You can get ocular migraines when you don’t sleep enough. Only 1 in 200 people who get migraines have experienced an ocular migraine. They can affect one or two eyes, and can last from several to 72 hours.
You can get ocular migraines when you don’t sleep enough. Only 1 in 200 people who get migraines have experienced an ocular migraine. They can affect one or two eyes, and can last from several to 72 hours.
Med school requires me to take some pretty tough classes like the human physiology and the underlying math basis. This class was really hard until I found some free homework solutions for the Calculus in Biography 3rd edition textbook.
Chloropromazine – Laborit, in 1950s, a surgeon in French navy found a drug that could block the autonomic mechanisms involved in shock. Side effect of parkinsonism was noticed. Patients discharged from mental hospitals would stop taking their pills to avoid the side effects.
William Halsted – In 1880-90s American surgeon at Johns Hopkins who became reknown for being a trainer of surgeons by setting up a residency program. Also used surgical gloves, sterile rooms, and masks.
Wilhelm Conrad Roentgen – in 1890s used a crookes tube to discover x-rays. Allowed for the nature of fractures to be understood as well as providing a visualization of kidney stones and bladder.
George Nuttal – American who in 1880s, found that blood had native humoral elements that could attack bacteria.
Kitasato – Japanese physician who in the 1890s found the tetanus bacilli
Tuberculin – Developed by Koch in 1890 as the cure for tuberculosis. Tuberculin was a failure, but did inflate the idea that drugs could cure the most vicious of diseases.
Behring – German physician who in 1890s developed the diphtheria anti-toxin in which the anti-toxin does not kill the bacteria, but neutralized the toxins it produced.
Carlos Finlay – Cuban physician who in 1880s discovered that mosquitoes were the cause of yellow fever, however he had no control group, and also no formal training in bacteriology, so his results did not attract much attention.
Walter Reed – American physician who in 1890s during the Spanish American War conducted experiments with a control to show that on yellow fever was transmitted by mosquitoes in Cuba.
Gorgas – American Physician who effectively eradicated yellow fever in Cuba and later in the Panama Canal. Showed that once the true nature of disease transmission was understood, prophylactic measures could be taken.
Patrick Manson – English physician who studied elephantiasis, and found that the disease was transmitted by mosquitoes.
Alphonse Laveran – French physician who in the 1880s found the malaria is caused by a blood parasite called plasmodium. Thought it was transmitted by contaminated water
Ronald Ross – British Physician who in 1890s found plasmodium in stomach of a mosquito and did experiments on birds to prove mosquito vector theory.
Arnold Berthold – in 1840s showed that livers most important function is to store glucose. Found that testes implanted on chickens would continue to secrete semen.
Brown-Sequard – made testicular extracts from various animals and injected it into animals and then himself. Started a craze of injecting extracts.
Frederick Banting – Canadian physician who in 1920s carried out experiments on dogs where he tied off pancreatic duct and waited for the pancreas to degenerate. Then made an extract. Injections into dogs with their pancreas removed reduced blood sugar levels and condition stabilized. Assistant was Best.
Macleod and Collip
Scurvy – deficiency of vitamin C, which was a major problem in the 18th century because ships had to rely upon stored food for months at a time. James Lind in 1740s did experiment on supplements, and found that oranges and lemons reduced scurvy incidence.
Beri-Beri – deficiency in thiamine, caused by new milling procedures for rice husks. Elkjman in Indonesia found that beri-beri was not caused by infection, but by lack of substance on outside of rice.
Pellagra – deficiency in niacin, primarily affected American Southern institutions when corn came into the diet. Goldberger in 1920s saw that none of the institutional staff ever got the disease and performed experiments in which he supplemented diet and pellagra would disappear.
Paul Ehrlich – German scientist who in 1900s developed salvarsan, a treatment for syphilis, and started chemotherapy, where chemicals are used to treat a disease.
Alexander Fleming – Scottish physician who by luck discovered penicillin in 1920s.
Gerhard Domagk – German physician who performed testing on animals of prontosil in the 1930s.
Howard Florey – Australian pathologist who brought in Ernst Chain from Germany and succeeded in isolating penicillin by setting up mold incubation containers. Carried out penicillin trials and scaled up in the United States
Selman Waksman – American biochemist who in the 1940s discovered streptomycin, which was a powerful antibiotic that could arrest the tubercle bacillus.
Polio – viral disease from oral ingestion of contaminated water. FDR got it and became national focus for polio. John Enders developed a vaccine and tested it out on a massive scale to find it was successful.
Fulton – American neurophysiologist who in the 1930s carried out surgical removal of frontal lobe. Discovered that monkeys without frontal lobes were calmer.
Egas Moniz – Portuguese neurologist who developed technique for drilling holes in brain of patient in 1940s. Claimed very great results in the relief of agitation, anxiety, and that many of his patients could leave hospital care and go home
How did concepts of disease change?
Hippocratic origins persisted until the 18th century, whereby physicians would look at intake and excretions from human body. Examinations were holistic in terms of looking at the patients history, weather, and the physician using his senses to gage what is wrong with the patient. The physician saw disease as a process, wherein timing was critical. Sickness was a deviation from a normal balance, whereby health could be restored by restoring the balance. Disease was highly non-localized, was thought of occurring in the whole body, but only manifesting itself in certain locations.
Theory of miasma, where various kinds of filth could give rise to bad smells that cause disease.
Louis Pasteur disproved spontaneous generation, the idea organic molecules self assembled into microscopic organisms.
Joseph Lister was an English surgeon who in the 1860s performed experiments of using carbolic acid
Robert Koch – used advanced microscopy with a camera.
Solid media: observed that bacteria could grow on a potato, and the colony would be homogeneous. Also lab assistant Petri invented the petri dish. Agar jelly was solid at room temperature, and could provide the nutrients microorganisms needed.
1880s: Koch’s postulates: take samples, and investigate them. They all have to show the presence of bacteria. He would culture the bacteria, then inoculate into an animal, and re-isolate the same bacterium. Isolated the TB bacilli.
Staining and counterstaining was very useful to make bacteria stand out against a complicated background.
French surgeon Ambroise Pare disliked the cauterization procedure used after amputations, so he developed a poultice made out of oil of roses, turpentine to use instead of cauterization, which involved heating a metal over a fire and applying it to the wound to stop bleeding. Pare thought that if cauterization did not work well for amputations, that it didn’t work well for gunshot wounds either. He used a procedure that involved tying the blood vessels off, which reduced the infection and inflammation, since dead cells were the breeding grounds for infectious bacteria.
For the most part, surgeons dealt with the hands on work that doctors largely avoided. Furthermore, before the advent of anesthetics and antiseptics, surgeons avoided abdominal, thoracic, and cranial cavities.
John Collins Warren and William Morton in 1840s used ether as an anesthetic in a surgery and demonstrated that the patient felt no pain. Because of this discovery, surgeons had the freedom to do more complex surgeries that take longer.
Lady Mary Wortley Montagu came to Turkey in 1710s because of her husband’s job as the Ambassador. She saw Turkish women take pus from a mild case of smallpox and with a needle scratch the person getting inoculated. Lady Mary Wortley had her own son inoculated by this procedure, and brought it back to England, where she did experiments on criminals and orphans. Lady Mary did not understand the mechanism of the disease, but began the widespread use of inoculation as a prophylactic measure. James Jenner was an English surgeon who took inoculations to the next level by testing the known rumors of milkmaids: that those who had cowpox were immune from smallpox. More critically, Jenner tested this theory in 23 cases in the 1790s. First on James Phipps. After giving the boy cowpox, Jenner tried numerous times to give him smallpox by inoculation, which did not work. Jenner had also been able to track the transmission of the disease: from the horse’s heel to the cow’s nipples, to the milk maid’s hands.
Ignaz Semmelweis (1840s)– Vienna General Hospital had two wards, one run by the midwives, and another run by the medical students. The death-rate in the latter ward was far higher. Semmelweis was able to employ a control group and statistics to drastically reduce puerperal fever rates. There were many theories about the origins of childbed fever, including miasma, single or un-wed mothers, even the weather. Semmelweis even tested a few theories of his own such as the psychological one, and low social class one, or the position that women gave birth in. After a former professor Kolletschka died when a pupil’s knife cut him, Semmelweis formed his theory of cadaveric particles, whereby students transferred the particles from post-mortem examination to their patients.
John Snow in the 1850s traced the outbreak of cholera to the Broad-street water pump, where the faecal matter was being mixed with drinking water. Found the cholera is transferred through the drinking excremental matter from those with cholera.
Tuberculosis was the largest killer in the Western World in the 19th century. Tuberculosis affected the poor far more than the romantics. The hereditary theory was not convincing because many families had members who did not develop consumption. Other theories were diet, stress, dirt, and poverty. As European cities grew during the industrial revolution, living conditions worsened. Overcrowding was common, bad air from burning coal was rampant. Diets in the 19th century were low in protein and vitamins and high in fats carbohydrates, and alcohol. Sanatoriums became widespread. Brehmer emphasized fresh air in the mountains coupled with exercise would cure tuberculosis.
Pasteur had discovered the microorganisms were essential in the production of alcohol. Also, he found that living matter in the air of the laboratory was what caused fermentation.
Prior to antiseptic techniques, surgery had a death rate of 1/3 of post-ops within the year. Pasteur had believed that putrefaction was fermentation in animal flesh and was carried by air (particularly oxygen). Joseph Lister in the 1860s tried out a dressing soaked in carbolic acid. Lister tried out his dressing on cases of compound fracture.
Morton’s ether and Warren in 1840s as the surgeon tested the anesthetics. Morton had tried to get a patent for it, but Warren convinced Morton that medical profession is forbidden to conceal any useful discovery.
Pasteur was able to give anthrax to a hen by cooling it in water. By lowering the body temperature of the hen, the anthrax bacilli could act.
Koch had used microscopy with cameras, staining of tissues, isolated from the body, cultured, and inoculated into other animals and repeat the same process
Roentgen’s discovery of X-rays allowed for immediate practical use. Surgeons could see the exact position of what was embedded in the tissue. Also the application of using x-rays to teach anatomy
American hospitals had a teaching function. The integration of hospitals and medical schools was necessary to give students the benefit of practical experience.
1890s brought asepsis like autoclaves, sterilized dressings, and rubber gloves
Yellow fever: the proposed germ had to be transportable, airborne (to account for neighbors getting it without intimate contact), and consistent with geographic selectivity (preferred hot, humid, and filthy conditions). Also had to be found using Koch’s procedure: discovered in the diseased animal, isolated in a pure culture, inoculated into a healthy animal, and recovered again. George Sternberg
Domingos Freire - claimed he had found the yellow fever microbe, but really just used samples of contaminated fingers of yellow fever patients.
Malaria followed the frontier. Quinine was able to remove symptoms of malaria, but not cure the disease. Miasmas did not fully explain malaria as it only occurred in certain places at certain times of the year. With the success of the germ theory in explaining and disproving the miasmatic origins of tuberculosis and cholera, researchers thought that a germ may be the cause of malaria as well. Laveran found plasmodium, Ross found the same plasmodium in mosquitoes. Koch found that malaria immunity was not genetic but acquired. The children became ill and as adults had immunity. Prophylactic techniques such as draining wetlands, coating bodies of water with oil and screens were especially good at preventing the spread of malaria. In the Panama Canal Zone, Gorgas had eradicated two diseases.
Yellow fever is transmitted by aedes agypti
Malaria is transmitted by anepholes
Cotton is an intensive hand labor crop, and sharecroppers were bunched on the most marginal land, which was likely to be swampy. In rice plantations, the farmers were wealthier and could afford screens and other prophylactic measures such as drainage. Poor could not afford to choose where they live, so usually lived near swamps.
Banting and Best in the 1920s tied off the pancreas to cause degeneration of the pancreas in dogs. Extract was then made, and injected into diabetic dogs, which caused a reduction in diabetic symptoms. Tried the injections on a diabetic boy, and blood sugar was reduced drastically.
Joseph Goldberger in 1910s notices that the staff at institutions never gets pellagra, a vitamin deficiency caused by lack of niacin (Vit B3). How can pellagra be an infectious disease when the staff does not contract this disease? Nurses and staff have access to a larger variety of food, and are usually first in choosing the variety for themselves. Goldberger found that pellagra is associated with rural and poverty. Even in poor cities, there is a larger variety of food in the diet. Goldberger later experimented with improving the diet at two orphanages and institutions, and found the rates of pellagra reduced to zero. Changed the portions of molasses and cereal to include milk, eggs, vegetables and beans. Also experimented on 11 prisoners who were granted pardons. 6 developed pellagra after being placed on a diet of cereals and syrup.
First trial of penicillin was unsuccessful because there was a lack of it, and patient died.
1920s Alexander Fleming saw mold on an agar plate, surrounded by a zone in which on bacteria was growing. Fleming had to give up because he and his assistants could not reproduce the creation of and purify penicillin. Antibiotics inhibit growth of or destroy other microorganisms. Florey (Austraillian), and Chain, a German tried to isolate and purify penicillin. Came to US to ramp up production, and also because London was being bombed and no British pharmaceutical companies wanted to produce it. Merck, Squibb and Sons, and Pfizer all were interested.
Controversy over streptomycin: Shatz had worked very hard in Waksman’s lab as a graduate student. Because Waksman got little credit, Lawsuit by Shatz settled in Shatz’s favor, and he got a money settlement
Streptomycin trial – randomly controlled, and blind such that patients did not know if they were placebo or trial case.
Major psychiatric illnesses rested on disordered brain chemistry
Genetic studies offered evidence for the genetic idea of psychiatry.
Family history offered the first evidence for the heritability factor.
To separate the effect of family environment from genetics, twin studies and adoption studies were used.
Twin studies involve identical, or monozygotic twins that come from a single fertilized ovum.
If one twin had a diseases like schizophrenia, 85% chance the other twin would have it. Also if a sibling had it, 12.5% change another sibling will have it.
1. Environment: population was much smaller than present day. Society was mostly agricultural with many villages and small towns, and very few large cities. In cities, people lived very close to each other
2. Food: much more subsistent; no problem of obesity
3. Types of diseases during this time:
i. Rickets: lack sun exposure and thus vitamin D
ii. Curvy: lack of vitamin C caused improper collagen formation
iii. Pellagra: lack of vitamin B3
i. Gout: too much protein; metabolic syndrome that caused collection of purine crystals in joints
i. Infectious diseases: malaria, dysentery, typhus, typhoid fever, pneumonia, tuberculosis, plague (gone due to quarantine measures), cholera (not yet an epidemic)
ii. Epidemics of infectious diseases: yellow fever, smallpox, measles, leprosy, syphilis, influenza
4. Approaches to spectrum of disease by physicians
a. Hippocratic approach: use senses, observe bodily discharges
5. Practitioners of medicine
a. Physicians: classical education (Latin, Greek) in university, consultant, dealt with internal diseases, very expensive for ordinary working man
b. Surgeons: trained by apprenticeship, much less educated, hands-on
c. Apothecaries: practitioner in small villages; only charged for drugs they sold
Introduction to Smallpox
1. Understanding Disease
a. Concept: disease seen as a process
i. Normal process in body became deranged
ii. Treatment: put process back into normal course and achieve balance of four humors
iii. Transmutation: disease states morphing into other disease states in the body
i. Lifestyle advice
iii. Purgatives: cleans bowels
iv. Emetics: cause vomiting
v. Sudorifics: sweating
vi. Most drugs were either deleterious or power placebos
i. Document pattern of change
ii. Close external observation
iii. Examining excretions
iv. However: little touching/palpating of patient
2. Smallpox: Cause, Rise, Patterns
a. Variola & Transmission: stable DNA virus that can remain outside of host for 2-3 years and still be infective. Can be transmitted by clothing and other things touched by patient
b. Clinical course
i. Epithelial cells, 12 day incubation period
ii. Dense rash (flat papule Vesicle (liquid inside) Scab) that covers epithelium inside and out
iii. Scabs shed
c. Native Americans:
i. Contact with Europeans brought a series of contagious diseases
ii. Genetic homogeneity (derived from small isolated group) population reduced to 5% of what it was after European diseases
d. Rise of Smallpox in early 1600s
i. Relatively mild disease, but became much more virulent and lethal in early 1600s
e. Age incidence/mortality: had greatest impact on the young
f. Survivors: male infertility, higher mortality in pregnant women, in small towns: periods of “rest” when the new generation of susceptibles were born
3. Prevention: Inoculation
a. Lady Mary Wortley Montagu: actively introduced inoculation into Europe in 1716-1720
b. James Jurin: collected evidence on effectiveness and danger of inoculation in 1721-1729; found 17% fatality rate in natural smallpox, compared to 1-2% fatality of inoculation
c. Resistance to inoculation: religious, medical (doctors heal, not give disease)
d. From 1750s on: life expectancy went on, techniques for inoculation improved
e. By 1790: inoculation became much more effective
4. Jenner: Vaccination
a. Edward Jenner: apprentice surgeon in countryside; cowpox lead to immunity from smallpox.
b. Published about cowpox inoculation on James Phipps in 1798
c. Vaccination spread rapidly because it was not as dangerous as inoculation
Physical Diagnosis/Paris Hospitals
1. 18th Century Legacies
a. Anatomy: historically not integrated into Western disease concept
i. Galen: 100 A.D. passing opportunities to look at human anatomy. Dissections not allowed
ii. Andreas Vesalius: 1543. Wrote The Fabric of the Human Body. Knowledge of anatomy still remained in books and physicians not personally exposed to it
iii. Private anatomical schools were taught by knowledgeable surgeons; 1770s on, anatomical knowledge has diffused but still voluntary
b. Medical Education
i. More common: apprenticeship for apothecaries, surgeons
ii. Less common: University book learning; Greek/Latin knowledge
c. Old hospitals: rare, where poor and homeless get long-term care, overcrowded. Not where students learn
d. Giovanni Baptista Morgagni: published SEATS (Seats & Causes of Disease as Investigated by Anatomy) in 1761;
i. First clinical anatomical correlation
ii. Focused on organ-based pathological anatomy
2. Medical Reform in France (Paris Hospital System)
a. Social reform: triggered by French Revolution to abolish old elitist institutions
b. Restructuring Medical Education
i. More open education; competitive examination
ii. System unites surgery and medicine; “manipulation will be united with theoretical concepts”
iii. “Little reading, much seeing, much doing”
c. Links to Reform Hospitals
i. Hospitals organized into one system in which medical training took place
ii. Had between 15k-20k patients at a given time
iii. Internship: integration of education & service to develop medical skills
d. Hospitals: Museums of Disease
i. Specialized hospitals for different types of diseases
ii. Opportunity to observe disease very closely and see variations due to age, nutrition, gender
e. Frequency of autopsy: citizen responsibility – anyone who entered system gave permission for postmortem examination
3. Physical Diagnosis/Lesion
a. Marie François Xavier Bichat: 1771-1802: autopsy fanatic
i. Key concept : pathology takes place within tissues (homogeneous anatomical structure)
ii. Lesion: where disease gets into thebody
b. Leopold Auenbrugger: Viennese physician. Technique of percussion. Wrote book in 1761 (largely neglected)
c. Jean-Nicolas Corvisart: resurrected Auenbrugger’s book and used percussion to diagnose heart problems
d. René Laennec: mediate auscultation; developed stethoscope (first in 1816)
e. New meaning of disease: localized; doctor is to use physical diagnosis to locate disease
4. Statistical Concept of Disease
a. Aggregate and look for principles, generalities
b. Pierre Louis: tested treatment by aggregating results of one group who gets treatment and one group who does not
c. Rise of statistics: compare and classify facts about disease
1. Frameworks of Pathology
a. Paris: centered around hospital; autopsy was only to confirm diagnosis on the same patient; not truly objective
b. Vienna: pathology research
i. Carl von Rokitansky: initially trained in Vienna, then Paris; came back to Vienna; full-time duty was to perform autopsies at the Vienna General Hospital
c. Virchow: Reformer Revolutionary
i. Rudolf Virchow (1821-1902): studied with and was assistant to Johannes Müller; also carried out autopsies
ii. Concept: pathological anatomy should be both gross and microscopic
iii. Science of anatomy defined by physiological & chemical experiments
d. Institutes: Wurzburg
i. Virchow was welcomed to Wurzburg, Bavaria, after being fired by the Prussian government after being outspoken about Silesia’s social problems
ii. Organized an institution for medical sciences
iii. Central instrument: microscope
2. Microscopes & Cells
a. Old microscopes: simple lens system; 40x-100x magnification, low resolution despite increased magnification; only good for dissection
b. Improvements c. 1830:
i. Better lens grinding technique
ii. Calculation of lens systems by Lensmaker’s equation
iii. This allowed for improved microscopes to become available to students
c. Müller & Pupils
i. Johannes Müller: Virchow’s teacher; made microscopes available to students despite himself preferring naked-eye anatomy. Progressive enough to train students in microscopic anatomy
d. Schwann & Cell Theory
i. Theodore Schwann: student of Müller; focused on embryonic development
ii. Published first book on cell theory in 1839
iii. 1840s: linked up with French idea of tissues; new definition of tissue – a population of homogeneous cells. Study of tissues = histology
e. Training & Clinical Applications: microscopes & cell theory changed medical training by providing a focus of training that supplemented gross anatomy with microscopic anatomy
3. Virchow’s Pathology
a. Thrombi & Embolism
i. c.1844: new definition for thrombus and embolism
ii. Virchow used microscope to show that thrombi go back up veins into ventricle pulmonary artery lungs to cause embolism
iii. Testing: made artificial thrombi and injected into veins; effects were like embolism
b. Leukemia: Virchow observed that the color of a sick girl’s blood was paler
i. Microscopic observation: enormous number of white blood cells (leukocytes); disease named leukemia
c. Collaboration with Albert von Kölliker: studied microscopic structures of body fluids, tissues
i. Embryological development: model for how tissues originated
ii. Omnis cellula e cellula: cells only come from previous cells
d. Cellular Pathology: 1858
i. Virchow gave a series of lectures on cellular pathology (all pathology is based on malfunction of cells)
ii. Emphasized training and usage of microscopes
e. Cells & tumors: by 1860s, recognized that tumors were caused by out of control cell division
4. German Laboratory
a. Vitalism to Materialism: scientific approach to all phemonema; growth of laboratory approach in cognitive sciences
b. Liebig & Analysis
i. Justus von Liebig: professor at the University of Giessen
ii. Developed first laboratory that was designed to teach a subject in a manual, manipulative way by doing a regimented set of courses
iii. Development of analytical techniques by training hands, eyes, and minds
iv. By 1840s: laboratories are developed for medical students to study: physiological chemistry, physiological experiments, microscope work
v. Concept: laboratories created the kind of physicians that society needed
c. New Institutes: Ludwig
i. Karl Ludwig: director of Physiological Institute in Leipzig (1865); building in shape of an E (histology/anatomy, physiological chemistry, physiological prlblems)
ii. Also developed kymograph: graphical representation of physical processes (drum with paper rotates and connected to a stylus)
d. Analysis of Blood & Urine
i. Usage of microscope = shift to laboratory medicine from hospital medicine to come up with new ways of understanding disease
Urban: Cholera, Typhoid Fever
1. Urban Growth
a. Industrial growth & factories
i. Change in textile industry due to Industrial Revolution: replaced human power with steam engine machines which required much investment
ii. Result: large, dense populations around industrial growth
i. 1750s: improvements in roads
ii. 1790s: building of canals, bulk goods transportation
iii. 1820s: steam ships
iv. 1830s: railroads, steam-powered trains
i. 1840s: dense network of transportation means migration of people
ii. Countryside towns
iii. Europe America (also triggered by crop failures in Germany and Ireland
i. Migration lead to rapid growth of city size and density
ii. Transportation within cities did not improve
iii. Development of tenements
e. Sanitary conditions
i. Lack of water and sewage infrastructure dirty water
2. Origins of Urban Diseases: Debates in Early 19th Century
a. Contagion idea: limited to smallpox, measles, mumps
b. Objections: if disease is contagious, quarantine must be in place which stops goods from moving in/out of city bad for economy
c. Vector: lack of idea about vectors; no belief in insect/water-borne diseases
d. Miasma: presence & corruption of miasmas caused disease
i. Various filth (human waste, industrial waste) gave rise to emanations that are affected by weathers and geography
e. Epidemic chain: emanations did not become epidemic until there is influence. A ship that comes in may contain filth that corrupt local emanations which affect individual depending on heredity, nutrition, temperament, diet
3. Reform of Sanitarians
a. Early phase: 1790s-1830s: not much traction
b. Change in 1830s-1840s: society is wealthy and growing rapidly, but still suffering from recurring crises
i. Utilitarianism (Jeremy Bentham) : “Greatest good for the greatest number” improving circumstances for the poor
c. England: Farr & Surveillance
i. William Farr: 1837, Registrar General (recorded birth, marriage, death, and causes of death) compiled reports on causes of disease
4. Cholera: New to Europe/America
a. Vibrio: comma shaped bacteria, animal and human parasites; transmitted via water and prefers alkaline environment (gastrointestinal tract below stomach)
b. Clinical course:
i. Individual drinks contaminated water
ii. Stomach is strong natural defense (pH~1)
iii. If vibrio gets past stomach into small intestine rapid multiplication; releases toxin that breaks down epithelium of small intestine
iv. Lose large amounts of fluids & electrolytes
v. Blood thickens and nervous functions shut down (hallucinations) death
vi. Fatality: 40-60% if not treated
i. Endemic in India, parts of SE Asia
ii. Moved to Europe as result of expansion of British empire (India Egypt Russia Europe)
5. John Snow & Cholera
a. John Snow (1813-1858), young British surgeon, son of farmer
b. First ideas about cholera after outbreak in 1849
i. Recognized it as gastrointestinal disease caused by ingested toxin
ii. 1854: new outbreak. Theory of food-borne or water-borne disease
c. Broad Street Pump
i. Snow asked families of sick and concluded that they all got water from the pump
ii. Bricking around side of well was broken and water was contaminated by oozing brown substance
iii. Snow removed pump and no more cases reported
d. Water Companies
i. Water pumped in by water company from Thames River
ii. Vauxhall & Southwark got it straight out of city Thames
iii. Lambeth got it upstream the Thames in an aqueduct
iv. All cases of cholera came from those served by Vauxhall even in areas ofoverlap
e. Objections & Vindication
i. After publications (talks, speeches, testimonies before Parliament), a campaign started to contain human waste and provide clean water
ii. 1866 epidemic was thus contained
Puerperal Fever & Tuberculosis
1. Background: Disease, Places, Persons
a. Puerperal fever: woman gives birth, has fever and pain in 5-7 days, and increases until patient begins to hallucinate. Death within 10-14 days
i. Modern terms: hemolytic streptococcus
ii. Bacteria invades where placenta detaches
b. Relation to Hospitals
i. Increased hospital births lead to: decreased infant mortality rate, and increased maternal mortality rate
ii. Within given hospital, there will be periodic epidemics of puerperal fever
c. Vienna General Hospital
i. Separate maternity wards tended by midwives and medical students
i. Ignaz Semmelweis: born in Budapest as son of merchant; grew up Hungarian
ii. Went to Vienna to study law, but changed to medicine after fascination with autopsies
iii. Became assistant to professor of obstetrics Johann Klein
iv. Famous colleagues: Carl von Rokitansky, Skoda (percussion/auscultation), Hebra (dermatology), Jakob Kolletschka (pathology)
e. Theories of Puerperal Fever
i. Changes in blood once mother delivers; correlated with milk suppression (not coming in immediately)
ii. Lack of cleanliness (English belief)
iii. Miasma (most common belief)
iv. 1846: puerperal fever outbreak in Vienna General Hospital; rising death rate only took place in wards tended by medical students, but not in the one tended by midwives
2. Origins, Success, Failure
a. 1846: Private Pursue
i. Tried to deliver women in the same way midwives did (on their side); women continued to die of puerperal fever
b. 1847: Action & Troubleshooting
i. Spring of 1847: Kolletschka died after medical student slipped and cut him with scalpel
ii. Autopsy determined pathology to be same as women who died in puerperal fever
iii. Idea: medical students brought cadaveric particles out of the morgue on their hands and contaminated women during examinations
iv. Solution: wash hands and dip in solution of chloride of lime
v. Immediate results: hated by medical students, but death rates went down
vi. A few months later: death rate went back up; discovered that students did not disinfect hands between examinations of different women
i. Klein was not pleased by Semmelweis’s doings
ii. After a revolution, Semmelweis was fired and sent back to Budapest
d. 1850s: Garbled Messages
i. Semmelweis tried to get message out by personal teachings since he did not like writing journals; his message was garbled by those who taught his ideas
e. 1861: wrote book; large section was a criticism of current obstetricians
i. Semmelweis then became mentally unstable and died in an insane asylum
3. Captain of Death: Tuberculosis
a. Ancient Origins: widespread. 10-20 million new cases in the world. Over 3 million die in the world today
i. Tubercle Bacillus: genus microbacterium (family of soil bacterium)
ii. Small, innocuous, not invasive
b. Exposure & Disease: spread by droplet infection (sneezing/coughing)
c. Variable Slow Course
i. Slow, but well-adapted to become chronic disease
ii. Tubercle bacillus has strong resistive coating that prevents it from being killed by macrophages
iii. Causes buildup of dead macrophage + scar tissue + tubercle bacilli
iv. Human body fights it but never kills it completely. Weakened immune system disease comes back
v. “Consumption” because body is frail, sick; loss of weight
vi. Death: loss of respiratory capability due to more and more lesions caused by bacteria
vii. By the peak of TB in 1830s, caused 1/3 of adult deaths
4. High Water of TB: 1800-1850
i. Related to environmental conditions
ii. Malnutrition, alcohol consumption, exposure to dust (low level inflammation in lung), female (younger than 30), male (older than 30) predisposed to worse outcome
iii. Lack of protein (malnutrition, working class), low vitamin D (lack of sun exposure)
b. The Lesion: multiple points of body
c. Unitary Disease: lesion in different points of body is cause by the same tubercle bacillus
d. Heredity & Locality
i. Heredity: seemed hereditary because if parents have it, then children have ittoo
ii. Locality: high latitude = bad, low latitude = improvement
e. Improvement by Climate: N. Europeans improved after moving to Mediterranean
f. Sanitarium (1860s+)
i. Curative institution based on theories of disease origins
ii. Hermann Berhamer: German internist; discovered patients who adopted outdoor lifestyle got better
iii. Opened facility in mountainous area south of Berlin (Gobertorr) to spend time outside, exercise, eat health high protein diet patient improvement
Traditional Surgery to Anesthesia
1. Deep Roots
a. Egyptians & Romans
i. Trepanation: grind skull until dura matter is exposed; effective in decompressing brain edema (however, ancient tradition is to make evil spirits in brain escape)
ii. Egypt: papyrus medical text (1700 B.C. transcription of 3000 B.C. text) found in Luxor temple; deciphered in 1920s and published
iii. Greeks: well versed in internal medicine
iv. Romans: practical, military, more need for surgeons
v. Pompeii: preserved surgeon’s tools (knives, lancets, retractors, speculums)
b. Medieval Craft
i. Works of Galen preserved in Islamic world; reintroduced to universities around 1200
c. Paré as Renaissance Surgeon
i. Ambrose Paré: French surgeon; learned skills in army
ii. Specialized in treatment of gunshot wounds & amputations
i. Routine treatment involved cauterization with hot oil
ii. By accident, Paré ran out of hot oil and made a poultice on demand to put on wounds
iii. Soldiers with boiling oil treatment did much worse
iv. Typical amputation: cut muscle quickly, expose bone, saw through bone; sign of good surgeon to amputate very quickly (<1min) and cauterize with hot iron
v. Paré: instead of cauterizing (which was bad for gunshot wounds), he pulled out blood vessels and tied them off lower infection rate due to lack of necrotic tissue
2. John Hunter/Scientific Surgery
a. Hospitals/Hospital Schools
i. 1750s: growth of urban hospitals (became natural training institutions for surgeons)
b. John Hunter’s Life & Teachings
i. John Hunter: gifted anatomist, experimentalist, founded school of anatomy in 1770s with his brother; trained Edward Jenner as one of his apprentices
c. Experimentation & Museums
i. Hunter was interested in inflammations: course, spread, duration
ii. Self-inoculation with gonorrhea and got syphilis (to prove that they’re the same disease. FAIL)
d. 1820s: Crime & Regulations
i. Sources of bodies became problem for anatomical training
ii. Surgeons contracted with “resurrectionists” to rob graves
iii. Ediburgh: William Burke/William Hare participated in 20-30 murders to deliver bodies
iv. 1832: Parliament passed the Anatomy Act (gave teaching bodies, license necessary)
v. Surgery in 1840s: surgeons approaching prestige of physicians; trained by apprenticeship but also in hospitals/anatomical schools. Need to be licensed (pass written + practical examination)
3. Operations Great & Small to 1840s
a. Boldness: McDowell
i. Ephraim McDowell: removed 15-lb ovarian tumor; woman recovered well. McDowell then performed 5 more removals resulting in only one death
b. Low Level in Hospital: hospital surgery was still low
i. Common to operate only one day a week (still dangerous)
ii. Stayed out of abdominal, thoracic, an cranial cavities; only worked on periphery
c. Normal Practice
i. Open cysts, set broken bones, sew lacerations, reduce dislocation
4. Gases & Pain
a. Attitudes Towards Pain: Unavoidable Tolerable
b. Types of Analgesia
i. Only dulled pain, but never removed it
ii. Alcohol (CNS depressor; OD causes death), concussion (skull fracture), nerve compression (can result in permanent damage)
iii. Carotid compression: can cause brain damage for lack of blood supply
iv. Narcotics: poppy opium laudanum; morphine (extracted from opium), heroin
c. Discovery of Gases: CO2, H2, N2, O2, Cl2; nitrogen oxides: NO, NO2, N2O
d. Davy & Faraday: Davy suggested that nitrous oxide (N2O) might be a good anesthesia because it has pleasant effects
a. Why the U.S.?
i. 1840s: anesthesia discovered in U.S. due to widespread recreational drug usage
ii. Diethyl ether & nitrous oxide
iii. Dentistry: also more advanced than Europe; catered to patient need for less pain
b. Private: Clarke & Long
i. Inhalation anesthesia to carry out procedure
ii. Clarke: tooth extraction
iii. Long: tumor removalon arm
iv. Private experiments: not carried out systematically, and not reported
Pasteur, Lister, Antiseptic Surgery
1. 1840s: Anesthesia
a. Failure: Wells & N2O
i. Horace Wells: well trained, respected dentist; used nitrous oxide for tooth extractions with some success
ii. Approached John Collins Warren (Boston surgeon) to demonstrate usage
iii. Demonstration failed because patient did not breathe deeply
b. Success: Morton & Ether
i. William Morton: aware of nitrous oxide, but had alternative: diethyl ether
ii. Also approached John Collins Warren
iii. Oct. 16, 1846: patient was prepared with ether and Warren started surgery. Success!
c. Rapid expansion:
i. Morton and Wells did not publish results
ii. Warren and colleagues wrote protocol for ether usage
iii. Chloroform also used (Queen Victoria used in birth of next child)
iv. Benefit: more time for careful and better procedures
v. Downside: more surgical sepsis because surgery became increasingly invasive
2. Inflammation & Sepsis
a. Nature of inflammation: calor (heat), dolor (pain), rubor (redness), tumor (swelling)
b. Expanding surgery: more and more sepsis
c. Microbial world: pus = white blood cells
3. Pasteur & Microbes
a. Louis Pasteur (1822-1895): born in SE France, lower middle-class
i. Was great at taking exams scholarships into the local lycée scholarship to Paristo study at École Normale Surfrieur
ii. Personality: competitive, ruthless, not afraid to be practical
b. Chemistry: specificity of life
i. Many molecules have two different enantiomers that rotate polarized light in different directions (dextrorotatory/levorotatory)
ii. Chemicals are generally racemic mixtures of the two forms
iii. One particular enantiomer was associated with life
c. Fermentation studies: 1850s
i. Milk spoils because it was being converted to lactic acid by a specific set of microorganisms
ii. Fermentation of alcohol: caused by a form of yeast, and not an inorganic process as believed by most chemists at the time
d. Germ/Inflammation/Spontanous Generation
i. Pasteur attacked idea of spontaneous generation
ii. Showed that nutrient media, when boiled and plugged, remained sterile for very long time (showed that spores from outside contaminate the nutrient media)
iii. Fought theory that oxygen was needed for spontaneous generation
4. Lister & Antisepsis
a. Joseph Lister (1827-1912): English Quaker, trained as scientific physician and surgeon
i. Father was wine merchant and amateur microscopist Joseph Jackson Lister, among those who worked out key features of improved microscope c. 1830
b. Scotland & Hospitalism: job in Edinburgh, Scotland
i. Outbreak of hospitalism: virulent strain of microorganism that was carried on clothing of staff and impossible to get rid of
ii. Infection particularly bad in compound fractures
c. Analogous Reasoning
i. Tissue exposed to oxygen inflammation (similar to fermentation, which is a breakdown of tissues and substances)
ii. Lister converted to idea that exposure to outside spores resulted in tissue necrosis after reading Pasteur’s papers
iii. Read about sewage treatment with carbolic acid (phenol) which is a powerful disinfectant & antibacterial agent
i. Lister developed technique to use carbolic acid for wounds in 1865-67
ii. Developed spray engine to clean air in surgical theater; also cleaned instruments and hands with carbolic acid
iii. Problem: carbolic acid was very irritating to skin and wounds
1. Convergence in 1870s: set framework & background for determining individual species of germs as individual causes of diseases
a. Microscopy: improved, cheaper microscopes
i. Staining: natural and synthetic dyes (1860s+, important also in textile industry)
ii. Microscopic sections: shave slices of object imbedded in something hard
b. Cells & Microorganisms: cell theory became ubiquitous
c. Sepsis/Putrefaction: sepsis is a microscopic/cellular process caused by bacteria
d. Sanitation policies: rapidly organized in Europe/N.A.; sewage/water treatment
e. Doubts about nature of microorganisms
i. Devaine: French veterinarian; transferred blood of anthrax into healthy animal. Healthy animal got anthrax
ii. Conclusion: toxin caused anthrax, and blood sample contained toxin. Microorganisms are just spectators in this infection
2. Young Koch & Laboratory Medicine
a. Robert Koch: born 1843 and grew up in countryside
b. Went to local University of Göttingen with famous faculty (organic chemist Wöhler, math professor J.F. Gauss, physics professor Wilhelm Weber
c. Koch worked under J. Henle & Wöhler (study of succinic acid, human fat metabolism)
d. In 1850s-60s: French hospital system is shifting to German laboratory model (research, publish papers, lab practical examinations)
e. Wollstein: became local medical official with salary from government
3. Anthrax as Model
a. Disease & Cause
i. Anthrax is an animal disease that infects sheep, cattle, small animals. Causes fever and disorientation that leads to death
ii. Flocks grazing on grass where dead animal was buried for a few years would be infected
iii. Koch started lab experiment with tissue samples; found round object in spleen
b. Isolation/Serial passage
i. Mice was inoculated and died overnight.
ii. Koch took spleen sample and inoculated a second mouse. Repeated 20 times and recovered the same object from spleen showed that disease-causing agent was not a toxin but a replicating organism (bacillus anthracis)
c. Hanging drop
i. To obtain pure sample, Koch placed a small amount of tissue into nutrient medium on a glass plate with dip, that he can continuously observe under themicroscope
ii. Flame near experiment to keep it warm dried out the medium
iii. Koch discovered that bacteria formed spores as area dried out (resists degradation)
d. Demonstration in Breslau, 1876
i. Demonstration to receive feedback. First showed to botanist Cohn
ii. Koch was lucky: anthrax was a good model organism: large, did not need staining, generally not harmful to humans
4. Tuberculosis, Cholera, Establishment of Bacteriology
a. Koch’s Career, 1876-1889
i. Developed whole series of lab practices for bacteriology
ii. Developed techniques of microphotography since drawings are not reliable
iii. Experimental animals: guinea pig (subject to many human diseases)
iv. Wound infections: cultured bacteria that caused infections
b. Solid Media
i. Potato slice: discovered each colony was homogeneous (from single progenitor); solid slice = no mixing of bacteria
ii. Flat plates with agar gel (solid at room temperature)
iii. Eventually, William Petri developed the Petri dish (flat dish, straight walls)
c. Tuberculosis, c. 1880
i. Koch got a job at Berlin at the Imperial Health Office
ii. Identification and isolation of tubercle bacillus was difficult: need right medium, slow growing
iii. Koch’s postulate: collect sample and show they have the same bacterium culture bacterium inoculate into animal host re-isolate same bacterium from animal
iv. Gave series of lectures and wrote 4 large papers describing details of lab techniques
v. To identify tubercle bacillus, used methylene blue with counterstain to make it stand out against complicated background
d. Germs as Necessary Cause
i. Problem: people with tubercle bacillus is not necessarily sick
ii. Koch: Germ is necessary but not always sufficient to cause disease
i. After 1884, worked on cholera during an outbreak in the Middle East
ii. Identified cholera as caused by vibrio (bacterium with vibratory flagella)
1. Institutions & Professions for Mental Illness, 19th Century
a. Soul to Mind
i. Late 18th Century: mental illness was considered as an issue of the deranged soul, and a burden of individual family
ii. Possession by the devil or evil spirits
iii. Shift towards idea that it was something wrong with the mind, not the soul
iv. Moral treatment: innovation; treat someone mentally ill with care and comfort in a structured environment, and they’ll come out of the illness
b. The Curative Asylum
i. Embodiment of the moral treatment idea
ii. A number of reformers developed ideas (Pinel, Esquirel) that one needed a kind of environment that supported the mentally ill patient, and can gently lead them towards finding their right mind
iii. Was believed to be able to cure mental illness
c. A Profession Emerges
i. 1810: individuals who were trained as physicians and hired as superintendents of asylums – intended to be physician and father-figure; treat and oversee curative environment
ii. Developed quickly in Europe; in Paris, every single district had an asylum all under supervision of a physician
iii. Alienist: insane person is alienated from their right self; person who treated them were alienists
d. First Biological Psychiatry
i. Supplemented the “alienists” in mid-1800s
ii. By this time, the structure/function of the brain was elucidated: neurons, synapses modern discipline of neurology
iii. Psychiatrists started to take up ideas of neurology origins of mental illness is within the brain itself (brain psychiatry)
iv. Studies were done on brains of criminals; could not find any consistent connections between brains structures and illness nor differences between brains of healthy and mentally ill individuals
e. Types of Mental Illnesses
i. Worked out a topology of major kinds of serious mental illnesses
ii. Psychosis: individual gets detached from reality (such as schizophrenia); hear voices telling them to do things. Have beliefs that they’re sent by God to do things. Some have visual hallucinations in addition to auditory
iii. Depression: melancholia; recognized as a long-term state of low mood, no or little interest in things, no energy, disturbances of sleep; most common mental illness in the U.S. today (8-10% of the population sometime in their life)
iv. Bipolar: manic depressive; hyper-manic swing, incredible energy, all based on misperception of what you can do
i. Sigmund Freud: psychodynamic theories; trained as neurologist
ii. Abandoned traditional brain psychiatry and developed idea that mental illness was due to stresses: childhood development, family, social/environmental stress
iii. Freud was more interested in the “walking sick” (neurotic), not the kind of disease that sent one to an asylum
iv. Enormously popular in the U.S., even more so than in Europe where Freud was from
g. Institutions Failing
i. Started to fail because they became so overburdened
ii. Mentally ill people never left the institution
iii. Beginning of the development of bio-therapies
2. First Bio-Therapies (1900-1940s)
a. Water, Sterilization
i. Water: calm someone down by putting them in a bath, wrapped in wet sheets, sprayed
ii. Sterilization: beginning in 1920s; most often applied to men in hospitals. Found empirically that it made the man more passive, less aggressive, less strong. Some psychiatrists thought it was a way to modify their mental state
i. In 1918: an Austrian who was in charge of a hospital for patients suffering from general paresis (tertiary syphilis symptoms) discovered that when some of his patients got bad cases of malaria, they got high fevers that alleviated psychiatric symptoms
ii. Worked out a malaria/fever therapy for these particular kinds of mental patients; tried to cure syphilis-related mania
iii. Some truth: high fevers can kill the syphilis that salvarsan did not reach
c. Chemical Shock
i. Insulin shock: injection of too much insulin hypoglycemia, shock, convulsions
ii. Discovered that the shock process can improve certain kinds of conditions, especially conditions related to depression
iii. Termination of shock by dose of glucose to raise blood sugar levels
d. Electroconvulsion Therapy
i. Most prominent of shock treatments; developed by an Italian in 1938
ii. A jolt of electricity that brings on convulsions like epilepsy
iii. Discovered that depressed patients got better after a seizure
iv. Beginning in 1940s, ECT started being used in particular kinds of mental illness (depression)
3. Surgical Cure: Frontal Lobotomy
a. Brain Knowledge: 1930s
i. By 1930s, a fair amount was known about the human brain (not including neurotransmitters, electrical signal processing)
ii. Localization studies: relatively large area of the brain called the frontal lobe did not seem to have many explicit functions that can be discovered immediately
b. Fulton at Yale
i. John Fulton, American neurophysiologist; Harvard, Rhodes scholarship to Oxford, endowed professorship at Yale (age 29); married a wealthy woman
ii. He and his colleagues focused on discovering the functions of the frontal lobe; well-endowed lab carrying out many experiments on monkeys
iii. Early 1930s: Fulton and colleague Carlyle Jacobson carried out a program of various surgical sections and removals of the frontal lobe
iv. Discovered that large excision of the frontal lobe does not result in much functional change at first, but aggressive monkeys became more calm after de-linking the frontal lobe from the rest of the brain without much deficits
v. 1945: Fulton/Jacobson went to the International Congress of Neurology and gave a report on these experiments on damping of agitation without other obvious problem
c. Egas Moniz
i. Portuguese neurologist: among the audience at the International Congress of Neurology that Fulton/Jacobson gave report on
ii. Became inspired to do the same to his psychiatry patients
iii. Started developing a technique with a neurosurgeon to drill holes in the brains of patients, insert a special cutting knife that released the blade after insertion, and cut some tracts
iv. Claimed very great results in the relief of agitation, anxiety, and that many of his patients could leave hospital care and go home
v. Continued this series of treatment and got the Nobel Prize in 1949
d. Freeman & Spread in U.S.
i. Walter Freeman: also at the Congress in 1935; also worked in a mental hospital situation as staff neurologist at St. Elizabeth’s hospital outside Washington D.C.
ii. Knew hundreds of patients who were so aggressive that they needed to be strapped down
iii. With a neurosurgical colleague, developed functional detaching the frontal lobes
iv. Reported decrease in agitation, anxiety, happier families, and 1/3 of patients were “cured”, 1/3 “clearly improved”, and 1/3 “no visible improvement”
v. Started to teach this technique to neurologists and psychiatrists in mental hospitals all over the U.S.
vi. At first followed an identifiable surgical procedure, but later he found that approach from below (trans-orbital approach): sharp steel tube inserted at an angle at the orbit of the eye to carry out frontal lobotomies (a common ice pick can do the trick)
vii. Spread very rapidly; with 10 years, at least 1500 lobotomies were done on the worst cases of mental illness
viii. The procedure started looking worse and worse
ix. By 1950 (peak of procedure), the psychiatric community was in a movement to stop this procedure; frontal lobe is now known to have “executive” functions (lobotomy resulted in patients being less agitated, and more vegetable-like)
i. Object of this treatment: women were disproportionately the objects of the lobotomists’ ice pick because types of aggressive behavior are more intolerable in women than in men
i. Why would well-trained professionals do this?
ii. Ambience of psychiatry between 1920-1950: getting more and more incurable patients dumped on them; patients reached 2-3x hospital capacity
iii. Every other field of medicine was progressing except psychiatry
iv. It gave psychiatrists a feeling that s/he can actually do something, even though it later turned out to be a wrong thing
v. Series of drug discoveries in 1950s that stopped the lobotomy craze
4. 1950s: Drugs
a. Big Pharmaceuticals/Making Molecules
i. By 1950s, there was a highly developed, wealthy, aggressive set of international companies that made a lot of money making various kinds of drugs
ii. Merck, Pfizer, Eli Lilly: had chemists who were good at molecular synthesis
iii. Able to synthesize substances that were found naturally: hormones, neurotransmitters, antihistamines
iv. Immediate post-war period: industrial power in making and testing molecules as a result of the chemotherapy effort and making targeting molecules
b. Chlorpromazine Origins
i. Built around the phenothiazine molecule
ii. Discovered that derivatives of the phenothiazine molecule were useful as antihistamines, antidiuretics
iii. Rhone-Poulenc (French drug company) developed a molecule for physicians to test as a surgical adjuant (alleviate effects of shock from surgery, furthering effects of anesthesia, etc.)
c. Tests & Spread
i. French surgeon Henri Laborit noticed that it had a sedative, anti-anxiety effect when he tested this in 1952, and passed it along to psychiatric colleagues
ii. Among them: Jean Delay & Pierre Deniker did the first clinical trials
iii. Discovered that among psychotics (worst patients) given this drug over a few weeks, show distinct anti-psychotic effect
iv. In Montreal: Heinz Lehmann (originally German, fled Nazi) tested chlorpromazine on a large scale
v. Tried on experimental animals, characterized physiological reactions, then tried on a group of psychotic patients
vi. Patients became less assertive, less aggressive, less anxious; much easier to manage; did not become sleepy, and consciousness did not become clouded
vii. Patients were passive, but aware of their own improvement; over 50% showed either great or moderate improvement, only a very small minority were unaffected
viii. Published c.1954, and circulated among the psychiatric community in North America, and within 2-3 years, became widely used in mental hospitals all over Europe/NA
d. Lithium & Mogens Schou
i. Treatment for manic depressives, especially the manic phase of activity
ii. Theory worked out by Australian named John Cave; believed that the Li+ ion has an effect on decreasing the pathological manic phase. Published in a small Australian weekly journal
iii. 1952: Danish psychiatrist Mogens Schou read the Cave article (was looking for drug treatments for manic depressives because it struck in his own family), carried out a placebo-controlled double-blind test
iv. Found that over half the patients were positively affected by lithium, and the subsequent depressive cycle was cut
v. However, use of lithium did not spread as much as chlorpromazine (patented drug, lots of energy invested by company to push the usage)
e. Kuhn, Geigy, & Depression
i. Geigy found another molecule (tricyclic structure), and tested out by Roland Kuhn
ii. Started a study on depressed patients; within 2 months, had good results
iii. Published in 1956; by 1957-1958, tricyclic was widely used in psychiatric institutions
i. Miltown, c.1956; discovered to have a relaxing effect
ii. Became a leading prescribed drug in the U.S.
g. Social Effects: Deinstitutionalization
i. Rapidly between 1950-1958, various different drugs were manufactured and deployed
ii. Effect: rapidly decline of lobotomies (chemical solution without the same level of damage)
iii. Movement in 1960: deinstitutionalization. Seriously mentally ill people can get out of mental hospitals, go back into society, and lead more normal lives
1. Waksman + Streptomycin
a. Waksman’s life
i. Selman Waksman, 1888-1973, from Ukraine. Parents fleeing from Russian pogroms against Jews. Won a scholarship to Rutgers University in NJ. Originally wanted to do medicine, but turned more to science. Graduated in 1915 with a degree in agriculture science specializing in soil bacteria. Came to UC Berkeley, got a PHD in 1918 in biochemistry.
ii. Student was Rene Dubos, who replicated Waksman’s skill set, was first to discover a soil based antibiotic – Gramicidin in 1938. He approached Merck, and developed a high screening process that could spread out individual species of microorganisms and separate them out.
b. Soil microbiologists
i. Waksman put together a lot of graduate students.
ii. Schatz studied the substance secreted by a species of soil bacteria (streptomyces) and called it streptomycin
iii. Powerful, relatively broad spectrum antibiotic
iv. One of the bacterial types that could arrest the tubercle bacillus.
c. Screening approaches
d. Discovery, 1941
e. Clinical trials
i. Arranged to carry out trials at the Mayo Clinic in 1943. Found that streptomyces did not stop the tubercle bacillus immediately, but that they had to give it over an extended period of time. It also had side effects that were tolerable
f. Effectiveness in TB
i. By 1945, new drug was deployed as a therapy for tuberculosis.
ii. By 1945, tuberculosis was already a disease on the decline, because the discovery of a way of identifying it in humans led to more effective public health action. Sanitariums were widespread. And isolation of people with TB was effective.
2. Discovery of viruses
i. Charles Chamberland – around 1884, developed a filter that would purify water by filtering out the bacteria. Used a filter made out of unglazed porcelain. Certain disease causing substances could still pass through filter. Light microscopes reached their physical limit because the wavelengths of visible light, you would not be able to see beyond a certain sized object.
b. Pasteur’s vaccine
c. Ivanovsky + TMD
i. Tobacco mosaic disease – occurred on tobacco leaves in Russia.
d. Beijernick: concept 1898
i. Not a microbe, could pass through filter, ultramicroscopic, could only infect growing cells, could be dried and still not lose its infectivity, inactivated by boiling,
e. Viruses post 1910
i. Smallpox, measles, mumps, yellow fever, influenza were identified as viral diseases.
f. Rockefeller institute
i. An emerging model of how you do scientific medicine. Rockefeller institute found by Rockefeller money, had a large permanent staff of world-class scientists, had its own experimental hospital
i. 7-8 nm in diameter. You get the disease by an oral means of ingestion, mostly through contaminated water. Virus attacks ventral horn cells that translate commands from brain that make your muscles move.
c. Clinical manifestations
d. Endemic to epidemic: why?
i. Went from endemic to epidemic because we all got too clean, so that when we were exposed, especially individuals who were not infants, the incidence of these symptoms where ventral horn cells are destroyed increased. Of all cases, .1% actually become paralytic.
e. U.S. outbreaks
i. Boston 1893, Vermont 1894, NYC 1916 – 27,000 cases, and 6,000 deaths.
ii. Rockefeller center recognized polio as a virus. Found that it likes humans and primates.
iii. Swimming pools were potential sources of infection.
f. FDR National attention
i. FDR got a case of paralytic polio in his 40s. His legs were completely paralyzed.
ii. Became national focus for polio
g. Warm springs and treatment
i. Warm Springs in late 20s had financial problems, and FDR bought spa and converted it into a center of treatment for children who had developed paralysis.
h. NFIP – O’Connor
i. O’Connor was a lawyer who had contact with wealthy NY families, and one of his siblings came down with infantile paralysis. O’Conner became more and more active in polio, and founded National Foundation for Infantile Paralysis.
4. Salk and Vaccines
a. Life and training
i. Jonas Salk 1914-1995. Came from a poor Jewish family, child from immigrant family. Graduated from high school when he was 15. Graduated from college at 19 from City College of New York. Got an MD from NYU in 1939.
b. Francis and Influenza
i. Thomas Francis – a virus researcher at Rockefeller institute. Mentor to Salk. Francis had been working on influenza for 15 years. It was already recognized that influenza was a viral disease. You try to generate an attenuated virus. Salk joined Francis in 1941. Wanted to develop a vaccine that killed and inactivated the virus.
c. Own lab and NFIP
i. After war, Salk got his own laboratory at University of Pittsburgh. Worked at first on Influenza, and then shifted in 1948 to working on polio. Got grants from NFIP.
d. Enders and human tissue culture
i. John Enders from Harvard Medical School. Contrasted with Salk, because Enders came from a wealthy New England family. Became interested in tissue culture. Through the war Enders worked on this, and tried to culture the poliovirus from human embryonic tissue.
e. Rapid development, 1952-54
i. Inoculated himself, wife, and children, and all developed antibodies.
ii. Next group was children from custodial institutions: school for mentally disabled and school for physically disabled. In 1953 reported his results and all had developed high antibodies titres (concentrations), so vaccine was a success.
f. Test 1954
i. Organized 300k nurses and doctors, vaccinated 400k children, 400k got the placebo, 400k were controls where nothing was done. The tests were a huge success.
g. Mass Application
i. After successful tests, there was mass deployment of vaccine.
1. Anti-microbials: “magic bullets” – 1870s-1915
a. Bacterial antagonism
i. John Tyndall – in 1870s noticed that when certain substances were mixed with bacteria cultures, the bacteria could be stopped in their growth and be killed. For example, in a pure culture of anthrax, addition of other bacteria and urine can impact the culture’s growth.
b. 1890s – pyocyanase
i. 1890 – Emmerich noticed that bacteria in wounds secreted a substance that excluded other bacteria. One of these substances was pyocyanase, which he got patented. Found that the toxicity and dangers of using it were greater than expected. The effectiveness was not as great as previously thought, and dangers were greater than expected.
c. Paul Ehrlich
i. Paul Ehrlich – German laboratory research scientist 1854-1915
ii. Trained in Eastern Germany. In 1876, got interested in the Kochian staining and dyeing procedure. His belief was that a dye works because you have a cell or tissue substrate, and this tissue has various kinds of molecules on its surface. A chemical attached itself to these molecules. Called it the Lock and Key analogy. In 1890s, worked with Kitasato and Behring on tetanus and Diphtheria. Always tried to develop the theoretical underpinnings of these immunological combinations.
d. A magic bullet
i. Magic because it could hit destination only. Awarded Nobel prize in 1908
ii. Looked for arsenic compounds for lab animals infected by tirypanosomiasis.
iii. Got money from Speyer foundation, which allowed him to try various molecules that contained arsenic.
e. Route to 606
i. In 1909, got to #606 (salvarsan) compound of arsenic, that had minimum toxicity against cells, and maximum toxicity against tirypanosomes.
ii. 1904-1905 – treponema Pallidum Syphilis. Ehrlich found that his #606 was a chemotherapy technique against syphilis
iii. 1912 – found neo-salvarsan, which was less toxic against cells. Salvarsan was the first scientifically derived chemotherapy technique against microbials.
f. Success (Syphilis) and Failure
2. Private: Fleming and Penicillin, 1905-1930
a. Training, war and St. Mary’s
i. Alexander Fleming – 1881-1955: raised in Scotland. Great at competitive examinations. Got scholarships to medical school at St. Mary’s, and stayed on stayed on to be an assistant to Wright. Used a specialty practice of administering salvarsan to cure syphilis to fund lab practice. During WW1, got good at treating war wounds and wound infections. Got a strong sense that chemical agents are too strong to use in human medicine. A wound that has antiseptic exposes both human tissue and bacteria to chemical antiseptic. Antiseptic would indiscriminately damage tissue layer.
b. Antibacterial search: lysozyme
i. Fleming tried to find something that was relatively benign, and harmless to human cells. In 1921, discovered lysozyme. Lysozyme is found is tears, nasal secretions, and had a wide range of acitivity in inhibiting the growth of bacteria. Turned out that all bacteria lysozyme could cure was actually benign. Found he could use it as a separating material that kills benign bacteria and separates it from his cultures.
c. Legends and facts
i. Fleming saw that mold on one of his cultures killed bacteria. Ronald Hare decided to “rediscover” penicillin, and recreated Flemings discovery, but could not do so.
d. Staph, mold, and temperature
i. Tried culturing staph at room temperature, in which the staph grew very slowly. The mold cannot keep up with staph, and does not grow as fast. So Hare had to set up experiment such that mold could grow at the same rate as staph colonies. The mold itself is penicillium notatium, which is a rare and unusual mold. Fleming had left experiments running for 2 weeks in September 1928, in which temperature in London never got above 60 oF. The mold could only grow at temperature less than 62 oF.
i. Extracted mold juice, which inhibit growth of many bacterial pathogens. Was also effective at enormous dilutions. Was also very non-toxic, could put on wounds, inject into an infected animal
f. Failure to isolate
i. Fleming tried to isolate, but after heating it disappeared.
ii. 1931 – failed
3. Proprietary: Domagk and sulfa drugs 1920-1945
a. Gerhard Domagk
i. 1898-1964 – Was a medic on eastern front in Germany during WW1. Got an MD in 1921. In 1928, contacted by I.G. Farben (dye company/works)
b. Dye Works
i. Dye company wanted to look for things that attached to tissue, and make therapeutic agents out of them. Domagk had experience doing animal testing in a laboratory.
ii. The chemist Josef Klarer found molecules, Domagk would do the testing on animals.
c. Prontosil, 1932+
i. Klarer synthesized prontosil, a red dye in 1932. Was especially good against strep bacteria. Wasn’t announced until 1935. The prontosil dye consisted of dye + sulfonamide molecules. Sulfonamide was patented 30 years before. I.G> Farben waited 3 years so they could patent.
d. Childbed fever, 1935
i. Immediately put to use in childbed fever, which is a streptococcal infection.
ii. Childbed fever mortality rates fell from 26% to 4 %.
e. Proliferation, problems and politics
i. By 1945, there were 5400 variants of sulfonamide molecule.
ii. The core molecules are either antibiotics, toxic, or diuretics.
iii. In 1939, Domagk was awarded the Nobel prize for discovery of sulfonamide drugs.
4. Public: Development of penicillin, 1930-1945
a. Howard Florey
i. Was a Rhodes Scholar who went to Oxford. Combined many skills: was a pathologist, physiologist, and biochemistry.
b. Oxford work w/Chain
i. Appointed to a very well endowed Oxford lab in 1935 – the Sir William Dunn institutive of pathology.
ii. Beefed up the biochemistry and chemistry.
iii. Brought in Jewish refugee chemist Ernst Chain from Germany. Looked at antibacterial agents that were in the literature, looked at lysozyme.
c. Isolation process, 1938+
i. Took penicillin mold from Fleming’s lab, and used the technique of freeze drying. You freeze a sample, then put it under low pressure so that water is removed such that no denaturing takes place. They succeeded in isolating the penicillin. Set up mold incubation containers.
d. Human trials
i. In 1941 carried out human trials with 9 patients.
e. Scaling up in United States
i. Realized that only place where experiment could be scaled up was in United States. Went to Midwest where Eli Lily had good facilities for deep vat fermentation, where they could produce penicillin in huge quantities. In 1944 D-day, all medics had supply of penicillin.
1. Scurvy and Seafaring
a. Disease and vitamin C
i. Caused by a lack of L-ascorbic acid (vitamin C). Humans cannot synthesize their own vitamin C, so we are dependent upon a dietary source. Can get vitamin C from vegetables or oranges or lemons. Synthesis of proline to hydroxyproline, which is a key ingredient of collagen.
ii. When you can’t replace collagen that is turning over in your body, you have capillaries that are leaky, decay in regeneration of gum, collagen tissues start breaking down so body becomes painful.
iii. This was not a problem until ships came along. Ships could stay off of land for longer, and had to rely upon stored food that was given to sailors.
iv. Daily diet: 1 pound of hardtack (bread biscuit), dipped in water, 1 gallon day allotment of beer, 5 oz of salt beef, 2 oz of salt pork, 2 oz of dried peas, 2 oz of cheese. It was not deficient in calories, but in certain vitamins.
b. European Expansion
i. 700-800 men on single ship that would not dock in ports for months at a time.
ii. Anson from 1740-1744, had 961 men on 6 ships. When he came back, only 250 men. Great majority had died from scurvy.
c. James Lind, 1747-1753
i. Theories: seaman to sleep below, sea air was salty, diet did not have a proper amount of acid or alkali.
ii. In 1747, Lind carried a trial that there was a lack of an acid substance in the diet. Took 12 men, and gave them various kinds of supplements: 2 got cider, 2 got a dilute solution of sulfuric acid, 2 got vinegar, 2 were given saltwater, 2 given oranges and lemons, 2 given nutmeg. Only 2 who got better were those who ate oranges and lemons. Lind published 6 years later, but emphasized that oranges and lemons were mild acids, similar to cider. His interpretation of data was incorrect.
d. Blane Success 1795
i. Gilbert Blane – surgeon in West Indies fleet. Believed in role of physician as someone who works out diet. Commander of West Indies fleet was Admiral Rodney, who instituted a better diet with fresh fruit and vegetables. But these fleets were rarely out of sea for longer than a week.
ii. During Napoleonic wars, ships had to be away from ports for months at a time. In these circumstances, scurvy came up again. Blane convinced Rodney in 1793 to include orange juice or lemon juice. Tried a lemon juice ration, and not a single man died from scurvy. By the end of the Napoleonic wars, the British navy was consuming 1.6 million gallons of lemon juice per year.
e. 19th century failures
i. Lemons were obtained from Spain, then the British switched to Lime with high level of Vitamin C. Then switched again to a Lime with virtually no Vitamin C content.
f. Animal model
g. Norwegian Axel Holst around 1900 started feeding animals various vegetable substances to try to get a scurvy like illness. After experimenting on Guinea Pigs, he found that citrus was the most important factor in influencing scurvy in animals.
h. Isolation: 1930s
i. Biochemists succeeded in 1930s of isolating ascorbic acid, determining its structural formula, and being able to synthesize it.
2. Beri-Beri + Rice Economies
a. Disease: Thiamine (Vitamin B1)
i. Beri-Beri is an unusual disease that arose in a particular time and place. In the mid 19th century, because of expanding civilization. The lack of Thiamine is the basic cause. Thiamine is present in meat, beans. Lack of thiamine has a cardiac effect, enlarged heart.
ii. Wernicke’s encephalopathy – an individual on a long term lack of thiamine diet develops confusion, muscular weakness. Can occur in vegans and alcoholics.
iii. Cure is simply to get an IV with nutrients, person is better in 24-48 hours.
b. Late 19th century outbreaks
i. A procedure was worked out for milling rice, where the husk would get milled off, leaving the white rice. By milling it off, the main source of thiamine was eliminated from a portion of the world where rice was essential in diet. As a result, in 1850s, 60s, and 70s, there were isolated reports of outbreaks of Beri-Beri. The Dutch were the main colonial players in this region.
ii. Japan had built up navy in its modernization. Ships were coal powered or steam powered and could stay at sea for months. Beri-Beri started to show up. Kachiro Kakaki’s research showed that for a 272 voyage, of 276 men started, 169 contracted Beri-Beri, and 25 died. None of them was an officer, because officers had better diets. Kakaki realized that in order to have a proper nutrition, you needed a proper Nitrogen Carbon balance. Got permission to try this on a new voyage of similar proportions. Only 14 cases of Beri-Beri, and no deaths.
c. EIkjman in Indonesia
i. Indonesia was also suffering from Beri-Beri. Sent out a commission
ii. Christian Eijkman – Dutch, educated in physiological chemistry and bacteriology, sent to Indonesia in 1886 to work on this disease.
iii. Had to disprove that growth of mold caused a toxin
iv. Also disproved that the mold was caused by an infectious agent.
v. Encountered an outbreak of Beri-Beri in chickens. Chickens were fed the white rice… Only lasted from July to November, when cook had pity on chickens and fed them white rice. Eijkman found that it was a substance on the outside of the rice that a lack of caused Beri-Beri.
d. Funk + characterization
i. Polish/English biochemist named Casimer Funk. Funk gathered information about various cases in which it seemed like the lack of something in a diet produced a certain disease. Funk proposed that Vital Amines (or vitamins)
e. Isolation in 1930s
3. Pellagra and Southern Corn Economies
a. Disease – Niacin
i. 4 Ds – dermatitis (reddening of skin), dementia (confusion, deviating from reality), Diarrhea (weight loss), Death
b. Pellagra in Europe and US
i. Became a problem when corn became a common crop in southern Europe (Spain and Italy).
ii. Corn came into the diets of Spain and Italy. Corn was especially common during poor conditions.
iii. American Indian diet always supplemented corn with various kinds of vegetables, especially beans, which is a very rich source of niacin.
iv. Did not get investigated until 1900 when pellagra broke out all over the American South. Places like orphanages and prisons, and mill towns.
c. Goldberger and background
i. Joseph Goldberger – came from poor Jewish family. Got his MD in 1895, and joined the US public Health Service in 1899. 1914, investigated Pellagra. Several theories – infectious theory, mold produced toxins. Goldberger was trained in epidemiology to know that neither of these theories was valid.
d. Epidemiology of Pellagra
i. Goldberger saw that none of the managerial staff ever got the disease.
ii. People who got pellagra all had poor diet – little protein, overabundance of corn based products, no vegetables, almost no meat.
e. Demonstration of Causality
i. Got permission to systematically supplement diet, and within a short period of time, pellagra would disappear. First step to prove if dietary deficiency was the cause, supplement was the first step. Secondly, he performed experiments to produce the disease. Thirdly, he did self-experiments in order to prove that it was non-infectious. Had filth parties…
f. Resistance and Breakthrough in 1940s
i. Between 1910-1920, there was an understanding of a more general category of deficiency diseases.
1. Birth of Endocrinocogy 1840s+1850s
a. Problem: glands and functions
i. Thyroid gland function was unknown. Anatomists did not know the functions of various glands.
b. Berthold and testes
i. Castrated boys did not have deep voices, grow body hair, but function of testes were still unknown.
ii. Arnold Adolph Berthold had done detailed work on the anatomy of animal testes. Did work on cocks, and tried to find relationship between the testicles and the comb. Snipped of testicles, and reimplanted the testicles under the skin of the cock (male chicken). Found that the testicles continued to secrete semen and chicken exhibited secondary male characteristics. Berthold published in 1849.
c. Bernard and internal secretions
i. Showed that one of liver’s most important function is to serve as a storage point for glucose … glycogenic function of liver.
ii. Internal secretion – 1855
d. Addisions disease
i. Thomas Addison – 1850s, saw cases of a lack of energy, heart had feeble action, pigmentation was bronzed. Addison performed the autopsy, and found that the adrenal glands were degenerated. Proposed that disease was caused by lack of substance produced by adrenal glands.
ii. Showed that there was pathology connected with the degeneration of an organ. An extirpation of that organ could be performed, and possibly a transplant to restore the function that was lots.
2. The Extract Craze 1885-1905
a. Brown-Sequard’s extracts
i. Edward Brown-Sequard – 1817-1894 – ultimately ended up in Paris. Was an experimenter. Had been interested in relationship between vitality and state of organs. Carried out experiments where he made testicular extracts from various animals (especially goats), and inject it into animals and then himself. In 1889, he published a paper in which he told how his muscular strength increased, and how he could pee farther. Everyone thought he had discovered the fountain of youth. His testicular extract was called “orchitic extract”. Initiated a period in which there was a very intense examination of glands and their extracts.
b. Thyroid and Myxoedema
i. Thyroid: Surgeons started doing thyroidectomies, where a large thyroid could be reduced so it appeared normal.
ii. Myxoedema –
iii. George Murray – British physician, and tried doing an organ extract and applying to the thyroid. Tried it on a patient named Mrs. S. aged 46, brought in by her husband who thought that she had changed over the past few years. She seemed to be tired, features had grown courser, hands and feet had increased in size. Made an organ extract of the thyroid, and gave it to Mrs. S. Got sheep thyroids, chopped them up, tried it on animals, then gave Mrs. S. injections. Almost immediately, the characteristics of the symptoms were disappearing.
c. Thryoxin, 1891
i. Isolated and eventually synthesized.
d. Adrenals and Adrenaline: 1890s
i. Oliver and Schafer discovered that you can take extract of adrenal gland (interior part madulla), and the extract had powerful physiological effects. Extract was isolated as a pure drug, then later synthesized.
e. Target: Secretin 1900-1902
f. Hormone Concept: 1905
i. Hormone – from Greek “I excite”.
3. Diabetes and Banting
a. The disease
i. Diabetes Mbilitus – 1660s. Symptoms: frequent urination, inability to process nutrition, eventual weakness then death, urine was sweet
b. Experimental diabetes 1889
i. Straussburg 1889
ii. Pancreas secretes pancreatic juice. Jesoph von Mering and Oskar Minkowski took out the pancreas from dogs. Then saw how well the dogs could emulsify fats. They noticed the dogs were urinating frequently. Found that urine did have increased sugar. The pancreas had an extrinsic function (to produce pancreatic juice), but also an endocrine function (internal secretion).
iii. Dissection of pancreas showed that acinous cells created the pancreatic juice; islets of langerhans (source of endocrine secretions insulin and glucagon)
c. Search for pancreatic extract
i. The pancreatic juice of the acinous destroys the endocrine secretion. So raw pancreatic extract did not work as a cure.
d. Young Banting
i. Frederick Banting – raised in Canada. Born in 1891 on a farm in Ontario. Went to University of Toronto with aim of becoming a minister. Changed to medicine. Interested in chemistry and biology
e. WW1 Surgeon
i. Because ww1 broke out, the medical school was altered so he could graduate early and work as a surgeon during the war. His private practice after the war failed, so he got a job as a physiology expert.
4. Toronto: 1920-1925
a. Suggestion and idea: 1920
i. Patient had suffered from pancreatic lithiasis. Stones had blocked the pancreatic duct, and pancreatic juice could not flow out. The pancreas had started to shrink and shrivel. Banting had the idea to tie off the pancreatic duct, and allow the pancreas to shrink and degenerate, and then try to extract the hormone from an animal.
b. Resources and Best
i. Macleod (an expert in carbohydrate metabolism) gave him resources and an assistant named Charles Best, who was 20 years old.
c. Summer, 1921
i. Carried out experiments on dogs, tied off pancreatic duct, wait 6-8 weeks while the pancreas degenerated, then an extract was made, and tested for anti-diabetes activity. Injected into a dog with experimental diabetes (a dog with a pancreas removed). The blood sugar levels were reduced until the dogs condition was stabilized.
d. Successful Experiment
e. Sources of insulin
i. Islet cells means island or insula (from Latin), new hormone was called insulin. Fetal calf pancreases were a perfect source for insulin. Banting was a poor public speaker, so Macleod got most of the credit.
f. Clinical trials
g. Noble prize 1923
i. Nobel prize was given to Banting and Macleod. Banting split his prize money with Best, and Macleod split his prize money with the biochemist Collip.