Until 30 years ago, Creutzfeldt–Jakob disease was an obscure form of dementia unknown to most physicians. The name is now familiar to the medical community as the major transmissible spongiform ...encephalopathy (or prion disease) in humans and to research scientists because of its strange causative agent with novel modes of replication and transmission. Furthermore, the term “Creutzfeldt–Jakob disease” has caused distress to patients who have been notified that they may have received tainted blood or blood products, and it has been popularized by extensive media coverage of bovine spongiform encephalopathy (“mad cow disease”), with its profound economic impact in Europe . . .
The transmissible spongiform encephalopathies constitute a group of uniformly fatal neurodegenerative diseases. These diseases include Creutzfeldt–Jakob disease and kuru, among others, in humans,
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scrapie in sheep and goats, and spongiform encephalopathy in cattle.
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Spongiform encephalopathies are characterized by spongiform degeneration of the brain, reactive gliosis in the cortical and subcortical gray matter, and the presence of the abnormal isoform of the cellular prion protein.
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These degenerative encephalopathies are transmissible when the infectious agent is experimentally inoculated into laboratory animals.
There is an urgent need for a premortem diagnostic test that can identify humans and animals with transmissible spongiform encephalopathy. . . .
Hepatitis E is an important medical pathogen in many developing countries but is rarely reported from the United States, although antibody to hepatitis E virus (anti-HEV) is found in > 1% of U.S. ...citizens. Zoonotic spread of the virus is suspected. Sera obtained from 239 wild rats trapped in widely separated regions of the United States were tested for anti-HEV. Seventy-seven percent of rats from Maryland, 90% from Hawaii, and 44% from Louisiana were seropositive for anti-HEV. Rats from urban as well as rural areas were seropositive and the prevalence of anti-HEV IgG increased in parallel with the estimated age of the rats, leading to speculation that they might be involved in the puzzling high prevalence of anti-HEV among some U.S. city dwellers. The discovery of a in rats in the United States and the recently reported discovery that HEV is endemic in U.S. swine raise many questions about transmission, reservoirs, and strains of HEV in developed countries.
We present a synthesis of clinical, neuropathological, and biological details of the National Institutes of Health series of 300 experimentally transmitted cases of spongiform encephalopathy from ...among more than 1,000 cases of various neurological disorders inoculated into nonhuman primates during the past 30 years. The series comprises 278 subjects with Creutzfeldt-Jakob disease, of whom 234 had sporadic, 36 familial, and 8 iatrogenic disease; 18 patients with kuru; and 4 patients with Gerstmann-Strüssler-Scheinker syndrome. Sporadic Creutzfeldt-Jakob disease, numerically by far the most important representative, showed an average age at onset of 60 years, with the frequent early appearance of cerebellar and visual/oculomotor signs, and a broad spectrum of clinical features during the subsequent course of illness, which was usually fatal in less than 6 months. Characteristic spongiform neuropathology was present in all but 2 subjects. Microscopically visible kuru-type amyloid plaques were found in 5% of patients with Creutzfeldt-Jakob disease, 75% of those with kuru, and 100% of those with Gerstmann-Sträussler-Scheinker syndrome; brain biopsy was diagnostic in 95% of cases later confirmed at autopsy, and proteinase-resistant amyloid protein was identified in Western blots of brain extracts from 88% of tested subjects. Experimental transmission rates were highest for iatrogenic Creutzfeldt-Jakob disease (100%), kuru (95%), and sporadic Creutzfeldt-Jakob disease (90%), and considerably lower for most familial forms of disease (68%). Incubation periods as well as the durations and character of illness showed great variability, even in animals receiving the same inoculum, mirroring the spectrum of clinical profiles seen in human disease. Infectivity reached average levels of nearly 10(5) median lethal doses/gm of brain tissue, but was only irregularly present (and at much lower levels) in tissues outside the brain, and, except for cerebrospinal fluid, was never detected in bodily secretions or excretions.
The infectious form of the scrapie amyloid (prion) precursor, PrP(Sc), is a host-derived protein and a component of the infectious agent causing scrapie. PrP(Sc) and the carboxyl-terminal proteinase ...K resistant core, PrP27-30, have the potential to form amyloid as a result of a post-translational event or conformational abnormality. We have studied the conformational transitions of both proteins reconstituted into liposomes, associated in solid state in thin films, and dissociated by guanidine HCl. The secondary structure of PrP(Sc) in liposomes deduced from analysis of circular dichroism spectra contained approximately 34% beta-sheets, approximately 20% alpha-helix, and approximately 46%,8-turns and random coil. Cleavage of the amino-terminal region of PrP(Sc) resulted in all-beta PrP27-30, with an estimated approximate 43% beta-sheet, no alpha-helix, and approximately 57% beta-turns and random coil. The PrP(Sc) associated in thin films with a tertiary structure perturbation corresponding to unfolding, while the secondary structure was preserved. The PrP27-30 assembled into the solid state with a similar perturbation of tertiary structure but with a large increase in the beta-sheet content, probably due to an intermolecular alignment of the external beta-sheets, or to a secondary structure transition, or both. The various conformational states had little or no impact on infectivity. Equilibrium dissociation and unfolding demonstrated a greater resistance of PrP27-30 to denaturation. The dissociated monomers unfolded through intermediate(s), suggesting the presence of protein domains with distinct secondary structure stabilities. The results provide experimental evidence for the beta-sheet type assembly of scrapie amyloid PrP27-30 in the solid state and demonstrate the importance of amino-terminal cleavage in the stability and alignment of the amyloid-forming monomers
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This report identifies human skeletal diseases associated with mutations in
WNT1
in a family with dominantly inherited early-onset osteoporosis and in another family with recessive osteogenesis ...imperfecta. WNT1 is shown to be an important ligand for regulating bone mass.
Osteoporosis is a common skeletal disorder characterized by low bone mineral density (BMD), impaired bone quality, and fragility fractures.
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Although multiple genetic loci, including those for WNT ligands, have been defined on the basis of genomewide association studies in patients with osteoporosis, the known loci are generally associated with odds ratios for fracture that are below 1.1.
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Recently, novel metabolic pathways in bone cells have been discovered in patients with osteogenesis imperfecta, a mendelian disease characterized by brittle bones.
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The role of the WNT pathway in bone formation and maintenance has been extensively studied since the identification of mutations in . . .
Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo- ...controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval CI, 82%–99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%–94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.
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2001 Mars Odyssey Mission Summary Saunders, R S; Arvidson, R E; Badhwar, G D ...
Space science reviews,
2004, Volume:
110, Issue:
1-2
Journal Article
Peer reviewed
The 2001 Mars Odyssey spacecraft, now in orbit at Mars, will observe the Martian surface at infrared and visible wavelengths to determine surface mineralogy and morphology, acquire global gamma ray ...and neutron observations for a full Martian year, and study the Mars radiation environment from orbit. The science objectives of this mission are to: (l) globally map the elemental composition of the surface, (2) determine the abundance of hydrogen in the shallow subsurface, (3) acquire high spatial and spectral resolution images of the surface mineralogy, (4) provide information on the morphology of the surface, and (5) characterize the Martian near-space radiation environment as related to radiation-induced risk to human explorers. To accomplish these objectives, the 2001 Mars Odyssey science payload includes a Gamma Ray Spectrometer (GRS), a multi-spectral Thermal Emission Imaging System (THEMIS), and a radiation detector, the Martian Radiation Environment Experiment (MARIE). THEMIS and MARIE are mounted on the spacecraft with THEMIS pointed at nadir. GRS is a suite of three instruments: a Gamma Subsystem (GSS), a Neutron Spectrometer (NS) and a High-Energy Neutron Detector (HEND). The HEND and NS instruments are mounted on the spacecraft body while the GSS is on a 6-m boom. Some science data were collected during the cruise and aerobraking phases of the mission before the prime mission started. THEMIS acquired infrared and visible images of the Earth-Moon system and of the southern hemisphere of Mars. MARIE monitored the radiation environment during cruise. The GRS collected calibration data during cruise and aerobraking. Early GRS observations in Mars orbit indicated a hydrogen-rich layer in the upper meter of the subsurface in the Southern Hemisphere. Also, atmospheric densities, scale heights, temperatures, and pressures were observed by spacecraft accelerometers during aerobraking as the spacecraft skimmed the upper portions of the Martian atmosphere. This provided the first in-situ evidence of winter polar warming in the Mars upper atmosphere. The prime mission for 2001 Mars Odyssey began in February 2002 and will continue until August 2004. During this prime mission, the 2001 Mars Odyssey spacecraft will also provide radio relays for the National Aeronautics and Space Administration (NASA) and European landers in early 2004. Science data from 2001 Mars Odyssey instruments will be provided to the science community via NASA's Planetary Data System (PDS). The first PDS release of Odyssey data was in October 2002; subsequent releases occur every 3 months.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Gerstmann-StrSussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the priori protein gene (PRNP), is phenotypically heterogeneous. The ...molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.
The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between ...codons 51 and 91. We screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. We identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had "wobble" nucleotide substitutions. We also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.
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