Tissue classification for the epidemiological assessment of surgical transmission of sporadic Creutzfeldt-Jakob disease. A proposal on hypothetical risk levels

BACKGROUND: Epidemiological studies on the potential role of surgery in Creutzfeldt-Jakob Disease transmission have disclosed associations with history of specific surgical interventions or reported negative results. METHODS: Within the context of a case-control study designed to address surgical risk of sporadic Creutzfeldt-Jakob Disease in Nordic European countries (EUROSURGYCJD Project), a strategy was adopted to categorise reported surgical procedures in terms of potential risk of Creutzfeldt-Jakob Disease acquisition. We took into account elements of biological plausibility, either clinically or experimentally demonstrated, such as tissue infectivity, PrP expression content or successful route of infection. RESULTS: We propose a classification of exposed tissues and anatomic structures, drawn up on the basis of their specific putative role as entry site for prion transmission through contact with surgical instruments that are not fully decontaminated. CONCLUSIONS: This classification can serve as a reference, both in our study and in further epidemiological research, for categorisation of surgical procedures in terms of risk level of Creutzfeldt-Jakob Disease acquisition

Nosocomial transmission of sporadic Creutzfeldt–Jakob disease: results from a risk-based assessment of surgical interventions

OBJECTIVES: Evidence of surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD) remains debatable in part due to misclassification of exposure levels. In a registry-based case-control study, the authors applied a risk-based classification of surgical interventions to determine the association between a history of surgery and sCJD. DESIGN: Case-control study, allowing for detailed analysis according to time since exposure. SETTING: National populations of Denmark and Sweden. PARTICIPANTS: From national registries of Denmark and Sweden, the authors included 167 definite and probable sCJD cases with onset during the period 1987-2003, 835 age-, sex- and residence-matched controls and 2224 unmatched. Surgical procedures were categorised by anatomical structure and presumed risk of transmission level. The authors used logistic regression to determine the odds ratio (OR) for sCJD by surgical interventions in specified time-windows before disease-onset. RESULTS: From comparisons with matched controls, procedures involving retina and optic nerve were associated with an increased risk at a latency of ≥1 year OR (95% CI) 5.53 (1.08 to 28.0). At latencies of 10 to 19 years, interventions on peripheral nerves 4.41 (1.17 to 16.6) and skeletal muscle 1.58 (1.01 to 2.48) were directly associated. Interventions on blood vessels 4.54 (1.01 to 20.0), peritoneum 2.38 (1.14 to 4.96) and skeletal muscle 2.04 (1.06 to 3.92), interventions conducted by vaginal approach 2.26 (1.14 to 4.47) and a pooled category of lower-risk procedures 2.81 (1.62 to 4.88) had an increased risk after ≥20 years. Similar results were found when comparing with unmatched controls. INTERPRETATION: This observation is in concordance with animal models of prion neuroinvasion and is likely to represent a causal relation of surgery with a non-negligible proportion of sCJD cases.Funding was obtained from The Research Commission EU, Concerted Action QLRG3-CT-2002-81223, NEUROPRION, and the Spanish RECSP C03-09, CIEN C03-06 and CIBERNED networks.S

Towards an age-dependent transmission model of acquired and sporadic Creutzfeldt-Jakob disease

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) might be transmitted by surgery. The purpose of this study was to investigate potential susceptibility to sCJD from surgery at juvenile age and in early adulthood. METHODS: From Danish and Swedish national registries we identified 167 definite and probable sCJD cases with onset from 1987 through 2003, and 835 age-, sex- and residence-matched controls along with their surgical histories. Main, anatomically or etiologically classified surgical procedures followed by a ≥20-year lag were analyzed using logistic regression, and stratified by age at first-registered surgical discharge. RESULTS: The risk of having a diagnosis of CJD depended strongly on age at first surgery with odds ratio (OR) of 12.80 (95% CI 2.56-64.0) in patients <30 years, 3.04 (95% 1.26-7.33) in 30-39 years, and 1.75 (95% CI 0.89-3.45) in ≥40 years, for anatomically classified surgical procedures. Similar figures were obtained for etiologically classified surgical procedures. CONCLUSIONS: Risk of surgical-acquired sCJD depends on age at exposure; this pattern is similar to age-specific profiles reported for CJD accidentally transmitted by human pituitary-derived growth hormone and susceptibility curves for variant CJD estimated after adjustment for dietary exposure to bovine spongiform encephalopathy. There might be an age-at-exposure-related susceptibility to acquire all CJD forms, including sCJD from routine surgery.Funding was obtained from the EU Research Commission, Concerted Action QLRG3-CT-2002-81223 NEUROPRION and the Spanish Centro de Investigaciones en enfermedades Neurológicas (CIEN C03-06), and Consortium for Biomedical Research in Neurodegenerative Diseases (CIBERNED) networks, and from the Karolinska and Carlos III National Health Institutes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

In vitro inhibition of topoisomerase IIα by reduced glutathione

In most cells, the major intracellular redox buffer is glutathione (GSH) and its disulfide-oxidized (GSSG) form. The GSH/GSSG system maintains the intracellular redox balance and the essential thiol status of proteins by thiol disulfide exchange. Topoisomerases are thiol proteins and are a target of thiol-reactive substances. In this study, the inhibitory effect of physiological concentration of GSH and GSSG on topoisomerase IIα activity in vitro was investigated. GSH (0-10 mM) inhibited topoisomerase IIα in a concentration-dependent manner while GSSG (1-100 µM) had no significant effect. These findings suggest that the GSH/GSSG system could have a potential in vivo role in regulating topoisomerase IIα activity

Potential age-at-exposure-related susceptibility for the following different CJD forms and exposures:

<p>(a) Age-susceptibility function for vCJD in the UK <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-Ghani1" target="_blank">[12]</a>, and results from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone-0109412-t001" target="_blank">Table 1</a> for risk of sCJD from age at first hospital discharge associated with a registered, main surgical procedure, at a lag of ≥20 years. (b) Reported estimated risks relating to 5- to 10-year age groups, after adjustment for dietary exposure to bovine material and average incubation period established at 12.6 years for variant CJD in the UK <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-Boelle1" target="_blank">[13]</a>, and plotted results from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone-0109412-t001" target="_blank">Table 1</a> for risk of sCJD from age at first hospital discharge associated with an etiologically reclassified <i>higher-risk</i> or <i>lower-risk</i> procedure, at a lag of ≥20 years. (c) Reported rate ratios of accidentally transmitted CJD (iCJD), for ever treatement vs never treatement with pituitary growth hormone (all treatments) at specific ages <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-Swerdlow1" target="_blank">[11]</a>. Reference: all other ages at treatment. (d) Reported rate ratios of accidentally transmitted CJD (iCJD) for ever treatment vs never treatment with pituitary growth hormone processed with the Hartree-modified Wilhelmi method (an hGH preparation associated with highest risk of iCJD among hGH-treated cohorts) at specific ages <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-Swerdlow1" target="_blank">[11]</a>. Reference: all other ages at treatment.</p

Associations for surgical procedures predating the time point of clinical onset in cases or the corresponding index date in controls by ≥20 years.

<p>Models 1 and 2, anatomic SP classification; models 3 and 4, etiologic SP classification. Other risk SPs encompass three reported etiologic SP categories, i.e., <i>lowest-risk</i>, <i>no-risk</i>, and <i>not reclassified</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-dePedroCuesta2" target="_blank">[7]</a>. Age subcategories <30, 30–39, and ≥40 years at first-registered surgery.</p>a<p>Subsidiary procedures' is a heterogeneous category that includes minor surgery (punctures, needle aspiration or biopsy, superficial incisions), other non-surgical, potentially invasive procedures, such as transluminal endoscopies (with or without biopsy), and, in a few instances in Denmark, blood transfusion.</p><p>SP-code distribution by body system groups in exposed cases.</p>b<p>n = 15. Female genital organs and obstetric SP, 7; Digestive system and spleen, 3; Other groups, 5.</p>c<p>n = 15. Female genital organs and obstetric SP, 8; Digestive system and spleen, 3, Other groups, 4.</p>d<p>n = 37. Female genital organs and obstetric SP, 18; Digestive system and spleen, 8; Peripheral vessels and lymphatic system, 5; Other groups, 6.</p>e<p>HR or LR SPs: acronym for <i>higher-risk</i> or <i>lower-risk</i> SPs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109412#pone.0109412-dePedroCuesta2" target="_blank">[7]</a>.</p><p>Associations for surgical procedures predating the time point of clinical onset in cases or the corresponding index date in controls by ≥20 years.</p