MEMORY

                                                                Memory.

                                                PKGhatak, MD

Barbara Streisand sings in her famous song the "Memory” --

"Midnight, not a sound from the pavement
Has the moon lost her memory?
She is smiling alone
In the lamplight, the withered leaves collect at my feet
And the wind begins to moan.............

All alone with the memory
Of my days in the sun
If you touch me, you'll understand what happiness is
Look, a new day has begun."

https://www.youtube.com/watch?v=MWoQW-b6Ph8

What is memory.

One medical dictionary says– “the mental faculty that enables one to retain and recall previous experienced sensations, impressions, information, and ideas.”

But this definition does say anything about how the mental faculty enables. Intensive research is going on currently to address that question.

It is easier to answer where memory is stored in the brain than how memory is formed. With the wide use of brain imaging tools, MRI has advanced research greatly at the macroscopic level. Functional MRI locates memory centers very precisely and the location is based on the nature of information, emotion associated with it and how long the memory is stored. The Hippocampus, Neocortex, Amygdala, Cerebellum, and prefrontal cortex serve as memory centers. The hippocampus is the initial place where memory is formed. The long term memory is shifted to the neocortex from the hippocampus, and when the process is complete,  the memory disappears from the Hippocampus. Emotional or fear provoking memories are generated with input from the Amygdala. Body movement associated memories are stored in the cerebellum.

Memory formation.

Humans are capable of remembering a vast amount of information. If one has any doubt just watch TV the Jeopardy show, and you will be simply amazed.

You need not be surprised that the vast amount of written literature is accomplished with only 26 letters of the alphabet and a few punctuation marks and simple rules of grammar.

And the computer memory is written by just two inputs 0 and 1. Brain cells use Long Term Potentiation (LTP) and Long Term Depression (LPD) to record memory.

LTP and LTD.

Two types of effects are observed in memory formation. LTP is observed when information is strong and repeated. LTD happens when information is received once or only a few times and the memory lasts maybe a minute only. LTP and LTD are alphabets of memory. Synaptic plasticity and neurons are the punctuation and grammar of memory. Memory is formed from persistent changes in the strength of connections between the neurons. Different groups of neurons are responsible for different information and thoughts

Synaptic Plasticity.

Synaptic plasticity describes persistent changes in the strength of connections between the neurons producing structural changes both in the synapses and neurons and the creation of new synapses. And new neurons are formed in the hippocampus when information is repeated often.

Molecule of Memory.

The molecule that is universally present in all nucleated cells is called Calmodulin.

Calcium ion (Ca++) is only selectively admitted inside the cells when a stimulus arrives at the synaptic junction or neuron. Inside the cells, Ca++ combines with calmodulin to form Calcium / Calmodulin dependent protein kinase (CaMKII).

CaMKII is widely used in many important cell functions. Inside the neurons, the CaMKII exists as isomers; and for memory generation, four isomers of CaMKII are involved. Each isomer functions independently and only in one aspect of memory formation.

Calmodulin acts as a messenger carrying information from the cell cytoplasm to the nucleus of the cell. Kinase is an enzyme that breaks down high energy ATP (adenosine triphosphate) and the released energy that is utilized in chemical reactions.

CaMKII by repeated interaction with the nucleus induces gene variations and results in new mRNA generation. CaMKII activates downstream the line Kinases for chemical reactions. Many other molecules have also been identified that play various roles in storing and retrieving information from neurons.

Types of memory.

Memories develop in two phases. Short term and Long-lasting memory.

The short term memory-

In the initial phase, the learning of short term memory the brain retains the information only for a brief period of time. According to Meffert of Johns Hopkins, the brain only makes transient changes of the memory molecules already exist and minutes later the molecule is recycled or destroyed.

Long lasting memory.

Meffert thinks the brain cells not only make changes in the molecules already present but also change the gene expressions – turning on and turning off genes. Neurons produce new proteins, increase the rate of production, or shut down lines of proteins.

The strengthening of synaptic connections, forming new connections, and enlargement of neuron partnerships are also part of this process.

Memories are Explicit or Declarative, and Implicit or Non-declarative.

Explicit memories deal with facts, events, people, places and objects. The center is located in the Hippocampus. Implicit memories are motor skills and perceptual. The cerebellum is involved. The reflex action in invertebrates is equivalent to the explicit memory of vertebrates.

Taken from Richard F. Thompson and Jeansok J. Kim. PNSA, Nov.26,1996.

Episodic memories.

Telving called another type of memory - the Episodic Memory. Episodic memory allows us to replay old experiences in our own mind, resulting in refinement, making associations with similar experiences that result in enhancement of that experience. If emotions are generated during the replay, then the Amygdala stores that memory. In a recent publication, Dr. Reddy from France says in human "Time Cells" which are present in the hippocampus, fire repeatedly and link time, place, person of an event as the hippocampus is developing the memory. That is why we remember not only the event but when and under the circumstance - like "what were you doing when you heard that President Kennedy was shot"

Memory development, retention and recall are subjects of serious study at present. There are many more molecules, enzymes and cell groups involved in many aspects of memory. The increasing incidence of dementia in the elderly has produced a strain on the finances of medical care and personnel. A clear understanding of different aspects of memory is urgently needed so that the fundamental pathology of dementia will be understood and properly addressed.

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SLEEP

                                                                 Sleep

                                                PKGhatak, MD

Sleep is a state of the body during which most of the bodily functions are suspended, consciousness and voluntary actions are absent but readily reversible to external stimuli.

Sleep is a compulsory phase of daily occurrence for all animals - even whales sleep in water; and sharks who must move in order to force water through the gills to meet oxygen requirements, undertake a kind of restfulness, a phase equivalent to sleep. Young dolphins are seen sleeping while swimming but remaining in bodily contact with others within the pods. Plant physiologists have observed sleep like state in plants. Developing human fetuses also sleep in the mother's womb. Newborns sleep most of the time with short periods of wakefulness, which gradually increases as the child advances in age. Adults sleep 6 to 8 hrs. a day, the elderly require less sleep and octogenarians experience short periods of awakening during nocturnal sleep.

People who work shift duty jobs have difficulties in falling asleep after switching over and most of them develop hypertension, diabetes, obesity, metabolic syndrome, ulcers, increased irritability and behavioral changes. Night duty workers have a 10 % reduction in longevity compared with the workers doing the same job during the daytime.

Sleep deprivation causes increased Cortisol release, increased Ghrelin secretion, decreased Leptin and increased hunger and appetite.

The circadian rhythm controls hormone release; at the start of darkness, Melatonin is released from the pineal gland, which prepares the body to fall asleep. During sleep, cortisol level falls, and the antidiuretic hormone release is stopped. Pituitary Growth hormone is released. Cytokines - tissue necrosis factor (TNF), and interleukin 1(IL-1) are released and help tissue repair at night; also, TNF and IL-6 levels increase, which activates the liver cell regeneration.

Long term memory development takes place during sleep, and growth in children accelerates during sleep. The BP, heart rate, and respiration rate decrease. The voluntary muscles cease to function temporarily but the cardiac and smooth muscles continue to work. As we begin to wake up, all the above changes are reversed. Increased cortisol secretion and elevation of BP may trigger a heart attack in patients with coronary artery disease.

Dreams during sleep are a natural occurrence, many remember the dream on waking up, but most others fail to recall. Scientists believe rewiring neurons in the Neocortex and Hippocampus during sleep generates dreams. Many believe octopuses dream during sleep as evidenced by the color changes.

Young children develop nightmares during their dreams, which experts think is a benign phase of brain development. Sleepwalking at a young age is also a benign condition but in adults, it is not normal.

Sleep apnea in an obese person is a risk factor for hypertension, cardiac arrhythmia, and heart attacks. This condition is due to the decreased tone of muscles of the glottis and tongue falling backward, obstructing the entry of air into the laryngopharynx. Snoring during sleep is a similar condition but airways still remain partially open and breathing does not stop.

In any discussion on sleep, REM (rapid eye movement) and Non-REM (NREM) are discussed. In adults, NREM sleep takes place about 70% of sleep time. Scientists have divided NREM into 3 phases based on the frequency of the brain waves. Phase 3 of NREM is deep sleep, and most of the bodily functions are lowest during this period but at the same time, tissue repairs, healing and rejuvenation of the body and mind take place here. The changeover from one stage to the next does not necessarily follow any particular order. In babies, REM happens 50% of sleep time. In younger adults, NREM takes place at the beginning of sleep, followed by REM about 90 minutes later. Initial REM sleep lasts only 10 minutes and increases progressively and at the end may last 60 minutes. Heart rate, BP and respiration increase during this phase and dreams, that can be recalled, happen during REM sleep, though scientists believe humans dream in each phase of sleep. Reinforcement of memory happens in REM sleep. The brain switches REM and NREM in some order initially but in older individuals, no particular pattern is recognizable. In old age, REM and NREM switch back and forth in short order and even at the onset of sleep and no order is observed.

Narcolepsy and Restless Leg Syndrome are neurological disorders and are not discussed here.

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Folic Acid

                                                                Folic Acid

                                                  PKGhatak, MD

Folic acid is a water soluble yellow crystalline substance. It is a chemical made of Pteridine, p-aminobenzoic acid, and Glutamic acid. Glutamic acid may be present as monoglutamate but usually exists in polyglutamine forms, containing anywhere from 2 to 7 glutamic acid residues. About 30 different derivatives of folic acid are present in nature. In the plasma, the Folic Acid (FA) is pteroylmonoglutamic acid, but within the cells, folic acid exists in polyglutamic form. In the blood, the majority of folic acid is present in RBC. The normal Plasma FA level in adults is 3 to 17 ng/ml. RBC folate level resembles body storage and deficiency appears 90 days before low plasma FA.

Other names.

Citrovorum factor. An essential growth factor for bacteria Leuconostoc citrovorum was detected and named citrovorum factor and later was identified to be folic acid but the name remains. At one time FA was called vitamin B9.

Folic acid, however, cannot enter the cells as such, until it is reduced to Tetrahydrofolate (THF) by the enzyme THF Reductase, B12 methyl coenzyme and NADH acting as H donors. Once inside the cells, lysosomal enzymes convert it into polyglutamate and then combine with substrates to form Folic acid coenzymes.

Folic acid coenzymes are single C-atom transfer and utilization agents. One [C-atom] maybe 1. Formyl group [-CHO], 2. Formate [- H COOH] , 3. Hydroxymethyl [– CH2.OH]. These three groups are metabolically interchangeable. THF coenzymes combine with one of the above, one atom C, and form and play a very important role in DNA, RNA and phospholipids synthesis.

Dietary source.

Source - fruits, leafy vegetables, field mushrooms, liver, and fortified food items.

Daily requirement is 400 micrograms for adults and for pregnant women 600 mcg/day. A FA dose of 5000 mcg/day to pregnant women is harmful to the developing child, and increased incidence in respiratory allergy, insulin resistance and delayed psychomotor development are seen in these children.

The Folic acid storage in the liver is good for 3 months of use and the total amount is 5 mg.

Absorption of FA.

Polyglutamic FA in food is converted to monoglutamate in the intestinal mucosa, then FA is absorbed in the upper small intestinal epithelial brushed border by a transported protein. Renal tubular cells reabsorb FA from glomerular filtrate.

Transport of FA in and out of cells requires conversion of FA to polyglutamate and monoglutamate and vice versa. And each phase requires a specific transporter protein.

Actions of FA coenzymes are necessary for methylation. Folic acid is required in the formation of choline, Serine, Glycine, Methionine, and histidine.

Purine and thymine are used in DNA synthesis.

FA coenzymes convert amino acid histidine to glutamic acid through an intermediate step where foraminmonoglutamic acid is formed. This is the basis of the Figlu test to detect folic acid deficiency. This test is just of historical importance, the blood FA test has replaced the Figlu test.

The function of FA.

It is an essential vitamin for all cells of the body for cell growth, maturation, and repair. FA is utilized for DNA, RNA, mRNA and phospholipid synthesis. It is necessary for the methylation of fatty acids, metabolism of several amino acids. Growth and development of the fetus. 

FA deficiency.

Deficiency. Alcoholism, dietary habits, overcooked vegetables in a large volume of water.

Drug interference- anticonvulsants, oral contraceptives, Methotrexate. Trimethoprim-sulfamethoxazole and Sulfadiazine. Aminopterin (MTX) is a permanent folic acid antagonist and is used in the treatment of Leukemia and immunosuppressant, used as an adjunct in order to reduce steroid dose.

The medical condition leading to deficiency - pregnancy, hemolytic anemia, exfoliative dermatitis, GI mucosal atrophy, psoriasis.

Effects of FA deficiency.

The tissues which turn over rapidly exhibit the earliest changes in the development of the nucleus but the cytoplasm continues to develop normally. Blood cells- RBC, WBC, and Platelets are not only decreased in number but also deformed. Since RBCs have no nucleus, the nuclear abnormality is clearly visible in peripheral WBC. CBC. Anemia. Most RBCs are large and come in various thicknesses and sizes, giving an increase in RWD, PVC, and a low HCT. Leukopenia and polysegmented neutrophils and decreased Platelet count. Erythroblasts in peripheral blood. 

Neurological.

Changes are noted in a fetus and newborn, commonly spina bifida and anencephaly.

Folic acid deficiency is common in pregnancy due to increased demand by the fetus which cannot be met by diet alone. WHO recommends fortification of rice, cereals, flour, pasta and bread with folic acid. It plays a vital role in the synthesis of the nucleus of all cells.

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Vitamin B12

 

                                                              Vitamin B 12

                                                 PKGhatak, MD

Vitamin B12 is a water soluble vitamin, a chemical compound containing a cobalt atom. Vitamin B12 is essential for humans and must be supplied in food. Liver, meat, milk, egg, herring, and mackerel fish are the chief source of B12; vegetables are nearly devoid of B12. Stomach acid and pepsin release B12 from the food, B12 then combines with a glycoprotein. B12 is absorbed in the terminal ileum. The liver is the principal store of B12. Breast milk contains enough B12 to meet a developing child's requirements. The daily requirement for adults is 3 micrograms, for infants 0.3 micrograms and for children the amount varies according to age. Adults have about 3 3-year reserve of B12 in the liver.

Chemistry:

B12 was originally obtained from the liver by Dr. Castleman in 1948. The isolated compound was light sensitive but when combined with a cyanide group, B12 becomes a stable crystalline form - cyanocobalamin. The central part of the molecule is four pyrrole rings surrounding a single six-valent cobalt atom. This ring is called the Corrin ring system. The corrin ring is synthesized from delta-aminolaevulinic acid by a process where the methyl group is supplied by methionine (amino acid). The central cobalt atom is attached to the N molecule of each of the four pyrrole rings. The 5th valence of Cobalt is attached to the N molecule

 of 5,6-dimethyl benzimidazole ribose phosphate and the 6th valent of the cobalt is attached to a variable group, R - cyano or 5-deoxyadenosyl or a methyl group. These forms are interchangeable with the cells. The R binding compound gives the type of B12 that will be formed, eg, cyanocobalamin and adenosylcobalamin. In food, B12 presents as Adenosyl B12, Hydoxyadenosyl B12, Methyl B12, Cyano B12 and Sulphito B12, of which the first two forms are commonly found.

In nature, B12 is also present as hydroxocobalamin, a red color compound and nitrocobalamin. Methylcobalamin and  Hydroxycobalamin are therapeutically active and last longer in the body. B12 in plasma is bound to plasma proteins in variable amounts. The intracellular B12 level in the mitochondria is dependent on the amount of free B12 present in the serum. 

Physiology:

Acid and pepsin in the stomach release B12 from the food. The intrinsic factor (IF) of Castle, a glycoprotein, secreted by the parietal cells of the stomach, combines with B12 in the duodenum and prevents B12 from digestion by GI enzymes and keeps it safe from gut bacteria using it. As B12 reaches the terminal ileum, the receptors present on the surface epithelial cell of the ileum bind with it, then release B12 from the IF. Only free B12 is available for absorption. About 1 to 2 % B12 is absorbed by simple diffusion, the rest is ferried across the cells by an active process and carried by the Transporter I protein. The Transporter II protein carries B12 to the liver, bone marrow and other tissues. The proportion of B12 absorbed from food is limited by the amount of available IF. As a result, only about 20% is absorbed; that amount generally satisfies the daily 3 micrograms of B12 requirement. In macrocytic anemia or pernicious anemia, 1500 to 3000 micrograms of B12 are prescribed and 1 to 2% absorption by diffusion meets the therapeutic needs. The only source of B12 for the herbivorous animal is that produced by gut bacteria. 

B12 inside the cells.

B12 with the attached transport protein enters the cells. The lysozymes free the B12. The B12 then is taken up by mitochondria. Here B12 first converted to Cobalamin II alamin. Then cobalamin II alamin is converted to adenosylcobalamin and methylcobalamin. Hydroxycobalamin is also present in the cytoplasm. 

The action of coenzymes:

Methylcobalamin is the cofactor of methionine synthase. Methionine synthase converts Homocysteine to Methionine. In another reaction, methionine synthase transfers the methyl group from 5-methyltetrahydrofolate (THF) to homocysteine. THF is the active form of vitamin Folic Acid. THF is essential in DNA synthesis.

The adenosylcobalamin is the cofactor of methylmalonyl CoA mutase (CoA means coenzyme A). Methylmalonyl CoA mutase converts methylmalonyl CoA to Succinyl CoA in the Krebs tricarboxylic acid cycle.  Energy supplying amino acid metabolism requires to pass through the succinyl CoA step. Similarly, the fatty acid metabolism is also dependent on this methyl B12 coenzyme.

The function of B12:

B12 coenzymes are required for the synthesis of 

1. Purine Nucleotides,

 2. metabolism of several amino acids and fatty acids 

3. the normal growth and development of cells.

Myelin sheath of nerve fibers.

In the initial steps of myelin sheath synthesis, the B12 coenzyme produces methylmalonyl-CoA from branched amino acids threonine, isoleucine and valine. In B12 deficiency malonyl CoA is reduced and methylmalonyl-CoA is substituted. This results in defective myelin and early breakdown of the myelin sheath.

Causes of B12 deficiency.

Dietary.

 B12 deficiency is expected in strict vegetarian Hindus in India. In the west, vegans are similarly affected.

Diseases of the stomach.

Acid suppression by pantoprazole over a prolonged period, atrophic gastritis, partial gastrectomy,

Intrinsic factor (IF) deficiency.

Congenital absence of IF.

Acquired autoimmune disease producing antibodies to the parietal cells or antibodies to IF.

Diseases of the terminal ileum.

Crohn's disease. Surgical removal of terminal ilium, Celiac disease. Tropical sprue. Malabsorption syndrome. HIV infection, Frequent bacterial enteritis. Change of gut bacterial population.

Intestinal parasite. Diphyllobothrium latum, a fish water fluke, infestation of the gut.

Diseases associated with Megaloblastic anemia.

Type 1 diabetes mellitus, Graves disease, Hypothyroidism, Addison's disease. Parkinson syndrome.

Risk factors. North European ancestry. Alcoholism.

Diagnosis of B12 deficiency:

1. Blood test.

B12 deficiency is easily detected by obtaining blood B12 levels.

2. Associated abnormalities of blood picture.

CBC. Any or all of these features may be present. Anemia, Macrocytic RBCs, 

Increased RWD (Red blood cell width distribution), Ovalocytes, Leukopenia, and hypersegmented neutrophils. Thrombocytopenia, pancytopenia. Increased blood LDH, Bilirubin, and AST. Decreased Haptoglobin, and increased serum Methylmalonic acid and Homocysteine.

Some neurological symptoms are suspected to be from the B12 deficiency but the serum B12 levels may be normal. The B12 deficiency is confirmed by finding a blood methylmalonic acid over 1000 mcg/ml and high homocysteine levels.

Diagnosis of Pernicious Anemia.  

1. Presence of megaloblastic anemia and 2. deficiency of Intrinsic factor.

Intrinsic factor deficiency may be due to congenital or hereditary.  Acquired causes are due to the presence of antibodies. Antibodies are of two types. 1. Complement fixing antibodies to parietal cells and, 2. antibodies against the Intrinsic factor.

Symptoms of B12 deficiency.

Weakness, glossitis, anemia.

Neurological.

Some or none of the following symptoms are usual findings.

Peripheral neuritis, Depression, dementia, Psychosis, Cerebellar ataxia, Subacute combined degeneration of the spinal cord. Optic atrophy. Cranial nerve nephropathy.

In general, Megaloblastic anemia is common in B12 deficiency, neurological manifestations are variable and occasionally appear before hematological changes.

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Thalamus and Outline of Sensory System.

                                      Thalamus and Outline of the Sensory System

                                                PKGhatak, MD

Thalamus:

The thalamus is a collection of neurons in the midbrain; in fact, there are two in number, the thalami. Thalami are placed close together in the middle of the midbrain, separated by the Third Ventricle containing CSF (cerebrospinal fluid). They are the mirror image of each other. The thalamus is the initial sensory receiving center of all the incoming information from the body, namely 1. the somatic sensation from the skin - touch, pain, cold and hot sensations. 2. Proprioceptor sensation of the body - positions of limbs, head in relation with each other. 3. visceral sensation from chest, abdomen and pelvis - the sense of bloating, cramps, pain and discomfort. 4. special senses from eyes, ears, tongue - visual, auditory, taste but not the smell sensation.

Thalamus relays the sensory input received from different parts of the body to specialized areas of the cerebral cortex for detailed analysis, at the same time receives communications from the cerebral cortex. The interplay of this back and forth information between the thalamus and cerebral cortex determines the final sensory appreciation, the body's response to sensory information, memory formation and association. Thalamus also generates local sleep patterns - namely sleep and wake rhythm during the non-rapid eye movement sleep.

To achieve these functions, the thalamus is extensively connected with all major nuclei of the midbrain - hypothalamus, amygdala, hippocampus, etc., and the cerebellum, medulla oblongata and cerebral cortex.

There are 6 functional groups of thalamic nuclei. These are 1. Anterior thalamic nuclei- facing the forehead. 2. Lateral thalamic nuclei- facing towards the ear of the same side. 3. Medial nuclei - facing each other across the midline. 4. Paraventricular-located next to the 3^rd ventricle. 5. Interthalamic - making the connection between the two thalami. 6. Reticular a net-like nuclei is located at the bottom of the thalamus.

Anterior thalamic nuclei: Afferent fibers relay here from Limbic strictures and the medial mammary nucleus. Efferent fibers from the thalamus connect to the Cingulate gyrus, parahippocampal nuclei, the perforated substance and the limbic nuclei.

Function: Emotion, memory, alertness.

Lateral thalamic nuclei: Receives afferent fibers from Globus pallidus, substantial nigra. Efferent connection to the frontal lobe of the cerebral cortex, and the Interthalamic nuclei.

Function. Planning and initiating movement.

Ventral thalamic nuclei are the Ventrolateral and Ventromedial groups of nuclei.

Ventromedial: receives input from the contralateral cerebellum, the ipsilateral motor cortex.

Efferent output to the primary motor cortex and premotor cortex.

Function. Motor response and integration of sensory and motor functions.

Venteroposterior:

Afferent input from lateral spinothalamic and dorsal spinothalamic tracts. These are the main sensory receiving nuclei of the thalamus. Also, fibers from medial lemniscus and trigeminal thalamic sensory fibers end here.

Efferent output to the sensory parietal cortex, insular cortex.

Function. The initial sensation of pain, temperature, touch, discriminating touch, and conscious proprioception.

Other thalamic nuclei receive and communicate with various midbrain nuclei, different areas of the cerebral cortex and cerebellum.

Sensory system.

A general outline of the somatic sensory system consists of receptors, neurons, ascending tract in the spinal cord and hindbrain, and nerve centers.

 The Receptors are: -

Naked nerve ending. It is sensitive to pain stimuli. Ruffini endorgan records stretch sensation, deformities, warm temperature. The end bulb of Krouse detects cold, these are also present in the mucous membrane of the eyes, mouth and genitalia. Meissner's corpuscles are onion like layered receptors that receive slow vibration from the skin and bones and also touch sensation. Merkel discs receive light touch and two-point discriminating tactile sensations, sustained pressure and touch. Pacinian's corpuscles record deep pressures and fast vibrations. The hair follicle plexus is stimulated by the movement of hair. Muscle spindles record muscle contractions, cramps, and stretch sensation. Golgi tendon organ records the stretch produced in the tendons. Bulbous corpuscles are stimulated by the stretch of the capsule of joints.

A number of skin receptors are also present in joint capsules, tendons and bones.

Joint kinesthetic receptors. These are responsible for information generated from limbs and joints during movement.

Vestibular organs. Present in the middle ears, these receptors record position of the head on three dimensional axis.

 The Neurons: -

 The neuron with its long arm - afferent/axon, carries the impulse towards the central nerve center. The short arm of the neuron, called dendrons, makes a synaptic connection with the 2nd order neuron. The nerve bundles in the spinal cord take the impulses all the way up till they reach the medulla oblongata, then the fibers cross the midline to the contralateral thalamus. So, the thalamus of one side receives the sensory information from the opposite side of the body. The 3^rd order neuron of the thalamus carries the impulses to specific areas of the parietal sensory cortex of the brain located on the same side as the thalamus is located.

 The Pathways to the Thalamus:

The neurons for skin sensations are located in the dorsal root ganglion of the spinal nerves. The axons enter the spinal cord by the dorsal root. Thereafter the fibers make three ascending paths to the thalamus on the opposite side and end in the contralateral thalamus.

Pain, two-point discrimination touch, and vibratory sensation pathway.

Axion carrying the sensation turns upwards in the spinal cord along the posterior ascending column. Below the T6 level, ascending fibers are placed in the medial position, then fibers from each higher segment are placed lateral to the fibers already present – somatotopy organization. The fibers make synaptic connections with neurons called Nucleus Gracile located in the lower medulla. The second order neurons cross the midline - decussate in the medulla oblongata and ascend to the ventromedial nuclei of the contralateral Thalamus via the medial lemniscus.

The axon above the T6 level to C1 similarly ascends up the spinal cord lateral to the Ascending tract of Gracile. Similar somatotopy organization is present in this tract. At the lower medulla and fibers make synaptic connections with a collection of neurons called the Nucleus Cuneatus. Then follow the same path as the tract of Gracile. 

Cold/hot sensation and pain pathway:

1^st order neurons are the dorsal root ganglions. The axons enter the spinal cord via the posterior root and move up or down 1 or 2 segments, then make synapses with the second order neurons located in the posterior horn. The fibers cross the midline in front of the central spinal canal and then ascend upwards occupying a lateral position in the spinal cord known as the lateral spinothalamic tract. These fibers reach the ventromedial nuclei of the thalamus via the medial lemniscus and there they make synapses. The rest of the pathway is similar to tracts of Gracile and Cuneatus.

Crude touch and firm pressure pathway:

The layout is similar to the lateral spinothalamic tract except the 1^st order axons cross the midline immediately and synapse with the 2^nd order neurons. And that tract occupies a more anterior position in the spinal cord. The rest of the track follows the temperature path.

Proprioceptive sensory tract:

The 1^st order neurons are the dorsal root ganglions. The axons after entering the spinal cord take one of the three paths.

Those carrying proprioceptive destined to reach the conscious level follow the fibers of the somatic sensory fibers, traveling up along the tracts of the Gracile and Cuneatus. One big difference is that the proprioceptor fibers do not cross the midline and enter the ipsilateral cerebellum through the inferior cerebellar peduncle and make synaptic relay with the nuclei present in the vermis and para ventral nuclei of the cerebellum. The dendrons carry the information to the deep nuclei of the cerebellum, and the 3^rd order neurons carry the information to the thalamus and other midbrain nuclei.

Unconscious proprioceptor sensory information.

Below L2 Level.

Central axons of the 1^st order neurons end by making synapses with the posterior horn nuclei. The ascending fibers of the 2^nd order neurons immediately cross the midline in front of the spinal channel. Then ascend to the midbrain at the junction of the midbrain and medulla, then cross the midline again and enter the cerebellum through the superior cerebellar peduncle. The spinal cord location of these fibers is called the Anterior spinothalamic tract.

Above the L2 level and up to the T1 level.

The axons of the 1^st order neuron terminate in the Clarke nucleus of the posterior horn of the same side of the spinal cord. The ascending axons of Clarke nuclei remain on the same side of the spinal cord and travel up as the posterior spinocerebellar tract. Then, reaching the medulla enters the cerebellum through the inferior cerebellar peduncle.

Above T1 level.

The axons of 1st order neurons ascend with the Cuneatus tract and make synapses with accessory Cuneatus nuclei. The fibers enter the cerebellum through the inferior cerebellar peduncle.

 The Trigeminal nerve.

The skin of the forehead, face and lower jaw are innervated by the 5^th cranial nerve- The trigeminal nerve. The nucleus is known as the trigeminal ganglion located on the petrous process of the temporal bone. The second order neurons are located in a long structure extending from the upper cervical cord to the lower midbrain. The axons from these neurons cross the midline and join the medial lemniscus to the thalamus.

Visceral senses.

The general outlay of the sensory information reaching the brain is different. One reason is the viscera are not paired – one heart, one liver, one large gut and on the small intestine, etc. Only there are two lungs.

The second reason is that visceral sensations are carried both by the sympathetic and parasympathetic nervous systems. The parasympathetic system carries the general sensation and the sympathetic system carries general and also the pain sensation. There is no hard and fast distinction of senses into ipsilateral or contralateral representation in the thalamus or in the cerebral cortex. In most cases, the thalamus and the cerebral cortex area receive visceralsensory information from both sides of the body.

Parasympathetic visceral sensory system:

The receptors: The receptors are present in all the layers of the small and large intestines. Glands and solid organs likewise have several receptors.

The parasympathetic sensory outlay is a bit different from the general sensory system, again are of two groups - A. all viscera located in the thorax, abdomen including the medial 2/3^rd of the transverse colon, B. the lateral 1/3 of transverse colon, sigmoid colon, rectum, anal canal, urinary bladder, urethra and organ of sex.

A. Upper abdominal visceral path of parasympathetic:

The Vagus nerve.

Sensory information from the thoracic viscera, abdominal viscera, and the medial 2/3 rd. of the transverse colon is carried by the sensory division of the vagus nerve to the Nucleus Nodosa of the vagus situated in the medulla on the ipsilateral side.  The second order neuron of the vagus carries the sensation upward in Tactus Soliterious to both the Thalami. The 3^rd order neurons take that information to the sensory cerebral cortex.

B. Lower abdominal visceral parasympathetic:

 The Hypogastric nerve.

The afferent fibers of parasympathetic 1^st order neurons are located in the posterior horn of the T10 to S2 segments of the spinal cord. These fibers entering the spinal cord make synapse with the second order neuron of the parasympathetic system. They travel upwards to the medulla along with somatic sensory fibers in the Gracile tract and the end of the fiber in the sensory dorsal nucleus of the vagus.

  The Inferior hypogastric nerve.

The nucleus is located in the dorsal root ganglion of S2 to S4 segments. The axons travel along with the pelvic and pudendal nerves to innervate the remaining pelvic organs and sex organs. The upward journey starts with the fibers of the Gracile and ends in the sensory nuclei of the Vagus in the medulla.

Sympathetic sensory system.

Receptors. Similar to parasympathetic, sympathetic receptors are present from all layers of viscera and glands and in addition, unmedullated C-fibers carry pain sensation. The first-order neuron is located in the dorsal root ganglia of the entire spinal cord.

The pain of cutting, burning, crushing is not carried from the viscera but inflammation, necrosis, obstruction related pain is carried from the visceral wall by the undulated C-fibers of sympathetic nerves. On their onward journey to the spinal cord, the fibers accompany the sympathetic tract carrying efferent sympathetic stimuli.

 Sensation from eyes, lachrymal glands, nose, palate, and salivary glands.

 Sympathetic afferent fibers pass through the cervical sympathetic ganglia, then accompany the postganglionic sympathetic fibers. The fibers leave the sympathetic nerve and join the white rami to join the mixed spinal nerve and enter the spinal cord via the white rami by the dorsal root. It makes a synaptic connection with the thoracolumbar sympathetic neurons. The second order neurons carry the sensation along with the somatic senses of the thalamus.

 The sensory sympathetic innervation of the heart, the trachea, and the bronchi.

 The dorsal root ganglions of C4 to T5 segments carry sensory information and fibers pass through the celiac ganglion. Then the upward path is the same as above.

Innervation of the stomach, liver, bile duct, gall bladder, spleen, kidneys, pancreas and small intestine.

The T6 to T11 segments supply sensory fibers and the fibers pass through the superior mesenteric ganglion.

 The rest of the GI organs and pelvic organs send sympathetic sensory information.

 The sensory afferent fibers originate in T12 to L2 segments. The fibers pass through the Inferior mesenteric ganglion.

 L3 to S5 segments innervate blood vessels of the perineum and inferior extremity.

Special senses:

Visual.

The visual receptors are rods and cones of the retina.

The right optic nerve carries visual input from the temporal half of the right eye and the nasal half of the left eye. The left optic nerve has fibers from the temporal half of the left eye and the nasal half of the right eye. The crossing of nasal fibers is known as the optic chiasma. These fibers then sweep around the midbrain and make a synaptic connection in the lateral geniculate body of the ipsilateral side. The lateral geniculate body is a special section of the lateral dorsal thalamus. The visual sensation reaches the visual cortex by way of the optic radiation. The visual sensation of one side of the visual field is projected to the same side of the visual cortex but contains images from both retinas. This is because there is an overlap of the image when placed close to the nose, each eye captures the image but at a different half of the retina.

Taste sensory pathway.

Receptors:

The tongue, soft palate and throat contain taste buds. These buds are distributed widely but some are more concentrated in one area than the rest. The tip of the tongue contains sweet sensory taste buds and the sides of the tongue contain salt and sour taste buds, the dorsal surface of the tongue for all taste buds, and the back of the tongue for the bitter. The anterior two thirds of the tongue is innervated by the tympanic branch of the 7^th cranial nerve, the Facial nerve. The distal 1/3rd of the tongue and throat by the Glossopharyngeal nerve, the 9th cranial nerve. The epiglottis taste buds are innervated by the Vagus nerve, the 10th cranial nerve. The neurons for the taste sensation of the 7th nerve are located in the Trigeminal nucleus, the neurons for the glossopharyngeal are present in the Petrosal ganglion and vagus sensory neurons are located in the medulla and are known as the Dorsal nucleus of the vagus. The dendrons of these nerves are carried in the tractus solitaries of the vagus. The ascending fibers from these ganglia cross the midline to the opposite side and reach the poster ventral nucleus of the thalamus by way of the Medial lemniscus. The thalamic nuclei relay the taste sensation to the Gustatory cerebral cortex and anterior insular cortex.

These three nerves also carry the general visceral sensation from the tongue, mouth, palate, epiglottis and throat in a separate group of fibers but follow the same path the rest of the way.

Auditory Pathways:

The receptors of sound are hair cells of the organ of Corti located in the cochlea of the middle ear. The 1st order neurons are cochlear neurons carrying the sound impulses to the Superior Olive nucleus of both sides but mostly to the opposite side. The second order neurons of the superior olive pass through the reticular formation of the midbrain and terminate in the lateral geniculate body of the same side. Like the medial geniculate body, the lateral geniculate body is a part of the thalamus and both bodies are located close together. From the lateral geniculate body, the last relay takes the sound sensation to the auditory center in the cerebral cortex. One side of the auditory cortex receives sounds from both ears.

Smell sensation.

The thalamus is not the initial nerve center for the smell.

Receptors: Nasal epithelium contains olfactory sensory cells. The axons pass through the cribriform plate of the ethmoid bone. These neurons relay information with the neurons of the olfactory bulb located above the cribriform plate. The information goes to the ipsilateral primary smell center by the fiber bundle called the olfactory tract. The olfactory tract splits into medial and lateral tracts, and the medial tract carrying the smell sensation terminates in the olfactory cortex. The lateral tact connects with the thalamus, amygdala, and other midbrain nuclei. 

Sexual sensation.

The receptors are locaated in subcuteous tissues of erective organs in bothe sexes, these receptors are similar to Krouse corpuslces. Touch and vibratory senses are received and caries along the lateral spinothalamic tract to the brain. The efferent actions do not depaned on higher connections, the reactions are mostly refex in nature but greatly modified by hypathalmus and cerebarl cortex.

The brain receives a condition of the heart rate. BP, O2 saturation and respiration are continuously monitored by sensory input via the paths described under visceral sensation. The second set of information the brain receives is from the skin and bones and joints via the dorsal ascending column, spinothalamic tracts and spinocerebellar tracts. Integration of all the internal and external sensations and their reflex actions and cerebral motor actions is the basic survival requirement of the species.

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Adrenal Glands.

 

                                                          Adrenal Glands

                                                PKGhatak, MD

A pair of endocrine glands, one sitting on the top of each kidney, separate but closed in by the same kidney capsule and are essential for health and life. Adrenals are also called Suprarenal glands. In adults, the adrenals are small in size, but very vascular, getting the most blood supply per gram of tissue. Like the pituitary gland, the adrenal gland consists of two different endocrine glands - one mesodermal origin endocrine gland, the other neuroectodermal origin endocrine gland. In the developing fetus and newborn adrenal, the size is large in comparison to the whole body. Adrenals are larger than the kidneys at birth and weigh 5 gm. In childhood, the glands start to regress in size but the glands start to grow again at age 4-5 yr., then after the end of the growth period, the size begins to shrink to a mere 4 grams each in adults.

Adrenals lie behind the parietal peritoneum, attached firmly at the back to the pillars of the diaphragm. The right adrenal gland is taller and shaped like a pyramid, and the left one has a wider base and looks like a Napoleon hat; each gland measures about 3 cm x 5 cm x 0.1 cm in height, width and thickness respectively.

The growth and development of adrenal glands are quite distinct in humans and not matched in other mammals except perhaps that of chimpanzees. The fetal adrenals function differently than adult adrenals and in association with the placenta provide estrogen for fetal growth.

Fetal adrenal glands.

Some of the neuroectodermal cells of the neural crest migrate near the dorsal aorta at 6 weeks of gestation and by 9 weeks come close together to form the fetal medulla of the adrenal gland, one on each side of the dorsal aorta, close to the site of developing fetal Adrenal cortex and genitourinary ridge. A layer of cells from the fetal adrenal cortex surrounds the fetal medulla at 8 weeks of gestation and is called the Definitive zone. The neuronal derived cells take up chromium stain and are so named chromaffin cells and these cells remain scattered in small groups in the fetal cortex. The outer layer of cortical cells is in the proliferative stage, whereas the inner cells develop organelles in order to produce cortisone. It is still debated whether the production of cortisol in the early fetal stage is truly independent of adrenal action or under the influence of pituitary ACTH (adrenocorticotropic). At 12 weeks, a new cell layer called the Transitional zone develops in between the layers. Definitive zone cells reduce the production of cortisol and the cells of the transitional zone begin producing Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S). DHEA and DHEA-S are converted to Estrogen in the placenta. Estrogen is needed for fetal growth. At 24 weeks, the size of the fetal cortex is reduced in size and the transitional zone is now called zona fasciculata and the outer definitive zone is called the Granulosa zone. The granulosa zone keeps producing cortisone under the influence of ACTH. At birth, the medulla of the adrenal gland is still rudimentary and does not secrete hormones and the cortex has only two zones – a larger granulosa zone and a smaller fasciculata zone.

In newborns, the medulla remains inactive, growth starts at 8 months of age and reaches the maximum at 12 to 18 months.

Hormones of the adult adrenal glands.

The adrenal cortex hormones are called Steroid hormones, majority of adrenal hormones have one hydroxyl group (-OH) bound to the carbon atom in the side chain and are therefore also called Sterols.

Cholesterol is the prime chemical from which all steroids are produced. Cholesterol is obtained from the LDH cholesterol of the blood. If the blood level of LDL is low, LDL cholesterol is synthesized in the adrenal cortex. The first step in steroid synthesis is to cleave the side chain of cholesterol and oxidation to generate Pregnenolone. ACTH influences this initial step. This conversion takes place in mitochondria and is then transported to the endoplasmic reticulum of the cell. The endoplasmic reticulum contains specific enzymes for the production of a specific hormone, specific for a zone of the adrenal cortex.

Zona Glomerulosa.

Pregnenolone is converted to Progesterone then oxidized to 11- Deoxycorticosterone. The next step is 18- Hydroxycorticosterone then the final product is Aldosterone. Aldosterone exists in two forms namely 18-aldehyde form and 11-helical form.

Zona Fasciculata.

Pregnenolone is converted to 17 alfa-Hydoxypregnenolone. The next step is 11-Deoxycortisol by hydroxylation then to 11-Deoxycortisol and the final step is Hydrocortisone and Cortisone.

Zona Reticulosa.

The cells of this zone work differently from other zones. Gonadotropin Releasing Hormone of the Anterior pituitary regulates the production of these sex hormones. There are two releasing hormones - Luteinizing releasing hormone (LHRH)and follicular stimulating releasing hormone (FSRH).

Pregnenolone is converted to 17-alfa-Hydroxypregnenolone; then the next step is Dehydroepiandrosterone. The next product is Androstenedione and the final product is Testosterone. The primary adrenal androgens are dehydroepiandrosterone and androstenedione and a tiny amount of testosterone. The gonads of individuals produce most of the sex hormones, stimulated by the pituitary hormones and reproductive cycle and growth period by way of negative feedback.

Adrenal Medulla.

Hormones produced by the adrenal medulla are important but not essential for life. The medulla is in fact a special structure of the sympathetic nerve ganglion. The hormone is known by the generic name Catecholamines, it can be gotten from other sympathetic nerve ganglions. Catecholamines are Nor-adrenaline and Adrenaline, as the Britishers call them, the universal names are Norepinephrine and Epinephrine. About 80 % of catecholamines are epinephrine and 20 % of the rest are norepinephrine.

The catecholamines are derived from the amino acids  -  Phenylalanine and Tyrosine. Tyrosine is converted to L-Dopa ( Levo-dihydroxyphenylalanine) and the next stage is Dopamine. Then to Norepinephrine to Epinephrine. Epinephrine is stored in the chromaffin cells as granules till it is time to release into the circulation.

Regulatory control of Steroid hormones.

Negative feedback is the common control system for all endocrine glands. Both the hypothalamus and pituitary gland monitor blood levels of adrenal hormones. When the blood level falls, say aldosterone, the hypothalamus releases ACTH Releasing Hormone (ACTHRH) and that results in the production of more aldosterone. As the aldosterone level rises the ACTHRH from the pituitary is turned off. Several other paths for steroid hormone production exist.

Aldosterone.

By the Glomerular Apparatus of the Kidney.

In each kidney, there are about 1 million glomeruli, a tuft of capillaries enclosed by a funnel like structure known as the Bowman capsule. A branch of the renal arteriole feeds the glomerulus with blood and is called the afferent arteriole, and blood exits after filtration by the efferent arteriole. A loop of distal convoluted tubule of a nephron at this site and a group of juxtaglomerular mesangial cells of Lacis (Lacis cells) form the Glomerular apparatus. Special muscle cells of afferent and fewer muscle cells of efferent glomerular arterioles lie in layers like a cuff. The modified epithelial cells of the distal convoluted tubule are tall and have a prominent nucleus known as Macula Densa. Extraglomerular mesangial cells are loose networks of connective tissue cells located around the afferent and efferent arterioles. Macula densa monitors sodium and potassium concentration of the urine. The receptor of BP in the afferent arteriole communicates directly with the juxtaglomerular cells(JG cells), and the JG cells release Renin. Renin converts the angiotensinogen of blood to angiotensin I, which is converted to angiotensin II by ACE (angiotensin converting enzyme). ACE is produced by pulmonary endothelium and endothelium kidneys and also by the epithelium of renal proximal tubules.  Angiotensin II acts on the adrenal cortex to increase aldosterone production and release. The Lacis cells produce selective vasoconstriction or vasodilatation of the arterioles based on the nature of the input. Angiotensin I and angiotensin II are broken down by an enzyme angiotensinase to angiotensin III & IV.

The second path is the sympathetic nervous system. In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal to the adrenal cortex directly to the chromaffin cells without forming synapses and aldosterone is released in the blood in response.

Glucocorticoids.

Similar systems of sensors for glucocorticoids are present in tissues, and information is relayed to the hypothalamic-pituitary-adrenal axis (H-P-A axis). Release of glucocorticoid hormone results. Cortisol breaks down hepatic glycogen to glucose. Glucose generation from amino acids and fatty acids- commonly called glucogenesis happens. Glucose levels are normalized.

The 2nd pathway is through the sympathetic nervous system via the hypothalamus and via the close relationship with epinephrine and norepinephrine.

Regulation of Sex Hormones of Adrenal Cortex.

Gonadal hormones are the main source of sex hormones. Pituitary FSHRH and LHRH, Growth hormone and adrenocortical DHEA, DHEA-S and Testosterone are integrated by the Hypothalamic-Pituitary axis. Adrenal sex hormones are taken up by the gonads and used as the raw material for gonadal sex hormones production. Gonads also produce DHEA and DHEA-S, the initial steps of LH and FSH production.

This scheme of regulation of hormone production is a simplified version. There are much more intricate relationships between hormones, tissue cytokines, chemokines and the production of hormone carrier proteins by the liver. The role of cytochrome P 450, Cyclic AMP, and other enzymes is too complex for this simple presentation. The cytoskeleton of mitochondria and endoplasmic reticulum, the protein messengers for communication between organelle, have a special role also. Aromatase CYP 19 is essential in the conversion of androgen to estrogen. 

Physiological functions of Adrenal hormones.

Steroid hormones are regulators of the whole body homeostasis. Metabolism of carbohydrates, protein and fatty acids is under control by glucocorticoids to maintain an adequate supply of glucose to the tissues. The new sugar is made from protein and fat (glucogenesis), and sugar is freed from glycogen stores called glycogenolysis. Under the prolonged influence of glucocorticoids, the matrix of bone (made of protein) is thinned out and calcium moves out of bone and bones become brittle (osteoporosis). Excess calcium, magnesium,  and uric acid are excreted in the urine.  Renal calcification and urinary stones are common complications. Aldosterone maintains extracellular volume by controlling Sodium loss by the kidney, excreting potassium and hydrogen ions in exchange for sodium. Corticosteroids have profound effects on the cardiovascular system, musculoskeletal system, and central nervous system. Corticoids are suppressors of acute inflammation/infection. The immune cell and lymphocyte functions are downregulated. The production of antibodies is delayed and downregulated. Fetal growth by steroid hormone and maturation of various systems, specially lungs in pre and postnatal stages, is provided by corticosteroids.

A detailed description can be found elsewhere.

Regulation of Catecholamines of the adrenal medulla.

In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal directly to the chromaffin cells of the adrenal medulla. Regulation and release depend on local tissue negative feedback in addition to nerve hypothalamic control. Noradrenaline increases vasoconstriction, and BP, acceleration of conduction of cardiac impulses, tachycardia.

Epinephrine dilates blood vessels of muscles, increases blood sugar, and dilates bronchial wall and cardiac output.

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Mycoplasma pneumoniae Pneumonia

                                     Mycoplasma pneumoniae Pneumonia

                                         PKGhatak, MD

 

The bacterial Mycoplasma pneumoniae is more intriguing than the pulmonary diseases it produces in humans. Mycoplasma is the smallest self replicating organism that has the smallest genomes. It is a small bacterium without a cell wall. Phylogenetically Mycoplasma pneumoniae (M. pneumoniae) belongs to Clostridia. The bacterial body is covered by a single layer of membrane (the bacterial body has double layered membrane). The cytoplasm has very few organelles and no limiting membrane. The nucleus is a circular double helix without a nuclear membrane. The nucleus contains only 500 to 1,000 base pairs. M. pneumoniae is dependent on the host for nutrients because of having only a limited number of enzymes and protein manufacturing capacity, The bacteria are pleomorphic mostly short filaments measuring 100 nm (nanometer) X 1000nm exists as a parasite in living organisms, and round or oval forms measuring 300 nm are detected in laboratory grown culture medium. It can change shape because of an absence of a cell wall, and it passes through bacterial filters. It is poorly stained, and requires a special DNA stain, Hoechst stain. It is difficult to observe under an ordinary microscope because of its small size. 

 

 In nature, M. pneumonia lives as a saprophyte and parasite. The infective filamentous form has a harpoon like terminal organelle and is used to attach to the respiratory epithelium, and is able to resist removal by the mucociliary escalator. A protein, P 1, is present on the surface membrane, it performs multiple important functions – it is an adhesion protein to respiratory epithelial cells, P 1 gives the bacteria its virulence, P 1 is antigenic and antibodies are produced against it. Human RBC contains P I/i protein. M. pneumoniae antibodies react with this RBC antigen and produce hemagglutination. Mycoplasma uses the terminal filament for gliding motion in a liquid medium. The bacteria are difficult to grow in the laboratories, require cholesterol and other nutrients, including the newborn calf's serum, to grow. Laboratories nicknamed Mycoplasma “crabgrass” because the bacteria are difficult to detect, easily contaminate lab equipment and especially cell culture lines, and are difficult to get rid of. It can be successfully cultured on a special agar plate and takes about 3 weeks to grow. The colony looks like fried eggs with the sunny side up. 

  

The bacteria multiply by binary fission, and subsequently, the filaments break into coccus forms. The growing bacterial bodies often do not separate completely and appear as branches fungus like and so named as Mycoplasma ( mykes = fungus, plasma = formed). Also has a tender nickname Mollicute. (molli = soft, cute = skin). The nuclear material is passed to the dividing bacteria by a terminal disc like organelle. At times the nuclear separation is incomplete and appears as a multinucleated form. In infection, the bacteria produce H2O2, superoxide radicals and malondialdehyde at the infection site and which are toxic to tissues and resulting in the desquamation of respiratory epithelium. Denuded respiratory epithelium triggers the cough reflex. The cough continues, even if the infection is controlled because the regrowth of surface epithelium takes time to cover the denuded area.

The biochemical peculiarities of Mycoplasma are also colorful, but not entered into because this will be an unnecessary diversion.

The infection is due to person to person transmission via large sized droplets, and the bacteria remain attached to the respiratory epithelium and thus remain infective. The incubation period is 3 weeks. Children under 6 months of age are protected due to maternal antibodies. Children of kindergarten age show significant infection in the winter months. Older children in high school age and junior college age students have the highest infection rate. Repeated infections are a natural order, adults are much less susceptible. Many studies show high antibodies in the adult population confirming the notion that infection is much more common than recognized.

Signs and symptoms of upper respiratory infection due to M. pneumoniae are not anything as spectacular as the colorful bacterial features. However, M. pneumoniae pneumonia has some interesting aspects. M. pneumoniae pneumonia was one of the many causes of Atypical Pneumonia and Community Acquired pneumonia. Beginning in 1930, the atypical pneumonia was called Walking Pneumonia. In 1944, M. pneumoniae pneumonia was named after Dr. Monroe Eaton as Eaton Agent pneumonia. He demonstrated bacterial filter filtrate of infected secretion from animals produces the same disease in susceptible animals (Koch's postulate), later Dr. Eaton successfully grew M. pneumoniae in eggs. Between 1945 and 1955, M. pneumoniae infections were also called Pleurodynia like organism pneumonia. Finally, in 1955 M. pneumoniae was named M. pneumoniae pneumonia. In 1889 Albert Bernhard Frank coined the name Mycoplasma after detecting fungus like organisms in the plant cell cytoplasm. Endemic M. pneumoniae pneumonia appears in cycles of 3 to 7 years. Many students in summer camps, military recruits, adults and children are especially hit hard during epidemics.

The COVID-19 pandemic has educated the general public that the virus can produce deadly diseases from its effects on cytokines, chemokines and immune cells.  Mycoplasma pneumoniae can cause complications by all these mechanisms. Mycoplasma pneumoniae prefers to be a parasite and produces locally tissue damage from toxins. Symptoms are persistent cough, increased respiratory discharge, low grade fever and headaches. Pneumonia when it develops is patchy, interstitial, sub-segmental and usually peribranchial. A small amount of pleural effusion may also occur. In x-rays, pneumonia appears more extensive than clinically suspected.

At about 7 days after infection, the body begins generating IgM antibodies. Both IgG and IgM antibodies are produced. IgM antibodies are short lived and their presence indicates a recent infection. IgG-complement-fixing antibodies used to be the main laboratory test for the detection of a recent M. pneumoniae infection. The IgG antibodies can persist for up to 4 years. A rising titer of 4 times to 64 times is used as the diagnostic criteria by some labs.

In the first few days of respiratory infection, antibodies produced are cold sensitive, and cause hemagglutination at a low temperature (0 degree C), but appear only in about 50% of cases and last only a week. Moreover, other infections/ diseases can produce cold agglutinins also. Fortunately, all these tests are abandoned or in the process of being abandoned and should be considered as relics of the past. The direct detection of Mycoplasma antigen by DNA probe, bacterial DNA detection by nuclear amplification, PCR and various other modified PCR test technologies have replaced serological tests for the diagnosis of acute M. pneumoniae pneumonia. But serology tests have their place in research. 

Complications.

The incidence of extrapulmonary complications is about 25 %. Most commonly seen in skin, manifested as erythema multiforme. Steven Johnson syndrome rarely happens. Complications involving the GI tract, musculoskeletal and other systems are seen but are minor and self-limiting. More serious complications are Hematological and neurological.

Hemolytic anemia.

Hemolytic anemia is a serious complication of Mycoplasma infection. Antibodies produced against the P1 surface antigen of Mycoplasma pneumoniae cross react with RBC I antigen and produce hemolysis in cold temperatures. This is called cold hemagglutination. This is not however unique to Mycoplasma. This is also seen in Infectious mononucleosis, Cytomegalovirus infection, SARS-CoV2 viral infection, and Aggressive B-cell lymphoma.

Hemophagocytic lymphohistiocytosis (HLH) syndrome.

It is rare but important because this is a potentially fatal disease. Macrophages become cannibalistic and start to devour RBC, Platelets, WBC and the precursor cells in the bone marrow. This transformation of macrophages is brought about by cytokines. Enlarged spleen, jaundice and pancytopenia are distinctive features. An increase in acute phase reactants in serum and in the peripheral smears erythrophagocytosis in macrophages are seen. In delayed diagnosis the outcome is bad.

Neurological complication.

The neurological complications are many. But fortunately, only about 1 to 7 % of cases develop neurological complications. The neurological complications are of two categories- early and late. 

 Early. Aseptic meningitis is due to M. pneumoniae invasion of the CNS (central nervous system). But controversies of the pathogenesis of neurological diseases continue. Those who support direct invasion mention that the blood vessels develop endothelial cellular gaps making entry of bacteria to the meninges possible. The DNA of M. pneumoniae is detected in the cerebrospinal fluid in 10 out of 17 cases in one series, but only in 1 to 10 % of cases of other CNS complications.

Late.  Transverse myelitis and thrombotic lesions of CNS are due to microvascular platelet thrombi. Gillian-Barrie syndrome, Polyradiculitis are considered autoimmune manifestations. It is known that M. pneumoniae surface glycolipid is antigenic and antibodies cross-react with the myelin of the nerve sheath or to the neurons. Other CNS diseases are encephalitis and meningoencephalitis. All these late neurological complications are due to Cytokines induced or autoimmune diseases.

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Respiratory Failure. (Simplified version of Pathophysiology)

                                                    Respiratory Failure

                                            PKGhatak, MD

 Lungs are vital for survival. Disease, congenital abnormality, advanced age, or environmental condition produce changes in the structural and functional state of the lung to a degree that sustaining life becomes precarious and the condition is called respiratory insufficiency. When respiratory insufficiency, producing a low partial pressure of oxygen of arterial blood at or below PaO2 50 mmHg or partial pressure of arterial blood carbon dioxide PaCO2 of 50 mmHg or above, usually both at the same time, is known as respiratory failure.

Lack of Oxygen: It is widely understood that oxygen is essential for cellular respiration and normal bodily functions. Brain cells are particularly vulnerable to low O2, next are the heart, kidneys, and liver.

Why CO2 accumulation is bad: CO2, when dissolved in the blood, forms an organic acid CO2 + H2O = H2CO3. The H2CO3 immediately breaks down to  H2CO3 = H +HCO3. [H+] enters the cells (RBC) and K[+] is pushed out from the RBC into plasma and excreted in urine; the [HCO3-] combines with Na[+] inside the RBC and forms Na + HCO3 = NaHCO3. NaHCO3 reenters the plasma of blood. The enzyme carbonic anhydrase helps this reaction both ways. By this action, the blood manages to keep the pH at an optimal 7.4. When this Bicarbonate buffer system is overwhelmed by the rapid accumulation of CO2, two other blood buffers, namely Phosphate buffer and Protein buffer, try to maintain pH. The more CO2 accumulates, the pH becomes lower and lower, 7.3 ->  7.2->  7.1. And at this acid pH most cells function poorly and soon will die if the condition persists.

Effects of high CO2 in alveolar O2: Air entering the lung becomes fully saturated with water vapor. That means air pressure is 760-47 = 713 mmHg. The partial pressure of alveolar air O2, PAO2 is 20% of 713 = 160 mmHg. O2 is diluted further by CO2, as CO2 enters the alveoli from blood. Normal PaCO2 is 40 mm Hg. The O2 pressure now is 160 - 40 = 120 mmHg and arterial PaO2 is 110 mmHg (120 to 110) happens during the transition called A-a gradient. Oxygen saturation at PaO2 110 mmHg is 100 %.

In acute respiratory failure, assume that the CO2 is 70 mmHg, and the PAO2 will be 160-70=90 mmHg. At PAO2 90 mmHg arterial blood oxygen saturation is 87 %. That is hypoxemia. (the normal O2 saturation of arterial blood is 93 to 100 %).

 A simplified version of the lung is like a bellow seen in a blacksmith workshop. Lungs expand, taking in the fresh air and blowing out stale air by breathing out. Lungs are encased in an elastic box made up of vertebrae, ribs, intercostal and abdominal wall muscles and a muscular diaphragm. The respiratory center is situated in the hindbrain (actually three in number, inspiratory, expiratory in the medulla and pneumotactic center in the pons). The aortic body monitors O2, CO2 and pH of the blood and the Carotid bodies monitor O2. The motor nerve for the diaphragm is the phrenic nerve, the neurons are situated in the cervical 4^th and a few in C3 and C5 spinal cord segments and spinal motor nerves for the respiratory muscles are supplied by the thoracic T1 to T12 and lumbar L2 segments of the spinal cord.

The heart pumps blood to the lung alveoli to pick up oxygen before the oxygen can be distributed to all living tissues of the body and at the same time, the accumulated waste product of energy generation is carbon dioxide and which must to eliminated. Like a heat exchanger, the lung capillaries exchange CO2 of blood for O2 of the air in the alveoli. The transfer of gases is governed by laws of differential pressure gradient and solubility coefficient. O2 has a high affinity for hemoglobin and CO2 is forced out by an enzyme, carbonic anhydrase.

Like a well lubricated machine, the airways of the lungs are kept moist and free of debris by mucus, and the airspace inside of the alveoli is kept open by surfactant. Any malfunction, of the above components or a combination of some of them, will cause respiratory insufficiency that may eventually lead to respiratory failure. Respiratory failure may develop suddenly, as in strangulation or drowning, called Acute Respiratory failure or after a prolonged period of an illness called Chronic Respiratory Failure as seen in pulmonary emphysema or kyphoscoliosis.

 Common causes of Respiratory Insufficiency that may lead to Respiratory Failure.

A. Chest wall: Multiple broken rib fractures and fracture of the sternum produce a frail chest wall limiting patients' ability to inhale. Pleurisy, herpes zoster and other painful chest wall pain can produce respiratory insufficiency. Severe spinal deformities, either congenital or acquired, usually lead to respiratory failure.

B. Reduced Space in the chest cavity: Massive pleural effusion, hemorrhagic effusion, empyema makes less space available for the lungs to expand.

C. Space occupying lesions: Thymoma, Lymphoma.

D. Loss of Lung volume: Pneumonectomy, pulmonary emphysema with bullous formation, pneumothorax, extensive cavitary disease of the lung.

E. Consolidation of lungs: Pneumonia specially in the elderly in nursing homes. If pneumonia is bilateral, usually viral pneumonia like COVID, the alveolar surface area available for gas exchange becomes limited, accumulated secretion in the airways prevents normal air turnover in the lungs. That results in low O2 and accumulation of CO2 respectively.

F. Airway obstruction: Obstruction of the trachea by a foreign body, tumors, hemorrhage, large peritonsillar abscess.

G. Airway disease:  COPD, Asthma, cancers of main bronchus and trachea. These conditions produce limitations of air entry and exit in the lungs.

H. External pressure on major airways: Strangulation, invasive carcinoma of the thyroid gland.

I. Diseases of mucus and mucus clearance mechanism.: Cystic fibrosis, ciliary dyskinesia, bronchiectasis. Microorganisms flourish under those conditions, producing pneumonia and destruction of lung tissues.

J. Reduced capillary bed: Emphysema, recurrent pulmonary emboli, micro-platelet thrombi in covid, ATTP. Pulmonary fibrosis. These conditions prune surface areas of alveoli and capillaries making O2 transfer difficult.

K. Ventilation - Circulation Mismatch: a segment of the lung may have limitations of air entry due to airway disease or produce reduced blood circulation due to emboli, consolidation, or atelectasis. That will lead to wasted ventilation or transfer of O2.

L. Liquid filled alveolar space: Congestive heart failure, pulmonary edema, intrapulmonary hemorrhage, drowning. Air from the alveoli is pushed out by the liquids.

 M. Pump failure: Acute left ventricular failure, massive pericardial effusion, or traumatic pericardial effusion.

 N. Diseases of the nerves supplying respiratory muscles: Poliomyelitis, Guillain-Barré syndrome, ascending polyneuritis. Succinylcholine intentional use. Botulinum poisoning. Paralysis of muscles that move the chest wall in and out results in ventilatory failure.

 O. Central nervous diseases: Respiratory centers are robust and keep functioning as long as the blood supply to the respiratory center remains intact. Herniation of the brain from pressure following a massive brain hemorrhage, or removal of CSF by a spinal tap in inappropriate conditions. Opioid overdose.

An abnormal condition of alveolar capillaries, severe iron deficient anemia, emboli in the lung and pulmonary fibrosis, and loss of surface area of alveoli produce low arterial oxygen, whereas, under the same circumstances, CO2 easily crosses from blood to alveolar air. That is because before any gas has to combine with hemoglobin or leave hemoglobin for the air in alveoli, that gas has to dissolve in the blood first. And CO2 is 160 times more soluble in blood than O2. The only way CO2 can accumulate in blood if the exchange of air in the alveoli lags behind. That is known as Ventilatory Failure. When a low O2 in arterial blood is present, it is called Hypoxemia.

Respiratory Failure.

The common causes of Chronic Respiratory Failures are - advanced COPD, Pneumonia in chronic renal, hepatic, or cardiac failure and pneumonia in the elderly in debilitated conditions. In patients surviving more than 3 days with acute respiratory failure, the kidneys start generating bicarbonate and turn acute to chronic respiratory failure, into chronic respiratory failure. 

The common cause of Acute Respiratory Failure is – COPD with pneumonia, Narcotic overdose, sudden myocardial infarction, cardiac arrest and massive hemorrhage, and pulmonary edema.

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