A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report

Background: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion. Case presentation: We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine. Conclusions: A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were compatible with sporadic Creutzfeldt-Jakob disease, the molecular subtype with the abnormal prion protein isoforms showing enhanced protease sensitivity was reminiscent of the "protease-sensitive prionopathy". It remains to be established whether the differences found between the latter and this case are due to the polymorphism at codon 129. Different degrees of proteinase K susceptibility were easily determined with the chemical polymer detection system which could help to detect proteinase-susceptible pathologic prion protein in diseases other than the classical ones.

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease

BACKGROUND: The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. METHODS: Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. RESULTS: Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. CONCLUSIONS: This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

Mapping the parameters of prion-induced neuropathology

We present a theoretical framework that enables us to dissect out the parametric dependencies of the pathogenesis of prion diseases. We are able to determine the influence of both host-dependent factors (connectivity, cell density, protein synthesis rate, and cell death) and strain-dependent factors (cell tropism, virulence, and replication rate). We use a model based on a linked system of differential equations on a lattice to explore how the regional distribution of central nervous system pathology in Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia relates to each of these factors. The model then is used to make qualitative predictions about the pathology for two possible hypothetical triggers of neuronal loss in prion diseases. Pathological progression in overexpressing mouse models has been shown to depend on the site of initial infection. The model allows us to compare the pathologies resulting from different inoculation routes.

Fatal myocardial infarction at 4.5 years in a case of homozygous familial hypercholesterolaemia

Management of homozygous familial hypercholesterolaemia is notoriously difficult. For these patients, LDL apheresis is considered the treatment of choice. Treatment initiation is advocated generally from the age of seven years onwards (Thompson et al., Atherosclerosis 198:247-255, 2008). Here, we present the case of a young girl from a large inbred family of Turkish descent with homozygous familial hypercholesterolaemia and fatal outcome at the early age of 4(1/2) years.In conclusion, this case suggests that management of homozygous familial hypercholesterolaemia may require earlier and more aggressive treatment, including LDL apheresis before the age of seven years.

Familial malignant osteopetrosis in children: A case report

The clinical, radiological, pathological and laboratory findings of two brothers with autosomal recessive malignant osteopetrosis are presented. Our findings are similar to characteristics previously reported in the literature about patients with osteopetrosis. The 6-year-old male patient was pale and had petechiae on his arms and legs. He also had macrocephalia, splenomegaly, severe pancytopenia, genu valgus, hypocalcemia, amaurosis, cessation of physical development, generalized bone sclerosis and recurrent infections with a history of multiple incidences of acute otitis media. Generalized bone sclerosis and irregular sclerosis of the maxilla and mandible were seen on radiographs. The oral mucosa was apparently normal but permanent tooth eruption was delayed although there was early loss of deciduous teeth. The recommended treatment was blood transfusion and therapy with antibiotics when necessary; a bone marrow transplant was not possible due to lack of a compatible donor.

Persistence of biological traces in gun Barrels after fatal contact shots

Backspatter from wounds caused by contact shots against a biological target had before been shown to be propelled into firearms' barrels where they can persist and be retrieved from as relevant forensic evidence. Herein, that insight was applied to the investigation of a case of multiple familial homicide with a firearm. Samples of backspatter were collected from the firearm using DNA-free swabs. DNA was extracted from the swabs, and 16 STR systems were PCR-amplified to generate DNA profiles of all victims shot by the firearm. The quality of the resulting DNA profiles was sufficient to exclude the perpetrator as donor and to differentiate the three closely related victims thereby proving that all three victims had been shot by the same firearm from very close or contact distance. A key insight gained from this case was that not only a firearms' barrel inside but other inner surfaces may be charged with profilable DNA.

Fatal motorcycle crashes in north Queensland : characteristics and potential interventions

Aims: The Rural and Remote Road Safety Study (RRRSS) addresses a recognised need for greater research on road trauma in rural and remote Australia, the costs of which are disproportionately high compared with urban areas. The 5-year multi-phase study with whole-of-government support concluded in June 2008. Drawing on RRRSS data, we analysed fatal motorcycle crashes which occurred over 39 months to provide a description of crash characteristics, contributing factors and people involved. The descriptive analysis and discussion may inform development of tailored motorcycle safety interventions. Methods: RRRSS criteria sought vehicle crashes resulting in death or hospitalisation for 24 hours minimum of at least 1 person aged 16 years or over, in the study area defined roughly as the Queensland area north from Bowen in the east and Boulia in the west (excluding Townsville and Cairns urban areas). Fatal motorcycle crashes were selected from the RRRSS dataset. Analysis considered medical data covering injury types and severity, evidence of alcohol, drugs and prior medical conditions, as well as crash descriptions supplied by police to Queensland Transport on contributing circumstances, vehicle types, environmental conditions and people involved. Crash data were plotted in a geographic information system (MapInfo) for spatial analysis. Results: There were 23 deaths from 22 motorcycle crashes on public roads meeting RRRSS criteria. Of these, half were single vehicle crashes and half involved 2 or more vehicles. In contrast to general patterns for driver/rider age distribution in crashes, riders below 25 years of age were represented proportionally within the population. Riders in their thirties comprised 41% of fatalities, with a further 36% accounted for by riders in their fifties. 18 crashes occurred in the Far North Statistical Division (SD), with 2 crashes in both the Northern and North West SDs. Behavioural factors comprised the vast majority of contributing circumstances cited by police, with adverse environmental conditions noted in only 4 cases. Conclusions: Fatal motorcycle crashes were more likely to involve another vehicle and less likely to involve a young rider than non-fatal crashes recorded by the RRRSS. Rider behaviour contributed to the majority of crashes and should be a major focus of research, education and policy development, while other road users’ behaviour and awareness also remains important. With 68% of crashes occurring on major and secondary roads within a 130km radius of Cairns, efforts should focus on this geographic area.

Contemporary examples where doctors are not immune from non-fatal offences against a person

While it is uncontested that the medical profession makes a valuable contribution to society, doctors should not always be beyond the reach of the criminal law and they should not automatically be treated as God. Doctors should act reasonably and be conscious of their position of trust. In this sense, the notion of “doctors” is construed broadly to include a range of health care professionals such as podiatrists, radiographers, surgeons and general practitioners. This paper will explore contemporary Australian examples where doctors have acted inappropriately and been convicted of non-fatal offences against the person. The physical invasiveness involved in these scenarios varies significantly. In one example, a doctor penetrates a patient’s private body part with a probe for their own sexual gratification, and in another, a doctor covertly visually records a naked patient. The examples will be connected to the theories underpinning criminalisation, particularly social welfare and individual autonomy, with a view to framing guidelines on when doctors should not be immune from non-fatal offences against a person, and thus where the criminal law should respond.

Risk factors for fatal crashes in rural Australia

This paper presents findings from the rural and remote road safety study, conducted in Queensland, Australia, from March 2004 till June 2007, and compares fatal crashes and non-fatal but serious crashes in respect of their environmental, vehicle and operator factors. During the study period there were 613 non-fatal crashes resulting in 684 hospitalised casualties and 119 fatal crashes resulting in 130 fatalities. Additional information from police sources was available on 103 fatal and 309 non-fatal serious crashes. Over three quarters of both fatal and hospitalised casualties were male and the median age in both groups was 34 years. Fatal crashes were more likely to involve speed, alcohol and violations of road rules and fatal crash victims were 2 and a 1/2 times more likely to be unrestrained inside the vehicle than non-fatal casualties, consistent with current international evidence. After controlling for human factors, vehicle and road conditions made a minimal contribution to the seriousness of the crash outcome. Targeted interventions to prevent fatalities on rural and remote roads should focus on reducing speed and drink driving and promoting seatbelt wearing.

Predicting single-vehicle fatal crashes for two-lane rural highways in Southeastern United States

The rural two-lane highway in the southeastern United States is frequently associated with a disproportionate number of serious and fatal crashes and as such remains a focus of considerable safety research. The Georgia Department of Transportation spearheaded a regional fatal crash analysis to identify various safety performances of two-lane rural highways and to offer guidance for identifying suitable countermeasures with which to mitigate fatal crashes. The fatal crash data used in this study were compiled from Alabama, Georgia, Mississippi, and South Carolina. The database, developed for an earlier study, included 557 randomly selected fatal crashes from 1997 or 1998 or both (this varied by state). Each participating state identified the candidate crashes and performed physical or video site visits to construct crash databases with enhance site-specific information. Motivated by the hypothesis that single- and multiple-vehicle crashes arise from fundamentally different circumstances, the research team applied binary logit models to predict the probability that a fatal crash is a single-vehicle run-off-road fatal crash given roadway design characteristics, roadside environment features, and traffic conditions proximal to the crash site. A wide variety of factors appears to influence or be associated with single-vehicle fatal crashes. In a model transferability assessment, the authors determined that lane width, horizontal curvature, and ambient lighting are the only three significant variables that are consistent for single-vehicle run-off-road crashes for all study locations.