Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, psychiatric and cognitive decline. Marked neuronal loss occurs in the cortex and striatum. HD is ...inherited in an autosomal dominant fashion and caused by a trinucleotide repeat expansion (CAG) in the gene encoding the protein huntingtin. Predictive genetic testing has revealed early cognitive deficits in asymptomatic gene carriers at a time when there is little evidence for cell death, suggesting that impaired cognition results from a cellular or synaptic deficit, such as aberrant synaptic plasticity. Altered hippocampal long-term potentiation has been reported in mouse models of HD; however, the relationship between synaptic dysfunction and phenotype progression has not previously been characterized. We examined the age-dependency of aberrant hippocampal synaptic plasticity in the R6/1 mouse model of HD. Long-term depression (LTD) is a developmentally regulated form of plasticity, which normally declines by early adulthood. Young R6/1 mice follow the same pattern of LTD expression as controls, in that they express LTD in the first weeks of life, and then lose the ability with age. Unlike controls, R6/1 synapses later regain the ability to support LTD. This is associated with nuclear localization of mutant huntingtin, but occurs months prior to the formation of nuclear aggregates. We present the first detailed description of a progressive derailment of a functional neural correlate of cognitive processing in HD.
This work reports a precise measurement of the reactor antineutrino flux using 2.2 million inverse beta decay (IBD) events collected with the Daya Bay near detectors in 1230 days. The dominant ...uncertainty on the neutron detection efficiency is reduced by 56% with respect to the previous measurement through a comprehensive neutron calibration and detailed data and simulation analysis. The new average IBD yield is determined to be (5.91±0.09)×10−43 cm2/fission with total uncertainty improved by 29%. The corresponding mean fission fractions from the four main fission isotopes U235, U238, Pu239, and Pu241 are 0.564, 0.076, 0.304, and 0.056, respectively. The ratio of measured to predicted antineutrino yield is found to be 0.952±0.014±0.023 (1.001±0.015±0.027) for the Huber-Mueller (ILL-Vogel) model, where the first and second uncertainty are experimental and theoretical model uncertainty, respectively. This measurement confirms the discrepancy between the world average of reactor antineutrino flux and the Huber-Mueller model.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were ...investigated.
Circulating biomarkers of cell death (nucleosomal DNA (nDNA) and cytokeratin 18 (CK18)), and circulating FLT3 ligand, a potential biomarker of myelosuppression, were assessed before and serially after standard chemotherapy in 49 patients with Hodgkin and non-Hodgkin lymphoma. Cytokeratin 18 is not expressed in lymphoma cells so is a potential biomarker of epithelial toxicity in this setting. Tumour response was assessed before and after completion of chemotherapy by 2D and 3D computed tomography radiological response.
Baseline nDNA level was significantly higher in all lymphoma subtypes compared with 61 healthy controls and was prognostic for progression-free survival in diffuse large B-cell lymphoma (DLBCL). Decreases in nDNA levels were observed in the first week after chemotherapy; in FL, early falls in nDNA predicted for long remission following therapy. In DLBCL, elevations in nDNA occurred in cases with progressive disease. Circulating CK18 increased within 48 h of chemotherapy and was significantly higher in patients experiencing epithelial toxicity graded >3 by Common Terminology for Classification of Adverse Events criteria. FLT3 ligand was elevated within 3-8 days of chemotherapy initiation and predicted those patients who subsequently developed neutropenic sepsis.
These data suggest circulating biomarkers contribute useful information regarding tumour response and toxicity in patients receiving standard chemotherapy and have potential utility in the development of individualised treatment approaches in lymphoma. These biomarkers are now being tested within multicentre phase III trials to progress their qualification.
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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, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Our knowledge of the prevalence and sources of pain within hospital is limited. The present study is an epidemiological investigation of pain in a pediatric hospital. All children who were inpatients ...in a tertiary care hospital (excluding Neonatal ICU and psychiatry patients) and one parent per child were potential subjects. Interviews were conducted on three weekdays. Parent interviews were used for children less than 5 years of age (n = 102); child interviews were used for children age 5 years and older (n = 98). Subjects reported the intensity and source of the worst, usual and current pain during the past 24 h, and help received for pain. Medical and demographic variables and analgesics prescribed and administered were obtained from the medical record. Forty-nine percent of subjects reported clinically significant levels of worst pain. Twenty-one percent of subjects had clinically significant levels of usual pain. Causes of pain were variable and included disease, surgery, and intravenous lines (I.V.). Pain intensity was not significantly related to age, gender, patient type (medical, surgical), or diagnostic category. Children were given significantly less medication than was prescribed, regardless of their reported pain level. Nurses, mothers, and 'no-one' were frequently reported as helping with pain. Medications and nonpharmacological methods were reported as helpful in managing pain. Many children endure unacceptable levels of pain during hospitalization. Pain prevention and management must be more aggressive. Pain assessment should be approached with the same attention as vital signs. Improvements in analgesic prescription and administration practices and non-pharmacological pain control methods are needed.
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IJS, IMTLJ, KILJ, SBCE, SBJE, UPUK
This article describes a 10-year cooperative effort between the U.S. National Institute of Standards and Technology (NIST) and five major journals in the field of thermophysical and thermochemical ...properties to improve the quality of published reports of experimental data. The journals are Journal of Chemical and Engineering Data, The Journal of Chemical Thermodynamics, Fluid Phase Equilibria, Thermochimica Acta, and International Journal of Thermophysics. The history of this unique cooperation is outlined, together with an overview of software tools and procedures that have been developed and implemented to aid authors, editors, and reviewers at all stages of the publication process, including experiment planning. Both successes and failures are highlighted. The procedures are now well established and are designed to yield maximum benefit to all stakeholders (authors, editors, reviewers, publishers, readers, data users, etc.) through the establishment of procedures and support tools that efficiently serve the specific interests of those involved. All specially designed tools and procedures are described fully, together with their benefits and examples of application. A key feature of the cooperation is the efficient validation of experimental data after peer review but before acceptance for publication. Nearly 1000 articles per year are considered within the scope of this work, with significant problems identified in roughly one-third of these. Full statistics for the findings are given, and a variety of examples of common problems found are given.
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IJS, KILJ, NUK, PNG, UL, UM
Recent advances in developing disease‐modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a ...paradigm shift of health‐care systems toward biomarker‐guided early detection, diagnosis, and therapeutic decision‐making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs—once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state‐of‐the‐art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP‐associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
P-selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein ligand for P- and E-selectin on myeloid cells and a subset of lymphocytes. We used flow cytometry and immunohistochemistry to ...examine expression of PSGL-1 on minor leukocyte populations, differentiating hematopoietic cells, and nonhematopoietic tissues using two monoclonal antibodies to distinct protein epitopes on PSGL-1. In the bone marrow, PSGL-1 was expressed on myeloid cells from the myeloblast stage to the segmented neutrophil, but was not detected on erythroblasts or megakaryocytes. All types of circulating myeloid cells expressed PSGL-1, and PSGL-1 was retained after extravasation of myeloid cells into tissues. PSGL-1 was also expressed on circulating dendritic cells, monocyte-derived dendritic cells, dendritic cells in lymphoid tissues and epidermis, and follicular dendritic cells. All types of lymphoid cells examined expressed PSGL-1, including immature and mature thymocytes, naive and memory T cells, γ/δ T cells, natural killer cells, B cells, and CD34+ progenitor cells. However, PSGL-1 levels were substantially lower on tonsillar lymphocytes than on circulating lymphocytes, suggesting that PSGL-1 expression is down-regulated during or after entry of lymphocytes into secondary lymphoid tissue. Although PSGL-1 antigen was detected primarily on hematopoietic cells, it was also present on the epithelium of the fallopian tube. Furthermore, PSGL-1 antigen was detected sporadically on microvascular endothelium in some pathologic tissues. This suggests that PSGL-1 may have functions other than mediating leukocyte adhesion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Swift Gamma-Ray Burst Mission Gehrels, N; Chincarini, G; Giommi, P ...
The Astrophysical journal,
08/2004, Volume:
611, Issue:
2
Journal Article
Peer reviewed
The Swift mission, scheduled for launch in 2004, is a multiwavelength observatory for gamma-ray burst (GRB) astronomy. It is a first-of-its-kind autonomous rapid-slewing satellite for transient ...astronomy and pioneers the way for future rapid-reaction and multiwavelength missions. It will be far more powerful than any previous GRB mission, observing more than 100 bursts yr super(-1) and performing detailed X-ray and UV/optical afterglow observations spanning timescales from 1 minute to several days after the burst. The objectives are to (1) determine the origin of GRBs, (2) classify GRBs and search for new types, (3) study the interaction of the ultrarelativistic outflows of GRBs with their surrounding medium, and (4) use GRBs to study the early universe out to z > 10. The mission is being developed by a NASA-led international collaboration. It will carry three instruments: a new-generation wide-field gamma-ray (15-150 keV) detector that will detect bursts, calculate 1arcmin-4arcmin positions, and trigger autonomous spacecraft slews; a narrow-field X-ray telescope that will give 5arc sec positions and perform spectroscopy in the 0.2-10 keV band; and a narrow-field UV/optical telescope that will operate in the 170-600 nm band and provide 0!!3 positions and optical finding charts. Redshift determinations will be made for most bursts. In addition to the primary GRB science, the mission will perform a hard X-ray survey to a sensitivity of approx1 mcrab (approx2 x 10 super(-11) ergs cm super(-2) s super(-1) in the 15-150 keV band), more than an order of magnitude better than HEAO 1 A-4. A flexible data and operations system will allow rapid follow-up observations of all types of high-energy transients, with rapid data downlink and uplink available through the NASA TDRSS system. Swift transient data will be rapidly distributed to the astronomical community, and all interested observers are encouraged to participate in follow- up measurements. A Guest Investigator program for the mission will provide funding for community involvement. Innovations from the Swift program applicable to the future include (1) a large-area gamma-ray detector using the new CdZnTe detectors, (2) an autonomous rapid-slewing spacecraft, (3) a multiwavelength payload combining optical, X-ray, and gamma-ray instruments, (4) an observing program coordinated with other ground-based and space-based observatories, and (5) immediate multiwavelength data flow to the community. The mission is currently funded for 2 yr of operations, and the spacecraft will have a lifetime to orbital decay of approx8 yr.
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