STATE vs PRIVATE HOSPITAL MEDICINE

Main difference is that with PRIVATE HOSPITAL MEDICINE, the Specialist gives all the orders. In State (Free) Hospital Medicine Specialists have to allow Junior doctor trainees to make decisions. If they make mistakes, that's Life. In Toronto. Doctors go to Private USA Hospitals such as the Cleveland Clinic for Heart Surgery. Dana-Farber Cancer Hospital in Boston, and Sloane-Kettering Cancer Hosp in New York. The Mayo clinic in wealthy Scottsdale,a Northern suburb of Phoenix (1.5-million)is recommended over the Rochester Mayo, a small (110,000) agricultural town Quebec now has Private Hospitals. Montreal has the two ROCKLAND MD Hosps. RocklandMD MEDICAL CLINIC DOWNTOWN MONTREAL 1538 Sherbrooke ouest, Office 500, Montreal (Quebec) H3A 1L5 Guy-Concordia Metro Opening hours Monday to Friday from 8:00 am. to 4:00 pm Phone 514-667-3383 option 1 Toll Free 1-866-677-3383 Fax : 514-667-3834 EMAIL : info@rocklandmd.com clinique, chirurgie, clinique privée, clinique médicale ROCKLANDMD MEDICAL CLINIC VILLE MOUNT-ROYAL 100 Rockland road, suite 110, Ville Mont-Royal (Québec) H3P 2V9 Acadie metro Opening hours Monday to Friday 7:00 am to 6:00 pm Saturday from 8:00 am to 4:00 pm Phone 514-667-3383 option 1 Toll Free 1-866-677-3383 Fax : 514-667-3834 EMAIL : info@rocklandmd.com clinique, chirurgie, clinique privée, clinique médicale ROCKLANDMD SURGERY CENTER VILLE MOUNT-ROYAL 100 Rockland road, 115A, Ville Mount-Royal (Quebec) H3P 2V9 Acadie metro Opening hours Monday to Friday from 7:30 am to 18:00 pm Phone 514-667-3383 option 2 Toll Free 1-866-677-3383 Fax : 514-667-3834 EMAIL : info@rocklandmd.com

USA CDC: POXVIRUS VIABILITY & SIGNATURES IN HISTORICAL RELICS

Volume 20, Number 2—February 2014 Synopsis Poxvirus Viability and Signatures in Historical Relics Andrea M. McCollumComments to Author , Yu Li, Kimberly Wilkins, Kevin L. Karem, Whitni B. Davidson, Christopher D. Paddock, Mary G. Reynolds, and Inger K. Damon Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA Although it has been >30 years since the eradication of smallpox, the unearthing of well-preserved tissue material in which the virus may reside has called into question the viability of variola virus decades or centuries after its original occurrence. Experimental data to address the long-term stability and viability of the virus are limited. There are several instances of well-preserved corpses and tissues that have been examined for poxvirus viability and viral DNA. These historical specimens cause concern for potential exposures, and each situation should be approached cautiously and independently with the available information. Nevertheless, these specimens provide information on the history of a major disease and vaccination against it. Chinese writings from 1122 bce contain references to smallpox-like disease, and it has been hypothesized that smallpox caused the death of Ramses V in Egypt in ≈1157 bce because poxvirus-like lesions were seen on the mummy (1,2). The most recent epidemics of smallpox occurred through the 1900s, and the last naturally occurring case of smallpox was seen in Somalia in 1977 (3). Historical tissue specimens and artifacts yield useful information about the history of and vaccination against smallpox. However, the absolute viability of poxviruses in well-preserved samples has not been determined. Thus, it is not known what risks these artifacts might pose to persons who come into contact with them. Figure 1 Thumbnail of Patient with smallpox. Photograph by Jean Roy, provided by the Public Health Image Library, Centers for Disease Control and Prevention, Atlanta, GA, USA. Figure 1. . . Patient with smallpox. Photograph by Jean Roy, provided by the Public Health Image Library, Centers for Disease Control and Prevention, Atlanta, GA, USA. Smallpox is caused by variola virus (genus Orthopoxvirus). Illness is characterized by 3 phases: incubation, prodrome, and rash. The incubation phase is ≈10–14 days. During the prodromal period, which lasts 2–4 days, persons with smallpox typically have fever, malaise, vomiting, headache, backache, and myalgia. The rash phase can be moderate or severe and is characterized by a centrifugal distribution of lesions in the same stage of development (Figure 1) in any 1 area of the body. Lesions, including their crusts, contain infectious virus through all stages of the rash. Thus, contact with infectious lesion exudate and tissue (including crusts) can result in virus transmission. However, the most common route of transmission is inhalation of infectious respiratory droplets. Patients who survive an infection often have life-long scarring, and they maintain some level of immunity to orthopoxvirus infection (1,4,5). Elimination and eradication of smallpox were feasible, in part, because there is no animal reservoir for variola virus. The World Health Organization (WHO) announced worldwide eradication of smallpox in 1980. Successful eradication was accomplished by vaccinating populations and contacts of ill persons with live vaccinia virus, a closely related orthopoxvirus that confers immunity to variola virus. Once smallpox was eradicated, WHO recommended that routine vaccination be discontinued and that the vaccine be used only for select groups at risk for exposure to orthopoxviruses. Thus, persons born after 1980 are likely to not have residual immunity (1,6). Intentional arm-to-arm transfer of virus by dried scab or lesion exudate from a recent vaccinee was common in nineteenth century Great Britain (7). Crusts were collected, stored, and sent to others to aid vaccination before mass production and distribution of vaccine stocks. Scab material from patients with smallpox was often used for variolation, the practice of deliberately infecting a person with smallpox to (hopefully) induce a mild infection and subsequent immunity. Variolation continued into the twentieth century in some regions (1). Present-day stocks of variola virus are maintained at 2 WHO reference laboratories: the Centers for Disease Control and Prevention (CDC) (Atlanta, GA, USA) and the State Research Center of Virology and Biotechnology (VECTOR) (Koltsovo, Russia). There is concern that if variola virus is present outside these 2 laboratories, its accidental or intentional release could cause illness in a population increasingly composed of unvaccinated persons. Anecdotal reports and formal scientific evidence have not ruled out the possibility that the virus may survive prolonged periods in preserved skin and tissue material, such as those that might be on display in museums, or in unearthed human remains. For example, permafrost is an environment that closely mirrors laboratory freezer storage of live virus, and the maintenance of viable smallpox virus in human remains found in such an environment has been debated (8). Environmental contamination with potentially live variola virus recovered from historical relics could threaten our confidence that the disease has been eradicated. In addition to immediate public health concern about such relics, there is much to be gained from investigation of artifacts in terms of scientific and historical interests. We reviewed experimental data that address virus longevity in a variety of environments. There are several accounts of historical smallpox specimens in the form of unearthed remains and lesion crusts. The Poxvirus Laboratory at CDC recently reviewed this data and reexamined specimens from the inventory to revisit the existence of sections of intact DNA by using more modern methods. We also address the role of public health and scientific interest in such specimens. We found published articles by searching PubMed for material on virus viability and historical specimens. Search terms included viability smallpox, viability variola, viability orthopoxvirus, and smallpox and corpse. References from articles that cited previous work on virus viability or historical specimens were also reviewed. Studies were also included if they contained experimental data on the viability of an orthopoxvirus on fomites or preserved tissue material (e.g., crusts). Studies or reports on historical specimens were included if there was suspicion of variola virus. Existing specimens at the CDC Poxvirus Laboratory (tissues from Egypt, Italy, and England) were reexamined by using modern molecular techniques. In addition, we examined newer relic specimens (tissues from Kentucky and New York, New York, and crusts from Virginia, New Mexico, and Arkansas) for molecular signatures of poxviruses. Non-variola orthopoxvirus DNA signatures were amplified by using real-time PCR (9). Experimental Data The infectiousness of preserved skin and tissue material from patients with smallpox has been a matter of concern, particularly as worldwide smallpox eradication was achieved (1,10–12). Circumstantial evidence had long placed infectious fomites as the cause of many outbreaks; however, there is little evidence that fomites were a frequent cause for disease transmission (13–15). Nevertheless, smallpox lesion material is infectious, and it is conceivable that such material was present on fomites, such as clothing, linens, and letters, and that those fomites were responsible for transmission of variola virus (15,16). During the smallpox era, one source of live virus was lesion crusts or scabs. Crusts were successfully used for variolation in many areas before vaccination with vaccinia virus. Virus content in crusts is not correlated with the vaccination status of the patient, severity of illness, or time during the course of infection (17). Thus, crusts from any patient with smallpox could harbor infectious virus. Experimental studies on the infectiousness of lesion crusts, specifically in preserved specimens, are limited. However, a few experimental studies share some common conclusions about the infectious nature of crusts (Table 1). During smallpox outbreaks in the 1940s, Downie and Dumbell (18) tested dried crusts and vesicle fluid that were obtained from patients with smallpox (vesicle fluid was dried on glass slides before examination). Specimens were stored at room temperature and sampled at regular intervals. Viable virus was detected from vesicle fluid contained on a glass slide stored in daylight for ≤35 days and in the dark for ≤84 days. Moreover, crusts that had been stored for 417 days at room temperature and for 432 days in a refrigerator also contained viable virus. Further testing was not possible because of insufficient crust material. Nevertheless, that study was one of the first to show that viable virus could be isolated from patient material many months after collection and that optimal storage likely included dark and cool conditions (18). In the mid-twentieth century, there was concern for inadvertent importation of variola virus into Great Britain in raw cotton shipped in from tropical areas (22). Suspicion was raised for this vehicle of importation after outbreaks occurred in British workers who handled raw cotton. An experiment was conducted to test the viability of variola virus derived from smallpox lesion crusts found in imported raw cotton (19). Viable virus was obtained ≤530 days from crusts stored in indirect light at room temperature. Crusts stored at higher humidity (73% and 84%) were viable until 70 and 60 days, respectively. Similar results were obtained from a study in Bangladesh, which found viable virus could be isolated from crusts stored at lower temperatures (21). However, crusts stored at higher temperatures and humidity did not retain viable virus after several weeks or months (21). Wolff and Croon (20) conducted the longest study of variola viability in crusts from smallpox patients. For the study, crusts were collected from patients, individually placed in envelopes, and stored at room temperature. Viability of virus in these crusts was tested yearly for 13 years. Although the number of viable particles decreased with time, live variola virus was isolated from crusts 13 years after their initial storage. The experiment was discontinued after 13 years because crust specimens were depleted. Further examination of variola virus viability on clothing and other objects indicated that the virus is not viable after exposure to direct sunlight for 30 min to 3 h; even indirect sunlight had an effect on viability (15). Although experimental studies have not yielded a well-defined period at which viable variola virus can survive in a preserved state (either deliberate experimental preservation or part of the natural process of tissue preservation), there is an overriding conjecture reached by these studies. If stored in cool, dry, and dark conditions, variola virus can survive in lesion crusts or tissues for months or years. Because each historical specimen and account is unique and the circumstances of preservation differ, it is essential to test suspicious specimens for viable variola virus. Historical and Scientific Accounts of Specimens There have been several published and unpublished reports of suspected smallpox specimens surfacing since eradication (Table 2). Some reports involve scabs or crusts, and others involve entire corpses. These specimens offer an illuminating glimpse into the past, but their presence may also cause some concern for public safety in the event that any of these specimens contain viable variola virus. We present the historical and scientific accounts of each of these specimens with their respective laboratory results, which represent published and more recent data from the CDC Poxvirus Laboratory. Corpses An anecdote from eighteenth century England describes an outbreak of smallpox believed, at the time, to be caused by exposure to a long-buried corpse. The grave of a person with smallpox who died 30 years earlier was unearthed in the process of preparing a second grave nearby, and several of the funeral attendees became ill with smallpox (12,31). Whether these grieving attendees contracted smallpox from the graveside or from another ill person in the community, a likely occurrence during an outbreak, is unknown. However, occupationally derived smallpox infections beset mortuary workers and those who had close contact with bodies of deceased patients with smallpox. In these cases, the disease was likely contracted by contact with virus in or on the corpse or on contaminated clothing or linens (19,32). These infections may have occurred because of exposure to a recently deceased patient with smallpox, but a question remains with us now: can live virus be maintained in well-preserved ancient corpses and mummies? Egyptian Mummies—Twelfth Century BCE An early examination of evidence for variola virus was conducted on a piece of skin from a male mummy housed at the Cairo Museum of Antiquities. The mummy had vesicular cutaneous lesions distributed in a pattern characteristic of smallpox. A portion of skin processed for light microscopy did not show definitive pathologic characteristics of smallpox. However, these ancient tissues were not ideally preserved for histological examination (24). The discovery of lesions present in a typical distribution on the mummified body of Ramses V implicated smallpox as the young pharaoh’s cause of death and shed new light on ancient Egyptian history, as well as that of variola virus (2). Centuries after his death, skin taken from the shroud of the mummy of Ramses V showed some viral particles and had faint immunologic reactivity (23); however, the sampling method was noted to have potentially been flawed and no live virus or viral DNA was isolated or amplified from specimens (2). Human DNA was also not detected in these specimens. Thus, although there is no laboratory data to firmly support a postmortem diagnosis, the visual appearance was suggestive of a variola infection before his death (2). Archeologic Excavations There have been 2 examples of corpses exhumed from crypts during archeologic excavations in the twentieth century. In both examples, the corpses had what were described as typical variola lesions, and the bodies had been contained in cool, dark environments. No live virus, viral DNA, or human DNA remained within these corpses. However, a corpse from sixteenth century Italy showed immunologic electron microscopy results that were consistent with those expected for orthopoxvirus infection (25,26,29). An archeologic excavation of a known Native American grave site (1640–1650) in Ontario, Canada, recovered bones from an adult male. The bones had visual scarring and an appearance consistent with osteomyelitis variolosa, a disease manifestation of smallpox in the bones and joints. On the basis of extensive document review and bone analysis, the investigators determined that the person likely had smallpox before 1639 and survived the infection with long-term osteomyelitis variolosa (27). Permafrost in Russia Two corpses with questionable lesions and that had been contained within permafrost in Siberia have been unearthed: one was unearthed naturally during flooding, and the other during an archeologic excavation. Dating of the corpses to the late seventeenth or early eighteenth century matched with written accounts of smallpox epidemics in the local communities for one of the sites, but no live virus was obtained from these remains (28,30). The more recent archeologically excavated corpse was sampled as soon as graves and mummified remains were exposed to the surface. The corpse yielded DNA closely related to more recent variola virus specimens. This finding provided further insight into the strain of variola that was circulating in northeastern Siberia during the late seventeenth or early eighteenth centuries (28). Construction Sites in Kentucky and New York, New York, USA—Nineteenth Century Figure 2 Thumbnail of Mummified remains of a woman buried in an iron coffin, New York, New York, USA, mid-1800s. Photograph provided by Don Weiss. Figure 2. . . Mummified remains of a woman buried in an iron coffin, New York, New York, USA, mid-1800s. Photograph provided by Don Weiss. There are 2 accounts of remains with suspicious lesions that were accidently unearthed during construction at a burial site. In 2000, mummified remains were discovered at a construction site in Kentucky. No live virus or viral DNA was isolated from these remains. More recently in 2011, the remains of a woman buried in an iron coffin were uncovered during construction at a known African-American cemetery in New York, New York. Preservation of the body was remarkable because of the airtight environment provided by the iron coffin (33). The presence on the body of lesions with the characteristic deep-seated, umbilicated appearance and in a centrifugal distribution of smallpox lesions immediately prompted concern for unearthed smallpox (Figure 2). No live virus or viral DNA was isolated from or visualized in any of multiple specimens taken from the body and evaluated by cell culture, molecular methods, or immunohistochemical stains. Human DNA was isolated from a tooth pulp specimen. Thus, the results do not conclusively verify the hypothesis of smallpox as the cause of death. However, visual inspection cast little doubt on this hypothesis. Crusts from Patients Some accounts from the eighteenth century report that material used in variolation (often scab material) was stored for ≤8 years before successful use (34). Thus, long-term storage and subsequent use of variola virus from preserved specimens have long been recognized. However, during the era of eradication, 45 scab specimens were collected from variolators and tested 9 months after collection; live virus was not isolated from any of the specimens (35). Nevertheless, stored crusts have caused immediate concern for potential exposures and their discovery has caused immediate exposure mitigation and testing. Figure 3 Thumbnail of Recovered crusts. A) Lesion crust material from Virginia, USA, photographed after gamma irradiation. Photograph by James Gathany. B) Lesion crust material from an envelope contained within a book, New Mexico, USA, nineteenth century. Photograph by Russell L. Regnery. C) Lesion crust material from a jar on display in a museum, Arkansas, USA. Photograph provided by Erin Goldman. Figure 3. . . Recovered crusts. A) Lesion crust material from Virginia, USA, photographed after gamma irradiation. Photograph by James Gathany. B) Lesion crust material from an envelope contained within a book, New... In the past 10 years, suspected variola crusts have been discovered in the United States on 3 occasions. In Virginia, a crust labeled as a smallpox scab was on display at a museum and was accompanied by a letter describing its origin (Figure 3, panel A). The letter and crust were sent from 1 family member to another in Virginia in 1876, and the correspondence stated that the crusts came from the arm of an infant and were to be used to vaccinate others. No live virus was isolated from this crust. However, non-variola orthopoxvirus DNA and human DNA were successfully extracted. This rare letter and scab are evidence to support arm-to-arm vaccination in the United States around the same time that it was also performed in Great Britain (7). A second incident of suspected smallpox scabs on display at a local museum occurred in Arkansas (Figure 3, panel B). These relics were donated by the family of a physician who practiced in Arkansas during 1871–1926. In 1905, there was a large smallpox outbreak in Arkansas (36). No live variola virus, viral DNA, or human DNA were isolated from the specimens. The crusts were affixed to blocks of wood with a dense resin, and the resin may have been inhibitory to the PCR or DNA stability. The origins and species of these specimens will continue to remain a mystery. In 2003, a librarian in New Mexico opened a book and an envelope containing lesion crusts fell out of the book (Figure 3, panel C). The envelope was labeled “scabs from vaccination of W.B. Yarrington’s children,” and the book was dated 1888. Similar to the relic from Virginia, no live virus was isolated from this material, but non-variola orthopoxvirus DNA was isolated. In this instance, human DNA was not amplified. The question of precisely what virus was used in vaccination in the United States in the nineteenth century is intriguing from the perspective of historical significance and the evolution of orthopoxviruses. Public Health Historical specimens come to the attention of public health authorities when there is a perception that they may constitute a potential risk to those who are handling or may have handled the artifacts. This concern extends to specific groups of persons who might work routinely with historical specimens, including archeologists and museum archivists, as well as those who may stumble upon these specimens on an irregular basis, such as construction workers or the general public. Although live variola virus has never been isolated from historical tissues, this finding does not eliminate the possibility of live variola virus resurfacing from well-preserved tissue material (10,12). Moreover, variola virus has been absent for >30 years, and there is an increasingly large population of susceptible persons who have never been vaccinated against smallpox. The discovery of a series of corpses and mummies with suspected smallpox lesions in the late 1970s and 1980s sparked a series of commentaries over the risks to archeologists and anthropologists and the potential need for vaccination of workers (19,23,33,34). This proposition has been hotly debated, and opponents have argued that live variola virus has never been isolated from archeologic specimens and that live virus vaccination carries its own risks. This debate underscores the lack of firm scientific evidence to enable an informed assessment of risk to those who come into contact with artifacts and relics potentially contaminated with variola virus. The inability to exclude the possibility of risk led to the vaccination of 3 archeologists who handled a corpse with suspect lesions in London in 1985 (29). Current recommendations from the Advisory Committee on Immunization Practices do not specifically address vaccination for those who work with antiquities, including corpses and tissue material (6). Although routine vaccination is not recommended, prudent preparation and recognition of potential smallpox relics is advised for those who work with potentially contaminated tissues and corpses (29). If a suspected smallpox relic or body of a person who died of smallpox has been discovered, local and state public health departments are an excellent resource. Public health officials can work closely with those who have handled any suspect artifacts, determine risks, help mitigate concern, and arrange for appropriate testing. Testing can be performed on a suspected specimen to definitively determine if live virus is present. The WHO smallpox reference laboratories can perform these tests and have successfully participated in inquiries involving historical specimens (Table 1). Conclusions Aside from immediate public health concerns surrounding a suspected smallpox specimen, historical cases help highlight disease history in terms of the society and patient in question. Historical specimens might also help explain the history of smallpox epidemics and vaccine development. Recent exhumation of a corpse from permafrost in Siberia led to sequence characterization of an older strain of variola virus, which shed light on the evolutionary history of the virus (28). Today, the smallpox vaccine consists of an intradermal inoculation with vaccinia virus, and the premise and method of this vaccination has not changed since the time of Jenner (7). However, the species of virus that Jenner used to vaccinate persons is still debated (37). Irrespective of the debate, most scientists agree that Jenner and generations of persons since him have used an orthopoxvirus species in vaccinations to confer immunity to smallpox. Accounts of vaccination exist in historical records, but descriptions of which virus was used, how it was used, and who was performing procedures (e.g., physicians, communities) are sparse. Thus, our understanding of the history of smallpox vaccination is incomplete. Information obtained from historic relics helps build an understanding and picture of vaccination before the twentieth century (1). Modern molecular approaches can be used with historical specimens to confirm the presence of variola or another orthopoxvirus and elucidate the evolutionary history of the virus. Full genome, gene, or partial gene sequencing of isolates enables investigating the history of 1 virus compared with others. Long-term stability of smallpox virus DNA is not well characterized. However, constant low temperatures, such as those in crypts and permafrost, are believed to be key to the stability of DNA molecules. Theoretically, DNA can survive up to ≈1 million years in cold environments (38). Specific characteristics that make orthopoxviruses stable and viable over long periods are unknown. However, for viruses embedded in tissue (such as those in crusts or skin specimens), it is reasonable to postulate that being surrounded by a protein or organic matrix may provide some protection to the virus. Archival specimens offer opportunities to delve into the past and capture a glimpse of the history of an eradicated disease. There are no published reports of residual live microbes found in archeologic relics. Furthermore, on the basis of experiences in the past several decades, risks for transmission of live organisms from such relics would seem to be nonexistent; nevertheless, archeologic specimens should be handled with caution. Each situation should be approached independently and with vigilance and attention. Special attention to the scientific value of a specimen will yield useful data about smallpox and vaccination history that might provide useful information about the virus and affected populations. Dr McCollum is an epidemiologist in the Poxvirus and Rabies Branch, Centers for Disease Control and Prevention, Atlanta, Georgia. Her research interests include the epidemiology, ecology, and population genetics of infectious diseases. Acknowledgment We thank Erin Goldman, the New Mexico Department of Health, the Arkansas Department of Health, the Virginia Department of Health, the Kentucky Department for Public Health, the New York City Department of Health and Mental Hygiene, and the New York City Office of Chief Medical Examiner for their contributions; and Hermann Meyer for comments on an earlier version of this manuscript. References Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization; 1988. Hopkins DR. Ramses V. Earliest known victim? World Health. 1980, May 22 [cited 2013 Dec 2]. http://whqlibdoc.who.int/smallpox/WH_1980.pdf Adobe PDF fileExternal Web Site Icon Deria A, Jezek Z, Markvart K, Carrasco P, Weisfeld J. The world’s last endemic case of smallpox: surveillance and containment measures. Bull World Health Organ. 1980;58:279–83 .PubMedExternal Web Site Icon Breman JG, Henderson DA. Diagnosis and management of smallpox. 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Razzell P. Smallpox extinction: a note of caution. New Sci. 1976;71:35. A letter blamed for an epidemic of small-pox. New York Medical Journal. 1901;73:600. Boobbyer P. Small-pox in Nottingham. BMJ. 1901;1:1054. DOIExternal Web Site Icon Rao AR. Infected inanimate objects (fomites) and their role in transmission of smallpox. WHO Document WHO/SE/7240. Geneva: World Health Organization; 1972. Frederiksen H, Motameni ST. The 1954–1955 epidemic of smallpox in Tabriz. Am J Trop Med Hyg. 1957;6:853–7 .PubMedExternal Web Site Icon Mitra AC, Sarkar JK, Mukherjee MK. Virus content of smallpox scabs. Bull World Health Organ. 1974;51:106–7 .PubMedExternal Web Site Icon Downie AW, Dumbell KR. Survival of variola virus in dried exudate and crusts from smallpox patients. Lancet. 1947;1:550–3. DOIExternal Web Site IconPubMedExternal Web Site Icon MacCallum FO, McDonald JR. Survival of variola virus in raw cotton. Bull World Health Organ. 1957;16:247–54 .PubMedExternal Web Site Icon Wolff HL, Croon JJ. The survival of smallpox virus (variola minor) in natural circumstances. Bull World Health Organ. 1968;38:492–3 .PubMedExternal Web Site Icon Huq F. Viability of variola virus in crusts at different temperatures and humidities. WHO document WHO/SE/7793. Geneva: World Health Organization; 1977. Dixon CW. Smallpox. London: J. & A. Churchill Ltd; 1962. Lewin PK. Mummy riddles unraveled. Bulletin of the Microscopical Society of Canada. 1984;12:3–8. Ruffer MA, Ferguson AR. Note on an eruption resembling that of variola in the skin of a mummy of the twentieth dynasty (1200–1100 B.C.). J Pathol. 1911;15:1–3. DOIExternal Web Site Icon Marennikova SS, Shelukhina EM, Zhukova OA, Yanova NN, Loparev VN. Smallpox diagnosed 400 years later: results of skin lesions examination of 16th century Italian mummy. 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JAMA. 1985;254:3038. DOIExternal Web Site IconPubMedExternal Web Site Icon Hopkins DR, Lane JM, Cummings EC, Millar JD. Two funeral-associated smallpox outbreaks in Sierra Leone. Am J Epidemiol. 1971;94:341–7 .PubMedExternal Web Site Icon Owsley DW, Bruwelheide KS, Cartmell LW, Burgess LE, Foote SJ, Chang SM, The man in the iron coffin: an interdisciplinary effort to name the past. Hist Archaeol. 2006;40:89–108. Razzell PE, Bradley L. The smallpox controversy. Local Popul Stud. 1974;12:42–4 .PubMedExternal Web Site Icon Arita I. Can we stop smallpox vaccination? World Health. 1980; (May):27–9 [cited 2013 Dec 2]. http://whqlibdoc.who.int/smallpox/WH_5_1980_p27.pdf Adobe PDF fileExternal Web Site Icon Public health weekly reports for February 3, 1905. Public Health Rep. 1905;20:163–98 .PubMedExternal Web Site Icon Baxby D. The origins of vaccinia virus. J Infect Dis. 1977;136:453–5. DOIExternal Web Site IconPubMedExternal Web Site Icon Willerslev E, Cooper A. Ancient DNA. 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Emerg Infect Dis [Internet]. 2014 Feb [date cited]. http://dx.doi.org/10.3201/eid2002.131098External Web Site Icon DOI: 10.3201/eid2002.131098

DAILY MAIL: DANGER of GUIDELINES followed slavishly.

Junior doctor in tears at inquest after she revealed how senior colleagues LAUGHED at her when she suggested a consultant examine a four-year-old who later died Tragic Freya Wells died at Kingston Hospital from a severe infection Doctor Hilary Towse repeatedly raised her concerns about the treatment But she was made to feel 'ridiculous' and 'laughed' at by a senior doctor By Daily Mail Reporter PUBLISHED: 18:21 GMT, 16 January 2014 | UPDATED: 20:21 GMT, 16 January 2014 A junior doctor was laughed at by a senior colleague when she suggested a consultant should examine a four-year-old girl who died hours later, an inquest has heard. Tragic youngster Freya Wells died after she was administered antibiotics orally to treat a severe infection, the hearing was told. But when junior doctor Hilary Towse repeatedly raised her concerns about the treatment she claims she was made to feel 'ridiculous' and 'laughed' at by a senior doctor. Freya Wells, 4, died at Kingston Hospital in Surrey (pictured) from a severe infection after doctors failed to give her antibiotics by the correct method, a hearing was told +3 Freya Wells, 4, died at Kingston Hospital in Surrey (pictured) from a severe infection after doctors failed to give her antibiotics by the correct method, a hearing was told Freya had been vomiting and suffering from diarrhoea for around three days when she was admitted to Kingston hospital in south west London after her condition did not improve following a visit to a GP, the inquest heard. More... Mother describes horrific moment her husband found their 23-month-old son face down in a paddling pool where he drowned GP's wife fell to her death down powerful waterfall in front of devastated husband who desperately tried to reach her after she slipped Police arrest 21-year-old woman on suspicion of assisting a suicide - making her 'the youngest' in Britain to potentially face the charge When she arrived at the hospital on November 21st, 2012, she had an infection and was also suffering from breathing difficulties. She was quickly transferred to the paediatric Sunshine Ward. West London Coroner’s Court heard that in A&E, Registrar Rosita Ibrahim prescribed Freya oral antibiotics, but that her junior colleague and nurses did not agree with that course of treatment. Fatal mistake: The inquest heard that other medics felt the antibiotics should have been administered intravenously not orally +3 Fatal mistake: The inquest heard that other medics felt the antibiotics should have been administered intravenously not orally Doctor Towse told the inquest that she thought the four-year-old should have been receiving intravenous antibiotics. She said that around 1am the following morning when she saw Dr Ibrahim she again expressed her concerns. Dr Towse said: 'I specifically said that she needed to have a bolus [fluids straight into the blood]. 'I specifically said that she needed to have IV antibiotics, and I specifically said that I thought she needed intensive care.' However, she added: 'She (Dr Ibrahim) seemed to be able at each point to give a reason.' Breaking down in tears, Dr Towse added: 'She thought that what I was saying was ridiculous - I recall that she laughed.' The court heard that the response Dr Towse received led her to believe that perhaps she was 'over-reacting' but also that her senior was 'under-reacting'. Dr Towse continued: 'I felt I was repeatedly raising my concerns about what I thought was going on and she, to me, would acknowledge it and take it on board, but didn’t agree.' When Freya’s condition deteriorated later that night and Dr Towse could not initially reach Dr Ibrahim, she considered contacting a consultant, but was eventually able to get through to the doctor. Dr Towse was asked by Shaheen Raham, representing Dr Ibrahim, why she had not called for a consultant herself if she was so worried. She replied: 'It will always be something I regret for the rest of my life - it would never normally be the role of the SHO [senior house officer] to do that. 'But I had some experience where I had been entirely appropriate to speak to consultants, but they had not listened to me because I was an SHO.' The inquest heard that after Freya’s vomit became 'coffee coloured' Dr Towse took it upon herself to deliver intravenous antibiotics, but was part-way through the procedure when Dr Ibrahim returned from a crash call elsewhere in the hospital and inserted the line herself. The inquest heard that Freya died the following morning at 5.45am after suffering from septic shock. Assistant coroner Dr Sean Cummings told Dr Ibrahim that many clinicians have given evidence that they asked her about the antibiotics. West London Coroner's Court heard that in A&E, Registrar Rosita Ibrahim prescribed Freya oral antibiotics, but that her junior colleague and nurses did not agree with that course of treatment +3 West London Coroner's Court heard that in A&E, Registrar Rosita Ibrahim prescribed Freya oral antibiotics, but that her junior colleague and nurses did not agree with that course of treatment 'There seems to have been a great concern that Freya should have been given IV antibiotics,' he said. 'Everybody seems to be clear that you decided that wasn't going to be the case.' Dr Ibrahim, who first saw the girl at 10pm the previous evening, told the court that, despite Freya's high heart and respiratory rates, she followed guidelines which stated that children suffering from severe pneumonia should be given oral antibiotics to reduce their discomfort. But she said it was planned for the next dose of antibiotics - due at 7am - to be given by IV. 'I realise now it should not have been the case,' she said. 'She should have received intravenous antibiotics right after her vomit in A&E.' Dr Ibrahim accepted Mr Baker's assertion that it should have taken 'a matter of minutes' to see that Freya was seriously ill. 'I just simply did not appreciate how unwell Freya was,' she added. Dr Ibrahim insisted that she had 'no recollection' of laughing 'at anything' on that night, and told the inquest that, from her memory, the only staff member who came to her with concern was Dr Towse. 'I have been over that evening so many times in my head and I cannot recollect multiple people coming up to me and telling me how concerned they are,' she said. 'It is my normal practice to listen to nurses. They are very experienced. If they are concerned then I take it on board.' She added: 'Had I known that the nurses were very worried about her I would have just called the consultant straight away.' The inquest was adjourned until 10am tomorrow, when the final evidence is expected to be heard Read more: http://www.dailymail.co.uk/news/article-2540768/Junior-doctor-tears-inquest-revealed-senior-colleagues-LAUGHED-suggested-consultant-examine-four-year-old-later-died.html#ixzz2qbjIL7o5 Follow us: @MailOnline on Twitter | DailyMail on Facebook

CANCER CELL: Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts mediate Proteasome inhibitor resistance in "Multiple Myeloma.

Cancer Cell, Volume 24, Issue 3, 289-304, 9 September 2013 Copyright © 2013 Elsevier Inc. All rights reserved. 10.1016/j.ccr.2013.08.009 Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma Authors Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart(SCOTTSDALE MAYO CLINIC), Donna E. Reece,(Toronto Princess Marg.Hosp) Kim Chan Chung, Rodger E. Tiedemann (Tor.Princess Marg.Hosp) Highlights MM tumors contain Xbp1s− progenitors that survive proteasome inhibition Xbp1s absence arrests secretory maturation and ER loading, reducing ERAD dependence PI resistance mechanisms in patients differ from in vitro models These data help explain the failure to cure MM with current therapy Summary Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s− tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure. COMMENT from SCIENCE Cancer Researchers Discover Root Cause of Multiple Myeloma Relapse Sep. 9, 2013 — Clinical researchers at Princess Margaret Cancer Centre ( and SCOTTSDALE MAYO CLINIC) have discovered why multiple myeloma, an incurable cancer of the bone marrow, persistently escapes cure by an initially effective treatment that can keep the disease at bay for up to several years. The reason, explains research published online today in Cancer Cell, is intrinsic resistance found in immature progenitor cells that are the root cause of the disease -- and relapse -- says principal investigator Dr. Rodger Tiedemann, a hematologist specializing in multiple myeloma and lymphoma at the Princess Margaret, University Health Network (UHN). Dr. Tiedemann is also an Assistant Professor in the Faculty of Medicine, University of Toronto. The research demonstrates that the progenitor cells are untouched by mainstay therapy that uses a proteasome inhibitor drug ("Velcade") to kill the plasma cells that make up most of the tumour. The progenitor cells then proliferate and mature to reboot the disease process, even in patients who appeared to be in complete remission. "Our findings reveal a way forward toward a cure for multiple myeloma, which involves targeting both the progenitor cells and the plasma cells at the same time," says Dr. Tiedemann. "Now that we know that progenitor cells persist and lead to relapse after treatment, we can move quickly into clinical trials, measure this residual disease in patients, and attempt to target it with new drugs or with drugs that may already exist. Dr. Tiedemann talks about his findings: click here to watch. In tackling the dilemma of treatment failure, the researchers identified a cancer cell maturation hierarchy within multiple myeloma tumors and demonstrated the critical role of myeloma cell maturation in proteasome inhibitor sensitivity. The implication is clear for current drug research focused on developing new proteasome inhibitors: targeting this route alone will never cure multiple myeloma. Dr. Tiedemann says: "If you think of multiple myeloma as a weed, then proteasome inhibitors such as Velcade are like a persnickety goat that eats the mature foliage above ground, producing a remission, but doesn't eat the roots, so that one day the weed returns." The research team initially analyzed high-throughput screening assays of 7,500 genes in multiple myeloma cells to identify effectors of drug response, and then studied bone marrow biopsies from patients to further understand their results. The process identified two genes (IRE1 and XBP1) that modulate response to the proteasome inhibitor Velcade and the mechanism underlying the drug resistance that is the barrier to cure. Dr. Tiedemann is part of the latest generation of cancer researchers at UHN building on the international legacy of Drs. James Till and the late Ernest McCulloch, who pioneered a new field of science in 1961 with their discovery that some cells ("stem cells") can self-renew repeatedly. The science has continued to advance unabated ever since, and notably with key discoveries by Dr. John Dick of cancer stem cells first in leukemia and next in colon cancer. Dr. Tiedemann's new findings underscore the clinical importance of understanding how cells are organized in the disease process.

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SWISS MEDICAL WEEKLY: PLATELET TRANSFUSION

Platelet transfusion: basic aspects Nowadays platelet transfusions are an essential part of the supportive care of thrombocytopenic ­patients. The number of platelet transfusions continues to grow as a result of the increasing number of patients treated for haemato-oncological diseases, and of extension of the indications for platelet transfusions to include, for example, drug-related platelet dysfunction. This review focuses on current platelet component production and storage techniques, indications for platelet transfusion, and safety issues such as alloimmunisation and management of refractory platelet transfusion. Abstract In the 1950s, platelet transfusions were found to prevent major haemorrhage and improve survival in thrombocytopenic patients. Since then, their use has grown and continues to grow: nowadays, more than ­4 million platelet components are transfused worldwide each year. However, a number of questions have arisen related to the optimal preparation and storage of platelet components, and the indications for, and the safety and efficacy of, platelet transfusions. Platelet components can be obtained either from whole blood donations or by single donor apheresis. Both techniques have advantages and disadvantages. Platelet components derived from whole blood donations are produced by pooling either platelet rich plasma or buffy coats from multiple donors, using different sequential centrifugation steps. For the production of single donor apheresis platelet concentrates, donor availability is a major limitation of this process. Although specific ­adverse effects of platelet apheresis are well recognised, the process is considered safe and can even be safely performed in donors with mild anaemia and low iron stores. Platelet components are stored at 22 ± 2 °C under gentle agitation. Because possibly contaminating bacteria can grow well under these conditions, duration of storage is limited to 4–7 days, depending on whether bacterial ­detection methods or pathogen reduction are used. Various pathogen reduction techniques have been developed in recent years. One such technique, now mandatory in Switzerland, involves amotosalen, a psoralen ­derivative which binds to nucleic acids and, upon activation with ultraviolet-A, crosslinks them. An absorbing device then removes residual amotosalen (figure). Platelets can be transfused in order to prevent bleeding (prophylactic transfusion) or to stop bleeding (therapeutic transfusion) both in thrombocytopenic patients and in patients with normal platelet counts. The vast majority of recipients of platelet transfusions are thrombocytopenic patients with haemato-oncological diseases. Drug-induced platelet dysfunction is another indication for platelet transfusion. Assessment of the efficacy of platelet transfusion is very important and a major challenge. Several criteria have been developed and evaluated; most of them ­include the post-transfusion platelet count. Various factors have a direct or indirect influence on the efficacy of platelet transfusions. These can be product-related and patient-related, immune and nonimmune. Bleeding, infection/sepsis, splenomegaly and graft-­versus-host disease are the most common nonimmune causes for refractoriness to platelet transfusions. Drugs are also important causes of refractoriness. Immune factors are responsible for platelet transfusion refractoriness in approximately 20% of cases, with human ­leucocyte antigen (HLA) antibodies being most commonly involved. Platelet transfusions can be associated with various transfusion reactions, including, among others, febrile transfusion reactions (the most frequent), allergic reactions (generally mild), haemolysis due to donor iso­haemagglutinins and the risk of microbial contamination, which can lead to fatal sepsis. Alloimmunisation can be a problem in patients receiving multiple transfusions. It is related to residual red blood cells and leucocytes in the platelet components, as well as platelet ­antigens. Studies on alternatives to platelet transfusions and other methods to improve haemostasis in bleeding ­patients are under investigation. Development of platelets from haematopoietic stem cells, human embryonic stem cells and human induced pluripotent stem cells and expansion of ex-vivo generated platelets are further exciting fields of research. This is a summary of a paper that was published on www.smw.ch. Must be cited as: Holbro A, Infanti L, Sigle J, Buser A. Platelet transfusion: basic aspects. Swiss Med Wkly. 2013;143:w13885. - See more at: http://blog.smw.ch/platelet-transfusion-basic-aspects/#sthash.8Ndl4ZQ2.dpuf

SCIENCE INSIDER:SHIP OWNER D.K.LUDWIG leaves $540-million for Cancer Research

A trust fund created by billionaire shipping tycoon Daniel K. Ludwig ends today with a bang and a gift to research. Six U.S. medical centers will receive $540 million—$90 million each—from the fund to endow cancer studies in perpetuity, or until cancer is no longer a problem, as specified in the will left by Ludwig, who died in 1992. In all, his estate has given $2.5 billion to cancer research since the 1970s. The new money goes to Ludwig Centers already located at six elite research institutions: Harvard Medical School in Boston; Johns Hopkins University in Baltimore, Maryland; the Massachusetts Institute of Technology in Cambridge; the Memorial Sloan-Kettering Cancer Center in New York City; Stanford University in Palo Alto; and the University of Chicago. The Ludwig trust had established the same centers in 2006. The funding by the Ludwig trust has been “sort of under the radar,” says oncologist Kenneth Kinzler, who, along with Bert Vogelstein, co-directs the Ludwig Center at Hopkins. These are among the most coveted awards in biomedicine, Kinzler says. The money is held as an endowment and comes with few strings attached—just a mandate to investigate cancer and find ways to stop it. There are no progress reports or renewal applications to write, Kinzler says, which “allows you to focus on what you think will yield the most important results without being concerned about meeting artificial intermediate deadlines.” The Ludwig group seeks clinical outcomes, Kinzler says, a goal that he and Vogelstein strongly endorse. Without the Ludwig money, the Hopkins group would not have been able to do the cancer genetics studies they’re famous for, he notes—for example, the duo has used exome surveys to identify genes associated with colon and breast cancers. The sheer size of the Ludwig endowments makes a difference, says cancer immunologist Jedd Wolchok at Memorial Sloan-Kettering: “It allows for a respectable research budget.” Wolchok figures that his group’s budget for cancer immunology research will double this year, rising by “several million dollars,” and likely will continue to grow, thanks to the money earned by the endowment. For Wolchok, that means that “we can go from concept to clinical investigation very, very quickly.” For example, he expects his group to launch a clinical trial in 2 months to test a therapeutic antibody developed by a Japanese company that could be used to modulate T cells that regulate the immune response. The Memorial Sloan-Kettering team also has a series of clinical trials under way to monitor immune system reactions to various cancer therapies, including radiation. Ludwig, a friend of President Richard Nixon, was a stalwart backer of Nixon’s “War on Cancer,” which was linked to the congressional legislation that reestablished the U.S. National Cancer Institute in 1971. That year, the shipping magnate created an independent outfit in New York City, the Ludwig Institute for Cancer Research. The organization now has an endowment of more than $1.2 billion and employs more than 600 people, including scientists in six countries outside the United States, according to institute CEO Edward McDermott Jr. The philosophy that drives this research network, McDermott says, is the one that drove Ludwig “in his personal business enterprises—to find the best people and resource them well.” McDermott adds: “We invest in scientists, not particular science. … We are not in the business of discovery for discovery's sake. It's a means to an end, which is improved patient outcomes. So we are very committed to … infrastructures that allow us to take our discoveries from bench to bedside.” McDermott says that the institute has sponsored more than 100 clinical trials and has eight under way right now. All of these focus on cancer immunotherapy.

PROMED: H1N1 British Columbia

INFLUENZA (02): CANADA (BRITISH COLUMBIA), H1N1, HOSPITALIZED PATIENTS ********************************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Sun 5 Jan 2014 Source: CBC [edited] Dr. Paul Van Buynder, with Fraser Health, said Friday [3 Jan 2014] that 15 patients, many of them otherwise healthy young people, were recently admitted to intensive care units in hospitals in the region. By Sunday [5 Jan 2014], he added 5 more to the total for those in intensive care in B.C., where at least 40 people have been hospitalized due to H1N1 influenza this season [2013-14]. Fraser Health says an outbreak of H1N1 flu has sent at least 40 people in B.C. to hospital, with around half of them ending up in intensive care units. "It is a lot for us at this particular time, especially because there is not a lot of circulating disease in the community at this point, and so we're worried that this has happened to so many people so quickly," he said. He said the ages of the patients turning up with H1N1 flu span the spectrum, and include those in their 30s. He also said at least one of the patients is pregnant, and also that one person may have died from this flu strain. "I have one person who hasn't been confirmed, but I'm pretty sure did pass away from this," Van Buynder told CBC News. "People should always be concerned about influenza in winter. It does kill people. It makes people very ill." Van Buynder said medical officials are seeing small pockets of H1N1 breaking out across the region, in a pattern mirroring the flu's spread in Alberta, Ontario, and Texas. Alberta's Health Minister Fred Horne said last week that there have been 965 lab-confirmed cases; another 251 people have been hospitalized due to influenza, and 5 people have died so far this flu season [2013-14]. In Ontario, 6 people are believed to have died from H1N1 influenza, and 3 have died from the virus in Saskatchewan.

BLOOMBERG BUSINESSWEEK: DOCTORS on DEMAND

In his various professional incarnations, Phillip “Dr. Phil” McGraw has been a practicing psychologist, bestselling author, television personality, and spokesman for weight-loss products of dubious efficacy. Now he’s got a part-time gig as an adviser to a startup called Doctor On Demand, which is announcing itself to the public today. The service will try to increase online access to doctors, which could have far-reaching effects on health care. McGraw helped conceive the San Francisco-based startup with his son Jay McGraw, a reality TV producer. The company has raised $3 million from investors including Google Ventures (GOOG), Andreessen Horowitz, Venrock, and Shasta Ventures. (Bloomberg LP, the parent of Bloomberg Businessweek, is an investor in Andreessen.) The startup seeks to help people bypass costly in-person visits to crowded medical offices and emergency rooms by letting them use mobile devices to set up video chats with doctors. “There are 1.2 billion ambulatory care visits every year, and the vast majority of people are walking in for something like colds or urinary tract infections that are very amenable to an initial consult over video,” says Adam Jackson, the company’s co-founder and chief executive officer. Blog: Dr. Phil Backs a Startup, Seed Cash From Mom and Dad, Refunds for Main Street: Dec. 11 Each online consultation costs $40. Doctors who enlist in the company’s network will collect $30 per session. They can diagnose illnesses, prescribe medicine, or refer a case to a caregiver if it seems like an emergency or requires lab work or an in-person examination. “It’s the bane of my existence, but everyone has a smartphone, which means everyone has a video camera. Everyone is paparazzi,” says McGraw, a shareholder and adviser to Doctor on Demand. “There are also many good things to come from this change in technology and telemedicine is one of them. It’s a giant step forward and a great opportunity to help people live healthier lives.” The service goes live today in 15 states, including California, Florida, New Jersey, New York, Ohio, and Texas. (Many states have laws preventing Doctor on Demand from setting up shop.) The company says it has enlisted more than 1,000 doctors to offer video consults a day or two per week. The company trains physicians to use its service, and it handles all the extras, including patient questionnaires, pharmacy networks, and malpractice insurance.

Brand "DOCTOR of MEDICINE"

Image important. Court Lawyers and Judges look the part and are paid accordingly . Trend of (male) MDs to look "working class" by avoiding ties and white coats. Fashion of draping "shorty" stethoscope around the neck looks absurd. Better to wear Doppler and Pulse-Oximeter. Or ELECTRONIC STETHOSCOPE to visually separate Consultants from Nursing assistants.(e.g. LITTMANN # 3200) A profitable 2014 to the Blog's World Readers. Comments welcome. NB: NO ADS. United States 11680 Canada 3910 United Kingdom 3486 Turkey 3043 Germany 1239 Russia 773 France 557 Sweden 367 Australia 256 Latvia 232