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109-578: Ibb has been occupied since ancient times, and due to its strategic importance, the Ottomans used it as an administrative center. It thrived as a market town and the Ottomans established the Wednesday market in Ibb. Ibb was governed by a semi-autonomous emir until 1944, when the emirate was abolished. At times in its history many people have migrated to Ibb from areas of Yemen experiencing drought, to find work in farming. In

218-410: 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

327-577: A cardiac arrest when visiting his daughter. No post-mortem was carried out on his body because of the risk of smallpox infection. On 6 September 1978, Henry Bedson, head of the Birmingham Medical School microbiology department, cut his throat in the garden shed while in quarantine at his home in Cockthorpe Close, Harborne . He died at Birmingham Accident Hospital a few days later. His suicide note read: I am sorry to have misplaced

436-443: 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

545-415: 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

654-513: 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

763-451: 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

872-614: 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

981-587: 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

1090-423: 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

1199-421: 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

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1308-588: 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,

1417-582: 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

1526-420: 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

1635-486: 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

1744-541: 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

1853-411: 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

1962-488: 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

2071-447: 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

2180-441: 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

2289-415: 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

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2398-479: Is one of the wettest areas of Yemen, typically receiving around 500 mm of rain per annum. The city is noted for its towering stone houses, with geometrical friezes and circular stained glass windows known as qamiriya . The main mosque was built during the Ottoman period, and there are other mosques and also a fortress in the vicinity, closed to visitors. An ancient overhead aqueduct still remains. Ibb University

2507-493: 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

2616-453: 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

2725-674: 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

2834-614: The Health and Safety Executive announced their intention to prosecute the university for breach of safety legislation. The case was heard in October 1979 at Birmingham Magistrates' Court . Although the source of infection was traced, the mode and cause of transmission was not. Evidence presented by several internationally recognised experts, including Kevin McCarthy , Allan Watt Downie and Keith R. Dumbell , showed that airborne transmission from

2943-609: The Robin Hood Crematorium was thoroughly cleaned afterwards. Concerns over the survival of infectious virus in Parker's body were well-founded, and at the inquest the coroner , who signed Parker's cremation certificate, disallowed an autopsy for safety reasons. Many people had close contact with Parker before she was admitted to hospital. The outbreak prevention response included 260 people being immediately quarantined, several of them at Catherine-de-Barnes Hospital, including

3052-451: The University of Birmingham was acquitted following a prosecution for breach of Health and Safety legislation connected with Parker's death. Several internationally recognised experts produced evidence during the prosecution to show that it was unlikely that Parker was infected by airborne transmission in this way. Although there is general agreement that the source of Parker's infection was

3161-574: The West Midlands , five of whom were quarantined in Witton Isolation Hospital in Birmingham. There are no records of any formal enquiries on the source of this outbreak despite concerns expressed by the then head of the laboratory, Peter Wildy . In 1977, the WHO had told Henry Bedson that his application for his laboratory to become a Smallpox Collaborating Centre had been rejected. This

3270-655: The World Health Organization (WHO), The Health and Safety Executive and the Trades Union Congress . The inquiry's report noted that Bedson had failed to inform the authorities of changes in his research that could have affected safety. Shooter's enquiry discovered that the Dangerous Pathogens Advisory Group had inspected the laboratory on two occasions and each time recommended that the smallpox research be continued there, even though

3379-422: 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

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3488-460: 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 the characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease

3597-470: 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

3706-468: 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

3815-624: 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

3924-752: 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 ,

4033-510: The United Kingdom resulted in the death of Janet Parker, a British medical photographer, who became the last recorded person to die from the disease. Her illness and death, which was connected to the deaths of two other people, led to the Shooter Inquiry, an official investigation by government-appointed experts triggering radical changes in how dangerous pathogens were studied in the UK and named after

4142-793: 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,

4251-507: 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

4360-517: 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

4469-507: 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

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4578-533: The ambulance driver who transported Parker. Over 500 people who had been (or had possibly been) in contact with Parker were given vaccinations against smallpox. On 26 August, health officials went to Parker's house in Burford Park Road, Kings Norton, and fumigated her home and car. On 28 August, five hundred people were placed in quarantine in their homes for two weeks. Parker's mother contracted smallpox on 7 September, despite having been vaccinated against

4687-448: 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

4796-477: 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

4905-503: 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

5014-621: 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

5123-403: 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

5232-547: The disease on 24 August. Her case was described as "very minor" and she was subsequently declared free from infection and was discharged from hospital on 22 September. Other than Parker's mother, no further cases occurred. The other close contacts, which included two biomedical scientists from the Regional Virus Laboratory, were released from quarantine in Catherine-de-Barnes on 10 October 1978. Birmingham

5341-554: The facilities at the laboratory fell far short of those required by law. Several of the staff at the laboratory had received no special training. Inspectors from the WHO had told Bedson that the physical facilities at the laboratory did not meet WHO standards, but had nonetheless only recommended a few changes in laboratory procedures. Bedson misled the WHO about the volume of work handled by the laboratory, telling them that it had progressively declined since 1973, when in fact it had risen substantially as Bedson tried to finish his work before

5450-408: 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

5559-429: 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

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5668-495: 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 ,

5777-563: The issues with those then arising from genetic manipulation. Harassed as the chosen 'villain' of the tragedy, Henry Bedson's normally stable personality broke down and he took his own life. It could be said that he was a victim of his own dedicated conscientiousness, and of his extreme sense of responsibility. An official government inquiry into Parker's death was conducted by a panel led by microbiologist R.A. Shooter , and comprising Christopher Booth , Sir David Evans , J.R. McDonald , David Tyrrell and Sir Robert Williams , with observers from

5886-514: The laboratory closed. Shooter also found that while Parker had been vaccinated, it had not been done recently enough to protect her against smallpox. A foreword by the Secretary of State for Social Services, Patrick Jenkin , noted that the University of Birmingham disputed the report's findings. The report concluded that Parker had been infected by a strain of smallpox virus called Abid (named after

5995-408: The laboratory to the telephone room where Parker was supposedly infected was highly improbable. The experts calculated that it would require 53,700 litres (11,812 imp gal) of virus fluid to have been aspirated (meaning, in this context, removed by suction of fluid and cells through a needle ) and it would take 20,000 years for one particle to travel to the telephone room at the rate the fluid

6104-436: 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

6213-406: 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

6322-408: 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

6431-482: The mid-1950s there was reportedly an outbreak of smallpox in the city. German explorer Hermann Burchardt photographed the city in 1901; these photos are now held at the Ethnological Museum of Berlin . Ibb is located at an altitude of 2,050 metres (6,730 ft) on a spur of Mount Shamāḥī. Due to its high altitude, Ibb has a dry-winter humid subtropical climate ( Köppen climate classification : Cwa ), and

6540-404: 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

6649-429: 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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6758-464: 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

6867-523: 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,

6976-453: The panel's leader. The Shooter Inquiry found that Parker was accidentally exposed to a strain of smallpox virus that had been grown in a research laboratory on the floor below her workplace at the University of Birmingham Medical School . Shooter concluded that the mode of transmission was most likely airborne through a poorly maintained service duct between the two floors. However, this assertion has been subsequently challenged, including when

7085-573: 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

7194-493: 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

7303-491: 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)

7412-454: 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

7521-479: 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

7630-491: 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

7739-516: The smallpox could not have escaped from the laboratory and gone to Janet Parker, the overwhelming inference is that Janet Parker must, in some way or other, have come to the smallpox. How that came about, I don't know, we shall never know, but I think from those facts it is an inevitable inference and nothing else really stands up to any commonsense view. In light of this incident, all known stocks of smallpox were destroyed or transferred to one of two WHO reference laboratories which had BSL-4 facilities:

7848-468: The smallpox virus grown at the Medical School laboratory, how Parker contracted the disease remains unknown. Smallpox is an infectious disease unique to humans, caused by either of two virus variants named Variola major and Variola minor , with the latter typically producing a milder disease. The World Health Organization (WHO) had established a smallpox eradication programme and, by 1978,

7957-427: 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)

8066-520: 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

8175-425: 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

8284-454: The three-year-old Pakistani boy from whom it had originally been isolated), which was being handled in the smallpox laboratory during 24–25 July 1978. It found that there was "no doubt" that Parker had been infected at her workplace, and identified three possible ways in which this could have occurred: air current transmission; personal contact; or contact with contaminated apparatus. The report favoured air current transmission and concluded that

8393-411: 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

8502-665: The transmission of the virus have not been generally accepted. Professor Mark Pallen , who wrote a book about the case, says that the air duct theory "was not really believed by anyone in the know". Brian Escott-Cox QC, who successfully defended the university in the subsequent prosecution, said in 2018: It was clear to me before the case even started that we were going to be able to prove absolutely beyond any question of doubt whatsoever, that airborne infection of smallpox cannot take place other than between two people who are face to face, less than ten inches apart. Unhappily, inevitably, once you have proven beyond any question of doubt that

8611-454: The trust which so many of my friends and colleagues have placed in me and my work. In Bedson's Munk's Roll biography published by the Royal College of Physicians , virologist Peter Wildy and Sir Gordon Wolstenholme wrote: Journalists launched a relentless effort to fix the blame on him and his staff for a breach of technique, and union officials stirred up public fears by confusing

8720-475: 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

8829-439: 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

8938-526: The virus could have travelled in air currents up a service duct from the laboratory below to a room in the Anatomy Department that was used for telephone calls. On 25 July, Parker had spent much more time there than usual ordering photographic materials because the financial year was about to end. Since Shooter's Report potentially played an important role in the court case against the university for breach of safety legislation, its official publication

9047-442: 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

9156-551: 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

9265-606: 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 the New World , resulting in large swathes of Native Americans dying . In 18th-century Europe, it

9374-636: Was admitted to East Birmingham Hospital and a clinical diagnosis of Variola major , the most serious type of smallpox, was made by consultant Alasdair Geddes . By this time the rash had spread and covered all Parker's body, including the palms of her hands and soles of her feet, and it was confluent (i.e. the lesions had merged) on her face. At 10   pm she was on her way to Catherine-de-Barnes Isolation Hospital near Solihull . By 11   pm all her close contacts, including her parents, were placed in quarantine. Her parents were later also transferred to Catherine-de-Barnes. The next day, poxvirus infection

9483-431: 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

9592-462: Was aspirated. It was additionally found that although the Shooter Inquiry noted the poor state of the duct sealing in the laboratory, this was caused after the outbreak by engineers fumigating the laboratory and ducts. The university was found not guilty of causing Parker's death. In August 1981, following a formal claim for damages made by the trade union Association of Scientific, Technical and Managerial Staffs in 1979, Parker's husband, Joseph,

9701-411: Was awarded £25,000 in compensation. Although it seems clear that the source of Parker's infection was the smallpox virus grown at the University of Birmingham Medical School laboratory, it remains unknown how Parker came to be infected. Shooter's criticisms of the laboratory's procedures triggered radical changes in how dangerous pathogens were studied in the UK, but the inquiry's conclusions on

9810-491: Was close to declaring that the disease had been eradicated globally. The last naturally occurring infection was of Variola minor in Somalia in 1977. At the time of the 1978 outbreak, a laboratory at University of Birmingham Medical School had been conducting research on variants of smallpox virus known as "whitepox viruses", which were considered to be a threat to the success of the WHO's eradication programme. The laboratory

9919-529: Was confirmed by Henry Bedson, then Head of the Smallpox laboratory at the Medical School, by electron microscopy of vesicle fluid, which Geddes had sampled from Parker's rash. Samples of the fluid were also collected by a biomedical scientist for examination at the Regional Virus Laboratory, which was in East Birmingham Hospital. Parker died of smallpox at Catherine-de-Barnes on 11 September 1978. She

10028-604: Was declared officially free of smallpox on 16 October 1978. Over a year later, in October 1979, the university authorities fumigated the Medical School East Wing. The ward at Catherine-de-Barnes Hospital in which Parker had died was still sealed off five years after her death, all the furniture and equipment inside left untouched. On 5 September 1978, Parker's 71-year-old father, Frederick Witcomb, of Myrtle Avenue, Kings Heath , died while in quarantine at Catherine-de-Barnes Hospital. He appeared to have died following

10137-437: Was employed as a medical photographer in the Anatomy Department. She often worked in a darkroom above the laboratory where research on smallpox viruses was being conducted. On 11 August 1978, Parker (who had been vaccinated against smallpox in 1966, but not since ) fell ill; she had a headache and pains in her muscles. She developed spots that were thought to be a benign rash, or chickenpox . On 20 August at 3   pm, she

10246-422: Was established in 1996. The main football team is Al Sha'ab Ibb . [REDACTED] Media related to Ibb at Wikimedia Commons 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 was diagnosed in October 1977, and the World Health Organization (WHO) certified

10355-400: Was expecting to retrieve the body from a fridge in the mortuary, but... it was stored in a body bag that was kept on the floor of a garage away from the main hospital building. She was in a transparent body bag packed with wood shavings and sawdust. There was also some kind of liquid and I remember that I was frightened that the bag would split open. The body was covered in sores and scars – it

10464-428: 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

10573-442: 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

10682-421: 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

10791-499: Was part of the Microbiology Department, the head of which was virologist Henry Bedson , son of Sir Samuel Phillips Bedson . A smallpox outbreak in the area had occurred in 1966, when Tony McLennan, a medical photographer working at the medical school, contracted the disease. He had a mild form of the disease, which was not diagnosed for eight weeks. He was not quarantined and there were at least twelve further cases in

10900-542: Was partly because of safety concerns; the WHO wanted as few laboratories as possible handling the virus. Parker was born in March 1938, and was the only daughter of Frederick and Hilda Witcomb (née Linscott). She was married to Joseph Parker, a Post Office engineer, and lived in the Kings Norton area of Birmingham. After several years as a police photographer, she joined the University of Birmingham Medical School , where she

11009-536: Was postponed until the outcome of the trial was known, and it was not published until 1980. Once it was published it had a significant impact. Shooter's report was debated by Parliament . Nicolas Hawkes wrote, in 1979, that: Shooter's report was leaked to the press by Clive Jenkins, the general secretary of the trade union to which Mrs. Parker belonged. Shooter's report is one of the most damning documents ever produced by an official enquiry in Britain. On 1 December 1978

11118-478: Was quite horrific. I was on my own and I needed help to lift the body... but I managed to get her into the van. People from the hospital were very wary of helping me... When the day of the funeral arrived, the cars were given an escort by unmarked police vehicles just in case there was an accident... The body had to be cremated because there was a chance the virus could have thrived in the ground if Mrs Parker had been buried. All other funerals were cancelled that day and

11227-456: 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

11336-487: Was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known. 1978 smallpox outbreak in the United Kingdom In 1978, an outbreak of smallpox in

11445-440: 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

11554-463: Was the last recorded person to die from smallpox. Special disease control measures had to be put into place for Parker's funeral. Ron Fleet from Sheldon , who at the time of Parker's death worked for Solihull funeral director Bastocks and later for the BBC at Pebble Mill , recalled that he was told that authorities "would not allow the body to be stored in a fridge in case the virus managed to multiply": I

11663-404: 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

11772-511: 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

11881-420: 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 the disease was eradicated. The risk of death

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