Whipple's disease

 

Whipple's disease:

Whipple's disease is a bacterial infection of jejunum manifest as malabsorption of fat, fat soluble vitamins and protein.

Dr. George Whipple, in 1907, described the first case in a 36 yr old man presented with malabsorption associated with lymph nodes enlargement of the mesentery and increased skin pigmentation. He found small rod-shaped organism in the tissue stained by silver stain but could nor grow it in any artificial media to make a positive identification but predicted the possibility of a bacterial infection. In 1992 a gram positive coccobacillus was identified in the biopsy tissue by electron microscopy. The bacteria was PAS(periodic acid-Schiff stain) positive and Acid-fast stain negative, The organism is named- Tropheryma whipplei (T. whipplei). T. whipplei belongs to Actinomycetes group and its pathology has many similarities with Mycobacterium avium intercellari infection.

The natural habitat of T. whipplei is in the soil and farmers are three times more likely to develop clinical signs of infection over people in other professions. 51% of world population are positive for T. whipplei antibodies, however, only 3 in 1 million develop clinical signs of illness. This is due to cellular immune deficiency contributes to the development of illness. Farmers who are haplotype for HLA B27, having phagocytes which fail to digest engulfed bacteria because of lack of activation CD 11b (integrin alpha) by TH1 lymphocytes.

Mode of infection and incubation period.

The mode of infection and the incubation period are not known preciously but oral route is most likely. This bacteria have a three layered outer membrane and that helps them to withstand digestion by the strong Hydrochloric acid (HCl) in the stomach. Once T. whipplei are in the duodenum and Jejunum they infect the surface cells of the villi. The cellular infiltration follows and it produces edema of the villi and this is the beginning of abdominal symptoms of bloating, cramps and diarrhea. The macrophages engulf the T. whipplei but unable to kill and the bacteria. Macrophages move to lymph follicles in the lamina propria. Nodularity of lymph follicles develop in lamina propria and also in the mesentery. These two features – edema of villi and enlarged lymph follicles - are characteristics of Whipple's disease.

The second most frequent clinical feature is a reactive type of arthritis of the finger joints and metacarpal phalangeal joints resembling Rheumatoid arthritis but Rh factor is negative and erosion of bones does not develop. Similar symptoms is also occur in the sacroiliac joints, ankles and knees but less frequently. Other feature are anemia, low grade fever, lymph node enlargement, increased skin pigmentation. Occasionally cerebellar ataxia, peripheral neuropathy, headaches, oculomotor palsy and seizures may be present. These, non GI symptoms are due to increased production of acute-phase reactants as a result of infection of the GI tact by T. whipplei.

Diagnosis.

Investigation of Malabsorption syndrome includes an upper GI endoscopy with biopsy and the T. whipplei infection can be identified by histopathology, electron microscopy, PAS and Acid fast staining and also by PCR identification of bacterial DNA.

Treatment:

T. whipplei, not unlike Mycobacterium avium intercellari, requires prolonged antibacterial therapy followed by a year or two of chemoprophylaxis.

For acute phase infection.

The standard regimen. Ceftriaxone 1 gm IV every 12 hrs., or, high dose of Penicillin IV for 2 to 4 weeks. Followed by one to two years of Sulfamethoxazole Trimethoprim 800 mg/160mg tablet twice a day for 1 to 2 years.

Alternate regimen. Doxycycline 200 mg, by mouth daily every12 hrs. plus Hydroxychloroquine 600 mg orally, once daily for 18 months, followed by Doxycycline 200 mg orally daily for life time.

For CNS symptoms. Ceftriaxone  2 gm IV every 12 hrs. for 6 weeks followed by Sulfamethoxazole Trimethoprim twice a day for 1 to 2 years.

Whipple's disease is a bacterial disease due to immune system's failure in eliminating the pathogenic organism from the body. Articles presented earlier, dealt with a virus that remains in hibernation after an infection and  subsequently causes new disease - Burkitt lymphoma virus. Similarly, a fungus -Pneumocystis jirovecii, and a protozoa – Toxoplasma gondii were discussed. This article on Whipple's disease concludes this section.

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Stories Nails tell

 

Stories nails tell.

Nails are skin appendages. Finger nails are colorless and semitransparent; the blood vessels underneath show through the finger nail-beds. Medical practitioners have been observing and deducting the state of health of their patients for centuries. This examination skill is dying out in present days, due to the use of technologies which are more precise, but not all of them are readily available at the bed side and they increase the cost of medical care.

Fingernails grow about 3.5 mm a month. It takes 6 months for the nail to reach the tip of the finger. So, nails have many stories to tell about the health condition of an individual over a period of the past 6 months. Some of the physicians who described changes in nails as a result from the underlying diseases, have their names attached to those conditions and are sill in use today – a few examples are as follows.

Beau's Lines. Lines form across the nails seen in Raynaud's disease, injuries to the nails and chemotherapy and nutritional deficiency. Cold sensitive constriction of arteries of hands, producing severe blanching of fingers followed by severe pain in fingers and blue discoloration of nail beds and tip of fingers, nose and ears is known as Raynaud's disease.

Muehrcke's Line. In protein deficiency in Nephrotic syndrome, Cirrhosis of liver and famine white lines develop across the nails.

Drier's disease. An autosomal dominant inherited multisystem disorder appears in late childhood and early adolescence, manifests as short stature, greasy confluent skin rashes, generally in legs, and deformed finger nails with vertical striations.

Color changes indicating underlying diseases:

1.Cyanosis.

Blueish discoloration of nail beds due to hypoxemia can arise from vasoconstriction of vessels of the hands or due to under saturation of arterial blood from diseases of lungs or admixture of venous and arterial blood in the heart chamber due to defects in the partitioning septal walls producing right to left shunt (called Central Cause, in short). In Central Cyanosis the tongue turns blue. In vasoconstriction the nail beds are blue but the tongue remains normal pink color.

2.Methemoglobinemia.

The RBCs carry oxygen in a loose combination with hemoglobin and the iron molecule in the hemoglobin remains in ferrous form; a less than 3 % of oxygen is carried as an oxidized compound – methemoglobin. Here the iron is oxidized to a ferric form. The ferric iron does not part oxygen to the tissue and tissue suffers from hypoxia. Abnormally high concentration of oxidized hemoglobin in blood may happens following local anesthesia with benzocaine or tetracaine. The nail beds turns gray in color. Drugs containing aniline, benzene derivatives and nitrite commonly produce similar changes in hemoglobin – most common among the group are dapsone ( use of leprosy) , nitrates ( used for angina pectoris) and benzocaine ( local anesthetic).

Congenital Methemoglobinemia.

Navajo and Athabaskan Indian tribes have higher instances of Cytochrome b5 encoding gene mutations and congenital methemoglobinemia. G6PG (glucose 6 phosphate dehydrogenase deficiency) also produces congenital methemoglobinemia.

Hypoxia in methemoglobinemia is not reversed by Oxygen. Methylene blue an other reducing agents are used therapeutically for that purpose.

3.Carbon monoxide poisoning:

Smokers' blood contain a low level of carbon monoxide (CO). Accidental exposure to CO happens in winter months from indoor coal burning or keep a gas cooking range burning through the night for heat. Incomplete burning of coal and natural gas produces CO and inhaled CO produces high levels of Carboxyhemoglobin in blood. The nails change to cherry red color. Unless promptly treated, CO poisoning is usually fatal or leaves patients with serious neurological deficiencies,

4.Anemia.

Pale finger nails in anemia is a late sign, the tongue and the conjunctive of the lower eyelids become pale much earlier.

5.Obstructive jaundice.

When bile duct is blocked by gall stones or carcinoma of the head of the pancreas, the bile can not drain into the small intestine, The accumulated bilirubin turns, conjunctiva, skin and nails deep yellow.

Other congenital abnormalities of nails.

1.Yellow nail patella syndrome.

Yellow nail patella syndrome is a multisystem structural abnormalities of skeletal. dermal and neurological systems. The chromosome 9 carries the genetic mutation which normally encodes transcription factor for early separation of dermatomes into neuroectoderm, ectoderm and mesoderm. All three divisions exhibit developmental abnormalities of varying degrees, however, changes in patella and nail are constant. It is inherited by autosomal dominant mode with variable penetrance. The patella is hypoplastic or often absent, the finger nails are deformed or small and yellow in color and brittle; less frequently toe nails are deformed also. Finger joints and elbow joints are hyperextensible. The iliac bones show horn like outgrowths and the neck is long like a swan. The separation of neurons into dopamine and serotonin producing lines are defective. The connective tissue formation around the developing eyes and podocytes of glomerulus of kidney are defective. Some children develop condition similar to Duchene muscular dystrophy.

2. Nonsyndromic congenital deformed nails condition 10.

This is an autosomal recessive inherited disorder of the EZD6 gene which encodes Frizzld6 protein of nails. Both finer and toe nails are extremely thick and hard and easily separates from the nail bed. At times some toes and fingers are missing.

3.Psoriasis.

Psoriasis is an autoimmune disease of the skin, dead skin cells accumulates under the nail and nails are pitted.

Genome-wide association showed 60 susceptible regions of genes involved in Thymic 17 cell actions which are linked to psoriasis. Linkage analysis identified 9 additional regions - PSORS 1 to PSORS 9. PSORS 2 is inherited in an autosomal dominant mode and it is the common variant in North America. CARD 14 gene, normally encodes an adapter protein of skin keratinocytes and mutation of this gene is linked to psoriasis.

Nearly 80 % psoriatic patients have one or more changes in finger nails and also in the toe nails. The common presentation is pitted nails. The other changes are white, brown or yellow discoloration, heaped up dead skin underneath the nail separating the nail from the nail bed, and brittle nails. Flame shaped hemorrhagic steaks are occasionally seen.

Fungal infection.

Diabetic patients are more susceptible to fungal infection of toe nails and less commonly to finer nails. Dishwashers and other professions in which contact with water is nearly constant are subjects of fungal nail infections. Candida species and Trichophyton fungi are common fungal infection of nails.

Common manifestation of fungal nail infections are change of color to white, black, green or yellow. Thickening of nails are also seen often. Nails become brittle and take unusual shapes and textures. Pain on pressure is common finding. Toe nail fungal infection is much more common in diabetic and workers require to wear boots for long hours.

Systemic illness.

1.Splinter hemorrhages.

Red blood streaks appear under the finger nails due to exude of blood from the capillaries. These are 1 to 3 mm long run vertically and in multiple nails. Besides bacterial infection of endothelium, leukemia, use of anticoagulants, certain cancer drugs and nail injuries and lupus erythromatosus. also responsible for splinter hemorrhages.

2. Clubbing.

The fingers normally tapers from palm to the finger tip. Clubbing is an acquired deformity of the tip of finger appearing like a drum stick with a bulbous ends. Many lung conditions results in chronic low blood oxygen produce finger clubbing, chief among them are Bronchiectasis, Non- Small cell cancer of lung, Mesothelioma, Cystic fibrosis, lung abscess. Other less often causes are empyema, amyloidosis, idiopathic pulmonary fibrosis and Sarcoidosis. Some non-pulmonary causes are Coarctation of aorta, aneurysm of subclavian artery, A-V fistula, Congenital heart diseases, Crohn's disease and ulcerative colitis, cirrhosis of liver, malabsorption syndrome, Graves disease of thyroid gland.

Other less frequent nail changes.

Hollowed out nail beds resembling spoons are seen in malnutrition.

Dark gray to black streak along the length should raise suspension of melanoma.

Some people have habits of pushing back the cuticles of nails repeatedly producing multiple ridges and grooves in the center of nail beds. It is called Onchotillomania.

Half white and half pink nails are common in chronic renal failure patients.

In cirrhosis of liver nails turn white. White spots on nails are preset in Zinc and iron deficiency

People engaged in silver mining develop blueish nails. In a congenital Copper metabolic disease, Wilson's disease blue mails may be present due to deposition of copper in the tissues.

In vitamin B12 deficiency anemia nails may turn black in color. In injury to nails blood under the nail beds appear black. The normal half moon of nail beds may be absent in chronic lung and heart diseases.

Use of hair coloring shampoo usually stains fingernails of varies colors but colors are just stains and can be easily be removed by nail polish remover.

Paronychia.

Paronychia is infection of the soft tissues on the sides of the nail. When the cuticle of the finer nail is damaged, bacteria and fungi grow and an abscess may develop. Paronychia is painful and requires local treatment with antibiotic ointment and rarely incision and drainage of abscess. Streptococcus pyogen and Staph aureus and common bacteria, if damage of the skin is from water, Pseudonymous bacteria is responsible and the the pus is green in color.  Of the fungi, Candida species is common.

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Heart Failure

 

Heart failure:

The human heart is divided into 4 chambers, two upper chambers receives blood and two lower chambers - right and left ventricles discharge blood and are muscular in nature and called muscular pumps. The right ventricle sends venous blood to the lungs for collecting fresh Oxygen and discharge Carbon dioxide. The distance between the right ventricle and lungs is short and right ventricle has to generate just enough pressure to send blood in the pulmonary capillaries.

The left ventricle is responsible for sending fully oxygenated blood and nutrients to very cells of the body and requires to generate much higher pressure and has a thick muscular wall.

The failure of one or both ventricles to send blood out to their respective destinations happens when ventricular muscles become weaker. This is in medical term called heart failure; it may happen only on the right side then it is called Right ventricular failure and likewise, when only left ventricle fails is called left ventricular failure. Often, one ventricular failure progress to both heart failures and also both hearts may fail simultaneously. If heart failure happens suddenly it is called acute heart failure – either acute right hear failure or acute left heart failure. And when heart failure develop over the years is called Chronic Heart failure – chronic right heart failure or chronic left heart failure or simple heart failure. Heart failure or ventricular failure is the same; and one term is used for the other quite frequently.

The cause of heart failure:

Blood is the vital fluid, circulation of blood to every cells of the body is the only function of the heart. But if there is no blood in the body or marked loss of blood then even the best heart fails.

Those conditions will not be discussed here.

Heart fails for various medical conditions and due to congenital or acquired structural abnormalities.

1. Coronary artery disease.

Ventricles of the heart are full of blood but unable to use that blood for their oxygen and nutritional requirements. Coronary arteries supply blood to the heart. Coronary artery disease is the most common reason heart fails to supply blood to the heart. It may happens suddenly – known as acute coronary event and unless immediate hospital treatment, devastating result follows ; heart may fail slowly over the years – in this situation angina pectoris ( pain in heart) is the main symptom. Then heart muscles slowly weaken and fails.

High BP, high cholesterol, obesity, genetic predisposition, and diabetes are risk factors for the development of coronary artery disease. Initially the endothelial cell damage, separates cells and serum sips underneath the endothelial lining. A waxy deposit forms, pushing it inside the lumen of the vessel, blood flow slows and that manifests as angina pectoris. From time to time the waxy plaque breaks and sends the tissue derbies further into smaller arteriole and precipitates a heart attack. In the raw are of the wall- the site of plaque break, platelets accumulate to plug the raw area by forming a platelet clot, followed by blood clot develops and block off the coronary artery. 

2. Diabetes mellitus.

This condition is steadily increasing all over the world as more and more people are consuming factory produced prepackage food. Diabetes produces microvascular changes in the coronary vessels and many other organs. Plaque formation in coronary artery leads to heart attacks as described above.

{wish to know how DM produce microvascular changes....https://humihealth.blogspot.com/2022/01/diabetes-mellitus-and-microvascular.html }

High BP effects ventricular muscles to undergo hypertrophy in order to over come resistance offered by high BP. Coronary arteries pass through the layers of the heart muscle and every time ventricles contact the coronary artery is pinched off. More higher BP means more pinching and less and less blood flow to the ventricles. If high BP is not controlled heart muscles weaken and fail.

These three above conditions are the main causes of heart failure.

   4. Pulmonary embolism.

Deep seated veins of the thigh and pelvis under certain conditions spontaneously develop blood clots. Venous clots are fragile and easily break off and are carried by the venous blood to the right side of the heart. Right ventricle pushes these clots into the pulmonary artery and the clots block pulmonary arterial circulation. Patients experience severe chest pain and palpitation begins to sweat and soon go into shock. Blood returning to the left ventricle from the lungs are markedly undersaturated and patients develop central cyanosis. Symptoms of hypoxemia soon followed by cardiac arrhythmias and shock which does not reverses with bet adrenergic drugs and other measures. Death follows hours or in a day or two.

The above 4 are also examples of output failure of the ventricles.

5. Cardiac tamponade and pericardial effusion.

When the pericardial cavity is filled with blood because of a direct injury or due to rupture of the heart from other causes, there is little space remains in ventricles to receive blood. This condition produce stagnation of blood in pulmonary circulation and followed by systemic circulation. Cardiac arrhythmia and shock soon follows.

6. Constrictive pericarditis.

Certain infective pericarditis ends in thickening the pericardium and sometimes develop calcification. The symptoms produced in this condition is not that dramatic but never the less serious enough to threaten life of a patient if prompt treatment is nor forthcoming.

7. Myocarditis and dilated cardiomyopathy.

Virus commonly produce myocarditis are Adenovirus, Parvovirus B19, Human Herpes virus 6, Epstein -Barr virus, Human Cytomegalovirus and Enterovirus. Initial inflammatory cell infiltration of the myocardium is followed by fibrosis. The ventricular muscles become weak and unable to meet body's demand and heart fails. In this condition dilated cardiomyopathy and atrial fibrillation and ventricular fibrillation may end life earlier than heart failure.

8. Subacute bacterial endocarditis.

Streptococcus viridans infects damaged or deformed heart valves – mitral and aortic valves are mostly bacterial growth. This produce further damages to valves and other venerable ventricular structures and systemic sepsis leads to organ failure and deaths.

Staphylococcus and many other bacteria and fungus are capable of causing myocarditis and more easily damage heart structures.

9. infiltrative diseases of the heart.

Like inflammatory cells, other substances like iron, copper, and amyloid- a proteinaceous materiel, infiltrate ventricular muscles. This interferes ventricular functions and eventually the heart fails.

10. Radiation and chemotherapy.

Doxorubicin and other chemotherapy drugs and radiation therapy are cardiotoxic and ultimately produce cardiac fibrosis and heart failure.

Examples 5 to 10 are also considered diastolic dysfunction of ventricles (defect in receiving blood).

Other less common but significant causes of heat failure.

1. Morbid obesity and Kyphoscoliosis.

The way the heart function normally, requires free movements inside the chest cavity, as it beats. These two examples and several conditions put stain on the heart and the right ventricle fails first.

2.Malignancy.

Tumors of the heart is rare. Rarely sarcoma of heart is encounter. It is not an easy task to care for.

3. Congenial defects of the heart.

The advent of Doppler Sonography makes it possible to examine a developing child in utero and if there are structural defects of the heart that can be surgically repaired at that time or shortly after birth. This has eliminated many instances of heart failures. Just to mention some well known congenital heart lesions are Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Pulmonary Stenosis (PS), Fallot Tetralogy and Transposition of Great Vessels. Hypertrophic cardiomyopathy is congenital but symptoms starts at age 16 -18. In congenital anomalous origin of coronary artery arising from coronary sinus, venous blood circulates myocardium. In postpartum the baby fails to thrive and die if the condition is not recognized soon enough. 

4. Acquired heart valve defects.

Rheumatic fever, at an earlier times, produced havoc with the lives of many young individual. The streptococcus sore throat is the initial illness followed by 2 weeks later by joint pain and heart murmurs, Mitral valve is always affected and often associated with Aortic valve

5. Atrial fibrillation and ventricular fibrillation.

These two heart rhythm abnormalities are seen less frequently in otherwise younger healthy individual and consider as diseases of the old. However, cocaine, amphetamine and cannabis users they are distinct heath hazard. When ventricles pump 250 -300 beats per minute, these is hardly time blood to enter the ventricles and cardiac output falls precipitously. It does not take much for patients to loos consciousness and without treatment die from shock. In ventricular fibrillation, heart does not actually contract and blood remains in the cavities of the ventricles and  blood circulation ceases.

 The New York Heart Association classified heart failure into 4 categories based on the severity of the symptoms. In category 1 - patients have minimal symptoms, in category IV - patients are bed ridden and totally depended on others for the activities of daily living. Category II and III are in between category II and III.

This list of causes of heart failure is short , conditions which are not primarily cardiac are not included in this article.

This bog may be better understood if a previous blog -Human Heart is also reviewed at the same time.

https://humihealth.blogspot.com/2019/03/the-heart-and-heart-failure.html   (Copy and paste on your browser).

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Toxoplasma gondii

         Toxoplasma gondii infection

                     P.K.Ghatak, MD 

Toxoplasma gondii

Toxoplasma gondii is a protozoa. It lives in cat's intestine as a parasite and is eliminated from cats' body in the feces in a cystic from which can infect mammals and birds. Rodents and small mammals are intermediate and humans are also intermediate host and victims.

Toxoplasma needs a higher concentration of arachidonic acid, a long chain fatty acid, for sexual maturity and reproduction. All species of cat family provide that environment because the enzyme, delta-6-desaturase (D6D), which breaks down arachidonic acid during metabolism, is lacking in he cats' small intestine.

Toxoplasmosis is a medical term describing clinical features of Toxoplasma gondii (T. gondii) infection T. gondii is an obligate intracellular parasite in human and other mammals.

Eating under cooked meat, raw fruits, vegetables and drinking unfiltered water contaminated with cats feces are the main source of human infection. In rare cases blood transfusion, organ transplantation and transplacental infection to the developing fetus can occur. Most infected people show no symptoms, however, the fetuses of women infected for first time during pregnancy and Immunosuppressed people become sick.

There are three infectious forms of T. gondii, - 1.sporozoites - present in the feces of cat as oocysts ( thick wall cysts containing multiple larvae), 2.tachyzoites ( rapidly multiplying by asexual cell division) and 3. bradyzoites (slow growing or dormant) - present in the muscles and organs of infected mammals.

Life cycle of Toxoplasma.

T. gondii has a complex life cycle.

In cats:

All species of cat family are carnivorous , when they devour infected preys , the cysts are released in the small intestine. The wall of the cysts opens and releases sporozoites. Subsequent development of T. gondii takes two different pathways.

1. As a intestinal parasite.

In 3 to 10 days the sporozoites mature as male and female gametes and after mating and begins to reproduce. Million of cysts are excreted daily in the feces for 14 days. In the soil these cysts matures further and becomes infectious in a day or two. The cysts can survive about a year in the soil and water

2. As cysts in muscles and organs,

Some of the released sporozoites penetrate intestinal wall and are carries by the blood to different organs and muscles. The sporozoites asexually divide rapidly and are called tachyzoites. Later, tachyzoites stop dividing and form cysts and are known as bradyzoites. Cysts in the muscles, heart,eyes and other organs can complete their life journey if other carnivores eat the cat.

In rodents, mammals and human:

Infection is via oral route. In the intestine the T. gondii follows the 2nd path described for cat.

                                         Taken from CDC publication.

Primary infection is healthy adults.

About 50% of infected people have no symptoms , the rest have symptoms resembling a flu with slight fever, body aches, cough and sneezing. Cervical lymph node enlargement is a distinct feature, at times, lymph nodes draining the thorax may enlarge. Viral pneumonia like symptoms may develop in some. Rarely skin lesions of various definitions are also described. Cysts, containing a live T. gondii remain in the muscles, brain, heart, eyes and other organ for the rest of the life of an individual.

Pregnancy:

In the first trimester of pregnancy if a woman is infected, there is a good chance that infection from the placenta will pass to the fetus. This may result in a miscarriage and spontaneous abortion. A growing fetus examined by ultrasonography shows growth retardation and a characteristic triad of hydrocephalus, chorioretinitis and areas of calcification of the brain. Eye infection leads to congenital blindness. And sensory deafness in 30% cases.

In last trimester of infection produces mainly blindness.

Latency:

In all healthy people, T. gondii after the initial infection, remains in an inactive state. The organism however is still alive within the cysts and last for the rest of life of the individual.

Reactivation:

When inter-current infections and HIV infection in particular, lowers the cellular resistance or immunosuppressed drugs are used, the cellular resistance breaks down and T. gondii spread through out the body. The CNS and eye symptoms predominate.

The Brain:

Mass lesions, like cerebral lymphoma , are present in many cases; in most of the cases necrotizing lymphocytic vasculitis and microglial nodules around the cysts are present. These produce seizures and symptoms of encephalitis. The common areas of brain are the symmetrical lesions in the white matter of cerebral cortex, thalamus, brain stem, and cerebellum. Symptoms are headaches, confusion, seizure, inability to concentrate, clumsiness of movements, fever and nausea and vomiting.

Eyes:

Necrotizing lesions of choroid and retina of the eyes produce poor vision and blindness.

Diagnosis:

The initial test is IgM and IgG antibodies against T. gondii. If a biopsy is performed the T. gondii is visible within the cells. In most cases, PCR test to detect DNA of T. gondii has become a standard test. In encephalitis the PCR test of CSF is 100% positive .

In suspected mother to fetal transmission, an amniocentesis and PCR test is performed on the amniotic fluid.

Treatment:

Normal adult people with T. gondii infection requires no medication. In a developing fetus, even infection is confirmed, no anti- protozoal drugs are prescribed because of adverse effects. After the birth of the baby the choice of therapy is a combination of Pyrimethamine and Sulfadiazine. Infections of pregnant women if the child is not infected - Spiramycin is preferred therapy. If the child is infected then no treatment is given to mothers in the first trimester because drugs can cause deformed brain development and low platelet count of the child. After 16 weeks of pregnancy, Pyrimethamine and Sulfadiazine plus folinic acid are prescribed.

In all other infections the drug of choice is a combination of Pyrimethamine and Sulfadiazine; Folinic acid is added to prevent anemia.

Children with congenital deafness 16 months of therapy is advocated.

Prophylaxis in HIV infection and immunosuppressed individual.

Pyrimethamine plus Sulfadiazine should be continued.

Vaccine:

No vaccine is available.

Prevention:

Good hygienic measures and avoiding under cooked meat and unwashed fruits and vegetable.

Burkitt Lymphoma Virus

 

Burkitt-Lymphoma Virus 

Now known as Epstein - Barr Virus

P.K.Ghatak,MD.

Epstein-Barr Virus (EBV) was originally known as Burkitt Lymphoma Virus.     Dr. Denis P. Burkitt ( from Ireland) a surgeon working in Uganda reported a highly aggressive Head and Neck lymphoma of children in 1958. He send biopsy specimens to Dr. Epstein, a Pathologist in UK. Dr. Epstein, Barr- a virologist from Ireland and Dr. Achlonga, a Pathologist with interest in electron microscopy from Trinidad, worked together and identified a virus in the biopsy tissue. They reported their finding in 1964 and named the virus - Burkitt lymphoma virus. This is the first virus identified as the cause of human malignancy – the first human oncogene. The virus is known today as Epstein-Barr virus - EBV in short.

This articles on EBV is the 3rd and last of a series virus after producing the primary illness, enter in a latent period. In certain circumstances the virus is reactivated and produce different illnesses. The EBV infects B-lymphocytes and B-memory cells and remains dormant in these cells. EBV is known to produce a number malignancies and other medical illnesses when reactivates.

In a previous blog, many aspects of the EBV was discussed, this article is a supplement to - 

https://humihealth.blogspot.com/search?q=Epstein+Barr+virus.

EBV infects children and young adults worldwide. Saliva of the infected people contains EBV and kissing is the common mode of spread of EBV. Contaminated utensils, food and drinks are additional modes of spread. Blood transfusion, organ transplants and sexual activity also spread EBV.

Infectious Mononucleosis is the primary illness.

Incubation period is long, 4 to 6 weeks. The symptoms are that of an URI but distinctive features of EB virus infection are enlarged and edematous tonsils. Posterior cervical lymph node enlargement in addition to enlarged circular and longitudinal chains of cervical nodes and occasionally intrathoracic and axillary lymph nodes enlargement. Spleen is enlarged and may rupture with minor trauma. Liver enlargement is also seen

Another distinguishing feature is salmon colored morbilliform eruptions on the trunk in about 10% cases; those who do not have skin lesions will develop itchy but similar skin eruptions if they receive Ampicillin. Peripheral blood examination shows lymphocytosis and large atypical lymphocytes - resembling monocytes and that was the basis calling the illness as Infectious mononucleosis. IgM antibody appear early and persists for 6 weeks, the IgG antibody appears later and remains positive for the life of the patient.

Latent period:

The latency is divided into 3 stages.

In the 1^st stage of latency the virus remains totally inactive, except in Burkitt lymphoma. The initial adenopathy progress to lymphoma in a short time.

In the 2^nd stage the virus is only partly active and interferes with nucleic acid synthesis of the host cells, this results in gene mutation and subsequently chromosome breakage and fusion of genes.

In the final 3^rd stage the EBV is fully active and produces a number of malignancy and illnesses as listed below.

Illness produced after the virus is reactivated:

A. Malignancy-

Evidence points directly to EBV.

1. Burkitt lymphoma.

2. Undifferentiated Nasopharyngeal carcinoma.

3. Hodgkin lymphoma and perhaps non-Hodgkin lymphoma.

4. Lymphomas - designate as 1. Diffuse Large. 2. B-cell. 3. Extranodal T/NK. 4. Plasmablastic.5. Primary diffuse.

5. Hairy cell leukemia.

Evidence of EBV is strong but question remains -

1. Epithelial cell cancer of stomach.

2. Epithelial cells cancers of Tonsils, Thymus, Breasts, Skin, Uterine cervix,

3. Lymphoepithelial cancer of salivary glands.

Questionable association with EBV -

1. Renal cell cancer

2. Thyroid gland

3. Urinary bladder.

4. Leiomyoma / Leiomyosarcoma.

B. Non-Malignant Diseases.

Autoimmune diseases like 1.Sjorgen's syndrome 2. Rheumatoid arthritis. 3. SLE, 4.Type 1 Diabetes mellitus. 5. Hashimoto thyroiditis. 6.Graves' disease. 7. Multiple Sclerosis. 8. Hairy Leukoplakia.

Chronic illness.

    1.Long COVID-19

2. Chronic Mononucleosis. Symptoms are fatigue, fever, lymph node enlargement, Hepatosplenomegaly, headaches, joint pain and muscle pain.

3. Parkinson's disease and Acute cerebellar ataxia.

4. Irritable Bowl syndrome.

5. Chronic fatigue syndrome.

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Chickenpox

                                Chickenpox ( varicella)

                               P.K.Ghtak,MD.

Varicella virus causes Chickenpox when a person contact the virus for the first time. After recovery, the virus remains dormant in the nerve cells of the cranial nerve ganglia,  dorsal root ganglions of the spinal cord and autonomic ganglions for the entire life of the individual. In opportune moment, the virus re-emerges and produce Zoster (Shingles) and occasionally produce more serious neurological complications. The virus called Varicella Zoster Virus (VZV)

VZV is a alpha herpesvirus. It is human herpesvirus 3 and has almost identical genomes of Simian Pox virus (SPV). Some of the pathophysiological features of VZV are similar to Cytomegalovirus.

VZV has a double stranded DNA genome, surrounded by a nucleocapsid followed by a protein tegument and a lipid envelop.

The initial infection activates cellular immune reactions followed by IgM, IgG, and IgA antibodies production. Cellular immunity provides life long lifelong protection.

In the USA a vaccine is routinely administered as a part of childhood vaccination, the vaccine is made from attenuated life VZV. Adults over 50 yrs of age are urged to take a second approved Zoster vaccine. This is a non-live recombinant zoster vaccine. It is given by intramuscular injection – two doses 2 to 6 months apart. It reduces the risk of herpes zoster by 92 %. The vaccine is named Shringrix and it protects vaccinated people for up to 9 years.

Clinical feature of Chickenpox.

Chickenpox infection is a common infection of childhood. It is a highly communicable disease. It is estimated that over 90 % of the world population had chickenpox. The mode of infection is by droplets and also the virus becomes airborne from raw wound of an open vesicles. The incubation period in 10 to 15 days may be delayed to 3 weeks. The initial symptoms are cold and cough, fever, and body aches followed by erythematous skin rashes follows by papular eruptions appears the next day. The papular lesions appear first on the chest, back and then on the face followed by outwards spread to arms and legs but no lesions appear on the palms and soles. In 2 to3 days vesicles become embellicated and crusted. Mixed rashes consisting of papules, vesicles and crusted lesions are present at anytime which is a distinguishing feature of chickenpox from small pox. The skin rashes are intensely itchy. In about one week the scabs begin to fall off. From the day of onset of respiratory symptoms to crusting all vesicles the patient remain infectious.

Venerable population are pregnant women who did not have chickenpox before. HIV infection, cancer chemotherapy, long term steroid therapy and organ transplant patients.

Complications:

Young adult male and adult males in some instances develop orchitis, epididymitis and testicular atrophy. In a few cases pancreatitis is reported. In rare cases viral pneumonia can occur.

Neurological complication from Chickenpox.

The common neurological complication is cerebellititis (infection of cerebellum). In rare cases central vein thrombosis and stokes are recorded.

Since childhood vaccination is introduced in the USA, hardly any new chickenpox is seen. Immune status is judged by serology. It is a mandatory test for all prenatal care in the USA.

Diagnosis and Treatment:

Clinical features are distinct and since most older adults had chickenpox that helps them in diagnosis. In doubtful cases viral DNA, specimen obtained from a vesicle, by PCR may be required.

The choice of antivirus drug is Acyclovir. The oral dose is 800 mg  given 5 times a day for 5 days.(200mg/Kg/day). Other antiviral used in Cytomegalovirus infection are also effective in chickenpox.

Varicella-Zoster Immune Globulin (VZIG):

VZIG is given as IM injection, never by IV. The therapy is a passive transfer of immunity in life threating situations.

Indication of VZIG.

Premature infants of immune-negative mothers. Pregnant women past 1 weeks of gestation with unvaccinated or negative history of previous VZV infection (seronegative). Bone marrow transplants in seronegative patents. Immune compromised patients.  Passive immunity is followed by vaccination. 

Reactivation of VZV.

Immunosuppressive conditions lead to the reactivation of VZV.  Nerve cells of all cranial nerve ganglions, Autonomic ganglion and sensory Dorsal Root Ganglion of spinal nerves are at risk of resurgence and Zoster lesions. The virus produces vasculopathy with loss of cells and focal migration of inflammatory cells and giant cell formation. This causes pain and paresthesia and loss of motor function of the dermatome the nerves supply. The pain is sharp and severe and localized to the dermatome involved and strictly limited to one side of the body. The motor fibers of the spinal are commonly effected producing palsy ( partial paralysis). The vesicles appear as bunches, like grapes are strictly limited to the side of the body and do not cross the mid line. Multiple dermatomes and contiguous dermatome and multiple dermatomes of different areas of the body may be involved. In some instances no skin lesions develop, only pain is experienced.

The common places herpes zoster appear are the chest wall followed by the face. Of the cranial nerve the 5^th cranial nerve zoster is most common. It produces pain and vesicular lesions of one half of the face, eyelids and forehead.

In rare circumstances the virus travels to the brain and meninges via the sensory nerve from the Geniculate ganglion (ganglion of the 5th cranial nerve) producing meningoencephalitis.

Ramsay Haunt Syndrome:

Ramsay-Hunt syndrome is a special case of herpes zoster involving multiple cranial nerves. The ganglia of the 7^th,8^th, 9^th and 10^th nerves are involved. this causes severe pain, vesicular eruptions on dermatomes and mouth, tongue and throat of the area supplied by the nerves.. Skin lesions appear on the external ear canal, pinna (supply by 10^th), one half of anterior 2/3rd of the tongue and soft palate and uvula. 7^th cranial nerve lesions produce lower motor neuron paralysis and stapedius muscle. 8^th cranial nerve lesion produces loss of hearing hearing, tinnitus, nausea, vomiting, vertigo and nystagmus. 9^th and 10^th cranial nerve lesions result in paralysis of tongue, muscles of deglutition. Chorda tympani nerve lesion causes loss of taste sensation.

Diagnosis and treatment:

Clinical feature is diagnostic and confirmation if required the PCR test for viral antigen is available. The choice of  antiviral agent is Acyclovir. Other antiviral agents used in  chickenpox are also effective in Zoster lesions.. In addition to viral therapy, prevention of secondary bacterial infection of the skin and mouth lesions and adequate management of pain by opioid derivates by mouth should be provided.

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Cytomegalovirus

 

Draft Cytomegalovirus;

P.K.Ghatak,MD.

                                                        Cytomegalovirus.

Cytomegalovirus belongs to the Beta Herpesvirus group. Cytomegalovirus is species specific. Herpesvirus 5 is a Human Herpesvirus. Genome specific virulence is characteristic of this virus. It prefer to grow in human fibrocytes and produces a large inclusion body. This gave this virus its name as ” large cell” Cytomegalovirus 5 (CMV ). Once inside the human body it produces primary infection and after the infection subside CMV hibernates in lymphocytes, monocytes, dendritic cells and CD34+ cells and remains dormant for the entire life of the person.

The virus is large in size, has a diameter 200 nanometer and the nucleus contains double stranded DNA and the virus is shaped like a disk. CMV has a large genome with a icosahedral capsid and a dense core surrounded by an amorphous matrix.

Humans are infected in several ways –

 1. when come in close contact with infected person.

2. Through contact with saliva and ingestion of contaminated food and drinks.

3. Via blood transfusion, bone marrow and solid organ transplantation.

 4. Sexual contact.

 5. Placental transmission to fetus.

6. Through breast milk.

The percentage of population infected with CMV varies from 100% in underdeveloped countries to 40 to 60 % in advanced nations.

The incubation is 8 days to 8 weeks, majority of infections , in both healthy child and adults, produce minor cold symptoms or no symptoms at all. Only evidence of infection is the séropositive.

In Immunodeficient patients:

The infection is widespread in immunodeficient patients and people on immune suppressed drugs. CMV infects any organ of the body and in the majority of cases most organs are infected and the outcome is generally bad. Cell mediated immunity is the primary defense against CMV infection. HIV infection and other clinical conditions where CD4+ and CD8+ cell counts are low, the widespread infection is common. Even after a successful antiviral therapy, the recurrence of infection and chronic infection are common.

CMV remains dormant within the cells and reemerges following other viral infection or other illnesses. This characteristic is similar to varicella virus and Epstein Barr virus and Toxoplasma gondii ( a protozoa).

Clinical picture:

The young symptomatic patients present with fever, pharyngitis, cervical adenopathy, and upper and lower respiratory infection. A morbilliform skin rash is generally present, however, skin rashes of various other kinds are also seen. Blood tests may show atypical lymphocytes but the heterophile antibody test is negative (modified Paul Bunuel Test)

In more serious infections - hemolytic anemia and thrombocytopenia are be present. Gastritis and colitis may develop. When GI and urinary systems are infected. a prolonged viral shedding is common occurrence. Meningoencephalitis, myelitis, retinitis, uveitis and neuropathy are some of the serious aspect of nervous system infection.

The CMV infection is difficult to differentiate on clinical ground from Infections Mononucleosis. In CMV the fever generally last longer and lymph nodes enlargements are less extensive.

The definitive diagnosis is by detecting DNS of CMV by PCR method. Blood, urine, and saliva are suitable for PCR test but blood test gives the most conclusive evidence of CMV infection. In post transplant patients tissue biopsy is the preferred test.

Important clinical situation of CMV infection.

A. Congenital CMV (cCMV) infection.

B. Stem cell transplantation in hematological malignancy and solid organ transplantation.

A. Congenital CMV infection (cCMV).

If previously uninfected pregnant woman acquire CMV infection in first trimester, the virus infects the placenta and then infects the developing embryo. Two areas of infections are most critical.

1. Brain development abnormalities and related symptoms.2. Sensory deafness and blindness.

1. Congenital CMV brain and clinical features (cCMV)

Microcephaly, seizure disorder, cerebral atrophy, cystic lesions in the temporal lobes, periventricular calcification and dilated cerebral ventricles, and demyelination. Delayed fetal growth is common.

These changes clinically resemble Cerebral palsy, Multiple sclerosis, Peripheral neuropathies, Leukoencephlomyelitis, and Aicardi-Goutières syndrome (a rare congenital gene mutations resulting in deformed brain and skin lesions).

2. The cCMV is the leading viral, non-genetic, cause of congenital sensory deafness.

Congenital eye infection is a leading cause of childhood vision problem and blindness. Chorioretinitis, uveitis, ophthalmitis and optic atrophy are manifestions of CVM infection. Blindness is due to optic atrophy and detached retina from fibrosis as chorioretinitis heals.

B. Stem Cell Transplants and Solid Organ Transplant is relation with CMV.

General consideration.

The CMV status of the recipients is determined by the presence of IgM and IgG antibodies. In allogenic hemopoietic stem cell transplants, the donor CMV antibody status and immunohistopathology examination of tissue are collected. After the transplantation, if recurrence of CMV is suspected, several additional tests are performed. Presence of Leukocyte CMV pp65 antigen indicates infection and QNAT(quantitative nucleic acid test) is done to determine the viral load.

In both stem cell and sold organ of transplants, if the recipient is seropositive but the donor is seronegative then the outcome of the transplant is the best. The worst outcome in situation where the recipient is seronegative and the donor is seropositive. CMV virus reactivates because of use of immunosuppressive drugs depresses T-Cell count. Immunosuppression is needed to prevent transplant rejection. The graft versus host disease is another cause of reactivation of CMV. Loss of life occurs in overwhelming CMV infection.

T-cell and Hemopoietic transplant.

During pre-transplant phase, high dose of immunosuppressed drugs are use to wipe out all malignant cells from the body. The T-cell count falls to lowest levels. This is the prime reason for the subsequent reinfection.

Prophylaxis against CMV infection.

The choice of drug is Valganciclovir. It is an oral prodrug of Ganciclovir. Ganciclovir is converted to triphosphate form and inhibits DNA replication of CMV. It can produce cytopenia.

Acyclovir is also is used. It is given 800 mg 4 times a day for 12 weeks. Nephrotoxicity and cytopenia are main side effects.

Other drugs:

a. Leterovir. It inhibits viral terminasse enzyme and thereby viral replication. Leterovir can be used more than 100 days without any additional side effects.

b. Foscarnet. It is a phosphate analog of ganciclovir. It inhibit polymerase enzyme. It is less toxic to bone marrow .

c. Mribavir. It is a benzimidazole antiviral drug. It prevent viral UL97 enzyme. It inhibits viral polymerase.

d. Cidofovir. It is anucleotide analong inhibits polymerase enzyme, given IV weekly.

e. Brincidofovir. It is a oral analog of Cidofovir.

Adoptive T -cell therapy.

Harvested T cells, matched for HLA are incubated with specific CMV antigen protein.. The engineered T-Cells are made to multiply in large numbers and then transfused. This is a newer method to control infection in CMV resistant to all drugs.

Vaccine:

A vaccine – Transvax contains viral plasmid that encodes pp 65 and gB glycoprotein is in use in pilot study. Two other vaccines CyMectin and AVX601 contain viral DNA subunit and use a victor to deliver it .

Treatment of CMV infection/recurrence.

Drug of choice for treatment of CMV viral infection and recurrence is Ganciclovir. Ganciclovir is given 5 mg/Kg/ every 12 hrs. for 14 to 21 days.

Acyclovir is effective but response in individual patient varies. It is given IV 500 mg per square meter of body surface every 8 hrs. for 2 weeks. A small amount of TNF given with Acyclovir greatly increase the therapeutic effects of acyclovir.

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Prion Diseases

                                     Prion Diseases

                                               P.K.Ghatak,MD

Draft CJD:

Creutzfel

1.Creutzfeldt-Jakob Disease.

In 1922, a German neurologist Hans Gerhard Creutzfeldt described a patient with a neurogenerative disease. Alfon Maria Jakob described 4 more cases of rapidly progressive neurodegenerative disease, just as Creutzfeldt described. Dr. Jackob credited this new disease to Dr. Creutzfeldt. This rare but an important infectious disease is known as Creutzfeldt-Jackob disease (CJD).

What causes CJD.

It is a Prion (PrP)

These are several ways people can be infected.

1. Spontaneously evolved – spPrP.

2. Consuming beef of animal suffering from Mad-Cow-Disease.

3. PNRP ( gene controlling Prion generation) mutated gene inherited in Autosomal dominant manner.

4. Receiving contaminated Corneal transplants, and injections of Pituitary Growth Hormone extracted from cadavers.

The CJD is a very rare disease, the incident is about 1 in 1 million in the general population worldwide and inherited CJD is only 7.5% cases of CJD, the remaining 85 % cases arise sporadically from unknown cause.

Symptoms:

In the majority of cases the initial symptoms are progressive dementia, ataxia and behavioral abnormalities, beginning age of 55 to 75. Soon patients have dysarthria, myoclonus and mutism There is rapid deterioration of condition and the majority of the patients are dead within 6 months, rarely a few survives for 2 years.

Diagnosis:

EEG shows triphasic sharp waves.

CSF :

Recently a new laboratory method is used, called QUIC or RC QUIC to multiply  PrP sc protein in the CSF or other tissues in sufficient amount for a positive identification of CJD disease.

MRI of the brain typically shows punctate holes in the caudate nuclei.

Histopathology:

A combination of neuronal, gliosis of Astrocytes and spongiform lesions.

Diagnostic test is Western blot detecting PrP sc protein. QUIC is a prefer test nowadays.

2.Variant CJD.

In 1996 the first human case of mad-cow disease was described. It is called Variant CJD (vCJD) to distinguish from from non-animal source of Prion disease. Clinically and pathologically both forms of CJD are the same. Prion particles are concentrated in the brain and nervous tissue of cow, once the practice of adding nerve tissues of dead animal to animal feeds was discontinued the Mad cow disease and vCJD disappeared.

3.Gerstmann-Straussler-Scheinker syndrome (GSS) is very rare disease.

Symptoms develop with dysarthria followed by cerebellar truncal ataxia and progressive dementia. GSS is also a highly progressive and fatal disease.

The defective gene in GSS is not the same as CJD. The P102L gene mutation on chromosome 20 is present in GSS.

4.Fatal Familiar Insomnia.

Initially symptoms are hallucination and panic attacks. A few months later patients are unable to fall asleep and rapidly loose weight and develop dementia and death. Mutation of PRNP gene is responsible for this disease.

5.Kuru.

Headhunters of Papua New Guinea used to be cannibals. They ate the brain of their victims and cooked the brain of their deceased relatives and consumed it during funeral ceremonies, They suffered a terrible neurodegenerative diseases involving muscles of the trunk and extremities.

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Prion

 

                                                        Prion

                                P.K.Ghatak,MD

Dr. Daniel Carleton Gajdusek in 1957, while studying a spongiform encephalitis called Kuru, in the local population of Papua New Guinea who were cannibals, proved that Kuru was an infectious disease when he successfully reproduced the disease by injection the brain extract of Kuru victims in chimpanzees. He theorized Kuru was due a slow growing unknown virus. It became evident that it was not a virus because Ultraviolet radiation did not kill the infective agent, on the other hand, was sterilized by a protein alerting chemical, bleach.

 In 1982,Stanley Prusiner of UC at SF called the infective agent "a proteinaceous particle and named it  Prion.

Prion is simply a protein molecule made up of 259 amino acids. All living animals and plants including yeast have prion in the cell membrane and in the cytoplasm. Neurons have the highest concentration of normal Prion molecules.

Chemical compounds like toxins, snake poison etc. are also compounds of proteins but Prions differ from toxins in that Prions multiply in huge numbers in the victims body, whereas, poison and toxins do not. The Medical community was naturally skeptical that an inert protein molecule could multiply in a victim with having no Nucleic acids or, DNA or, RNA.

Dr. Prusiner proved that the infectious Prion ( PrP sc) , once introduced in to the living cells, it induces change of configuration of normal similar protein molecules to adopt the shape and appearance of the PrPsc. The newly formed PrPsc, in turn make changes more protein molecules and the chain reaction follows.

Normal protein molecule is alpha helical in its molecular folding but abnormal Prion takes beta helical folding. Misfolded protein molecules prevent cells from carrying out normal cell functions, including elimination of metabolic wastes. Accumulated wastes cloak cells to death. Brain cells have high concentration of Prion molecules. As the misfolded cells die, they leave behind many small voids in the brain matters. Loss of vital functions of brain cells result in progressive dementia and movement disorder and other symptoms leading to premature end of life. The pathological process is called spongiform encephalopathy because of the resemblance with a sponge.

In normal individual, the nature has provided a gene called PRNP gene, that regulates rate of conversion of misfolded proteins. When mutation occurs in PRNP gene, the mutation is passed to the next generation by Autosomal Dominant fashion. Normal prion protein PRNP codon 129  also exists in polymorphic forms in association with variants Type 1 and Type 2 genes, arise out of coding errors for amino acid methionine and valine respectively. The combination of these mutations results in 6 subtypes. This explain the variable penetration and low frequency of disease in spite of dominant inheritance.

Daniel Carleton Gajdusek and Stanley Prusiner received Noble prize in medicine in 1976 and 1999 respectively.

These are the notation used when referring a particular Prion and a prion disease.

Normal- PrP.  Scrapi - PrPsc.  Creutzfeldt-Jackob disease - CJD.  Variant CJD - vCJD   Familial - f CJD , Spontaneous -sp CJD.

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Diseases caused by prions in humans are

CJD Creutzfeldt-Jacob Disease.

vCJD (variant CJD).

Kuru.

Gerstmann Straussler -Scheinker syndrome (GSSS),

Fatal Familial insomnia,

In mammals prion causes Scrapie in sheep,

Mad-cow-disease in cattle.

Chronic wasting disease in deer, elk, moose, reindeer and caribou.

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