Demystifying Medicine Demystifying MedicineThere are at least five unrelated viruses which primarily infect hepatocytes and cause hepatitis of varied severity. Hepatitis A and E viruses are transmitted by fecal-oral route, do not cause chronic liver disease and have low mortality (less than 1%, with a few exceptions). Hepatitis B, C, and D (which requires concomitant HBV infectiuon) are transmitted by percutaneous or permucosal exposure to blood or body fluids containing the virus, can result in chronic liver disease and hepatocellular carcinoma.
More than 500 million people worldwide are persistently infected with HBV (a DNA virus) and/or HCV (an RNA virus). Despite many shared pathogenetic features, the viruses differ in structure, virologic properties and immune escape and survival strategies. There is an effective vaccine for HBV; none (as yet) for HCV. Drug treatment is partially effective with both diseases.
Discovery of HBV and, later, HCV resulted in virtual elimination of hepatitis after blood transfusion.
Consider the following:
Several factors have combined to change drastically opinions regarding our ability to prevent, treat and cure infectious diseases which were believed to have been accomplished in early antibiotic era (1960-1980). The emergence of drug resistant bacteria (i.e., toxicogenic E Coli, staph aureus, TB); "new" viruses (i.e., HIV, HCV); an immunologically suppressed population (i.e., HIV, drugs) and societal changes (deforestation, rapid global transpoirtation, malnutrition, increased elderly population, illicit drug use, and unprotected sexual transmission of disease) combined to restore infectious agents to their dominant role seen in earlier centuries. Advances in biologic science and technology combined to introduce a new element into global societal disruption and chaos, namely, bioterrorism. Prior to 1990, USSR and USA (and probably other countries) manufactured huge quantities of biologic agents for possible use in warfare. These efforts were curtailed by international agreement. However, new forms of terrorism coupled with naturally occurring lethal diseases and those engineered by perverse science confront society with potential global disaster.
Anthrax, ebola and smallpox invariably head the list of diseases of potential biologic terrorism. The session of Demystifying Medicine on February 14th will review the biology of these agents and how they produce disease, where we stand with regard to prevention (i.e., vaccination), treatment and control and basic and clinical problems confront science and medicine.
Our speakers, John Robbins (NICHD) and Gary Nabel (NIAID) are experts in these topics.
* For a nonscientific but accurate presentation of Ebola, see The Hot Zone; for Anthrax and Smallpox, see The Demon in the Freezer. Both books were written by Robert Preston and are available in paperback.
Malaria has been noted for more than 4,000 years. From the Italian for "bad air," malaria has probably influenced to a great extent human populations and human history.
Every year, malaria causes up to 3 million deaths throughout the world Africa bears over 90 percent of the malaria burden of the world 58 percent of malaria cases occur in the poorest 20 % of the world’s population. In malarious areas of Africa, among children with fever (and thus with suspected malaria) barely more than half (53 percent) receive treatment with an antimalarial drug.
Ancient History (2700 BCE-340 CE)
The symptoms of malaria were described in ancient Chinese medical writings. In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching, The Canon of Medicine). Nei Ching was edited by Emperor Huang Ti. Malaria became widely recognized in Greece by the 4th century BCE, and it was responsible for the decline of many of the city-state populations. Hippocrates noted the principal symptoms. By the age of Pericles, there were extensive references to malaria in the literature and depopulation of rural areas was recorded. In the Susruta, a Sanskrit medical treatise, the symptoms of malarial fever were described and attributed to the bites of certain insects. A number of Roman writers attributed malarial diseases to the swamps.
In China, during the second century BCE, the Qinghao plant (Artemisia annua L) was described in the medical treatise, 52 Remedies, found in the Mawangdui Tomb. In the United States, this plant is known as the annual or sweet wormwood.) In 340 CE, the anti-fever properties of Qinghao were first described by Ge Hong of the East Yin Dynasty. The active ingredient of Qinghao was isolated by Chinese scientists in 1971. Known as artemisinin, it is today a very potent and effective antimalarial drug, especially in combination with other medicines.
Quinine (Early 17th Century)
Following their arrival in the New World, the Spanish learned of a medicine used for the treatment of fevers. Spanish Jesuit missionaries in South America learned of a medicinal bark from indigenous Indian tribes. With this bark, the Countess of Chinchón, the wife of the Viceroy of Peru, was cured of her fever. The bark from the tree was then called Peruvian bark and the tree was named Cinchona after the countess. The medicine from the bark is now known as the antimalarial, quinine. Along with artemisinin, quinine is one of the most effective antimalarial drugs available today.
Discovery of the Malaria Parasite (1880)
Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria. This occurred on the 6th of November 1880. For his discovery, Laveran was awarded the Nobel Prize in 1907.
Differentiation of Species of Malaria (1886)
Camillo Golgi, an Italian neurophysiologist, established that there were at least two forms of the disease, one with tertian periodicity (fever every other day) and one with quartan periodicity (fever every third day). He also observed that the forms produced differing numbers of merozoites (new parasites) upon maturity and that fever coincided with the rupture and release of merozoites into the blood stream. He was awarded a Nobel Prize in Medicine for his discoveries in neurophysiology in 1906.
Naming of Human Malaria Parasites (1890,1897)
The Italian investigators Giovanni Batista Grassi and Raimondo Filetti first introduced the names Plasmodium vivax and P. malariae for two of the malaria parasites that affect humans in 1890. Laveran had believed that there was only one species, Oscillaria malariae. An American, William H. Welch, reviewed the subject and, in 1897, he named the malignant tertian malaria parasite, P. falciparum. There were many arguments against the use of this name; however, the use was so extensive in the literature that a change back to the name given by Laveran was no longer thought possible. In 1922, John William Watson Stephens described the fourth human malaria parasite, P. ovale.
Discovery That Mosquitoes Transmit Malaria Parasites (1897-1898)
On August 20th, 1897, Ronald Ross, a British officer in the Indian Medical Service, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes. In further work with bird malaria, Ross showed that mosquitoes could transmit malaria parasites from bird to bird. This necessitated a sporogonic cycle (the time interval during which the parasite developed in the mosquito). Thus, the problem of malaria transmission was solved. For his discovery, Ross was awarded the Nobel Prize in 1902.
Discovery of the Transmission of the Human Malaria Parasites Plasmodium (1898-1899)
Led by Giovanni Batista Grassi, a team of Italian investigators, which included Amico Bignami and Giuseppe Bastianelli, collected Anopheles claviger mosquitoes and fed them on malarial patients. The complete sporogonic cycle of Plasmodium falciparum, P. vivax, and P. malariae was demonstrated. In 1899, mosquitoes infected by feeding on a patient in Rome were sent to London where they fed on two volunteers, both of whom developed benign tertian malaria.
The Panama Canal (1905-1910)
The construction of the Panama Canal was made possible only after yellow fever and malaria were controlled in the area. These two diseases were a major cause of death and disease among workers in the area. In 1906, there were over 26,000 employees working on the Canal. Of these, over 21,000 were hospitalized for malaria at some time during their work. By 1912, there were over 50,000 employees, and the number of hospitalized workers had decreased to approximately 5,600. Through the leadership and efforts of William Crawford Gorgas, Joseph Augustin LePrince, and Samuel Taylor Darling, yellow fever was eliminated and malaria incidence markedly reduced through an integrated program of insect and malaria control.
Chloroquine (Resochin) (1934, 1946)
Chloroquine was discovered by a German, Hans Andersag, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. He named his compound resochin. Through a series of lapses and confusion brought about during the war, chloroquine was finally recognized and established as an effective and safe antimalarial in 1946 by British and U.S. scientists.
Dichloro-diphenyl-trichloroethane (DDT) (1939)
A German chemistry student, Othmer Zeidler, synthesized DDT in 1874, for his thesis. The insecticidal property of DDT was not discovered until 1939 by Paul Müller in Switzerland. Various militaries in WWII utilized the new insecticide initially for louse-borne typhus. DDT was used for malaria control at the end of WWII after it had proven effective against malaria-carrying mosquitoes by British, Italian, and American scientists. Müller won the Nobel Prize for Medicine in 1948.
Eradication of Malaria in the United States (1947-1951)
The National Malaria Eradication Program, a cooperative undertaking by state and local health agencies of 13 Southeastern states and the CDC, originally proposed by Louis Laval Williams, commenced operations on July 1, 1947. By the end of 1949, over 4,650,000 housespray applications had been made. In 1947, 15,000 malaria cases were reported. By 1950, only 2,000 cases were reported. By 1951, malaria was considered eradicated from the United States.
Eradication Efforts Worldwide: Success and Failure (1955-1978)
With the success of DDT, the advent of less toxic, more effective synthetic antimalarials, and the enthusiastic and urgent belief that time and money were of the essence, the World Health Organization (WHO) submitted at the World Health Assembly in 1955 an ambitious proposal for the eradication of malaria worldwide. Eradication efforts began and focused on house spraying with residual insecticides, antimalarial drug treatment, and surveillance, and would be carried out in 4 successive steps: preparation, attack, consolidation, and maintenance. Successes included eradication in nations with temperate climates and seasonal malaria transmission. Some countries such as India and Sri Lanka had sharp reductions in the number of cases, followed by increases to substantial levels after efforts ceased. Other nations had negligible progress (such as Indonesia, Afghanistan, Haiti, and Nicaragua). Some nations were excluded completely from the eradication campaign (most of sub-Saharan Africa). The emergence of drug resistance, widespread resistance to available insecticides, wars and massive population movements, difficulties in obtaining sustained funding from donor countries, and lack of community participation made the long-term maintenance of the effort untenable. Completion of the eradication campaign was eventually abandoned to one of control.
TODAY malaria is the major killer of the world’s population. Many forms are resistant to all known drugs. Malaria has reappeared in USA through military returning home, immigration and impaired mosquito control (southern USA primarily).
Physicians and scientists have long wanted to see what goes on dynamically in organs and cells. In medicine, this quest is directly linked to improved diagnosis as dramatically illustrated by changes in neurology, cardiovascular disease and cancer. Surgery has been made more precise, successful and safer. Virtually all parts of the body are now accessible to biopsy through imaging-guided instruments. In biology, this quest is directly linked to understanding of cell dynamics, function and elucidation of pathways and controls.
Among the clinically applicable imaging tools are ultrasound, computerized axial tomography (CAT scan), nuclear magneticesnonance (NMR scan) and positron emmission tomography (PET scan). In biology, the use of fluorescent protein chimeric probes and associated techniques including fluorescence recovery after photobleaching (FRAP), fluorescent loss in photobleaching (FLIP) and fluorescence energy transfer (FRET) have permitted amazing understanding of basic cellular functions in health and disease.
These techniques have provided quantitative information regarding the dynamiuc function of organs, cells, organelles and genes.
"….O brave new world…"
Parkinson's disease (PD) is characterized by an insidious onset with slowing of emotional and voluntary movement, muscular rigidity, postural abnormality, and tremor. Parkinson's disease was first described in 1817 by James Parkinson in a paper entitled "An Essay on the Shaking Palsy." It is a common neurological disorder with a prevalence of 1-2 per 1000 overall. However the incidence rises after the age of 50, such that 1-2% of the elderly in USA are affected. The disease is due to the striatal deficiency of dopamine following neuronal degeneration within the substantia nigra.
Dopamine, a sympathomimetic amine vasopressor, is the naturally occurring immediate precursor of norepinephrine. Dopamine hydrochloride is a white to off-white crystalline powder, which may have a slight odor of hydrochloric acid. It is freely soluble in water and soluble in alcohol. Dopamine HCl is sensitive to alkalies, iron salts, and oxidizing agents. Chemically it is designated as 4-(2-aminoethyl) pyrocatechol hydrochloride, and its molecular formula is C8H11NO2HCl. The molecular weight is 189.64.
