Measurements of the radioactivity of the cloud from the accident at Windscale Works (Sellafield, England) in October 1957: data submitted to the International Geophysical Year (IGY; July 1957-December 1958).

A fire in a nuclear reactor at Windscale Works (Sellafield, England) in October 1957 led to an uncontrolled aerial release of radionuclides. At the time of the accident air was sampled at various locations in Europe to monitor atmospheric pollution, and the opportunity was taken to measure the sampling filters for activity concentrations of iodine-131, caesium-137 and polonium-210 at the Harwell research establishment (United Kingdom); when it was not possible to perform measurements at Harwell, original measurement data were supplied. This programme of activity measurements was performed in the context of work by the Advisory Committee on Nuclear Radiation of the International Geophysical Year (IGY; July 1957-December 1958). The International Geophysical Year was an international programme of research into a comprehensive range of geophysical phenomena. The results of this measurement programme were originally reported in Harwell Memorandum AERE-M857 (1961) and this Harwell report is reproduced in this paper because of its historical interest and because it is no longer readily accessible to researchers.

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

The Grb2 binding domain of mSos1 is not required for downstream signal transduction.

Cellular Ras proteins are activated primarily by specific guanine-nucleotide releasing factors such as the Son of Sevenless (Sos) proteins. This activation event is thought to occur in response to plasma membrane localization of a complex containing Sos and a small adapter protein Grb2. We have isolated a dominant mutant allele of mSos1 which transforms Rat1 cells, yet is no longer able to bind Grb2. Biochemical experiments reveal that the subcellular distribution of this truncated Sos protein is not altered with respect to the wild type Sos protein. These data argue against a role for Grb2 in the direct recruitment of Sos proteins to the plasma membrane and suggest that Grb2 may function to overcome negative regulation of Sos by its C terminus.

Genealogies of mouse inbred strains.

The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently.

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse.

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.

A method to determine the available UV-C dose for the decontamination of filtering facepiece respirators.

AIMS: To develop a method to assess model-specific parameters for ultraviolet-C (UV-C, 254 nm) decontamination of filtering facepiece respirators (FFRs). METHODS AND RESULTS: UV-C transmittance was quantified for the distinct composite layers of six N95 FFR models and used to calculate model-specific α-values, the percentage of the surface UV-C irradiance available for the internal filtering medium (IFM). Circular coupons, excised from the FFRs, were exposed to aerosolized particles containing MS2 coliphage and treated with IFM-specific UV-C doses ranging from 38 to 4707 J m(-2). Models exposed to a minimum IFM dose of 1000 J m(-2) demonstrated at least a 3 log reduction (LR) in viable MS2. Model-specific exposure times to achieve this IFM dose ranged from 2 to 266 min. CONCLUSIONS: UV-C transmits into and through FFR materials. LR of MS2 was a function of model-specific IFM UV-C doses. SIGNIFICANCE AND IMPACT OF THE STUDY: Filtering facepiece respirators are in high demand during infectious disease outbreaks, potentially leading to supply shortages. Reuse of disposable FFRs after decontamination has been discussed as a possible remediation strategy, but to date lacks supporting scientific evidence. The methods described here can be used to assess the likelihood that UV-C decontamination will be successful for specific FFR models.

Mouse autosomal trisomy: two's company, three's a crowd.

Autosomal trisomy causes a large proportion of all human pregnancy loss and so is a significant source of lethality in the human population. The autosomal trisomy syndromes each have a different phenotype and are probably caused by the effects of specific genes that are present in three copies, rather than the normal two. Identifying these genes will require the application of classical genetic and new genome-manipulation approaches. Recent advances in chromosome engineering are now allowing us to create precisely defined autosomal trisomies in the mouse, and so provide new routes to identifying the critical, dosage-sensitive genes that are responsible for these highly deleterious, yet very common, syndromes.

Turner syndrome: the case of the missing sex chromosome.

Turner syndrome is the phenotype associated with the absence of a second sex chromosome in humans. Recent observations support the hypothesis that the phenotype results from haploid dosage of genes that are common to the X and Y chromosomes and that escape X inactivation. A goal of current studies is the identification of these "Turner' genes.

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefèvre syndrome.

Papillon Lefèvre syndrome (PLS) is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is caused by mutations in the cathepsin C gene (CTSC) that maps to chromosome 11q14. CTSC gene mutations associated with PLS have been correlated with significantly decreased enzyme activity. Mutational analysis of the CTSC gene in three North American families segregating PLS identified four mutations, including a novel mutation p.G139R. All mutations were associated with dramatically reduced CTSC protease enzyme activity. A homozygous c.96T>G transversion resulting in a p.Y32X change was present in a Mexican PLS proband, while one Caucasian PLS proband was a compound heterozygote for the p.Y32X and p.R272P (c.815G>C) mutations. The other Caucasian PLS proband was a compound heterozygote for c.415G>A transition and c.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respectively. The c.415G>A was not present in more than 300 controls, suggesting it is not a CTSC polymorphism. Biochemical analysis demonstrated almost no detectable CTSC activity in leukocytes of all three probands. These mutations altered restriction enzyme sites in the highly conserved CTSC gene. Sequence analysis of CTSC exon 3 confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethnically diverse populations studied.

Chromosome 3 linked frontotemporal dementia (FTD-3).

BACKGROUND: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. METHODS: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. RESULTS: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H2 15 O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. CONCLUSIONS: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Examination of the human prion protein-like gene doppel for genetic susceptibility to sporadic and variant Creutzfeldt-Jakob disease.

A novel human gene named Doppel (DPL) that has homology to the prion protein gene (PRNP) has recently been identified on chromosome 20p. By automated sequencing we have found a common (M174T, 48%) and an uncommon coding polymorphism. The polymorphic frequency of the M174T allele was examined in cases of variant and sporadic Creutzfeldt-Jakob Disease and compared with the frequency in the normal UK population. In sharp distinction to the M129V polymorphism of PRNP we have not found any evidence of disease association nor is there any association with age of onset, disease duration, or prion protein (PrP(Sc)) strain type.

The kinesin light chain gene: its mapping and exclusion in mouse and human forms of inherited motor neuron degeneration.

The underlying genetic cause is known for only 10-20% of familial motor neuron disease (MND). Thus the genes involved in the aetiology of 80-90% of familial MND remain to be determined, and animal models are powerful tools for undertaking this task. We have mapped a heritable form of motor neuron degeneration in the mouse to a region that has homology to human chromosome 14q32.1-qter. This region contains the kinesin light chain gene (KLC1), which is a candidate for involvement in motor neuron degeneration because of its function in the motor-protein kinesin, and its neuronal expression. To investigate the role of KLC1 in a mouse motor neuron degeneration mutant that we are studying, we have identified mouse Klc1 gene sequences and mapped them with respect to our mutant locus. We have also investigated KLC1 in human patients with familial MND. Based on recombination and the absence of mutations in the coding region of KLC1, this gene can be excluded as a candidate gene in our mouse mutation and, where we have investigated, it is normal in human familial MND.

SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice.

Mouse models of neurological abnormalities are only valuable if accurately assessed. The three-stage SHIRPA procedure is used for the standardised assessment of mouse phenotype and has been reported in a high throughput experiment in which different mutants were ascertained at one age point using stage 1 of the protocol. In this study we have validated SHIRPA using a large cohort with one single mutation, 'legs at odd angles that causes neurological dysfunction. The cohort aged from 1 to 16 months during this study and this is the first longitudinal SHIRPA analysis.

Photorefractive keratectomy for myopia with a 15 Hz repetition rate.

PURPOSE: To evaluate excimer laser photorefractive keratectomy (PRK) for myopia using a repetition rate of 15 Hz instead of 10 Hz. SETTING: The Cornea and Laser Eye Institute, Teaneck, and Department of Ophthalmology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA. METHODS: Photorefractive keratectomy using a 15 Hz repetition rate was performed in 23 eyes of 14 patients by a single surgeon at 1 center. The attempted corrections ranged from -2.8 diopters (D) to -5.5 D. Preoperative and postoperative uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), predictability, corneal haze, and subjective glare/halo were evaluated over 6 months. RESULTS: At 6 months, UCVA was 20/32 or better in all eyes and at least 20/20 in 14 eyes (73.7%). Two eyes (10.5%) lost 2 or more Snellen lines of BSCVA; postoperative BSCVA was at least 20/25 in 100% of eyes and 20/20 or better in 95.0%. Fifteen eyes (78.9%) were within +/-0.5 D of attempted correction, and 19 (100%) were within +/-1.0 D. Mean spherical equivalent refraction was -4.62 D preoperatively, +0.15 D at 1 month, -0.09 D at 3 months, and -0.37 D at 6 months. At 6 months, 4 eyes (21.0%) had no corneal haze and 14 (73.7%) had trace subepithelial haze. Fifteen eyes (78.9%) had no glare/halo effect at 6 months, and 4 (21.0%) had minimal glare/halo effect. CONCLUSIONS: Clinical outcomes after excimer laser PRK for myopia using an increased repetition rate of 15 Hz were good and similar to those in studies conducted with a 10 Hz repetition rate.

Orosensory factors in the ingestion of corn oil/sucrose mixtures by the rat.

The experiments reported here were designed to study the orosensory factors contributing to the ingestion of sucrose/corn oil mixtures. When a flavor aversion was conditioned to the sucrose/corn oil mixture, the subsequent aversion to the mixture strongly generalized to the corn oil but very little to the sucrose. Rats conditioned with corn oil show a more profound aversion to the sucrose/corn oil mixture than rats conditioned with sucrose, indicating that the salient feature of the sucrose/corn oil mixture is the oil. Aversion to the sucrose/corn oil mixture does not generalize to a sucrose/mineral oil mixture, giving evidence that the textural aspects of the oil do not play a major role in its perception. This flavor aversion to the mixture is further illustrated in very short-term tests where postingestive factors are minimized, indicating a role for the gustatory system in the detection of the sucrose/corn oil mixture. Preliminary experiments are reported where conditioning tests were run with mixtures of sucrose and linoleic acid, one of the fatty acids that is possibly derived from a breakdown of the corn oil in the oral cavity by lingual lipase from von Ebner's Gland.

Genetic variation and inferences about perceived taste intensity in mice and men.

The study of genetic variation in taste produces parallels between mice and men. In mice, genetic variation across strains has been documented with psychophysical and anatomical measures as well as with recordings from whole nerves. In humans, the variation has been documented with psychophysical and anatomical measures. Whole-nerve recordings from animals and psychophysical ratings of perceived intensities from human subjects have a similar logical limitation: absolute comparisons across individuals require a standard stimulus that can be assumed equally intense to all. Comparisons across whole-nerve recordings are aided by single-fiber recordings. Comparisons across psychophysical ratings of perceived intensity have been aided by recent advances in methodology; these advances now reveal that the magnitude of genetic variation in human subjects is larger than previously suspected. In females, hormones further contribute to variation in taste. There is evidence that the ability to taste (particularly bitter) cycles with hormones in women of child-bearing age, rises to a maximum early in pregnancy and declines after menopause. Taste affects food preferences, which in turn affect dietary behavior and thus disease risks. Valid assessment of taste variation now permits measurement of the impact of taste variation on health. Advances in psychophysical methodology were essential to understanding genetic variation in taste. In turn, the association of perceived taste intensities with tongue anatomy now provides a new tool for psychophysics. The ability of a psychophysical scale to provide across-subject comparisons can be assessed through its ability to show the fungiform papillae density-taste association.

Reliability of a utilization review instrument in a large field study.

One important question for a utilization management program is whether the utilization review instrument is consistent or stable when used on many occasions by the same abstractor (intrarater reliability) or by several abstractors (inter-rater reliability). As part of a nationwide study of inappropriate utilization of inpatient services by the Department of Veterans Affairs, we conducted a thorough investigation of the inter-rater reliability of a widely used utilization review instrument by 27 nurse abstractors. All abstractors were extensively trained, both by the developers of the instrument and by use of practice medical records. A standard protocol for resolving questions was implemented, with immediate communication of decisions to abstractors. The results of three reliability assessments, conducted immediately after formal training, after several weeks of reviewing practice records, and midway through review of the study records, demonstrated good to excellent reliability, both when comparing the nurse abstractors with a physician gold standard and among themselves. Therefore, with appropriate training and monitoring, utilization management programs in large hospitals, multihospital systems, and other health care organizations needing to examine inpatient utilization should feel confident that they can achieve reviews that would be in close agreement with physician and other nurse abstractors. Such confidence should increase the acceptability of utilization management programs.

Inappropriate hospital care and severity of illness: results from a nationwide study.

Little is known about the clinical characteristics of hospital patients who do not meet standard utilization review criteria for acute care settings. This study examined whether patients with either inappropriate hospital admissions or days of care were less severely ill on a number of indicators compared to those designated as appropriate by a widely used utilization review instrument. Using data from a probability sample of 6063 medical and surgical hospitalizations at 50 Department of Veterans Affairs medical centers, we found strong associations between the appropriateness of admissions and days of care and four indicators of severity of illness. These results suggest that utilization management programs and preadmission screening probably successfully screen out less severely ill patients who have less need of hospital-level services.

MS2 Coliphage as a Surrogate for 2009 Pandemic Influenza A (H1N1) Virus (pH1N1) in Surface Survival Studies on N95 Filtering Facepiece Respirators.

Research on influenza viruses regarding transmission and survival has surged in the recent years due to infectious emerging strains and outbreaks such as the 2009 Influenza A (H1N1) pandemic. MS2 coliphage has been applied as a surrogate for pathogenic respiratory viruses, such as influenza, as it's safe for personnel to handle and requires less time and labor to measure virus infectivity. However, direct comparisons to determine the effectiveness of coliphage as a surrogate for influenza virus regarding droplet persistence on personal protective equipment such as N95 filtering facepiece respirators (FFRs) are lacking. Persistence of viral droplets deposited on FFRs in healthcare settings is important to discern due to the potential risk of infection via indirect fomite transmission. The objective of this study was to determine if MS2 coliphage could be applied as a surrogate for influenza A viruses for studying persistence when applied to the FFRs as a droplet. The persistence of MS2 coliphage and 2009 Pandemic Influenza A (H1N1) Virus on FFR coupons in different matrices (viral media, 2% fetal bovine serum, and 5 mg ml-1 mucin) were compared over time (4, 12, 24, 48, 72, and 144 hours) in typical absolute humidity conditions (4.1 × 105 mPa [18°C/20% relative humidity (RH)]). Data revealed significant differences in viral infectivity over the 6-day period (H1N1- P <0.0001; MS2 - P <0.005), although a significant correlation of viral log10 reduction in 2% FBS (P <0.01) was illustrated. Overall, MS2 coliphage was not determined to be a sufficient surrogate for influenza A virus with respect to droplet persistence when applied to the N95 FFR as a droplet.