Penicillin Allergy

                                                               Penicillin Allergy

                                                        PKGhatak, MD

Penicillin was the first antibiotic that came into the medical field and it proved far superior to sulfonamides. On the battlefields, Penicillin was the only antibiotic available for the treatment of wound infections.

Soon, Penicillin was prescribed on a wider scale for the public. Reports of allergic reactions and anaphylaxis began to surface, making doctors take a careful history of penicillin allergy before prescribing penicillin.

10 % of patients reported being allergic to penicillin G, penicillin related compounds, and cephalosporins. At present, true penicillin allergy is seen in 3 % of users, and the rest of the reactions are nonallergic minor symptoms.

Molecular basis of Penicillin allergy.

Penicillin is a Dipeptide. The structure of penicillin consists of a beta-lactam ring, a thiazolidine ring, and a side chain of 6 amino acids. The allergenic property of penicillin lies within the β-lactam ring. Penicillin is a Hepten. It binds readily with plasma protein and becomes antigenic in susceptible individuals.

Why do certain people develop a Penicillin allergy:

The adaptive immune system produces IgM (Ig = immunoglobulin) and IgG classes of antibodies; IgA class antibodies in the GI, Respiratory, and Genitourinary tracts. IgE( immunoglobulin E) antibody is produced in the regional lymph nodes draining the location where the offending organism entered the body. However, the antigen must have these characteristics:

1. The antigen must be a small molecule of protein; if the antigen is not a protein, then it must be a Hapten. A hapten binds readily with a protein and becomes an antigen.

2. The antigen must be soluble so that the Dendritic cells can recognize it as a foreign substance.

3. The molecule of antigen has to be small. 

The plasma cells, in the lymph node genome center, switch IgE antibody production under the influence of CD4 and Th2 (thymic 2) cells. A low dose exposure of Penicillin on the Th2 cells produces Interleukin IL-4 and IL-13. Those two Interleukins are the molecular switch for IgM and IgG production. If penicillin exposure is large, then Th1 cells are activated. Th1 cells produce IFN gamma (interferon-gamma), IFN gamma acts as a brake on Th2 cells, and Th2 cells stop producing IgM and IgG antibodies.

Penicillin-induced Hypersensitivities are in two categories. 1. Immediate,

 2. Delayed.

 The reactions are also referred to as Type I to 4 Hypersensitive Reactions.

Immediate Reaction.

Type I. - Immunoglobulin E-mediated immediate reaction, occurs minutes to hours after exposure to the antigen.

Delayed Reaction.

Type II. -  Immunoglobulins IgM and IgG mediated Cytotoxic reaction, occurs 72 hours after exposure.

Type III. - Immune Complex reaction occurs 10 to 12 days after exposure.

Type IV. - Cell-mediated Delayed reaction occurs 4  days after exposure.

Special features of IgE.

IgE differs from other Ig classes of antibody in being locally produced and most abundant in local tissue. IgE has a high affinity for the skin resident Mast cells, FCεRI receptors. IgE also binds to some degree to eosinophils and basophils. Repeat exposure to the antigen releases pre-formed Bradykinins, Histamine, and other enzymes locally. That produces allergic symptoms. In Anaphylaxis, the mast cells, eosinophils, and basophils all empty preformed enzymes simultaneously, producing swelling of the mucosa of the tongue, pharynx, upper airway, obstruction, hypotension, hypoxemia, and cardiovascular collapse.

Detecting IgE in Allergy and Anaphylaxis.

The tests are in two groups, namely, Skin Tests and Blood Tests. The skin tests are the Scratch test, Intradermal test, and Patch test. The first two tests are for detecting IgE antibody against Penicillin, and the Patch test is for detecting delayed skin reaction to Penicillin. The scratch test is performed on the forearm. A drop of a standard solution of penicilloyl-polylysine or undegraded penicillin is applied to the skin. A fine needle is used to lightly scratch the skin through the liquid. In 15 to 20 minutes, a wheal should appear if the person is allergic to penicillin. The wheal is measured with a ruler. The degree of sensitivity is proportional to the diameter of the wheal.

The specificity and sensitivity of the scratch test can be improved by injecting the same penicillin solution between the layers of the skin. And the resultant wheal is measured the same way the scratch test is done.

The patch test is described later under delayed hypersensitivity reaction.

A skin test is generally considered a standard test for allergies. This test, however, has considerable risk. It may precipitate a severe allergic reaction or anaphylaxis.

That risk is totally eliminated by performing a blood test. A modified RAST       (radio-allergo-sorbent test) blood test - CAP RAST or  CAP FEIA (fluorescence enzyme immune test). Blood is collected from the patient. At the laboratory, tiny discs coated with penicillin are mixed with serum. After a certain time, when the IgE antibodies bind with the antigen is complete and the unbound IgE is washed away. The bound IgE is quantified by fluorescent enzyme immunoassay.

The blood test has a significant false positive result, but a negative result is confirmation of the absence of penicillin allergy.

Type II Penicillin Hypersensitivity.

Penicillin molecule at times binds with the normal cells' surface receptors. This new molecule is perceived by the immune cells as foreign. Antibodies of class IgM and IgG are generated. The antibodies attack the penicillin-bound normal tissue or the extracellular matrix. This triggers the activation of complement, producing matrix destruction and loss of function. Examples of type II hypersensitivity are acquired hemolytic anemia, Thrombocytopenia, and Leukopenia.

Type III penicillin Hypersensitivity.

In type III hypersensitivity, the IgG antibody is combined with penicillin. These antigen-antibody complexes are deposited in tissues. The immune cells are activated against this complex. The immune inflammatory reaction causes tissue damage and loss of function. Examples are Serum sickness (fever, arthralgia, urticaria, lymphadenopathy, and glomerulonephritis), Vasculitis (multiple organ involvement – hepatitis, nephritis, pneumonitis, skin lesions, etc.). Interstitial nephritis.

Type IV penicillin Hypersensitivity.

Penicillin ointments, creams, and drops were used to treat wounds. Penicillin sensitized the skin's immune cells. Sensitized immune cells produce inflammation in the skin area and the condition is called contact dermatitis. This preexposure to penicillin produced penicillin resistant bacteria. Now, this practice is abandoned, and contact dermatitis due to penicillin has greatly disappeared. Examples of delayed reactions are - Contact dermatitis, morbilliform skin eruptions, Stevens-Johnson Syndrome (SJS), and a more severe form of SJS, Toxic Epidermal Necrosis (TEN).

Footnote:

Skin test for Type IV reaction. A small piece of sterile dressing soaked with penicillin solution is applied to the back of the patient and kept in place by an occlusive dressing for 4 days. When the dressing is removed and the presence of skin lesions is noted.

Stevens-Johnson Syndrome: Flue like symptoms, rapidly spreading skin lesions which quickly turn into blisters. Mouth, lips, and throat swell and become painful and bleed easily, and becomes fatigued. Shedding of layers of skin and rapid deterioration of the condition, an emergency situation develops.

edited June 2025.

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Insulin Resistance.

                                                    Insulin Resistance

                                               PKGhatak, MD

Insulin is an essential hormone for glucose utilization. In the absence of Insulin, blood sugar is elevated and the body is unable to generate an adequate amount of energy and many other metabolic processes are derailed. Unless Insulin is administered, death is inevitable. This is called Type I Diabetes mellitus (DM1). Type I diabetes is not a part of today's insulin resistance discussion.

In Type II Diabetes mellitus (DM2) the Insulin is either structurally abnormal or due to the presence of circulating antibodies making Insulin less effective. In this condition, the blood sugar is high and Insulin levels are high to high normal. A recent study from Japan showed DM2 might result from an increased renal insulin clearance and high sugar is due to relative insulin deficiency. WHO reported that    Covid-19 can destroy beta cells of the pancreas as documented in long covid.

An outline of Insulin activities.

Chemically Insulin is a polypeptide. Polypeptide hormones are prone to structural abnormalities due to minor defects in the cleavage of the long chain amino acids, which make the polypeptides. Some other non-insulin polypeptides have Insulin-like actions. Notable among them are Insulin-like growth factor I and II (IGF1 and IGF2).

Insulin Carrier Proteins:

Insulin molecules are transported by carrier proteins to cells. The cell surface contains receptors for Insulin. Insulin receptors are made up of two units - an A unit and a B unit. The distribution of A and B units is not uniform in the tissues. The binding of insulin with a specific receptor A or B determines the metabolic path the glucose molecule takes inside the cell. Moreover, when Insulin binds with one unit, then the other unit becomes inactive. In the Liver, however, Insulin binds with both units A and B. As a result, Insulin in the liver makes multiple metabolic paths unlike in other tissues. Insulin, on binding with the cell receptors, facilitates Glucose entry inside the cell and also stimulates the hexokinase pathway for the utilization of glucose and ATP generation.

Transport of Glucose molecules in and out of cells:

The glucose transport proteins belong to two groups. One is energy-independent Glucose transport proteins (GTP 1 to 13) and the second one is Sodium-Glucose Linked Transporters (SGLTs) and this requires energy expenditure.

GTP 1. This transporter helps a low-level glucose entry into all cells for tissue respiration.

GTP 2. This transporter is bidirectional. In the intestine, renal tubules and beta cells of the pancreas GTP 2 ferries glucose in and out of cells under the concentration gradient.

GTP 3. This transporter is most active in the nerve cells of the brain and spinal cord.

GTP 4. It is most prevalent in cardiac and skeletal muscles.

Energy dependent SGLT.

Energy is used for Sodium, Potassium, and H ion exchanges to maintain Intracellular pH and blood/cytosol Na and K concentration gradients.

During this process, Glucose enters the cell when a relative Na+ ion (sodium ion) deficiency develops. In high plasma glucose concentration, the process is reversed. In post digestion, glucose absorption in the small intestine and renal tubular conservation of filtered glucose are examples of SGLT1 transport.

Besides these sites, three other sites - Liver, Muscles and White Fat Cells (WFC) are the main focus of Insulin resistance and require attention.

Liver: The liver is the prime metabolic workshop. 1. Glucose is metabolized via tricarboxylic acid cycle, 2. Excess glucose is converted to glycogen, 3. Glucose is generated from fatty acids and amino acids and 4. Glycogen is broken down to glucose. All these metabolic processes are enzyme driven and take place in cellular mitochondria and endoplasmic reticulum (EPR).

Muscles: 1. Glucose is utilized in the muscles as fuel, 2. Excess glucose is stored as glycogen, and 3. glucose is generated from glycogen.

White fat cells (adipocytes): 1. Fatty acids are stored as fat molecules. 2. And fat provides energy when needed by turning back into fatty acids and glycerol.

Just as these organs differ the way glucose is utilized, similarly when Insulin resistance develops, these organs are affected in different ways and the degree of effects are variable.

Clinical entities associated with Insulin resistance.

1. Metabolic syndrome. This entry consists of hypertension, fatty liver, hyperlipidemia, high blood sugar and abdominal obesity.

2. Polycystic ovary syndrome.

3. Pre-diabetic stage.

4. Lipodystrophy.

5. Non-alcoholic fatty liver disease.

Mechanism of intracellular Insulin resistance in Type II Diabetes mellitus.

1. Structural abnormality of Insulin.

2. Presence of circulating Insulin antibodies.

3. Inherited mutation of genes expressing Glucose transport proteins and glucose receptors of cells.

4. Acquired mutation of genes expressing glucose transport proteins and glucose receptors. 

5. Stress and Inflammation.

Stress.

Stress. Excess accumulation of lipids inside the cells diverts the metabolic path from the tricarboxylic cycle to the utilization of fat. This puts an extra burden on mitochondria and the endoplasmic reticulum.

Inflammation

Inflammation. Inside the cell cytoplasm, various inflammatory cytokines like IL-6, IL-10, and TNF-alpha1 accumulate. Obesity is now considered as a chronic inflammatory condition of fatty tissue.

 6. Molecules of intermediate products of metabolism like bioactive lipids, diacetyl- ceramide, acyl carnitine produce mitochondrial stress and inflammatory cytokines. 

7. Glucagon or ACTH, glucocorticoids secreting tumors

8.  Endocrine abnormality. - Hyperthyroidism, Gigantism and Acromegaly. Cushing disease.

9. Growth hormone of the anterior pituitary is antagonistic to Insulin in the skeletal muscles and liver.

10. Medication. - A common cause of high blood sugar is chronic use of systemic steroids used in immunosuppression following organ transplants and asthma and certain hematological malignancies. Other drugs may elevate sugar are Hydrochlorothiazide, Statins, Beta blockers, Amiodarone, Niacin, Antipsychotic drugs and Prostaglandin E1.

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Immune Reaction

                                                              Immune Reaction

                                                     PKGhatak, MD

While reading any medical journal one usually encounters various descriptions of tissue response to injuries, infections, and illnesses, described as reactions. Immune reactions are the body's attempts to stamp out or control infection, cancer and diseases in an orderly fashion by the use of specialized cells and biochemical molecules.

Our body is pre-programmed to respond by a set pattern of actions called Innate or inherited immune reaction. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune reaction.

Innate reaction.

The skin, surface layer of the nose, mouth, GI, Respiratory and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders or cancer cells. These immune cells are Dendritic cells. They recognize the molecular patterns of the invaders' surface membrane, and they attach themselves to it, like a key fits a lock, and release the chemicals, called Cytokines. In response to cytokines, neutrophils, monocytes, eosinophils, phagocytes and complements gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation and temporary loss of function.

The complement pathway of action is described as the Classical Pathway. Other pathways are also present, these are Alternate Pathway, and Mannose-Lectin Pathway. These pathways are activated by yeasts, viruses and certain bacteria.

The end result of this action is that the invasion is checked, the invaders are paralyzed and eaten alive by the macrophages and the dead bodies are removed from the area in order for healing to take place.

Adaptive Immune Reaction:

Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen, a signature part of the pathogen - usually, a protein molecule called antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which combines with that antigen and neutralizes the pathogen. This antigen remains in memory in a subset of B -B-cells in the regional lymph nodes, but the memory is short-lived. Some memory B-cells move to the bone marrow and there retain memory permanently. 

Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.

Adaptive immunity has a wide range of actions on pathogens and can be obtained in various ways.

Classification of adaptive immunity.

A. Natural

1. Passive immunity. A developing child in the mother's womb gets antibodies from the mother's blood via the placenta, and in some cases also from breast milk.

2. Active immunity is acquired from prior infection by that pathogen.

B. Artificial.

1. Active. Use of a vaccine to generate antibodies, which protects an individual for a while depending on the nature of the pathogen.

2. Passive. By giving IV antibodies, obtained from recovered patients or generated in animals by inoculating the animal, or obtained in the laboratory by the cell culture methods.

Abnormal Immune reaction.

Not every attempt to generate an adequate number of immune cells and antibodies against a pathogen will go smoothly. In some cases, the defect may lie in abnormal genes in a family or gene mutation of the individual. The response may be either excessive called Hypersensitivity reactions or cross reacts with normal body cells called Autoimmune diseases.

A. Hypersensitivity.

1. Immediate. The reaction happens within 24 hours after exposure to an allergen (pathogen).

Immediate hypersensitivity is of 3 different types.

Type I hypersensitivity reaction.

Also known as Immediate immune reaction, Allergy, Anaphylaxis and Atopy. The body produces Immunoglobulin E (IgE) instead of Immunoglobulin M or G (IgM, IgG). The circulating IgE binds with the Mast cell receptors. When sensitized mast cells encounter the same pathogen again (like pollen, bee stings, peanuts, etc.), the encounter causes the mast cell to release the preformed granules containing Histamine, and other enzymes at the site, and the consequence of that is the dilated blood vessels, fluid escaping locally. Nasal discharge, cough, paroxysm, and itching are produced depending on whether it occurs in the nose, lungs, or skin respectively.

Anaphylaxis.

Anaphylaxis is an excessive amount of cytokines released in a minute after exposure resulting in a drop in blood pressure, severe tightness in the chest, low blood oxygen, and cardiovascular collapse.

Type II hypersensitivity reaction.

In type II reaction, the IgM and IgG antibodies are involved. Examples of clinical conditions are Acquired hemolytic anemia, Rheumatic heart disease, Good Posture syndrome, Myasthenia gravis, Pemphigus Vulgaris, etc. 

Type III hypersensitive reaction.

Type III reaction is known as Immune complex mediated reactions. Here IgG, complement and neutrophils are involved. Clinical examples are Serum sickness, Rheumatoid arthritis, Lupus erythematosus, Glomerulonephritis, Hypersensitive pneumonitis, etc.

B. Delayed reaction.

The delayed hypersensitive reaction is also known as Type IV reaction, Cytotoxic or Cell mediated hypersensitive reaction. The reaction starts at 48 to 72 hours after exposure.

In type IV reaction, Thymic Th1 and Th17 cells are participants. Clinical examples are Contact dermatitis, poison ivy, Chronic transplant rejection, Multiple sclerosis, Celiac disease, Hashimoto thyroiditis, Granuloma annulare, etc.

Autoimmune disease.

The acquisition of knowledge by the immune cells that are foreign is gained in the developing T cells in the thymus in the developing embryo, and the learning process continues at a slow pace during the rest of life.

                                         [https://humihealth.blogspot.com/2021/08/thymus.html]

The mutated genes, either inherited or acquired gene mutation, result in misdirected immune attacks against the own normal tissue or organ.

Clinical examples are Crohn's disease, Acquired hemophiliac anemia, Aplastic anemia, Thrombotic thrombocytopenic purpura (TTP), SLE, Multiple sclerosis, Rheumatoid arthritis, Type1 Diabetes mellitus. Pernicious anemia, etc.

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Interleukin- 6

                                                          Interleukin- 6 (IL-6)

                                                 PKGhatak, MD

Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoter but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases, cancers, and at the same time must be available for repairs of diseased or damaged tissues.

Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COVID-19 virus inflammatory reactions. In a previous blog, dated July 2020, a general outline of Interleukin was presented. In this article, a more detailed mechanism of action of IL-6 in inflammation is discussed.

Cells capable of secreting IL-6. IL-6 producing cells are Macrophages, endothelial cells of blood vessels, epithelial cells of the gut, and T & B cells (lymphocytes).

Normal serum levels of IL-6 are 0 pmg/ml to 1.8 pmg/ml.(pmg=picomiligram)

How activation of immunocytes occurs.

Bacterial glycoprotein fits the pattern of the Pathogen Associated Molecular Pattern (PAMP) Receptors. Other receptors are Toll Like Receptors (TL) are activated by bacterial lipopolysaccharide [Toll is a german word meaning stunning]. Once these antigens bind with the appropriate receptor IL-6 is produced. Immunocytes can also be activated by cellular metabolic changes, hypoxia, viral infection, activated nuclear factor (NF) k-B (killer B-cells), and NF-IL6 composites.

A general outline of IL-6 effects in the body.

1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation(hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break-up.

Nature of IL-6.

IL-6 is a small protein molecule containing 212 amino acid residues. IL-6 molecule attaches to its target cells by two pathways. One is by attaching with the universal glycoprotein g130 surface receptors, the other by the IL-6R receptors. The IL-6R receptors are present in very limited cell lines – in hepatocytes, macrophages, B-cells and a subset of T-cells.

IL-6 must first bind with IL-6R present on the cell surface, then this composite allows the IL-6 to bind with g130 receptors. As a result, IL-6 R limits IL-6 activities to limited tissues. This is the Classical Path of Activation of immunocytes and the effect on the body is Anti-inflammatory.

Role of Metalloprotease in Cytokines production.

Activated metalloprotease strips IL-6R from the cell surface membrane. The free IL-6 receptors easily bind with IL-6. Then these composites can easily bind and activate a number of cells in different tissues.

This pathway leads to the unregulated production of cytokines and other mediators. This pathway of immunocyte activation is seen in cancers, autoimmune diseases, arteritis (inflammation of the smooth muscular layer of blood vessels), muscles of the GI tract, heart muscles, brain cells and other tissues. This path of activation of immunocytes is Pro-inflammatory.

IL-6 induced acute inflammation.

IL-6 acts through intermediate cytokines like TNF (tissue necrosis factor), PGE (prostaglandins E) and other interleukins (IL).

Acute phase inflammatory reactants.

Most of the acute phase reactants (APR) are produced and released by hepatocytes. The liver secretes increasing amounts of C-Reactive Protein, hepcidin, and haptoglobin. Fibrinogen, serum amyloid proteins from IL-6 stimulation.

Macrophage.

Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.

Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono_c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.

Macrophage hyperactivation.

Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.

This hyperactive IL-6 is seen often in covid related bilateral interstitial pneumonia and multisystem failure and deaths.

 IL-6 plays an important function in both innate and acquired immunity - first to limit infection, and invasion of harmful pathogens, toxins, venom, and cancers. Then in the second phase, it helps to heal the tissue by removing debris and dead pathogens, followed by the formation of collagen fibers, new cells and new blood vessel growth.  In the initial stage of infection, treatment should promote inflammation and not limit it. In macrophage induced hyperactive stage, intervention should be directed to stop cytokines or neutralize cytokines in limiting tissue damage. If interventions are not properly timed, then such interventions do more harm than good. For example, at the beginning of the COVID infection and symptoms, if drugs are used to kill the virus, or antibody infusion to neutralize the virus, then these interventions are beneficial. Medications and biological agents that limit acute inflammatory reactions are detrimental when used in this phase of infection.

In any discussion of COVID, specially in newspapers and social media, there is hardly any attention paid to what and when such interventions were done. Such discussions are useless and harmful.

Role of IL-6 in a few select organs.

Brain.

IL-6 crosses the blood-brain barrier. IL-6 induces PGE2 (prostaglandin E2) in the Hypothalamus. (Hypothalamus acts as the Thermostat of the body temperature). In response, the skeletal muscles generate body heat by non-shivering thermogenesis, catabolism of fatty acids and depletion of body fat.  It also improves glucose utilization by increasing GLP-1 (glucagon like peptide) and Amylin secretion from the pancreas.

Lungs.

In normal circumstances, IL-6 helps to maintain the integrity of lung elastic tissues, alveolar membrane, maintain pulmonary BP, and preserve pulmonary microcirculation. In overactive IL-6, the proinflammatory effects override the anti-inflammatory functions and produce the following changes -

 IL-6 induced cytokines damage pneumocytes II and damages endothelial cells of the pulmonary capillaries. It produces alveolar and interstitial edema and micro atelectasis. Pulmonary hypertension develops due to platelet microemboli. Gas exchanges are hampered and hypoxia develops.

Liver.

Increased production of the acute phase reactants is already mentioned. The liver also reduces the production and release of Fibronectin and Transferrin into circulation.

GI tract.

Increased hepcidin blocks the action of Ferroproteins (normally carry iron from the gut to bone marrow for RBC production) leading to anemia of infection.

On other viruses.

Enterovirus 71. It causes Hand- Foot - Mouth disease in humans. Under IL6 stimulation enterovirus 71 invades the brain and produces encephalitis.

Herpes virus increases its virulence and produces Kaposi sarcoma.

IL6 is implicated in the following diseases.

Diabetes mellitus, Alzheimer's disease. Amyloidosis, Rheumatoid arthritis, Lupus erythematosus, Multiple myeloma, Bechet disease, Multiple sclerosis, Neuromyelitis Optica, Prostatic cancer.

Interleukin 6 is an important Cytokine and possesses a multitude of functional potentials. The covid pandemic has brought IL-6 cytokine to the general public domain. Covid discussions are commonplace in social media and everyone has an opinion with or without the basic knowledge of Interleukins, specially IL-6.

Covid vaccine is as sure a preventive measure as one can possibly create but the vaccines are kept in warehouses while unvaccinated people are engaged in endless debate over the use of antiviral drugs and biological immunosuppressive, and Immunopotentiation therapies.

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Lactic Dehydrogease. (LDH)

                                                 Lactic Dehydrogenase (LDH)

                                               PKGhatak, MD

Lactic Dehydrogenase is an enzyme present in all tissues. LDH catalyzes, in a reversible reaction, lactate to pyruvate. LDH transfers 2 electrons and one hydrogen ion to NAD and in the process generates 2 molecules of ATP per molecule of glucose. LDH is an intracellular enzyme and consists of 5 isoenzymes. The individual organ contains one predominant isoenzyme and also small but variable quantities of other isoenzymes. Tissues are capable of producing any isoenzymes given the proper substrate concentration, pH, and oxygen supply.

LDH concentration is higher in the RBC, liver, heart, brain, lungs, kidneys and bones. Any disease or infection that damages any organ will release LDH in the blood and the serum level of LDH rises - twice or many times higher than normal. LHD is an anaerobic enzyme that belongs to the oxidoreductase group.  LDH is present both in the cell cytoplasm (Cytosol) and in mitochondria. The mitochondrial LDH is called mL-LDH (mitochondrial Levo LDH). The mL-LDH facilitates the oxidation of lactate to pyruvate. The RBC has no mitochondria and lacks mL-LDH as a result, unable to metabolize lactate further.

Action of LDH.

The chemical reaction of LDH is as follows -

CH3 CHOH COOH+ NAD + LDH = converted to CH3 CO COOH + NADH + H+ and in reverse action -

Pyruvate + NADH + H+ in presence of LDH = Lactate + NAD +. (See footnote 2 Cori cycle)

Pyruvate then enters the Krebs cycle (see footnote 1) and generates 36 ATP molecules during its full utilization in the generating energy. Excess accumulation of NADH is the triggering point of the reverse action and produces lactate.

Blood levels of LDA.

Serum LDH level is higher than plasma level because clotting of blood releases LDH.

Normal serum level if LDH

Newborn	135 to 750 units/L. In CSF < 70 units / L
Children up to 12 years	180 to 435 units/L
12 to 18 years	122 to 222 units/L
Adults	140 to 280 units/L
CSF LDH in adults	Less than 40 units/L

Falsely elevated LDH.

Following general anesthesia, Aspirin use, alcohol, and procainamide may elevate LDH levels.

Falsely low LDH.

Vitamin C use.

LDH isoenzymes and structure;

LDH has 5 isoenzymes - 1 to 5. And each LDH molecule is a combination of two units, H and M units. H stands for heart and M for skeletal muscle.

LDH isoenzymes and composition

Name	Units	Higher levels in
LDH1	4 H units	Heart
LDH 2	3 H units + 1 M unit	RBC, Spleen, Bone marrow.
LDH 3	2 H units + 2 M units	Lungs
LDH 4	1 H unit + 3 M units	Kidneys
LDH 5	4 M units	Skeletal muscles, Liver.

All tissues have the above 5 isoenzymes in variable amounts. The H Unit binds faster with the substrate but has a slow rate of metabolic activities.

Two chromosomes, 11 and 12, encode LDH. The genes of the two chromosomes are designated as LHD- A, B, C, D genes. LDH-A.B.C genes encode L- LDH (Levo LDH) isomer and LDH-D gene encodes d-LDH isomer. Levo isomers are required in Lactate utilization and the Krebs cycle

Congenital absence of LDH.

The encoding genes for LHD are 4 in number, designated as A, B, C, & D. The mode of inheritance is autosomal recessive. LDH deficiency is very rare, Japan reported most cases; the incidence in Japan is 1 per million people. And known as congenital LDH – A and LDH- B deficiencies.

Deficiency in LDH-A results in absent LDH 5. Patients present with easy fatigability, muscle cramps and pain, myoglobinuria, and renal failure.

LDH -B deficiency causes LDH- 1 deficiency. The heart muscles are capable of generating energy from using other sources and patients show no effects from this deficiency.

Covid-19 and LDH.

In every study published on COVID-19 virus infected hospitalized patients, the serum LDH is universally elevated. NIH calculated that an elevated LDH increases a 6-fold increase in serious illness and a 16-fold increase in mortality. In multisystem failure, all LDH isoenzymes are elevated, the higher the number, the worse is the outcome. In platelet microthrombi and interstitial pneumonia, LDH3 is very high. Accumulation of lactate in tissue increases the H ion concentration and a fall in the pH, Low pH enhances macrophage metalloprotease and initiates new blood vessel growth in the inflammatory tissues.

LDH activity in the specific organ/tissue.

Muscle.

Muscular activities utilize oxygen, and in a sustained activity like in a marathon run, a severe hypoxic condition is created. Since oxygen is the final electron acceptor, the ATP generation stops but the muscles continue to function by creating ATP through NAD+. The serum levels of LDH 5 are high in muscular dystrophy, HIV infection, crush injury and rhabdomyolysis. The damaged muscles release myoglobin and kidney damage is common in significant myoglobinuria.

Brain.

In normal conditions, the brain uses lactate to generate 30% of its energy needs. In anoxia, the brain can raise it to 60%. Excess lactate enters the CSF. CSF lactate levels are used for diagnosis of anoxic brain injury, and bacterial meningitis but LDH usually remains normal in viral meningitis. The CSF LDH levels are very high in subarachnoid bleeding, and high in metastatic carcinoma, CNS lymphoma, and Leukemic infiltration to the brain.

Heart.

In myocardial infarction (MI), the LDH level rises within 24 hours and stays up for 4 days then returns to a normal level. A normal heart generates LDH2. In MI the LDH1 rises over the LDH2. The elevated LDH1/LGD2 ratio is helpful in the diagnosis of MI.

Pleural effusion.

In inflammatory pleural effusion, the ratio of LDH of pleural fluid and serum LDH is >0.6.

Liver.

In cirrhosis of the liver and hepatitis, the LDH2 is proportionally higher than LDH4. In toxic hepatitis, LDH is 10 times the normal serum LDH.

Lungs.

In microvascular pulmonary embolism, LDH3 is very high, so also in pulmonary emboli and infarction, necrotizing pneumonia.

B12 deficiency and macrocytic anemia.

LDH levels are high, and the levels fall with adequate therapy.

Cancer.

All cancer cells produce excess LDH and high serum levels reflect the aggressiveness of cancer. Many cancer cells are capable of copying mitochondrial mL-LDH and use it to generate extra energy for cancer growth. This is known as the Warburg effect (see footnote 3).

Malignant melanoma metastases are associated with very high serum LDH levels, usually over 50 times the normal value. Leukemia. Lymphoma, Multiple myeloma, testicular and ovarian cancers also produce high serum LDH.

When treatment of cancer is effective the LDH level falls. The LDH level is used as a serum marker for monitoring cancer recurrence.

In colorectal, esophageal, nasopharyngeal, prostrate, germ cell cancers and malignant melanoma, the LDH levels over 1000 units/L signify a poor prognosis.

An interesting side note.

Malaria parasites lack the tricarboxylic acid cycle and depend on LDH for energy generation. Attempts are now being made to block LDH in malaria parasites and if successful it will help to control malaria.

Footnotes-

1. Krebs cycle is also called the tricarboxylic cycle. Two carbon compounds generated from the metabolism of glucose, fatty acids, and glucogenic amino acids combine with the enzyme CoA and form Acetyl CoA. Acetyl CoA combines with Oxaloacetate to form Citric acid and enters a cycle that runs strep wise, in reversible actions, and generates ATP, CO2, and H20.

2. Cori Cycle.

The Cori cycle explains the steps in the conversion of lactate to Glucose. The newly formed glucose (neoglucogenesis) is added to the blood to keep blood sugar within the range.

3. Warburg Effect.

This is a biochemical process of speeding the rate of glucose conversion to lactate in aerobic conditions. Cancer cells use this to generate extra energy.

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Pulmonary Function Tests.

 

                                               Pulmonary Function Tests

                                             PKGhatak, MD

Pulmonary Function Tests (PFTs) are aptly named; these tests delineate the functional status of the lungs and allow one to track the progression of a disease or improvement. The tests are also sensitive in the early stages of a pulmonary disease, when other tests, such as chest X-rays, CT scans, and blood tests, are likely to be normal. The PFTs are an integral part of good management of asthma, where patients themselves can adjust medications on a day-to-day basis. Tests are simple enough and can be repeated frequently.

A complete PFT is performed in a pulmonary lab by a technician and consists of several tests requiring maximum effort of the patient and a brief period is allowed for the patient to recover, but in one visit. 

From the patient's side, the patient is required to breathe in and out, as best he/she can, into a mouthpiece attached to a machine. And there is no need for a blood sample or any injections.

The electronic machines are amazingly efficient and fast, and can spit out numbers instantly. If the report is delayed, that is likely due to the time taken to interpret those numbers by an expert.

Why PFTs are needed:

1. It is an essential test to monitor a lung disease from day to day.

2. Patients use this device to detect early warning signs of trouble and seek proper help ahead of the problem begins

3. In certain pulmonary diseases, the functional state is more important than just a diagnosis. An example is asthma.

4. An essential tool for detecting very early cases of asthma. And then categorize asthma according to severity, in order to prescribe appropriate medications and dose adjustments.

5.PFTs are sensitive tests utilized in detecting the cause when the breathlessness of patient is the only symptom.

6. These tests differentiate obstructive lung diseases from those diseases that prevent the lung from expanding fully to its capacity (restrictive lung disease).

Normal breathing.

We breathe 12 times a minute, one cycle takes about 5 seconds, which includes two phases, inhalation and expiration. If one listens with a stethoscope, the movement of air during inhalation makes a gentle sound, whereas expiration is very short, and only in the early part of expiration is audible. That is due to the fact that the elastic recoil of the lungs and the chest wall does all the work during expiration.

Let's take a look at this test result together. Note that there is a small oval graph within the larger one, and a horizontal line runs across the graphs. The horizontal line is the baseline. The lower half of the graph represents the movement of air into the lungs, and the upper part represents air moving out of the lungs. For the lower half, the pen inscribes from Right to Left. The pen inscribes on the upper part from Left to Right.

The smaller graph depicts the air moving in and out of the lungs during normal breathing.

The larger graph is inscribed when the patient took in as much air in his lungs as possible and then forced out air as fast as he could and continued to push out air from his lungs with the constant cheering of the technician. This graph represents Forced vital capacity, or simply the Vital Capacity.

The horizontal line within the graphs represents the Volume of air in Liters, the vertical line depicts the Flow Rate of air in Liters per Second.

The difference between the two graphs is the Reserve Volume of the lungs, both in the inspiratory and expiratory phases.

FEV1.

The amount of air that expired under maximum efforts in the First second is known as the forced expired volume in the first one second (FEV1). A normal person can expel 80 % or more in the first second. In obstruction of the airway (COPD), the FEV1 is less than 75%. In asthma, the FEV1 should return to a normal level after a brief inhalation of a bronchodilator. In suspected cases of asthma, the initial EFV1 may be normal but the FEV1 will fall below 80% after a Methacholine challenge test, also known as Bronchial Provocation Test

The results of the PFT are reported with the actual patient's performance numbers and also as a percentage of his performance when compared with a normal person with his age/ sex/ethnic background/ height/ and ideal weight for the age and height.

Methacholine Challenge test.

A forced vital capacity is recorded first. Only if PFT is normal, then the methacholine challenge test is performed; because this test is a test to document hyperactive airways, if that is already demonstrable, then there is no point in doing the test.

The subject is asked to breathe in and out normally, a nebulizing solution starting with a dose of 1 to 3 micrograms of methacholine and observing and documenting changes in flow rates of the forceful expiration. The test is continued with an increased dose of methacholine till the maximum dose is given or a reduction of flow rate is observed. 

A decrease of 20% of FEV1 is necessary to call a test positive.

Total Lung Capacity.

After a maximum expiratory effort, a significant amount of air is still left in the lungs because the lungs cannot be squeezed further, as the chest wall will not yield because of rigidity. The amount of air that will not be expelled is called Residual Volume.

On adding the residual volume to the forced vital capacity volume, the Total Lung Capacity (TLC) number is obtained.

Direct measurement of TLC.

To determine the TLC, a known amount of inert gas, Helium (harmless, non-absorbable, not soluble in water or blood), is used. A mixture of oxygen and helium is inhaled from a closed system and the subject is allowed to breathe in and out within the closed system to ensure the proper distribution of helium in the lungs. Then the expired air is analyzed for the final concentration of the helium gas. Knowing the initial gas concentration and the final gas concentration of helium, the volume of the Total Air present in the lungs is easily calculated.

In emphysema, the reserve volume increases at the expense of inspiratory reserve volume and the TLC also increases due to the loss of the elastic tissue and the chest expands outwards, commonly referred to as a Barrel Chest.

In chest wall deformities, e.g., Kyphoscoliosis, and in pulmonary fibrosis, the TLC and the FVC are reduced.

Diffusion Capacity.

The diffusion capacity of the lung is also known as the transfer factor, DLCO (diffusion of carbon monoxide), TLCO. The diffusion capacity is a measure of the health of the delicate tissue at the junction of air sacs (alveoli) and pulmonary capillaries, where the oxygen molecules from the alveoli move across the membrane and bind with the Hemoglobin in the RBCs.

In a biological system, multiple factors are at play, so also in DLCO. One has to accept that under the condition of the test, just one factor is variable. After the result is obtained, a correction is made, if necessary. As an example, significant anemia will appear as decreased DLCO due to less hemoglobin available to bind oxygen and not due to a damaged membrane.

To test DLCO, the subject exhales forcefully first, then inhales a known amount of a mixture of oxygen, nitrogen, helium and carbon monoxide (CO) from a closed system, and holds breath for 10 seconds. The expired air is sampled at the mid portion of expiration and analyzed by a rapid CO analyzer. The amount of CO transferred is calculated and expressed in CO mmol/min/k Pa or SI units. And a ratio of the expected normal value.

DLCO is reduced in pulmonary emphysema, pulmonary fibrosis, loss of lung tissue from lung surgery, or other diseases. Also, damage to the pulmonary capillaries from platelet microthrombi, Pulmonary embolism, poison gases, radiation, etc.

Very Useful gadgets developed from PFT.

Peak Flow Meter.

A peak flow meter is easy to use, and the inexpensive gadget is an integral part of asthma management.

A maker on a tube records the highest flow generated with forceful expiration. A sudden fall in the Peak Flow indicates fatigue is setting in, a sustained asthma attack - also called Status Asthmaticus. Patients are well coached to seek medical attention right away.

Vitalograph.

A simple vital capacity measuring device uses a rubber bag to collect expired air and a pen records the volume and flow rates on graph paper. Patients with neurological conditions like Guillain-Barré syndrome, ascending paralysis, or ALS and their caregivers are taught to use the gadget and call their doctors when they detect deterioration. The use of these devices prevents time intervention and avoids ER trips.

Volumetric Incentive Spirometer.

This device is a simpler gadget than a vitalograph, but basically performs the same function.

edited: June 2025.

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Diabetes Mellitus and Microvascular Changes.

                                 Diabetes Mellitus Causing Microvascular Changes

                                          PKGhatak, MD

Diabetes mellitus is a disease that lasts a lifetime. People with diabetes follow their fasting blood sugars and some also understand the value of HbA1c in the management of diabetes. However, a silent killer is working incessantly and burning away the smallest arterial branches like a smoldering brush fire. This killer is called Microvascular complications of diabetes.

Diabetes is actually of two types. Type I diabetes is due to a complete lack of Insulin. Type II diabetes is much more complex to categorize in one sentence. There are several reasons why a person develops diabetes in adult life; some due to insulin resistance, others the presence of insulin antibodies, and still there are more causes. But no matter which one is responsible for diabetes, in the long run, diabetics are at risk of developing one or more organ damages, which may happen in 50% of cases. It may result in visual impairment, renal failure, peripheral neuritis, skin ulcers and loss of a foot, heart disease and many other diseases.

Pathological changes in organs from diabetes are well described, but the way the changes happen is still not fully understood. Scientists experiment on lab animals, usually on mice, and not all their findings are squarely applicable to humans.

Blood sugar is Glucose. Besides blood glucose, the liver and muscles store glucose in a different chemical form called glycogen. The liver also turns excess fat and some amino acids into glucose. The heart uses glucose for energy and also uses fatty acids and ketones for the same purpose.

The blood sugar is kept between 80 to 100 mg in a fasting state by the interactions of several hormones. The chief among them is Insulin. Insulin combines with certain components of the cell membrane and makes a passage for glucose molecules to enter the interior of cells. The glucose molecule goes to the mitochondria where the oxygen molecule reacts with glucose to release energy.

Like anything in excess, an excess amount does not always bring happiness, excess sugar has a dark secret. It burns the tissue, slowly and steadily.

In the biological system, all chemical reactions are the results of enzyme actions similar to Catalysts in chemical reactions. In diabetes, due to high blood glucose, the Superoxide, Sorbitol and Glycation of the substrate are overproduced. These substances are responsible for the thickening of the basement membrane, increased endothelial permeability, extravascular protein deposition and coagulation.

The microvascular changes in the eyes can be observed under direct vision with an Ophthalmoscope and so it is well documented but similar changes are also happening in other organs but the severity varies from individual to individual. In addition to the eyes, kidneys, Peripheral nerves, autonomic nerves the heart and skeletal muscles are affected.

Researchers have identified multiple biochemical pathways through which microvascular changes take place. The important ones among them are Protein Kinase C (PKC), Mitogen Activated Protein Kinase (MAPK), Diacylglycerol Kinase (DAG), Activated Protein Kinase (AMPK), Polyop pathway, and non-enzymatic Glycation End Products (GEPs), Kallikrein-Bradykinin system, Renin-Angiotensin system, and others. Hypertension acts as an accelerator of change.

PKC.

PKC is a family of closely related enzymes active with messenger calcium ions and DAG. PKC upregulates the Endothelial Growth Factor (EGF) through NADPH (nucleotide adenosine dehydrophosphatase hydrogen). The final result is the increased production of endothelin I, Vascular endothelial growth factor and connective tissue growth factor IV. The functional alterations are endothelial leaks, increased vascular permeability, angiogenesis, cell growth, and apoptosis. And deregulation of cellular functions, dilation of small vessels, extracellular matrix expansion, and altered fatty acid metabolism.

MAPK.

MAPK is involved in the direct cellular response to mitogen, osmotic stress, gene expression, cell differentiation, mitosis, and cell survival.

DGK

DGK is an enzyme family, used in the phosphorylation of diacylglycerol (DG) and transforming it to phosphatidic acid (PA). Both DG and PA are important signal molecules.

AMPK.

AMPK acts as a master switch regulating glucose and fatty acid metabolism. It is capable of sensing energy needs. It is activated by skeletal muscle contraction and cardiac ischemia. In the liver, it enhances fatty acid oxidation and decreases the production of glucose, cholesterol and triglycerides.

NAD/NADH and NADP/NADPH systems.

These are coenzymes, which act as hydrogen ions and electron donors and receivers. NADP/NADPH is issued in anabolic (formation of new products) reactions and NAD/NADH is active in catabolic reactions.

Dextrose Monophosphate Shunt.

This is an alternate but parallel path through which glucose is utilized to 5-carbon pentose sugars. As the pentose is metabolized it generates Ribose and deoxyribose used in nucleoprotein synthesis.

Polyol / Sorbitol Pathway.

In diabetes, the hyperactive stage of this pathway leads to the accumulation of NADPH and reduced glutathione, which are responsible for the overproduction of collagen fibers.

In diabetes, the above enzyme systems are overactive. The consequence is the following - Cell signaling dysfunction. Toxic AGE, Oxidants and Methyl glycol accumulation in the tissues. Altered osmols and redox potentials.

These are stressful situations within the cells and the response is manifested by the release of inflammatory cytokines and leukotrienes, decreased Insulin effectiveness, Kallikrein-Bradykinin activation. The end results are vascular changes of diabetes.

Organ changes in Diabetes mellitus.

Kidneys.

The initial change is the expansion of the mesangium and increased matrix production. The thickening of the basement membrane of the glomeruli is the result of it. Glomerular sclerosis and hyalinization of glomeruli lead to glomerular atrophy and hypertension and renal insufficiency.

Eyes.

Retinal changes are observable by an ophthalmoscope or retinoscope.

Micro aneurysm formation, retinal flame shaped hemorrhage, exudate and arterial atrophy, and macular edema are usually in various combinations in individual cases. This is the primary cause of visual loss and blindness.

Nervous system

The central, peripheral and autonomic nervous systems are affected in diabetes.

The changes are in the tiny arterioles supplying blood to the nervous tissues. Lack of oxygen and nutrients break down myelin sheath and in advanced cases, the axon is also damaged.

Cranial nerve palsy leads to double vision, and paralysis of the lateral rectus muscle is seen. The long peripheral nerves supplying the toes and fingers are the first to suffer damage. Loss of pain, touch and vibration sensations are lost initially, then temperature sensations. Muscle weakness may develop due to motor nerve palsy. Neuritis pain in the legs is distressing for patients. Skin cuts and bruises and cigarette burns produce chronic ulcers and ultimately may end up requiring an amputation. Autonomic nervous system involvement produces impotence in men and postural hypotension. Nonspecific Gastric and intestinal symptoms may occur, and some also develop bladder and bowel evacuation difficulties.

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The changes in the heart, muscles and pancreas, liver and other organs can be found in previous blogs.

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Extragonadal Germinal Cell Tumors

 

                                 Primary Extragonadal Germinal Cell Tumors

                                      PKGhatak, MD

Primary extragonadal germinal cell tumors.

The germinal cell produces sperm or an ovum. Under normal circumstances, the germinal cells are present only in the gonads (Testicles and Ovaries).

In a rare embryonic mishap, the germinal cells are present in the Pineal gland, Mediastinum and Retroperitoneal areas. Germinal cells in these locations may turn into tumors, both benign and malignant tumors.

A short review of the origin of germinal cells is essential in understanding these aberrant locations of the germinal cells.

Gonads and germinal cells have separate lines of origin. Gonads are mesodermal tissues, whereas germinal cells originate in the Yolk Sac of the developing embryo. At 5 weeks the germinal cells leave the yolk sac and migrate to the developing fetus, and travel along the Allantois behind the hindgut, behind the peritoneum and move all the way to the developing neural tube which later develops into the brain. Most of the germinal cells migrate to the genital ridge and lodge in the gonadal tissue, the rest of the germinal cells disappear.

The allantois is a narrow tube through which placental blood vessels run to and from the fetus and placenta. The fetus and extra fetal tissues (yolk sac) lie submerged in amniotic fluid in the amnion sac, the membrane of the sac is called the coelomic epithelium.

Due to developmental errors, a few germinal cells remain in the brain, mediastinum and retroperitoneal tissues. Tumors that develop at these locations are called extragonadal (non-gonadal) germinal cell tumors.

Histopathological Types.

Germ cell tumors in unusual locations may be benign or malignant. The benign tumors are called teratomas.

Teratoma.

The germ cells are endowed with the power to produce any or all cell lines and are progenitors of the Totipotent stem cells. In teratomas, this characteristic is maintained, as a result, the teratomas contain hair, teeth, nails, sweat glands and other tissues. Tumors are generally multicyclic. In males, the tumor, though benign by the pathological criteria but behaves like a malignant tumor. Teratomas are diverse in histology and also vary in biological behavior. In women, teratomas are benign multicyclic tumors containing hairs, teeth, nails, glands, bone and cartilage. 

Malignant germinal tumors.

The tumors are mixed cell types but one cell line dominates and is named accordingly. The usual varieties are Embryonal cell carcinoma, Choriocarcinoma. Yolk cell Carcinoma, and Seminoma.

Location of tumors.

Germinal cell tumors are midline tumors. In the brain, the usual site is the pineal gland and occasionally appears in the Pituitary gland. In the mediastinum, they are in the anterior mediastinum in between the lungs and behind the thymus gland. The abdominal site is usually in the sacrum behind the hindgut and peritoneum.

Pineal gland germinal cell tumors.

These tumors are generally malignant. Symptoms are of three categories. A growing tumor increases cerebrospinal fluid pressure and produces headaches, nausea, vomiting, and the 6^th cranial nerve palsy. Local infiltration of tumor-cerebellar dysfunction affects balance and walking. The hormone of the pineal gland is Melatonin. Disruption of melatonin production results in sleep rhythm change, and difficulty falling asleep.

The malignant tumors secrete Chorionic gonadotropin and Alpha fetoprotein. The blood levels of these two are elevated in nearly all cases and in 1/3 of cases the CSF levels are also high. It is well known that in raised CSF pressure situation, the spinal tap is contraindicated; in this circumstance, the CSF is obtained by the 4^th ventricle puncture. Blood chorionic gonadotropin is not specific for gonadal cell tumors, it is elevated in pregnancy and pregnancy related complications and in menopause. Alpha fetoprotein is also elevated in hepatic cell carcinoma and neonatal hepatitis. High chorionic gonadotropin and alpha fetoprotein in addition to an MRI of the brain suggestive of a pineal growth, in non-pregnant women, is as good as biopsy confirmed pineal germinal cell tumors.

In gonadal cell tumors of the brain, after the initial diagnosis, surgery is essential first step,no matter wheather the tumor is benign or not. Biopsy of pineal gland tumors is reserved for tumor recurrence. At that time cell types help to direct more specific chemotherapy agents and additional surgery.

Mediastinal germinal cell tumors.

Germinal cell tumors are the second most mediastinal malignant tumors in childhood. Teratomas do not elevate blood fetoprotein and chorionic gonadotropin.

Chest x-ray detects tumors, and most patients are asymptomatic at the time of diagnosis. Biopsy of the tumor can be safely performed by the retrosternal approach. At times teratomas are detected in the thymus gland, rather than behind it.

Symptoms vary from asymptomatic to obstructive symptoms of the trachea, bronchi, and blood vessels of the mediastinum. Treatment is surgery, and chemotherapy and radiation are added if the tumors are malignant. In certain circumstances, chemotherapy and radiation are followed by surgery.

Ovarian germinal cell tumors are mostly benign cystic. The testicular germinal cell tumors are generally malignant seminoma and non-seminoma, appearing in equal frequency. Testicular malignant tumors do not secrete chorionic gonadotropin and alpha fetoprotein.

Retroperitoneal germinal cell tumors are generally benign teratomas. And carry the best prognosis of the three locations.

Extragonadal germinal cell tumors are rare. Tumors are seen in children and young adults. Except for the sacral location, most of the tumors are either malignant or potentially malignant. Intracranial germinal cell tumors pose a diagnostic challenge but blood and CSF markers along with MRI images are virtually diagnostic.

The prognosis of sacral tumors is the best. Mediastinal seminomas have a better prognosis than Non seminomas. Overall, the 5- year survival rate is between 40 to 90 %.

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Hearing in Old Age.

                                                      Hearing in Old Age

                                               PKGhatak, MD

If one has passed 65 years of age, and for the first time hears someone telling he/she is short of hearing. The person feels a bit startled and annoyed. But the same person did not feel the same way when they had to get a pair of reading glasses. Dealing with the deficit in hearing is different due to social stigmata. And wearing a hearing aid is a no-no.

The Latin term for old age hearing deficiency is Presbycusis. In the USA, one in three are over the age of 65 yrs. and nearly one in two over 75 yrs. has difficulty in hearing.

Persistent exposure to loud noise damages the delicate hearing organ and results in selective deafness for the frequency of sound overexposed to and once th hearing organ is damaged it fails to grow back.

 In normal conversation, the sound waves are like ripples on a slow flowing stream, the noise in the work environment is like winds in winter storms, and the noise that hits the ears in a live concert is like tsunami waves. The delicate hearing organs are not designed for mega loudspeakers and music synthesizers and the sound receptors simply wither away.

A short account of the hearing should make this clear.

The receptors of sound are called the Organ of Corti. The Organ of Corti is located in the inner ear called the Cochlea because it resembles a snail. Inside the bony cochlea, all along the entire length, there is another canal made of the membrane. Both the bony and membranous canals are filled with fluids, however, the fluids of the two canals are different in composition. The fluid of the bony canal is called Perilymph and has a high concentration of Sodium, the fluid in the membranous canal is called Endolymph, which has higher Potassium levels.

Organ of Corti.

On the base layer of the membranous canal called the Basement Membrane, several groups of Hair Cells are situated on it. The hair cells are arranged in 4 layers of cells and bunched together in groups. A nerve fiber is attached to the lower pole of each hair cell. The tall hair cells have cilia like projections on the top, which are in close proximity to the in the top layer of the membranous canal. When the basement membrane moves up and down, the hair bends and pores on the cilia open and Potassium from the endolymph enters the hair calles and inintiate an elctrical signal.  The electrical signal is caries to the hearing center in the brain. 

The hair cells at the beginning of the canal respond to high frequency sounds and the hair cells on the middle section of the spiral canal respond to lower frequency sounds. And in between the hair cells respond to sound from high to low frequencies.

The three outer layers of hair cells receive signals from the brain and function as sound amplifiers to the outgoing impulse to the brain like transistors in radios.

The tension of the basement membrane has regional variation based on the thickness and composition of tissues. The region of the high tension area of the basement membrane vibrates to high frequency sounds and the low frequency sounds move the low tension area.

Functions of the other parts of the ear.

The outer ear, the pinna, collects sound waves, concentrates the sound waves and sends them down the ear canal. The eardrum vibrates and the vibration is transmitted to the three small bones and fianlly the sound is tranmitted to the perilymph by the stirrup-like tiny piece on the Oval Window. and tissues around the bone make the joint airtight. Since the surface area of the oval window is 1/20th of the eardrum, the sound wave is magnified 20 times at the oval window.  The movement of the perilymph moves the endolymph in the membranous canal. As the endolymph moves, the basement membrane moves up and down generating nerve impulses. The 3 turns of the cochlea with progressive narrowing, amplify sounds further as the sound waves move to the far end of the cochlea.

The cause of hearing loss in the elderly.

Like any organ, age takes its toll, but misuse and abuse accelerate the degenerative changes leading to loss of function. And in this modern age, humans are surrounded by air pollution, water pollution, light and sound pollution. The OSA regulations aim to protect the employees but the compliance is not universal and is particularly true for companies with seasonal employees and mom and pop shops. And those weekend homeowners using lawnmowers, chain saws or leaf-blowers are likely to have a hearing deficit.

Genes are blamed for most maladies and so are presbycusis also. But the blame lies squarely on misuse.

The deficit due to presbycusis is detected on both ears. In an acquired illness, deafness may also be unilateral.

The world around us:

Plants.

Some claim plants can hear us. Talking to them, which makes plants grow healthier and faster. But plants have no nervous system at all. So, it is up to future scientists to find that truth.

The unicellular organism onward up to the worm:

The perception of sound in these organisms is through the surface in contact with the environment. The worms have nerve innervation of the segmental body, the nerve ends detect ground vibrations.

Insects:

The majority of insects can hear. An insect's so-called ear is an open tube, the opening of the tube is covered with overlapping cuticles. The location of sound receptors varies from one species to the other. It can be located in the abdomen, thorax, or head. Insects can hear a wide range of sounds.

Amphibians:

Salamander has primitive hearing organs inside the head and a tiny opening, one on each side admitting sound waves to the inner ear.  Frogs can hear in water and on land.

Fish:

Fish have the most elaborate hearing system. Fish have well developed inner ears on each side of the head. In addition, the lateral line of fish has nerves connected with receptors called cilia. Cilia move with the vibration of water. In some fish, the swim bladder has projections reaching the inner ears and act as sound receptors. The head of some bony fish acts as a receptor of wave movement. In some bony fish, the pectoral fin bones function as additional water vibration receptors. Fish, being underwater animals, hear only low frequency sounds.

Reptiles:

Snakes.  Snakes have no external or middle ears but have well developed internal ears. A special bone in the head connected with other bones by ligaments acts as the sound receiver. Snakes also feel ground vibrations with the body.

Lizards have the middle and inner ears but not the external ear. Ground burrowing lizards have a hearing system like snakes.

Birds:

Birds have ears, but not the pinna. The outside opening of the external canal is covered with special feathers without any burs. In vultures and condors, the external ear openings are easily visible. Songbirds have a wide range of hearing.

Mammals:

Whales and dolphins used to be land mammals, later they went back to the water. The pinna of aquatic mammals has disappeared, and the ear canals are filled with either wax or oil to prevent water entry but conduct water vibration well. Water being dense and not easily compressible, the sounds travel far and wide.

Dolphins can hear in water and out of water. In water, they hear through the vibration receptors of the lower jaw bone. When out of the water, the dolphins hear like land animals, the air enters the ears through two small openings on the side of the head. In addition, dolphins have an echolocation box on the head, a specialized receptor for ultrasonic sounds, and as the ultrasounds are received, the dolphins reconstitute the ultrasound in the form of images of the prey and the immediate surroundings.

Whales:

Baleen whales (toothless) have two small external openings for the ear canal and the canal is filled with wax. The inner hearing organ is like land animals.

Toothed whales have no openings for their ears. They have a specialized structure on the lower jaw bone which acts as a receiver of sound waves. Whales can hear from very long distances but only low frequency sounds.

Land animals.

Dogs: Dog is the hearing champion among territorial mammals. A dog can move pinna in any direction by using some of the 30 muscles. A dog's hearing range is 20 to 40,000 cycles per second (Hertz); far beyond the human hearing range of 20 to 4,000 Hertz.

A look at the range of hearing of some animals.

Moth – up to 300,000 Hertz

Bullfrog - 50 – 4,000 Hertz

Owl – 200 – 12,000 Hertz

Songbird - 1000 – 8000 Hertz

Dolphin - 75 – 15,000 Hertz

Beluga whale -1000 -12,000 Hertz

Human - 64 – 23,000 Hertz

Dog - 20 – 45,000 Hertz.

The champion of hearing is the Moth.

Presbycusis comes with old age but by using ear covers in a loud, noisy environment, the hearing deficit can be delayed, or completely prevented.

Edited: January 2026

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