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89-505: The founder of the Mạc dynasty was a descendant of the famed Trần dynasty scholar Mạc Đĩnh Chi . Mạc Đăng Dung chose to enter the military and ascended the ranks to become the senior general in the Lê dynasty army. Later he seized power and ruled Vietnam from 1527 till his death in 1541. Mạc Đăng Dung, got his start as a bodyguard for Lê Uy Mục , the unpopular Lê Emperor, around 1506. Over time, despite

178-639: A dutongshisi : a category only slightly higher than a chieftaincy. After 1540, the Ming received tribute from both the Lê dynasty and the Mạc, a state of affairs that continued through the end of the Southern Ming at which point the two sides became tributary states of the Qing dynasty. 16°28′N 107°36′E  /  16.467°N 107.600°E  / 16.467; 107.600 Tr%E1%BA%A7n dynasty Too Many Requests If you report this error to

267-410: A marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether

356-443: A clinical case was observed, smallpox was confirmed using laboratory tests. Microscopically , poxviruses produce characteristic cytoplasmic inclusion bodies , the most important of which are known as Guarnieri bodies , and are the sites of viral replication . Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but

445-415: A discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach

534-518: A doctor in Berkeley, Gloucestershire , rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the root word vacca , which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox

623-455: A fatality rate of around 30%, while variola minor’s mortality rate was about 1%. Throughout the 18th century, variola major was responsible for around 400,000 deaths annually in Europe alone. Survivors of the disease often faced lifelong consequences, such as blindness and severe scarring, which were nearly universal among those who recovered. In the first half of the 20th century, variola major

712-614: A host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in

801-749: A new revolt against the Mạc Emperors. A new revolt was led by Nguyễn Kim (father of Nguyễn Hoàng, the first of the Nguyễn lords who later ruled southern Vietnam ) and his subordinate and son-in-law Trịnh Kiểm (the first of the Trịnh lords who later ruled Đàng Ngoài ). They installed Lê Trang Tông as Emperor of the Revival Lê dynasty and built their base in Thanh Hóa and Nghệ An provinces to resist against Mạc Đăng Dung. Both sides tried to pull in allies, mainly

890-601: A potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on

979-423: A region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with

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1068-421: A source of infection”; noted that “Current recommendations for control of secondary smallpox infections emphasize transmission ‘by expelled droplets to close contacts (those within 6–7 feet)’”; but warned that the “emphasis on spread via large droplets may reduce the vigilance with which more difficult airborne precautions [i.e. against finer droplets capable of traveling longer distances and penetrating deeply into

1157-401: A year later. Then, in 1592, Trịnh Tùng unleashed a massive invasion of the north and conquered Hanoi along with the rest of the northern provinces. Mạc Mậu Hợp was captured during the retreat and was cut to pieces over three days. The Mạc had lost control over most of Northern Vietnam, only retaining areas in and around Cao Bằng Province under the formal protection of the Ming army. In 1592,

1246-602: A year. The final known fatal case occurred in the United Kingdom in 1978 . Inoculation for smallpox appears to have started in China around the 1500s. Europe adopted this practice from Asia in the first half of the 18th century. In 1796, Edward Jenner introduced the modern smallpox vaccine. In 1967, the WHO intensified efforts to eliminate the disease. Smallpox is one of two infectious diseases to have been eradicated,

1335-582: Is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox

1424-420: Is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond

1513-490: Is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during

1602-541: Is believed to have had a mortality rate of less than 1%, as compared to variola major's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through

1691-411: Is caused by infection with variola virus, which belongs to the family Poxviridae , subfamily Chordopoxvirinae , genus Orthopoxvirus . The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade

1780-488: Is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus . To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses , the most important of which is a viral-associated DNA-dependent RNA polymerase . Both enveloped and unenveloped virions are infectious. The viral envelope

1869-447: Is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c.  1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in

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1958-415: Is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain, known for its significantly higher mortality rate compared to its counterpart, variola minor. Variola major had

2047-493: Is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in

2136-453: Is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this

2225-698: The East India Company stationed in China and another by Clopton Havers . Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire , writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where

2314-512: The Ming dynasty but also from King Phothisarat I of Lan Xang (modern-day Laos ). Mạc Đăng Dung, through submissive diplomacy and massive bribes, convinced the Ming not to attack in 1528. He then abdicated his position as Emperor in favor of his son, Mạc Đăng Doanh a year later. However, this was done purely to solidify his son's position, Mạc Đăng Dung continued to rule with the title of Senior Emperor (Viet: Thái thượng hoàng). The revolt of

2403-597: The New World , resulting in large swathes of Native Americans dying . In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox. Smallpox is estimated to have killed up to 300 million people in the 20th century and around 500 million people in the last 100 years of its existence. Earlier deaths included six European monarchs , including Louis XV of France in 1774. As recently as 1967, 15 million cases occurred

2492-422: The common cold : fever of at least 38.3 °C (101 °F), muscle pain , malaise , headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate , and throat, and

2581-470: The horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that

2670-468: The replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of

2759-624: The 18th and 19th centuries. Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. Four orthopoxviruses cause infection in humans: variola, vaccinia , cowpox , and monkeypox . Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses

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2848-779: The Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul , which he successfully did in 1768. In 1796, Edward Jenner ,

2937-626: The Kangxi Emperor demanded in 1667 that Trịnh Tạc return Cao Bằng Province to the Mạc. In 1673, the Qing had lost interest in mediating the conflict on behalf of the Mạc. In 1677, the Revolt of the Three Feudatories in southern China prompted the Qing to enlist the aid of the Lê, who accused the Mạc of joining the rebels. The Kangxi Emperor and his advisors agreed to arrest Mạc Kính Vũ as he fled into Guangxi , China, leading to

3026-566: The Lê title of Thông quốc công , reducing the Mạc realm to a duchy under the Lê dynasty. After the fall of the Southern Ming, the Qing dynasty became the mediator in the Lê-Mạc conflict while receiving tribute from both sides. The Kangxi Emperor attempted to negotiate peace between the two states. After the Lê attacked and gained control of Cao Bằng Province without permission from the Qing,

3115-560: The Ming. The Ming official position was that the Mạc should rule over the northern half of Vietnam, while the Lê should rule over the southern half (in other words, below the Red River). The Nguyễn and the Trịnh refused to accept this division of the country and the war continued. In 1541, Mạc Đăng Dung died and was succeeded by his grandson Mạc Phúc Hải . Mạc Phúc Hải ruled only for six years before he died due to illness. During his rule, he

3204-635: The Revival Lê in the south gathered strength and over the next three years all the provinces south of the Red River were captured by the Lê armies. In 1533 the figurehead Lê Emperor, Lê Trang Tông, was officially crowned at the recaptured Tây Đô castle . This marked the beginning of the Southern and Northern dynasties era . The Lê and Mạc would continue the lengthy civil war over the next 40 years. In 1540, Mạc Đăng Doanh died and Mạc Đăng Dung reclaimed

3293-488: The Trịnh. The Trịnh requested and received aid from the Nguyễn and the joint army (with Nguyễn Hoàng ) defeated the Mạc. In 1598, yet another official Ming commission declared the Mạc to be rulers over Cao Bằng province and so the Mạc rulers stayed in this protected area, occasionally launching raids into Trịnh controlled Vietnam. In 1627, the Lê army attacked Cao Bằng, the Mạc ruler Mạc Kính Khoan had to surrender and accept

3382-833: The United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox,

3471-565: The United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor

3560-531: The WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add

3649-531: The Wikimedia System Administrators, please include the details below. Request from 172.68.168.226 via cp1108 cp1108, Varnish XID 223236210 Upstream caches: cp1108 int Error: 429, Too Many Requests at Thu, 28 Nov 2024 08:46:59 GMT Smallpox Smallpox was an infectious disease caused by variola virus (often called smallpox virus), which belongs to the genus Orthopoxvirus . The last naturally occurring case

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3738-507: The absence of Guarnieri bodies could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections. Definitive laboratory identification of variola virus involved growing

3827-448: The bloodstream in large numbers, a condition known as viremia . This resulted in the second wave of multiplication in the spleen , bone marrow , and lymph nodes. The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause. When

3916-477: The central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses. The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate

4005-516: The characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or rarely via contaminated objects . Prevention was achieved mainly through the smallpox vaccine . Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after

4094-503: The closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized

4183-621: The course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off. Concern about possible use of smallpox for biological warfare led in 2002 to Donald K. Milton's detailed review of existing research on its transmission and of then-current recommendations for controlling its spread. He agreed, citing Rao, Fenner and others, that “careful epidemiologic investigation rarely implicated fomites as

4272-415: The court ensued to the level of a civil war. From 1516 to 1520, the warlords of Nguyễn Hoàng Dụ and Trịnh Duy Sản , Nguyễn Kính and Trần Cao were fighting for power. Mạc Đăng Dung initially led the forces loyal to King Lê Chiêu Tông against the warlords, he eventually defeated the warlords and gained enough power to force Lê Chiêu Tông to abdicate in 1522 and install the puppet Emperor Lê Cung Hoàng to

4361-416: The deaths of several emperors, Mạc Đăng Dung increased his power and gained many supporters. However, he also gained the enmity of other rivals for power. After a series of political crises that made both Lê Uy Mục and his successor Lê Tương Dực assassinated, Mạc Đăng Dung continued to gain power and rank in the military. With the enthronement of the young emperor Lê Chiêu Tông in 1516, a power struggle in

4450-450: The demise of the Mạc dynasty. The Lê dynasty held a tributary relationship with the Ming dynasty in exchange for recognition and military protection. As part of their tributary relationship, the Ming provided external military support to the Lê state against the Mạc beginning in 1537. After the 1540 surrender of the Mạc to the Ming, the Ming court ceremonially revoked the Lê dynasty's status as an independent kingdom and reclassified it as

4539-403: The diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly

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4628-512: The disease was eradicated. The risk of death was about 30%, with higher rates among babies. Often, those who survived had extensive scarring of their skin, and some were left blind. The earliest evidence of the disease dates to around 1500 BC in Egyptian mummies . The disease historically occurred in outbreaks . It was one of several diseases introduced by the Columbian exchange to

4717-408: The genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to

4806-429: The group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. Smallpox

4895-498: The hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA. Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop ,

4984-436: The lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia . The prodromal symptoms continued even after

5073-406: The lower respiratory tract] are maintained”. Once inhaled, the variola virus invaded the mucous membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in

5162-408: The malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by

5251-400: The new Mạc leader was Mạc Kính Chỉ. He managed to assemble a large army which defeated the army of Trịnh Tùng but a year later, he and his army were wiped out by a new Trịnh army under Trịnh Tùng. Later, his brother Mạc Kính Cung withdrawn to Cao Bằng province and ruled for more than thirty years (1593–1625). Based out of Van Ninh ( Quảng Ninh Province ) the Mạc army staged many attacks against

5340-404: The onset of the rash. The rash on the mucous membranes ( enanthem ) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox

5429-429: The oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox

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5518-464: The other being rinderpest (a disease of even-toed ungulates ) in 2011. The term "smallpox" was first used in England in the 16th century to distinguish the disease from syphilis , which was then known as the "great pox". Other historical names for the disease include pox, speckled monster, and red plague. The United States and Russia retain samples of variola virus in laboratories, which has sparked debates over safety . There are two forms of

5607-523: The outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form,

5696-588: The person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of smallpox. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of

5785-447: The practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty . If successful, inoculation produced lasting immunity to smallpox. Because

5874-491: The prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox)

5963-454: The same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases. The earliest procedure used to prevent smallpox was inoculation with variola minor virus (a method later known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before

6052-479: The second day of the rash the macules had become raised papules . By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles . This fluid became opaque and turbid within 24–48 hours, resulting in pustules . By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to

6141-491: The separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses , the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. While this

6230-427: The smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical ( asymptomatic ) infections with variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash)

6319-520: The spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There

6408-425: The temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva. Variola virus tended to attack skin cells, causing the characteristic pimples, or macules , associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to

6497-492: The throne. Lê Chiêu Tông fled the court with the support of the warlord Trịnh Tuy to Thanh Hóa where they fought against Mạc Đăng Dung until they were defeated and captured in 1526. In 1527 Mạc Đăng Dung removed Lê Cung Hoàng and proclaimed himself as Emperor of the new Mạc dynasty under the title Minh Đức. The usurpation was not well received by the Confucian officials in the government. Some were killed, others fled to join

6586-464: The throne. The Ming dynasty threatened Mạc Đăng Dung with an invasion of 110,000 men ready to invade Vietnam from Guangxi. Mac acceded to Chinese pressure and complied with bitter Ming demands, including crawling barefoot in front of the Chinese officials, giving up land to China, downgrading his status from the Emperor to Governor ( Đô thống sứ 都統使) and giving up official documents like tax registers to

6675-411: The touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars. Ordinary smallpox generally produced

6764-475: The vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on

6853-439: The virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. Smallpox

6942-442: The virus on chorioallantoic membrane (part of a chicken embryo ) and examining the resulting pock lesions under defined temperature conditions. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in

7031-554: The whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and

7120-431: Was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of

7209-408: Was defeated by the Trịnh army and lost more territories. He was succeeded by Mạc Phúc Nguyên (ruled from 1546 to 1561) who had to fight against his uncle Mạc Chính Trung to enthrone. In 1561, he died because of smallpox . Mạc Mậu Hợp succeeded the throne, and ruled from 1562 to 1592. He was the last significant Mạc ruler. In 1572 the capital was captured by the Trịnh army but then he recaptured it

7298-478: Was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated to date. The initial symptoms of the disease included fever and vomiting. This was followed by formation of ulcers in the mouth and a skin rash . Over a number of days, the skin rash turned into

7387-428: Was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation

7476-442: Was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from

7565-421: Was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs. Hemorrhagic smallpox

7654-456: Was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture . In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal. The initial symptoms were similar to other viral diseases that are still extant, such as influenza and

7743-440: Was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout

7832-404: Was the primary cause of smallpox outbreaks across Asia and most of Africa. Meanwhile, variola minor was more commonly found in regions of Europe, North America, South America, and certain parts of Africa. Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it

7921-516: Was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed

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