Therapeutic approaches targeting the prion receptor LRP/LR.

Transmissible spongiform encephalopathies known as prion diseases are a group of fatal neurodegenerative disorders that affect both humans and animals. The generally accepted principle of the disease is that the conversion of the cellular prion protein (PrP(c)) into the disease associated isoform PrP(Sc) leads to spongiform degeneration of the brain and amyloid plaque formation. Until now no therapy leading to potential alleviation or even cure of the disease exists. It is therefore important to develop therapeutic approaches for the treatment of TSEs since these infections are inevitably fatal and, especially in the case of vCJD, they affect youngsters. Besides current conventional therapeutic strategies, this review summarizes new therapeutic tools targeting the prion receptor LRP/LR.

Bax deletion does not protect neurons from BSE-induced death.

Neurodegeneration is a common neuropathological feature of prion diseases. Although evidence of apoptosis was found in natural and experimental prion diseases, the precise mechanisms by which neurons die are poorly understood. The pro-apoptotic BAX protein, a key factor of the mitochondrial pathway, plays a central role in the regulation of neuronal apoptosis. Recently, BAX was implicated in neuronal death in a transgenic model of inherited prion disease. Nevertheless, whether neurodegeneration occurs by similar mechanisms in other prion diseases remains unknown. Here, using mice knocked out for the Bax gene, we investigated BAX implication in neuronal death induced by a prion disease of infectious origin. A mouse-adapted prion strain of bovine spongiform encephalopathy (BSE) was inoculated intracerebrally into Bax-/- mice and their wild-type littermates. We found that Bax inactivation did not alter the development of the disease. Clinical illness was not prevented. PrP(res) deposition and astrogliosis occurred to the usual extent. Neuronal integrity was not maintained, and neurons in hippocampus and thalamus were not protected. These results demonstrated that BAX is not necessary for neuron death induced by the BSE strain. They suggest the existence of multiple molecular death pathways in prion diseases.

Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease: background and implications for nursing practice.

Creutzfeldt-Jakob disease belongs to a group of rapidly progressive, fatal neurological disorders. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neurosurgery and corneal grafting. The total number of people affected by CJD is unknown at this time, and it will remain unknown for some time to come. High infectious risks classification includes the brain, spinal cord, and eyes. Transmissible spongiform encephalopathy (TSE) prions are resistant to steam sterilization, dry heat, ethylene oxide gas, and chemical disinfection. Prevention of prion transmission must be taken into account in daily practice. Efficient sterilization procedures should be determined.

[Transmissible spongiform encephalopathies in humans]. / Transmissible spongiforme Enzephalopathien beim Menschen.

Transmissible spongiform encephalopathies (TSE) are dementing diseases and have been known to affect humans for over 90 years. The most common of these is the sporadic form of Creutzfeldt-Jakob disease (sCJD), followed by its familial (fCJD) and an iatrogenic (iCJD) form. 1996 a variant of CJD (vCJD) has been described in the UK, of which so far 131 cases have been observed worldwide. Specific biochemical and neuropathological signatures allow to distinguish between vCJD and sCJD and lead to the hypothesis that vCJD is due to transmission of BSE prions to humans. Although promising therapeutical approaches are being investigated, human TSE remain untreatable entities. Thus preventive measures are essential. In Switzerland the population has been exposed to BSE prions, too, but no case of vCJD as described in the UK has been observed until now. Since 2001, however, a so far unexplained increase of sCJD cases is being observed.

[Transmissible spongiform encephalopathies--anesthesiologic and intensive care management]. / Ubertragbare spongiforme Enzephalopathien--Anaesthesiologisches und intensivmedizinisches Management.

The transmissible spongiform encephalopathies (TSE) are known to affect humans and various animals. The bovine spongiform encephalopathy (BSE) and the human Creutzfeldt-Jacob disease (CJD) are among the most notable degenerative disorders caused by prions. Considering the BSE epidemic and the description of a new variant of Creutzfeldt-Jacob disease (nvCJD), which is probably related to bovine spongiform encephalopathy, TSE have recently gained a lot of public attention. Although the causative factors (prions, viruses) are still under discussion, none of the present concepts are explanatory for all aspects of the human CJD. CJD may present as a sporadic, genetic, or infectious illness and there is now considerable concern that bovine prions may have been passed to humans. To exclude transmission of CJD via medical products and instruments, the effectiveness of cleaning, disinfection and sterilization procedures must be firmly established. This manuscript presents an overview to anaesthesiology and intensive care medicine of recommended inactivation procedures and assessed these procedures in the light of the inactivation of prions.

Temporal aspects of the epidemic of bovine spongiform encephalopathy in Great Britain: holding-associated risk factors for the disease.

The objectives of this study were first to describe the pattern of the epidemic of bovine spongiform encephalopathy (BSE) in Great Britain in terms of the temporal change in the proportion of all cattle holdings that had experienced at least one confirmed case of BSE to June 30, 1997, and secondly to identify risk factors that influenced the date of onset of a holding's first confirmed BSE case. The analyses were based on the population of British cattle at risk, derived from agricultural census data collected between 1986 and 1996, and the BSE case data collected up to June 30, 1997. The unit of interest was the cattle holding and included all those recorded at least once on annual agricultural censuses conducted between June 30, 1986, and June 30, 1996. The outcome of interest was the date on which clinical signs were recorded in a holding's first confirmed case of BSE, termed the BSE onset date. Univariate and multivariate survival analysis techniques were used to describe the temporal pattern of the epidemic. The BSE epidemic in Great Britain started in November 1986, with the majority of affected holdings having their BSE onset date after February 1992. After adjusting for the effect of the size and type of holding, holdings in the south of England (specifically those in the Eastern, South east and South west regions) had 2.22 to 2.43 (95 per cent confidence interval [CI] 2.07 to 2.58) times as great a monthly hazard of having a BSE index case as holdings in Scotland. After adjusting for the effect of region and type of holding, holdings with more than 53 adult cattle had 5.91 (95 per cent CI 5.62 to 6.21) times as great a monthly hazard of having a BSE index case as holdings with seven to 21 adult cattle. Dairy holdings had 3.06 (95 per cent CI 2.96 to 3.16) times as great a monthly hazard of having a BSE index case as beef suckler holdings. These analyses show that there were different rates of onset in different regions and in holdings of different sizes and types, that the epidemic was propagated most strongly in the south of the country, and that the growth of the epidemic followed essentially the same pattern in each region of the country, with modest temporal lags between them. The control measures imposed in 1988 and 1990 brought the expansion of the epidemic under control, although the rate of progress was slowed by those regions where the effectiveness of the control methods took some time to take full effect.

Prion diseases and the BSE crisis.

Bovine spongiform encephalopathy (BSE) and human Creutzfeldt-Jakob disease (CJD) are among the most notable central nervous system degenerative disorders caused by prions. CJD may present as a sporadic, genetic, or infectious illness. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular prion protein (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content. It is thought that BSE is a result of cannibalism in which faulty industrial practices produced prion-contaminated feed for cattle. There is now considerable concern that bovine prions may have been passed to humans, resulting in a new form of CJD.