus   and the cytoplasmic loop between T2 and T3, shown in fig: 2. The CX-26 expresses both in the skin epidermis and inner cochlea cells, mostly with co-expression of other connexin, it expresses in hair follicles, sweat gland, also play an important role in keratinocyte proliferation, inter follicular cells. Cx-26 co-localized with CX-30 in the inner ear and perform important function in maintenance of homeostasis of inner ear. It is essential for cycling of K⁺ ion, which is required for the balance of ionic composition of endolymph and endo-cochlear potential, also play an important role in intercellular signaling, by the release of Ca⁺ oscillation and waves which are mediated by the diffusion of inositol 1,4,5-trisphosphate (IP₃) in corti of the inner ear. 

                 

Figure 2: Structure of cx-26, consist of CT, CL, NT four domain segment, and loop EL1, EL2.

Gjb2 mutation

Mutation in the Gjb2 gene encode defective protein which is the major cause of non-syndromic hearing loss, to date more than 100 mutations have been identified for Gjb2 which inherited either in recessive or dominant mode to cause deafness, syndromic disorder with hearing loss, and many skin diseases. These mutations may be appearing in the form of missense, nonsense, small deletion or insertion.  That leads to truncated protein, which bring defect in Gjb2 protein structure, like 35delG effect extracellular loop EL1, 235delC effect T2, V95M effect CL domain of Cx-26 all of these appear in autosomal recessive manner. AD inheritance includes like W44C, R75Q mutations which effect EL1 of CX-26. Their epidemiology varies in different ethnic group, for example 167delG mutation is more prevails among Jews, W24X and W77X appear to be most common in south Asian countries like India, Bangladesh and Pakistan, similarly high frequency of 235delC mutation prevails in East Asian country.  

Hearing loss| Types of deafness |causes and treatment.

 Hearing loss or Deafness

Hearing impairment is defined as, “the inability to perceive sound either partially or completely”.  Deafness is common and congenital disease in the US which affect 1 to 3 per 1000 infants at birth while 1 to 6 have milder impairment. However, in Pakistan it is estimated that about 10% of the population is deaf, means from every 1000 individuals 3.5 are effected. Hearing impairment is the world's third chronic disease.  About 250 million peoples suffer from deafness worldwide. Of that more than 4000 new-born children conceived loss of hearing every year and in these children most of them have genetic diseases. Approximately 60% of hearing loss is because of hereditary variables.

       Deafness can be either, congenital deafness which is present at birth due to both environmental and genetic factors, in every 1000 birth 1 is suffering from congenital deafness.  It may be acquired which are not present at birth but appear later due to some sort of abnormalities, disease, infection or injury both in children and adults mostly environmental responsible for acquired deafness. 

Onset Of Deafness

Onset of deafness might be pre-lingual, post-lingual or Presbycusis.

Ø  When hearing loss occur in early infancy or at congenital condition, before the child seek speech and perception skills referred as pre-lingual hearing loss.

Ø   Deafness occur after the acquisition of basic speech, learning and perception skills known as post-lingual deafness.

Ø  Presbycusis is hearing loss associated with age. About 25% individual have 65 year and about 50% have 80 years.

Types OF Deafness

Deafness categorized into five types namely conductive deafness, sensory or neural deafness, mixed deafness, neural deafness and central deafness.

Ø  Conductive deafness, any obstruction or damage when occur to the outer and middle ear causes conductive deafness.

Ø  Sensory deafness or Sensorineural, caused due to deformities in the middle ear like damage or abnormalities to the nerves or cochlea hair.

Ø   Mixed deafness, related to both outer and middle ear deformities.

Ø   Neural deafness related to deformities occur in the vestibule-cochlear nerves (8 cranial nerves) may cause neural deafness.

Ø  Central deafness, when deformities occur in the auditory nerves responsible for conduction in the central nervous system may cause central deafness.

Degree Of Severity

On the basis of degree of severity and gradual decline of hearing capability it is categorized into the four distinct classes ranges from “no impairment to profound” on the basis of threshold frequency measured in decibels.

Degree of severity of hearing loss in decibels

Degree of severity of hearing loss	Hearing threshold in decibels
0 to 25	Normal
26 to 40	Slight or mild
41 to 60	Moderate
61 to 80	Severe
>80	Profound

 Factors

In a particular population two main factors contributes for deafness, Environmental and Genetic.

Environmental Factors

It is estimated that from total 100% about 60% deafness is caused by environmental factors and remaining 40% is due to genetic factors. Many Environmental factors contributes for deafness, for example ototoxic medication, like Aminoglycosides, Aspirin, Nonsteroidal, Bleomycin, and Tetracycline due to their ototoxicity may damage the hair cell and nerves which cause deafness. Due to certain Infectious agent, which may be prenatal, during pregnancy mother acquired certain infection such as CMV Cytomegalovirus and rubella. Which cause congenital hearing defect. Exposure to noise or loud sound to prolong period is another factor for acquired deafness. Ear diseases such as otitis media, birth conditions which i-e low birth weight, severe neonatal jaundice, and presbycusis which is age related hearing impairment all are the environmental factors that may cause deafness in an individual.

Genetic Factors

Genetic factors are also responsible for deafness, about 80% congenital deafness is caused by genetic factors. Over 100 faulty gene have been identified which are associated with deafness. Similarly, genetically determined deafness may be either congenital present at birth, late-onset which is later appear in life, stable that remain same, or it may be progressive that appear worst with the passage of time. On the basis of Genetics   hearing loss categorized into syndromic hearing loss (SHL) and non-syndromic hearing loss (NSHL).

Syndromic Hearing Loss (SH)

It is estimated that about 30% genetic defect is due to syndromic hearing. Many gene identified for SHL like CACNA1D which causes sinoatrial node dysfunction and deafness. 400 syndrome have been identified which are associated with syndromic hearing loss. Several syndromes identified like, Neurofibromatosis 2 (NF2), Jervell and Lange-Nielsen syndrome, Wardenburg syndrome and Branchial-oto-renal syndrome which may have associated with deafness. Their transmission may be autosomal dominant, recessive and X-linked.

Table of genetic syndromes, their related gene and type of deafness.

Genetic syndrome	Gene	Type	Inheritance
Neurofibromatosis 2 (NF2),	NF2	Sensorineural	Autosomal  dominant
Jervell and Lange-Nielsen syndrome	KCNQ1 KCNE1	Sensorineural	Autosomal recessive
Wardenburg syndrome	WS-I/(PAX3)     WS-II/ (MITF) WS-III/(PAX3) WS-IV/ (EDN3orEDNRB)	Sensorineural	Autosomal dominant
Pendred syndrome	SLC246	sensorineural	Autosomal recessive
Alport Syndrome	COL4A5	sensorineural	X-linked

 Non-Syndromic Hearing Loss (NSHL)

It is investigated that about 70% deafness is due to non-syndromic hearing loss. Approximately 120 gene loci have been known associated with NSHL, which are involve in of ear structure and function development. It is further classified into X linked, autosomal dominant, autosomal recessive, and mitochondrial deafness.

Mitochondrial hearing loss

Mitochondria, contribute 0.5% to 1% in ratio from total hearing impairment. Mitochondrial deafness is maternally inherited and effect both gender equally, it may cause sever to profound hearing loss. Gene like MT-TS and MT-RNR1 causes deafness. Several mutation have been identified which are, A7445G, 7472insC, T7510Cand T7511C which may cause deafness.

Table of Mitochondrial deafness, related gene and their mutation.

Gene	Mutation	Type
MT-RNR1	1494C>T 1555A>G	Sensorineural/severity variable
MT-TS1	7445A>G 7472insC  7510T>C 7511T	Sensorineural/ severity variable
MT-CO1	7444G>A	Sensorineural

 X-linked deafness

X-link deafness prefix as (DFNX) nearly 1 % deafness cases are caused by X-linked deafness. Almost 6 gene loci are presently identified, only 3 gene associated with deafness and present on X-chromosome, more over it is much rear. PRPS1 gene located on locus DFNX1 at Xq22 arm, POU3F4 which located on DFN3 at Xq21.1, and DMD located on Xp21.2 at locus DFNX4.

 Table of X-linked loci related gene and deafness.

Locus	Gene	Type
DNFX1   (DNF2)	PRPS1	Sensorineural
DNFX2 (DFN3)	POU3F4	Mixed
DFNX4 (DFN6)	DMD	Sensorineural

Autosomal dominant hearing loss

Autosomal dominant prefix as (DFNA), It causes 20% of non-syndromic hearing defect. About 54 gene loci have been identified, which are located on different chromosome, from which 19 genes responsible for autosomal dominant deafness. Most common genes are GJB3, GJB2, GJB6, POU4F3 and MYO7A.  It is extremely heterogeneous, and can be transfer either when one copy of alter gene is present.  NSADHL mainly non-congenital, or post-lingual, progressive and severe to profound but with some exception like DFNA3, DFNA8 and DFNA12 which may cause pre-lingual hearing loss.

Table of NSADHL, related locus their gene and type deafness.

Locus	Gene	Type
DFNA1	DIAPH1	Post-lingual/sensorineural/progressive
DFNA2	KCNQ4GJB3	Post-lingual/Progressive/sensorineural  Post-lingual/ progressive/sensorineural
DFNA3	GJB2 GJB6	Per-lingual/mild-to-profound/ progressive/ sensorineural
DFNA4	MYH14	Post-lingual/sever to profound /sensorineural  /progressive
DFNA5	DFNA5	Post-lingual/monogenic /sensorineural / progressive/ age related
DFNA6/14/38	WFS1	Per-lingual/ sensorineural
DFNA8/12	TECTA	Pre-lingual/ moderate to severe/  stable or non-progressive/ sensorineural
DFNA9	COCH	Post-lingual/sensorineural/progressive /profound

Autosomal recessive hearing loss

Autosomal recessive prefix as (DFNB), It accomplish major portion of non-syndromic hearing loss up to 80%. Currently 67 gene loci have been identified for it, Up to 700 mutation identified on 42 gene loci present on various chromosome which causes deafness the well-known genes are MYO7A, GJB2 and GJB6. As many of the world population 50% ARHL occur due to mutation in Gjb2 and remaining are the contribution of other mutated gene. Most of the ARNSHL may cause pre-lingual severe-to-profound hearing loss with exceptional cases like DNFB8.

Table of autosomal recessive loci and their related gene.

Locus	Gene	Type
DFNB1	Gjb2 Gjb6	Sensorineural/pre-lingual/ congenital/sever to profound
DFNB2	MYO7A	Pre-post lingual /sensorineural / severe-to-profound
DFNB3	MYO15A	Sensorineural/sever to profound
DFNB4	SLC26A4	Sensorineural or mixed /progressive/ pre-lingual/ post lingual
DFNB6	TMIE	Pre-lingual/sensorineural
DFNB7/11	TMC1	Sensorineural/profound/ congenital
DFNB8\10	TMPRSS3	Pre-lingual/post-lingual/Sensorineural
DFNB9	OTOF	Neural/profound/pre-lingual/

 

Figure represent the Genetic and Environmental, Syndromic and Non-syndromic, ADNSHL, ARNSHL, X-Linked and Mitochondrial contribution on the basis of percentage

Treatment of Hearing Loss

Hearing loss after examination can be cured by the following treatment based in the cause and severity of once hearing loss.

Surgical procedure:  this procedure medical intervention after examination the specialist perform surgery, when the abnormalities occur in middle and inner ear due to some infection or abnormalities in eardrum or ossicles (ear bones).

Cochlear implantation:  it is also a surgical implantation of cochlea due to some defect in it.

Medication:  if the hearing loss is due to any infection, it will treated by medication.