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From: TSS ()
Published on: Friday, December 15, 2006 Wire Services WASHINGTON (AP) - A blood substitute the military wants to test on civilian trauma victims is urgently needed to save lives on the battlefield in places like Iraq, a Navy official told federal advisers Thursday. The Navy wants to test the product, derived from cow blood, on roughly 1,100 trauma victims in emergency situations. It proposes doing so without obtaining the customary informed consent of patients in advance. The substitute blood, called Hemopure, would be given on the way to the hospital to patients ages 18 to 69 who have lost dangerous amounts of blood. It would substitute for the saline fluids typically given in ambulances when donated blood is unavailable for transfusion. In Iraq, 68 percent of the U.S. troops who die of trauma before reaching a hospital suffer severe bleeding as part of their injuries, the Navy's deputy surgeon general, Rear Adm. John Mateczun, told a panel of federal health advisers. An available blood substitute could save many of those lives, he added. "We urgently need an oxygen-carrying capability that does not require refrigeration, is universally compatible and can be readily administered in a field setting," Mateczun said in remarks to a Food and Drug Administration panel convened to consider whether the agency should lift a hold on the experiment. The FDA isn't required to follow the recommendations of its advisory committees, but usually does. Three times since June 2005, the FDA has blocked Hemopure trials from starting. Each time, it has cited safety concerns. Hemopure's manufacturer, Biopure Corp., based in Cambridge, Mass., contends its benefits outweigh its risks, as does the Navy. The Naval Medical Research Center, which is overseeing the government-funded study, has since revised its design for the experiment. It now says the product won't be given to patients 70 or older, and it's limiting the amount of Hemopure that would be given to trauma victims. Many of them are expected to be young men under the influence of alcohol. The battlefield is too uncontrolled to do the research, an FDA spokeswoman said. The proposed changes have moved the FDA closer to giving its go-ahead to the experiment, which is required for the product to eventually win approval, according to agency review documents. Still, the proposed experiment came under sharp questioning Thursday by agency staff, who said it was hard to determine whether the trial's benefits outweighed its risks, the agency spokeswoman said. One critic said the proposed trial is unethical and the FDA's previous reasons for blocking the trial remain valid. "Human subjects would be exposed to an unreasonable and significant risk," said Dr. Sidney Wolfe of the watchdog group Public Citizen. Thursday's meeting originally was to have been held in secret in July but the FDA postponed it at the last minute after Public Citizen sued. Researchers say blood substitutes can both counter a dangerous drop in blood pressure in bleeding victims and carry oxygen from the lungs to the body. Saline fluids can do the former but not the latter. While blood can do both, it has its own limitations. Unlike blood, blood substitutes theoretically could be stored for years and then used without concern for infection or blood type. The development and testing of experimental blood substitutes has been fraught with controversy: Deerfield, Ill.-based Baxter International Inc. stopped research on one such product in 1998 when more than 20 patients given the substitute died. A second company, Evanston, Ill.-based Northfield Laboratories Inc., began clinical trials in 2004 of another product, called Polyheme, giving it to trauma patients without their consent on the way to - and later, at - the hospital. Hemopure would be given only en route to the hospital. On the Net: Biopure Corp.: http://www.biopure.com/ Food and Drug Administration: http://www.fda.gov/ http://www.saukvalley.com/articles/2006/12/15/news/state/15684057276998.txt Transfusion STUDY DESIGN AND METHODS: BSE was passaged through macaque monkeys and then adapted to the prosimian microcebe (Microcebus murinus). Brain homogenate and buffy coat from an affected microcebe were separately inoculated intracerebrally into three healthy microcebes (two animals received brain and one received buffy coat). RESULTS: All three inoculated microcebes became ill after incubation periods of 16 to 18 months. Clinical, histopathologic, and immunocytologic features were similar in each of the recipients. CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months earlier with BSE contained the infectious agent. This observation represents the first documented transmission of BSE from the blood of an experimentally infected primate, which in view of rodent buffy coat infectivity precedents and the known host range of BSE is neither unexpected nor cause for alarm. DECEMBER 2006 The Lancet 2006; 368:2061-2067 DOI:10.1016/S0140-6736(06)69835-8 Articles Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob Stephen J Wroe FRCP a b, Suvankar Pal MRCP a b, Durrenajaf Siddique MRCP a Summary Methods Findings Interpretation Affiliations a. National Prion Clinic, National Hospital for Neurology and Neurosurgery, Correspondence to: Prof John Collinge http://www.thelancet.com/journals/lancet/article/PIIS0140673606698358/abstract Neurobiology Edited by D. Carleton Gajdusek, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France, and approved December 7, 2000 (received for review October 16, 2000) http://www.pnas.org/cgi/content/full/98/7/4142 PERSPECTIVE On the Question of Sporadic or Atypical Bovine SpongiformEncephalopathy and Creutzfeldt-Jakob Disease Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§ Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk for orally acquired disease, or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence of sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12). The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12). To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17). On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters. Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative. For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5). Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared. SNIP... Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain 6:30 Close of Day One There is a growing number of human CJD cases, and they were presented last He estimates that it may be up to 14 or 15 persons which display selectively MARCH 26, 2003 RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc? Singeltary, Sr et al. JAMA.2001; 285: 733-734. http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf THE SEVEN SCIENTIST REPORT *** http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000490-vol40.pdf SEROLOGICALS CORPORATION http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000383-01-vol35.pdf Embassy of Japan Dockets Entered on December 22, 2005 03-025IFA 03-025IFA-6 Jason Frost [PDF] http://www.fsis.usda.gov/OPPDE/Comments/03-025IF/03-025IF-589.pdf Terry S. Singeltary SR.
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