[Doctor Francoise Cathala and history of prions diseases]. / Le docteur Francoise Cathala Pagesy et l'histoire des maladies à prions.

Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant of Creutzfeldt-Jakob human epidemics, paradigmatic food safety crisis bringing together the poles of production (beef and meat-and-bone meal) and consumption, and leading to an unexpected social bang. Through Françoise Cathala exemplary life, the history of French, and more generally of worldwide prions diseases is dealt with.

Draft mitogenomes of the invasive ant Lepisiota frauenfeldi (Mayr 1855) (Hymenoptera: Formicidae).

We present the draft mitochondrial genomes (mitogenomes) of two Lepisiota frauenfeldi (Mayr 1855) workers from two separate invasive populations detected in Western Australia (Perth OK569858) and Queensland (Brisbane OK5569859), Australia. The draft mitogenomes ranged between 16,657 and 17,090 bp and contained 37 genes (13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and two ribosomal RNA (rRNA) genes). As with other arthropod mitogenomes, we observed high A + T content (A: 39.4-39.8%, T: 40.55-41.5%). We confirmed the species identity by molecular diagnostics based on the partial mtCOI gene that showed >99% similarity between the Australian populations and other L. frauenfeldi sequences reported to date, and in the process identified putative origins of the invasive populations as Pakistan and India for the WA and Qld incursions respectively that suggested separate introductions.

EPID-guided 3D dose verification of lung SBRT.

PURPOSE: To investigate the feasibility of utilizing tumor tracks from electronic portal imaging device (EPID) images taken during treatment to verify the delivered dose. METHODS: The proposed method is based on a computation of the delivered fluence by utilizing the planned fluence and the tumor motion track for each field. A phantom study was designed to assess the feasibility of the method. The CIRS dynamic thorax phantom was utilized with a realistic soft resin tumor, modeled after a real patient tumor. The dose calculated with the proposed method was compared to direct measurements taken with 15 metal oxide semiconductor field effect transistors (MOSFETs) inserted in small fissures made in the tumor model. The phantom was irradiated with the tumor static and moved with different range of motions and setup errors. EPID images were recorded throughout all deliveries and the tumor model was tracked post-treatment with in-house developed software. The planned fluence for each field was convolved with the tumor motion tracks to obtain the delivered fluence. Utilizing the delivered fluence from each field, the delivered dose was calculated. The estimated delivered dose was compared to the dose directly measured with the MOSFETs. The feasibility of the proposed method was also demonstrated on a real lung cancer patient, treated with stereotactic body radiotherapy. RESULTS: The calculation of delivered dose with the delivered fluence method was in good agreement with the MOSFET measurements, with average differences ranging from 0.8% to 8.3% depending on the proximity of a dose gradient. For the patient treatment, the planned and delivered dose volume histograms were compared and verified the overall good coverage of the target volume. CONCLUSIONS: The delivered fluence method was applied successfully on phantom and clinical data and its accuracy was evaluated. Verifying each treatment fraction may enable correction strategies that can be applied during the course of treatment to ensure the desired dose coverage.

Structure and Processes of Existing Practice in Radiotherapy Peer Review: A Systematic Review of the Literature.

Peer review in radiotherapy is an essential step in clinical quality assurance to avoid planning-related errors that can impact on patient safety and treatment outcomes. Despite recommendations that radiotherapy centres should include peer review in their regular quality assurance pathway, adoption of the practice has not been universal, and to date there have been no formal guidelines set out to standardise the process. We undertook a systematic review of the literature to determine existing practice in radiotherapy peer review internationally, with respect to meeting structure and processes, in order to define a standardised framework. A PubMed and Web of Science search identified 17 articles detailing peer review practice. The results revealed significant variation in peer review processes between institutions, and a lack of consensus on documentation and reporting. Variations in the grading of outcomes of peer review were also noted. Taking into account the results of this review, a framework for standardising the process and outcome documentation for peer review has been developed. This can be utilised by radiotherapy centres introducing or updating peer review practice, and can facilitate meaningful evaluation of the clinical impact of peer review in the future.

MRIgRT head and neck anthropomorphic QA phantom: Design, development, reproducibility, and feasibility study.

PURPOSE: The purpose of this paper was to design, manufacture, and evaluate a tissue equivalent, dual magnetic resonance/computed tomography (MR/CT) visible anthropomorphic head and neck (H&N) phantom. This phantom was specially designed as an end-to-end quality assurance (QA) tool for MR imaging guided radiotherapy (MRIgRT) systems participating in NCI-sponsored clinical trials. METHOD: The MRIgRT H&N phantom was constructed using a water-fillable acrylic shell and a custom insert that mimics an organ at risk (OAR) and target structures. The insert consists of a primary and secondary planning target volume (PTV) manufactured of a synthetic Clear Ballistic gel, an acrylic OAR and surrounding tissue fabricated using melted Superflab. Radiochromic EBT3 film and thermoluminescent detectors (TLDs) were used to measure the dose distribution and absolute dose, respectively. The phantom was evaluated by conducting an end-to-end test that included: imaging on a GE Lightspeed CT simulator, planning on Monaco treatment planning software (TPS), verifying treatment setup with MR, and irradiating on Elekta's 1.5 T Unity MR linac system. The phantom was irradiated three times using the same plan to determine reproducibility. Three institutions, equipped with either ViewRay MRIdian 60 Co or ViewRay MRIdian Linac, were used to conduct a feasibility study by performing independent end-to-end studies. Thermoluminescent detectors were evaluated in both reproducibility and feasibility studies by comparing ratios of measured TLD to reported TPS calculated values. Radiochromic film was used to compare measured planar dose distributions to expected TPS distributions. Film was evaluated by using an in-house gamma analysis software to measure the discrepancies between film and TPS. RESULTS: The MRIgRT H&N phantom on the Unity system resulted in reproducible TLD doses (SD < 1.5%). The measured TLD to calculated dose ratios for the Unity system ranged from 0.94 to 0.98. The Viewray dose result comparisons had a larger range (0.95-1.03) but these depended on the TPS dose calculations from each site. Using a 7%/4 mm gamma analysis, Viewray institutions had average axial and sagittal passing rates of 97.3% and 96.2% and the Unity system had average passing rates of 97.8% and 89.7%, respectively. All of the results were within the Imaging and Radiation Oncology Core in Houston (IROC-Houston) standard credentialing criteria of 7% on TLDs, and >85% of pixels passing gamma analysis using 7%/4 mm on films. CONCLUSIONS: An MRIgRT H&N phantom that is tissue equivalent and visible on both CT and MR was developed. The results from initial reproducibility and feasibility testing of the MRIgRT H&N phantom using the tested MGIgRT systems suggests the phantom's potential utility as a credentialing tool for NCI-clinical trials.

Investigation of TLD and EBT3 performance under the presence of 1.5T, 0.35T, and 0T magnetic field strengths in MR/CT visible materials.

PURPOSE: The aim of this study was to investigate thermoluminescent dosimeters (TLD) and radiochromic EBT3 film inside MR/CT visible geometric head and thorax phantoms in the presence of: 0, 0.35, and 1.5 T magnetic fields. METHODS: Thermoluminescent Dosimeters reproducibility studies were examined by irradiating IROC-Houston's TLD acrylic block five times under 0 and 1.5 T configurations of Elekta's Unity system and three times under 0 and 0.35 T configurations of ViewRay's MRIdian Cobalt-60 (60 Co) system. Both systems were irradiated with an equivalent 10 × 10 cm2 field size, and a prescribed dose of 3 Gy to the maximum depth deposition (dmax). EBT3 film and TLDs were investigated using two geometrical Magnetic Resonance (MR)-guided Radiation Therapy (MRgRT) head and thorax phantoms. Each geometrical phantom had eight quadrants that combined to create a centrally located rectangular tumor (3 × 3 × 5 cm3 ) surrounded by tissue to form a 15 × 15 × 15 cm3 cubic phantom. Liquid polyvinyl chloride plastic and Superflab were used to simulate the tumor and surrounding tissue in the head phantom, respectively. Synthetic ballistic gel and a heterogeneous in-house mixture were used to construct the tumor and surrounding tissue in the thorax phantom, respectively. EBT3 and double-loaded TLDs were used in the phantoms to compare beam profiles and point dose measurements with and without magnetic fields. GEANT4 Monte Carlo simulations were performed to validate the detectors for both Unity 0 T/1.5 T and MRIdian 0 T/0.35 T configurations. RESULTS: Average TLD block measurements which, compared the magnetic field effects (magnetic field vs 0 T) on the Unity and MRIdian systems, were 0.5% and 0.6%, respectively. The average ratios between magnetic field effects for the geometric thorax and head phantoms under the Unity system were -0.2% and 1.6% and for the MRIdian system were 0.2% and -0.3%, respectively. Beam profiles generated with both systems agreed with Monte Carlo measurements and previous literature findings. CONCLUSIONS: TLDs and EBT3 film dosimeters could potentially be used in MR/CT visible tissue equivalent phantoms that will experience a magnetic field environment.

MRIgRT dynamic lung motion thorax anthropomorphic QA phantom: Design, development, reproducibility, and feasibility study.

PURPOSE: To design, manufacture, and evaluate a dynamic magnetic resonance imaging/computed tomography (MRI/CT)-compatible anthropomorphic thorax phantom used to credential MR image-guided radiotherapy (MRIgRT) systems participating in NCI-sponsored clinical trials. METHOD: The dynamic anthropomorphic thorax phantom was constructed from a water-fillable acrylic shell that contained several internal structures representing radiation-sensitive organs within the thoracic region. A custom MR/CT visible cylindrical insert was designed to simulate the left lung with a centrally located tumor target. The surrounding lung tissue was constructed from a heterogeneous in-house mixture using petroleum jelly and miniature (2-4 mm diameter) styrofoam balls and the tumor structure was manufactured from liquid PVC plastic. An MR conditional pneumatic system was developed to allow the MRIgRT insert to move in similar inhale/exhale motions. TLDs and radiochromic EBT3 film were inserted into the phantom to measure absolute point doses and dose distributions, respectively. The dynamic MRIgRT thorax phantom was evaluated through a reproducibility study and a feasibility study. Comprehensive end-to-end examinations were done where the phantom was imaged on a CT, an IMRT treatment plan was created and an MR image was captured to verify treatment setup. Then, the phantom was treated on an MRIgRT system. The reproducibility study evaluated how well the phantom could be reproduced in an MRIgRT system by irradiating three times on an Elekta's 1.5 T Unity system. The phantom was shipped to three independent institutions and was irradiated on either an MRIdian cobalt-60 (60 Co) or an MRIdian linear accelerator system. Treatment evaluations used TLDs and radiochromic film to compare the planned treatment reported on the treatment planning software against the measured dose on the dosimeters. RESULTS: The phantom on the Unity system had reproducible TLD doses measurements (SD < 1.5%). The measured TLD to calculated dose ratios from the reproducibility and feasibility studies ranged from 0.93 to 1.01 and 0.96 to 1.03, respectively. Using a 7%/5 mm gamma analysis criteria, the reproducibility and feasibility studies resulted in an average passing rate of 93.3% and 96.8%, respectively. No difference was noted in the results between the MRIdian 60 Co and MRIdian 6 MV linac delivery to the phantom and all treatment evaluations were within IROC-Houston's acceptable criterion. CONCLUSIONS: A dosimetrically tissue equivalent, CT/MR visible, motion-enabled anthropomorphic MRIgRT thorax phantom was constructed to simulate a lung cancer patient and was evaluated as an appropriate NIH credentialing tool used for MRIgRT systems.

Options for combining altered fractionation with IMRT.

We set out to investigate IMRT-based concomitant boost. Eight patients with stage III/IV squamous cell carcinoma of the head and neck treated with once daily with chemoradiotherapy at the Dana-Farber/Brigham and Women's Hospital had their treatment plans reviewed with IRB approval. Each case was replanned for treatment with a a concomitant boost regimen. Plans delivered 1.9 Gy in 30 fractions to 57 Gy with a boost of 1.5 Gy in 10 fractions for a total dose of 72 Gy. The boost was planned with both IMRT and 3-D conformal, to compare the two techniques. For each patient, both plans (IMRT-IMRT and IMRT-3DCRT) were evaluated for target and avoidance coverage, monitor units and integral dose. Finally, we evaluated the plans for time to completion. The IMRT-IMRT and IMRT-3-DCRT techniques were equivalent for target coverage. 100% coverage of the GTV and PTV was achieved with 97% of the prescription dose. Hot spots were seen 104% to 108% with IMRT-IMRT plan and from 102-111% with the IMRT-3DCRT plans. The IMRT-IMRT boost had double the monitor units as the 3-DCRT boosts. When the total monitor units from both the initial and boost portions of the plans were e combined there was not a significant difference. There was a slight increase in integral dose with the IMRT-IMRT plans of mean 3.8%. Planning time was increased for the 3-DCRT boost as opposed to the IMRT boost (mean 3.5 hours vs. 1.5 hours). More time was needed for quality assurance of the IMRT-IMRT plans (3.0 hours vs. 1.5 hours for IMRT-3-DCRT). We found that both IMRT-based concomitant-boost strategies are achievable and produce good dosimetric results.

Innovations in Radiotherapy Technology.

Many low- and middle-income countries, together with remote and low socioeconomic populations within high-income countries, lack the resources and services to deal with cancer. The challenges in upgrading or introducing the necessary services are enormous, from screening and diagnosis to radiotherapy planning/treatment and quality assurance. There are severe shortages not only in equipment, but also in the capacity to train, recruit and retain staff as well as in their ongoing professional development via effective international peer-review and collaboration. Here we describe some examples of emerging technology innovations based on real-time software and cloud-based capabilities that have the potential to redress some of these areas. These include: (i) automatic treatment planning to reduce physics staffing shortages, (ii) real-time image-guided adaptive radiotherapy technologies, (iii) fixed-beam radiotherapy treatment units that use patient (rather than gantry) rotation to reduce infrastructure costs and staff-to-patient ratios, (iv) cloud-based infrastructure programmes to facilitate international collaboration and quality assurance and (v) high dose rate mobile cobalt brachytherapy techniques for intraoperative radiotherapy.

Novel molecular approach to define pest species status and tritrophic interactions from historical Bemisia specimens.

Museum specimens represent valuable genomic resources for understanding host-endosymbiont/parasitoid evolutionary relationships, resolving species complexes and nomenclatural problems. However, museum collections suffer DNA degradation, making them challenging for molecular-based studies. Here, the mitogenomes of a single 1912 Sri Lankan Bemisia emiliae cotype puparium, and of a 1942 Japanese Bemisia puparium are characterised using a Next-Generation Sequencing approach. Whiteflies are small sap-sucking insects including B. tabaci pest species complex. Bemisia emiliae's draft mitogenome showed a high degree of homology with published B. tabaci mitogenomes, and exhibited 98-100% partial mitochondrial DNA Cytochrome Oxidase I (mtCOI) gene identity with the B. tabaci species known as Asia II-7. The partial mtCOI gene of the Japanese specimen shared 99% sequence identity with the Bemisia 'JpL' genetic group. Metagenomic analysis identified bacterial sequences in both Bemisia specimens, while hymenopteran sequences were also identified in the Japanese Bemisia puparium, including complete mtCOI and rRNA genes, and various partial mtDNA genes. At 88-90% mtCOI sequence identity to Aphelinidae wasps, we concluded that the 1942 Bemisia nymph was parasitized by an Eretmocerus parasitoid wasp. Our approach enables the characterisation of genomes and associated metagenomic communities of museum specimens using 1.5 ng gDNA, and to infer historical tritrophic relationships in Bemisia whiteflies.

The complete mitochondrial DNA genome of Aedes vigilax (Diptera: Culicidae).

The complete mitochondrial genomes of two main clades of the medically significant saltmarsh mosquito Aedes vigilax Skuse (Diptera: Culicidae) were obtained using combined Illumina and Sanger sequencing. The two 15,877 bp circular genomes share 99.0% nucleotide identity and encode 37 genes with identical gene arrangement similar to previously published Culicidae species with a non-coding A + T rich region between rns and tRNA-Ile. Protein initiation codon is ATN apart from ND5 (GTG) and COX1 (TCG). Eight protein-coding genes encode full TAA stop codon, while five are completed by mRNA polyadenylation. Typical cloverleaf structures containing DHU and TΨC stem and loops can be inferred for all 22 tRNAs.

The complete mitochondrial DNA genomes for two lineages of Aedes notoscriptus (Diptera: Culicidae).

The complete mitochondrial genomes for two deeply divergent lineages of the urban adapted mosquito Aedes notoscriptus Skuse (Diptera: Culicidae) in Australia were sequenced using a combination of next generation Illumina and traditional Sanger sequencing. The 15,846 and 15,851 bp circular genomes share 95.0% nucleotide identity. They both have the full complement of 37 metazoan genes and identical gene arrangements to previously published Culicidae species with the one non-coding A + T rich control region present between rns and tRNA-Ile. All protein initiation codons are ATN apart from COX1 (TCG). Eight protein coding genes encode full TAA stop codons, one uses an incomplete TA and four use T. Typical cloverleaf structures containing DHU and TΨC stem and loops can be inferred for all 22 tRNAs.

Complete mitochondrial DNA genome of Bemisia tabaci cryptic pest species complex Asia I (Hemiptera: Aleyrodidae).

The complete length of the Asia I member of the Bemisia tabaci species complex mitochondrial DNA genome (mitogenome) is 15,210 bp (GenBank accession no. KJ778614) with an A-T biased nucleotide composition (A: 32.7%; T: 42.4%; G: 14.0%; C: 10.8%). The mitogenome consists of 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNA (rRNAs) and a 467 bp putative control region which also includes the A+T rich repeat region. All PCGs have an ATA (n = 8) or ATG (n = 5) start codon. Gene synteny of Asia I is overall similar to B. afer and two other members of the B. tabaci species complex Mediterranean and New World 1, and contains the tRNA-Ser2 located between the Cytb and ND1 genes found in Mediterranean and New World 1, but which is absent in B. afer. The orientation of the tRNA-Arg in Asia I is on the "plus" strand and differed from Mediterranean which is found on the "minus" strand. The Asia I mitogenome size is currently ranked the second smallest after B. afer (14,968 bp) followed by New World 1 (15,322 bp) and Mediterranean (15,632 bp).

EEG profile of intravenous zolpidem in healthy volunteers.

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological and sleep alterations in experimental mouse rabies.

Changes in the spontaneous brain electrical activity and sleep organization were investigated in 5 mice strains during the evolution of experimental fixed rabies infection. Cortical electrodes were chronically implanted for continuous EEG recording and spectral analysis until death. Three evolutionary phases were individualized. The initial phase exhibited alterations of sleep stages, REM sleep disappearance, pseudoperiodic facial myoclonus and first clinical signs. The mature phase was characterized by a generalized EEG slowing (2-4 cycles/s). The terminal phase occurring with extinction of hippocampal rhythmic slow activity showed a flattening of cortical activity. The brain electrical activity ceased about 30 min before the cardiac arrest. Paroxysmal activities appeared during the course of the disease as bursts of rhythmic slow waves, pseudoperiodic spikes or occasionally ictal epileptic discharges. Spectral analysis revealed a progressive and characteristic clustering of the EEG frequency band power values. The spread of infection in the CNS was monitored by specific immunofluorescence studies which revealed the presence of rabies virus antigen in the pons, the cerebellum, the thalamus and the cortex during the initial phase. The pyramidal field of the hippocampus was infected during the mature phase but the gyrus dentatus was never infected even at the terminal phase. These studies show that particular neuronal functions are impaired during rabies virus infection suggesting that neuronal alterations may be involved in the pathogenic mechanisms leading to lethality.

Sleep alterations in experimental street rabies virus infection occur in the absence of major EEG abnormalities.

Brain electrical activity and sleep organization were investigated in chronically implanted mice during street rabies virus infection. Continuous EEG recordings showed no gross electrical abnormalities until a few hours before the fatal issue. In contrast, alterations of sleep stages were observed at an early stage during the course of rabies virus infection, at a time when clinical signs were absent. Quantification by spectral analysis showed that the main feature was the early decrease of REM-sleep stages and the increase of the duration of waking stages. Neuromuscular disorders which could occur early were also observed during the disease. Comparison of these data with those obtained from fixed rabies virus infection shows that in the latter the EEG recordings demonstrated early alterations and a progressive deterioration with disappearance of both sleep and waking stages, which were replaced by a pathological sleep stage. In order to evaluate the potential role of the host-specific immune response in promoting brain electrophysiological alterations, EEG recordings and spectral analysis were also performed in cyclophosphamide-treated mice. Street rabies virus-infected and immunosuppressed mice showed identical physiopathological changes as those observed in immunocompetent mice. The implication of these viral-induced electrophysiological alterations in the context of the pathogenic mechanisms of rabies virus is discussed.

Spread of scrapie agent to the central nervous system: study of a rat model.

Invasion of scrapie agent into the central nervous system (CNS) was studied in rats following intracerebral and peripheral inoculation, the latter by injection into intact or transected sciatic nerve. Comparison of sleep-wakefulness alterations, neuropathological features, and time lag of electroencephalographic and clinical signs in the 3 groups suggests that hematogenous spread of infection to the CNS may predominate over neural transport, and that peripheral inoculation may closely approximate natural infection.

Changes in the serotonergic, noradrenergic and dopaminergic levels in the brain of scrapie-infected rats.

Levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethyleneglycol (DHPG) were determined by high-performance liquid chromatography in different brain areas of scrapie-infected rats, 8.5 months after intracerebral inoculation of a rat-adapted strain from mice brain (C 506). At this time, rats developed early clinical signs of the disease. Scrapie-infected rats showed a reduction in the levels of 5-HT and 5-HIAA (frontal cortex, hippocampus, mesolimbic structure). Concentrations of DHPG decreased in the frontal and parietal cortices but remained unchanged in the hippocampus. DOPAC levels decreased in the striatum but not in the mesolimbic structure. These results confirm that the serotonergic, noradrenergic and dopaminergic systems are altered in the brain of scrapie-infected rats. They can partly account for clinical signs of scrapie and are in agreement with the scarce data provided by the postmortem analysis of Creutzfeldt-Jakob disease brains.

Sleep abnormalities with REM disorder in experimental Creutzfeldt-Jakob disease in cats: a new pathological feature.

Alterations in sleep organization were studied during the clinical phase of experimental Creutzfeldt-Jakob disease (CJD) in cats. Twenty months after intracerebral inoculation of a CJD agent, cats developed clinical signs including behavioral changes, diminished grooming activity, dysmetria, startle reflex, myoclonus, and unusual sleep abnormalities. Rapid eye movement (REM) sleep displayed a new and irreversible organization, with a continuous and constant pseudoperiodic pattern of rapid eye movements, synchronous with diffuse bursts of cortical abnormalities and with ponto-geniculo-occipital (PGO) wave activity. Computer analysis revealed a constant morphology of cortical bursts and their temporal relationship with ocular episodes. Induction of PGO wave activity with benzoquinolizine derivative Ro 4-1284 demonstrated the PGO-dependent nature of the cortical alterations. Abnormal unresponsive states were observed during REM sleep phases and arousal thresholds were increased in CJD cats during REM sleep. The percentages of wakefulness and slow-wave sleep were reversed in these animals. Preliminary neuropathological observations included discrete to minimal spongiosis of cerebral gray matter and a remarkably focalized intracytoplasmic vacuolation in neurons of the raphé system. Our findings suggest that particular neuronal systems involved in sleep regulation are impaired in CJD cats.

Monoamine abnormalities in the brain of scrapie-infected rats.

The effects of the scrapie agent on the levels of monoamines and their metabolites, and on choline acetyltransferase (CAT) activity have been investigated in discrete brain areas in the rat. Two strains of scrapie (8745 from sheep brain and C506 M3 from mice brain) were inoculated. Scrapie-infected rats showed a reduction in the levels of serotonin (prefrontal cortex, hippocampus, striatum) and dopamine (striatum) and an elevation of 5-HIAA levels (cerebral cortex, striatum, thalamus). Noradrenaline levels were decreased only in the cerebral cortex and cerebellum of rats infected with the scrapie strain C506 M3. CAT activity remained unchanged. These data suggest that the scrapie agent causes a derangement of noradrenergic, serotonergic and dopaminergic systems in the rat brain.