Monday, March 14, 2016

Signs Symptoms and Treatment of Syphilis

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, and tertiary). The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration) but there may be multiple sores. In secondary syphilis a diffuse rash which frequently involves the palms of the hands and soles of the feet occurs. There may also be sores in the mouth or vagina. In latent syphilis there are little to no symptoms which can last for years. In tertiary syphilis there are gummas (soft non-cancerous growths), neurological, or heart symptoms. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.

Syphilis is most commonly spread through sexual activity. It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis. Other human diseases caused by related Treponema pallidum include yaws (subspecies pertenue), pinta (subspecies carateum), and bejel (subspecies endemicum). Diagnosis is usually made by using blood tests; the bacteria can also be detected using dark field microscopy. The Center for Disease Control recommends all pregnant women be tested.

The risk of syphilis can be decreased by latex condom use or not having sex. Syphilis can be effectively treated with antibiotics. The preferred antibiotic for most cases is benzathine penicillin G injected into a muscle. In those who have a severe penicillin allergy, doxycycline or tetracycline may be used. In those with neurosyphilis intravenous penicillin G potassium or ceftriaxone is recommended. During treatment people may develop fever, headache, and muscle pains, a reaction known as Jarisch-Herxheimer.

In 2013 syphilis infected about 315,000 people. During 2010 it caused about 113,000 deaths down from 202,000 in 1990. After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV). This is believed to be partly due to increased promiscuity, prostitution, decreasing use of condoms, and unsafe sexual practices among men who have sex with men. In 2015, Cuba became the first country in the world to eliminate mother-to-child transmission of syphilis.

Signs and symptoms
Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary, and may also occur congenitally. It was referred to as "the great imitator" by Sir William Osler due to its varied presentations.

Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 3 to 90 days after the initial exposure (average 21 days) a skin lesion, called a chancre, appears at the point of contact. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders between 0.3 and 3.0 cm in size. The lesion may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur outside of the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally relatively commonly in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the area of infection, occurring seven to 10 days after chancre formation. The lesion may persist for three to six weeks without treatment.

Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions known as condyloma latum on mucous membranes. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classic chancre of primary syphilis.

Latent syphilis is defined as having serologic proof of infection without symptoms of disease. It is further described as either early (less than 1 year after secondary syphilis) or late (more than 1 year after secondary syphilis) in the United States. The United Kingdom uses a cut-off of two years for early and late latent syphilis. Early latent syphilis may have a relapse of symptoms. Late latent syphilis is asymptomatic, and not as contagious as early latent syphilis.

Tertiary syphilis may occur approximately 3 to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%). Without treatment, a third of infected people develop tertiary disease. People with tertiary syphilis are not infectious.

Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years. This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size. They typically affect the skin, bone, and liver, but can occur anywhere.

Neurosyphilis refers to an infection involving the central nervous system. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis, which is associated with poor balance and lightning pains in the lower extremities. Late neurosyphilis typically occurs 4 to 25 years after the initial infection. Meningovascular syphilis typically presents with apathy and seizure, and general paresis with dementia and tabes dorsalis. Also, there may be Argyll Robertson pupils, which are bilateral small pupils that constrict when the person focuses on near objects, but do not constrict when exposed to bright light.

Cardiovascular syphilis usually occurs 10–30 years after the initial infection. The most common complication is syphilitic aortitis, which may result in aneurysm formation.

Congenital syphilis is that which is transmitted during pregnancy or during birth. Two-thirds of syphilitic infants are born without symptoms. Common symptoms that develop over the first couple of years of life include enlargement of the liver and spleen (70%), rash (70%), fever (40%), neurosyphilis (20%), and lung inflammation (20%). If untreated, late congenital syphilis may occur in 40%, including saddle nose deformation, Higoumenakis sign, saber shin, or Clutton's joints among others

Cause of Syphilis

Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium. Three other human diseases are caused by related Treponema pallidum, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum). Unlike subtype pallidum, they do not cause neurological disease. Humans are the only known natural reservoir for subspecies pallidum. It is unable to survive without a host for more than a few days. This is due to its small genome (1.14 MDa) failing to encode the metabolic pathways necessary to make most of its macronutrients. It has a slow doubling time of greater than 30 hours.

Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her fetus; the spirochaete is able to pass through intact mucous membranes or compromised skin. It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex. Approximately 30 to 60% of those exposed to primary or secondary syphilis will get the disease. Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected. Most (60%) of new cases in the United States occur in men who have sex with men. It can be transmitted via blood products. It is tested for in many countries and thus the risk is low. The risk of transmission from sharing needles appears limited.

It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing. This is mainly because the bacteria die very quickly outside of the body, making transmission via objects extremely difficult.

Syphilis is difficult to diagnose clinically early in its presentation. Confirmation is either via blood tests or direct visual inspection using microscopy. Blood tests are more commonly used, as they are easier to perform. Diagnostic tests are unable to distinguish between the stages of the disease.

Blood tests
Blood tests are divided into nontreponemal and treponemal tests. Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin tests. As these tests are occasionally false positives, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs). False positives on the nontreponemal tests can occur with some viral infections such as varicella and measles, as well as with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy. Treponemal antibody tests usually become positive two to five weeks after the initial infection. Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection

Direct testing
Dark ground microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. Hospitals do not always have equipment or experienced staff members, whereas testing must be done within 10 minutes of acquiring the sample. Sensitivity has been reported to be nearly 80%, thus can only be used to confirm a diagnosis but not rule one out. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody testing and nucleic acid amplification tests. Direct fluorescent testing uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while nucleic acid amplification uses techniques, such as the polymerase chain reaction, to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis

As of 2010, there is no vaccine effective for prevention. Several vaccines based on treponemal proteins reduce lesion development in an animal model, and research is ongoing. Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis, as is the proper use of a latex condom. Condom use does not completely eliminate the risk. Thus, the Centers for Disease Control and Prevention recommends a long-term, mutually monogamous relationship with an uninfected partner and the avoidance of substances such as alcohol and other drugs that increase risky sexual behavior.

Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women, while the World Health Organization recommends all women be tested at their first antenatal visit and again in the third trimester. If they are positive, they recommend their partners also be treated. Congenital syphilis is still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others receive does not include screening, and it still occasionally occurs in the developed world, as those most likely to acquire syphilis (through drug use, etc.) are least likely to receive care during pregnancy. Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries.

Syphilis is a notifiable disease in many countries, including Canada the European Union, and the United States. This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the person's partners. Physicians may also encourage patients to send their partners to seek care. The CDC recommends that sexually active men who have sex with men be tested at least yearly.

Several strategies have been found to improve follow-up for STI testing including email and text messaging as reminders of appointments

Early infections
The first-choice treatment for uncomplicated syphilis remains a single dose of intramuscular benzathine penicillin G. Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects these are not recommended for pregnant women. Resistance to macrolides, rifampin, and clindamycin is often present. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment. It is recommended that a treated person avoid sex until the sores are healed.

Late infections
For neurosyphilis, due to the poor penetration of penicillin G into the central nervous system, those affected are recommended to be given large doses of intravenous penicillin for a minimum of 10 days. If a person is allergic, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular penicillin G for three weeks. If allergic, as in the case of early disease, doxycycline or tetracycline may be used, albeit for a longer duration. Treatment at this stage limits further progression, but has only slight effect on damage which has already occurred.

Jarisch-Herxheimer reaction
One of the potential side effects of treatment is the Jarisch-Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscles pains, headache, and a fast heart rate. It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.

History of syphilis
The history of syphilis has been well studied, but the exact origin of syphilis is unknown. There are two primary hypotheses: one proposes that syphilis was carried to Europe from the Americas by the crew of Christopher Columbus, the other proposes that syphilis previously existed in Europe but went unrecognized. These are referred to as the "Columbian" and "pre-Columbian" hypotheses.

In late 2011, newly published evidence suggested that the Columbian hypothesis is the valid one.

The first written records of an outbreak of syphilis in Europe occurred in 1494/1495 in Naples, Italy, during a French invasion. Because it was spread by returning French troops, the disease was known as "French disease", and it was not until 1530 that the term "syphilis" was first applied by the Italian physician and poet Girolamo Fracastoro. The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann in 1905. The first effective treatment (Salvarsan) was developed in 1910 by Sahachirō Hata in the laboratory of Paul Ehrlich which was followed by the introduction of penicillin in 1943. Many famous historical figures including Franz Schubert, Arthur Schopenhauer, and Édouard Manet are believed to have had the disease.


The exact origin of syphilis is unknown. Two primary theories have been proposed. It is widely agreed upon by historians and anthropologists that syphilis was present among the indigenous peoples of the Americas before Europeans traveled to and from the New World. However, whether strains of syphilis were present in the entire world for millennia, or if the disease was confined to the Americas in the pre-Columbian era, has been debated.

The Columbian theory holds that syphilis was a New World disease brought back by Columbus and Martín Alonso Pinzón. This would be an example of a Columbian Exchange. Columbus's voyages to the Americas occurred three years before the Naples syphilis outbreak of 1494. This theory is supported by genetic studies of venereal syphilis and related bacteria, which found a disease intermediate between yaws and syphilis in Guyana, South America.
The pre-Columbian theory holds that syphilis was present in Europe before the arrival of Europeans in the Americas. Some scholars during the 18th and 19th centuries believed that the symptoms of syphilis in its tertiary form were described by Hippocrates in Classical Greece. Skeletons in pre-Columbus Pompeii and Metaponto in Italy with damage somewhat similar to that caused by congenital syphilis have also been found.[ However, these claims have not been submitted for peer review, and the evidence that has been made available to other scientists is weak. Nevertheless Douglas W. Owsley, a physical anthropologist at the Smithsonian Institution, and other supporters of this idea, say that many medieval European cases of leprosy, colloquially called lepra, were actually cases of syphilis. Although folklore claimed that syphilis was unknown in Europe until the return of the diseased sailors of the Columbian voyages, Owsley says that "syphilis probably cannot be "blamed"—as it often is—on any geographical area or specific race. The evidence suggests that the disease existed in both hemispheres from prehistoric times. It is only coincidental with the Columbus expeditions that the syphilis previously thought of as "lepra" flared into virulence at the end of the 15th century." Lobdell and Owsley wrote that a European writer who recorded an outbreak of "lepra" in 1303 was "clearly describing syphilis."
Historian Alfred Crosby suggests both theories are partly correct in a "combination theory". Crosby says that the bacterium that causes syphilis belongs to the same phylogenetic family as the bacteria that cause yaws and several other diseases. Despite the tradition of assigning the homeland of yaws to sub-Saharan Africa, Crosby notes that there is no unequivocal evidence of any related disease having been present in pre-Columbian Europe, Africa, or Asia. Crosby writes, "It is not impossible that the organisms causing treponematosis arrived from America in the 1490s...and evolved into both venereal and non-venereal syphilis and yaws." However, Crosby considers it more likely that a highly contagious ancestral species of the bacteria moved with early human ancestors across the land bridge of the Bering Straits many thousands of years ago without dying out in the original source population. He hypothesizes that "the differing ecological conditions produced different types of treponematosis and, in time, closely related but different diseases."

However, in late 2011 the Yearbook of Physical Anthropology published an appraisal by George Armelagos of Emory University, Molly Zuckerman, and Kristin Harper of previous studies that the "skeletal data bolsters the case that syphilis did not exist in Europe before Columbus set sail." The scientific evidence as determined by a systematic review of all published, peer-reviewed instances, best supports the theory that syphilis was unknown in Europe until Columbus returned from the Americas.

Skeletal evidence that reputedly showed signs of syphilis in Europe and other parts of the Old World before Christopher Columbus made his voyage in 1492 does not hold up when subjected to standardized analyses for diagnosis and dating, according to an appraisal in the current Yearbook of Physical Anthropology. This is the first time that all 54 previously published cases have been evaluated systematically, and bolsters the case that syphilis came from the New World.

— Science Daily, Skeletons point to Columbus voyage for syphilis origins
The historical origin of syphilis has modern social effects. The arrival of Europeans in the New World resulted in the damaging effects of colonialism and the spread of deadly diseases like smallpox that European explorers unintentionally brought to the Americas. According to biologist Marlene Zuk, "The origin of syphilis has always held an implied accusation: if Europeans brought it to the New World, the disease is one more symbol of Western imperialism run amok, one more grudge to hold against colonialism."

European outbreak

The first well-recorded European outbreak of what is now known as syphilis occurred in 1495 among French troops besieging Naples, Italy. It may have been transmitted to the French via Spanish mercenaries serving King Charles of France in that siege. From this centre, the disease swept across Europe. As Jared Diamond describes it, "[W]hen syphilis was first definitely recorded in Europe in 1495, its pustules often covered the body from the head to the knees, caused flesh to fall from people's faces, and led to death within a few months." The disease then was much more lethal than it is today. Diamond concludes,"[B]y 1546, the disease had evolved into the disease with the symptoms so well known to us today." The epidemiology of this first syphilis epidemic shows that the disease was either new or a mutated form of an earlier disease.

Researchers concluded that syphilis was carried from the New World to Europe after Columbus' voyages. Many of the crew members who served on this voyage later joined the army of King Charles VIII in his invasion of Italy in 1495, resulting in the spreading of the disease across Europe and as many as five million deaths. The findings suggested Europeans could have carried the nonvenereal tropical bacteria home, where the organisms may have mutated into a more deadly form in the different conditions and low immunity of the population of Europe. Syphilis was a major killer in Europe during the Renaissance. In his Serpentine Malady (Seville, 1539) Ruy Diaz de Isla estimated that over a million people were infected in Europe.

Historical terms
The name "syphilis" was coined by the Italian physician and poet Girolamo Fracastoro in his pastoral noted poem, written in Latin, titled Syphilis sive morbus gallicus (Latin for "Syphilis or The French Disease") in 1530. The protagonist of the poem is a shepherd named Syphilus (perhaps a variant spelling of Sipylus, a character in Ovid's Metamorphoses). Syphilus is presented as the first man to contract the disease, sent by the god Apollo as punishment for the defiance that Syphilus and his followers had shown him. From this character Fracastoro derived a new name for the disease, which he also used in his medical text De Contagionibus ("On Contagious Diseases").

Until that time, as Fracastoro notes,[not in citation given] syphilis had been called the "French disease" in Italy, Poland and Germany, and the "Italian disease" in France. In addition, the Dutch called it the "Spanish disease", the Russians called it the "Polish disease", and the Turks called it the "Christian disease" or "Frank (Western European) disease" (frengi). These "national" names were generally reflective of contemporary political spite between nations and frequently served as a sort of propaganda; the Dutch, for example, had a colonial rivalry with the Spanish, so referring to Syphilis as the 'Spanish' disease reinforced a politically useful perception that the Spanish were immoral or unworthy. The inherent xenophobia of the terms also stemmed from the disease's particular epidemiology, often being spread by foreign sailors and soldiers during their frequent sexual contact with local prostitutes.

During the 16th century, it was called "great pox" in order to distinguish it from smallpox. In its early stages, the great pox produced a rash similar to smallpox (also known as variola). However, the name is misleading, as smallpox was a far more deadly disease. The terms "Lues" (or Lues venerea, Latin for "venereal plague") and "Cupid's disease" have also been used to refer to syphilis. In Scotland, syphilis was referred to as the Grandgore. The ulcers suffered by British soldiers in Portugal were termed "The Black Lion"

Historical treatments
There were originally no effective treatments for syphilis, although a number of remedies were tried. Mercury was a common, long-standing treatment for syphilis, and its use has been suggested to date back to The Canon of Medicine (1025) by the Persian physician Ibn Sina (Avicenna), although this is only possible if syphilis existed in the Old World prior to Columbus (see Origins section). Giorgio Sommariva of Verona is recorded to have used mercury to treat syphilis in 1496, and is often recognized as the first physician to have done so, although he may not have been a physician. During the sixteenth century, mercury was administered to syphilitic patients in various ways, including by rubbing it on the skin, by applying a plaster, and by mouth. A "Fumigation" method of administering mercury was also used, in which mercury was vaporized over a fire and the patients were exposed to the resulting steam, either by being placed in a bottomless seat over the hot coals, or by having their entire bodies except for the head enclosed in a box (called a "tabernacle") that received the steam. The goal of mercury treatment was to cause the patient to salivate, which was thought to expel the disease. Unpleasant side effects of mercury treatment included gum ulcers and loose teeth. Mercury continued to be used in syphilis treatment for centuries; an 1869 article by TJ Walker discussed administering mercury by injection for this purpose.

Guaiacum was a popular treatment in the sixteenth century and was strongly advocated by Ulrich Von Hutten and others. Because guaiacum came from Hispaniola where Columbus had landed, proponents of the Columbian theory contended that God had provided a cure in the same location from which the disease originated. In 1525, the Spanish priest Francisco Delicado, who himself suffered from syphilis, wrote El modo de adoperare el legno de India discussing the use of guaiacum for treatment of syphilis. Although guaiacum did not have the unpleasant side effects of mercury, guaiacum was not particularly effective, at least not beyond the short term, and mercury was thought to be more effective. Some physicians continued to use both mercury and guaiacum on patients. After 1522, the Blatterhaus — an Augsburg municipal hospital for the syphilitic poor — would administer guaiacum (as a hot drink, followed by a sweating cure) as the first treatment, and use mercury as the treatment of last resort.

Another sixteenth-century treatment advocated by the Italian physician Antonio Musa Brassavola was the oral administration of Root of China, a form of sarsaparilla (Smilax). In the seventeenth century, English physician and herbalist Nicholas Culpeper recommended the use of heartsease (wild pansy).

Before effective treatments were available, syphilis could sometimes be disfiguring in the long term, leading to defects of the face and nose ("nasal collapse"). Syphilis was a stigmatized disease due to its sexually transmissible nature. Such defects marked the person as a social pariah, and a symbol of sexual deviancy. Artificial noses were sometimes used to improve this appearance. The pioneering work of the facial surgeon Gasparo Tagliacozzi in the 16th century marked one of the earliest attempts to surgically reconstruct nose defects. Before the invention of the free flap, only local tissue adjacent to the defect could be harvested for use, as the blood supply was a vital determining factor in the survival of the flap. Tagliacozzi's technique was to harvest tissue from the arm without removing its pedicle from the blood supply on the arm. The patient would have to stay with their arm strapped to their face until new blood vessels grew at the recipient site, and the flap could finally be separated from the arm during a second procedure.

As the disease became better understood, more effective treatments were found. An antimicrobial used for treating disease was the organo-arsenical drug Salvarsan, developed in 1908 by Sahachiro Hata in the laboratory of Nobel prize winner Paul Ehrlich. This group later discovered the related arsenic, Neosalvarsan, which is less toxic. Unfortunately, these drugs were not 100% effective, especially in late disease, and were sometimes unpredictably toxic to patients.

It was observed that sometimes patients who developed high fevers were cured of syphilis. Thus, for a brief time malaria was used as treatment for tertiary syphilis because it produced prolonged and high fevers (a form of pyrotherapy). This was considered an acceptable risk because the malaria could later be treated with quinine, which was available at that time. Malaria as a treatment for syphilis was usually reserved for late disease, especially neurosyphilis, and then followed by either Salvarsan or Neosalvarsan as adjuvant therapy. This discovery was championed by Julius Wagner-Jauregg, who won the 1927 Nobel Prize for Medicine for his discovery of the therapeutic value of malaria inoculation in the treatment of neurosyphilis. Later, hyperthermal cabinets (sweat-boxes) were used for the same purpose. These treatments were finally rendered obsolete by the discovery of penicillin, and its widespread manufacture after World War II allowed syphilis to be effectively and reliably cured.

History of diagnosis
In 1905, Schaudinn and Hoffmann discovered Treponema pallidum in tissue of patients with syphilis. One year later, the first effective test for syphilis, the Wassermann test, was developed. Although it had some false positive results, it was a major advance in the detection and prevention of syphilis. By allowing testing before the acute symptoms of the disease had developed, this test allowed the prevention of transmission of syphilis to others, even though it did not provide a cure for those infected. In the 1930s the Hinton test, developed by William Augustus Hinton, and based on flocculation, was shown to have fewer false positive reactions than the Wassermann test. Both of these early tests have been superseded by newer analytical methods.

While working at the Rockefeller University (then called the Rockefeller Institute for Medical Research) in 1913, Hideyo Noguchi, a Japanese scientist, demonstrated the presence of the spirochete Treponema pallidum in the brain of a progressive paralysis patient, associating Treponema pallidum with neurosyphilis. Prior to Noguchi's discovery, syphilis had been a burden to humanity in many lands. Without its cause being understood, it was sometimes misdiagnosed and often misattributed to damage by political enemies. It is called "the great pretender" for its variety of symptoms. Felix Milgrom developed a test for syphilis. The Hideyo Noguchi Africa Prize, was named to honor the man who identified the agent in association with the late form of the infectious disease

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