161-459: Joseph II (13 March 1741 – 20 February 1790) was Holy Roman Emperor from 18 August 1765 and sole ruler of the Habsburg monarchy from 29 November 1780 until his death. He was the eldest son of Empress Maria Theresa and her husband, Emperor Francis I , and the brother of Marie Antoinette , Leopold II , Maria Carolina of Austria , and Maria Amalia, Duchess of Parma . He was thus the first ruler in
322-410: 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
483-403: 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 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
644-557: A 20% death rate in the new hospital; the city nevertheless became preeminent in the medical field in the next century. Joseph's policy of religious "toleration" was the most aggressive of any state in Europe. Probably the most unpopular of all his reforms was his attempted modernization of the highly traditional Catholic Church , which in medieval times had helped establish the Holy Roman Empire beginning with Charlemagne . Calling himself
805-548: A Lodge himself. Freemasonry attracted many anticlericals and was condemned by the Church. Joseph's feelings towards religion are reflected in a witticism he once spoke in Paris. While being given a tour of the Sorbonne 's library, the archivist took Joseph to a dark room containing religious documents and lamented the lack of light which prevented Joseph from being able to read them. Joseph put
966-561: A best friend and confidant in her husband's sister, Maria Christina, Duchess of Teschen . The marriage of Joseph and Isabella resulted in the birth of a daughter, Maria Theresa . Isabella was fearful of pregnancy and early death, largely a result of the early loss of her mother. Her own pregnancy proved especially difficult as she suffered symptoms of pain, illness and melancholy both during and afterward, though Joseph attended to her and tried to comfort her. She remained bedridden for six weeks after their daughter's birth. Almost immediately on
1127-443: 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
1288-568: A definite system for the good of all. He undertook the spread of education, the secularization of church lands, the reduction of the religious orders and the clergy, in general, to complete submission to the lay state, the issue of the Patent of Toleration (1781) providing limited guarantee of freedom of worship , and the promotion of unity by the compulsory use of the German language (replacing Latin or in some instances local languages)—everything which from
1449-513: 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
1610-402: 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
1771-851: A great strain on her patience and temper, as in the case of the First Partition of Poland and the War of the Bavarian Succession of 1778–1779, but in the last resort the empress spoke the final word. Therefore, until the death of his mother in 1780, Joseph was never quite free to follow his own instincts. During these years, Joseph traveled much. He met Frederick the Great privately at Neisse in 1769 (later painted in The Meeting of Frederick II and Joseph II in Neisse in 1769 ), and again at Mährisch-Neustadt in 1770;
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#17330849546091932-487: A hierarchy under himself as a supreme autocrat. The personnel of government was expected to be imbued with the same dedicated spirit of service to the state that he himself had. It was recruited without favor for a class or ethnic origins, and promotion was solely by merit. To further uniformity, the emperor made German the compulsory language of official business throughout the Habsburg Monarchy, which affected especially
2093-614: 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
2254-577: 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) 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,
2415-417: A literate citizenry, elementary education was made compulsory for all boys and girls, and higher education on practical lines was offered for a select few. Joseph created scholarships for talented poor students and allowed the establishment of schools for Jews and other religious minorities. In 1784 he ordered that the country change its language of instruction from Latin to German, a highly controversial step in
2576-466: A man of the Enlightenment he ridiculed the contemplative monastic orders, which he considered unproductive. Accordingly, he suppressed a third of the monasteries (over 700 were closed) and reduced the number of monks and nuns from 65,000 to 27,000. The Church's ecclesiastical tribunals were abolished and marriage was defined as a civil contract outside the jurisdiction of the Church. Joseph sharply cut
2737-565: A multilingual empire. By the 18th century, centralization was the trend in medicine because more and better-educated doctors were requesting improved facilities. Cities lacked the budgets to fund local hospitals, and the monarchy wanted to end costly epidemics and quarantines. Joseph attempted to centralize medical care in Vienna through the construction of a single, large hospital, the famous Allgemeines Krankenhaus , which opened in 1784. Centralization worsened sanitation problems, causing epidemics and
2898-587: 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
3059-423: 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
3220-424: A single and egalitarian tax on land. The goal was to modernize the relationship of dependence between the landowners and peasantry, relieve some of the tax burden on the peasantry, and increase state revenues. Joseph looked on the tax and land reforms as being interconnected and strove to implement them at the same time. The various commissions he established to formulate and carry out the reforms met resistance among
3381-421: 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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#17330849546093542-523: A visit to his sister the queen of France, Marie Antoinette of Austria , traveling under the name of "Count Falkenstein". He was well received and much flattered by the Encyclopedists, but his observations led him to predict the approaching downfall of the French monarchy, and he was not impressed favorably by the French army or navy. In 1778, he commanded the troops collected to oppose Frederick, who supported
3703-649: A visit with the Russian empress Catherine, which started talks that would later lead to the Austro-Russian Alliance (1781) , including an offensive clause to be used against the Ottomans. This was a significant diplomatic development, as it neutralised the previous Russian-Prussian alliance which had threatened the monarchy into peace during the War of the Bavarian Succession. The agreement with Russia would later lead Austria into
3864-528: Is a modern shorthand for "emperor of the Holy Roman Empire" not corresponding to the historical style or title, i.e., the adjective "holy" is not intended as modifying "emperor"; the English term "Holy Roman Emperor" gained currency in the interbellum period (the 1920s to 1930s); formerly the title had also been rendered as "German-Roman emperor" in English. The elective monarchy of the Kingdom of Germany goes back to
4025-582: 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
4186-420: 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
4347-486: 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
4508-541: 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
4669-411: 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
4830-488: 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
4991-447: 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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5152-415: 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
5313-493: 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
5474-453: 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
5635-414: The 1756 defensive pact between France and Austria. (The bride's mother, Princess Louise Élisabeth , was the eldest daughter of Louis XV of France and his popular wife, Queen Marie Leczinska . Isabella's father was Philip, Duke of Parma .) Joseph loved his bride, Isabella, finding her both stimulating and charming, and she sought with special care to cultivate his favor and affection. Isabella also found
5796-722: 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
5957-622: The Holy Roman Empire . Under the Ottonians , much of the former Carolingian kingdom of Eastern Francia fell within the boundaries of the Holy Roman Empire. Since 911, the various German princes had elected the King of the Germans from among their peers. The King of the Germans would then be crowned as emperor following the precedent set by Charlemagne, during the period of 962–1530. Charles V
6118-652: The King of the Franks and King of Italy , for securing his life and position. By this time, the Eastern Emperor Constantine VI had been deposed in 797 and replaced as monarch by his mother, Irene . Under the pretext that a woman could not rule the empire, Pope Leo III declared the throne vacant and crowned Charlemagne Emperor of the Romans ( Imperator Romanorum ), the successor of Constantine VI as Roman emperor, using
6279-463: The Kingdom of Hungary . The Diet of Hungary was stripped of its prerogatives, and not even called together. As privy finance minister, Count Karl von Zinzendorf (1739–1813) introduced a uniform system of accounting for state revenues, expenditures, and debts of the territories of the Austrian crown. Austria was more successful than France in meeting regular expenditures and in gaining credit. However,
6440-554: The archbishop of Mainz , the archbishop of Trier , the archbishop of Cologne , the king of Bohemia , the count palatine of the Rhine , the duke of Saxony and the margrave of Brandenburg . After 1438, the title remained in the House of Habsburg and Habsburg-Lorraine , with the brief exception of Charles VII , who was a Wittelsbach . Maximilian I (emperor 1508–1519) and his successors no longer traveled to Rome to be crowned as emperor by
6601-470: 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
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6762-437: The power of the state when directed by reason . As an absolutist ruler, however, he was also convinced of his right to speak for the state uncontrolled by laws, and of the wisdom of his own rule. He had also inherited from his mother the belief of the House of Austria in its "August" quality and its claim to acquire whatever it found desirable for its power or profit. He was unable to understand that his philosophical plans for
6923-468: 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
7084-559: 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 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
7245-568: The (Germanic) Holy Roman emperors as the inheritors of the title of emperor of the Western Roman Empire , despite the continued existence of the Eastern Roman Empire. In German-language historiography, the term Römisch-deutscher Kaiser ("Roman-German emperor") is used to distinguish the title from that of Roman emperor on one hand, and that of German emperor ( Deutscher Kaiser ) on the other. The English term "Holy Roman Emperor"
7406-624: 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
7567-456: 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, 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
7728-582: The 5th to 8th centuries were convoked by the Eastern Roman Emperors . In Western Europe , the title of Emperor in the West lapsed after the death of Julius Nepos in 480, although the rulers of the barbarian kingdoms continued to recognize the authority of the Eastern Emperor at least nominally well into the 6th century. While the reconquest of Justinian I had re-established Byzantine presence in
7889-521: The Austrian dominions of the union of the Houses of Habsburg and Lorraine , styled Habsburg-Lorraine . Joseph was a proponent of enlightened absolutism ; however, his commitment to secularizing, liberalizing and modernizing reforms resulted in significant opposition, which resulted in failure to fully implement his programs. Meanwhile, despite making some territorial gains, his reckless foreign policy badly isolated Austria. He has been ranked with Catherine
8050-704: 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 ,
8211-801: The Emperor was obvious to Frederick II of Prussia, who, after their first interview in 1769, described him as ambitious, and as capable of setting the world on fire. The French minister Vergennes , who met Joseph when he was traveling incognito in 1777, judged him to be "ambitious and despotic". After the death of his father in 1765, he became emperor and was made co-regent by his mother in the Austrian dominions. As emperor, he had little true power, and his mother had resolved that neither her husband nor her son should ever deprive her of sovereign control in her hereditary dominions. Joseph, by threatening to resign his place as co-regent, could induce his mother to abate her dislike for religious toleration. He could and did place
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#17330849546098372-437: The Great of Russia and Frederick the Great of Prussia as one of the three great Enlightenment monarchs. False but influential letters depict him as a somewhat more radical philosophe than he probably was. His policies are now known as Josephinism . He was a supporter of the arts, particularly of composers such as Wolfgang Amadeus Mozart and Antonio Salieri . He died with no known surviving legitimate offspring and
8533-595: The Habsburg monarchy the greatest of the European powers. His main goal was to acquire Bavaria, if necessary in exchange for the Austrian Netherlands , but in 1778 and again in 1785 he was thwarted by King Frederick II of Prussia, whom he feared greatly; on the second occasion, a number of other German princes, wary of Joseph's designs on their lands, joined Frederick's side. Joseph's travels through Russia in 1780 included
8694-528: The Holy Roman Empire (800–1806). Several rulers were crowned king of the Romans (king of Germany) but not emperor, although they styled themselves thus, among whom were: Conrad I and Henry the Fowler in the 10th century, and Conrad IV , Rudolf I , Adolf and Albert I during the interregnum of the late 13th century. Traditional historiography assumes a continuity between the Carolingian Empire and
8855-411: The Holy Roman Empire, while a modern convention takes the coronation of Otto I in 962 as the starting point of the Holy Roman Empire (although the term Sacrum Imperium Romanum was not in use before the 13th century). On Christmas Day, 800, Charlemagne, King of the Franks, was crowned Emperor of the Romans ( Imperator Romanorum ) by Pope Leo III , in opposition to Empress Irene , who was then ruling
9016-736: The Italian Peninsula , religious frictions existed with the Papacy who sought dominance over the Church of Constantinople . Toward the end of the 8th century, the Papacy still recognised the ruler at Constantinople as the Roman Emperor, though Byzantine military support in Italy had increasingly waned, leading to the Papacy to look to the Franks for protection. In 800 Pope Leo III owed a great debt to Charlemagne ,
9177-449: The Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and 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
9338-630: The Roman Empire from Constantinople. Charlemagne's descendants from the Carolingian Dynasty continued to be crowned Emperor until 899, excepting a brief period when the Imperial crown was awarded to the Widonid Dukes of Spoleto . There is some contention as to whether the Holy Roman Empire dates as far back as Charlemagne, some histories consider the Carolingian Empire to be a distinct polity from
9499-793: 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,
9660-557: 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
9821-517: 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
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#17330849546099982-507: 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
10143-630: The back of their newfound parenthood, the couple then endured two consecutive miscarriages—an ordeal particularly hard on Isabella—followed quickly by another pregnancy. Pregnancy was again provoking melancholy, fears and dread in Isabella. In November 1763, while six months pregnant, Isabella fell ill with smallpox and went into premature labor, resulting in the birth of their second child, Archduchess Maria Christina (b.d November 22 1763), who died shortly after being born. Progressively ill with smallpox and strained by sudden childbirth and tragedy, Isabella died
10304-448: 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
10465-452: The by now completely estranged French Queen. When Maria Theresa died, Joseph started issuing edicts, over 6,000 in all, plus 11,000 new laws designed to regulate and reorder every aspect of the empire. The spirit of Josephinism was benevolent and paternal. He intended to make his people happy, but strictly in accordance with his own criteria. Joseph set about building a rationalized, centralized, and uniform government for his diverse lands,
10626-424: 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, the prodromal illness still occurred but may have been less severe than in
10787-477: 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
10948-503: 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
11109-420: The concept of translatio imperii . On his coins, the name and title used by Charlemagne is Karolus Imperator Augustus . In documents, he used Imperator Augustus Romanum gubernans Imperium ("Emperor Augustus, governing the Roman Empire") and serenissimus Augustus a Deo coronatus, magnus pacificus Imperator Romanorum gubernans Imperium ("most serene Augustus crowned by God, great peaceful emperor governing
11270-623: The coronation of Henry VII, Holy Roman Emperor . The period of free election ended with the ascension of the Austrian House of Habsburg , as an unbroken line of Habsburgs held the imperial throne until the 18th century. Later a cadet branch known as the House of Habsburg-Lorraine passed it from father to son until the abolition of the Empire in 1806. Notably, from the 16th century, the Habsburgs dispensed with
11431-621: 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
11592-465: The crown and taxes were levied upon all income derived from land. The landlords, however, found their economic position threatened, and eventually reversed the policy. Indeed, in Hungary and Transylvania, the resistance of the magnates was such that Joseph had to content himself for a while with halfway measures. Of the five million Hungarians, 40,000 were nobles, of whom 4,000 were magnates who owned and ruled
11753-401: The destruction of the autonomous guilds, already weakened during the age of mercantilism. Joseph II's tax reforms and the institution of Katastralgemeinde (tax districts for the large estates) served this purpose, and new factory privileges ended guild rights while customs laws aimed at economic unity. Physiocratic influence also led to the inclusion of agriculture in these reforms. To produce
11914-403: 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
12075-400: 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 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,
12236-454: The early 10th century, the election of Conrad I of Germany in 911 following the death without issue of Louis the Child , the last Carolingian ruler of Germany. Elections meant the kingship of Germany was only partially hereditary, unlike the kingship of England , although sovereignty frequently remained in a dynasty until there were no more male successors. The process of an election meant that
12397-492: The election of Rudolf I of Germany (1273). Rudolf was not crowned emperor, nor were his successors Adolf and Albert . The next emperor was Henry VII , crowned on 29 June 1312 by Pope Clement V . In 1508, Pope Julius II allowed Maximilian I to use the title of Emperor without coronation in Rome, though the title was qualified as Electus Romanorum Imperator ("elected Emperor of the Romans"). Maximilian's successors each adopted
12558-459: The election procedure by (unnamed) princes of the realm, reserving for the pope the right to approve of the candidates. A letter of Pope Urban IV (1263), in the context of the disputed vote of 1256 and the subsequent interregnum , suggests that by " immemorial custom ", seven princes had the right to elect the king and future emperor. The seven prince-electors are named in the Golden Bull of 1356 :
12719-471: The elector palatine was restored, as the eighth elector. The Electorate of Hanover was added as a ninth elector in 1692, confirmed by the Imperial Diet in 1708. The whole college was reshuffled in the German mediatization of 1803 with a total of ten electors, a mere three years before the dissolution of the Empire. This list includes all 47 German monarchs crowned from Charlemagne until the dissolution of
12880-564: The emperor chosen by the prince-electors . Various royal houses of Europe, at different times, became de facto hereditary holders of the title, notably the Ottonians (962–1024) and the Salians (1027–1125). Following the late medieval crisis of government , the Habsburgs kept possession of the title (with only one interruption ) from 1440 to 1806. The final emperors were from the House of Habsburg-Lorraine , from 1765 to 1806. The Holy Roman Empire
13041-529: The empire of the Romans"). The Eastern Empire eventually relented to recognizing Charlemagne and his successors as emperors, but as "Frankish" and "German emperors", at no point referring to them as Roman, a label they reserved for themselves. The title of emperor in the West implied recognition by the pope. As the power of the papacy grew during the Middle Ages, popes and emperors came into conflict over church administration. The best-known and most bitter conflict
13202-667: The empire was considered by the Catholic Church to be the only successor of the Roman Empire during the Middle Ages and the early modern period . Thus, in theory and diplomacy, the emperors were considered primus inter pares , regarded as first among equals among other Catholic monarchs across Europe. From an autocracy in Carolingian times (AD 800–924), the title by the 13th century evolved into an elective monarchy , with
13363-474: The event of Frederick's death, was to advance into Prussia and demand Silesia (a territory Frederick had conquered from Maria Theresa in the War of the Austrian Succession ). However, Frederick recovered, and thereafter became wary and mistrustful of Joseph. Joseph was also eager to enforce Austria's claim on Bavaria upon the death of the elector Maximilian III in 1777. In April of that year, he paid
13524-450: The events of Joseph II's last years also suggest that the government was financially vulnerable to the European wars that ensued after 1792. The Emperor also attempted to simplify the administration of his dominions, often a patchwork of states united in personal union by the Habsburg monarch. As an example, in 1786 he abolished the separate administration of the Duchy of Mantua , merging it with
13685-406: The example of his contemporary (and sometimes rival) King Frederick II of Prussia . His practical training was conferred by government officials, who were directed to instruct him in the mechanical details of the administration of the numerous states composing the Austrian dominions and the Holy Roman Empire. Joseph married Princess Isabella of Parma in October 1760, a union fashioned to bolster
13846-496: The expensive and largely futile Austro-Turkish War (1787–1791) . Joseph II travelled with only a few servants on horseback as "Count Falkenstein". He preferred to stop at a regular inn—forcing Catherine II to convert a wing of her palace, cajoling her gardener to act as inn-keeper. Joseph's participation in the Ottoman war was reluctant, attributable not to his usual acquisitiveness, but rather to his close ties to Russia, which he saw as
14007-435: 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 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
14168-423: The first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate , and throat, and 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
14329-680: The following week. The loss of his beloved wife and their newborn child was devastating for Joseph, after which he felt keenly reluctant to remarry, though he dearly loved his daughter and remained a devoted father to Maria Theresa. For political reasons, and under constant pressure, in 1765, he relented and married his second cousin , Princess Maria Josepha of Bavaria , the daughter of Charles VII, Holy Roman Emperor , and Archduchess Maria Amalia of Austria . This marriage proved extremely unhappy, albeit brief, as it lasted only two years. Though Maria Josepha loved her husband, she felt timid and inferior in his company. Lacking common interests or pleasures,
14490-408: 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
14651-467: The genus Orthopoxvirus . The last naturally occurring case 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
14812-429: 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
14973-519: The guardian of Catholicism, Joseph II struck vigorously at papal power . He tried to make the Catholic Church in his territories the tool of the state, independent of Rome. Clergymen were deprived of the tithe and ordered to study in seminaries under government supervision, while bishops had to take a formal oath of loyalty to the crown. He financed the large increase in bishoprics, parishes, and secular clergy by extensive sales of monastic lands. As
15134-495: 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 ,
15295-408: The land; most of the remainder were serfs legally tied to particular estates. After the collapse of the peasant revolt of Horea , 1784–1785, in which over a hundred nobles were killed, the emperor acted. His Imperial Patent of 1785 abolished serfdom but did not give the peasants ownership of the land or freedom from dues owed to the landowning nobles. It did give them personal freedom. Emancipation of
15456-457: 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 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
15617-465: The later Holy Roman Empire as established under Otto I in 962. Nephew and adopted son of Charles III While earlier Frankish and Italian monarchs had been crowned as Roman emperors, the actual Holy Roman Empire is often considered to have begun with the crowning of Otto I , at the time Duke of Saxony and King of Germany . Because the King of Germany was an elected position, being elected King of Germany
15778-436: 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
15939-406: 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
16100-452: 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 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,
16261-473: The man at rest by saying "Ah, when it comes to theology, there is never much light." Thus, Joseph was undoubtedly a much laxer Catholic than his mother. In 1789 he issued a charter of religious toleration for the Jews of Galicia , a region with a large Yiddish-speaking traditional Jewish population. The charter abolished communal autonomy whereby the Jews controlled their internal affairs; it promoted Germanization and
16422-426: The moulding of humanity could meet with pardonable opposition. Joseph was documented by contemporaries as being impressive, but not necessarily likable. In 1760, his arranged consort , the well educated Isabella of Parma, was handed over to him. Joseph appears to have been completely in love with her, but Isabella preferred the companionship of Joseph's sister, Marie Christine of Austria . The overweening character of
16583-630: The necessary price to be paid for the security of his people. After initial defeats, the Austrians won a string of victories in 1789, including the capture of Belgrade , a key Turkish fortress in the Balkans. These victories however would not amount to any significant gains for the monarchy. Under the threat of Prussian intervention and with the worrying state of the revolution in France, the Treaty of Sistova of 1791 ended
16744-540: The neighbouring Duchy of Milan . Local opposition to the change forced his successor Leopold II to reverse this measure and restore the duchy in 1791. The busy Joseph inspired a complete reform of the legal system, abolished brutal punishments and the death penalty in most instances, and imposed the principle of complete equality of treatment for all offenders. He lightened censorship of the press and theatre. In 1781–1782, he extended full legal freedom to serfs . Rentals paid by peasants were to be regulated by officials of
16905-459: The nobility, clergy, merchants and the peasants, since their barter economy lacked money. Joseph also abolished the death penalty in 1787, a reform that remained until 1795. After the outbreak of the French Revolution in 1789, Joseph sought to help the family of his estranged sister Queen Marie Antoinette of France and her husband King Louis XVI . Joseph kept an eye on the development of
17066-424: The nobility, the peasantry, and some officials. Most of the reforms were abrogated shortly before or after Joseph's death in 1790; they were doomed to failure from the start because they tried to change too much in too short a time, and tried to radically alter the traditional customs and relationships that the villagers had long depended upon. In the cities, the new economic principles of the Enlightenment called for
17227-494: The number of holy days to be observed in the Habsburg monarchy and ordered ornamentation in churches to be reduced. He forcibly simplified the manner in which the Mass (the central Catholic act of worship) was celebrated. Opponents of the reforms blamed them for revealing Protestant tendencies, with the rise of Enlightenment rationalism and the emergence of a liberal class of bourgeois officials. Anti-clericalism emerged and persisted, while
17388-404: 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
17549-429: 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
17710-416: 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)
17871-456: The peasantry of feudal burdens, and to remove restrictions on trade and knowledge. In these, he did not differ from Frederick, or his own brother and successor Leopold II, all enlightened rulers of the 18th century. He tried to liberate serfs , but that did not last after his death. Where Joseph differed from great contemporary rulers, and was akin to the Jacobins in the intensity of his belief in
18032-459: The peasants from the Kingdom of Hungary promoted the growth of a new class of taxable landholders, but it did not abolish the deep-seated ills of feudalism and the exploitation of the landless squatters. Feudalism in the Habsburg monarchy finally ended in 1848. To equalize the incidence of taxation, Joseph caused an appraisal of all the lands of the Habsburg monarchy to be made so that he might impose
18193-573: 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
18354-508: The point of view of 18th-century philosophy, the Age of Enlightenment , appeared "reasonable". He strove for administrative unity with characteristic haste to reach results without preparation. Joseph carried out measures of the emancipation of the peasantry , which his mother had begun, and abolished serfdom in 1781. In 1789, he decreed that peasants must be paid in cash payments rather than labor obligations. These policies were violently rejected by
18515-455: The pope. Maximilian, therefore, named himself elected Roman emperor ( Erwählter Römischer Kaiser ) in 1508 with papal approval. This title was in use by all his uncrowned successors. Of his successors, only Charles V , the immediate one, received a papal coronation . The elector palatine's seat was conferred on the duke of Bavaria in 1621, but in 1648, in the wake of the Thirty Years' War ,
18676-563: The position was viewed as a defender of the Catholic faith. Until Maximilian I in 1508, the Emperor-elect ( Imperator electus ) was required to be crowned by the pope before assuming the imperial title. Charles V was the last to be crowned by the pope in 1530. Even after the Reformation , the elected emperor was always a Catholic . There were short periods in history when the electoral college
18837-493: 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
18998-404: The prime candidate had to make concessions, by which the voters were kept on his side, which was known as Wahlkapitulationen ( electoral capitulation ). Conrad was elected by the German dukes , and it is not known precisely when the system of seven prince-electors was established. The papal decree Venerabilem by Innocent III (1202), addressed to Berthold V, Duke of Zähringen , establishes
19159-416: 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 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
19320-634: The relationship offered little for Joseph, who confessed he felt no love (nor attraction) for her in return. He adapted by distancing himself from his wife to the point of near total avoidance, seeing her only at meals and upon retiring to bed. Maria Josepha, in turn, suffered considerable misery in finding herself locked in a cold, loveless union. Four months after the second anniversary of their wedding, Maria Josepha grew ill and died from smallpox. Joseph neither visited her during her illness nor attended her funeral, though he later expressed regret for not having shown her more kindness, respect, or warmth. One thing
19481-402: The requirement that emperors be crowned by the pope before exercising their office. Starting with Ferdinand I , all successive emperors forwent the traditional coronation. The interregnum of the Holy Roman Empire is taken to have lasted from the deposition of Frederick II by Pope Innocent IV in 1245 (or alternatively from Frederick's death in 1250 or from the death of Conrad IV in 1254) to
19642-413: The revolution, and became actively involved in the planning of a rescue attempt. These plans failed, however, either due to Marie Antoinette's refusal to leave her children behind in favor of a faster carriage or Louis XVI's reluctance to become a fugitive king. Joseph died in 1790, making negotiations with Austria about possible rescue attempts more difficult. It was not until 21 June 1791 that an attempt
19803-403: The rival claimant to Bavaria. This was the War of the Bavarian Succession . Real fighting was averted by the unwillingness of Frederick to embark on a new war and by Maria Theresa's determination to maintain peace. However, the war cost Joseph most of his influence over the other German princes, who were wary of his potential designs on their lands, and looked to Frederick as their protector. As
19964-454: 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
20125-725: The same titulature, usually on becoming the sole ruler of the Holy Roman Empire. Maximilian's predecessor Frederick III was the last to be crowned Emperor by the Pope in Rome, while Maximilian's successor Charles V was the last to be crowned by the pope, though in Bologna , in 1530. The Emperor was crowned in a special ceremony, traditionally performed by the Pope in Rome . Without that coronation, no king, despite exercising all powers, could call himself Emperor. In 1508, Pope Julius II allowed Maximilian I to use
20286-491: 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
20447-405: 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 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,
20608-481: 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 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
20769-462: The son of Francis I, Joseph succeeded him as titular Duke of Lorraine and Bar , which had been surrendered to France on his father's marriage, and titular King of Jerusalem and Duke of Calabria (as a proxy for the Kingdom of Naples ). The death of Maria Theresa on 29 November 1780 left Joseph free to pursue his own policy, and he immediately directed his government on a new course, attempting to realize his ideal of enlightened despotism acting on
20930-486: The spiritual health of their subjects, and after Constantine they had a duty to help the Church define and maintain orthodoxy . The emperor's role was to enforce doctrine, root out heresies , and uphold ecclesiastical unity. Both the title and connection between Emperor and Church continued in the Eastern Roman Empire throughout the medieval period ( in exile during 1204–1261). The ecumenical councils of
21091-520: 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
21252-481: The title of Emperor without coronation in Rome, though the title was qualified as Electus Romanorum Imperator ("elected Emperor of the Romans"). Maximilian's successors adopted the same titulature, usually when they became the sole ruler of the Holy Roman Empire. Maximilian's first successor Charles V was the last to be crowned Emperor. Smallpox Smallpox was an infectious disease caused by variola virus (often called smallpox virus), which belongs to
21413-465: The traditional Catholics were energized in opposition to the emperor. Joseph's Patent of Toleration in 1781 was a major shift away from the inquisitive religious policies of the Counter Reformation that were previously predominant in the monarchy. Limited religious freedom of worship was given to major non-Catholic Christian sects, although conversion from Catholicism was still restricted. This
21574-530: The two rulers initially got along well. On the second occasion, he was accompanied by Prince Kaunitz , whose conversation with Frederick may be said to mark the starting point of the First Partition of Poland. To this and to every other measure which promised to extend the dominions of his house, Joseph gave hearty approval. Thus, when Frederick fell severely ill in 1775, Joseph assembled an army in Bohemia which, in
21735-430: The union did provide him was the improved possibility of laying claim to a portion of Bavaria, though this would ultimately lead to the War of the Bavarian Succession . Joseph never remarried. In 1770, Joseph's only surviving child, the seven-year-old Maria Theresa, became ill with pleurisy and died. The loss of his daughter was deeply traumatic for him and left him grief-stricken and scarred. Lacking children, Joseph II
21896-475: 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
22057-439: 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
22218-442: 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
22379-553: The war with only token gains. Holy Roman Emperor The Holy Roman Emperor , originally and officially the Emperor of the Romans ( Latin : Imperator Romanorum ; German : Kaiser der Römer ) during the Middle Ages, and also known as the Romano-German Emperor since the early modern period ( Latin : Imperator Germanorum ; German : Römisch-deutscher Kaiser , lit. 'Roman-German emperor'),
22540-521: The wearing of non-Jewish clothing. The Habsburg Empire also had a policy of war, expansion, colonization and trade as well as exporting intellectual influences. While opposing Prussia and Turkey, Austria maintained its defensive alliance with France and was friendly to Russia though trying to remove the Danubian Principalities from Russian influence. Mayer argues that Joseph was an excessively belligerent, expansionist leader, who sought to make
22701-427: Was "August Emperor of the Romans" ( Romanorum Imperator Augustus ). When Charlemagne was crowned in 800, he was styled as "most serene Augustus, crowned by God, great and pacific emperor, governing the Roman Empire," thus constituting the elements of "Holy" and "Roman" in the imperial title. The word Roman was a reflection of the principle of translatio imperii (or in this case restauratio imperii ) that regarded
22862-431: 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
23023-525: Was dissolved by Francis II , after a devastating defeat by Napoleon at the Battle of Austerlitz . The emperor was widely perceived to rule by divine right , though he often contradicted or rivaled the pope , most notably during the Investiture controversy . The Holy Roman Empire never had an empress regnant , though women such as Theophanu and Maria Theresa exerted strong influence. Throughout its history,
23184-601: Was dominated by Protestants , and the electors usually voted in their own political interest. From the time of Constantine I ( r. 306–337 ), the Roman Emperors had, with very few exceptions, taken on a role as promoters and defenders of Christianity . The reign of Constantine established a precedent for the position of the Christian emperor in the Great Church . Emperors considered themselves responsible to God for
23345-623: Was followed by the Edict of Tolerance in 1782, removing many restrictions and regulations on Jews. The Secularization Decree issued on 12 January 1782 banned several monastic orders not involved in teaching or healing and liquidated 140 monasteries (home to 1484 monks and 190 nuns). The banned monastic orders: Jesuits, Camaldolese , Order of Friars Minor Capuchin , Carmelites , Carthusians , Poor Clares , Order of Saint Benedict , Cistercians , Dominican Order (Order of Preachers), Franciscans , Pauline Fathers and Premonstratensians , and their wealth
23506-554: Was functionally a pre-requisite to being crowned Holy Roman Emperor. By the 13th century, the Prince-electors became formalized as a specific body of seven electors, consisting of three bishops and four secular princes. Through the middle 15th century, the electors chose freely from among a number of dynasties. A period of dispute during the second half of the 13th century over the kingship of Germany led to there being no emperor crowned for several decades, though this ended in 1312 with
23667-428: 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
23828-442: 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
23989-428: Was made , with the help of Count Fersen , a Swedish general who had been favored at the courts of both Marie Antoinette and Joseph. The attempt failed after the King was recognized from the back of a coin. Marie Antoinette became increasingly desperate for help from her homeland, even giving French military secrets to Austria. Nevertheless, even though Austria was at war with France at the time, it refused to directly help
24150-421: 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
24311-532: 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 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
24472-440: 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
24633-481: Was succeeded by his younger brother Leopold II . He was baptised under the full name Josephus Benedictus Joannes Antonius Michael Adamus, born an archduke of Austria. Joseph was born in the midst of the early upheavals of the War of the Austrian Succession . His formal education was provided through the writings of David Hume , Edward Gibbon , Voltaire , Jean-Jacques Rousseau , and the Encyclopédistes , and by
24794-514: Was taken over by the Religious Fund. His anticlerical and liberal innovations induced Pope Pius VI to pay him a visit in March 1782. Joseph received the Pope politely and showed himself a good Catholic, but refused to be influenced. On the other hand, Joseph was very friendly to Freemasonry , as he found it highly compatible with his own Enlightenment philosophy, although he apparently never joined
24955-472: Was that known as the investiture controversy , fought during the 11th century between Henry IV and Pope Gregory VII . After the coronation of Charlemagne, his successors maintained the title until the death of Berengar I of Italy in 924. The comparatively brief interregnum between 924 and the coronation of Otto the Great in 962 is taken as marking the transition from the Frankish Empire to
25116-583: Was the last emperor to be crowned by the pope, and his successor, Ferdinand I , merely adopted the title of "Emperor elect" in 1558. The final Holy Roman emperor-elect, Francis II , abdicated in 1806 during the Napoleonic Wars that saw the Empire's final dissolution. The term sacrum (i.e., "holy") in connection with the German Roman Empire was first used in 1157 under Frederick I Barbarossa . The Holy Roman Emperor's standard designation
25277-404: 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
25438-512: Was the ruler and head of state of the Holy Roman Empire . The title was held in conjunction with the title of King of Italy ( Rex Italiae ) from the 8th to the 16th century, and, almost without interruption, with the title of King of Germany ( Rex Teutonicorum , lit. ' King of the Teutons ' ) throughout the 12th to 18th centuries. The Holy Roman Emperor title provided the highest prestige among medieval Catholic monarchs , because
25599-511: 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
25760-401: 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 the smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is
25921-402: Was ultimately succeeded by his younger brother, who became Leopold II . Joseph was made a member of the constituted council of state ( Staatsrat ) and began to draw up minutes for his mother to read. These papers contain the germs of his later policy, and of all the disasters that finally overtook him. He was a friend to religious toleration, anxious to reduce the power of the church, to relieve
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