Variant Creutzfeldt-Jacob Disease Research Articles

Foot in Mouth: Animals, Disease, and the Cannibal Complex

Although the title of this paper invokes a disease of sheep as well as cattle, my primary concern is with the outbreak of another illness whose history in animal (and human) populations is more cryptic and more recent: so-called “mad cow” disease, or BSE (Bovine Spongiform Encephalopathy). Both the 2001 foot and mouth scourge in Britain and “mad cow” disease were (and are) widely represented in the media as disasters or catastrophes, in the case of foot and mouth for the sheep industry, and BSE for Britain’s beef producers. The detection of a single cow with BSE on a Washington (US) farm in 2004 had major financial repercussions for Canada’s farmers when the United States banned imports of Canadian cattle and meat products allegedly to protect its herds (and humans) from BSE and new variant Creutzfeldt- Jacob disease. The animals (especially sheep) caught up in the foot and mouth outbreak in Britain were slaughtered and then burnt in huge pyres, a holocaust similar to that following the mass killing of over a million cattle in Britain in 1987.

Problems with precaution: the transfusion medicine experience

The precautionary principle is a dominant paradigm governing risk-based decision-making. Today, there are increasing pressures to re-examine aggressive precautionary approaches, and to assess how the principle should be applied in the modern system. In this paper, we examined three key applications of precautionary approaches in the field of transfusion medicine to provide insight into the risks and benefits of these approaches. The three case studies examined were the donor deferral policies to safeguard against transfusion transmission of human immunodeficiency virus, variant Creutzfeldt–Jacob disease, and, lastly, xenotropic murine leukemia virus-related virus. Characterization of precautionary applications was conducted using an embedded case study design. Our findings indicate that transfusion transmission mitigation strategies have become increasingly aggressive in the face of theoretical risks. In contrast, the review processes for implementation and reversal of precautionary policies have been slow, and historical donor deferral policies are still in place today. Application of precautionary approaches has proved challenging with both benefits and pitfalls. In light of emerging threats to the blood system, policy-makers should consider the implementation of frameworks to guide the appropriate application of precaution in transfusion medicine in the future.

Control Points To Reduce Movement of Central Nervous System Tissue during Beef Slaughter

Consumption of central nervous system tissue (CNST) from cattle with bovine spongiform encephalopathy (BSE) is thought to cause the human neurological disease, variant Creutzfeldt-Jacob disease. To identify points of cross-contamination of beef carcasses with CNST, 55 young beef cattle were slaughtered and processed through a federally inspected multispecies abattoir. The objectives of this study were to evaluate CNST spread following the placement of a plug in the penetration site of the skull after captive bolt stunning, to evaluate cross-contamination of carcasses before and after splitting, to compare the effects of hot water pasteurization (84°C for 10 s) versus cold water wash (10°C for 30 s) for reducing CNST on the carcass, and to examine other possible sources of cross-contamination in the abattoir. Results indicated that the use of a plastic plug reduced CNST contamination near the bolt penetration site. This study also confirmed that carcass splitting resulted in an increase in CNST contamination at various areas of the carcass. Hot water pasteurization appeared to be an effective means of removing CNST contamination from carcasses in most of the areas sampled.

Immunological complications of blood transfusions

Most adverse blood transfusion (BT) events are immune-mediated and in the majority of severe reactions antibodies can be identified as causal factors. Alloimmunization not only causes symptomatic reactions, transfused cells can also be (silently) destroyed. Immunization by BT can contribute to hemolytic disease of the newborn as well as to allograft rejection after transplantation. Reversely, pregnancy and transplantation may evoke immunity hampering transfusion therapy. Besides causing mortality and morbidity, alloimmunization has a huge economic impact. Transfusion reactions prolong hospital stay, require diagnostic tests and complex donor selection procedures and create the need for typed donor registries. In the 1970s, Opeltz and colleagues described that pre-transplantation BT impaired rejection of renal transplants. Leukocytes were essential for this immunosuppressive BT effect that raised concern about negative effects on cancer growth and resistance against infections. Studies on the mechanism were however preliminary abandoned when calcineurin inhibitors for prevention of graft rejection became available and since all blood products underwent leukoreduction in most countries as precautionary measure against transmission of variant Creutzfeldt-Jacob disease. Whether current leukoreduced BT are immunosuppressive and for which patients or circumstances this may contribute to worse outcome, is unknown. The last decades of the previous century, leukoreduction of cellular blood products for leukemia patients significantly reduced the incidence of immunological platelet transfusion refractoriness. The first decade of this century the avoidance of plasma- and platelet-products from females, that may contain donor-derived leukocyte antibodies, decreased transfusion related acute lung injury (TRALI) by more than 30%. These were major achievements. Challenge for the near future is to further reduce alloimmunization in particular against red blood cells (RBC) as a cause of severe hemolytic transfusion reactions and problems to find compatible donors. This can be achieved by extended matching. Inventory limitations prevent to match all BT for clinically relevant RBC antigens. A (European-wide) registration of clinical and genetic risk factors associated with alloimmunization could support effective use of matched blood products.

Patients’ perception of infection prevention in dental practice

Patient's perceptions of risk from bloodborne viruses (BBVs) and variant Creutzfeldt-Jacob Disease (vCJD) in relation to attendance at dental practice is understudied. This survey of an opportunistic sample of 50 dental practice patients examined patients' perceptions of the risk of acquiring BBVs and vCJD following dental treatment. Major concerns of patients revolved around hand hygiene practices rather than risks from BBVs or vCJD. No patient had avoided or delayed a visit to the dentist because of concerns over risks of cross infection.

Use of modelling to inform public health policy: a case study on the blood-borne transmission of variant-CJD

Since the identification of variant Creutzfeldt–Jacob Disease in the late 1980s, the possibility that this disease might be passed on via blood transfusion has presented challenging policy questions for Government and blood services in the UK. This paper discusses the use of mathematical modelling to inform policy in this area of health protection. We focus on the use of a relatively simple analytical model to explore how many such infections might eventually be expected to result in clinical cases under a range of alternative scenarios of interest to policy, and on the potential impact of possible additional counter measures. We comment on the value of triangulating between findings generated using distinct modelling approaches and observational data.

New fears surrounding the spread of variant Creutzfeldt-Jacob disease

In humans, variant Creutzfeldt-Jacob disease (vCJD) is a fatal, non-curable brain disease. It has been estimated that 1 in 2000 of the population could unknowingly be silent carriers of the prion responsible for the disease. Chris Biela discusses the impact of vCJD on organ transplantation.

Asynchronous Onset of Clinical Disease in BSE-Infected Macaques

To estimate the effect of the variability of prion disease onset on primary bovine spongiform encephalopathy transmission to humans, we studied 6 cynomolgus macaques. The preclinical incubation period was significantly prolonged in 2 animals, implying that onset of variant Creutzfeldt-Jacob disease in humans could be more diverse than previously expected.

New Variant Creutzfeldt-Jacob Disease Presenting With Catatonia: A Rare Presentation

New Variant Creutzfeldt-Jacob Disease Presenting With Catatonia: A Rare Presentation

Infusion of P‐Capt prion‐filtered red blood cell products demonstrate acceptable in vivo viability and no evidence of neoantigen formation

Transmission of variant Creutzfeldt-Jacob disease (vCJD) is a major concern in blood transfusion. The P-Capt filter has been shown to remove around 4 log ID(50) prion infectivity from prion-spiked human red blood cells (RBCs). Two independent, single-center, randomized, open-label studies were designed to analyze the safety of P-Capt-filtered RBCs. RBCs prepared from leukoreduced whole blood from 43 eligible subjects were randomly assigned to P-Capt filtration and/or storage in plasma or SAGM and stored for 28 or 42 days. Stored RBCs were analyzed for in vivo 24-hour recovery, hemolysis, metabolic variables, blood group antigen expression, neoantigen formation, and safety after autologous infusion. Mean P-Capt filtration times for leukoreduced RBCs were 41 (SAGM) to 51 (plasma) minutes. Thirteen of 14 subjects receiving P-Capt-filtered RBCs had 24-hour RBC recoveries of 75% or more after 42-day storage, with a mean hemolysis of less than 0.6%. No loss of RBC antigen expression or formation of neoantigens was observed. In both studies, RBCs had white blood cell counts of less than 1 × 10(6)/unit after leukofiltration. P-Capt prion filtration provided an additional greater than 0.8 log leukoreduction. No serious or unexpected adverse events were observed after infusion of P-Capt-filtered full-volume RBC units. P-Capt-filtered, stored RBCs demonstrated acceptable viability and no detectable neoantigen expression, immunogenic responses. or safety issues after infusion of a complete unit. The additional filtration time and modest reduction in RBC content are within acceptable levels for implementation in countries with transfusion transmission of vCJD.

Early dysfunction of central 5-HT system in a murine model of bovine spongiform encephalopathy

The hypothesis of an early vulnerability of the serotonergic system to prion infection was investigated in a murine model of bovine spongiform encephalopathy (BSE). Behavioral tests targeted to 5-HT functions were performed in the course of infection to evaluate circadian activity, anxiety-like behavior, pain sensitivity and the 5-HT syndrome. The first behavioral change was a decrease in nocturnal activity detected at 30% of incubation time. Further behavioral alterations including nocturnal hyperactivity, reduced anxiety, hyperalgesia and exaggerated 5-HT syndrome were observed at 60%–70% of incubation time, before the onset of clinical signs. The same tests performed in 5-HT-depleted mice and in prion protein–deficient mice revealed behavioral abnormalities similar in many aspects to those of BSE-infected mice. Histological and biochemical analysis showed alterations of the serotonergic system in BSE-infected and prion protein–deficient mice. These results indicate that BSE infection affects the homeostasis of serotonergic neurons and suggest that the disruption of prion protein normal function contributes to the early pathological changes in our mouse model of BSE. A similar process may occur in the human variant Creutzfeldt-Jacob disease, as suggested by the early symptoms of alterations in mood, sleep and pain sensitivity.

Infection control during GI endoscopy

This is one of a series of statements discussing the use of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy (ASGE) prepared this text. In preparing this guideline, a search of the medical literature was performed by using PubMed, supplemented by accessing the "related articles" feature of PubMed. Additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Guidelines for appropriate use of endoscopy are based on a critical review of the available data and expert consensus at the time the guidelines are drafted. Further controlled clinical studies may be needed to clarify aspects of this guideline. This guideline may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. The recommendations were based on reviewed studies and were graded on the strength of the supporting evidence (Table 1). This guideline is intended to be an educational device to provide information that may assist endoscopists in providing care to patients. This guideline is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment. Clinical decisions in any particular case involve a complex analysis of the patient's condition and available courses of action. Therefore, clinical considerations may lead an endoscopist to take a course of action that varies from these guidelines.

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE strain-infected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.

Unusual brain disease death in the United Kingdom: possible implications for variant Creutzfeldt-Jacob disease

Unusual brain disease death in the United Kingdom: possible implications for variant Creutzfeldt-Jacob disease

The effect of ultrasonic cleaning on the elimination of postoperative residual protein from the proseal™ laryngeal mask airway

Background: Reusable ProsealTM laryngeal mask airways (PLMAs) can act as a vector for the transmission of prion diseases such as variant Creutzfeldt-Jacob disease. This study tested the hypothesis that supplementary ultrasonic cleaning facilitates the removal of protein deposits on PLMAs after anesthesia. Methods: After clinical use, 40 PLMAs were randomly allocated into two groups. In the first group, the PLMAs were washed by hand and were then subsequently placed in an autoclave at 134oC for 40 min (Group 1, n = 20). In the second group, the PLMAs were washed by hand and ultrasonic cleaning using an enzymatic solution for 5 min, and were then subsequently placed in an autoclave (Group 2, n = 20). In both groups, protein deposits were detected on PLMAs by erythrosin staining. A staining score designated as none (0%), mild (0−20%), moderate (20−80%) and severe (80−100%), was assigned to each site (outer surface, inner surface and edges of the cuff, airway and drain tube, finger strap) according to the percentage of the stained surface area. Results: Despite the cleaning of the masks, residual protein was found on the outer surface, inner surface and edge of the cuff, airway and drain tube, and finger strap of the PLMAs in both groups. Similar scores were observed for each part of the cleaned PLMAs in both groups, except for the outer surface of the PLMAs in Group 2 (P ＜ 0.05). Conclusions: We conclude that the use of an ultrasonic cleaner with an enzymatic solution may be effective to cleanse the outer surface of the PLMAs, but there were no differences in the total scores for both groups.

Variant Creutzfeldt–Jacob disease: the second case in Portugal and in the same geographical region

We present the second variant Creutzfeldt–Jacob patient in the same district of northwest Portugal as was previously reported. A 14-year-old previously healthy girl had unexplained pain in the left leg,...

Variant Creutzfeldt–Jacob disease – the availability of a screening test will be the beginning, not the end, of difficult transfusion-related issues

Georgetown University Hospital, Washington DC, USA Correspondence to S. Gerald Sandler, MD, Professor of Medicine and Pathology, Department of Laboratory Medicine, Room M1306, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington DC 20007, USA Tel: +1 202 444 8520; fax: +1 202 444 2440; e-mail: [email protected]

Hemophilia Therapy and Blood-Borne Pathogen Risk

For a brief period, modern medical science was considered to have relegated infectious disease to that of a minor clinical challenge. However, several infectious diseases have emerged or re-emerged in recent years, raising epidemiological concerns, as well as issues over the availability of effective measures of control and treatment. Invariably, these infectious agents have been studied carefully in relation to the safety of blood products, often resulting in concern and action. Emerging diseases arise from many sources. Some are the result of viruses crossing the species barrier from animals to humans. In addition, combinations of these newly identified viruses may make each more difficult to treat, as in the case of human immunodeficiency virus and hepatitis C virus coinfection. Still others can arise from completely new biological mechanisms, such as the prion disease variant Creutzfeldt-Jacob disease, which has spread from infected cattle to humans, particularly in the United Kingdom. The emergence of new viruses and new disease sources has had a significant impact on coagulation factor therapies and blood donation policies. We must deal with these multiple threats and their potential to compromise the safety of our blood supply.

Predicted consequences of site-directed mutagenesis and the impact of species variation on prion protein misfolding through the N-terminal domain

Variant Creutzfeldt-Jacob disease (vCJD) is considered to afflict humans through the acquisition of variant isomers and misfolding of the normal cellular prion polypeptide, PrP(C). Although the exact mechanism of the misfolding is not been yet clearly understood, this paper provides four additional pieces of evidence in support of the hypothesis that misfolding within PrP(C) involves N-terminal residues, up to and including Asn178. Structural predictions for N-terminal residues between Leu4 and Gly124 revealed that Leu4-Leu19 might adopt a helical conformation. Furthermore, measurement of C(alpha) distance variations, as determined from available NMR solution structures of wild type, as well as the biologically significant Val166, Asn170 and Lys220 variants of PrP(C), revealed previously unreported global and local conformational differences may occur in PrP(C) as a result of these amino-acid substitutions. Notably, three regions, His140-Tyr150 and Met166-Phe175 showed deviations greater than 3 A in their C(alpha)-coordinates (cf wild type) indicating that the majority of the N-terminal domain is likely to contribute to the misfolding of PrP(C). Minor variations in the orientation of amino acids Thr193-Glu200, located towards the C terminus of the protein, were also noted. This most likely indicates the presence of a hinge mechanism, inherent to a Helix-Loop-helix (HLH) motif formed by amino acids within alpha2, LIII and alpha3, in order to accommodate reorientation of the motif in response to misalignment of the N-terminal domain. An unexpected 3 angstroms deviation from the coordinates of the wild type polypeptide, absent from either Val166, Asn170 variants was observed over the region Arg154-Tyr155 within the Val166 form of PrP(C). This may contribute to the explanation as to why patients carrying the Val166 isoform of PrP(C) may be more susceptible to vCJD.

The expression of prion protein (PrP(C)) in the megakaryocyte lineage.

Cellular prion protein (PrP(C)) is a naturally occurring protein in normal individuals which adopts an abnormal conformation, termed scrapie prion protein (PrP(Sc)) that is associated with disease. There is great concern that clinically asymptomatic variant Creutzfeldt-Jacob disease (vCJD) may transmit PrP(Sc) in blood transfusion products. PrP(C) is widely expressed and has been found in human blood. The majority of cellular borne PrP(C) is associated with platelets (84%). Although PrP(C) mRNA has been demonstrated in platelets, the quantity is unknown and may not reflect the total PrP(C) present. To investigate the expression of PrP(C) in the megakaryocyte lineage. The expression of PrP(C) was studied in CD34+ cells, cultured megakaryocytes and platelets using electron microscopy, flow cytometry, semi-quantitative RT-PCR and immunofluorescence confocal microscopy. The expression of PrP(C) appeared to increase with differentiation and polyploidization in the megakaryocyte lineage. PrP(C) was located within platelet alpha-granules and its source is likely to be from megakaryocyte precursors. If PrP(Sc) has a similar distribution, these results have implications for the selection of blood donors and preparation of cell-depleted blood products.