Archive for July, 2011

Rockaway Beach, NY:

By Jonathan Allen

NEW YORK (Reuters) Jul 27 – A New York City hospital has stopped asking many patients to dig out health insurance cards and fill in endless forms, instead identifying them by scanning the unique lattice of veins in their palm.

The new biometric technology employed by New York University’s Langone Medical Center was expected to speed up patient check-ins and eliminate medical errors.

“The primary reason we actually got into this was patient safety,” Bernard Birnbaum, the center’s vice dean and chief of hospital operations, said in a telephone interview on Wednesday.

The system also has the virtue of not requiring the patient to be conscious at the time of check-in, as is sometimes the case in emergency rooms.

“The benefits so greatly outweighed the disadvantages it was a no-brainer to implement,” Birnbaum said.

The scanners are made by the technology services company Fujitsu and  exploit the principle that, as with fingerprints and iris patterns, no two  individuals’ palm-vein configurations are quite the same.

Using near-infrared waves, an image is taken of an individual’s palm  veins, which software then matches with the person’s medical record.  The initial set-up for a new patient takes about a minute, the hospital  said, while subsequent scans only take about a second.

“We can then just ask one question: Has your insurance changed?”  Birnbaum said. “If ‘no’, you don’t have to fill out a single form.”

Since some 250 scanners were installed at the hospital in early June at a  cost of about $200,000, more than 25,000 patients have had their palm-vein patterns registered in the system, he said.

The hospital logs about 1.7 million patient visits in a typical year and is in the process of getting as many patients as possible to agree to inclusion in the system.

Registration into the new system is optional, but less than 1% of patients have demurred, Birnbaum said. The palm scan does not appear in the patient’s medical records, nor are the scans stored as images but instead are converted into a unique numeric code.

Although the technology has appeared at other hospitals in the United States, this is its first appearance in the Northeast region, a Fujitsu spokesman said.

Since its introduction in 2007, the technology has also been used to identify customers at ATMs in Japan, to monitor the movements of employees at firms, and to replace cash or cards in the canteens of the Pinellas County school system in Florida.

By Leland Kim

MAUI (KHNL) –  So far this year, six people have had close encounters with sharks in Hawaiian waters.  That’s up 50 percent from years previously.  The majority of Hawiian shark  attacks in the past two years, happened on Maui, according to the Department of Land and Natural Resources.

A doctor on the Valley Isle has become the go-to guy for shark attack cases.  In this pride of Hawaii report, KHNL News 8′s Leland Kim introduces us to a surgeon people call “the shark doc.”

Whether you’re catching a wave, or just enjoying the sun, South Maui beaches attract people from all over the world.  They continue to come, despite a shark attack near this beach last month.

“I won’t stop going in the ocean because of it, unless it was right then,” said Suzan Cunningham, a visitor from Northern California.  “If I saw shark fins, I’d probably get out.”

The latest shark attack happened just beyond a point at Wailea Beach Park. It’s the sixth shark incident so far this year, with four of them resulting in serious injuries.

If you get bit by a shark on Maui, chances are, you’ll end up in the capable hands of plastic surgeon Dr. Peter Galpin.

“I’ve been here on Maui for about thirteen years now, and during that period of time, I’ve taken care of a total of nine shark attack victims, including the gentleman most recently,” said Dr. Galpin.

The patient, a visitor from Southern California, suffered nerve damage, which had to be repaired.  But it could’ve been much worse.

“There were a couple of cuts on this gentleman, a couple of bites on this gentleman that could’ve been potentially life threatening if they had been only an inch or so different from one side to the next,” said Dr. Galpin.

A shark attack can cause major damage, just by the sheer power of its jaws.

“The biting force of a shark is about six tons per square inch,” said Dr. Galpin.  ”And so if they close their mouth on you, and they want to take whatever it is they’re holding onto, they can take it.”

Dr. Galpin says fixing up a shark bite victim is no different from taking care of a trauma patient.

After surgery, it’s a long road to recovery.

“You’re looking at two to three months of fairly limitation in activity just while you let the muscles heal up,” said Dr. Galpin.  “And let the skin heal, and gain strength back, and go through therapy and everything like that.”

While Maui’s waters may be gaining a murky reputation, Dr. Galpin is gaining a reputation of his own, as the clear choice if you get bit by a shark.  And deservedly so, he’s been able to save all of his shark bite patients.

For more on Dr. Galpin and his practice, click here or the link on this page.

A California man stuck a butter knife into his belly in a failed bid at self-surgery to remove a painful hernia.

A Glendale, California man stuck a butter knife into his belly in a failed bid at self-surgery to remove a painful hernia, police said Tuesday.

The wife of the 63-year-old Glendale man called 911 on Sunday night and told the emergency operator her husband was using a knife to remove a protruding hernia, according to Sergeant Tom Lorenz.

“She said he had impaled himself with a knife,” Lorenz said.

Officers found the man naked on a patio lounge chair outside his apartment with a 6-inch butter knife sticking out of his stomach.

The man’s wife told officers that her husband was upset about the hernia and wanted to take it out.

But while waiting for paramedics, the sergeant said, the man pulled out the knife and stuffed a cigarette he was smoking into the bleeding, open wound.

“What he was thinking, I don’t know. I don’t know if he was cauterizing it (the wound),” Lorenz said.

Based on his actions and statements from the wife, Lorenz said the man was placed on psychiatric hold and taken to Los Angeles County-USC Medical Center.

Because he’s on psychiatric hold for up to 72 hours under the state Welfare and Institutions Code, Lorenz said the man’s name and condition cannot be released.

“You just never know what to expect,” said Lorenz, who has been on the police force for 29 years. “I’ve seen self-mutilation, but not a maneuver like this.”

A Wonderful, Fascinating  History and Biography of a brilliant Army Surgeon.  Enough to make you feel proud to be an American, even today.

Find it here, at http://www.wramc.army.mil/visitors/visitcenter/history/pages/biography.aspx

 

Major Walter Reed Born in Virginia

On September 13, 1851, one of the world’s outstanding physicians and medical research scientists was born in Belroi, Gloucester County, Virginia, the son of a Methodist minister, Lemuel Sutton Reed, and his wife, Pharaba White Reed. At an early age, Walter Reed gave “evidence of the intellectual brilliancy and earnestness of purpose which distinguished him in later years.”

Reed Enjoys Early Academic Success

After his basic education at a private school in Charlottesville, Virginia, Walter Reed matriculated at the famed University of Virginia where he completed the two-year medical course in only one year and received his degree in 1869 at the age of seventeen. He remains the youngest student ever to graduate from the medical school. Since the University of Virginia had no hospital attached, he took a second degree at Bellevue Hospital Medical College in New York in 1870.

Reed’s Professional Traits Emerge

He competed for and won a position as assistant physician at Infants’ Hospital at Randall’s Island. He served his internship at Kings County Hospital in Brooklyn and also worked at the Brooklyn City Hospital. While interning at Kings County he was described as being “sociable and companionable with a special gift for conversation.” After further in hospital work at Brooklyn City Hospital with consultant status at Kings County, he was appointed one of the five inspectors on the Brooklyn Board of Health in 1873 at the age of twenty-two. He approached all his duties with enthusiasm and optimism, traits which contributed immeasurably to his success, both social and professional.

Reed Meets His Future Wife, Receives Army Commission

The turmoil of city life excited and stimulated him. He attended concerts at the Hippodrome and the Academy of Music and good lectures on literature and scientific subjects. In 1874, having served on the Boards of Health in Brooklyn and New York, he traveled to North Carolina to visit his father who was living in Murfreesboro. There he met his future wife, Emilie Lawrence, the daughter of a North Carolina planter. His letters to her revealed that he had decided to give up his civilian career and enter the Army as a surgeon. Because he felt the Army offered a good opportunity for travel, and also the financial security he felt he needed to marry his winsome fiancée, he applied and was accepted for an appointment in the Medical Department of the Army. Walter Reed passed the required examinations and was appointed Assistant Surgeon with the rank of first lieutenant on June 26, 1875.

Arizona to Baltimore to the Frontier to Alabama

So began for the young couple eighteen years of garrison life. After five years at Fort Lowell and Fort Apache, Arizona, where he served as a beloved family doctor visiting patients in the wild country surrounding his posts, he was promoted to captain, on June 26, 1880, and soon thereafter was transferred to Fort McHenry in Baltimore. In his spare time he became a student of physiology at Johns Hopkins University during 1881 and 1882.

After serving at Fort McHenry, Walter Reed was again assigned to the western frontier at Forts Omaha, Sidney and Robinson in Nebraska, and then to Mount Vernon Barracks, Alabama. One Walter Reed historian points out “one of the marvels of his life is that his relegation to frontier garrisons, unfavorable for intellectual contacts, did not ruin him.”

Medical Science Advances

It is significant that Walter Reed’s career coincided with the great flowering of medical science that took place in the 1880′s. The germ theory of infectious disease was now accepted as postulated and proved by Pasteur, and Robert Koch had perfected a method for studying bacteria. In the United States, George Miller Sternberg, later Army Surgeon General, with whom Walter Reed would develop a close professional relationship, was one of the founders of bacteriology.

Dr. Reed Furthers His Studies

Dr. Reed returned to Baltimore in 1890 as examiner of recruits. This assignment was quite welcome since it provided him with the opportunity for further study. He became a student of bacteriology and pathology under the tutelage of Dr. William Henry Welch, head of the Pathological Laboratory at Johns Hopkins and one of the foremost pathologist and medical bacteriologist in this country. These subjects had not been previously taught as part of the medical curriculum. It was during this period, that the mature scientific investigator began to be formed. He conducted his own individual research much to the delight and satisfaction of Dr. Welch who had been one of Pasteur’s students. His ties with Dr. Welch were strengthened, and Dr. Welch’s mutually admiring relationship with Sternberg was quite advantageous to Walter Reed.

A Final Western Tour of Duty

From 1891 to 1893 Walter Reed spent his last western tour at Ft. Snelling, Minnesota. A man of sterling character, religious by nature, prepared for practice and research, a soldier who had learned to endure hardships, a student and pathologist of the highest caliber, Walter Reed was now ready for the great achievements of his lifetime. He would live for only fifty-one years, but between 1893 and 1901, a year before his death, he was engaged in some of the most important work in the history of medicine. This took the form of research into the etiology (cause) and epidemiology (spread) of typhoid and yellow fever.

Reed Is Assigned to Army Medical School, Moves to Washington, D.C.

In 1893 Reed was promoted to major and brought to Washington, D.C. by the new Surgeon General, George Miller Sternberg. He took his post as Curator of the Army Medical Museum (now the National Museum of Health and Medicine, part of the Armed Forces Institute of Pathology) and professor of clinical microscopy in the Army Medical School (now the Walter Reed Army Institute of Research) opened in Washington that year by General Sternberg. He later took on additional duties as professor of bacteriology at the Columbian University (now the George Washington University). He worked industriously for five years, teaching and working in his specialty, bacteriology. His work, clinical and academic, was accurate and original. His long experience as a military doctor in the field gave him an excellent sense of judgment, valuable for investigating the causes of epidemic diseases and in making sanitary inspections at military posts. He was indeed needed as an instructor; medicine was making rapid advances and military doctors had to be informed of the new techniques. An anti-toxin for diphtheria had been prepared and there was a race to find the specific agents responsible for communicable diseases. This was the beginning of truly an era of great discovery. But the work of Koch and Pasteur were not well enough known; Major Reed, as a professor at the Army Medical School, served in a vital capacity teaching the new science of bacteriology.

Reed Begins His Search For a Cure

The rush of volunteers at the beginning of the Spanish American War in early 1898 presented special problems for the Army Medical Department. These volunteers were sent to various training camps mostly in the east and south. In these crowded camps typhoid became a terrible killer. In fact many more young soldiers died of disease, mostly typhoid, than were killed by the enemy in Cuba. It became a national disgrace. Surgeon General Sternberg appointed a board of officers headed by Major Reed to investigate this terrible problem of typhoid fever. The Typhoid Board performed its greatest service through the discovery that this deadly disease, prevalent at almost all U.S. Army encampments, was spread most commonly and disastrously by contact between persons and flies soiled with human excrement containing typhoid bacilli, by human carriers who shed bacilli by the billions, and by impure drinking water. This triumph for Army medicine demonstrated for the first time the effects of intestinal disease-producing agents. It also pointed out the failure of out-dated diagnostic techniques. In some camps there were not even microscopes available for diagnostic purposes. The report of these findings passed with little notice, but it proved beyond all doubt that proper diagnosis required microscopic investigations and, in some cases, autopsies. Further, it served to dispel old notions that such diseases were caused by miasmas or foul emanations from swamps and rivers.

The Challenge of Yellow Fever

Diseases, including yellow fever, killed more men in the Spanish-American War than did the enemy. Yellow fever may have first appeared in Central America in 1596, probably imported from Africa by slave ships. It may have been the disease from which members of Columbus’ second expedition suffered in 1495. Ninety epidemics struck the United States between 1596 and 1900. In 1793 an epidemic first hit Philadelphia, then the U.S. capital, causing the Government to flee as ten per cent of the population perished. Washington went to Mount Vernon while Jefferson fled the disorder caused by the onslaught of the disease. Because of frequent epidemics, which destroyed ninety per cent of his expeditionary forces in 1802, Napoleon was influenced to sell the Louisiana Territory. It was chiefly because of malaria and “yellow jack,” as the disease was nicknamed from the pennant which was flown during quarantine, that the French were unable to complete the Panama Canal. The danger of contaminating the southern states was considered to be a major factor in the annexation of Cuba.

The onset of yellow fever came with chills and a headache. Then followed severe pains in the back, arms and legs accompanied by high fever and vomiting. The feverish stage might last hours, days, or weeks. Jaundice, from which the fever derives its name, might then appear. Then came the so-called “stage of calm” when the severity of the symptoms subsided and the fever dropped. In less serious cases this stage indicated recovery. But in the main, this stage was followed by a return of the fever accompanied by internal bleeding which caused the dreaded “black vomit” when blood released into the stomach was ejected. Reed and Carroll had estimated that there were 300,000 cases in the United States between 1793 and 1900, which cost the nation almost $500,000,000 with a mortality rate usually at forty per cent but sometimes as high as eighty five per cent. The scourge of yellow fever had plagued the southeastern United States for almost two hundred years, but nowhere was it more prevalent than in Havana.

Following the end of the Spanish-American War, yellow fever loomed as a significant problem for the U.S. Army during its planned four year occupation of Cuba. In 1899, Reed and his assistant James Carroll published a paper refuting the claim of the respected Italian scientist Guiseppe Sanarelli that a bacterium he had discovered was the agent of yellow fever. Surgeon General Sternberg, the country’s leading expert on yellow fever, agreed with them completely. In the late spring of 1900, as the yellow fever season approached and the sanitary measures taken to protect the forces in Cuba were clearly less than adequate, Sternberg appointed a group of Army physicians to study the issue in Cuba.

Reed Appointed to Head Study of Yellow Fever

In May 1900 Major Reed was appointed president of this board “to study infectious diseases in Cuba paying particular attention to yellow fever.” The other members of the board were Reed’s friend Acting Assistant Surgeon James Carroll, and Acting Assistant Surgeons Jesse W. Lazear and Aristides Agramonte of Havana. Major Reed organized the Board in the following manner: he was in charge of the entire project; Dr. James Carroll was in charge of bacteriology; Dr. Jesse W. Lazear was to do laboratory work but fairly quickly took charge of the experimental mosquitoes; and Dr. Aristides Agramonte was in charge of pathology. As a result of the extraordinary work of this Yellow Fever Commission, very few people living today have any knowledge of this dread disease.

Disease Studies Begin

On June 25, 1900 Walter Reed arrived at Columbia Barracks in Quemados about six miles from Havana. Major Reed visited the hospital where his friend Major Jefferson R. Kean, Chief Surgeon of the Department of Western Cuba, was ill with yellow fever. It was the first active case Reed had ever seen, fortunately Kean recovered. Despite the fact that Reed and Carroll had published results contrary to it, the Commission members set out to see if they could validate Sanarelli’s theory. By August, 1900, however, they had found no causal relationship between Bacillus icteroides and yellow fever. Bacillus icteroides was actually a member of the hog-cholera group.

The Commission then decided that the best way to approach yellow fever was not by searching for a specific agent but rather by identifying the means by which the fever was transmitted. They turned their attention to the theory of Dr. Carlos Juan Finlay and examined it more carefully. For nineteen years this resident of Havana had contended that yellow fever was carried in the body of a common house mosquito which at that time was called Culex fasciatus, later Stegomyia fasciata, and is now known as Aedes aegypti. This theory had been expounded even earlier, but it was Finlay who was its staunchest exponent. However, after some 100 experimental innoculations had failed to produce any clear cases of the disease under strict laboratory control, Finlay was scoffed at; people referred to him as the “mosquito man.” There was evidence, however, that tended to lend credence to this theory, which even the Yellow Fever Commission, optimistic though it was, had doubted. First of all, the disease skipped erratically from house to house, jumping around corners. One member of a household might contract the disease while others in close contact never became ill or did so after a period of about two weeks had elapsed. This was quite unlike any other infectious disease except malaria, which had just recently been shown by Major Ronald Ross of the British Army to be spread by the Anopheles mosquito.

Reed Returns to Washington

Although Major Reed was called back to Washington to finish the Typhoid Commission report following the unexpected death of one of its members, the work of the Yellow Fever Commission went forward. Dr. Lazear had recently been working with malarial mosquitoes and attacked his duties with great enthusiasm in view of the information he had concerning the observations of Dr. Henry R. Carter of the Marine Hospital Service (now the Public Health Service). Dr. Carter, who was assigned in Cuba at the time, had observed that it took two or three weeks for the first case of yellow fever to produce the next case in a community. On the basis of this observation, he suspected that an insect might be the intermediary since this would account for the delay in transmission. He called this the “extrinsic incubation period.”

Dr. Finlay had given some of the black, cigar-shaped eggs to the Commission, and Lazear allowed them to hatch. In the warm summer months, it was not difficult to maintain a supply since the mosquitoes bred in any clean, still water. Several members of the research team (including Drs. Carroll and Lazear) then volunteered to be bitten but initially without producing illness. Later Carroll was bitten again and promptly developed a successful case of yellow fever but his case was experimentally defective since there may have been other sources of contamination. Despite a very severe case, Carroll fortunately recovered and went on with his work in bacteriology. Next, Lazear asked Private William Dean of Ohio if he would consent to be bitten. Answering that he wasn’t “afraid of any little old gnat” Dean permitted the female Aedes aegypti to dine on him. He developed the first unquestionable experimental case. Dean survived.

Dr. Lazear Dies, Reed Rejoins the Study

Dr. Lazear himself came down with yellow fever and tragically died after several days of delirium and black vomit – a true martyr to science. The exact details of how he acquired his illness will probably never be known, as he had several possible exposures, including possibly from self-experimentation.

With the Typhoid Report completed and word of Lazear’s death, Major Reed quickly returned to Cuba. Although grieved at Lazear’s death, he was excited at the prospect of successfully tracking down the secret of the fever. Dr. Lazear’s notebook, found by Lieutenant Albert E. Truby, yielded the key. In it, through the carefully recorded controlled experiments, Walter Reed found that in order for a mosquito to become infected, it had to bite a yellow fever patient during the first three days of his illness; only during that time was the agent present in the bloodstream. Further, it required at least twelve days for the agent to incubate in the female mosquito (only the female aegypti draws blood) before the fever could be passed to another person.

Progress Announced

In October 1900, Major Reed was able to announce to the annual meeting of the American Public Health Association that “the mosquito serves as the intermediate host for the parasite of yellow fever.” These two cases, although sufficient to convince the Yellow Fever Commission that they were at last experiencing some success, were not enough for the thorough scientific mind of Walter Reed, nor would they be for a public that the press had instructed in the “foolishness” of the mosquito theory. With the express permission and financial support of General Leonard Wood, Governor General of Cuba, Camp Lazear, named for their fallen comrade, became operational on November 20, 1900.

Human Volunteers Begin Participation in Yellow Fever Study

Dr. Carroll had exhausted the list of experimental animals, rats and the like normally used for scientific research, failing to find any susceptible to yellow fever. Human volunteers would be needed. General Wood also authorized the Commission to use and pay American and Spanish volunteers to participate in the experiments.

Reed Proves Method of Transmission

In addition to the mosquito theory, Dr. Reed also desired to disprove the seemingly fallacious belief that yellow fever could be transmitted and induced from clothing and bedding soiled by the body fluids and excrement of yellow fever sufferers. These articles were known as fomites and were commonly thought to carry the disease. Just as “everybody knew” that the mosquito theory was foolish, so “everybody knew” that fomites were dangerous.

In November, 1900, Camp Lazear was established one mile from Quemados and placed under strict quarantine. At this experimental station Private John R. Kissinger permitted himself to be bitten and developed the first case of controlled experimental yellow fever. This case have been deemed as important to medical science as Robert Koch’s discovery of the tubercle bacillus and the development of the diphtheria anti-toxin. Kissinger and John J. Moran (who was bitten but did not develop yellow fever) had volunteered on condition that they would receive no gratuities, performing their service “solely in the interest of science and the cause of humanity.” In a truly unprecedented step, the Commission got informed consent from its research subjects, having them sign a consent form that was written in English and Spanish. This almost unrecognized contribution of the Commission was a landmark event in the evolution of ethical human experimentation.

Then, in order to prove the theory for all time and to destroy the fomite myth, two specially constructed buildings were erected in Camp Lazear. Building Number One, or the “Infected Clothing Building,” was composed of one room, 14 x 20 feet heated by a stove to ninety-five degrees. For twenty nights Dr. Robert P. Cooke and Privates Folk and Jernegan hung offensive clothing and bedding around the walls. They slept on sheets and pillows befouled by the blood and vomit of yellow fever victims. Not one of the volunteers contracted the disease. On December 19, 1900, they were relieved by Privates Hanberry and England who, in turn, were finally relieved by Privates Hildebrand and Andrus. From November 30, 1900 to January 31, 1901 the experiment ran to completion, disproving the fomite theory of transmission and thereby demonstrating the uselessness of destroying the personal effects of yellow fever victims, thus saving thousands of dollars in property.

The second building was similarly constructed and was called the “Infected Mosquito Building.” It was divided into two parts separated by a screen with screens on the windows as well. John J. Moran, a clerk in General Fitzhugh Lee’s office, volunteered again and was bitten by fifteen infected mosquitoes, developed the fever and recovered. The other volunteers, who were separated and thereby protected by the screen, escaped infection.

In February, 1901 Walter Reed presented their results to the Pan-American Medical Congress in Havana. The results were readily accepted in Havana but on his return to the United States there was not universal acceptance. Despite the acclaim he received, he remained modest and reserved. His constant hope of doing something to relieve the suffering of mankind had been fulfilled; his dedication to duty, sound judgment, and thorough scientific methods was an inspiration to the generations of medical researchers.

Dr. Carroll Finds the Final Key to Yellow Fever

In the late summer of 1901, Dr. Carroll returned to Cuba and through further experiments proved that the specific agent of yellow fever was sub-microscopic and too small to be caught in the pores of the diatomaceous filter that retained bacteria. Thus the last key to the disease was found. Carroll had proved through a series of injections of filtered blood that a filterable agent (a virus) could cause disease in man.

Yellow fever was produced in twenty-two American and Spanish volunteers either by direct mosquito bites or by injections of infected blood or filtered blood. These injections proved that the specific agent of yellow fever is in the blood and that passage through the body of a mosquito is not necessary to its development. Neither the brilliance of their thoroughness nor the genius of their experimental design could have bequeathed the Commission the extraordinary luck they had, for not a single one of their volunteers had died.

Yellow Fever Volunteers Honored

The courage of the volunteers is inestimable. A unique honor helps keep alive the memory of the gallant men who participated in these experiment. In 1929 Congress awarded a special gold medal to each man or his next of kin. In addition, their names are recorded in the Army Roll of Honor.

Yellow Fever Eradication Strategy Implemented

Had it not been for Major Reed’s fair and thoroughly scientific approach to the problem and misconceptions concerning the disease, especially the whole contagion theory, yellow fever might have continued for years. As a result of the Yellow Fever Commission’s success, Major William Crawford Gorgas, then Chief Sanitary Officer for the Department of Cuba, rid the island of this longtime pestilence. Realizing that the mosquitoes never stray far from human dwelling places in order to get their meals of blood necessary for them to lay their eggs, Major Gorgas organized inspection parties to check all homes in Havana for possible breeding places, insuring that the only standing water in the homes was needed for family use and properly screened. All other water receptacles were to be emptied. Yellow fever which had ravaged Havana for 150 years was essentially eradicated in 150 days. The whole world was astounded by the results.

As the mosquito clean-up campaign was starting, Major Gorgas was not convinced that it was going to be successful in controlling yellow fever. While he believed the validity of the commission’s experiments, he felt that the disease was also transmitted by other means and that killing all the mosquitoes, if that was even possible, was not all that would be needed.

The Search For a Vaccine

Gorgas and a Cuban yellow fever expert, Dr. Juan Guitéras, wanted to see if intentionally causing a mild case of yellow fever could be used as a way to “vaccinate” against the disease. They had been impressed that almost all yellow fever cases produced by the commission had been relatively mild. A separate Inoculation Station was established at the Las Animas Hospital outside Havana and Drs. Gorgas and Guitéras successfully produced a case of yellow fever by the bite of a loaded mosquito in February 1901. It was a mild case and the patient survived. During the next six months all subsequent attempts to produce cases were unsuccessful. In August 1901, they succeeded in infecting eight out of sixteen volunteers. Tragically, three of these eight cases turned out to be fatal.

The only American among the Gorgas and Guitéras volunteers was a 25 year old nurse from New Jersey, Clara Maass. She had volunteered during the Spanish American War in 1898 and had served at stateside camps and in Cuba. She worked as a contract nurse as there were no nurses on active duty at that time. Later she volunteered again and served in the Philippines but returned home because of illness. After she recovered, she wrote Major Gorgas and ask if he need her help. Following his positive response, she returned to Cuba to work in the Las Animas Hospital. She volunteered for the Gorgas and Guitéras mosquito experiments and was bitten numerous times during March, May, and June without results. She was bitten one last time on August 14, 1901. She became ill on the 18th and despite the best care possible, died on the 24th. Her death and the two others sent shock waves through the Army that reverberated all the way back to Washington and eventually lead to the cessation of human experimentation.

Yellow Fever, Malaria Controlled in Canal Zone

Several years later, now Colonel Gorgas applied the same techniques in the Canal Zone, controlling yellow fever and malaria, permitting the United States to complete the Panama Canal so vital for commerce and deployment of the Pacific fleet. Thus the menace which had struck in the southern United States and Caribbean every year since 1648 was for all practical purposes eradicated.

Yellow Fever Vaccine Developed

The Commission’s discoveries were confirmed by the Board of Health of Havana and later a commission of the Pasteur Institute confirmed the agent’s filterability. In 1927 it was found that certain species of monkeys were susceptible to the virus, thereby eliminating the need for human subjects. In 1937 a vaccine against yellow fever, called 17-D, was produced by scientists of the International Health Division of the Rockefeller Foundation. The use of this vaccine became routine in the United States Army in 1942. Since yellow fever is still endemic in the jungles of Central America and Africa where anti-mosquito measures are almost impossible, the fever still exists. A distinction is therefore made between “urban” yellow fever which is under control and the jungle variety which persists. As yet there is no cure for the disease, only inoculation against it.

Reed Resumes Post at Army Medical School

After his return to the United States in February 1901, Dr. Reed resumed his position as professor of bacteriology in the Army Medical School, and as professor of pathology and bacteriology at the Columbian (George Washington) University Medical School. In the summer of 1902 he was awarded two honorary degrees: a Master of Arts from Harvard University and a Doctor of Laws degree from the University of Michigan. He was appointed librarian of the Surgeon General’s Library on November 1, 1902.

Walter Reed Dies

Reed’s health had appeared in decline for some time, following an appendectomy, he died of peritonitis on November 23, 1902. He was buried in Arlington National Cemetery. On his simple monument is inscribed the following epitaph, taken from the remarks of President Eliot when Harvard University conferred the Master of Arts degree: “He gave to man control over that dreadful scourge, yellow fever.”

Dr. Walter Reed’s Legacy

Today a great hospital and medical center stand in constant tribute to Walter Reed. Due to the untiring efforts of Major William Cline Borden who was the initiator, planner and effective mover for the creation, location, and first Congressional support of the Medical Center, it is still referred to today as “Borden’s Dream.” Walter Reed General Hospital, as it was then known, opened its doors on May 1, 1909 to ten patients. Fourteen years later, General John J. Pershing signed the War Department Order creating the Army Medical Center. In September 1951 on the one hundredth anniversary of Walter Reed’s birth, the entire complex became known as Walter Reed Army Medical Center, in further tribute to this hero of medical science. In 1945 he was elected to the Hall of Fame of Great Americans at New York University, the first physician to be so honored. On November 21, 1966, a memorial and bronze bust of Major Reed were unveiled by President Eisenhower on the grounds of Walter Reed Army Medical Center. The bust and memorial were donated by the Walter Reed Memorial Association, an organization which, since its inception in 1903, had resolved to erect a memorial in Washington to perpetuate his memory.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Historic Army hospital to move to new location in Bethesda, Md.

WASHINGTON — The storied Walter Reed Army Medical Center is retiring its ceremonial flags on Wednesday, as it prepares to close its doors after more than a century of treating wounded American fighters and presidents.

Walter Reed has treated some 18,000 troops that fought in Iraq and Afghanistan as well as U.S. President Dwight Eisenhower, who died there, and Gens. John J. Pershing and Douglas MacArthur.

The present facility, together with its current patients, will be moving to a new location in Bethesda, Md., throughout August, prior to shutting its doors on Sept. 15.

But the official “casing of the colors” at the 102-year-old institution — as the ceremony to retire the hospital’s flags is known — was taking place on Wednesday.

“The closing marks a transition to the next stage in the life of Walter Reed,” Walter Reed Army Medical Center Spokesman Chuck Dasey told Reuters, adding that the new joint services facility in Bethesda will be called the Walter Reed National Military Medical Center.

“The name will continue on to represent the new flagship of military medicine,” he added.

Citing aging facilities and cost-saving strategies, a military base review panel decided in 2005 to close the center’s campus in Washington, and merge its operations with the National Naval Medical Center in Bethesda, which will cost an estimated $2 billion. The hospital will also occupy a new hospital at Fort Belvoir, Va.

Low moments
The new facilities will have new colors.

The closure of the present facility will affect more than 5,000 workers. Many of their jobs will move to Bethesda and a new community hospital at Fort Belvoir in northern Virginia.

The U.S. State Department and the District of Columbia will assume ownership of the facility. Some of the buildings will be preserved by landmark status. Others will be torn down or converted to other uses, possibly even shops, Dasey said.

The venerable facility’s long history has not been without its low moments.

Problems at an adjunct building of Walter Reed Army Medical Center were brought to light by a Washington Post investigation published in 2007. It found recuperating soldiers were living in a dilapidated building infested with mice, mold and cockroaches.

The Washington Post reports were particularly embarrassing because former U.S. President George W. Bush and senior defense officials had repeatedly visited the wounded in the hospital to show their concern for those who served in battle.

Bush said while most of the people working at the hospital were dedicated professionals, “some of our troops at Walter Reed have experienced bureaucratic delays and living conditions that are less than they deserve.”

Walter Reed received his medical degree from the University of Virginia in 1869, and additional training at Bellvue Medical College, New York City in 1870.  

He was commisioned as Assistant Surgeon with the rank of Lieutenant, United States Army, and stationed at Fort Lowell, Arizona from 1876 to 1887. Was attending surgeon and examiner of recruits, Baltimore, Maryland, from 1890 to 1893. Was curator of the Army Medical Museum and promoted to Major, United States Army, 1893.

 

He was appointed chairman of a commission sent to study yellow fever among U.S. soldiers in Cuba in 1898, and proved that the disease was transmitted by mosquitos. In 1901-02 he was professor of pathology-bacteriology at Columbia Unviersity in Washington.

 

He died on November 22, 1902, at age 51, from a sudden case of appendicitis. The Army Medical Center in Washington is named for him. He is buried in Section 3 of Arlington National Cemetery.

 

His daughter, Blossom Reed (July 12, 1883-August 22, 1964), and his wife, Emilie Lawrence Reed (January 14, 1856-July 23, 1950), are buried with him.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

May Lead to Coming Bidding War to Retain General Surgeons

By Patrice Wendling:  http://www.facs.org/surgerynews/2011/sn0411.pdf 

Rural hospitals will need to devise unique strategies to enhance hiring and retention in the face of a looming shortage of almost 30,000 surgeons over the next 20 years.“We think this shortage will result in competition between urban and rural hospitals, maybe perpetuating in bidding wars,” Dr. Thomas E. Williams Jr. said at the annual meeting of the Central Surgical Association.

“In a sense, this shortage could be a perfect storm; an imperative for both the urban and rural hospitals we see in America today.”

The researchers previously reported that an estimated 101,838 surgeons will need to be trained by 2030 to address a projected shortage in the United States of 29,138 surgeons in seven surgical specialties: obstetrics and gynecology, orthopedic surgery, general surgery, otolaryngology, urology, neurosurgery, and thoracic surgery (Ann. Surg. 2009;250:590-7)

The current analysis went one step further, focusing on the average recruitment needs for the seven specialties in rural vs. urban hospitals in light of the projected U.S. population of 364 million by 2030. The model assumed that there will be equal population growth in urban and rural areas; that rural hospitals will need to recruit obstetric/gynecologic, orthopedic, and general surgeons; and that the percentage of the population receiving care at urban and rural hospitals will remain constant, Dr. Williams explained.

Currently, the American Hospital Association estimates that there are 3,012 urban hospitals in the United States. serving 82% of the population or 253 million Americans, and 1,998 rural hospitals serving 18% or 56 million Americans.

Based on these assumptions, the total number of surgical hires over the next 19 years will be 83,507 for urban hospitals and 13,953 for rural hospitals. This means urban hospitals must hire and retain 4,175 surgeons per year or 27.7 surgeons per hospital, while rural hospitals will need to hire 698 surgeons per year or 7 surgeons per hospital, said Dr. Williams of the department of surgery at Ohio State University in Columbus.

While the recruitment goals for urban hospitals might appear more daunting, rural hospitals are already facing a dramatic loss of general surgeons.

“In rural hospitals, general surgery is essential,” he said. “[General surgeons] account for 60% of the revenue. What’s happening now is that about 34% of general surgeons are notifying their administrators of retiring or leaving in 2 years. Thirty-three percent of rural hospitals are recruiting now.”

Factors that might make rural recruitment more difficult include professional and social isolation, cross coverage, insufficient training for the variety of procedures performed and pathologies encountered, and women’s preference for urban areas, he said.

Factors that positively influence rural recruitment include the chance to be a critical part of the community, independence, the wide spectrum of procedures, and hailing from a rural area.

One strategy that can tip a surgeon toward a rural hospital is doing a residency in a rural training program. The researchers estimate that half of general surgery residents who rotate through such a program will go on to practice in rural towns.

“It’s to the advantage of rural hospital administrators to establish rotations with medical schools in their hospitals, so they can have the opportunity to recruit some of the people that rotate through their rural hospitals,” Dr. Williams said.

Consideration of the needs of the surgeon’s family is another factor. Typically, this will be a two-income family that values education and will need either good public schools or the means to pay for private schools. Most couples will also have educational debts, some as high as $400,000 for a two-physician couple. Thus, educational loan repayment could be a potential “trump card” for rural hospitals in the future, he said.

Rural hospitals are already throwing out the welcome mat. Most offer hiring incentives such as a relocation allowance; signing bonus; health, disability, and life insurance; and malpractice coverage. Educational loan forgiveness was offered by 38% of hospitals last year, up 7% from 2009, Dr. Williams said. Still, competition for new hires is fierce.

“In many general surgery programs in the United States, senior residents are receiving as many as 50 offers for employment today,” he said.

To illustrate the point, Dr. Williams showed a recent classified ad in the New England Journal of Medicine offering a starting base salary of $600,000 for an orthopedic surgeon in coastal Georgia plus a sign-on and relocation bonus, full benefits, and a high-yield bonus. This is nearly double the median starting salary of $370,000 for an orthopedic surgeon identified in a recent Cejka Executive Search survey, he pointed out.

Median starting salaries for the seven surgical specialties studied ranged from a low of $260,000 for a general surgeon to a high of $450,000 for a neurosurgeon in the Cejka survey.

Invited discussant Dr. Nathaniel Soper, chair of the department of surgery at Northwestern University in Chicago, said, “It may end up being ultimately that these bidding wars are good for general surgeons, but I think it’s not going to be good for the population we serve, as there is going to be a shortage unless something is done.”

Dr. Sober suggested that the basic problem is not so much the division between rural vs. urban, but the supply of surgeons, and asked what can be done to meet the estimated shortfall. He also questioned the model’s assumption that the population would remain equal in rural and urban areas.

Co-author and colleague Dr. Bhagwan Satiani replied that the analysis included a simplified version of the federal model used to calculate supply and demand, but added that every projection in the last 50-75 years has been wrong. “You have to look at this model and say, ‘This is the best we can do right now,” he said.

According to Dr. Satiani, one of the best ways to increase the rural surgeon supply is through a comprehensive medical school rural program (MSRP). “If you took 10 medical students out of the class and put them into the MSRP program, you could double the number of rural surgeons. That’s how important that is,” said Dr. Satiani, medical director of the vascular surgery laboratory and a professor of clinical surgery at Ohio State University.

A recently published report from the Physician Shortage Area Program (PSAP) at Jefferson Medical College in Philadelphia provides a similar calculation for rural physicians and reports that 79%-87% of graduates from the two MSRPs with long-range rural outcomes – the PSAP and University of Minnesota at Duluth – remained in rural practice for up to 20 years (Acad. Med. 2011;86:272). It also notes that the Affordable Care Act authorized a new Rural Physician Training Grants program to provide grants to medical schools to develop or expand MSRPs.

Only 25 of the roughly 250 medical schools have general surgery programs, and just 10% of these could be considered programs that attract rural surgeons, according to Dr. Satiani. “I think American surgery is going to have to give this a separate tract within residency programs.”

Audience member Dr. Mark Malangoni, associate executive director of the American Board of Surgery in Philadelphia, pointed out that in such rural areas as Wyoming, the closest medical school is more than 1,000 miles away in Washington state. He suggested that one way to link rural hospitals and to counteract the professional isolation experienced by some rural physicians is through Web-based surgeon-to-surgeon consultations, an idea strongly supported by a recent survey of American College of Surgeons fellows.

If a new medical school were located in a rural area, Dr. Satiani said it could feed two to three nearby states, but not one of the new medical schools built in the last 5 years has been in truly rural areas.

Finally, several audience members suggested that efforts need to be made to eliminate the perception among residents that surgical specialists are somehow better than general surgeons.

“It’s the one-on-one thing that’s going to work with the residents, because all they see are these super-specialists,” Dr. Satiani said. “I think it has to come from the programs and the leadership; defining general surgery better, even going as far as changing the name, if that becomes an important issue.”

When asked in an interview what that new name might be, Dr. Satiani said the terms “master surgeon” and “omni surgeon” have been floated, with master surgeon more likely to resonate with the general public.

The authors reported no conflicts of interest.

Joseph E. Kutz, M.D. led a team of hand surgeons from the Kleinert Kutz Hand Care Center and the Christine M. Kleinert Institute to perform  the eighth hand transplant in our seventh recipient in a 14 ½ hour procedure on July 10, 2011.

 The recipient, Mr. Donnie Rickelman, is a 34 years old and is from Elwood, IN.  He  lost his hand in a factory accident in 1998.  The procedure went smoothly, and  surgeons were able to preserve some of Mr. Rickelman’s nerves in the remnant of  his left hand which should speed recovery of sensation and movement in the hand.  Mr. Rickelman was able to move his fingers the day after surgery and continues to  progress well.  Additional information on the transplant, as well as a video diary of  Mr. Rickelman’s progress can be found  at http://www.handtransplant.com/.    Recovery of the hand from the donor was  coordinated with KKA surgeons and a collaboration between the Kentucky Organ  Donor Affiliates (KODA) and the Indiana Organ Procurement Organization (IOPO).

The team for the transplant consisted of 19 hand surgeons and included:  Joseph E. Kutz, M, Huey Tien, MD, Rodrigo Moreno MD, MD, Tsu-Min Tsai, MD, Luis R. Scheker, MD, Tuna Ozyurekoglu, MD, Sunil M. Thirkannad, MD, and  Rodrigo Banegas, as well as Christiana Savviduo, MD, Joao Panattoni, MD, Timothy Prichnic, MD Bahar Bassiri, MD, Jose Couceiro, MD, Saad Elrahmany, MD, Elkin Galvis, MD, Jung-Hsien Hsieh, MD, Xueyuan Li, MD, , Antonio Rampazzo, MD, ,and Jiyao Zou, MD.

 

 

  

 

 

 

Mitali Sarkar-Tyson; Helen S Atkins

Future Microbiology. 2011;6(6):667-676.

 

Abstract  

The limitations of current antimicrobials for highly virulent pathogens considered as potential bioterrorism agents drives the requirement for new antimicrobials that are suitable for use in populations in the event of a deliberate release. Strategies targeting bacterial virulence offer the potential for new countermeasures to combat bacterial bioterrorism agents, including those active against a broad spectrum of pathogens. Although early in the development of antivirulence approaches, inhibitors of bacterial type III secretion systems and cell division mechanisms show promise for the future.

Bioterrorism

The circumstances associated with the potential use of biological agents for terrorism are unlike those associated with conventional attacks. For example, the detection of an attack may not be immediate and may not occur until significant numbers of people are diagnosed with a disease. Secondary transmissions and the occurrence of infections at locations other than the attack location may make confirming the details of the attack difficult. Infection control measures may be important in limiting the outbreak of disease and the implementation of available medical countermeasures (vaccines and antimicrobials) may be used to minimize the effect of the attack on individuals. Circumstances will be influenced by the biological agent used, particularly in terms of its infectivity and transmissability, virulence and lethality.

Bioterrorism Agents

The US CDC has listed biological agents into three principle categories: A–C [101]. Category A agents are the highest priority agents to address and are those considered the most dangerous agents because they are easily disseminated or transmitted from person to person, and have the potential to cause high mortality and for major public health impact. Category B agents are the second highest priority agents. They are considered moderately easy to disseminate and, although considered likely to cause low mortality rates, many are incapacitating and infection would result in moderate morbidity rates. Finally, category C agents are considered emerging pathogens that may be engineered for mass dissemination in the future due to their availability, ease of production and potential morbidity and mortality.

The development of effective antimicrobials for use against the potential bioterrorism agents presents unique and particular challenges. A key issue is that the traditional drug development route is not applicable, given the relatively small numbers of naturally occurring human cases of disease caused by the agents. Thus, in order to have scientific evidence of a drug’s effectiveness, animal models and in vitro models of infection are relied upon. It is therefore critical that suitable models of infection are developed and that results obtained in animal studies accurately predict outcomes in the human population. In addition, the potential use of antimicrobials for bioterrorism agents in the event of an attack is likely to be widespread, so considerations regarding the availability, distribution and safety of the antimicrobials for large populations need to be addressed (Box 1).

The CDC list of bioterrorism agents includes viruses, bacteria and bacterial-derived toxins. The category A and category B bacterial terrorism agents included are listed in Box 2. Category A includes three pathogenic bacteria that have the highest potential for use in large-scale bioterrorist attacks: Bacillus anthracis, Francisella tularensisand Yersinia pestis. Category B includes Brucella species, Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Coxiella burnetii and Rickettsia prowazekii. Category B also includes threats to food (e.g.,Salmonella species, Shigella and Escherichia coli O157:H7) and water (e.g., Vibrio cholera and Cryptosporidium), which are not included in Box 2.

Bacillus anthracis

B. anthracis is a Gram-positive spore-forming bacillus and the etiological agent of the zoonotic disease anthrax. The bacterium survives outside of the mammalian host in a dormant spore form, which is stable for many years.B. anthracis causes cutaneous, gastrointestinal or inhalational anthrax in humans, depending on the route of infection. Most cases occur by cutaneous infection via inoculation through the skin of material from infected animals or their products. Inhalational anthrax is the most acute form of the disease, associated with a high mortality rate. The infection is not known to spread from person to person, but outbreaks of inhalational anthrax, which have been well documented, demonstrate that infective spores can be effectively disseminated via aerosol. In 1979, an outbreak of inhalational anthrax occurred in Svedlorsk, Russia, where B. anthracis spores were released accidentally from a bioweapons manufacturing facility, resulting in 66 deaths from inhalational anthrax.^[1]More recently, in September 2001, B. anthracis spores sent through the US postal system resulted in 22 confirmed cases of anthrax infection.^[2]

At present, the only licensed vaccine for anthrax is BioThrax Anthrax Vaccine Adsorbed (AVA), which stimulates the development of antibodies against a protein produced by B. anthracis that binds to cellular receptors and facilitates the actions of toxins known to be key virulence factors for B. anthracis. In addition, B. anthracis is susceptible in vitro to a wide range of antimicrobial agents and many have been used successfully for the treatment of anthrax in humans. Most strains are sensitive to penicillin, as well as macrolides, aminoglycosides, tetracyclines and chloramphenicol.^[3] However, although patients with inhalational anthrax from the September 2001 outbreak were typically given multiple antibiotics to which the organism was susceptible, five of 11 individuals died. Those that recovered had presented in what was considered the initial stages of illness, suggesting that early antimicrobial therapy is essential for survival.

Ciprofloxacin (or a similar fluoroquinolone) is currently recommended as prophylaxis or early treatment for those considered at greatest risk of exposure following a large-scale release of anthrax spores in a deliberate attack. Studies in small animal models of inhalational B. anthracis infection have demonstrated the in vivo efficacy of ciprofloxacin and levofloxacin for postexposure prophylaxis of anthrax.^[4–6] In addition, ciprofloxacin was shown to be effective for postexposure prophylaxis of anthrax in nonhuman primates.^[7] Accordingly, the US FDA has provided an indication for ciprofloxacin for the prophylaxis of infection with B. anthracis. The FDA also approved levofloxacin for anthrax postexposure prophylaxis, an indication supported by in vitro hollow-fiber infection studies that replicate the pharmacokinetic profile of levofloxacin observed in humans or animals^[8] and efficacy studies in nonhuman primates using a humanized antibiotic dosing regimen.^[9] Doxycycline is the preferred tetracycline as a result of its proven efficacy in mice^[4,5] and primates,^[7] as well as its ease of administration.

Although cases of inhalational anthrax may be controlled by antibiotics, the treatment regimen has to be followed continuously for 60 days to ensure any residual spores are eliminated. Thus, protecting a civilian population against a bioterrorism attack with anthrax is difficult. Advance stockpiling of antibiotics would be required to ensure there is sufficient supply for a 60-day regimen per person. As a result, there is a clear need for cost-effective antimicrobials for anthrax.

Francisella tularensis

F. tularensis is a facultative intracellular bacterium and the etiological agent of the zoonotic disease tularemia. Human tularemia is endemic in North America and some parts of Northern Europe, where F. tularensis is usually transmitted to humans by the bite of a tick vector or through handling or eating infected carcasses. Thus, the most common form of tularemia in humans is ulceroglandular tularemia. The species is classified into four biovars on the basis of virulence and differences in 16S ribosomal DNA sequences: F. tularensis biovar tularensis(previously known as type A), holartica, mediaasiatica and novicida. The inhalation of F. tularensis results in the most severe form of tularemia in humans. Only low doses of F. tularensis are required for infection by this route and, without antibiotic treatment, a fatality rate of up to 30% occurs.^[10] These properties of F. tularensispreviously led to weaponization of the pathogen^[11] and contribute to its classification by CDC as category A.

At present, no licensed vaccine is available for tularemia. F. tularensis is generally considered treatable with antibiotics. However, some antibiotics are unsuitable for tularemia, including β-lactams and macrolides.^[11]Aminoglycosides, specifically streptomycin, are traditionally the postexposure prophylaxis of choice, although streptomycin is now avoided due to limited availability and toxicity, and gentamycin is now recommended by the UK Health Protection Agency (HPA).^[102] However, gentamycin is parenterally administered. Thus, in the event of a deliberate release HPA currently recommends postexposure prophylaxis with oral ciprofloxacin or doxycycline for 14 days.^[12] Early studies in a murine model of F. tularensis infection showed that ciprofloxacin and doxycycline were equally effective for postexposure prophylaxis, although neither antibiotic prevented relapse.^[13]

Fluoroquinolones are appealing because of their activity against Gram-negative bacilli and their intracellular penetration, which is particularly useful for the facultatively intracellular F. tularensis. In humans, the use of ciprofloxacin has generally been successful, although a 50% relapse rate has been reported.^[13] Other studies have indicated that relapse following therapy with ciprofloxacin is less likely than with streptomycin and doxycycline.^[14–17] More recently, levofloxacin has also been shown to be effective as postexposure prophylaxis against highly virulent strains of F. tularensis in mice^[6] and nonhuman primates,^[18] providing supporting efficacy data for the future indication of this antibiotic for tularemia.

Yersinia pestis

Yersinia pestis is a Gram-negative bacterium and the causative agent of plague, a disease that is endemic in Africa, Asia, South America and in south-western USA. Y. pestis primarily causes bubonic plague in humans, usually a consequence of the transmission of bacteria to humans via bites from fleas that have previously fed on infected rodents. More rarely, cases of pneumonic plague are reported, resulting from the acquisition of the bacterium via aerosols generated, for example, by coughing and sneezing or from the spread of Y. pestis following the bite of an infected flea. Pneumonic plague follows a rapid course and is associated with high mortality, which is the likely consequence of the use of Y. pestis as an aerosolized biological weapon.^[19]

A number of antibiotics are active against Y. pestis. Traditionally, streptomycin has been the antibiotic of choice for plague, given intramuscularly over 10 days; other regimens include oral tetracycline or intravenous chloramphenicol. Ciprofloxacin is also recommended for both therapeutic and prophylactic use. These recommendations are supported by in vitro studies^[20,21] and efficacy in animal models of pneumonic plague.^[22,23] However, mortality associated with pneumonic plague may be high even with antibiotic treatment. There is concern regarding the use of naturally occurring or genetically engineered strains of Y. pestis with increased antimicrobial resistance given the emergence of isolates from Madagascar containing transferable multidrug resistance plasmids,^[24,25] and a quinolone-resistant strain is a potential risk.^[20]

Burkholderia pseudomallei & Burkholderia mallei

Burkholderia pseudomallei and Burkholderia mallei are close phylogenetically related species. B. pseudomallei is a Gram-negative bacillus that is found predominantly in southeast Asia and northern Australia and is the causative agent of melioidosis. The infection of humans with B. pseudomallei may occur by various routes including via wounds and existing skin lesions, aspiration of contaminated water during near-drowning and inhalation of organisms. Melioidosis may present as an acute infection with pneumonia and septicemia and can be rapidly progressive with high mortality rates. However, sub-acute and chronic forms of melioidosis also exist and re-activation following sometimes lengthy latent periods is common.^[26,27] In comparison, B. mallei is the causative agent of glanders, primarily an equine disease. Although B. mallei infections in humans are uncommon, it has been used as a biological weapon, both in World War I^[28] and World War II.^[29] As with B. pseudomallei, B. mallei is highly infectious by the respiratory route and has a high mortality rate if left untreated.^[28]

The current recommended treatment for acute melioidosis infection is high-dose intravenous ceftazidime or a carbapenem, for at least 10–14 days, followed by oral eradication therapy.^[30] Both organisms are susceptible to the tetracyclines, trimethoprim-sulfamethoxazole (co-trimoxazole), amoxicillin-clavulanate (co-amoxiclav), third generation cephalosporins and chloramphenicol.^[30] Since there is little evidence available related to antibiotic treatment of glanders in humans it is recommended that cases should be treated with the same regimens used for melioidosis. There are few recommendations for postexposure prophylaxis in other circumstances, such as laboratory workers, although UK HPA guidance recommends co-trimoxazole (with or without doxycycline),^[31]supported by activity of these antibiotics in murine models of infection.^[32,33]

Multidrug resistance in B. pseudomallei is a significant problem in the treatment of melioidosis and there is no human vaccine currently licensed for protection against melioidosis or glanders. Furthermore, relapsing melioidosis can result from the re-activation of a latent infection of B. pseudomallei, often due to the withdrawal of antibiotics or the failure to complete prescribed courses of antibiotics. Thus, there is a requirement for safe and effective antibiotics for melioidosis and glanders, particularly to address the potential use of these pathogens as bioterror agents.

Need for New Antimicrobials

For most of the highest priority bacterial bioterror agents, there are antibiotics available that are reasonably effective. The fluoroquinolones, particularly ciprofloxacin, are generally effective against anthrax, tularemia and plague, although long dosing regimens may be required (in the case of anthrax) and relapse may occur upon removal of antibiotics. Some newer quinolones (temafloxacin, grepafloxacin and trovafloxacin) are associated with severe adverse effects, whereas the older quinolones (e.g., ciprofloxacin, ofloxacin and levofloxacin) are not.^[34] However, fluoroquinolones are not recommended for women during pregnancy, lactation or for young children owing to concerns about teratogenesis and cartilage toxicity. Additionally, a recent study comparing doxycycline with fluoroquinolones suggested that doxycycline should be considered for stockpiling as a first-line antibiotic for postexposure therapy of bioterrorism agents as a result of its significant activity against B. anthracis, F. tularensis, Brucella species, C. burnetti and, to a lesser extent, Y. pestis, and its lower cost and lower likelihood of resistance occurring when compared with fluoroquinolones.^[35] For other potential bioterrorism agents, such as the Burkholderia species, the fluoroquinolones and doxycycline are less effective. Overall, there is a need to develop new antibiotics for use in the event of a deliberate release of these pathogens. Broad-spectrum antibiotics in development within the industrial sector, particularly those active against Gram-negative bacteria, may have potential for use against bioterrorism agents. In addition, it is possible that existing antibiotics may be reformulated for improved efficacy against such agents, for example by formulating for inhalational delivery, although there is no guarantee that this approach would improve efficacy. However, new approaches are likely to be needed to ensure the future development of novel antibiotics active against the current and future spectrum of bioterrorism agents.

Antivirulence Strategy

Currently available antibiotics have a number of drawbacks, including the natural, or potentially deliberate, emergence of multidrug resistance, posing an increased risk to those who may encounter these agents following an intentional release.^[36–38] Specific antibiotic treatment is also dependent on knowing which infectious agent has been released, which may not occur for some time after the release event, leading to ineffective prophylaxis. The potential devastation caused by any such release has driven research for effective, novel antimicrobials. An antimicrobial development strategy to avoid some of these issues is to develop inhibitors to virulence-associated genes. Such virulence inhibitors would not perturb the development of commensal bacteria and there is likely to be a reduced risk of developing resistance due to reduced selective pressure.

Many pathogenic bacteria use common virulence strategies for survival and infectivity in the host. There is potential to target these common pathways, thereby producing novel antimicrobials with broad spectrum efficacy. In the context of biological defense, such antimicrobial prophylaxis may retract the need for a specific pathogen detection capability, reducing the time in which prophylaxis may be administered and decreasing casualty levels considerably. However, these are challenging aspirations. In some instances, to successfully combat bacterial bioterrorism agents, a combinational approach with traditional antibiotics and antivirulence inhibitors may be required to fight infection. The antivirulence approach to developing novel antimicrobials has been recognized for a number of years and several virulence-associated targets have been identified, yet the pursuit of inhibitors for bioterrorism agents is still in its early stages.

Approaches to the Identification of Virulence-associated Genes

Increased funding (particularly in the USA) for novel medical countermeasures for bacterial bioterrorism agents has led to the provision of a wealth of information regarding virulence-associated genes through projects involved in genome sequencing, transcriptome analysis and proteomic approaches. The genome sequence of the biological agents has identified genes involved in virulence and bacterial survival, all of which are potential targets for intervention.^[39–43]

The subsequent comparative analysis of the genomes, such as that of B. pseudomallei and B. mallei, has provided further insights into pathogens’ virulence mechanisms. For example, the B. malleigenome was found to be 1.41 Mb smaller than that of B. pseudomallei, likely a consequence of down-sizing to those genes necessary for only intracellular survival in the host.^[39,40,44] In B. pseudomallei a large proportion of the genome, not present in B. mallei, encodes for housekeeping genes, reflecting the adaptable nature of this organism and its ability to thrive in a number of ecological niches.^[39] Furthermore, comparisons between the etiological agent of plague, Y. pestis, to the closely related diarrhea-causing agent Y. pseudotuberculosis has revealed extra pseudogenes present in Y. pestis, which, if functional, could identify more virulence targets.^[45]

Bacterial genes that are essential for viability make particularly interesting targets. These genes are often labeled as essential when direct mutagenesis is impossible or difficult to achieve. A database for essential genes (DEG) listing these genes is available.^[46,47] Recently, this database has been used to select a list of genes that are potentially vital for Y. pseudotuberculosis, a closely related model organism for Y. pestis, as a starting point for antivirulence drug development.^[48] The selection of genes was based on evidence of essentiality, presence in a broad spectrum of pathogens, druggability, protein structure prediction properties and the lack of homology to human or mammalian proteins. Using these selection criteria, a number of genes involved in various cellular process and metabolism were selected and are currently being validated in Y. pseudotuberculosis. If indeed these targets are found to be essential and are broad spectrum, then they may be ideal candidates with which to move forward into a drug discovery program for inhibitors of Y. pestis and other pathogens.

A number of novel approaches have been used to identify virulence-associated genes, involving whole genome analysis, immunome analysis and signature tagged mutagenesis. Signature tagged mutagenesis is a powerful tool with which to analyze the entire genome to identify genes involved in virulence. Using this approach a number of virulence factors in bioterrorism agents have been identified.^[49–52] Genes encoding virulence factors involved in bacterial pathogenicity, such as polysaccharide biosynthesis, metabolic pathways and type III secretion systems, were identified (Box 2). The major virulence factors of B. pseudomallei and B. mallei, the lipopolysaccharide and capsular polysaccharide, have been identified using this approach. Genetic mutagenesis of genes involved in the production of these polysaccharides results in either attenutated or avirulent strains of B. pseudomallei in various models of infection, demonstrating their importance in virulence.^[53–56] The enzymes involved in the production of these macromolecules may be particularly attractive targets for intervention, but any inhibitors would likely be specific for B. pseudomallei and B. mallei rather than having a broad spectrum activity.

Novel virulence-associated genes have also been identified by microarray-based technology, particularly through mimicking conditions which upregulate virulence factors, such as iron-limited conditions. The expression of RNA transcripts of F. tularensis subspecies novicida was analyzed on a Francisella-specific DNA microarray, identifying 21 genes that were upregulated in iron-limited conditions.^[57] Further analysis identified a novel ‘hypothetical’ protein that, when mutated, resulted in attenuation in a mouse model of infection. This and other studies highlight that, although characterization of known virulence-associated genes is a valid approach for target evaluation, it is also important not to overlook ‘hypothetical’ proteins as potential targets for antimicrobials. Protein arrays have also been widely used to identify surface-located immunogenic proteins in bacteria for either immunological or detection purposes.^[58] For example, to identify immunodominant antigens a whole proteome array of F. tularensis live vaccine strain was screened using sera from immunized animals.^[57] Several immunodominant antigens were identified, including surface-located, hypothetical and metabolic proteins, some of which may be important for virulence. A similar approach has been used for B. pseudomallei, but using a partial array of 1205 proteins. The approach identified 170 antigens that were reactive to human convalescent sera.^[59]Some of these proteins are associated with pathogenicity islands and further characterization of these proteins may identify unique virulence factors.

Development of Inhibitors to Antivirulence Targets

Target selection for high throughput screening or rational drug design approaches has been the subject of much debate.^[60] Likely requirements for target selection are highlighted in Box 3. Arguably, the most pressing requirements are that targets are specific for bacteria with no human homologs and essential for bacterial virulence. However, practical issues, such as the ability to develop assays for protein activity and crystal structures for rational drug design, are likely to influence prioritization of the targets. For bioterrorism agents, the identification and development of antivirulence inhibitors is still in the preliminary stages (Table 1). However, two of the most documented antivirulence targets, the type III secretion system (TTSS) and cell division targets, are discussed below.

Type III Secretion System

The essential nature of TTSS to enable invasion into host cells make it an attractive antimicrobial target.^[61] TTSS is well characterized for Y. pestis, in particular. Defined as the system Yersinia outer proteins system, it is critical for in vivo virulence as it secretes effector proteins that help suppress host cell defense mechanisms, such as phagocytosis.^[62] The prevention of release of effector proteins allows host cells to initiate an effective immune response and clear bacterial infection. Since the closely related pathogens Y. pseuodotuberculosis and Y. enterocolitica also share the TTSS system, all of these bacterial species have been used for the identification of inhibitors of the system. High throughput screens (HTS) have identified inhibitory compounds to TTSS in several pathogenic bacteria.^[63–65] These inhibitors act on either the transcription or secretion of TTSS proteins.

The unusual physiological properties of Yersinia have enabled researchers to use in vitro HTS to identify inhibitors of TTSS.^[65,66] When grown at temperatures below 34°C, Y. pestis represses the expression of several proteins required for assembly of TTSS apparatus. Above this temperature the TTSS apparatus is formed but no or very little protein is released unless contact is made with host cells.^[67,68] Exploiting this system has identified several small inhibitory compounds. A luciferase reporter gene system in Y. pseudotuberculosis was used to screen a chemical library and identified inhibitors of gene signal expression and effector protein secretion.^[65] In particular, a compound that belongs to a class of acylated hydrazones of different salicylaldehydes specifically blocked secretion of effector proteins and attenuated Y. pseudotuberculosis in vitro.^[69] In another HTS study of Y. pseudotuberculosis, 13 compounds were identified of which six compounds had no toxic effects on either the host cell or pathogen, but inhibited translocation of effector proteins into host cells.^[70] Although these compounds showed no structural similarity, they are thought to act by disrupting the hydrophobic interactions between Y. pseudotuberculosis and the host cell, although the exact mechanisms are undefined.^[70] Similarly, HTS of a number of libraries consisting of almost 80,000 compounds yielded 431 hits against the Y. pestis Yersinia outer proteins system, four of which were examined in secondary screens and show promise as lead compounds.^[66]Due to the high homology of TTSS in Yersinia, Salmonella and Pseudomonas species it is possible that inhibitors of the TTSS would have broad spectrum activity.

Less is known about the TTSS of B. pseudomallei, although there are three known TTSS, perhaps a reason why this organism can thrive in diverse ecological niches.^[71] The type three secretion system 3 (TTSS3) is best characterized. It is homologous to the Inv/Mxi-Spa systems of Salmonella and Shigella and is important for invasion of nonphagocytic cells and for full virulence in vivo.^[72–74] Resolution of the crystal structure of BipD, a translocator protein showing homology to SipD from Salmonella will facilitate future inhibitor studies.^[75,76]

Cell Division

Cell division is essential for survival and propagation of bacteria and there are at least seven proteins involved in this process that are highly conserved in bacteria and absent in humans, making them attractive antimicrobial targets. Significant interest is focused on the cell division protein FtsZ,^[77–80] a homolog of eukaryotic tubulin, which has GTPase activity and forms a cytokinetic ring structure at the site of division during the early stages of cell division. Screening of a chemical library consisting of 18,320 compounds identified five structurally diverse compounds that inhibited the E. coli FtsZ GTPase activity;^[80] these were named Zantrins (Z1-Z5) (FtsZ guanosine triphosphate inhibitors). These Zantrins inhibited the growth of various Gram-positive and -negative bacteria. In particular, they were active against Bacillus cereus, a close relative to B. anthracis. Foss and Weibel took the most potent Zantrin (Z1) and tested this compound, including structurally related oligomers, against B. anthracis, demonstrating MIC values ranging from 5 to 0.16 µM. Furthermore, they showed that the development of resistance to these compounds is tenfold lower than that to commercially available antibiotics.^[81] Thus, these appear to be promising candidate antivirulence antimicrobials.

Future Perspective

The prevalence of infectious diseases worldwide and the continued emergence of resistance to antimicrobials in use continues to drive an urgent need for the development of new antimicrobials. In parallel, the pharmaceutical industry faces significant pressure to become more productive, providing new, innovative and cost-effective medicines without incurring unsustainable research and development costs; indeed this is the industry’s ‘grand challenge’.^[82] Thus, new approaches to the business of delivering new antimicrobials are required. This may be particularly true for the development of novel antimicrobials for bioterrorism agents since the potential market may not be as great or long term as for other chronic diseases of the Western world. Indeed, industry, academia and governments may need to work together in order to identify and exploit the most promising leads. Such a model of partnerships is now being followed by, for example, GlaxoSmithKline in its pursuit of new antibiotics, including those for bioterrorism.^[83]

Current antimicrobials for bioterrorism are available, yet concerns regarding incomplete clearance of infection, ability to protect against lethality, natural and engineered resistance and relapses drive the requirement for alternative antibiotics. The encouraging preliminary studies described in this article validate the antivirulence approach to developing novel antimicrobials. Thus, it is likely that, in coming years, the strategy will yield novel antibiotics that have activity against a range of bioterrorism agents and thus are suitable as alternative or supplementary medical countermeasures to fight bioterrorism. The challenges associated with combating these highly virulent pathogens in a timely and safe manner in large populations is significant and will require multidisciplinary partnerships to succeed.

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