MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.

High concentration potassium permanganate eliminates protein and particle contamination of the reusable Classic laryngeal mask airway.

In this three-stage study, we test the hypothesis that supplementary cleaning with potassium permanganate > or =4 mg.l(-1) eliminates protein and particle contamination from the reusable Classic laryngeal mask airway. The first stage involved supplementary cleaning of 70 1 x 1 cm segments from deliberately contaminated laryngeal mask airways using potassium permanganate at 0, 2, 4, 8, 16, 32 and 64 mg.l(-1) and testing for protein staining. This showed that the lowest concentration required to eliminate protein contamination was 8 mg.l(-1). The second stage involved supplementary cleaning of 50 used laryngeal mask airways with either potassium permanganate 8 mg.l(-1) or saline and testing for protein staining. This showed that protein contamination was lower in the potassium permanganate group (p < 0.00001): all laryngeal mask airways in the control group and none in the potassium permanganate group were contaminated. The third stage involved scanning electron microscopic examination of 1 x 1 cm segments from three laryngeal mask airways used in the control group, three from the potassium permanganate group, plus three brand new laryngeal mask airways. The mean density of > or =1 mum surface particles was lower in the potassium permanganate 8 mg.l(-1) than the control group (21 vs. 121 .cm(-2), p < 0.0001) and was similar to brand new laryngeal mask airways (24 .cm(-2)). We conclude that supplementary cleaning with potassium permanganate 8 mg.l(-1) eliminates protein deposits from reusable laryngeal mask airways and reduces particle contamination to similar levels to brand new laryngeal mask airways.

Schism and heresy in the development of orthodox medicine: the threat to medical hegemony.

Medical and scientific knowledge is not intrinsically different from other kinds of knowledge and has gone through the same processes in terms of its development. As a profession, medicine achieved its dominance in the 19th century and has subsequently consolidated its power base. A socio-historical perspective shows us that medicine has no more and no less fraud, heresy, schism, and relative knowledge than any other equivalent forms of knowledge. Orthodox medicine emerged from a number of healing systems in the 19th century by claiming the superiority and consequent authority of the biomedical model and its special relationship to laboratory science. This process has been seen by some to resemble the growth of religious orthodoxy and the emergence of alternative beliefs with the dissenting medical systems, based on different paradigms, becoming analogous to religious sects. An increasing body of opinion rejects the notion of "objective" knowledge and sees medical knowledge and practice as "socially constructed". An examination of HIV/AIDS measurement and 19th century craniology and contagion and anti-contagion theories indicates processes which are "contextual" rather than "objective". Heresy and schism are natural concomitants of socially constructed knowledge, functioning as providers of impetus and change and, as such, are to be welcomed as non-orthodox challenges.

Molecular pathology of fatal familial insomnia.

Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrPres), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrPres have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrPres recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrPres inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrPres is the underrepresentation of the unglycosylated PrPres form. Cell models indicate that the underrepresentation of this PrPres form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrPres fails to explain this finding since in both cases FFI PrPres is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.

[Handling of unconventional pathogens]. / Zum Umgang mit unkonventionellen Erregern.

This article summarizes decontamination problems in handling transmissible spongiform encephalopathies (TSE) in the field of human pathology. The combination of chemical (i.e. 1 M NaOH, 1 h, room temperature) and physical (i.e. autoclaving for 30 min at 131 degrees C) decontamination methods was proven to be suitable for instruments and other materials. Als for the autopsy of suspected TSE patients, safety measures have to be taken. The brain preparation, in particular, represents a considerable risk which must be minimized by appropriate safety measures. Conventional formaldehyde fixation does not decontaminate tissues! Embedding, cutting, deparaffinization and processing or staining have to be done with cautions; members of staff must be aware of the danger. After the handling of suspect materials, the hands should be washed without brushing the skin. In the case of percutaneous inoculation the injury must be decontaminated immediately using iodine- or phenol-containing preparations, 0.5 M NaOH or 1:3000 potassium permanganate.

Creutzfeldt-Jakob disease in recipients of human growth hormone in the United Kingdom: a clinical and radiographic study.

In the past 3 years there have been five further cases, in addition to one case reported in 1985, of Creutzfeldt-Jakob disease in recipients of human growth hormone in the United Kingdom. The clinical findings of two of these cases are described, demonstrating a typical presentation with a predominantly cerebellar syndrome at onset which is not commonly a presenting feature of sporadic Creutzfeldt-Jakob disease. In one case a 99mTc hexamethylpropylenamine single photon emission tomographic scan showed marked impairment of tracer uptake in the basal ganglia and cerebral cortex at a time when the clinical picture was predominantly cerebellar. This technique may be useful in early diagnosis. In the other case post mortem examination of the brain showed prominent amyloid deposition in the cerebellum, which has not been described previously in pituitary-hormone related Creutzfeldt-Jakob disease. The previously published cases of growth hormone-related Creutzfeldt-Jakob disease are reviewed and reasons for the particular clinical pattern seen are discussed.

Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Sträussler-Scheinker diseases.

A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Sträussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.

Kuru plaques in the brain of two cases with Creutzfeldt-Jakob disease. A common origin for the two diseases?

We present two patients aged 66 and 69, with a rapidly progressive disease (10 and 15 months' duration) in which the presenting symptom was instability of gait. Later dementia was also a prominent feature. One case had myoclonus. Repeated EEGs showed symmetrical slowing in one case and periodic generalised bursts of triphasic waves at 1 cps superimposed upon a slow (3-4 cps) background activity in the other. The pathological findings consisted of classical Creutzfeld-Jakob disease (CJD), Kuru plaques (KP) were disseminated in the brain, but were more numerous in the cerebellum, putamen and thalamus. Neurons with large vacuoles in the cytoplasm were numerous in the putamen, thalamus and anterior horns. Stress is laid upon the common findings in both CJD and Kuru (K) (clinical features, pathological data, lack of antibody response, transmissibility, change in pattern on transmission). The possibility of a common origin of the two diseases is discussed.