MRI

                                                                    MRI.

                                                           P.K. Ghatak, M.D.

                                                          ghatak3@gmail.com

The magnetic resonance imaging (MRI) is one of the most advanced bioengineering technologies introduced in medical diagnostic armaments.

The first ever use of MRI took place in Britain in 1980, and then in the USA. Then MRI spread across the globe, limited in the countries by their inability to pay for the high price of the machine and the non-availability of the infrastructure.

History of Magnetic Resonance:

Protons and Electrons when placed in an Electromagnetic field, become excited, either due to absorption or emission of Electromagnetic Radiation. This phenomenon was first observed by the Soviet scientist Y.K. Zavoysky in 1944. The Nuclear Magnetic Resonance was detected by physicists Bloch and Purcell in 1946.

The Nobel Prize in Medicine in 2003 was awarded to Paul Lauterburg, of the University of Illinois and Peter Mansfield of the University of Nottingham, UK, for their discoveries in MRI. However, it must be understood that these two scientists based their work on the works of so many other scientists, and notable among them, are Felix Bloch and Edward Purcell, a pair of Nobel Laureates in Physics in 1952, for their discovery that certain nuclei could absorb and emit radiofrequency energy (Rfw) when placed in a magnetic field.

How MRI came to the medical field:

In 1970, Raymond Damadian discovered that normal and cancer cells had different magnetic properties. John Mallard of the University of Aberdeen, Scotland, used this principle in producing a full body image in 1970. Subsequently, this machine was used at St. Bartholomew Hospital, London, from 1983 to 1993. John Millard was given credit for the first-ever use of MRI in the medical field.

Basic characteristics of human cells that are utilized in MRI.

Every living cell of the body contains water (H2O). The amount of water in normal cells of different tissues, and specially those cells that are diseased, has different levels of water content.

The hydrogen ion of the water is a Proton. In a strong magnetic field, the protons of the body can be manipulated to line up in one direction. A second magnetic field of different strengths and different orientations is pulsed several times a second. This energy knocks off the orientation of the protons and the protons take up another position. When the second magnetic field is completely switched off, the protons begin to go back to their original orientation and emit energy. The energy emitted by cells is proportional to their water content. This energy is collected and synthesized to generate an MRI.

There are two standard images, one is a T1-weighted image and the second is a T2-weighted image. Additional images are the Proton Density (PD) image and Fluid Attenuated Inversion Recovery Image (FLAIR).

T-1 Image:

T-1 image relates to how quickly the nuclei of Hydrogen atoms return to their equilibrium state after being disturbed by an external magnetic pulse. It measures the time taken for the longitudinal magnetization of a tissue to recover. T-1 is also called the Longitudinal Relaxation Time image. Different tissues have different T-1 values, leading to varying rates of recovery and influencing the contrast in MRI images.

T-2 image:

The T-2 image sequences are controlled by the Repetition Time (TR) and Echo Time (TE) values. It measures the signal decay in the transverse planes. It is also known as a transverse relaxation image.

By manipulating the timing of RF pulses and sequences, the T-I and T-2 images are generated. T-1 images show normal anatomy in great detail. The T-2 images highlight the inflamed area and edema.

Proton Density Image:

The tissues with a high concentration of protons generate a strong signal and appear as the brightest image by minimizing the impact of T- and T-2 differences, by using a long TR and a short TE.

FLAIR image:

It is designed to suppress the signal from the cerebrospinal fluid (CSF) and make signals coming from diseased portions of the brain and spinal cord more intense. The fluid appears dark and the pathological parts stand out due to enhanced contrast.

How different parts of brain appears under T-1, T-2, FLAIR and PD views:

Part	T-1	T-2	FLAIR	PD
CSF	Dark	Intermediate	Darker	Dark
Fat	Bright	Very bight	Bright	Very bright
Air / sinus	Dark	Dark	Dark	Dark
Blood	Dark	Dark	Dark	Dark
Blood vessels	Dark	Dark	Dark	Dark
White Brain Matter	Intermediate	Darker than Gray matter	Intermediate	Darker than Grey matter
Gary Brain Matter	Darker than white matter	Intermediate	Intermediate	Intermediate
Bone	Dark	Dark	Dark	Dark
Bone marrow	Bright	Variable	Dark	Variable
Brain Stem	Intermediate	Intermediate	Intermediate	Intermediate

The MRI images can be synthesized in three planes – Axial, sagittal and Coronal Planes.

Contraindications and precautions for MRI:

The MRI suite is specially built because a very strong magnetic field is generated in this room. Any ferromagnetic metal, free or embedded in the body, will be magnetized and move towards the strong magnetic force.

This is a prime concern for patients having a cardiac pacemaker, an internal cardiac defibrillator, and inferior vena cava filters implanted in their bodies. The current manufacturers of these kinds of medical devices have responded and now manufacture the devices with non–non-ferromagnetic metals.

The patients going for an MRI should bring to the attention of the MRI personnel if they have any of the following devices implanted in the body.

Cardiac pacemaker, implanted pacemaker, vascular shunt, Skull fracture, or craniotomy repaired with metals. Bullet or projectile injury, implanted simulators, deep-brain simulators, and Vegas nerve simulators. Stimulators of the urinary bladder, spine, and nerves. Metal replacement of joints. Cochlear implants. Insulin pump and narcotic or any medicine delivery devices. Programmable shunts, aneurysm clips or coils. Venous filters. Continuous glucose monitor. A medication patch is applied to any part of the body. Any other devices attached to the body are not mentioned.

It is important to note that not all of these devices implanted in the body are contraindications for taking MRI images, but the radiologist must know beforehand so that proper precautions are taken during the operation of the MRI machine and also for the correct interpretation of the images.

Actual procedure:

The patient is taken to the waiting room of the MRI suite, provided with a gown and asked to change. Asked to remove jewelry, watches, credit cards and hearing aids, pins, metal hair accessories, pens, pocketknives, nail clippers, multitool, and coins.

History of allergy to medication, iodine, shrimp and any IV medication or previous use of IV contrast.

The patient is taken to the scan room. The patient lies on a padded platform, ears are covered by noise-canceling ear pads and eyes are covered by a black eye patch. And provided with a panic button, just in case to call the operator's attention.

The patient is instructed to lie still and not to panic. The machine makes repeated loud bangs during scanning and parts of the machine come within inches of the parts under examination.

There are also open MRI machines. 

Duration of scanning:

It takes 45 minutes to an hour to complete a scan.

IV contrasts containing Gadolinium are often used to enhance the tumors or clearly delineate blood vessels or hematomas.

_________________________________________________________

footnote:

Ferromagnetic metals are Iron, Nickel, Cobalt, Gadolinium, Dysprosium, Terbium, Ferric Stainless Steel, Neodymium, and Iron-Boron Alloy

If you want to see what an MRI looks like, copy this link and paste it into the browser -

https://www.imaios.com/en/e-anatomy/brain/mri-axial-brain

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Bacteriology and Robert Koch

 

                             Bacteriology and Robert Koch

                                 P. K. Ghatak, M.D.

                                  ghatak3@gmail.com

The birth of Bacteriology had to wait till the microscope was invented. But there is considerable controversy regarding who actually invented the microscope. In 1590, Hans Lippershey in Holland applied for a patent for a microscope and naturally, he was credited for inventing the microscope. At the same time, Antonie van Leeuwenhoek lived in the same town. He made a microscope of his own design. He found living organisms in the rainwater and then he began examining everything with his handheld microscope. In 1676, he reported his findings to the Royal Society of London, England. He reported observing various forms of small and smaller living organisms and he called them Animalcules. The medical society credited him for his invention of the microscope.

Reproduction of the first compound microscope made by Hans and Zacharias Janssen, circa 1590. From the National Museum of Health and Medicine, Washington, D.C. (Image credit: Public domain.)                                         

The German scientist Ferdinand Cohn (1828 -1898), after years of painstaking study of the various contradictory and confused publications on this subject, put his straightforward classification of bacteria in 1870. Many consider Cohn the originator of bacteriology but the majority gave the credit to Robert Koch.

The Spontaneous Generation of Life:

Louis Pasteur proved spontaneous generation was a myth.

People believed in the spontaneous generation of life. This was an age-old concept from the observation that maggots grew on a piece of meat or cheese when left outside. Even Charles Darwin stated in his “Origin of Species” book that the human body could be conceived as a creature susceptible to the laws of nature.

 Louis Pasteur (1822-95) proved that the microscopic living organisms were turning grape juice into vinegar and the spoiling could be prevented by killing the microorganisms by heating the grape juice and then rapidly cooling it. This process is known as Pasteurization

Lois Pasteur became a household name for his rabies vaccine. In 1885, he saved the life of a nine-year-old boy, named Joseph Meister, who was mauled by a vicious rabid dog. Pasteur administered his own laboratory-grown vaccine. The Incubation period for rabies is 2 to 8 weeks, usually 3 weeks. If an adequate level of antibodies can be raised in the body by administering a vaccine during the incubation period, then rabies would not develop. Pasteur's vaccine saved Meister; he did not develop rabies. Pasteur was a pioneer in attenuating the virus by successively passing it through a suitable laboratory animal, thereby making the virus much less virulent but retaining the antigenic property, and then using that attenuated virus as a vaccine. He was working for several years with the rabies vaccine when Jeseph was brought to him by his mother,

Because Pasteur was dealing not only with bacteria but also with viruses, parasites and fungi, he called the study of the microscopic organisms Microbiology, instead of bacteriology.

Anthrax:

Like the wine industry in France, humans and livestock in Germany were dying from an unknown disease after a short illness. The task of finding the cause of illness and a cure fell on the shoulders of a multi-talented medical doctor and head of bacteriology of Prussia (then in Germany), Dr. Robert Koch. He pretty soon found a rod-shaped bacterium in the blood of the dead sheep.

He invented an oil immersion lens for a microscope for a close-up view. He developed ways to photograph the bacteria. He grew bacteria in pure culture in his specially formulated solid growing media on an agar plate. By producing pictures of bacteria, he left no doubt about the presence of the bacteria, Anthrax, which was killing the animals. He collected soil and vegetation from the pastures, detected spores of Anthrax and documented the full life cycle of Anthrax. Spores were also infectious; if the spores were ingested or inhaled, the spores germinated into the vegetative form and produced illness.  He recommended burning the carcass of the dead animal or buried deep underground, in order to prevent spore formation and limit the spread of anthrax.

The Germ Theory of Illness:

By providing direct evidence, he left no doubt that germs are the cause of illness and after he found Mycobacterium tuberculosis which was the cause of  TB, he put forward his Germ Theory of Illness.

Koch's Postulates:

After Koch discovered bacteria and medical communities accepted his germ theory, everywhere, many were finding bacteria and linking the bacterium to that illness. There were no checks and balances and no established criteria for verifying those claims. Koch designed 4 basic criteria for accepting a specific bacterium for a specific disease. It is known as Koch's Postulates.

Koch's four postulates are:

The organism causing the disease can be found in sick individuals but not in healthy ones.

The organism can be isolated and grown in pure culture.

The organism must cause the disease when it is introduced into a healthy animal.

The organism must be recovered from the infected animal and shown to be the same as the organism that was introduced.

The fundamental concept of Koch's postulates is still operative today with a few adjustments, for example, asymptomatic carriers like Typhoid Mary; recurrence of disease after apparent cure, as latent tuberculosis. Some human infectious disease has no real animal counterpart, as in the case of cholera.

Asepsis:

Due to sheer ignorance, doctors have killed thousands of patients over centuries, examples are plenty but to mention a few- bloodletting in Postpartum hemorrhage, antiphlogistic plaster in lobar pneumonia [https://digirepo.nlm.nih.gov/ext/dw/101299441/PDF/101299441.pdf] and performing an operation without scrubbing hands and delivering babies with unwashed hands.

Joseph Lister ( 1827 -1912).

He introduced soap and water washing hands and dipping hands in an antiseptic solution prior to vaginal deliveries. This simple hygienic method cuts postpartum infection and death to a minimum.

Edward Jenner (1660 -1720)

He introduced the cowpox vaccine for the sure prevention of smallpox – one of the three curses of ancient human civilization, the other two are Cholera and Leprosy.

Elie Metchnikoff (1845 – 1916).

In the early formative days of immunology, she demonstrated the phagocytic property of Neutrophils. Neutrophils devour bacteria before they have a chance to start an infection. The cellular immunity was born.

Emile Roux (1853 -1915) and Alexandre Emil Jean Yersin (1749 -1823):

They demonstrated the presence of the Diphtheria toxin in the liquid of the bacterial culture in broth.  This opened the door for an effective way to mitigate paralysis of the muscles of breathing and swallowing.

Paul Ehrlich (1854 – 1915):

He found an effective agent for African sickness and introduced Salvarsan for the treatment of Syphilis.

Alexander Fleming:

Fleming introduced the first ever antibiotic - Penicillin. Penicillin saved thousands of lives by healing the wound infections, especially of the WW soldiers.

Just looking at the dates of a few pioneers in infectious diseases barely mentioned here, one can see that microbiology had a precocious childhood and became an adolescent by the end of 1900s. Microbiology reached adulthood with the discovery of DNA and RNA analytic methodologies. The identification of microorganisms by stained slides and cultures is often unnecessary since rapid and more accurate identification is possible by detecting the specific DNA / RNA of bacteria and microorganisms by the PCR test.

                                                 Robert Koch.

The great German physician cum bacteriologist was born in Chausthal, Germany, in 1843. He graduated in Natural Science from the University of Gottingen in 1866. Then Koch went to work under the direction of Jacob Henle ( the man after whom the Loop of Henle of the Kidney is known), and there he came in contact with another great German, Rudolf Virchow. He subsequently entered the medical college and graduated in 1866. He received a microscope from his parents as a graduation gift. That changed the trajectory of his passion and he immersed himself in the pursuit of finding the cause of diseases. After finding the bacterium Anthrax and later a mycobacterium for Tuberculosis, he proposed the Germ Theory of Illness. And put an end to the myth – the spontaneous generation of life.

He was awarded the Nobel Prize in Medicine in 1905 for his research on tuberculosis.

A war broke out between Germany and France in 1870. He volunteered as an army doctor and served for 2 years. At the end of the war, he was made a district medical officer in Wotszten, Germany (now in Poland) and accepted the position of the director of the Bacteriology laboratory. His innovations in laboratory work are:

       1. New method of bacterial culture using solid media containing agar and gelatin.

2. Working with his associate, Richard Petri, he improved his solid culture media and made a disc-shaped culture medium, which is known as the Petri dish, which is still used in all bacteriology laboratories today.

3. Designed a condenser of light for the microscope.

 4. Used an oil immersion lens for further magnification of objects.

5. Developed Microphotography, direct photography through the microscope.

Anthrax and Koch's Postulates: - see the bacteriology section, above.

Cholera:

A cholera epidemic broke out in Egypt in 1883. The German government sent Dr. Koch to Egypt as the head of a medical mission with the task of finding the cause and control of infection. Because Dr. Koch was employed by the government, his research papers were not published in medical journals; instead, all his work on cholera was dispatched to the German government and those papers were made available to newspapers. He reported finding a comma-shaped bacterium in the mucosal layer of the small intestine during autopsy, but not in the blood vessels or in the distal organs and tissues. Before he could find a suitable animal for the experiment and grow the bacteria in a pure culture, the epidemic in Egypt subsided. He requested and was granted permission to move to Calcutta for the continuation of his research,  where cholera was still raging.

He arrived in Calcutta in December 1883. He was able to culture the comma-shaped organism. In one of his dispatches to the German government on January 7,1884, he stated that he had successfully isolated the bacteria in pure culture. The autopsy findings and the nature of the bacteria were the same as those in Egypt. He detected this curved bacterium in drinking water, ponds, rivers, and in the clothes of cholera victims and relatives, and even in the vegetation. He recommended boiling drinking water as a precaution. He did not find a suitable animal for further study of cholera. Dr. Koch found enteritis of the small bowel in cholera victims and predicted that the symptoms and fatalities in cholera were due to cholera toxins, and not due to septicemia.

The credit for identifying the cholera toxins and defining their properties went to Dr. Shambhu Nath Dey of the Medical College of Calcutta. In 1959, he published his research paper in the journal Nature and described an endotoxin and another toxin, the exotoxin of cholera. Endotoxin is heat-labile and produces severe watery diarrhea and hyponatremia and death. Endotoxin activates the enzyme Adenyl cyclase, which activates cyclic AMP. Cyclic AMP opens the pores of enterocytes of the entire small intestine, and the plasma of the blood is depleted rapidly and producing vasomotor collapse and death. The exotoxin is heat stable, antigenic, and has no enzymatic properties.

Tuberculosis:

Before Dr. Koch proved tuberculosis was a bacterial infection, people believed tuberculosis was an inherited disease. Koch was engaged in research on tuberculosis for many years. He developed a new bacterial staining technique by making the smears on a glass slide and covering the smear with a coverslip, and then treating it with Methylene blue and potassium hydroxide for 24 hrs. Using this stain, he was able to find a slender, long bacterium. He went to isolate the bacteria and fulfilled all 4 criteria of Koch's postulates. He announced his findings in the Berlin Physiological Society meeting on March 24, 1882.

Tuberculin:

Koch continued to work on tuberculosis in order to find a cure. He announced discovering a substance that could arrest tuberculosis at an international medical congress in August 1890. He called it Tuberculin. He did not reveal the chemical nature of tuberculin. He extracted a liquid from the tuberculosis culture and then dissolved it in glycerine. But tuberculin failed totally to control tuberculosis; instead,  the tuberculin reactivated old TB lesions and produced severe allergic reactions. Before tuberculin use was discontinued, 124 people died from reactions after receiving a tuberculin injection.

Tuberculin Test:

Clemens von Pirquet (1874 -1929), a professor in medicine at the University of Vienna ( who discovered Serum sickness and Antigen-Antibody Reaction), developed a skin test using Koch's tuberculin for the detection of TB infection. However, the skin test was unreliable due to the presence of contaminants.

Charles Mantoux purified the tuberculin and reintroduced the skin test, PPD             (purified protein derivative of tuberculin) in 1907 and named it the Pirquet test but now it is known as the Mantoux skin test used for detecting TB infection.

Koch's Phenomenon:

People who have active tuberculosis, if they receive the tuberculin or BCG vaccine, develop severe allergic skin reactions; the skin at the injection site becomes necrotic and ulcerates. This is known as Koch's phenomenon.

Local Immunity:

Koch went to German New Guinea to investigate malaria. He discovered that the local people carry a high amount of malaria parasites in their blood but do not suffer from malaria, whereas the visitors from other countries fell sick in a very short time. He explained this resistance to malaria in the local people was due to the development of immunity from prior infections. Investigators looked into it at a later date and found Koch was right.

Other areas of Koch's contribution:

In the early days of his long career, Dr Koch conducted the investigation of mitochondrial function and discovered the Succinic acid in the cycle, which is known today as the Krebs Cycle.

He also contributed to detecting the cause of the following diseases -

Typhoid fever, Trypanosomiasis. Diphtheria, Syphilis, and Plague.

Where Koch was wrong:

Introducing Tuberculin without further scrutiny and giving the manufacturing right to a private company was the biggest blunder of his distinguished career as an investigator.

He steadfastly believed that Bovine tuberculosis was not a danger to humans. It is an irony that his discovery of the bovine tubercular bacillus gave birth to the BBC vaccine which stemmed the tide of childhood infection of TB.

BCG vaccine:

Albert Camette of the Pasteur Institute, in collaboration with Camille Guerin, a veterinarian who was suffering from TB, began working on developing a bovine TB vaccine. After 230 subcultures in 13 years, they found a totally non-infectious TB bacillus but it retained its antigenic property. In 1921, they administered the vaccine to an infant whose mother was suffering from advanced TB. The vaccine saved the infant and the child remained healthy while the mother died of tuberculosis. That was the beginning of the BCG vaccine.

Downfall:

In 1893, Dr. Koch divorced his wife, and within two months, he married an actress. The fiasco with Tuberculin diminished him, and people also accused him of greed for giving the manufacturing rights of Tuberculin to a private company for money; at the same time, his research was supported by the German government. He was also accused of attempting to sell the license to an American company for a large sum of money for manufacturing and marketing.

He suffered a stroke and died in 1910.

A final word:

Among the giants in public health and clinical medicine, none stands taller than this trio - Jenner, Pasteur, and Koch. Koch's talent was multidisciplinary, from biochemistry to defining the parameters of immunology. Koch was an inventor of gadgets as well as a visionary. His work on tuberculosis alone will be remembered for centuries to come.

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Vaccination and Edward Jenner

                      Vaccination and Edward Jenner.

                        P.K.Ghatak, MD.

                      ghatak3@gmail.com

In 1980, the World Health Organization (WHO) declared Smallpox was eliminated from the earth forever. The world stopped to thank Edward Jenner for his gift, the Vaccine, to humanity.

It may seem strange but true that Dr. Edward Jenner was not the first person to notice that having cowpox provided lifelong immunity to smallpox; nor was he the first to produce a vaccine against smallpox. That honor goes to ancient India, China and Africa.

People, from the beginning of human civilization, learned from experience that surviving a smallpox ordeal protected them from future smallpox.

In India:

They searched and found a way to introduce smallpox under controlled conditions. They called the process Tika, and the court-appointed people who administered Tika were called Tikadars. They collected pus from smallpox pustules of a patient and applied a drop of the material on the skin of the arm of an uninfected individual and made superficial cuts with a sharp scalpel in the skin, going through the pus. The process was not fully safe; some developed full-blown smallpox and died. However, the vast majority of vaccinated people were protected. The vaccination was only available for the royal family and high officials. Vaccination reached China through Tibet.

In China:

The Chinese collected scabs from smallpox patients, dried and pulverized the scabs into a powder. They introduce this power in the right nostril of males by a silver blowpipe and in the left nostril of females. The Westerns called this a Variolation. China claimed variolation was an original Chinese invention.

In Istanbul, Turkey:

In 1718, Lady Mary W. Montague, the wife of the British ambassador to the court of the Ottoman sultan in Istanbul, observed and was impressed with Variolation. She asked Dr. Charles Maitland, the embassy surgeon, to variolate her 5 year old son. This was effective. She wrote to her friends in England about variolation in order to protect people from smallpox.

In England:

Lady Montague returned to England, and in 1721, she asked Dr. Maitland to variolate her 4 year daughter in the presence of royal physicians. This was also successful. Maitland was granted a license to practice variolation in England. In 1722, he successfully inoculated two daughters of the Prince of Wales. The process gradually spread all over Europe.

In a village in England:

In 1774, a farmer named Jesty, in Yetminster, knew from his own experience the protective property of cowpox. He deliberately infected his family with cowpox. Using the material from lesions on the cow's udder and making scratches on the skin with a stocking needle, and rubbing the material on the skin lesion. All of them survived the epidemic that was raging through the country.

An epithet is erected to memorialize the event, as shown below. [taken from BBC publication].

In another village:

In the 1760s, a country doctor, Dr. John Fewster, practiced vaccination in the village named Thronbury, Gloucestershire, England. His method of vaccination was almost similar to the one described earlier.

The virus:

The smallpox virus is known as Vaccinia. It belongs to Orthopoxvirus. Orthopox viruses are zoonotic (viruses can infect humans from animals). There are 12 important orthopox viruses. Some of these viruses are species-specific for one kind of animal, but most are infectious to a wide variety of mammals and birds.

Chickenpox appears close to smallpox clinically, but in fact, it is a completely different virus called the Herpes varicella zoster virus.

Cowpox virus is known as CPXV.

Monkeypox virus is called the Mpox virus.

Camel pox virus is called CMLV

Mice pox virus is called Ectromelia virus (ECTV).

Vaccinia virus is large, shaped like a brick, and contains 170 to 230 genes. It is a double-stranded DNA virus. The centrally located genomes are involved in replication within the cytoplasm of the cells, in contrast with most viruses, which replicate inside the nucleus. The peripherally located genes manipulate the victim's immune system and promote cell death.

Smallpox is called Variola in medical science. This term came from Switzerland in 570 AD, from a Latin word, Varius or Varus, meaning mark on the skin.

Chicken pox is called Varicella.

Dr. Edward Jenner:

Edward was born in 1749. Edward Jenner was Stephen Jenner's son, a priest in Berkeley, Gloucestershire, England. After completing his studies, at the age of 13, he went to work for a country surgeon. In there, he heard the story of dairymaids who had cowpox, did not contract smallpox and they had an unblemished face as proof (in contrast with pox-pox-marked ugly faces of survivors of smallpox). At age 21, he completed a two-year apprenticeship under the famous surgeon John Hunter and learned the systematic study of diseases. Thereafter, he returned to his own village and began a general practice. He studied the " mystery of cowpox in preventing smallpox." He understood the basic concept of immunity. He collected cowpox material and began inoculating people. Variolation and inoculation were often used interchangeably. [Inoculation, a Latin word meaning graft, the term was derived from it]

He experimented on a 8 year old boy with pus obtained from lesions on the hand of a dairymaid. Two months later, in July 1796, he inoculated the boy again with pus obtained from a smallpox patient. The boy did not develop any illness. He wrote this case report and added his concept of immunity, and sent the paper to the Royal Society for publication. But the paper refused to publish it. He resubmitted the paper with additional cases. In 1797, the paper was published. He named his procedure as Vaccination.[vacca = cow, vaccinia = cowpox.]

He began publicizing and teaching doctors about vaccination, even to the point of ruining his own practice. In 1802, the British parliament granted him 10,000 pounds and again 20,000 pounds to compensate his time and materials. Jenner supplied anyone who requested the vaccine and often sent his assistants to teach the procedure. Jenner sent his vaccine to Benjamin Waterhouse of Harvard University. Dr. Waterhouse gave some of it to Thomas Jefferson. Due to Jefferson's efforts, the Institute of National Vaccine Program was set up in the USA.

In 1840, by the act of the British parliament, the following law was adopted:

     I. Vaccination was official policy, and variolation was banned for smallpox inoculation.

2. The government provided the vaccine, made from cowpox, free of charge to all.

In the subsequent years, the vaccination against smallpox reached most European countries and the New World. And the WHO took the vaccine to every corner of the earth.

Jenner was the first person to use a scientific method to control an infectious disease by the use of a live agent. In the late 19^th century, it became evident that immunity declined over the years and revaccination was necessary. Jenner suffered a stroke and died several months later in 1823 and was buried in a Berkeley church.

The WHO and Vaccinia Vaccine:

In 1959, the World Health Organization took up the challenge of eliminating smallpox. The Soviet Union supplied the heat-stable, freeze-dried Vaccinia vaccine. On 8 May 1980, a little over 100 years after Jenner began vaccination in England, the WHO announced that the world was free of smallpox and recommended that all countries cease vaccination.

No one knows:

The smallpox virus genome structure is deciphered and is utilized to trace the interspecies migration of orthopoxvirus and mutations of the virus. It is a valuable tool for studying the source of an outbreak and how to start manufacturing vaccines. In 1939, scientists looked for the origin of the virus used for vaccination. To their surprise, they discovered that NONE of the 6 varieties of vaccine used in the worldwide vaccination program contained cowpox or horsepox virus. In fact, they have not come up with an answer as to when and how the switch of virus took place. However, the present vaccine has been found to be effective against Mpox. And new vaccines are on the way.

Plague

 

                                        Plague.

                                     P.K.Ghatak, M.D.

                                     ghatak3@gmail.com

Plague is an infectious disease of rodents and small wild mammals. It is caused by a bacterium, Yersinia pestis. Rats are the natural victims and also hosts of Yersinia pestis. Y. pestis spreads among the animals from the bites of the infected fleas known as Xenopsylla cheopis. Humans are accidental victims. Besides the bites of infected rat fleas, humans can also contract the infection while handling dead, infected animals with open skin lesions, consuming dead animals, and occasionally from a patient by inhaling aerosolized bacteria.

The bacteria:

Yersinia pestis belongs to the family of Enterobacteria.

Yersinia pestis evolved from Y. pseudotuberculosis. Y. pestis has acquired three important Plasmids over the years, which have made Y. pestis more aggressive, invasive, and successfully defeat host immune defense, weakening the endothelial adhesion between cells and producing extensive subcutaneous hemorrhage.

Y. pestis is a coccobacillus, measuring 0.5 to 1.0 micrometers by 3 micrometers. It has a rigid cell wall composed of peptoglycan, and another outer wall made with lipopolysaccharide, which secretes a biofilm, which enables Y. pestis to adhere to the cells of the victims. When stained with Giemsa stain, the bacterium resembles a safety pin due to the presence of metachromatic granules at both ends. Y. pestis is non motile. It grows in most culture media and prefers 28 degrees C, but can also remain active at 40 degrees C. It thrives equally well in high and low oxygen environments.

The Flea.

Out of two thousand fleas, only about 100 species of fleas are known to carry Yersinia and then, only three species are related to plague outbreaks. The most universal is Xenopsylla cheopis; the second one is X. brasiliensis, common in Africa, South America, and India; and the last one is X. astia, seen in Southeast Asia. In endemics,  Pulex irritants, a human flea and Ctenocephalides canis and felis, cat and dog fleas, also act as vectors.

The fleas are ectoparasites. The insect is small in size and grows to a maximum size of 6 mm. It is flat from side to side, has 3 body parts, but only the larger abdomen is visible without magnification. There are two appendages in the mouth with saw like serrated edges, used in cutting the skin of victims for blood. It can jump up to 2 feet with its long hind legs. Flea also finds house cats and dogs as good hosts, and the fleas can also infest humans.

Both male and female fleas must have a twice-daily blood meal for survival. The female fleas must have a blood meal before laying eggs in the rat holes. Fleas take 0.1 to 0.2 microM of blood from the victim. The fleas do not search for their prey; they wait till a victim arrives and detect by sensing temperature and humidity variations. Then it jumps and lands on the victim. 

If the rat is not infected, the fleas keep on living on that rat for 100 days; if infected, the fleas die. Only the female flea drops to the ground to lay eggs and then waits for her next victim. When the rat has plague bacilli, the bacillus starts to grow in the rat's gut, and the growing colony produces a biofilm in the gut. The lumen of the esophagus is narrow due to a sphincter, and the biofilm produces a complete block and intestinal obstruction. The fleas feel starved and change hosts and bite repeatedly but fail to swallow, instead regurgitate their gut content and thereby spreading the infection among the rats, small mammals and humans.

Life cycle of the flea.

The flea undergoes 4 stages to complete a life cycle:  egg, larva, pupa, and imago or adult. Each gravid flea lays 30 eggs in the dart of the rat hole, every day for 50 to 100 days. In a week, the eggs hatch. The larva eats rat feces, unhatched eggs, and organic compounds. It molts twice in 10 days. A cocoon is formed in which a pupa grows and 14 days later, an imago or adult flea is born. The young flea must have a blood meal before it can sexually mature.

The rat.

The common household black rat, the Rattus rattus, and the brown sewer rat, the Rattus norvegicus, act both as the reservoir and victims of the plague bacillus.

When an infected flea bites the rat, if the inoculum is small, the rat becomes sick but recovers and then develops a kind of immune understanding with Yersinia pestis. The bacterium multiplies in the rat and the rat survives. This creates a permanent rat reservoir of the plague bacillus. If the rat gets a heavy dose of Yersinia, it dies.

The humans.

The incubation period of plague is 2 to 8 days. At the site of a flea bite, an eschar develops. But it may be missed. A papule, nodule, vesicle, or pustule may be visible in some patients. The initial symptoms are chills, high fever, headaches, and prostration. The course of illness may take one of the three forms – Bubonic plague, Septicemic plague, or Pneumonic plague.

Bubonic plague:

In 24 hours after a flea bite and the beginning of fever, many marble-sized axillary or inguinal lymph nodes develop. These enlarging nodes are painful and warm to touch. After the initial regional lymph node enlargement, the nodes in the axilla and the cervical areas also enlarge. The nodes become matted together. The enlargement of the liver and spleen is common. Blotchy subcutaneous hemorrhage develops at various places, and the fingers and toes turn black from the development of gangrene. This gives the patients a black appearance and so the bubonic plague was also called Black Death. Without the use of antibiotics, the death rate from bubonic plague is 30 %.

If the initial immune reaction fails to limit the infection, the bacteria enter the blood vessels. The bacteria become widespread and septicemia develops. The signs indicating a poor outcome of septicemia are: hypotension, circulatory collapse, hypoxemia, and cerebral symptoms dominate. In the days with no antibiotics, the death rate was 100%.

Septicemic plague:

Septicemia develops from bubonic plague, but septicemic plague may also develop without the bubonic stage.

Pneumonic plague:

The Yersinia pestis can be airborne in droplets when a patient coughs. The bacteria enter the victim's body through the nose and throat. The symptoms are - high fever, sore throat, and cervical adenopathy. This is followed by cough, chest pain, shortness of breath, hypoxemia, and hemoptysis. Within a day or two, septicemia develops. Mortality was 100 percent in pre-antibiotic days.

Diagnosis of plague:

The CBC and other tests reveal an aggressive acute infection. A sample of fluid obtained from the base of a bubo detects pestis on stained smears. In septicemia, blood cultures and in pneumonic plague tracheal aspirates grow Yersinia on culture. In endemic areas of the world, the immunofluorescence assay of the capsular F1 antigen of Y. pestis is available and utilized. In more affluent countries, the Y. pestis antigen by PSA is performed. In the USA, Plague must be reported to the local health authorities and the CDC, and cultures are sent to the CDC for confirmation.

Treatment:

Gentamycin is generally prescribed; in some countries, Streptomycin is still in use. In addition, quinolines and tetracyclines are also effective. In meningoencephalitis, chloramphenicol is recommended.

The Scientists:

In 1894, two bacteriologists, Alexander Yersin, a Frenchman, and a Japanese associate, Ketasoto Shibasaburo, working independently, during an outbreak of bubonic plague in Hong Kong, identified a bacterium in the fluid taken from a bubo. Yersin confirmed the organism as the plague bacillus by injecting the fluid in an animal and subsequently recovering the same organism from its tissues after sacrificing it. He named the bacillus Pasteurella pestis. In 1970, the bacterium was renamed Yersinia pestis.

Another pair of French and Japanese, working independently, identified the rat as the reservoir and fleas as the vector. In 1897, Dr. Orgata Masanori found rat fleas carried the plague bacillus in Formosa, now called Taiwan. In 1898, a French investigator, Paul-Louis Simond from the Pasteur Institute, working in India, demonstrated the transmission of plague by the bites of infected fleas.

The Nobel Prize:

None of the above scientists was awarded the Nobel Prize in medicine, but in 1957, a French novelist, Albert Camus, was awarded the Nobel Prize in literature for his novel The Stranger and The Plague         ( 1947).

The Pandemics of Plague:

The earliest recorded history of the black death is present in ancient Buddhist texts. An outbreak of plague in Vasali (in Bihar province), India, and also been recorded its spread to Sri Lanka.

Scientists believe a mild variety of plague within rat colonies in Central Asia has persisted from ancient times. No one is sure when and how it became virulent and jumped to humans. In the early days, the disease was called pestilence. The priests blamed people for living a sinful life for pestilence and God punished them with pestilence. The priests recommended penance, self-flagellation, prayers, and puja to please God. No solution came from above, but a temporary relief was obtained from the inhalation of fragrant herbs and flowers.

The First Pandemic:

The first pandemic occurred during the time 541 to 544 of the Roman emperor Justinian. The disease originated in Abyssinia, Africa (now Ethiopia and Eritrea). It spread westwards to Alexandria and to the east to Jerusalem and to Constantinople (Istanbul). In Constantinople alone, 10,000 people died every day. Eventually, the plague reached Denmark, Ireland, the Middle East, and Asia Minor. In 542 estimated total deaths in Europe, Asia, and Africa were 100 000. It was the bubonic plague.

Plague continued to smolder with local endemics for another 200 years.

The Second Pandemic of 1342 to 1352. It is better known as The Black Death.

The black death originated in Asia Minor. The disease was carried to Kaffa (Fedosya in Ukraine) by the Tatar army of Khan Janibeg. It then spread to the port city of Crimea. By ship with rats and sick people carried the plague to Genoa and then to all the port cities of the Mediterranean, England, and Norway. The war ended in a stalemate and the Tatars returned home and carried the plague with them to Russia and then to India. A quarter of the population of India perished from the Bubonic plague, and 10 to 20 percent of people died in Europe.

A second wave of bubonic plague occurred in 1361 in England and took another 10% of the population with it.

The Quarantine. The 40 days of isolation.

The officials in Venice prohibited ships from unloading goods and did not allow people to leave the ships for 30 days, in order to control the spread of plague (the Trenta).

 However, not achieving the desired results, they extended the prohibition to 40 days. Soon, quarantine became a tool for the containment of any infectious disease. Different States in Europe restricted the movements of people from traveling during the period, and it became known as the Cordon Sanitaire.

The Great Plague of London of 1665 to 1666.

A major outbreak of Pneumonic plague occurred in London, England, in 1665, and 7,000 people died daily. The severity of the illness is aptly expressed in a nursery rhyme:

Ring, a-ring o'rosies

A pocketful of posies

Atishoo, atishoo

We all fell down.

In a simple form:

A red blistering rash

Fragrant herbs and flowers

Sneezing and coughing

All are dead.

The Third Pandemic of 1894.

In 1855, in Yunnan, China, a local outbreak of plague took place. It spread near and far along the opium smuggling routes. In 1984, Canton and then Hong saw an increasing number of bubonic plague victims. The plague arrived in Bombay, India (Mumbai) via cargo ships. It produced panic in Bombay, and people scattered out of the city; the plague went along with them wherever they went. This plague killed a third of the Indian population.

In 1900, the plague reached Australia, and local outbreaks continued till 1925.

The 3^rd pandemic ended in 1959. The total death is estimated to be 15 million.

It is not over:

In 1990, the island of Madagascar saw multi-drug-resistant Plague. The island is a potent source of new plague.

The Final Word:

From the very beginning, humanity faced an uncertain future on Earth. Infection took a major toll on sick children and the elderly; childbirth was a horror story. No one recorded the untimely demise of so many young mothers, leaving behind their families. The progress in medical science, public health, and vaccination was able to eliminate Smallpox and put Cholera out of most countries and cornered Plague with very effective antibiotics and public health measures.

However, like Heisenberg's uncertainty principle, the present generation is both here and there in their belief in public health and particularly in vaccination.

 In case a multi-drug-resistant laboratory-engineered airborne plague bacillus delivered and exploded over densely populated cities by a terrorist group, that action will take us back to the days of Penance, Payer, and Puja.

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Footnote:

A new study published today (June 18, 2026) in Nature claims to have identified deadly cases of plague in hunter-gatherers dating back some 5,500 years ago. The outbreak marks the earliest known cases of plague in human history. 

The researchers analyzed the remains of dozens of hunter-gatherers buried in cemeteries near Lake Baikal in what is now Siberia during the mid-Holocene—a period that spanned from about 7,000 to 5,000 years ago. Suggesting human-to-human transmission. Children between the ages of eight and 11 were particularly likely to die from this plague. 

Today the bacterium isn’t nearly as deadly as it once was—in large part thanks to antibiotics but also because of changes to its genome. Part of what made Y. pestis so deadly during the Black Death, for instance, was a mutation in the bacterium that allowed it to survive in fleas—and jump to humans via flea-infested rats. 

In the new study, the researchers hypothesize the bacterium may have jumped to humans from marmots, a kind of ground squirrel, remains of which were also found at the Siberian burial sites. 

edited: June 2025.

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Leprosy

 

                                                Leprosy 

                                            P.K.Ghatak, MD

                                           ghatak3@gmail.com

The perception of people is that the earliest example of Leprosy appeared first in the Bible, which describes how the “lepers” were healed by Divine grace. Much earlier than any other religious texts, the Vedas from India wrote about leprosy. In the Atharva Veda, leprosy was called Kustha, meaning a disease that eats away the flesh.

It is natural to think that leprosy originated in India and remained endemic in India. According to the WHO 182, 000 new cases were detected in 2023, and ½ of them came from India. In Surshururt Samhita, written in 600 BCE, a complete description of leprosy appeared, and Chaulmoogra oil was advised as the remedy. It is said that Alexander the Great brought leprosy to Europe from India with his troops. European colonists and slave traders brought leprosy to the Americas from Europe. The Chinese were the first to notice perforated nasal septum in leprosy, and one time, Roman included psoriasis, eczema, other chronic skin conditions, and even sebaceous cysts under leprosy. The earliest archeological evidence comes from Rajasthan, India. Leprosy was detected in a skeleton from the time of the Indus Valley Civilization 4000 years ago.

The old concepts of the origin and spread of leprosy have undergone modification due to DNA analysis of Mycobacterium leprae. This proved that all cases of leprosy originated from a single clone of a single Nucleotide polymorphism. It is now established that Leprosy originated in Eastern Africa or the Near East and then spread with human migration to different lands.

These are the 4 different strains of Mycobacterium leprae, one of which dominates in one location.

Strain 1. - East Africa, Asia, Pacific islands.

Strain 2. - Ethiopia, Malawi, Nepal, India, and New Caledonia.

Strain 3.- Europe, North Africa, Americas.

Strain 4. - West Africa and the Caribbean.

Mycobacterium leprae.

The organism Mycobacterium leprae was identified by a Norwegian physician, Dr. G.H. Armauer Hansen, in a tissue sample in 1873. These organisms are rod-shaped, bunched together side by side like a packet of cigarettes. When stained with acid-fast stain, they resemble Mycobacterium tuberculosis (M.TB) with the following differences: organisms are numerous and found within the cell bodies, rods are slightly curved, and some are branched.

Mycobacterium leprae are 1 to 8 micrometers long and 0.3 to 0.6 micrometers across, slightly curved, non-motile, have a thick waxy coat, and stain poorly with Gram stain. The organism prefers a low temperature to grow and takes 14 days to multiply. For a clinical diagnosis, culture is not necessary. Cultures are done for research purposes, taking samples from the skin lesions of patients and inoculating, into the foot pads of mice.  Recently, Mycobacterium leprae was successfully cultured in Sabouraud media fortified with thyroxine hormone. In the wild, the banded armadillo and certain rodents act as reservoirs and are an additional source of human infection.

Human to human infection is the usual mode of spread but requires prolonged exposure, spread by aerosolized droplets and contact with nasal secretion from an ulcerated lesion. Nasal mucosa and tattoos are the routes of infection. Leprosy is not sexually transmitted, and mother-to-child intrauterine transmission does not occur. Malnourished people living in unhygienic conditions are susceptible to leprosy. Those who have a deficiency in cellular immunity are predisposed to leprosy but the mode of transmission and mutated genes are not precisely known. The incubation period is between 5 and 30 years.

Inflammatory response to M. leprae infection.

Interleukin 2 (IL-2) and Interferon gamma initiate the activation of T-helper cells, which in turn activate T-2 cells and cyclooxygenase II locally. Two distinct types of reactions follow the infection – one is Tuberculoid leprosy and the second is Lepromatous leprosy. In tuberculoid leprosy, the granulomatous inflammation, like that produced by Mycobacterium tuberculosis, appears as skin tubercles. Generally, 5 tubercle lesions are seen in this type. The facial tubercles produce striking disfigurement.

 In lepromatous leprosy, the dermis is filled with parasitized macrophages, inflamed blood vessels, and destroyed dermal appendages. The peripheral nerve fibers in the dermis are typically thick. The skin appears shiny, devoid of hair and sweat, with hypopigmented or reddish patches, generally several but always more than 5 skin lesions. The lesions and the surrounding skin are insensitive to light touch and temperature.

 Mycobacterium leprae preferentially attach themselves to Schwann cells of the peripheral nerve fibers and as they grow, they damage the nerves. Loss of sensation is an important clinical feature. Loss of sensations results in injuries, infection, and gradual loss of digits of fingers and toes, and disfigurement of the face, often the nose is replaced by a simple opening. The pinna (cartilaginous part of the ear) is often fractured and falls off. Hairs from the eyebrows and eyelids are lost, giving an ire look to the patients.

Incidence of Leprosy.

Before Dapsone was used for the treatment of leprosy, there were tens of millions of infected people scattered in 160 countries. In 1960, the number of new cases fell to 250,000/year, and since then, the number has been decreasing. At present, India, Brazil, and Indonesia account for most new cases of leprosy, followed by Tanzania, Madagascar, and Mozambique in Africa. In the USA, about 200 cases are seen yearly, chiefly among the new immigrants.

Clinical features of leprosy.

Classically, clinical features of leprosy are discussed under Tubercular and Lepromatous leprosy. WHO uses different nomenclature – Paucibacillary and Multibacillary leprosy.

 The initial symptom of Paucibacillary is muscle weakness. Skeletal muscle atrophy, loss of digits and toes, and the presence of only a few patches of discolored skin.

In Multibacillary leprosy, common symptoms are Erythema nodosum, fever, loss of hair from eyebrows and eyelashes, and many patches of reddish pink patches.

Other symptoms equally shared by both are anesthesia, paresthesia, and dry skin. Itching, blisters, secondary infection, claw hand, foot pain, and disfigurement of the face.

Diagnosis.

In countries where leprosy is common, any superficial skin lesion with decreased sensation to touch and pain of the surrounding skin is considered leprosy. Skin scrapings are obtained and stained for fungus and acid-fast mycobacteria. If these tests are negativethen a biopsy of skin taken from the edge of the skin lesion and stained with acid-fast stain.

Treatment.

In an earlier time, somewhat effective treatment of leprosy was  Chaulmoogra oil, then came  Promin (sodium glucosulfone) in the 1940s, and Dapsone in the 1950s. Clofazine in the 1960s and Refampin in the 1970s. Newly introduced agents resulted in a more favorable outcome. In  1970, Dr. Schantaram Yawalkar in India used a combination of drug therapy with greater success. In 1981, WHO advocated triple therapy- a combination of Dapsone, Rifampicin, and Clofazimine.

Because of the drug resistance of M. leprae, the WHO modified the treatment regimen and has added Moxifloxacin and Clarithromycin, or Monocycline. The dose and duration of treatment are published by the WHO and should be obtained from the WHO publication. In general, for Tubercular leprosy, the duration of treatment is 12 months and for Lepromatous leprosy, for 24 months.

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