Prior studies have pointed to the role of the bacterial protein LcrV as a critical element of plague virulence. LcrV acts a molecular “needle” to inject toxins into host cells, and it also suppresses the immune response through two mechanisms. First, it stimulates the host to release interleukin-10 (IL-10), which dampens the innate immune response. Second, it prevents the release of two pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). This immunosuppressive activity makes native LcrV a poor vaccine candidate, despite its immunogenicity. Senior author Olaf Schneewind led the two research teams at the University of Chicago, whose results were published online Jul 28 in Science and in the August issue of Infection and Immunity. Aug 19, 2005 (CIDRAP News) – Two research reports on plague were recently released, one describing the mechanism that the plague bacterium uses to evade the body’s immune system and the other describing a potential vaccine that was tested successfully in mice. Today, about 1,000 to 3,000 cases of plague (primarily bubonic) occur worldwide each year, including approximately a dozen in the western and southwestern United States. Although plague killed hundreds of millions of people in past pandemics, no human plague vaccine is currently licensed in the United States. Marketon MM, Depaolo RW, Debord KL, et al. Plague bacteria target immune cells during infection. Science 2005 (published online Jul 28) [Abstract] The bacterium Yersinia pestis causes different forms of plague, depending on the route of exposure. Bubonic plague, infamous as the “Black Death” of the Middle Ages, is transmitted by flea bites. The disease persists in its natural reservoir of wild animals, primarily rodents, passing to humans via fleas that first bite an infected animal. Inhalation of the bacteria causes pneumonic plague, a disease that is seen less often in nature but could develop if aerosolized plague bacteria were released in an act of bioterrorism. Mice were first infected with the modified plague strains and then sacrificed and their spleen tissues separated into specific cell populations. Staining with CCF2-A dye allowed visualization of cells injected with Yop-Bla, because only cells containing this engineered protein glowed blue. Despite the predominance of CD4 and CD8 cells in the spleen, the majority of cells targeted by the modified Y pestis were macrophages, neutrophils, and dendritic cells. This strategy, the authors wrote, allows the bacterium to “destroy cells with innate immune function that represent the first line of defense, thereby preventing adaptive responses and precipitating the fatal outcome of plague.” Finally, the authors tested the rV10 protein in a mouse immunization experiment. The protein elicited high titers of immunoglobulin G (mean, 112,500 by ELISA), which were comparable to those induced by native LcrV. Additionally, two intramuscular doses of rV10 (100 mcg each, with alhydrogel adjuvant) protected 100% of mice challenged with heavy doses of Y pestis. In the Infection and Immunity article, the researchers describe how they investigated modified LcrV proteins for three criteria of a successful vaccine: lack of IL-10 stimulation, preservation of pro-inflammatory cytokine secretion, and robust antigenicity. The authors deleted sequential 30-amino-acid portions of LcrV to create 12 candidate deletion proteins. Two of these, rV7 and vV10, failed to induce IL-10 secretion in mouse macrophages. Further testing showed that the rV10 peptide was not capable of significantly suppressing TNF-alpha secretion. Overheim KA, Depaolo RW, Debord KL, et al. LcrV plague vaccine with altered immunomodulatory properties. Infect Immun 2005 Aug;73(8):5152-9 [Abstract] The authors of the Science paper wanted to know exactly which immune cells are targeted by plague. The authors engineered a protein to identify the cell types injected with toxin by the plague bacterium. They created a piece of DNA containing genes for both Yersinia outer proteins (Yop) effectors and beta-lactamase (Bla). Yops are the toxins normally injected by plague into host cells; Bla is an enzyme that cuts a dye called CCF2-AM, making it fluoresce blue instead of green. The team inserted this piece of DNA into Y pestis strains. Both studies received support from the National Institute of Allergy and Infectious Diseases. Thus rV10, the authors explained, “satisfied our experimental criteria and displayed significant defects in immune suppression without reducing the protective properties of plague vaccines.” They conclude, “It appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.” Without prompt antibiotic treatment, the case-fatality rate of plague approaches 100%. A major reason for this high mortality is that the invading bacteria suppress the body’s immune response. The plague bacterium uses a system that injects toxins directly into host cells. Previous studies have indicated that Y pestis evades the immune system by resisting phagocytosis and suppressing the inflammatory response. See also: CIDRAP plague overview
Dec 22, 2005 (CIDRAP News) – A new report says oseltamivir-resistant forms of H5N1 avian influenza virus were found in two Vietnamese girls who died of the infection, raising doubts about the antiviral drug that many countries are counting on to help protect them from a potential flu pandemic.One of the two girls died even though she started receiving oseltamivir (Tamiflu) within the first 2 days of her illness, the recommended window for effective treatment, according to the report in today’s New England Journal of Medicine. The other girl was not treated until the sixth day of her illness.The authors of the report say their findings suggest that a higher dosage, longer treatment course, or combination with other antiviral drugs may be necessary to ensure the effectiveness of oseltamivir.Roche, the manufacturer of oseltamivir, agrees with that assessment and says that studies of the safety of a higher dosage are about to get under way.Second study weighs in on stockpilingIn a separate article published today, a group of experts who have been monitoring resistance to oseltamivir and similar drugs says the evidence so far—including the New England Journal report—does not suggest that stockpiling of the drug is useless.”The available data do not indicate that potential oseltamivir resistance should be a deterrent to its stockpiling for pandemic response,” says the report by Frederick Hayden and other members of the Neuraminidase Inhibitor Susceptibility Network (NISN). It was published online today in Antiviral Therapy.The report on the Vietnamese patients was prepared by a team from the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, and Hong Kong University, with Menno D. de Jong of the Vietnamese hospital as first author.Their study focuses on eight patients who were treated for confirmed H5N1 infection at the Hospital for Tropical Diseases between February 2004 and January 2005. Throat samples were collected from the patients for analysis at admission and later in their illness. H5N1 infection was confirmed by polymerase chain reaction.All the patients were started on oseltamivir the day of admission to the hospital, which varied from 2 to 8 days after the onset of illness. They received the recommended regimen of 75 mg twice a day for 5 days. Four of the patients died.The researchers did a sequence analysis of the H5N1 virus’s neuraminidase gene to look for resistance, signaled by the substitution of tyrosine for histidine at amino acid position 274. This mutation was found in two patients, a 13-year-old girl and an 18-year-old girl.The 13-year-old was hospitalized the day after she fell ill with a fever and cough, which was also the day after her mother had died of H5N1 infection. Despite oseltamivir treatment, the girl’s condition worsened on her fourth day in the hospital, and she died of severe pneumonia on the seventh day.The viral load in her throat was higher by the time of her death than it had been earlier, which, along other laboratory evidence, suggests that “the development of drug resistance contributed to the failure of therapy and, ultimately, the death of this patient,” the report says.The 18-year-old was hospitalized and started on oseltamivir 6 days after she had fallen ill, but she died after 2 weeks in the hospital. Nonresistant H5N1 virus was found in a sample taken 2 days after she was hospitalized, but the resistant form was found 6 days later.Although the connection between viral resistance and the 18-year-old girl’s death was less clear than in the case of the 13-year-old, “The presence of replicating virus after 14 days of illness suggests an effect on the outcome,” the article says.It also says the viral load in throat specimens from the four patients who survived dropped quickly to undetectable levels during their treatment.”Our observations suggest that at least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication,” the authors write. Consequently, “Strategies aimed at improving antiviral efficacy (e.g., the use of higher doses, longer durations of therapy, or combination therapy) may deserve further evaluation.”Tamiflu manufacturer, study authors commentRoche, Swiss-based maker of Tamiflu, released a statement today agreeing that such strategies deserve consideration. The company said some data already support the safety of using a higher dosage of the drug, and clinical trials assessing the efficacy of a higher dose are scheduled. Roche is collaborating with the National Institutes of Health and the World Health Organization (WHO) on that research, the statement said.Tran Tinh Hien of the Hospital for Infectious Diseases, one of the study’s authors, says Vietnamese health officials are already recommending increasing the dosage of oseltamivir for avian flu patients, according to a Reuters report published today.”We still recommend the use of Tamiflu for bird flu cases as soon as possible and at higher doses as there is no replacement yet,” he said. He added that the Vietnamese Ministry of Health has increased the treatment period to 7 days from 5 days.The article published today by NISN, the experts who have been monitoring resistance to the neuraminidase inhibitors, say the new findings do not contraindicate stockpiling of oseltamivir, but much more research is needed. The neuraminidase inhibitors include oseltamivir and zanamivir (Relenza).The group said no one knows how often resistance emerges in H5N1 patients being treated with oseltamivir, and the clinical consequences of such resistance are also unclear.Many H5N1 patients treated with oseltamivir have died, but in most cases treatment was started late, after pneumonia had already developed, the report says. Some evidence suggests that the emergence of oseltamivir resistance early in treatment may lead to treatment failure, but more studies are needed.The group also said there is no indication that H5N1 viruses now circulating in birds are resistant to neuraminidase inhibitors. Further, the likelihood that oseltamivir-resistant strains will spread in the community appears low, in contrast to the situation with two older antiviral drugs, amantadine and rimantadine, to which ordinary flu viruses are often resistant. In animal studies, the article says, the mutation that confers resistance in both H5N1 and H1N1 viruses reduces infectiousness 100-fold and reduces viral replication more than 10-fold.The NISN statement also says that all avian and human H5N1 isolates tested so far by the Centers for Disease Control and Prevention have been susceptible to zanamivir. However, zanamivir, which is inhaled, has not been tried in human H5N1 patients.Despite this, “Inhaled zanamivir would be a therapeutic consideration if oseltamivir resistance were likely to be present,” the NISN members write. They also say the drug would be “an appropriate choice for pandemic response stockpiles.”Other experts offer opinionsTo infectious disease expert Michael T. Osterholm, PhD, MPH, the report from Vietnam “reminds us again that none of us know how much drug [oseltamivir] we have in the stockpile.” If a longer, higher-dose regimen is needed, a stockpile now described as 3 million treatment courses is actually smaller, said Osterholm, director of CIDRAP, publisher of this Web site.Osterholm also said the report suggests oseltamivir resistance can have much graver consequences in H5N1 cases than in ordinary flu. In the latter, drug resistance has not been associated with treatment failure or a severe outcome, but “with H5N1 this may be a very different outcome,” he said.Osterholm called for clinical studies of the use of oseltamivir very early in the illness and at a much higher dosage than is used in ordinary seasonal flu. If that approach improves outcomes, it would have “tremendous implications for how we get Tamiflu to patients in a timely manner,” he said.A WHO official said the resistance findings are “not necessarily alarming” but do point up the need for more information, according to the Reuters report.”What really is critical is understanding whether the way we are using the drugs contributes” to resistance, said Keiji Fukuda of the WHO’s global influenza program.Some resistance is expected whenever antivirals and antibiotics are used, Fukuda said, adding that using too-small doses or too short a treatment regimen can promote resistance.De Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005 Dec 22;353(25):2667-72 [Full text]Hayden F, Klimov A, Toshiro M, et al. Neuraminidase Inhibitor Susceptibility Network position statement: antiviral resistance in influenza A/H5N1 viruses. Antivir Ther 2005;10(8):873-7 [Abstract]See also:Dec 22 statement by Roche
(CIDRAP Business Source Weekly Briefing) – Next week the Center for Infectious Disease Research and Policy hosts the second national summit on business preparedness and pandemic influenza. I have the opportunity to address 300 or more business, government, and community leaders who will convene for the common purpose of better preparing the business world for the next pandemic. As we were planning the summit several months ago, I chose to title my talk, “The Fog of Pandemic Planning,” a takeoff on the concept of the fog of war. Let me explain why the title is even more appropriate now.The “fog of war” describes the level of ambiguity in situational awareness experienced by participants in military operations. The term captures the uncertainty regarding one’s own capability and the capability and intent of the adversary during battle. The conceptual similarities between the fog of war and the fog of pandemic preparedness are unmistakable:We really don’t understand our capability as a nation or international community to respond.We have only a very general sense of what the pandemic influenza virus is capable of doing in terms of human illness or the social, political, and economic collateral damage.We can’t predict with any certainty how the next pandemic virus will behave in humans and animals.Based on many discussions with business continuity planners and risk management officials around the country (and a few from outside the United States), I believe that the private sector is walking deeper and deeper into that fog of pandemic preparedness. While the private sector has been involved in pandemic preparedness planning (to varying degrees), sustaining the effort grows harder as more time passes from when those first urgent and sometimes dramatic warnings were issued to commence planning. The more time that passes, the more the fog thickens. I’m convinced that there are more doubters about the inevitability of the next pandemic than before. What they don’t realize is that, like earthquakes, hurricanes, and tsunamis, pandemics happen.Some organizations have tried to account for all eventualities with regard to their employees, supply chains, and even customers. Typically, the single biggest challenge relates to the ability to estimate the response of government, suppliers, providers of infrastructure support such as water and electricity, workers, and respective markets. With so many unknowns, one leading business continuity planner recently noted, “Planning for a pandemic is so different from anything we’ve done in business before that we’re writing the book as we go—and it won’t be finished until the virus is finished.”One way that companies are attempting to shore up preparedness is to require their suppliers to sign affidavits indicating they have a workable pandemic plan in place. In short, most of these affidavits are not worth the paper they are printed on, because their suppliers are in no better position to account and prepare for all aspects of the pandemic than are the companies demanding the affidavits. Furthermore, determining which preparedness activities need to be undertaken by any single company quickly becomes a Rubik’s cube of possibilities, given the interdependency of each company on outside suppliers, transportation, communications, utilities, and even government leadership and direction during a crisis.Another challenge for private sector preparedness was summarized in a September 2006 report by the Department of Homeland Security. This report stated, “Eighty-five percent of critical infrastructure resources reside in the private sector, which generally lacks individual and system-wide business continuity plans specifically for catastrophic health emergencies such as pandemic influenza. Many businesses have extensive contingency plans in response to threats from diverse natural and manmade disasters. While useful for their intended purpose, these plans may prove ineffective given they do not account for the extreme health impact assumptions and containment strategies projected for a severe pandemic influenza.”Despite the complexity, every organization must consider in its plan the combination of:The direct impact of influenza on the populationThe collateral damage from a potentially collapsing global just-in-time economyThe lack of comprehensive business continuity planningThe inability of governments around the world to provide exhaustive and immediate reliefEven if we can’t solve these issues, at least we can be honest about them and develop strategies that manage expectations in line with the potential realities. This is a tough message to deliver to those who want to enhance their organizations’ preparedness. But I believe it’s a fair and accurate assessment of our current state of pandemic preparedness—and particularly in the private sector.The key is that rigid pandemic planning is self-defeating, because we can’t predict every pandemic possibility. So we have to plan for resilience. We have to plan to cope with eventualities we never thought of and therefore couldn’t plan for.Our job now is to begin burning off that fog and keep pushing forward. I can only hope our summit provides some of the sunshine needed to do that.
In 2006 the number of WNV illnesses in the United States rose for the second year in a row, after a dramatic decline in 2004, suggesting that the virus will remain endemic, the CDC said in a Jun 8 MMWR report. “Our cities, towns, and Indian reservations are putting up a good fight against the Culex mosquito,” he said, adding that before 2002 few of the state’s communities had mosquito-control programs. “Now, nearly two thirds of our population lives in a community with some type of mosquito control program.” Jul 21, 2006, MMWR report on WNV activity from Jan 1Jul 18, 2006http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5528a4.htm Of the total cases reported so far this year, 34% (42) were West Nile neuroinvasive disease (WNND) (meningitis, encephalitis, or acute flaccid paralysis). Another 58% (71) were West Nile fever, and 7% (9) were unspecified. The virus has caused three deaths. See also: Lyle Peterson, director of the CDC’s vector-borne infection division, said the high number of cases so far is a warning that individuals and communities should be extremely vigilant, according to a New York Times report today. South Dakota reported its first WNV death 2 days ago, according to a press release from the South Dakota Department of Health (SDDH). The death, which is not yet reflected in the CDC tally, occurred in a patient in the 80- to 89-year-old age-group in whom WNV encephalitis developed. Jun 8, 2007, MMWR wrap-up article on 2006 WNV seasonhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5622a3.htm Jul 26, 2007 (CIDRAP News) The number of West Nile virus (WNV) cases reported so far this season has dramatically outpaced the number reported at about this time last summer, the US Centers for Disease Control and Prevention (CDC) said today. Lon Kightlinger, PhD, South Dakota’s state epidemiologist, told CIDRAP News that the Culex tarsalis mosquito, an efficient vector for the disease, is abundant in South Dakota, even in severe drought years. Ninety percent of WNV cases typically occur in August and early September, so it’s difficult to say if the trend will continue, he told the Times. The focus of the WNND and West Nile fever cases appears to be in California and the Dakotas. CDC. West Nile virus updateUnited States, January 1July 24, 2007. MMWR Jul 27;56(29):740-1 [Full text] Jul 24 SDDH press releasehttp://www.state.sd.us/news/showDoc.aspx?i=8662 Despite the growth of control programs, personal precautionssuch as wearing insect repellent, staying indoors during mosquito active periods, and eliminating standing waterare still vital for preventing WNV illnesses, Kightlinger said. The CDC, in tomorrow’s issue of Morbidity and Mortality Weekly Report (MMWR), said 122 cases of WNV illness have been reported as of Jul 24. Last summer, the CDC had reported only 15 cases as of the middle of July.
Source / photo: Večernji.hr; New sheet; Brodportal Many parts are thematically exhibited in Croatia, and some of them are permanently set up in the Pavletić Theme Park in Malin, but also in national parks, picnic areas and town squares. The exhibition in Malin was opened by Dragutin Pasarić, journalist, writer and president of the Matica hrvatska branch, and a review of the artistic sculptures was given by Mladen Mitar, professor of art history and curator of the Moslavina Museum. An exhibition of sculptures made of vines and olive trees has been set up in the settlement of Malino, which is located near Slavonski Brod. This type of ecological sculptures is unique in the world, and they were made by the Pavletić brothers, the founders of the Arteco association, reports Večernji.hr Also, the exhibition at the First Sea site not far from Dunat on Krk has been open for almost two years. “Part of the sculptures of the more monumental nature is mostly dedicated to animals and mythological motifs, while the one related to somewhat smaller creations of mostly religious or sacral nature, which, especially in carpentry, has always been an important and ubiquitous motif in our nation.”, Said the president of Artec Zoran Pavletić for Novi list. “The association was founded with the aim of connecting ecology and art, but also with the desire to connect all parts of our country, through the project of a mobile sculpture park.” You can find more about the Arteco Association and the Pavletić Theme Park HERE. The Pavletić brothers have announced that they have more plans for the Theme Park, but do not want to reveal them yet.
Local renters have the opportunity to show their excellence in Europe by applying for the competition for the best family tourism accommodation Best European Holiday Home (BEHH) organized by the European Holiday Home Association (EHHA). Applications are open until September 30, and prizes for the best in eight categories of family accommodation will be awarded on November 8 in Barcelona. The title of the best beach holiday home (Best beach holiday home) went to Villa Palma from Naplovac on the island of Korcula, for the best eco holiday home (Best Green holiday home) was chosen Villa Milica from Sajini near Pula, and the award for best house for a holiday with pets (Best pet holiday home) went into the hands of Green Frame from Klarić near Vodnjan. We remind you that last year’s competition was held in 14 categories, and among the 112 finalists there were as many as 15 Croatian houses, three of which were awarded prizes for the best holiday homes. In the last two years, Croatian holiday homes have received as many as seven of these prestigious awards Martina Nimac-Kalcina, president of the Family Tourism Association of the Croatian Chamber of Commerce, invites local renters to re-apply in as many numbers as possible. You can sign up HERE. “Thanks to last year’s success at the BEHH Awards, Croatia has built a country brand with the most beautiful villas and holiday homes. In the fierce competition, we have once again confirmed that we are not only a destination of crystal clear sea and beaches, but also top accommodation “, said Nimac-Kalcina, adding that for each registered facility this competition is a form of self-promotion and presentation to potential partners. “In case of winning the award, it is also a confirmation of the specialization of the facility according to certain categories of guests”, Says Nimac-Kalcina. This year’s awards for the best family tourism accommodation will be given in the categories of Best Accessible Holiday Home (holiday home that provides high quality facilities and opportunities for people with disabilities), Best Family Friendly Holiday Home (holiday home especially suitable for families with children), Best Green Holiday Home (eco holiday homes), Best Health and Wellness Holiday Home (health and wellness tourism houses), Best Holiday Home Beach House (beach houses), Best Holiday Home in European Capital (holiday homes in big cities ), Best Pet Holiday Home (pet holiday homes) and Best Unique Spot Holiday Home (best original holiday home). Each landlord can apply in a maximum of three categories