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1.  Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata—Possible Routes of Infection and Host Susceptibility  
BioMed Research International  2015;2015:396791.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an “environmental exposure” might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a “triple match” hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.
PMCID: PMC4589575  PMID: 26457299
2.  Could light meal jeopardize laboratory coagulation tests? 
Biochemia Medica  2014;24(3):343-349.
Presently the necessity of fasting time for coagulation tests is not standardized. Our hypothesis is that this can harm patient safety. This study is aimed at evaluating whether a light meal (i.e. breakfast) can jeopardize laboratory coagulation tests.
Materials and methods:
A blood sample was firstly collected from 17 fasting volunteers (12 h). Immediately after blood collection, the volunteers consumed a light meal. Then samples were collected at 1, 2 and 4 h after the meal. Coagulation tests included: activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fbg), antithrombin III (AT), protein C (PC) and protein S (PS). Differences between samples were assessed by Wilcoxon ranked-pairs test. The level of statistical significance was set at P < 0.05. Mean % differences were determined and differences between and baseline and 1, 2 and 4h samples were compared with reference change value (RCV).
A significantly higher % activity of AT was observed at 1 h and 4 h after meal vs. baseline specimen [113 (104–117) and 111 (107–120) vs. 109 (102–118), respectively; P = 0.029 and P = 0.016]. APTT at 2 h was found significantly lower than baseline samples [32.0 (29.9–34.8) vs. 34.1 (32.2–35.2), respectively; P = 0.041]. The results of both Fbg and PS tests were not influenced by a light meal. Furthermore, no coagulation tests had significant variation after comparison with RCV.
A light meal does not influence the laboratory coagulation tests we assessed, but we suggest that the laboratory quality managers standardize the fasting time for all blood tests at 12 hours, to completely metabolize the lipids intake.
PMCID: PMC4210254  PMID: 25351352
diagnostic errors; fasting; postprandial period; reference values; reproducibility of results
3.  Influence of a Regular, Standardized Meal on Clinical Chemistry Analytes 
Annals of Laboratory Medicine  2012;32(4):250-256.
Preanalytical variability, including biological variability and patient preparation, is an important source of variability in laboratory testing. In this study, we assessed whether a regular light meal might bias the results of routine clinical chemistry testing.
We studied 17 healthy volunteers who consumed light meals containing a standardized amount of carbohydrates, proteins, and lipids. We collected blood for routine clinical chemistry tests before the meal and 1, 2, and 4 hr thereafter.
One hour after the meal, triglycerides (TG), albumin (ALB), uric acid (UA), phosphatase (ALP), Ca, Fe, and Na levels significantly increased, whereas blood urea nitrogen (BUN) and P levels decreased. TG, ALB, Ca, Na, P, and total protein (TP) levels varied significantly. Two hours after the meal, TG, ALB, Ca, Fe, and Na levels remained significantly high, whereas BUN, P, UA, and total bilirubin (BT) levels decreased. Clinically significant variations were recorded for TG, ALB, ALT, Ca, Fe, Na, P, BT, and direct bilirubin (BD) levels. Four hours after the meal, TG, ALB, Ca, Fe, Na, lactate dehydrogenase (LDH), P, Mg, and K levels significantly increased, whereas UA and BT levels decreased. Clinically significant variations were observed for TG, ALB, ALT, Ca, Na, Mg, K, C-reactive protein (CRP), AST, UA, and BT levels.
A significant variation in the clinical chemistry parameters after a regular meal shows that fasting time needs to be carefully considered when performing tests to prevent spurious results and reduce laboratory errors, especially in an emergency setting.
PMCID: PMC3384805  PMID: 22779065
Blood specimen collection; Clinical laboratory techniques; Diagnostic errors; Eating; Fasting; Postprandial period; Reference values; Reproducibility of results; Quality control; Specimen handling
4.  Allelic Origin of Protease-Sensitive and Protease-Resistant Prion Protein Isoforms in Gerstmann-Sträussler-Scheinker Disease with the P102L Mutation 
PLoS ONE  2012;7(2):e32382.
Gerstmann-Sträussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrPSc, consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrPSc isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrPSc has been described. Here we analyze the molecular and pathological phenotype of six GSS P102L cases characterized by the presence of 21 and 8 kDa PrP fragments and two subjects with only the 8 kDa PrP fragment. Using sensitive protein separation techniques and Western blots with antibodies differentially recognizing wild-type and mutant PrP we observed a range of PrPSc allelic conformers, either resistant or sensitive to protease treatment in all investigated subjects. Additionally, tissue deposition of protease-sensitive wild-type PrPSc molecules was seen by conventional PrP immunohistochemistry and paraffin-embedded tissue blot. Our findings enlarge the spectrum of conformational allelic PrPSc quasispecies propagating in GSS P102L thus providing a molecular support to the spectrum of disease phenotypes, and, in addition, impact the diagnostic role of PrP immunohistochemistry in prion diseases.
PMCID: PMC3285667  PMID: 22384235
5.  Influence of a light meal on routine haematological tests 
Blood Transfusion  2010;8(2):94-99.
Patient-related variables, such as physical exercise, stress and fasting status are important sources of variability in laboratory testing. However, no clear indications about fasting requirements exist for routine haematological tests, nor has the influence of meals been assessed.
We studied 17 healthy volunteers who consumed a light meal containing a standardized amount of carbohydrates, protein and lipids. Blood was taken for routine haematological tests before the meal and 1, 2 and 4 hours thereafter.
One hour after the meal, neutrophil count and mean corpuscular haemoglobin (MHC) increased significantly, whereas lymphocyte and monocyte counts, red blood cell distribution width, haematocrit, and mean corpuscular volume decreased significantly. A clinically significant variation was only observed for lymphocytes. Two hours after the meal, a significant increase was observed for neutrophils and MCH, whereas lymphocytes, eosinophils, haemoglobin and haematocrit decreased significantly. Clinically significant variations were recorded for lymphocytes, red blood cells (RBC), haemoglobin, haematocrit and MCH. Four hours after the meal MCH was significantly increased, while lymphocytes, eosinophils, RBC, haemoglobin and haematocrit were significantly decreased. Clinically significant variations were recorded for neutrophils, eosinophils, RBC, hematocrit and MCH.
The significant variation of several haematological parameters after a light meal demonstrates that the fasting time needs to be carefully considered in order to interpret the results of haematological tests correctly.
PMCID: PMC2851212  PMID: 20383302
fasting; haematological tests; meal; pre-analytical variability
6.  Intraspecies Transmission of BASE Induces Clinical Dullness and Amyotrophic Changes 
PLoS Pathogens  2008;4(5):e1000075.
The disease phenotype of bovine spongiform encephalopathy (BSE) and the molecular/ biological properties of its prion strain, including the host range and the characteristics of BSE-related disorders, have been extensively studied since its discovery in 1986. In recent years, systematic testing of the brains of cattle coming to slaughter resulted in the identification of at least two atypical forms of BSE. These emerging disorders are characterized by novel conformers of the bovine pathological prion protein (PrPTSE), named high-type (BSE-H) and low-type (BSE-L). We recently reported two Italian atypical cases with a PrPTSE type identical to BSE-L, pathologically characterized by PrP amyloid plaques and known as bovine amyloidotic spongiform encephalopathy (BASE). Several lines of evidence suggest that BASE is highly virulent and easily transmissible to a wide host range. Experimental transmission to transgenic mice overexpressing bovine PrP (Tgbov XV) suggested that BASE is caused by a prion strain distinct from the BSE isolate. In the present study, we experimentally infected Friesian and Alpine brown cattle with Italian BSE and BASE isolates via the intracerebral route. BASE-infected cattle developed amyotrophic changes accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study provides clear evidence of BASE as a distinct prion isolate and discloses a novel disease phenotype in cattle.
Author Summary
For approximately two decades, bovine spongiform encephalopathy (BSE), now termed classical BSE (BSE-C), has been regarded as the only and exclusive prion disorder affecting cattle. However, over the last 4 years, two additional bovine prion strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered and characterized in Canada, the United States, Japan, and nine European countries, which applied an active surveillance program on slaughtered cattle. Although a total of 20 BSE-L and 16 BSE-H have been reported to date, the disease phenotype of these conditions remains largely unknown. Intriguingly, recent evidence has been provided that the BSE-C and BASE strains disclose converging properties after transmission to inbred mice. Here, we show that intraspecies transmission of BASE induces a disease phenotype characterized by dullness and progressive amyotrophy, the latter highly suggestive of a motor neuron disorder. This is at variance with the over-reactivity and hypersensitivity, but not muscle changes, observed in BSE-transmitted cattle. This study confirms that BASE and BSE represent two distinct prion disorders in cattle with diverging molecular features and disease phenotypes.
PMCID: PMC2374911  PMID: 18497860

Results 1-6 (6)