Treatment Of Creutzfeldt-Jakob Disease Research Articles

Bounds for the weight of external data in shrinkage estimation.

Shrinkage estimation in a meta-analysis framework may be used to facilitate dynamical borrowing of information. This framework might be used to analyze a new study in the light of previous data, which might differ in their design (e.g., a randomized controlled trial and a clinical registry). We show how the common study weights arise in effect and shrinkage estimation, and how these may be generalized to the case of Bayesian meta-analysis. Next we develop simple ways to compute bounds on the weights, so that the contribution of the external evidence may be assessed apriori. These considerations are illustrated and discussed using numerical examples, including applications in the treatment of Creutzfeldt-Jakob disease and in fetal monitoring to prevent the occurrence of metabolic acidosis. The target study's contribution to the resulting estimate is shown to be bounded below. Therefore, concerns of evidence being easily overwhelmed by external data are largelyunwarranted.

Feature of magnetic resonance imaging in patients with Creutzfeldt-Jakob disease

Objective: To assess the imaging features of 43 patients diagnosed as clinically possible or probable Creutzfeldt-Jakob disease (CJD) for providing referential information and experience on applications of MRI in the clinical diagnosis and treatment of CJD. Method: All patients who were diagnosed with "suspected CJD" and hospitalized in Xuanwu Hospital from January 2013 to November 2015 were collected, and their clinical information and MRI imaging features were analyzed retrospectively. Results: Totally 62 patients with "suspected CJD" were rectruited in this study, and 43 of them were diagnosied as probable and possible CJD when they were discharged.The typical MRI feature of CJD patients was "cortical ribbon" sign in MR DWI sequences and/or high signal in cortex or bilateral basal ganglia.In all patients, the simple coritcal involvement was the highest(76.47%, 26/34), followed by the cortical cortex and basal ganglia(23.53%, 8/34). MRI positive group had more prominent extrapyramidal symptoms than MRI negative group (26/31 vs 9/12, P=0.015), but no statistical difference in clinic feature was found between the group with simple cortex affected and the group with both cortex and bilateral basal ganglia affected (P>0.05). Conclusions: MRI images of patients with CJD have special characteristics and have corresponding changes when the patients are in different stages of disease. In combination with the clinical evaluation of disease progression, brain microscopic pathological changes of CJD patients can be assessed by regularly brain MRI examination.

Evaluation of quinacrine treatment for prion diseases.

Based on in vitro observations in scrapie-infected neuroblastoma cells, quinacrine has recently been proposed as a treatment for Creutzfeldt-Jakob disease (CJD), including a new variant CJD which is linked to contamination of food by the bovine spongiform encephalopathy (BSE) agent. The present study investigated possible mechanisms of action of quinacrine on prions. The ability of quinacrine to interact with and to reduce the protease resistance of PrP peptide aggregates and PrPres of human and animal origin were analyzed, together with its ability to inhibit the in vitro conversion of the normal prion protein (PrPc) to the abnormal form (PrPres). Furthermore, the efficiencies of quinacrine and chlorpromazine, another tricyclic compound, were examined in different in vitro models and in an experimental murine model of BSE. Quinacrine efficiently hampered de novo generation of fibrillogenic prion protein and PrPres accumulation in ScN2a cells. However, it was unable to affect the protease resistance of preexisting PrP fibrils and PrPres from brain homogenates, and a "curing" effect was obtained in ScGT1 cells only after lengthy treatment. In vivo, no detectable effect was observed in the animal model used, consistent with other recent studies and preliminary observations in humans. Despite its ability to cross the blood-brain barrier, the use of quinacrine for the treatment of CJD is questionable, at least as a monotherapy. The multistep experimental approach employed here could be used to test new therapeutic regimes before their use in human trials.

Factors affecting interactions between prion protein isoforms.

Interactions between normal, protease-sensitive prion protein (PrP-sen or PrP(C)) and its protease-resistant isoform (PrP-res or PrP(Sc)) are critical in transmissible spongiform encephalopathy (TSE) diseases. To investigate the propagation of PrP-res between cells we tested whether PrP-res in scrapie brain microsomes can induce the conversion of PrP-sen to PrP-res if the PrP-sen is bound to uninfected raft membranes. Surprisingly, no conversion was observed unless the microsomal and raft membranes were fused or PrP-sen was released from raft membranes. These results suggest that the propagation of infection between cells requires transfer of PrP-res into the membranes of the recipient cell. To assess potential cofactors in PrP conversion, we used cell-free PrP conversion assays to show that heparan sulphate can stimulate PrP-res formation, supporting the idea that endogenous sulphated glycosaminoglycans can act as important cofactors or modulators of PrP-res formation in vivo. In an effort to develop therapeutics, the antimalarial drug quinacrine was identified as an inhibitor of PrP-res formation in scrapie-infected cell cultures. Confirmation of the latter result by others has led to the initiation of human clinical trials as a treatment for Creutzfeldt-Jakob disease. PrP-res formation can also be inhibited using a variety of other types of small molecule, specific synthetic PrP peptides, and an antiserum directed at the C-terminus of PrP-sen. The latter results help to localize the sites of interaction between PrP-sen and PrP-res. Disruption of those interactions with antibodies or peptidomimetic drugs may be an attractive therapeutic strategy. The likelihood that PrP-res inhibitors can rid TSE-infected tissues of PrP-res would presumably be enhanced if PrP-res formation were reversible. However, our attempts to measure dissociation of PrP-sen from PrP-res have failed under non-denaturing conditions. Finally, we have attempted to induce the spontaneous conversion of PrP-sen into PrP-res using low concentrations of detergents. A conformational conversion from alpha-helical monomers into high-beta-sheet aggregates and fibrils was induced by low concentrations of the detergent sarkosyl; however, the aggregates had neither infectivity nor the characteristic protease-resistance ofPrP-res.

Revisión de la enfermedad de Creutzfeldt­Jakob y otras enfermedades priónicas

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia syndrome which is probably caused by prions. The annual incidence of this disease is 1/1,000,000. Most cases are sporadic in type, although 10-15% are familial. The total incidence of CJD has not changed following the epidemic due to a new variant (nv-CJD); however, this has led to greater awareness of the subject. To review current scientific knowledge of CJD. A search was made for relevant literature using MEDLINE. The criteria proposed for diagnosis of CJD include the presence of progressive dementia and at least two of the following characteristics: 1. Myoclonias, 2. Cortical blindness, 3. Pyramidal, extrapyramidal or cerebellar signs, 4. Akinetic mutism, or 5 Abnormal EEG. Laboratory and neuroimaging investigations may also help in diagnosis of CJD, although neuropathological confirmation is necessary for definite diagnosis. Two promising methods of pre mortem diagnosis of CJD are determination of 14-3-3 protein in the cerebrospinal fluid, in the case of sporadic CJD, and biopsy of the palatine tonsil in the case of nv-CJD. The physiopathology of CJD seems to be centred on the proteins forming prions, which are glycoproteins found in the plasmatic membrane and are very often expressed in the neurons, particularly at neuromuscular junctions and synapses. The pathological form resists proteolytic degradation, so that they accumulate in the CNS. The precise neurotoxic mechanism of these proteins is still not clear. There is still no treatment for CJD. Further studies of the physiopathological mechanisms of prion diseases may help in the development of treatment to delay the progress of this disease.