Near Drowning

                                                            Near Drowning

                                                   PKGhatak, MD

Some drowning victims are rescued in time and revived by cardiopulmonary resuscitation (CPR). They are designated as Near Drowning.

  The World Health Organization reported 236,000 drowning deaths in 2019. Drowning is the 3rd leading cause of accidental death in the world. Many believe that the number is actually over 500,000 because of a lack of information from less developed countries.

  Submersion is when the upper airways are underneath the liquid, cutting off the air supply. Immersion is when the body is underneath the liquid and the upper airways are above the liquid, maintaining an open path for air to reach the lungs. Both submersion and immersion generate several changes in the body, some are reflexes, others are biochemical and pathophysiological. Biological changes due to submersion are discussed here.

 Near Drowning may take place in warm water or cold water. The effects of water temperature have profound effects on the body.

 Diving Reflex.

 In submersion, the air is cut off, which triggers a reflex attempt to breathe and as a result, a small amount of water enters the airway. This produces laryngospasm and the glottis is blocked, and further water entry into the lungs is prevented. The breath holding continues as long as the face is completely underwater. Subsequent events differ between warm water submersion and cold water submersion.

 This reflex action involves the following cranial nerves: Trigeminal, Vagus, and Glossopharyngeal. Some fibers of the vagus nerve also supply the heart, and Sympathetic alpha fibers similarly innervate the heart.

  Warm water submersion produces vasodilatation and hypotension, which result in sinus tachycardia and tachypnea.

 Coldwater submersion produces vasoconstriction and bradycardia, increases peripheral vascular resistance, reduces blood flow to muscles, resulting in low oxygen and high carbon dioxide blood levels, causing proportionally increased blood flow to the brain.

 The respiratory center is situated in the brain stem. It produces breath withholding as long as submersion continues. The aortic and carotid bodies monitor hypoxia and produce vasoconstriction by alpha1 sympathetic nerves.

 Continued submersion produces cerebral anoxia, in spite of increased blood flow, and anoxia in vital neuronal centers results in the relaxation of muscles of the larynx and glottis, followed by water entry into the stomach and to the lungs. Underwater seizures may take place. Anorexic cerebral function loss can be extensive; some are reversible, others are not.

  Other injuries and effects of water submersion.

 Shallow water diving can produce fractures of cervical vertebrae, skull, and ribs. Weeds and other vegetation may enter the mouth and throat. Fresh water in the lung alveoli washes away surfactant and leads to atelectasis. Saltwater pulls water from capillaries due to higher osmotic pressure and then destroys the surfactant. Atelectasis causes a mismatch of ventilation and circulation and increases intrapulmonary shunt. In general, about 100 to 200 ml of water enters the lungs. That much water does not increase blood volume or electrolyte imbalance as previously thought, nor does significant hemolysis take place.

 Hypothermia is common. The core body temperature depends on the water temperature and duration of submersion. Effects on the heart in cold water submersion are sinus bradycardia, A-V nodal block, atrial tachycardia, and atrial fibrillation, but ventricular arrhythmias are less common. The cardiac arrest can happen.

 Bacteria, viruses, and parasites are usually found in lakes and tanks. Various infections should be anticipated. Aspiration of gastric content happens during or after resuscitation and produces anaerobic pneumonia.

 Non-Cardiac Pulmonary Edema: 

In saltwater drowning, hypertonic water draws water out of pulmonary capillaries and disrupts the endothelial cells of the alveolar capillaries. Plasma enters the alveolar space and pulmonary edema develops. The amount of seawater of 3 to 4 ml /Kg body weight can produce pulmonary edema,

 Cardiac collapse may develop after the initial rescue and revived by cardiopulmonary resuscitation (CPR). In deep water drowning, water pressure around the thorax increases cardiac output. CPR increases cardiac output further, causing cardiovascular collapse.

 CPR in Near Drowning is different from CPR for heart attack victims. The primary goal of CRP in Near Drowning is to correct hypoxemia as fast as possible and then correct other abnormalities, deliberately paced and not so fast, be vigilant and monitor the victim continuously. 

 The Red Cross publicizes CPR instructions for the general public and provides advanced training for first responders. CPR should be started as soon as the victim is brought to shallow water or on land by the rescuer and then call for additional help.

 No attempt should be made to drain water from the stomach. Those maneuvers only promote aspiration. Use of the defibrillator should be delayed because the carotid pulse is difficult to palpate on the cold and clammy skin of the victims. Without an ECG (EKG) confirmation, no attempt should be made to diagnose asystole or VF (ventricular fibrillation). Moreover, the chilled heart does not respond properly to external electric shocks applied.  Wet clothing should be removed and the body should be wrapped in a warm blanket.

 Warming the victim should only be done in hospitals equipped with extracorporeal heating and extrapulmonary membrane oxygenation facilities.

 All Near Drowning victims should be admitted to the hospital. Correcting hypoxia, hypercarbia, and acidosis in the presence of cerebral anoxia calls for Pulmonary / Critical care specialists. One should not use PEEP (positive end-expiratory pressure) without the input of PCWP (pulmonary capillary wedge pressure). Significant cerebral dysfunctions should be anticipated and addressed promptly and may require rehabilitation services upon discharge. Convulsion, hypoxia. Cerebral anoxia, hypotension, cardiac arrhythmia, pneumonia, and noncardiac pulmonary edema should be treated properly.

edited: June 2025.

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Spit Sputum Phlegm

                                                                 Sputum

                                                    PKGhatak, MD

Sputum is another name for spit. The word sputum is derived from Latin Spuere. The aristocratic name of spit is Phlegm. That word is derived from the Greek word Phlegein. The old French language modified it to Flume, the old English named it Fleem and finally modern English is Phlegm.

In India Phlegm is the answer to a trivia question - what is that substance that the poor discard it indiscriminately and the rich carefully save it in between the folds of monogrammed handkerchief and tuck it carefully in their pocket/purse.

When all the humor is removed, the sputum is made up of mostly water, a bit of mucin, and 1 % salt. Mucin is secreted by the Goblet cells of the respiratory tract. Chemically mucin is a polymer of glycoproteins. Mucin has a complex structure. The core is composed of structurally strong protein molecules composed of amino acids serine, proline, and threonine and the core protein is bonded to various oligosaccharides by O-glycosidic linkages. Then the pattern is repeated several times, the sequence of which is highly variable in length and amino acid composition.  90 % of mucin is carbohydrate. Mucin is highly hygroscopic and keeps particulate matter and microorganisms wrapped up tightly. In addition, the sputum contains a few shredded epithelial cells, WBCs, lysosomes, IgA antibodies, lactoferrin and usual respiratory and oral flora.

For the medical profession, the sputum is nothing to sneer about. Whatever is responsible for a disease of the lung, sooner or later it has to come out dead or alive, with the sputum. Naturally, the sputum examination provides a direct clue of an illness and is also used to monitor the progress of the disease.

Let's look at the sputum.

Generally, sputum is collected in the morning. The patient is instructed to rinse their mouth with water, then cough vigorously for several minutes and collect sputum in a sterile container provided by the lab. The sputum should contain secretion from deep inside the lung and not saliva. If the sample contains only a few WBCs and more than 20 epithelial cells per low power field, the lab rejects the specimen and marks "inadequate sample" and requests resubmission. In some lung diseases, the patient can hardly raise the sputum. To facilitate sputum collection, inhalation of nebulized 3% saline is used, at times assisted by chest percussion with cupped hands. If that fails, the samples are obtained at a bronchoscopic examination.

Sputum is examined for color, smell, amount, consistency, frothiness, foaminess, cellular debris, crystals, malignant cells, microorganisms, parasites, fungal spores, and filaments, amoeba. Then smears are made, properly stained and examined under a microscope to identify microorganisms.  Cultures are planted on proper media for bacteria and fungi. Special methods are used for malignant cells to obtain a better yield. Sputum is handled separately for tuberculosis. Alkaline digestion of the gastric aspirate sample was then centrifuged. The sediment is used for culture. Sputum from gastric content is another source in patients who are unable to raise sputum as in young children and unconscious patients.

Color of sputum and its significance:

The primary reason for sputum examination is an infection of the lungs, other important reasons are hemoptysis and lung cancer. Bacterial pneumonia produces thick yellow-green sputum; the green color is due to the presence of myeloperoxidase and the yellow color is from degenerated neutrophils.  Bloody sputum is due to hemorrhage in the lung. (see the section on hemoptysis blog).  Red jelly like sputum is from Klebsiella pneumonia.  Blood streaking sputum is generally due to cancer of the lung. Rusty color is from Pneumococcal pneumonia.  The brown color is from Cancer of the lung and tuberculosis.  Grayish white is from dehydration.  Pink frothy sputum is due to acute pulmonary edema.  White, opaque and scanty sputum is from asthma.  Green sputum is from Pseudomonas pneumonia. Black sputum is common in coal miners' pneumoconiosis, Aspergillus niger infection.   

Smell of sputum:

The putrid smell is associated with the breakdown of tissues from bacterial enzymes releasing gases containing hydrogen sulfide, aromatic compounds, aldehydes, and ketones.   Foul smelling sputum is from anaerobic bacterial infection, usually from a lung abscess, however, infection by an anaerobe from the gum to the lung generates a foul odor.   The wet fur smell is from Hemophilus influenza pneumonia.   The acrid smell from Bacteroides fragilis.  The burnt chocolate smell from Proteus mirabilis pneumonia. Some other Proteus species can produce an odor of rotten fish.  Dirty sneaker smell from Citrobacter.  The fecal odor from Pepto streptococcal infection. Pneumonia caused by Bacteroides, Proteus, and Peptostreptococcal is rare and seen in immunocompromised patients.   The buttery smell is from Streptococcal viridans infection.  The musty odor from Streptomyces.  The sweet fruity odor from Pseudomonas aeruginosa pneumonia.

Amount of sputum:

COPD patients with pneumonia can produce 100 to 200 ml sputum. Bronchiectasis, in general, produces over 150 ml of sputum a day. Patients with acute left ventricular failure can produce over 150ml of pink frothy sputum. In asthma and in pure pulmonary emphysema only a small amount of sputum is raised.

Consistency:

Watery sputum is just saliva. In a single nodular lesion due to suspected cancer or tuberculosis, no sputum may be generated and collected specimens are watery. Thick yellow sputum indicates bacterial pneumonia, and viral pneumonia can produce light yellow green sputum. Foamy sputum is from air bubbles trapped in the sputum, commonly seen in COPD. White frothy or pink frothy sputum in pulmonary edema. Thick sticky sputum is from Cystic fibrosis. Chocolate mousse sputum from ruptured amoebic liver abscess through the lung.

Parasites in sputum:

Ascaris lumbricoidis is usually coughed up alive and found wiggling in a sputum cup.

Strongyloides stercorales larvae, and hookworm larvae are also seen in heavy infestations.

Parasitic ova:  Paragonimus westernanii eggs are a common finding in that fluke infection of the lung. 

 Schistosoma eggs are occasionally coughed up in liver cirrhosis when a hepatopulmonary shunt is formed.

Entamoeba histolytica in sputum is seen in cases where amoeba invades the lung from the liver through adhesion.

Fungal Filaments:

Pneumonia from Aspergillus fumigatus, Candida albicans, Actinomycetes israeli, Nocardia (previously grouped with bacteria Actinomyces) cases, sputum contains fungal filaments.

Fungal yeast form: All dimorphic fungi are recovered in the sputum of disseminated infection. These fungi are Histoplasma capsulatum, Blastomycoses brazilianus, Coccidioides immitis, Sporothrix schenkii.

Fungal spores are seen in Candida, Cryptococcus, and Pneumocystis jirovecii lung infection.

Crystal in sputum: Calcium oxalate crystals are a hallmark in Aspergillus pulmonary infiltrative disease. The byproduct of growing Aspergillus is oxalic acid, which combines with serum calcium to form crystals. Charcot Leyden crystals are formed from degenerated eosinophils seen in asthmatics. Curchmann's spirals are coiled basophilic mucinous fibrils seen also in asthmatics.

Foreign Bodies:  

Foreign bodies are seen in coughed up sputum due to aspiration of food and drinks. Vegetable matter is often removed by bronchoscopy. Two groups are most susceptible to aspiration - young children and nursing home patients with bulbar palsy, stroke with dysphagia, and neurogenerative diseases. Uncommon objects found in the sputum are - broken toy pieces, magnets, glass beads, buttons, pennies, pins, small nails, partial dentures, small fruit seeds, decayed teeth, surgical sutures, hard candies, and others.

Distinctive features of Cystic fibrosis sputum are very sticky, green, and fruity in smell. In the case of bronchiectasis, the collected sputum separates into three layers, the bottom layer is the necrotic tissues, the clear middle layer and the top foamy layer.

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Noncardiac Pulmonary Edema.

                                      Noncardiac pulmonary edema (NCPE)

                                       PKGhatak, MD

Pulmonary Edema is an acute illness due to fluid accumulation in inter-alveolar connective tissues and in the alveolar spaces of the lung. The most common cause of acute pulmonary edema is Left Ventricular failure from a massive left ventricular infarction. However, pulmonary edema also happens from other than an acute left ventricular failure. These conditions are called Noncardiac Pulmonary Edema (NCPE)

NCPE: 

The basic mechanism of NCPE is alveolar capillary leak. There are various reasons or conditions leading to capillary leak producing pulmonary edema. The characteristic features of NCPE are that the pulmonary capillary wedge pressure (PCWP) and PAP (pulmonary artery pressure) remain normal or low, and the ratio of protein in pulmonary edema fluid and serum protein is over 0.7.

Common causes of NCPE.

 1.Covid-19 induced cytokine storm. 2. Adult respiratory distress syndrome (ARDS) resulting from gastric aspiration, pancreatitis, sepsis, open chest cardiac surgery, chest trauma, drug overdose. 3. Pulmonary embolism. 4. Neurogenic - seizures, Brain surgery, subarachnoid hemorrhage, meningitis. 5. Narcotic overdose. 6. High altitude pulmonary edema (HAPE). 6. Toxic gas inhalation, Thermal injury to lungs in open flame fire incidences. 7. Salicylate intoxication. 8. Transfusion related acute lung injury (TRALI) 8. Near drowning. 

Other causes of NCPE: - Reperfusion and re-expansion pulmonary edema. Fluid overload. Post obstructive. Following the lung transplant. Drug reaction and hypersensitivity reaction. Exercise induced. Air embolism.

Diagnosis.

When a patient presents with acute respiratory distress, coughing up pink frothy sputum, extreme anxiety and altered consciousness with signs of overworked muscles of respiration, central cyanosis, moist rales on auscultation, various degrees of shock, the diagnosis of Pulmonary edema is not difficult. Low oxygen saturation in digital oximetry, X-ray shows no cardiac enlargement, no dilatation of major branches of the pulmonary artery. Bilateral peripheral symmetrical " batwing" opacities, the diagnosis is made. ECG will show no right/left ventricular strain, hypertrophy or major arrhythmia. Rarely fluid/serum protein ratio or PCWP are required for the diagnosis of NCPE. The history of the illness will clearly point toward the cause.

The newer Ultrasound devices can detect septal edema, and thickened minor fissures in NCPE are reported as B lines. The B lines are artifacts generated by reverberations of sound waves and appear generally in a group of three, separated by 7 mm one group from the next group.

Treatment.

Immediate oxygen therapy is instituted by the first responders, then proper oxygenation has maintained by any means, and when respiratory failure is also present noninvasive or invasive mechanical ventilation is instituted.

Other modalities of therapy vary according to the etiology of NCPE.

Prognosis. NCPE outcome is much better than cardiac pulmonary edema.

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Eosinophil and Acute Eosinophilic Pneumonia.

                                        Eosinophil and Eosinophilic Pneumonia

                                             PKGhatak, MD

Eosinophils are white blood cells (WBCs), belong to cellular immunity and are called immunocytes. Eosinophils are strikingly different from the other WBCs.

The cytoplasm of the eosinophil contains many granules, stained red or pink with an acidic dye, Eosin. The name eosinophil means - love eosin. The nucleus of the cell is bi-lobed. The granules contain preformed enzymes, lysosomes, cytokines, prostaglandins, thromboxane. The cells also supply NO, O, H2O2, and OH groups. Cells exhibit amoeboid movement and phagocytic activities. The surface of cells contains various receptors, namely cytokine receptors, active receptors, lipid mediated receptors, pattern recognition receptors, FC fraction immunoglobulin receptors, and adhesion receptors.

In health, the eosinophils are present in the thymus gland, spleen, lymph nodes, entire GI tract with the sole exception of the esophagus, and in the bone marrow and peripheral blood. Eosinophils migrate to tissues when summoned by Interleukin IL-3 and IL-5. They move out of blood vessels by Brownian movement and attach to cells and tissue by adhesion receptors and then release stored chemicals. The chemical paralyzes parasites, stimulates phagocytosis by macrophages, may produce damage to tissues, and participate in inflammation, repair and remodeling and regeneration of organs/ tissues.

In the peripheral blood, the eosinophils count is 2 to 8 % of the total WBC. The actual number is between 500 to 800 per mcL. The life span of eosinophil in the peripheral blood is 2 to 4 days and in the tissues 14 days or longer by the action of interleukin.

Eosinophils produce airway constriction by histamine release from mast cells, increase mucus secretion from goblet cells, and promote the proliferation of intercellular matrix by TGFB.

When the eosinophil count increases over 800 /mcL the condition is known as eosinophilia. In chronic eosinophilic syndrome, the count is over 1,500 /mcL. In chronic eosinophilic leukemia, the count is over 100, 000 /mcL.

Eosinophils are very active in parasitic infestation, allergy, asthma, drug induced allergy, and cancers. There are some special diseases that arise from eosinophil dysfunctions and one of them is Acute eosinophilic pneumonia. 

Acute Eosinophilic Pneumonia:

Acute eosinophilic pneumonia is a rare disease but a serious illness. The illness develops most frequently in young males in 20 to 35 years. of age who are trying to start smoking cigarettes for the first time or have taken up smoking again after a brief period of quitting. Pneumonia once starts rapidly spreads to both lungs and in 4 to 7 days becomes quite extensive. The distinctive features of this rapidly spreading pneumonia are progressive shortness of breath and quick onset of respiratory failure. Blood count shows no increase in eosinophil count.

The pathological picture is of interstitial pneumonia with extensive infiltration of eosinophils. Other features are rapid loss of weight, night sweats, cough and fever.

The cause of the illness is unknown. Various theories are advanced but none are convincing. And no hereditary predisposition is known.

Clinical signs are typical interstitial pneumonia. Diagnosis is based solely on finding a large percentage of eosinophils in the bronchial lavage fluid obtained at the time of bronchoscopy, and/or demonstrating massive eosinophil infiltration of lung parenchyma in the biopsy specimens.

Treatment.

A marked drop in O2 saturation may develop at any time, so monitoring of patients in the ICU is essential and prompt correction of O2 deficiency is needed. Respiratory failure is treated with non-invasive ventilation or intubation and mechanical ventilation. High dose IV steroid shows quick response; 3 to 5 days later IV steroid is switched to the oral route and gradually completely withdrawn. Once recovered from an acute illness, there is no recurrence of pneumonia and the prognosis is excellent.

Acute eosinophilic pneumonia requires to be differentiated from Chronic eosinophilic pneumonia, Churg-Strauss syndrome, Loffler's syndrome and Tropical pulmonary eosinophilia.

Chronic eosinophilic pneumonia is not a disease of the young, the peak incidence is in the 5th decade and both sexes are equally affected. It is chronic and recurrent in nature and often accompanies asthma. Pneumonia does not lead to respiratory failure. Blood count shows high eosinophils in the peripheral blood in contrast to acute eosinophilic pneumonia.

Churg-Struss syndrome is a multisystem eosinophilic vasculitis with granuloma formation. Asthma is often an underlying condition, and blood eosinophil count is high. 50% of cases show the presence of c-ANCA (ANCA= antineutrophilic cytoplasmic antibody).

Loffler's syndrome is recurrent asthmatic episodes due to infiltration of the lungs by eosinophils resulting from larval migration through the lungs. The larvae are Ascaris lumbricoides and also larvae of other parasites. Blood eosinophil count is high.

Tropical eosinophilia is a prevalent disease in coastal areas in India and the Indian subcontinent. Eosinophil count is generally over 3,000 /mcL, serum IgE levels over 1,000 units and a positive filaria antigen test. Symptoms of wheezing, cough and asthma like attacks coincide with the periodic release of microfilaria into the blood by adult filaria worms residing in lymph nodes. The pathological picture varies according to the duration of the disease from simple pulmonary eosinophil infiltrates to pulmonary fibrosis.

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Pulmonary Arterial Hypertension - Basic Science and Rational of Therapeutics.

                                                Pulmonary Hypertension

                                            PKGhatak, MD

There are two separate circulatory systems - the greater and lesser circulatory systems. The greater system consists of the left atrium, left ventricle, aorta and its extensive branches to supply nutrients and oxygen to every living cell. This system is also called the Systemic Circulatory System. The lesser circulatory system consists of the right atrium, right ventricle and pulmonary artery and its branches to the lung alveoli. This is called the Pulmonary Circulatory system and this system delivers carbon dioxide to the lungs for elimination by ventilation and carries fully saturated oxygenated blood to the left atrium.

The circulating blood in the arterial tree exerts lateral pressure on the wall of the blood vessels and must overcome resistive wall pressure to propel forward. This wall resistance is called peripheral vascular resistance. This vascular resistance is commonly called Blood pressure - should be correctly called Systemic BP and Pulmonary BP.

Systemic blood pressure is easily measured on the arm by a BP instrument, either a mercury manometer or indirectly by a digital BP instrument which is properly calibrated. To measure the pulmonary arterial BP, a catheter must be inserted in the subclavian vein or femoral vein, then advanced to the right atrium, right ventricle, to the Pulmonary artery and then record the pulmonary arterial pressure. This invasive procedure is not practical for clinical practice.

In recent years, the Doppler Echocardiography and supplemented by 12 lead ECG, has to a greater extent, made monitoring pulmonary arterial BP much simpler and practical. The normal systemic BP is 120/80mm Hg and the normal pulmonary arterial BP is 20/10 mmHg.

These two circulatory systems are interconnected. The venous return of the systemic circulation comes to the right atrium via the superior vena cava and inferior vena cava. The venous blood from pulmonary circulation returns to the left atrium by pulmonary veins. This means diseases/ conditions of one, eventually, involve the other system.

Two other numbers are important in clinical practice - Mean Arterial Pressure (MAP) and Pulmonary Capillary Wedge Pressure (PCWR). MAP is the tissue perfusion pressure. The PCWR is a good approximation of the left atrial pressure.

MAP is calculated: MAP = (systolic BP /3) + (2x diastolic BP / 3).

The pulmonary artery/capillary wedge pressure is measured by a Swan Ganz catheter. This is obtained by advancing the catheter tip to the distant pulmonary arteriole and then inflating a small balloon to prevent pulmonary artery blood flow temporarily. The normal PCWR is 8 to 10 mm Hg.

In critically ill patients, pulmonary vascular resistance (PVR) is measured several times a day. PVR guides in adjusting fluids and vasopressor therapy, adjustment of ventilator settings, among other therapies. Pulmonary vascular resistance is calculated at the bedside from Swan Ganz catheter values.  Pulmonary artery pressure(PAP), pulmonary artery wedge pressure (PCWP) and cardiac output (CO) are necessary to calculate the PVR. 

 PVR =(PAP - PCWR) / CO.

In clinical medicine, PVR is expressed by using the Wood Unit.  Cardiac output is determined by thermodilution using cold saline. Woods unit is calculated using formula PVR = 80 x (PAP - PCWP) / CO. The normal PVR is 1 wood unit, a 3 Wood Unit is Pulmonary Arterial Hypertension or simply Pulmonary Hypertension.  In PAH the mean pulmonary BP is over 25 mm Hg, and PCWP is over 15mm Hg.

In physics, the Hagen-Poiseuille equation is used to determine the resistance of the tube using a formula R= 8 x L. n. r>4 (>4=raise to the power 4). Where R stands for resistance, L for the length of the tube, n for the viscosity of the fluid, and r for the radius of the tube.  In clinical medicine, the same equation remains valid. Variation of these parameters leads to pulmonary hypertension.

Pathological changes leading to hypertension:

Even a casual look at the Hagen-Poiseuille equation points out that a change in the lumen of the artery leads to a marked increase in BP. Regardless of different causes of PAH, there are common pathological changes in the pulmonary arterioles that produce narrowing of the arteriole lumen, increase PVR, hypertension and consequently right ventricular hypertrophy and cardiac failure and death. Pathological lesions are characterized by enhanced arteriolar smooth muscle contractility, dysfunctional arteriole due to aberrant remodeling of both endothelium and muscle layers and finally the microthrombi in capillaries.

Several of the following pathways are known to alter and result in pulmonary hypertension:

Nitrous oxide (NO) + soluble Guanylate cyclase pathway. The endothelial cells produce NO which binds with guanylate cyclase that produces guanosine triphosphate then transforms to guanosine monophosphate which is a potent vasodilator. It also prevents platelet aggregation and microthrombi.

Prostacyclin + Thromboxane A2 pathway. Prostacyclin is produced by the endothelial cells of arterioles. Prostacyclin binds with surface receptors of the smooth muscle cells, then activates ATP (adenosine triphosphate), and finally becomes cyclic AMP (adenosine monophosphate). AMP is anti-inflammatory and prevents platelet microthrombi.

Endothelin pathway.  Endothelin is a peptide, produced by the cell membrane of endothelial cells. It is a potent vasoconstrictor. Also produce smooth muscle hypertrophy, cell migration and fibrosis.

The reversible Hypoxic pathway.  The sympathetic nerve fibers abundantly supply even the smallest branches of pulmonary arterioles. The system is activated by chemoreceptors located in the carotid and aortic bodies. These receptors monitor PaO2 (partial pressure of oxygen); hypoxia causes reflex vasoconstriction and in prolonged hypoxemia migration of cells in and around arterioles produces fibrosis.

Clinical Classification of PAH:

PAH is categorized into 1. idiopathic, 2. familial, 3. secondary to other diseases, of which the most often are scleroderma and other collagen vascular diseases, HIV infection, portal hypertension, and congestive heart failure. 4. Drug induced and toxins.

Familial cases are due to the mutation of genes, the important gene mutations are: BMPR II, AIK I, ENG, SMAD 9, CAV 1, KCNK 3.

Drugs responsible for PAH are - Aminorex, Fenfluramine, Dexfenfluramine, Rapeseed oil, Benfluorex, several Serotonin reuptake inhibitors (SSRIs). Toxins - Tobacco smoke, chemical solvents.

Therapeutics:

There are no cures for pulmonary hypertension. Medications used for the treatment of systemic BP are ineffective in pulmonary hypertension. Treatment of pulmonary hypertension produces only slowing down the progression of the disease.

The following groups of drugs are used in pulmonary hypertension-

Phosphodiesterase inhibitors. - Sildenafil and Tadalafil.  Adenosine monophosphate and Guanosine monophosphates are converted to cyclic forms (c-AMP & c-GMP) by the action of adenylyl-cyclase and guanylyl-cyclase respectively. Cyclic AMP and cyclic GMP have a multitude of cellular functions including cell proliferation and growth. c-AMP and c-GMP are broken down by Phosphodiesterase. Sildenafil and Tadalafil inhibit the action of diesterase.

Soluble Guanylate cyclase stimulators. - Riociguat.  It increases intracellular cGMP.

Prostacyclin analogs. - Epoprostenol, Treprostinil, Iloprost. Prostacyclin produces smooth muscle relaxation, lowers pulmonary blood pressure, acts as an anti-inflammatory, inhibits platelet microthrombi.

Prostacyclin receptor agonist. - Selexipag. It is a vasodilator and prevents platelet adhesion.

Endothelial receptor antagonist. - Bosentan, Ambrisentan, Macitentan. Endothelin is a vasoconstrictor and increases pulmonary BP. These drugs prevent binding of Endothelin to its receptors and blunt the endothelin actions.

Additional agents used in the treatment of pulmonary hypertension are Oxygen, diuretics, nutrition and pulmonary rehabilitation.

Pulmonary hypertension detection by doppler echocardiogram is very useful for the diagnosis of new cases and monitoring the effects of therapy. More research is needed in pulmonary hypertension and in finding effective and less toxic drugs.

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Pleural Effusion - Cause and Mechanism:

 

                                                              Pleural Effusion

                                                      Mechanism and Causes

                                                    PKGhatak, MD

A small amount of pleural fluid is produced by the parietal pleura (a thin layer covering the inside of the chest wall, diaphragm and hilum), just enough to lubricate both layers of pleura so that during breathing the two surfaces slide smoothly one over the other without friction. The fluid does not accumulate because just as the fluid is produced continuously, the fluid is drained continuously by the lymphatic channels of the parietal pleura. Pleural effusion develops when excess fluid is produced or removal is delayed.

Clinical Types of Pleural Effusion:

It is useful to classify pleural effusion as Transudate and Exudate.

Transudate fluid is thin, has a low protein concentration, low LDH, and has none to two WBCs.

Transudate pleural effusion takes place because the fluid oozes out of the lung alveoli due to high capillary pressure. The most common cause of it is congestive heart failure, Nephrotic syndrome, cirrhosis of the liver, hypoalbuminemia from malabsorption syndrome, protein losing enteropathy and acute left ventricular failure, Pulmonary edema, and massive pulmonary embolism.

Mechanism of Transudate. Like liver nodules, the alveoli of the lung have a dual blood supply. The pulmonary artery brings in venous blood to the alveolar capillary. This is the source of most blood in the lung. In overloaded heart chambers in congestive heart failure, the pressure rises in heart chambers sharply. The back pressure is felt in the capillaries of the alveoli. When the pressure exceeds the oncotic pressure of blood, the water and dissolved solutes leak out in the interalveolar and pleural spaces resulting in pleural transudative pleural effusion.

Mechanism of Exudate: Inflammation of pleura by bacteria, mycobacteria tuberculosis, and fungus is generally due to the extension of lung infection. The pleural fluid is characterized by the presence of over 50% serum albumin concentration and over 60% LDH of the serum. The sugar concentration of the fluid in pneumococcal pleural effusion is low and has a high WBC count. 

Clinical subtypes of pleural effusion.

Empyema. In certain infections, the WBC numbers are so numerous that the pleural fluid becomes white cloudy- called empyema. Common causes of empyema are lung abscess rupturing in the pleural space, infected stab wounds, septicemia, post operative chest wounds. contaminated traumatic chest wall injuries.

Hemorrhagic Pleural Effusion. Traumatic chest wall injuries, contusion, laceration and infarction of the lung produce hemorrhage in the pleural space. Coagulation abnormalities either secondary to medical therapy, thrombocytopenia (platelet count 50,000 or less), deficiencies of coagulation factors or circulating anticoagulants may produce hemorrhagic pleural effusion.

Malignant Pleural Effusion. Malignant tumors of pleura are rather rare, only mesothelioma was an exception. In general, malignant pleural effusion is secondary to known lung malignancy, common in metastatic breast, ovary, colon cancers and primary lung cancer, lymphoma, and leukemias.

Chylous Pleural Effusion. The pleural fluid appears milky due to the presence of chylomicron. Chylomicrons contain long chain fatty acids, cholesterol esters, phospholipids. This condition results from obstruction or laceration of the thoracic duct. Cancer of the apical section of the lung. Pancoast tumors, lymphoma, and tuberculosis and filariasis cause obstruction of the thoracic duct. Fractures of 1st rib, sternum and upper thoracic vertebrae may cause laceration of the thoracic duct.

Bilateral Pleural Effusion. It is due to systemic diseases like CHF, nephrotic syndrome, cirrhosis, etc.

Unilateral Pleural Effusion. Unilateral effusion is due to one sided pleural disease but subsequently may be bilateral, if the disease spread to the other side. Example- pneumonia.

Localized Pleural effusion. The accumulated pleural fluid is walled off by fibrin and coagulated proteins.

Pleural Thickening. In tubercular pleural effusion, if the pleural fluid is not by evacuated by thoracentesis or drug therapy, layers of fibrous tissues are deposited over the surface of the lung like a straitjacket and prevent the expansion of the lung during breathing.

Cryptogenic or Unknown Causes of Pleural effusion. The effusion may start as unilateral or bilateral, and transudate effusion may turn exudate. In long term follow up and repeated pleural biopsies, detect about 10% due to mesothelioma or carcinoma of the lung. The cause of the remaining cases remains unknown.

Chronic Pleural Effusion. This condition is usually associated with end organ failure.

Rare causes of Pleural Effusion.

Meig's syndrome. Pleural effusion and ascites are associated with a benign ovarian tumor.

Ovarian Overstimulation Syndrome. Injectable fertility drugs to generate eggs in ovaries may produce capillary leaks and ascites and pleural effusion may develop.

Post Radiation Therapy also for the same reason produces this complication.

 Allergic drug reactions, Collagen vascular diseases and Autoimmune diseases can cause a mild form of vasculitis and pleural effusion.

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Multiple Myeloma

                                                          Multiple Myeloma

                                                   PKGhatak, MD

Multiple Myeloma (MM) is a cancerous disease of the Plasma cells of the bone marrow. It is a disease of the elderly and the condition is not inherited nor are there any known risk factors; but hepatitis C, HIV infection and Chronic Lymphocytic leukemia (CLL) patients have a higher incidence of MM.

MM is the final stage of a spectrum of plasma cell dyscrasias which starts as monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia to extramedullary myeloma and finally to MM with end organ damages.

Epidemiology:

MM is very rare in people under 35 years. old. The annual incidence of MM in the USA is 300,000/yr. and 12,000 people die from MM. The worldwide incidence of MM is 80,000/yr.  New Zealand and Australia have more MM per 100,000 population. In the USA, the rate is 8.2 in white men, 5.0 in women, 16.5 in black men and 12.0 in black women per 100,000 population. For Hispanic men and women, the rates are 8.2 and 5.7 respectively and the rate for Asian/Pacific islanders at 5.0 in men and 3.2 in women.

Plasma Cell.

                                            Plasma cell..

About 2 to 3% of cells in the normal bone marrow are plasma cells. Plasma cells are large and have an eccentric nucleus, coarse chromatin and large cytoplasm.

In health, the majority of plasma cells are found in the active bone marrow and a few are also found in the spleen, lymph nodes and other tissues. In adults, the most active marrow is located in the vertebrae, scapula, sternum, skull bones, ribs and pelvis. The plasma cells are derived from B-lymphocytes (B-cells). B-cells are activated by a specific foreign antigen, which is introduced to them by the Dendritic cells. Activated B-cells in lymph nodes survive only 4-5 days. Some activated B-cells move to the bone marrow and live for a very long time. Bone marrow plasma cell keeps that antigen memory permanently. When challenged again with the same antigen, they quickly produce IgM antibodies (Immunoglobulin) and 10 days later start making IgG antibodies and keep producing antibodies as long as that antigen remains in the body or is reintroduced at a later time. IgA, IgD, IgE antibodies are also produced by plasma cells in various amounts and based on their location in the tissue/organ.

Effects of Uncontrolled growth of Plasma cells.

Rapidly multiplying plasma cells displace other blood forming cells, and soon the plasma cells number grows to 60 to 80 % of the bone marrow blood forming cells. RBC, WBC and Platelet numbers decrease and anemia, recurrent infection and easy bruising develop. The secretory product of plasma cells is immunoglobulins. In MM the immunoglobulins are abnormal in both structure and amounts. The accumulated immunoglobulin in blood makes blood more viscous and blood circulation in capillaries becomes sluggish, particularly in the retinal vessels, producing retinal hemorrhage and decreased visual acuity. The lambda and kappa light chains of immunoglobulins are excreted in urine, and gradually renal function deteriorates. Bone spicules dissolve and lytic lesions are detected in an x-ray. Blood calcium levels rise in proportion to bone lysis and osteoporosis and high serum calcium usually leads to a serious medical emergency.

Symptoms of MM:

In those days before Google search, medical schools came up with mnemonics to help students memorize certain important symptoms of a disease. CRAB stood for symptoms of MM. C=calcium increase in blood, R= renal function deterioration, A= anemia, B=bone pain. Bone pain is worse at dawn and dusk and increases in intensity with physical activities. Another mnemonic is Poem syndrome. P=peripheral neuropathy, O=organomegaly,  E= endocrinopathy. M=macroglobulin levels. S=skin pigmentation changes.

 Various peripheral nerves are involved, the Liver, and the spleen are enlarged, and many endocrine secretions are suboptimal. Thicken skin, changes in hair growth over the face, chest, limbs, and edema of legs and feet may develop. Other symptoms are weight loss, weakness, fatigue, confusion, and dementia.

Clinical subtypes of MM:

1. Indolent MM - patients are asymptomatic, plasma cells are up 10% or more of the blood cells in the bone marrow. M protein in blood is 3gm/dl. or more.

2. Solitary Plasmacytoma of the bone - a single tumor is present and no symptoms.

3. Extramedullary Plasmacytoma - plasma cell tumors develop in the upper airways, nose, nasal sinuses, larynx, GI tract, breasts and brain.

4. Bence Jones proteinuria or presence of light chains in urine.

5. Nonsecreting Myeloma.

6. Waldenstrom macroglobulinemia. Both B-cells and Plasma cells produce excess Macroglobulin. Various symptoms develop due to high blood viscosity from the excess macroglobulin.

7. Rare IgD and IgE myeloma. IgD myeloma is seen at relatively younger age. IgE myeloma is an aggressive type.

Diagnosis of MM:

A bone marrow biopsy is essential. MM diagnosis is made when the Plasma cell population is over 10%, usually at the time of diagnosis plasma cells are over 50%. Other positive findings are high microglobulin in blood and urine. Bone x-ray show lytic lesions and pancytopenia but these additional findings are not required for the diagnosis of MM.

Staging:

The international staging system categorizes MM into 3 stages based on blood tests:

Stage I. - Serum beta-2 microglobulin over 3.5 mg/L and serum albumin at/ over 3.5 g/dL. 

Stage II. serum levels are between the values of stage I and stage III.

Stage III. - Serum beta-2 microglobulin at or over 5.5 mg/L and high LDH (lactic dehydrogenase).

Revised International staging system (R-ISS):

Stage I. B-2 microglobin  < 3.5mg/L, albumin > 3.5d/L, no cytogenic abnormalities in iFISH (interphase fluorescence in situ hybridization).

Stage III. B-2 microglobin  >3.5 mg/L, High LDH, Presence of iFISH abnormalities. In MM the iFish cytogenic abnormalities are - deletion of 17p and/or t 4;14, and/or t 14;16. (p= short arm of chromosome 17. t=translocation of oncogene at 14;4 location).

Treatment of MM:

The current trend in the treatment of hematological malignancy is to perform Stem Cell Transplantation early. In MM the preferred age for stem cell transplant is below 75 yrs. Two different stem cell transplants are possible in MM. These are Autologous (patient's own stem cells) and Allogenic (HLA matched stem cells from the donors).

Targeted Therapy.

  - Proteasome inhibitor therapy. Proteasome is a protein that clears unused protein molecules from a dividing cell. If that clearing protein is blocked, then the dividing cells are choked with proteins and die. That is the basis of proteasome treatment. Drugs available are Bortezomib, Carfilzomib and Ixazomab.

- Monoclonal antibody therapy (mAb). The commonly use mAbs are Daratumumab for bone pain, Elotuzumab for accelerated killing by phagocytes.

- Histone Deacetylase (HDAC) inhibitors. These drugs block cell division. The available drug is Panobinostat.

- BCL-2 Inhibitor. Helps to kill cancer cells. Drugs available are Veneloclax.

Immunotherapy. Thalidomide accelerates the killing of rapidly dividing malignant cells. Derivatives of thalidomide are more powerful than thalidomide. Available drugs are Lenalidomide and Pomalidomide.

CART Therapy.  Surveillance T-cells have surface receptors by which T-cells attach to the foreign antigen. Because cancer cell antigen closely resembles the normal cell of the body, at times the receptors fail to bind with the cancer antigen. Mutated cancer cells have acquired this strategy and evade detection and death. In the CART therapy laboratory engineered Chimeric Antigen Receptors and T-cells from the patient are incubated together. These special T-cells are made to multiply in the laboratory and later transfused to patients to enhance tumor killing.

Chemotherapy. - A combination of 4 to 6 chemotherapeutic agents is administered in 4 to 6 cycles over 6 months to induce remission. Cyclophosphamide, Doxorubicin and Etoposide are commonly used in MM.

Treatment strategy for MM. - The first step is to induce remission through a combination of immunotherapy, targeted therapy and chemotherapy. The number of agents used in the combination varies according to the disease stage of patients. Then Watchful Waiting. Maintaining remission is usually achieved by immunotherapeutic agents.

If a recurrence of MM is detected, a Stem cell transplant is advised provided there is no contradiction.

Then again, a watchful waiting with maintenance therapy, and surveillance.

Prognosis:

The prognosis: Survival used to be 5 years for stage I, and for stage II and stage III rates were 3.5 yrs. and 2.5 yrs. respectively. In a 2021 publication, the 5-year survival rate was noted to be 75% in early cases, and in late diagnosed cases the rate was 48%.

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Pituitary Gland

 

                                                   Pituitary gland

                                                   PKGhatak, MD

The pituitary gland is a small endocrine gland, located at the base of the skull in the middle fossa and sits in the Sella turcica (Turkish saddle) of the sphenoid bone. The roof of the nose is just below it and is separated by a thin perforated bone partition called the cribriform plate, the hypothalamus and the optic chiasma are located just above the pituitary gland. The pituitary is positioned in between the eyes when projected on the surface. The pituitary is connected with the hypothalamus by a stalk consisting of nerve fibers and blood vessels. The frontal cortex overhangs in front of the pituitary.

The pituitary gland is two glands in one structure - the anterior pituitary and posterior pituitary. Both parts are endocrine in nature. The posterior pituitary is an extension of the hypothalamus. In between the two pituitaries are cells that form the pars intermedia.

Embryology of Pituitary.

The ectoderm cells of the developing roof of the mouth grow upwards in the form of a pouch -  Rathke's pouch. The neurons from the floor of the 3^rd ventricle of the brain extend down as an outgrowth to meet Rathke's pouch. These two sources make up the Pituitary gland – the anterior pituitary (adenohypophysis) originates from the cells of the roof of the mouth, the posterior pituitary (neurohypophysis) from the extension of the brain. The line of junction of these two parts contains cells and is known as Pars Intermedia. Pars intermedia is ultimately incorporated in the anterior pituitary and these cells produce MSH - melanocyte stimulating hormone. 

The pituitary gland is the conductor of an endocrine orchestra. The orchestra players are the adrenal glands, thyroid, thymus, pancreas, pineal, and testis/ovaries. The nerve center of this orchestra is the hypothalamus. Hypothalamus with its nerve fibers and the portal circulatory system sends signals to both pituitary glands. The hypothalamus is the headquarters of the autonomic nervous system. The hypothalamus acts as a bridge between the CNS and the endocrine systems 

Special Three:

The pituitary, hypothalamus and pineal have a closer relationship. The pineal gland produces melatonin, a hormone and through melatonin, the pineal maintains the circadian cycle, sleep, and waking rhythm. The pineal gland is considered the spiritual center and so called the 3^rd eye. These three structures (Pituitary, hypothalamus and pineal gland) working together are responsible for the control of heart rate, BP, appetite, body temperature, respiration, emotion and behavior, sexuality and fertility, growth of bones & muscles. skin color, water & electrolyte balance and health.

The hypothalamus communicates with the anterior pituitary by releasing hormones. Every anterior pituitary hormone is produced by a separate cell line; so, the hypothalamus has multiple releasing hormones.              Examples: ACTRH (adrenocorticotropic releasing hormone), TSRH, GHRH, etc. The nerve fibers from the hypothalamus send signals to release preformed hormones - ADH (antidiuretic hormone) and Oxytocin.

The hormone secretion from the pituitary gland is not continuous. Every 2 to 3 hours hormones are released in circulation.

Hormones of Anterior Pituitary:

Anterior pituitary gland hormones are ACTH (adrenocortical stimulating hormone).

 TSH (thyroid stimulating hormones).

 Gonadotropins- LH (luteinizing hormone), FSH (follicle stimulating hormone).

 MSH (Melanocyte stimulating hormone).

Posterior Pituitary hormones are. ADH (antidiuretic hormone) and Oxytocin.

ADH is produced by neurons of the hypothalamus and travels down the nerve fibers to the posterior pituitary and is stored in the vesicles. With the appropriate signal from the hypothalamus, ADH is secreted.

Oxytocin. Oxytocin is likewise produced by neurons of the posterior pituitary, travels to the posterior pituitary like ADH.

The pituitary gland may overproduce or fail to produce adequate quantities of the hormone. It also may develop tumors. Benign tumors of the anterior pituitary are the majority of tumors.

Table of Pituitary hormones.

Hormone	Target organ	Excess production	Deficiency
GH- growth hormone	Bones and muscular system.	Gigantism in children, Acromegaly in adults.	Dwarfism, Growth retardation. Osteoporosis, muscular weakness, depression.
ACTH	Adrenal cortex	Cushing disease	Addison's disease
TSH- thyroid stimulating hormone	Thyroid gland	Hyperthyroidism	Hypothyroidism
Gonadotropin LH- luteinizing hormone	Germ cells of the Ovaries/testicles		Failure to conceive if female. Low sperm count in males.
Gonadotropin FSH- follicle stimulating hormone	Interstitial cells of ovaries/testicles	Many adverse effects on estrogen excess and hyper testosterone, Blood clots, and an increase in hepatic and other tumors.	Few and scanty menstruation to amenorrhea in females. Erectile disorder in a male.
Prolactin	Breast both sexes	Lactation without pregnancy. Milk secretion in males	Lactation deficiency in postpartum..
MSH- melanocyte stimulating hormone	Melanocytes of the skin	Production of pigments of the skin and hair	Vitiligo and albinism
ADH- antidiuretic hormone	Kidney tubules	Fluid overload and hyponatremia	Dehydration and inappropriate production of dilute urine
Oxytocin	Pregnant Uterus	Rupture uterus	Failure of placental separation and poor uterine contraction during labor.

A few special Pituitary disorders.

Chromophobe Adenomas of Pituitary. Chromophobe adenoma of the pituitary is the most common adenoma and is a benign tumor. Pituitary adenoma does not secrete any hormone. and cells contain no granules, however, under the electron microscope, a few granules are detected. Symptoms of adenoma are related to increased internal pressure and hypofunction of the pituitary but symptoms vary because all different cell lines are not equally affected. Often the prolactin levels are high and ACTH, TSH and GH are lower.

MENS 1. Multiple endocrine neoplasia type one. Tumors of the anterior pituitary (mostly of prolactin producing cells) arise in association with tumors of parathyroid glands, pancreatic tumors – insulinomas and glucagonomas, and tumors of small intestinal hormone producing cells. The disease is inherited in an autosomal dominant pattern. Additional tumors of the adrenal gland, carcinoids, angiofibroma and meningiomas may be associated.

Sheehan syndrome. Massive postpartum bleeding leads to shock and pituitary necrosis. If patients survive the shock, then hypothyroidism, adrenal insufficiency, and menopause develop.

Empty Sella syndrome. The pituitary sits in a bony cup, only the top is covered by soft tissues. In benign intracranial hypertension, the persistent high CSF pressure produces gradual atrophy of the pituitary and symptoms of hypopituitarism develop.

Prolactinoma. Tumors of prolactin producing cells are either microscopic tumors or macroscopic large tumors- both are benign. Excess prolactin is associated with a deficiency of other anterior pituitary hormones. Symptoms of low cortisol and hypothyroidism are most manifested initially. Macrotumors produce increased CSF pressures, visual field defects, and eye muscles palsy in addition to hormonal changes.

Nelson syndrome. Following bilateral adrenal gland removal in Addison syndrome, the cells producing ACTH in the pituitary grow in excess and form a tumor. Besides Cushnoid features, various visual symptoms and blindness may develop.

Craniopharyngioma. Craniopharyngiomas are benign cysts and occasionally solid adenomas developed from the remnant cells of Rathke's pouch. Symptoms are increased intracranial pressure and visual field defects. This entity is a childhood malady and is occasionally seen in adults.

Rathkes cleft cysts. Cysts develop in the remnant Rathke's pouch. The presentation is very similar to craniopharyngioma.

Lymphocytic hypophysitis. This entity is a rare complication seen in late pregnancy or early postpartum. It is an autoimmune disease with lymphocytic infiltration of the pituitary gland and results in various degrees of hypofunction of the pituitary. The cause is unknown, IgG4 and IgG1 antibodies were detected by some investigators pointing to heterogenic sources of antigen.

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Appendix

 

                                                             Appendix

                                                         PKGhatak, MD

Appendix means an attachment to a document. Centuries earlier when Geeks began to dissect cadavers to study human anatomy, they described a small narrow tube hanging from the cecum and called it an appendix. Appendix later received a nastier name in 1579 given by Yolanda Smith - Vermiform appendix (worm like appendix) and that name got tucked in the medical field.

 ..Before the days of general anesthesia and sterilization, infection of the appendix was bad news as bad as a death sentence. In 1735, Dr. Claudius Amyland in London, England successfully surgically removed an appendix from an 11-year-old. boy who had swallowed a needle that perforated his appendix and lodged in the scrotum.

..In the Journal of Evolution Biology H.F Smith et al described that Appendix evolved twice in the animal kingdom, the latest appearance was in marsupials. The appendix has largely disappeared from the animal kingdom and now the appendix is found only in humans, primates, rabbits, prehensile tailed porcupines, flying squirrels, meadow voles and wombats.

..There are wide variations in the anatomy of the cecum and appendix in mammals – some have only multi chambered cecum and appendix and no small bowels, some have a larger appendix and small cecum, and some only appendix and no cecum.

..Human appendix in adults is about 3 inches long, attached to the far end of the cecum next to the junction of the small intestine to the cecum. The appendix is richly supplied by arterial blood. The size of the appendix is much larger in the developing fetus and continues to grow through early childhood and starts to diminish in size with the onset of sex hormones secretion.

..A microscopic look at the appendix will convince anyone that the appendix belongs to the lymphatic system. The lymph follicles of the appendix are large compared to the rest of the tissues, the follicles are many and arranged in a circle. Structurally the appendicular lymph follicles resemble Peyer's patches of the small intestine and functionally perform like the thymus gland. In fact, calling the appendix the intestinal thymus is not that far off.

In the appendix, lymph follicles contain lymphocyte B-cells and T-cells. B-cells and T-cells communicate with each other and function like T & B-cells in any other tissue. The bacterial antigen and other antigens are identified and collected by T-cells then given to B-cells. Cytokines of T-cells act on lymph follicles and produce immunoglobulin IgA. IgA is the immunological defense of the GI tract and prevents the invasion of bacteria, fungi, viruses, and toxins. IgA is also produced in the lymphatic tissues of the rest of the intestine.

.. Besides immunological functions, the appendix is the home of beneficial bacteria in the large gut. When diarrheal diseases and the use of antibiotics wipe away the gut bacteria and the overgrowth of harmful bacteria produce illness, the appendix replenishes new batches of beneficial bacteria.

..In reconstructive surgery, the appendix is utilized and fashioned as a sphincter of a newly created urinary bladder out of a section of the gut and also use appendix as the replacement part of a removed ureter.

..In earlier days the appendix of ruminant animals was considered a storehouse of fermenting bacteria and that belief led Charles Darwin to consider the human appendix as a relic of leaf-eating humans.

..The incidence of appendicitis is about 1 million a year in the USA. The mortality rate is 0.3%. Today, the diagnosis of acute appendicitis is made easier by Ultrasound studies. A swollen appendix and local peritoneal ascites (fluid collection) mean acute appendicitis. In retrocecal appendicitis or in ectopic pregnancy an MRI is referable. Elucidating one finger tenderness at the McBurney and leukocytosis with a left shift are not solely relied upon, but are important clinical findings.

A recent trend in appendicitis treatment is the use of antibiotics alone, no surgery, and careful watch, provided ultrasound study does not show fluid collection.

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Color of Urine.

 

                                                        Color of Urine

                                               PKGhatak, MD

The normal color of urine is pale yellow. The hemoglobin breakdown product bilirubin is excreted by the liver in the bile. Most of the bilirubin is eliminated from the body in the stool, some 20 % is reabsorbed and filtered by the kidneys. In the urine it appears an urobilirubin and that colors the urine.

..Dehydration produces dark yellow color urine; pale urine is produced from drinking several glasses of beer. Urine color becomes barely noticeable or absent in common bile duct obstruction from impacted gall stones or pancreatic cancer.

..Consuming beetroot, carrots, and blackberries makes urine red and various shades of yellow. Green urine is likewise seen after eating asparagus. In the summer months, eating ice shavings with colored syrup and colored ice cream can give a variety of colored urine.

..People taking prescription medications, if they read the printed information given by the pharmacy, will find certain pills may discolor the urine.

 Drugs producing colored urine: -

..Orange color – Rifampin and other Rifampin derivatives, Sulfadiazine, Senna. Warfarin, Phenazopyridine.

..Pink color – Phenolphthalein, Vitamin B12, Senna.

..Brown color – Nitrofurantoin, Metronidazole, chloroquine.

 .Black color – Sorbitol, Methyldopa.

..Blue color – IV methylene blue. Indigo carmine.

..Green color – Promethazine, cimetidine, Amitriptyline, Indocin, Metoclopramide.

 Diseases producing colored urine: - Red urine. - Bleeding from the urinary bladder, kidneys and urinary tract due to stones, tumors, tuberculosis and trauma, including surgery.

..Brown urine. - Free hemoglobin and myoglobin (hemoglobin of skeletal muscles) in the urine. This may arise from crush injuries, Rhabdomyolysis. Prolonged march. Electric shock, Seizures. Massive pulmonary infarction and Intravascular hemolysis. Only a few important intramuscular hemolytic causes are mentioned here.

..Hemolytic anemia is classified as I. Inherited and II. Acquired.

 I. Inherited intravascular hemolysis due to 1. abnormal cell shape and size e.g. Thalassemia, Sickle cell anemia, Hereditary spherocytosis. Elliptocytosis.        2. Enzyme deficiency. G6PD (glucose 6 phosphatase deficiency) PKD (pyruvate kinase deficiency).

II Acquired hemolytic anemia. Burns. Autoantibodies –1. Immune hemolytic e.g., CLL (chronic lymphatic leukemia) Non-Hodgkin lymphoma. 2. Autoimmune hemolytic e.g., minor blood group, Lupus erythematosus. 3. Autoimmune hemolytic e.g., post transfusion hemolysis, Hydrops fetalis and hemolytic anemia in newborn – Rh negative mother sensitized by Rh positive baby during pregnancy, mother's antibodies cross the placenta and hemolyze fetal RBCs of the subsequent pregnancy. 4. Drug induced antibodies e.g., Penicillin, Cephalosporins, Levofloxacin, NSADS, Methyldopa, Nitrofurantoin. 5. Mechanical causes- e.g. RBC breaks down in the microcirculation e.g., TTP (thrombotic thrombocytopenic purpura). ITTP (idiopathic thrombocytopenic purpura. Mechanical cardiac valves. 6. Miscellaneous e.g., PNH (paroxysmal nocturnal hemoglobinuria.

Hemolysis is due to the presence of antibodies. e.g., Cold agglutinins in mycoplasma pneumonia.

.. Bacterial hemolysins – cholera toxin, Clostridium perfriengence (gas gangrene, CMV, Rickettsia, Brucella, Trypanosoma, EBV (Epstein Barr virus).

 Autoimmune hemolytic anemia. Paroxysmal nocturnal hemolysis. Mediterranean fever.

..Other causes – Acute renal tubular necrosis. Acute glomerulonephritis, Good Pasture syndrome, snake bite, CO poisoning, barbiturate poisoning, polymyositis. muscular dystrophy, McArdle syndrome.

 ..Intracellular Parasites- Malaria, Babesia, Trypanosoma.

.. Black urine: Malignant melanoma.

..White urine. Lymphatic obstruction. Fungal UTI. Cellular derbies from TB.

. Snowflake urine. Calcium phosphate crystals.

. White cloud in oxalosis.

. Standing urine open to air changing to dark or black due to Alkaptonuria.

.. Spurious color changes – red diaper syndrome due to growth of bacteria Serratia marcescens.

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Sarcoidosis.

 

                                                                     Sarcoidosis

                                                         PKGhatak, MD

In the old days of pulmonary tuberculosis, sarcoidosis was an interesting entity and entered into the differential diagnosis of pulmonary tuberculosis. Nowadays, sarcoidosis has taken that spot in the differential diagnosis of granulomatous diseases. This distinction is applied to sarcoidosis because the cause of sarcoidosis is unknown, it can and usually affect multiple organs. Sarcoidosis may be self-limited, progressive or chronic. Sarcoidosis passes through three stages – inflammation, granuloma formation, fibrosis. Many other diseases have similar pathological characteristics. In short, sarcoidosis is diagnosed when all known causes of a granulomatous disease are eliminated.

Granuloma is a tiny localized collection of densely packed immune cells, mostly macrophages, and epithelioid cells (elongated nucleus of macrophages), and a few Langhans giant cells (fusion of macrophages) surrounded by a zone of lymphocytes, eosinophils with some fibrosis at the periphery. The distinctive features of sarcoid granuloma are asteroid body, an eosinophilic star shaped structure, and rounded laminated partially calcified structures called Schaumann bodies. The foreign-body granuloma at the center of the granuloma contains a part of the foreign body. Sarcoid granuloma is described as Non-Caseating granuloma. In the case of tuberculosis, the bacterial toxin causes the death of cells and matted dead cells are called caseation.

Sarcoidosis is due to the response of the Immunocytes to foreign agents/antigens. But the identity of the antigen and mechanism of the derailed function of the Immune cells are not known. The hallmark of sarcoid is a granuloma. Immune cells fail to destroy the foreign antigen but contain it locally by forming a dense cellular wall around it.

 Common granulomatous diseases:

Foreign body – wood splinters, metal fragments, insect stings, spider bites. The ingrown root of the hair, tattoo ink, inhaled beryllium, dermal fillers collagen, forgotten sutures, aspiration of food particles in the lung.

Granulomatous polyangiitis or Wagner granulomas. - granuloma forms in the nasal passage, trachea, major bronchi. Hemoptysis is the presenting symptom.

Eosinophilic polyangiitis also called Churg-Struss syndrome, Necrotizing vasculitis of small and medium size vessels with peripheral eosinophilia and ANCA positive vasculitis. Patients present with asthma, weight loss and polyneuritis, bronchitis and other systemic symptoms.

Crohn's disease –  A chronic granulomas ulcerative lesion of the colon and terminal ilium and anal canal.

Rheumatic fever. Streptococcal antigen triggers granulomas on heart valves.

Rheumatoid arthritis. It is a debilitating chronic arthritis of the small joints of fingers, cervical spine, and knees; occasional granulomas in pleura and pulmonary fibrosis.

Mycobacteria infection. - Pulmonary tuberculosis, non-MT granulomatous diseases, Leprosy.

Bacterial. - Cat- scratch fever, Listeriosis,

Fungus. - Histoplasma, coccidioidomycosis, blastomycosis, Cryptococcus.

Parasites. -Leishmaniosis of skin, liver and spleen; pneumocystis.

Symptoms of sarcoidosis are variable based on organ involvement:

Pulmonary lesions are 

1. Hilar adenopathy in young adults must be differentiated from sarcoma by CT scan of the chest and abdomen and mediastinoscopy biopsy.

2. Pulmonary infiltrates with or without adenopathy resembling pulmonary tuberculosis. Interferon gamma release assay, sputum smear and cultures for AFB and rarely bronchoscopic biopsy may be required. 3. Cavitary pulmonary lesion presented with hemoptysis. 4. Extensive pulmonary fibrosis and loss of lung tissue.

Skin: Lesions are.

 1. Lupus pernio. - Disfiguring lesions of nose, cheeks, lips

.2. Granuloma annulare - flesh colored raised skin lesions on bony prominences and characterized by multiple rings. 

3. Polyarteritis nodosa. - Raised painful nodules, purplish blue color, appear in crops on the lower legs over the shin bones.

Heart. Heart block and other conduction abnormalities. Diagnosis is difficult if only a heart block is present. Liver biopsy is often diagnostic.

Eye. - Uveitis, chorioretinitis, sclerites, blindness. Dry eyes. Lachrymal gland biopsy may be required.

CNS. Facial nerve palsy is also called Bell's palsy, various neurological symptoms based on stages of the disease of CNS. Meningitis, seizures, dementia, polyneuropathy.

Kidneys. Recurrent renal stones.

Bones. Osteoporosis.

Blood. High calcium and markedly raised ACE (angiotensin converting enzyme), high ACE is also present in other granulomas but usually in the modest range. ACE is produced by granuloma cells.

Common symptoms at the time of presentation. The symptoms vary according to the organ involved. In the young adult male, hilar lymphadenopathy is usual. In general, the condition resolves spontaneously in 6 weeks. Recurrent skin lesions are common in blacks. Various eye lesions maybe not be so obvious initially but in chronic lesions, the eye involvement is usual. Dry eyes may require a biopsy of lacrimal glands for a diagnosis. Cavitary and progressive pulmonary fibrosis have a poor prognosis.

Treatment:

Treatment is urgent when eyes, heart, CNS sarcoid lesions are present. Hypercalcemia may require emergency medical therapy.

Prednisone is the primary drug. Because of major side effects, Methotrexate, Leflunomide, Hydroxychloroquine, Imuran, and cytotoxic drugs are added while the dose of prednisone is decreased or stopped.

Prognosis: Asymptomatic hilar lymphadenopathy has the best prognosis. Processive fibrosis has the worst outcome.

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