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Background: Human prion diseases, known collectively as Creutzfeldt-Jakob disease (CJD), are fatal, infectious neurodegenerative disorders that occur in all human populations.Objective: To summarize national surveillance data for CJD in Canada between January 1, 1998, and December 31, 2013.Methods: Detailed investigations were conducted of individual suspected CJD cases, with collaboration between Canadian health professionals and investigators affiliated with a central CJD surveillance registry operated by the Public Health Agency of Canada. Data were collected on the clinical profile, family history, and results of paraclinical and laboratory investigations, including post-mortem neuropathological examination.Results: A total of 662 deaths from definite and probable CJD were identified in Canadian residents during the study period, comprising 613 cases of sporadic CJD (92.6%), 43 cases of genetic prion disease (6.5%), 4 cases of iatrogenic CJD (0.6%), and 2 cases of variant CJD disease (0.3%). The overall crude mortality rate for sporadic CJD was 1.18 per million per year [95% confidence interval (CI): 1.08,1.27]. Age-specific rates ranged from 0.05 [95% CI: 0.03,0.08] in persons under 50 years of age to 7.11 [95% CI: 6.20,8.11] in those aged 70 to 79. A significant net upward trend in age-adjusted rates was observed over the study period. Standardized mortality ratios, calculated for 10 individual Canadian provinces with reference to national average mortality rates, did not differ significantly from 1.0.Conclusion: Creutzfeldt-Jakob disease remains rare in Canada, although mortality rates vary by two orders of magnitude between older and younger age groups. The upward trend in age-standardized sporadic CJD mortality rate over the study period can be better accounted for by gradually improving case ascertainment than by a real increase in incidence. [ABSTRACT FROM AUTHOR]

The incidence of West Nile virus (WNv) has waxed and waned in Canada over the past 12 years, but it is unlikely to disappear. Climate change models, which suggest warming temperatures and changing patterns of precipitation, predict an expansion of geographic range for WNv in some regions of Canada, such as the Prairie provinces. Such projected changes in WNv distribution might also be accompanied by genetic changes in the virus and/or the range of bird and insect host species it infects. To address this risk, emphasis should be placed on preventing exposure to infected mosquitoes, conducting high-quality surveillance of WNv and WNv disease, controlling mosquito vectors, and promoting public and professional education. [ABSTRACT FROM AUTHOR]

The prion diseases pose unique scientific, medical, veterinary and regulatory challenges. Here, we summarize current information bearing on the natural history, pathobiology and epidemiology of these disorders and public policy responses to the potential threats to public health posed, particularly, by bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease (vCJD). Six years after the first case reports of vCJD, there is still no clear indication of the magnitude of the primary epidemic, or of the likelihood of lateral transmission of this untreatable disease by iatrogenic means, particularly by blood and blood products. However, the unsettling nature of the available evidence warrants prudence regarding public health policy and regulation, as well as a forward-looking approach to research. [ABSTRACT FROM AUTHOR]

Abstract Background To better characterize the value of cerebrospinal fluid (CSF) proteins as diagnostic markers in a clinical population of subacute encephalopathy patients with relatively low prevalence of sporadic Creutzfeldt-Jakob disease (sCJD), we studied the diagnostic accuracies of several such markers (14-3-3, tau and S100B) in 1000 prospectively and sequentially recruited Canadian patients with clinically suspected sCJD. Methods The study included 127 patients with autopsy-confirmed sCJD (prevalence = 12.7%) and 873 with probable non-CJD diagnoses. Standard statistical measures of diagnostic accuracy were employed, including sensitivity (Se), specificity (Sp), predictive values (PVs), likelihood ratios (LRs), and Receiver Operating Characteristic (ROC) analysis. Results At optimal cutoff thresholds (empirically selected for 14-3-3, assayed by immunoblot; 976 pg/mL for tau and 2.5 ng/mL for S100B, both assayed by ELISA), Se and Sp respectively were 0.88 (95% CI, 0.81-0.93) and 0.72 (0.69-0.75) for 14-3-3; 0.91 (0.84-0.95) and 0.88 (0.85-0.90) for tau; and 0.87 (0.80-0.92) and 0.87 (0.84-0.89) for S100B. The observed differences in Sp between 14-3-3 and either of the other 2 markers were statistically significant. Positive LRs were 3.1 (2.8-3.6) for 14-3-3; 7.4 (6.9-7.8) for tau; and 6.6 (6.1-7.1) for S100B. Negative LRs were 0.16 (0.10-0.26) for 14-3-3; 0.10 (0.06-0.20) for tau; and 0.15 (0.09-0.20) for S100B. Estimates of areas under ROC curves were 0.947 (0.931-0.961) for tau and 0.908 (0.888-0.926) for S100B. Use of interval LRs (iLRs) significantly enhanced accuracy for patient subsets [e.g., 41/120 (34.2%) of tested sCJD patients displayed tau levels > 10,000 pg/mL, with an iLR of 56.4 (22.8-140.0)], as did combining tau and S100B [e.g., for tau > 976 pg/mL and S100B > 2.5 ng/mL, positive LR = 18.0 (12.9-25.0) and negative LR = 0.02 (0.01-0.09)]. Conclusions CSF 14-3-3, tau and S100B proteins are useful diagnostic markers of sCJD even in a low-prevalence clinical population. CSF tau showed better overall diagnostic accuracy than 14-3-3 or S100B. Reporting of quantitative assay results and combining tau with S100B could enhance case definitions used in diagnosis and surveillance of sCJD.

Abstract Background The objective of this study was to describe the diagnostic panorama of human transmissible spongiform encephalopathies across 11 countries. Methods From data collected for surveillance purposes, we describe annual proportions of deaths due to different human transmissible spongiform encephalopathies in eleven EUROCJD-consortium countries over the period 1993–2002, as well as variations in the use of diagnostic tests. Using logistic models we quantified international differences and changes across time. Results In general, pre-mortem use of diagnostic investigations increased with time. International differences in pathological confirmation of sporadic Creutzfeldt-Jakob disease, stable over time, were evident. Compared to their counterparts, some countries displayed remarkable patterns, such as: 1) the high proportion, increasing with time, of variant Creutzfeldt-Jakob disease in the United Kingdom, (OR 607.99 95%CI 84.72–4363.40), and France (OR 18.35, 95%CI 2.20–152.83); 2) high, decreasing proportions of iatrogenic Creutzfeldt-Jakob disease in France, (OR 5.81 95%CI 4.09–8.24), and the United Kingdom, (OR 1.54 95%CI 1.03–2.30); and, 3) high and stable ratios of genetic forms in Slovakia (OR 21.82 95%CI 12.42–38.33) and Italy (OR 2.12 95%CI 1.69–2.68). Conclusion Considerable international variation in aetiological subtypes of human transmissible spongiform encephalopathies was evident over the observation period. With the exception of variant Creutzfeldt-Jakob disease and iatrogenic Creutzfeldt-Jakob disease in France and the United Kingdom, these differences persisted across time.

Real-time quaking-induced conversion (RT-QuIC), a highly specific and sensitive assay able to detect low levels of the disease-inducing isoform of the prion protein (PrP(d)) in brain tissue biopsies and cerebral spinal fluid, has great potential to become a method for diagnosing prion disease ante mortem. In order to standardize the assay method for routine analysis, an understanding of how physical and chemical factors affect the stability of the recombinant prion protein (rPrP) substrate and the RT-QuIC assay's sensitivity, specificity, and reproducibility is required. In this study, using sporadic Creutzfeldt-Jakob Disease brain homogenate to seed the reactions and an in vitro-expressed recombinant prion protein, hamster rPrP, as the substrate, the following factors affecting the RT-QuIC assay were examined: salt and substrate concentrations, substrate storage, and pH. Results demonstrated that both the generation of the quality and quantities of rPrP substrate critical to the reaction, as well as the RT-QuIC reaction itself required strict adherence to specific physical and chemical conditions. Once optimized, the RT-QuIC assay was confirmed to be a very specific and sensitive assay method for sCJD detection. Findings in this study indicate that further optimization and standardization of RT-QuIC assay is required before it can be adopted as a routine diagnostic test.

A total of 10-15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12-88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt-Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term "gTSE" is preferable to "familial TSE". Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.

Genes that are expressed differentially in the central nervous system of mice during infection with mouse-adapted scrapie agents were identified in this study. cDNA microarrays were used to examine gene-expression profiles at early, middle (preclinical) and late (clinical) time points after inoculation. A number of genes that showed significant changes in expression during the clinical stage of disease were identified. Of these, 138 were upregulated and 20 were downregulated. A smaller number of genes showed differential expression at the early and middle stages of the disease time course. These genes are interesting, as they may reflect biological processes that are involved in the molecular pathogenesis of the prion agent. At present, little is known about the early events in the disease process that trigger neurodegeneration. Perhaps most interestingly, one group of genes that exhibited decreased expression in all tested stages of the disease was identified in this study. This cluster included four transcripts representing haematopoietic system-related genes, which suggests that the haematopoietic system is involved in the disease process from an early stage.

Invasive meningococcal disease is nationally reportable in Canada. In recent years, a serogroup C genotype, designated electrophoretic type 15 (ET15), has been the most frequently isolated meningococcal genotype in Canada and has caused epidemics across the country. Between August 1993 and September 1995, there were 9 cases of invasive meningococcal disease caused by a variant of this genotype, expressing group B capsular polysaccharide. The appearance of serogroup B:ET15 was related temporally and geographically to mass immunization campaigns designed to control serogroup C meningococcal disease in Canada. Since there is no vaccine available to control serogroup B meningococcal disease, the appearance of this variant may have public-health significance if it demonstrates the same epidemic potential as its serogroup C counterpart.

We surveyed genetic polymorphism by two-dimensional gel electrophoresis of male reproductive tract proteins in 20 isofemale lines each of Drosophila melanogaster and Drosophila simulans. After classifying 244 such proteins of Drosophila melanogaster and 271 of Drosophila simulans by their distribution between testes and accessory glands within the reproductive tract, significant correlations were found between genetic polymorphism and tissue distribution. In both species, gland-specific proteins were significantly more polymorphic than testis-specific proteins, as well as those found in both testes and glands. Simultaneously, in Drosophila simulans, proteins found in roughly equivalent relative abundance in both testes and glands were significantly less variable than gland-specific and testis-specific proteins, as well as those with a quantitative difference in relative abundance between testes and glands. These correlations may reflect general differences in variability between extracellular and intracellular proteins and between proteins with broad as opposed to tissue-specific distributions.

Genic variation was surveyed for 20 proteins of Drosophila melanogaster and 18 proteins of D. pseudoobscura. Analysis was by extraction and one-dimensional polyacrylamide gel electrophoresis under nondenaturing conditions, followed by staining with Coomassie Brilliant Blue to detect soluble proteins present in relatively large amounts ("abundant soluble proteins"). D. melanogaster was polymorphic for 65% of its protein loci and an individual was heterozygous for 10% of its loci. The respective figures for D pseudoobscura were 61% and 11%. These estimates of genic variation fall between previously published estimates obtained for these species by one-dimensional electrophoresis of soluble enzymes and those obtained by two-dimensional electrophoresis of solubilized abundant proteins. However, variation for both species could be strongly partitioned between loci, on the basis of tissue and stage expression of the proteins. The results are discussed with respect to their bearing on the possibility that abundant proteins constitute a distinct class of proteins less polymorphic than soluble enzymes.