Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland; and Salt Lake City-Veterans Affairs Geriatrics, Research, Education, and ...Clinical Center (GRECC) and University of Utah School of Medicine, Salt Lake City, Utah
The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of -bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.
Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine ...developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.
We present the first search for a dark matter annual modulation signal in the Southern Hemisphere conducted with NaI(Tl) detectors, performed by the DM-Ice17 experiment. Nuclear recoils from dark ...matter interactions are expected to yield an annually modulated signal independent of location within the Earth’s hemispheres. DM-Ice17, the first step in the DM-Ice experimental program, consists of 17 kg of NaI(Tl) located at the South Pole under 2200 m.w.e. overburden of Antarctic glacial ice. Taken over 3.6 years for a total exposure of 60.8 kg yr, DM-Ice17 data are consistent with no modulation in the energy range of 4–20 keV, providing the strongest limits on weakly interacting massive particle dark matter from a direct detection experiment located in the Southern Hemisphere. The successful deployment and stable long-term operation of DM-Ice17 establishes the South Pole ice as a viable location for future dark matter searches and in particular for a high-sensitivity NaI(Tl) dark matter experiment to directly test the DAMA/LIBRA claim of the observation of dark matter.
Background
New national guidance on urgent referral for investigation of colorectal cancer included faecal occult blood testing in 2015. A service evaluation of faecal immunochemical testing (FIT) ...and anaemia as risk stratification tools in symptomatic patients suspected of having CRC was undertaken.
Methods
Postal FIT was incorporated into the colorectal cancer 2‐week wait (2WW) pathway for all patients without rectal bleeding in 2016. Patients were investigated in the 2WW pathway as normal, and outcomes of investigations were recorded prospectively. Anaemia was defined as a haemoglobin level below 120 g/l in women and 130 g/l in men.
Results
FIT kits were sent to 1106 patients, with an 80·9 per cent return rate; 810 patients completed investigations and 40 colorectal cancers were diagnosed (4·9 per cent). FIT results were significantly higher in patients with anaemia (median (i.q.r.) 4·8 (0·8–34·1) versus 1·2 (0–6·4) μg Hb/g faeces in those without anaemia; P < 0·001). Some 60·4 per cent of patients (538 of 891) had a result lower than 4 μg haemoglobin (Hb) per g faeces (limit of detectability), and 69·7 per cent (621 of 891) had less than 10 μg Hb/g faeces. Some 60 per cent of patients with colorectal cancer had a FIT reading of 150 μg Hb/g faeces or more. For five colorectal cancers diagnosed in patients with a FIT value below 10 μg Hb/g faeces, there was either a palpable rectal mass or the patient was anaemic. A FIT result of more than 4 μg Hb/g faeces had 97·5 per cent sensitivity and 64·5 per cent specificity for a diagnosis of colorectal cancer. A FIT result above 4 μg Hb/g faeces and/or anaemia had a 100 per cent sensitivity and 45·3 per cent specificity for colorectal cancer diagnosis.
Conclusion
FIT is most useful at the extremes of detectability; strongly positive readings predict high rates of colorectal cancer and other significant pathology, whereas very low readings in the absence of anaemia or a palpable rectal mass identify a group with very low risk. High return rates for FIT within this 2WW pathway indicate its acceptability.
NICE guidance NG12 incorporated faecal occult blood testing into the urgent cancer diagnostic pathway. This article provides an analysis of the first pathway in England to incorporate faecal immunochemical testing (FIT). Return rates were high and FIT may allow risk stratification within this pathway.
“Getting FIT” aids colorectal cancer diagnosis
Abstract
As a part of the Tropical Cyclone Rapid Intensification Project (TCRI), observations were made of the rapid intensification of Hurricane Sally (2020) as it passed over the Gulf of Mexico. ...High-altitude dropsondes and radar observations from NOAA’s Gulfstream IV, radar observations from WP-3D aircraft, the WSR-88D ground radar network, satellite images, and satellite-detected lightning strikes are used to apply recently developed theoretical knowledge about tropical cyclone intensification. As observed in many other tropical cyclones, strong, bottom-heavy vertical mass flux profiles are correlated with low (but positive) values of low- to midlevel moist convective instability along with high column relative humidity. Such mass flux profiles produce rapid spinup at low levels and the environmental conditions giving rise to them are associated with an intense midlevel vortex. This low-level spinup underneath the midlevel vortex results in the vertical alignment of the vortex column, which is a key step in the rapid intensification process. In the case of Sally, the spinup of the low-level vortex resulted from vorticity stretching, while the spinup of the midlevel vortex at 6 km resulted from vorticity tilting produced by the interaction of convective ascent with moderate vertical shear.
Significance Statement
The purpose of this study is to investigate the rapid intensification of Hurricane Sally as it was approaching the Florida Panhandle. We do that by analyzing an unprecedented dataset from the NOAA WP-3D and Gulfstream-IV aircraft, together with ground-based radar and satellite data. We find that both the dynamics (vorticity structure and evolution) and thermodynamics (instability index, saturation fraction, heating/mass flux profiles) need to be considered in diagnosing intensification processes. Further field projects with continuous high-altitude dropsondes and research are needed to see if these are applicable to other reformation events as well as genesis.
Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and ...seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
BackgroundInvasive aspergillosis (IA) is the most common cause of death associated with fungal infection in the developed world. Historically, susceptibility to IA has been associated with prolonged ...neutropenia; however, IA has now become a major problem in patients on calcineurin inhibitors and allogenic hematopoetic stem cell transplant patients following engraftment. These observations suggest complex cellular mechanisms govern immunity to IA MethodsTo characterize the key early events that govern outcome from infection with Aspergillus fumigatus we performed a comparative immunochip microarray analysis of the pulmonary transcriptional response to IA between cyclophosphamide-treated mice and immunocompetent mice at 24 h after infection ResultsWe demonstrate that death due to infection is associated with a failure to generate an incremental interferon-γ response, increased levels of interleukin-5 and interleukin-17a transcript, coordinated expression of a network of tumor necrosis factor–α-related genes, and increased levels of tumor necrosis factor–α. In contrast, clearance of infection is associated with increased expression of a number genes encoding proteins involved in innate pathogen clearance, as well as apoptosis and control of inflammation ConclusionThis first organ-level immune response transcriptional analysis for IA has enabled us to gain new insights into the mechanisms that govern fungal immunity in the lung
Two isomers decaying by electromagnetic transitions with half-lives of 4.7(1.1) and 247(73) μs have been discovered in the heavy ^{254}Rf nucleus. The observation of the shorter-lived isomer was made ...possible by a novel application of a digital data acquisition system. The isomers were interpreted as the K^{π}=8^{-}, ν^{2}(7/2^{+}624,9/2^{-}734) two-quasineutron and the K^{π}=16^{+}, 8^{-}ν^{2}(7/2^{+}624,9/2^{-}734)⊗8^{-}π^{2}(7/2^{-}514,9/2^{+}624) four-quasiparticle configurations, respectively. Surprisingly, the lifetime of the two-quasiparticle isomer is more than 4 orders of magnitude shorter than what has been observed for analogous isomers in the lighter N=150 isotones. The four-quasiparticle isomer is longer lived than the ^{254}Rf ground state that decays exclusively by spontaneous fission with a half-life of 23.2(1.1) μs. The absence of sizable fission branches from either of the isomers implies unprecedented fission hindrance relative to the ground state.
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