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71.
Christopher A. Rice Beatrice L. Colon Mehmet Alp Hakan G?ker David W. Boykin Dennis E. Kyle 《Antimicrobial agents and chemotherapy》2015,59(4):2037-2044
Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. 相似文献
72.
Flavia M. Wehrle Markus A. Landolt Beatrice Latal Sarah Rometsch Matthias Greutmann 《Congenital heart disease》2020,15(5):301-308
Background: The risk for a severe disease course in case of infection
with SARS-CoV-2 in young adults with congenital heart disease is largely
unknown, potentially leading to uncertainty and anxiety among affected patients.
This study aims to investigate health-related concerns, health-related quality of
life and psychological adjustment in patients with congenital heart disease compared to healthy peers during the COVID-19 pandemic. Methods: One-hundred
patients with congenital heart disease and 50 controls (M = 29.7, SD = 3.8 years)
were recruited. They completed an online survey including the assessment of
health-related concerns regarding COVID-19, the 12-item Short Form Health Survey and the Brief Symptom Inventory. Results: Patients considered COVID-19 to
be a more serious issue (Generalized odds ratio [GenOR] = 1.67, p = 0.04), were
more concerned about becoming infected (GenOR = 2.93, p < 0.001) and
expressed more fear about leaving their homes (GenOR = 1.81, p = 0.004) while
general anxiety symptoms were not different between groups (p = 0.23). Patients
relied more on family and friends for support (30% vs. 2% in controls, p < 0.001)
and reported better compliance with protective measures (p = 0.03). Mental
health-related quality of life and psychological adjustment were not different
between groups (p = 0.17 and p = 0.68, respectively). Physical health-related
quality of life was lower in patients compared to controls (p = 0.03). Conclusions:
Young adults with congenital heart disease in Switzerland are more concerned
about their health during the COVID-19 pandemic compared to healthy peers.
These concerns, however, do not translate into generally impaired mental wellbeing. The impact of the easing of lockdown measures on long-term anxiety levels
and quality of life requires further study 相似文献
73.
Concurrent interaction of DCs with CD4+ and CD8+ T cells improves secondary CTL expansion: It takes three to tango 下载免费PDF全文
Stefanie Hoyer Sabrina Prommersberger Isabell A. Pfeiffer Beatrice Schuler‐Thurner Gerold Schuler Jan Dörrie Niels Schaft 《European journal of immunology》2014,44(12):3543-3559
T‐cell help is essential for CTL‐memory formation. Nevertheless, it is unclear whether the continuous presence of CD4+ T‐helper (Th) cells is required during dendritic cell (DC)/CD8+ T‐cell encounters, or whether a DC will remember the helper signal after the Th cell has departed. This question is relevant for the design of therapeutic cancer vaccines. Therefore, we investigated how human DCs need to interact with CD4+ T cells to mediate efficient repetitive CTL expansion in vitro. We established an autologous antigen‐specific in vitro system with monocyte‐derived DCs, as these are primarily used for cancer vaccination. Contrary to common belief, a sequential interaction of licensed DCs with CD8+ T cells barely improved CTL expansion. In sharp contrast, simultaneous encounter of Th cells and CTLs with the same DC during the first in vitro encounter is a prerequisite for optimal subsequent CTL expansion in our in vitro system. These data suggest that, in contrast to DC maturation, the activation of DCs by Th cells, which is necessary for optimal CTL stimulation, is transient. This knowledge has significant implications for the design of new and more effective DC‐based vaccination strategies. Furthermore, our in vitro system could be a valuable tool for preclinical immunotherapeutical studies. 相似文献
74.
Paolo Spirito Camillo Autore Francesco Formisano Gabriele Egidy Assenza Elena Biagini Tammy S. Haas Sergio Bongioanni Christopher Semsarian Emmanuela Devoto Beatrice Musumeci Francesco Lai Laura Yeates Maria Rosa Conte Claudio Rapezzi Luca Boni Barry J. Maron 《The American journal of cardiology》2014
75.
Elena Biagini Iacopo Olivotto Maria Iascone Maria I. Parodi Francesca Girolami Giulia Frisso Camillo Autore Giuseppe Limongelli Massimiliano Cecconi Barry J. Maron Martin S. Maron Stefania Rosmini Francesco Formisano Beatrice Musumeci Franco Cecchi Attilio Iacovoni Tammy S. Haas Maria L. Bacchi Reggiani Paolo Ferrazzi Francesco Salvatore Paolo Spirito Claudio Rapezzi 《The American journal of cardiology》2014
76.
Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR‐PI376, as highly potent agonists at the human histamine H4 receptor (hH4R). While imidazole‐containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six‐membered heterocycles (piperidine, morpholine, thiomorpholine, and N‐methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C3–C5) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand‐binding assays exhibited only very weak activity at the hH1R and hH3R, while nearly all compounds were inactive at the hH2R and hH4R. In the case of piperidine‐containing compounds, moderate affinities at the hH3R over the single‐digit micromolar range were detected. 相似文献
77.
Francesca Innocenti Alessandro Coppa Beatrice Del Taglia Federica Trausi Alberto Conti Maurizio Zanobetti Riccardo Pini 《Internal and emergency medicine》2014,9(4):467-474
The aims of this study were to compare outcome after a mild to moderate trauma in three subgroups of patients of increasing age (A1: <50, A2: 50–74, A3: >74 years) and to assess potential health-related quality of life (HRQOL) impairment. This is a follow-up study of a cohort of 418 trauma patients admitted to the High Dependency Unit of the Emergency Department of the University Hospital of Florence from July 2008 to February 2012. Six months after the event, a telephone interview using the Physical component summary (PCS) and Mental component summary (MCS) Health Composite Score (SF12) was conducted. Patients reported their QOL both at present and before trauma. In-hospital mortality was 10 of 418 (2.3 %); overall mortality was 27 of 244 (11 %) patients found at follow-up. No death was observed among A1 patients; overall mortality was (6/76) 7 % in A2 and (21/71) 30 % in A3 patients (p < 0.05 A1 vs A2, A1 vs A3 and A2 vs A3). Before the event, respectively, 94 and 96 % patients reported a normal MCS and PCS score (>39); after the event, the proportion of patients with a normal score value was significantly lower (MCS 70 %, p = 0.002; PCS 58 %, p < 0.0001). All subgroups showed a highly significant reduction in the scores’ value due to the trauma. After the event, the proportion of patients with normal scores was significantly lower (all p < 0.0001, except for MCS score in A1 subgroup, who showed p = 0.013) within all subgroups. Elderly patients’ prognosis was significantly worse compared with the younger counterpart; despite young patients’ optimal outcome, HRQOL was uniformly reduced across all age groups. 相似文献
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