Risk Of Creutzfeldt-Jakob Disease Research Articles

Absence of evidence of transfusion transmission risk of Creutzfeldt-Jakob disease in the United States: Results froma 28-year lookback study.

For many years, there has been concern about the risk of transmission of classic forms of Creutzfeldt-Jakob disease (CJD) by blood transfusion, particularly after the recognition of such transmission of variant CJD (vCJD). We report on a 28-year lookback study of recipients of blood from donors who subsequently developed CJD. Patients with diagnosed CJD and a history of blood donation were identified. Blood centers were asked to provide information about the distribution of the donations and consignees were requested to provide information about the recipients of the donations. Vital status of each available recipient was determined and, if deceased, the reported cause(s) of death were obtained primarily from the National Death Index. All recipients included in the study database contributed person-time up to the last recorded review of vital status. There were 84 eligible donors who gave 3284 transfusable components, and it was possible to evaluate 1245 recipients, totaling 6495 person-years of observation. The mean observation period per recipient was 5.5 years with a maximum of 51 years. No case of CJD or prion disease was reported among the recipient population. The study suggests that CJD may not be transfusion-transmissible, a position in agreement with similar findings from two similar European reports amounting to an overall observation period of 15,500 person-years. These studies have supported the conclusion that the risk, if any, of transmission of CJD by blood products is extremely small and remains theoretical.

Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6−/− and Stx6+/− mice differed by 12 days relative to wildtype. Similarly, in Stx6−/− mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6−/− animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6−/− mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Blood donor notification of variant Creutzfeldt-Jakob disease risk: Lessons in communicating donor deferral and risk.

In 2005, the blood service in England notified 101 donors by letter that they may be at risk of variant Creutzfeldt-Jakob disease (vCJD) because a recipient of their blood later developed vCJD. Donor experience of the notification was studied in a 2009 survey. Fifteen questions focused on satisfaction, emotional response and understanding of the notification letter. An average Likert score was calculated: 1 and 2= dissatisfied, 3= equivocal and 4 and 5= satisfied; the per cent satisfied and dissatisfied were calculated and characteristics compared using the Fisher and Chi-squared tests. The questionnaire was completed by 56 of 90 notified donors, mostly repeat, U.K.-born donors over 45 years of age. Four years after notification, many individuals still felt surprise (44%), upset (44%) or worry (50%) about the letter, with 10 feeling depressed. Thirty per cent were uncertain if they had vCJD or not. For future notifications, 57% would still favour a detailed letter and 36% would prefer a discussion in person. It was notable how many individuals, 4 years later, still felt continuing anxiety about the vCJD notification letter, not noted in earlier interviews. This highlights a need for on-going support required in donor notifications where outcome for the individual is highly uncertain.

Genetic Risk Factors of Creutzfeldt-Jakob Disease in the Population of Newborns in Slovakia.

The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of gCJD was confirmed in Orava region. The most common point mutation of the prion protein gene (PRNP) is E200K. CJD has a long asymptomatic phase and it is not known when the carriers of the mutation E200K become infectious. Precautions to prevent iCJD are focused especially on clinical CJD cases, but asymptomatic CJD-specific mutation carriers cannot be excluded, and represent a potential genetic CJD-risk group. The aim of this study was to determine the occurrence, frequency and geographic distribution of the E200K mutation among the newborns, comparing the areas of focal accumulation of gCJD with extra-focal ones, as well as distribution of the polymorphism M129V of the PRNP gene. A total of 2915 samples of dry blood spots from anonymous newborns were analyzed. We used RealTime PCR method to determine the presence of the E200K mutation and the M129V polymorphism. Genetic testing revealed 13 carriers of the E200K mutation. Investigation of the M129V polymorphism affirmed higher representation of methionine homozygotes (48% MM, 44% MV, 8% VV). Achieved results fully confirmed our previous observations concerning both the specific and nonspecific genetic CJD risk among the Slovak general population. The 48% of methionine homozygotes and 4 carriers of the E200K mutation among 1000 live-born children in Slovakia underline the benefits of genetic testing.

The First Meta-Analysis of the M129V Single Nucleotide Polymorphism (SNP) of the Prion Protein Gene ( <i>PRNP</i> ) with sporadic Creutzfeldt-Jako disease <i>PRNP</i>) with Sporadic Creutzfeldt-Jakob Disease

Background: Prion diseases are fatal, chronic and incurable neurodegenerative diseases caused by pathogenic forms of prion protein (PrPSc) derived from the endogenous forms of prion protein (PrPC). Several case-control and genome-wide association studies have reported that the M129V polymorphism of the human prion protein gene (PRNP) is significantly associated with susceptibility to sporadic Creutzfeldt-Jakob disease (CJD). However, since some case-control studies have not shown these associations, the results remain controversial. Methods: We collected data that contain the genotype and allele frequencies of the M129V single nucleotide polymorphism (SNP) of the PRNP gene and information on ethnic backgrounds from sporadic CJD patients. We performed a meta-analysis by collecting data from eligible studies to evaluate the association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. Interpretation: We found a very strong association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD using meta-analysis for the first time. We validated the eligibility of existing reports and found severe heterogeneity in some previous studies. We also found the strongest association with the risk of sporadic CJD in the heterozygote comparison model (MM vs. MV, odds ratio = 5.1354, 95% confidence interval: 3.6622; 7.2012, P=0). To the best of our knowledge, this was the first meta-analysis assessment of the relationship between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. Funding: This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2017R1A6A1A03015876). This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government (MSIT) (2021R1A2C1013213). Declaration of Interests: The authors declared no conflicts of interest.

Brain biopsies requiring Creutzfeldt-Jakob disease precautions in the Republic of Ireland 2005-2016.

Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in 'risk' groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n=21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. Of this 21-patient cohort, five were positive for CJD, four belonged to the 'at risk of CJD' category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n=4) in the 'at risk of CJD' group were diagnosed with tumour (n=2), inflammation (n=1) and non-specific changes (n=1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n=2), neurodegenerative (n=2), inflammatory (n=1), metabolic (n=2), vascular (n=2) and non-specific gliosis (n=3). More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel.

Cerebrospinal Fluid Levels of 14-3-3 Gamma: What Does It Tell Us About Sporadic Creutzfeldt-Jakob Disease?

Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by the analysis of Tau and 14-3-3 in the cerebrospinal fluid (CSF). In this short report, we report about a retrospective analysis performed on 2,296 routinely collected CSF samples, and 44 samples with a ratio of phosphoTau181/Tau <0.075 were selected. Analysis was performed with a novel 14-3-3 gamma CircuLex Elisa. We show that control levels were around 6,000 AU/mL and samples from Alzheimer patients were not different from those collected from healthy controls. Four cases of verified CJD had 14-3-3 CSF levels of >100,000 AU/mL, while 10 out of 12 suspected CJD samples with 14-3-3 CSF levels between 50,000-100,000 AU/mL were CJD positive. All samples with 14-3-3 levels between 15,000 and 50,000 AU/mL were not CJD cases but disorders with complex neuropathology. In conclusion, our data suggests that in CSF samples with a phospho-Tau-181/Tau ratio <0.075 CSF levels of 14-3-3 should be analyzed. Our data suggests a very high risk for CJD with 14-3-3 levels above 100,000 AU/mL and a probable diagnosis of CJD based on laboratory parameters above 50,000 AU/mL.

Donor Recruitment for Fecal Microbiota Transplantation

Increasing demand for fecal microbiota transplantation (FMT) has created a need for stool banks sourced from long-term healthy donors. Here, we describe our experience in recruiting and screening fecal donors. Mailbox, newspaper, and online advertisements were used. Potential donors were required to satisfy a prescreen telephone conversation, pass blood and stool investigations, then undertake a screening interview including medical history, physical examination, and evaluation of donor selection criteria. One hundred sixteen potential donors were prescreened of whom 74 failed-47 declined based on study donation requirements (primarily related to frequency and duration of donations), 13 had medical comorbidities, 6 variant Creutzfeldt-Jakob disease risk factors, 8 for other reasons. Thirty-eight completed stool and blood testing-1 failed blood testing (indeterminate hepatitis C serology), whereas 15 failed stool investigations (5 Dientamoeba fragilis, 5 Blastocystis hominis, 1 B. hominis and D. fragilis, 1 Giardia intestinalis plus D. fragilis, 1 Norovirus plus Clostridium difficile toxin positive, and 2 leucocytes or erythrocytes on stool microscopy). Of the 18 potential donors proceeding to screening interview, 6 were excluded (3 body mass index >30, 1 illicit drug use, 1 uncontrolled anxiety and concerns regarding compliance, 1 irregular bowel movements after new medication commencement). In total, only 12 of 116 (10%) potential donors were enrolled as study donors. Recruitment of fecal donors for FMT is challenging with only a small percentage ultimately serving as donors. Many were unable or unwilling to meet the donor commitment requirements. A surprisingly large proportion of healthy asymptomatic donors failed stool testing, primarily due to gastrointestinal parasites.

A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.

The role of the donor liaison officer at PlusLife (Perth Bone and Tissue Bank Inc.), Western Australia.

Femoral head donation at the time of hip replacement surgery provides a much needed resource of bone allograft to orthopaedic surgeons. Prior to 2005, potential femoral head donors were identified and consented in the hospital setting on the day of surgery. This resulted in over 40 % of donations failing post operatively suggesting that more effort could be given to pre-operative screening resulting in substantial savings in the cost associated with collection and testing of donors who were subsequently failed. The Donor Liaison role was implemented in 2005 to coordinate a Femoral Head Donation program maximising the number of successful donations through pre-operative screening. This study reviews the effectiveness of pre-operative screening of potential femoral head donors at PlusLife from 2002-2012. A retrospective audit of the database was undertaken 2002-2012 and medical/social reasons for pre-operative and postoperative failures were collated into 4 main categories to enable comparison: malignancy, autoimmune conditions, variant Creutzfeldt Jakob disease risk and general medical/social reasons. The number of femoral heads failed post operatively has decreased significantly from 26 % in 2003 to 6 % in 2012. A cost of $121,000 was expended on femoral heads failed post operatively in 2004, as compared to $20,350 in 2012. Donors excluded due to the 4 main categories (medical/social history) were identified pre-operatively in over 80 % of all cases. Preoperative screening of femoral head donors through a coordinated Femoral Head Donation Program is a safe and cost effective method.

A pilot study of a genetic CJD risk factor (E200K) in the general Slovak population.

Creutzfeldt-Jakob disease (CJD) is a fatal, incurable human transmissible spongiform encephalopathy, or prion disease. Classical CJD has been recognised since the 1920s. CJD occurs in three forms : sporadic, of unknown origin, genetic, related to disease specific point mutations, insertions or deletions of the prion protein gene (PRNP) and iatrogenic (iCJD), caused by accidental transmission of the disease in the course of medical or surgical treatment. A new variant of CJD, which is causally related to bovine spongiform encephalopathy (BSE) was first described by Will et al. in 1996. The risk of horizontal transmission of CJD has been confirmed in classical [1] as well as in variant CJD. Precautions and measures to prevent iCJD are focused mainly on clinical CJD patients, but a potential risk from preclinical cases, for example asymptomatic carriers of CJDspecific mutations of the PRNP, cannot be excluded. These carriers represent a ‘‘genetic CJD-risk group’’ in the general population. More than 37 disease-specific mutations have been described in the PRNP coding sequence. The most common point mutation associated with genetic CJD is at codon 200 (E200K) [2]. While in the majority of countries the genetic form represents about 10–15 % of all CJD patients, in Slovakia it has never been \65 % since 1975. [3]. Except for one case with the R208H mutation, all 202 genetic CJD patients in Slovakia carry the E200K mutation (gCJD). Most of these cases are concentrated in two clusters in central Slovakia [4]. Voluntary genetic testing of healthy blood relatives has revealed that 35 % carry the E200K mutation [3]. Besides the risk of gCJD (59 % of carriers will develop the disease) (3), ‘‘healthy’’ carriers could act as a source of iatrogenic infection. To our knowledge, the prevalence of the mutation E200K has not been studied. The aim of this pilot study is to investigate the occurrence and frequency of asymptomatic carries of E200K in the Slovak general population, comparing the areas of focal accumulation of gCJD with extrafocal areas, i.e. comparison of regions with contrasting incidence rates of gCJD. In the present study the occurrence of the mutation E200K and the distribution of the M129 V polymorphism of PRNP were analysed in 2,662 subjects with no known link to patients with gCJD. Tested were DNA from two different sources: 1. anonymised DNA samples of newborns provided by Slovak Newborn Screening Center were from regions with different incidence of gCJD: 1a) 893 samples from two focal accumulations (clusters) of gCJD in central Slovakia (mean incidence of gCJD 3.55/million) and 1b) 757 samples from extrafocal regions in western and E. Mitrova D. Kosorinova M. Gajdos I. Tomeckova Medical Faculty, Slovak Medical University, Bratislava, Slovakia

Managing the risk of iatrogenic transmission of Creutzfeldt–Jakob disease in the UK

With the emergence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in the UK, there is concern about iatrogenic transmission, and the approach to managing this risk is unique. To describe and review CJD incident management and the notification of individuals 'at increased risk' as a strategy for reducing iatrogenic transmission. A description of iatrogenic CJD transmission, the CJD Incidents Panel's role, the number and nature of CJD incidents reported and the individuals considered 'at increased risk' by mid-2012. Seventy-seven UK cases of CJD are likely to have resulted from iatrogenic transmission, among recipients of human-derived growth hormone (64 cases), dura mater grafts (eight cases), blood transfusions (four cases) and plasma products (one case). To limit transmission, the Panel reviewed 490 incidents and advised on look-backs, recalls of blood and plasma products, and quarantining and disposing of surgical instruments. Additionally, on Panel advice, around 6000 asymptomatic individuals have been informed they are at increased risk of CJD and have been asked to follow public health precautions. The strategy to reduce iatrogenic transmission of CJD has been developed in a context of scientific uncertainty. The rarity of transmission events could indicate that incident-related exposures present negligible transmission risks, or--given the prolonged incubation and subclinical phenotypes of CJD--infections could be yet to occur or have been undetected. Scientific developments, including better estimates of infection prevalence, a screening test, or improvements in decontaminating surgical instruments, may change future risk management.

Establishment of a bank of blood donor derived epstein barr virus specific cytotoxic T cell lines for treatment of post-transplant lymphoproliferative disease

Epstein-Barr virus (EBV) driven lymphomas associated with immunosuppression are a significant problem, particularly after transplantation. Conventional treatment (withdrawal of immunosuppression, administration of rituximab/chemotherapy) is often effective but risks organ rejection and causes significant side effects. EBV specific cytotoxic T cells (CTL) generated in vitro from autologous lymphocytes can be effective with few side effects, but take months to prepare so are difficult to use in clinical practice. We have established a bank of EBV CTLs derived from platelet / plasma donors for issuing ‘off the shelf product’ to partially human leucocyte antigen (HLA) matched patients on a named patient basis. Donors from the New Zealand platelet / plasma panel were sourced to reduce the risk of Creutzfeldt-Jakob disease (CJD). The current panel of donors selected was EBV positive, Blood Group O, and met all current requirements for mandatory virology markers. The panel was also chosen to maximize the probability of HLA class I and II matches and minimize the number of mismatches. We estimated that this initial panel of 25 donors should provide a partial match for at least three (HLA-A, -B, -DRB1) loci for ∼80% of Caucasian patients. So far, lymphoblastoid cell lines have been made from 25 donors ready for use in stimulating CTLs and 18 CTLs have been manufactured and cryopreserved for clinical use. Since the bank was granted a ‘Specials’ license by the MHRA for this Advanced Therapy Medicinal Product in January 2012, there have been enquiries about 14 patients: 4 improved on conventional therapy without requiring CTLs, 3 died before any cells could be issued and 6 cell lines have been released. The indications for issue have been: 3 cases of post-transplant lymphoproliferative disorder (1 CD20- rituximab resistant 1 with concomitant graft versus host disease precluding reduction of immunosuppression 1 unfit for chemotherapy) 2 cases with congenital immunosuppression as a bridge to allogeneic haematopoietic stem cell transplant and 1 case of EBV-associated leiomyosarcoma post-cardiac transplant (related donor). Clinical improvement has been seen in 4 out of 6 assessable patients. A 3rd party donor-derived anti-EBV CTL cell bank can be operated under current legislation and is a valuable addition to existing therapies for selected patients.

Iatrogenic Creutzfeldt-Jakob disease via surgical instruments

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative prion disease that can spread via contaminated neurosurgical instruments previously used on an infected patient. We examine current guidelines on how to recognize, handle, and prevent instrument-related iatrogenic CJD. Despite only four reported patients worldwide implicating contaminated neurosurgical instruments, and none in the past 30years, the public health consequences of potential instrument-related iatrogenic CJD can be far-reaching. Conventional sterilization and disinfection methods are inadequate in reducing prion infectivity of contaminated instruments, and World Health Organization recommendations for disinfection using bleach or sodium hydroxide are often impractical for routine decontamination. Recently, possible CJD exposure via infected surgical instruments was suspected at a large teaching hospital. Although CJD was later disproven, the intervening investigation exposed the difficulty in tracking infected surgical instruments and in protecting subsequent surgical patients from prion infection. To identify patients at risk for iatrogenic CJD, infectivity of instruments after this index patient is estimated using simple scenario modeling, assuming a certain log reduction of infectivity for each cleansing cycle. Scenario modeling predicts that after six cycles of instrument use with conventional cleansing following an index patient, other patients are highly unlikely to be at risk for iatrogenic CJD. Despite its rarity, the threat of iatrogenic CJD transmission via contaminated instruments poses tremendous challenges to neurosurgeons. Basic prevention strategies should be employed for patients with suspected CJD, including use of disposable instruments where possible and quarantining non-disposable instruments until the diagnosis is ascertained, or using special instrument reprocessing methods if CJD is suspected.

Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP) codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD). To describe the association between codon 129 polymorphisms and AD. We investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE) were evaluated. Codon 129 genotype distribution in AD 45.5% methionine (MM), 42.2% methionine valine (MV), 12.1% valine (VV); and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05). There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups. Codon 129 polymorphism is not a risk factor for AD in Brazilian patients.

Geographic Accumulation of Creutzfeldt-Jakob Disease in Slovakia - Environmental Metal Imbalance as a Possible Cofactor

Slovakia is characterised by an unusually high number of patients affected by genetic Creutzfeldt-Jakob disease (CJD) with E200K mutation at the PRNP gene. Penetrance of the mutation is incomplete (59%). Therefore, for the onset of the clinical manifestation, an influence of other endo- or exogenous factors could not be excluded. Experimental data suggest that copper and manganese levels may play an important role in the pathogenesis of prion diseases. The highest number of Slovak genetic CJD patients originates from Orava - the northern region of central Slovakia. Manganese is a dominant pollutant in Orava. The objective of this study was to clarify a possible exogenous influence of environmental Mn/Cu imbalance on the CJD clustering. Mn and Cu levels were analysed in the brain tissue of genetic CJD cases (from Orava and from control regions of Slovakia), as well as of sporadic CJD patients and controls. Analyses demonstrate i) significantly higher Mn level in focally accumulated, "clustering" genetic CJD cases in comparison to all other groups, ii) Cu status differences between compared groups were without statistical significance; decreased concentrations were found in genetic cases from extrafocal genetic CJD areas, iii) Mn/Cu ratios were increased in all CJD groups in comparison to controls. Metal ratios in clustering gCJD cases were significantly higher in comparison to sporadic cases and also to controls, but not to the extrafocal genetic CJD subgroup. These results indicate that more important than increasing Mn level in pathogenesis of CJD appears to be the role of the Mn/Cu imbalance in the CNS. The imbalance observed in the cluster of genetic CJD cases is probably a result of both: the excessive environmental Mn level and the disturbance of Mn/Cu ratios in the Orava region. Presented findings indicate an environmental Mn/Cu imbalance as a possible exogenous CJD risk co-factor which may, in coincidence with endogenous (genetic) CJD risk, contribute to the focal accumulation (cluster) of genetic CJD in Slovakia.

Lower Risk of Creutzfeldt-Jakob Disease in Pituitary Growth Hormone Recipients Initiating Treatment after 1977

Creutzfeldt-Jakob disease (CJD) caused by contaminated cadaveric pituitary-derived human GH (hGH) has been responsible for hundreds of deaths worldwide. Studies of U.S. National Hormone and Pituitary Program (NHPP) hGH recipients have found CJD only in patients treated before 1977, when a new purification procedure with column chromatography was implemented for hGH extraction. Our objective was to provide updated information on transmission of CJD to NHPP hGH recipients and determine whether recipients of hGH produced after 1977 had a significantly lower CJD risk than pre-1977 recipients. A total of 5570 NHPP hGH recipients were included in the study: 2099 in the pre-1977 cohort and 3471 in the post-1977 cohort. We used probability distribution functions to determine whether the observed number of CJD cases in the post-1977 cohort was significantly fewer than expected if the CJD risk was equal to that of the pre-1977 cohort, controlling for treatment duration and follow-up time. All 22 CJD cases (diagnosed from 1984-2009) occurred in the pre-1977 hGH recipients. Almost half (47.9%) of pre-1977 recipients had a treatment duration of at least 5 yr compared with only 13.8% for post-1977 recipients. Based on the rates present in the pre-1977 cohort, the probability of observing no cases in the post-1977 cohort by chance alone was low (P = 0.0019). Risk of acquiring CJD was significantly lower for post-1977 NHPP hGH recipients than for pre-1977 recipients, suggesting that the new purification procedure in 1977 may have greatly reduced or eliminated CJD agent in hGH.

Impact of Being Placed at Risk of Creutzfeldt-Jakob Disease: A Qualitative Study of Blood Donors to Variant CJD Cases and Patients Potentially Surgically Exposed to CJD

Background: The study objective was to describe the emotional and behavioural responses to Creutzfeldt-Jakob disease (CJD) risk notification. Methods: A qualitative study using 11 participants’ interviews, which were analysed thematically with Framework Analysis. Participants: Six participants purposively selected from people exposed to surgical instruments used previously on patients with or at risk of CJD (any type; n = 60), and 5 participants from a cohort of blood donors to patients who subsequently developed variant CJD (n = 110). Results: Notification was initially a shocking event, but with no lasting emotional impact. Those notified were convinced they were at extremely low risk of CJD and coped by not thinking about the information. Disclosure outside the immediate family was limited by fears of stigma. All expressed concern about the possibility of onward transmission and agreed notification was appropriate. Individual adherence to public health precautions varied from those who did nothing, apart from not donating blood, to those who consistently followed all advice given. This variation was informed by an assumption that information was always shared among health professionals. Conclusions: Factors contributing to minimising emotional distress following notification of CJD risk were evident. We found little evidence of sustained emotional distress. However, implementation of behaviours to minimise onward transmission, particularly in health care settings, was variable – this requires further investigation.

A polymorphism in the regulatory region of PRNPis associated with increased risk of sporadic Creutzfeldt-Jakob disease

BackgroundCreutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene.MethodsWe tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.ResultsWe found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).ConclusionsOur findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD.

Notification and support for people exposed to the risk of Creutzfeldt-Jakob disease (CJD) (or other prion diseases) through medical treatment (iatrogenically)

Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD) are rare and always-fatal diseases transmissible via certain medical procedures. If a person is exposed to the disease risk through medical treatment, they may need to be notified of this to prevent them passing the risk to others in healthcare settings and to enable additional infection control measures to be put in place for certain procedures. As CJD is incurable, and unable to be screened for or effectively treated, communicating this risk information after an exposure incident may have significant implications for the person at risk, their families/ carers and healthcare professionals. The best ways to notify people of their exposure to the risk of CJD or vCJD, and to support them subsequently, are currently unknown. To evaluate the effects of interventions to notify and support consumers (patients and their family members or carers) in situations where exposure to the risk of CJD or vCJD has occurred as a result of medical treatment (iatrogenically), on consumer, healthcare provider and healthcare system outcomes. We searched the Cochrane Consumers and Communication Review Group Specialised Register (10 February, 2009), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2009), MEDLINE (OVID SP), EMBASE (OVID SP), PsycINFO (OVID SP), CINAHL (EBSCO Host), Current Contents (OVID SP) and Dissertation Abstracts (Proquest) from start date to February 2009. We searched MEDLINE In-process and Other Non-indexed Citations (OVID SP) and Sociological Abstracts (CSA) in November 2009. We searched reference lists, websites, and contacted consumer groups and experts for details of relevant research. Randomised and quasi-randomised controlled studies, controlled before-and-after studies and interrupted time series analyses assessing the effects of any intervention to communicate with (notify or support) people exposed to the risk of CJD or vCJD through medical treatment were included. We sought outcomes relevant to consumers, health providers and health services, including both benefits and harms. Cochrane reviewTwo authors independently assessed studies for inclusion against selection criteria, and would have applied standard Cochrane review methodology were any studies identified.Thematic synthesisWe also conducted a thematic synthesis by systematically identifying and screening those studies that met the same population, intervention and outcome criteria as the Cochrane review, but that were identified from the broader literature providing evidence on policy implementation and consumer experiences. We systematically extracted and synthesised the data from these studies to produce a thematic synthesis, presented in appendices to this Cochrane review, which assembles evidence on the views, experiences and acceptability of notification and support strategies for people at risk. Results of the Cochrane reviewNo studies meeting the study design criteria were identified for inclusion in this Cochrane review.Results of thematic synthesisIn total, 49 studies and pieces of literature meeting the same population, intervention and outcome criteria as the Cochrane review, but identified from the broader literature providing evidence on policy implementation and consumer experiences, were included and formed the basis of a thematic synthesis, and which is presented in appendices to this Cochrane review. The thematic synthesis indicates that ideally communication may be considered as a longitudinal multicomponent programme, ensuring that notification and support are coordinated; that communication is tailored and responsive to need; and that activities to support individual risk communication, such as widespread education and monitoring of access to health care for those at risk, are in place. The thematic synthesis also indicates that poor communication practices may have negative impacts or cause harm, such as discrimination in accessing health care. There is insufficient rigorous evidence to determine the effects of interventions to notify people at CJD or vCJD risk and to support them subsequently, or to identify the best approach to communication in these situations. The thematic synthesis can be used to inform policy and practice decisions for communicating with people at risk in the absence of rigorous evaluative studies.