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81.
Sebastian S. S. Schmidt Angela Danielle Iuliano Lasse S. Vestergaard Clara MazagatosAteca Amparo Larrauri Jan M. Brauner Sonja J. Olsen Jens Nielsen Joshua A. Salomon Tyra G. Krause 《Influenza and other respiratory viruses》2022,16(4):707
BackgroundSeasonal influenza‐associated excess mortality estimates can be timely and provide useful information on the severity of an epidemic. This methodology can be leveraged during an emergency response or pandemic.MethodFor Denmark, Spain, and the United States, we estimated age‐stratified excess mortality for (i) all‐cause, (ii) respiratory and circulatory, (iii) circulatory, (iv) respiratory, and (v) pneumonia, and influenza causes of death for the 2015/2016 and 2016/2017 influenza seasons. We quantified differences between the countries and seasonal excess mortality estimates and the death categories. We used a time‐series linear regression model accounting for time and seasonal trends using mortality data from 2010 through 2017.ResultsThe respective periods of weekly excess mortality for all‐cause and cause‐specific deaths were similar in their chronological patterns. Seasonal all‐cause excess mortality rates for the 2015/2016 and 2016/2017 influenza seasons were 4.7 (3.3–6.1) and 14.3 (13.0–15.6) per 100,000 population, for the United States; 20.3 (15.8–25.0) and 24.0 (19.3–28.7) per 100,000 population for Denmark; and 22.9 (18.9–26.9) and 52.9 (49.1–56.8) per 100,000 population for Spain. Seasonal respiratory and circulatory excess mortality estimates were two to three times lower than the all‐cause estimates.DiscussionWe observed fewer influenza‐associated deaths when we examined cause‐specific death categories compared with all‐cause deaths and observed the same trends in peaks in deaths with all death causes. Because all‐cause deaths are more available, these models can be used to monitor virus activity in near real time. This approach may contribute to the development of timely mortality monitoring systems during public health emergencies. 相似文献
82.
Frølund B Jørgensen AT Tagmose L Stensbøl TB Vestergaard HT Engblom C Kristiansen U Sanchez C Krogsgaard-Larsen P Liljefors T 《Journal of medicinal chemistry》2002,45(12):2454-2468
A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K(i) = 9.1 microM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K(i) = 0.074 microM and K(i) = 0.049 microM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC(50) = 0.37 microM and IC(50) = 0.02 microM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC(50) = 0.24 microM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED(50) = 0.024 micromol/kg) and 7s (ED(50) = 0.21 micromol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity. 相似文献
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Quantitative immunoelectrophoretic analysis of human antibodies against herpes simplex virus antigens. 下载免费PDF全文
B F Vestergaard 《Infection and immunity》1979,23(3):553-558
By use of crossed immunoelectrophoresis with intermediate gel, antidbody titers against six individual herpes simplex virus (HSV) glycoproteins and two nonglycosylated proteins were determined in 100 human sera. High antibody titers were found against two different HSV type-common glycoproteins designated Ag8 and Ag11 (containing glycosylated polypeptides D and B, respectively). The anti-Ag8 and -Ag11 titers correlated with HSV neutralizing antibody titers. Most of the serological cross-reactivity between HSV type 1 and type 2 was probably caused by antibodies to Ag8 and Ag11. Human antibodies against one HSV type 1-specific glycoprotein (Ag6, containing glycosylated polypeptide C) and two HSV type 2 glycoproteins (Ag4 and Ag9) were also demonstrated, and the titers correlated better with neutralizing antibody titers of the homologous than of the heterologous virus type. The data presented can be directly applied to the further development of diagnostic reagents. 相似文献
85.
Bach A Clausen BH Møller M Vestergaard B Chi CN Round A Sørensen PL Nissen KB Kastrup JS Gajhede M Jemth P Kristensen AS Lundström P Lambertsen KL Strømgaard K 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(9):3317-3322
Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke. 相似文献
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In 1997, the United States Pharmacopeia (USP) established an Ad Hoc Outcomes/Cost Effectiveness Advisory Panel to consider the development of specifications for compiling, indexing, and evaluating outcomes research/cost-effectiveness literature on a disease-specific basis. Such a resource could be used to support pharmaceutical therapy choice decision making by a variety of potential users. The USP had developed a protype health outcomes and pharmacoeconomic annotated registry of the literature on the disease state, congestive heart failure. Other organizations have established and are marketing pharmacoeconomic and health outcome literature registries, with two examples being the HEED database (OHE-IFPMA Database Ltd.) and the University of York NHS Centre for Reviews and Dissemination (DARE).
OBJECTIVE: To share experiences and to identify the needs of decision makers for outcome/pharmacoeconomic information and to discuss whether they are being met by currently available literature sources. Decision makers include health care practitioners, managed care organizations, third party payers, industry and governments.
WORKSHOP FORMAT: The USP congestive heart failure protype literature registry will be described and compared to currently available pharmacoeconomic/outcome databases. Participants will share their assessment of the currently available abstracting service/databases and determine if there is a role for further developments.
DESIRED OUTCOME: To determine if there is a need for a collaborative approach among interested parties to make relevant health outcome/pharmacoeconomic information more accessible to the drug therapy decision makers in a format that is "user friendly." 相似文献
OBJECTIVE: To share experiences and to identify the needs of decision makers for outcome/pharmacoeconomic information and to discuss whether they are being met by currently available literature sources. Decision makers include health care practitioners, managed care organizations, third party payers, industry and governments.
WORKSHOP FORMAT: The USP congestive heart failure protype literature registry will be described and compared to currently available pharmacoeconomic/outcome databases. Participants will share their assessment of the currently available abstracting service/databases and determine if there is a role for further developments.
DESIRED OUTCOME: To determine if there is a need for a collaborative approach among interested parties to make relevant health outcome/pharmacoeconomic information more accessible to the drug therapy decision makers in a format that is "user friendly." 相似文献
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