Serine Protease Inhibitors Block Invasion of Host Cells by Toxoplasma gondii

We investigated the effect of protease inhibitors on the asexual development of the protozoan parasite Toxoplasma gondii. Among the inhibitors tested only two irreversible serine protease inhibitors, 3,4-dichloroisocoumarin and 4-(2-aminoethyl)-benzenesulfonyl fluoride, clearly prevented invasion of the host cells by specifically affecting parasite targets in a dose-dependent manner, with 50% inhibitory concentrations between 1 and 5 and 50 and 100 microM, respectively. Neither compound significantly affected parasite morphology, basic metabolism, or gliding motility within the range of the experimental conditions in which inhibition of invasion was demonstrated. No partial invasion was observed, meaning that inhibition occurred at an early stage of the interaction. These results suggest that at least one serine protease of the parasite is involved in the invasive process of T. gondii.     

Photochromic properties of a dithienylethene–indolinooxazolidine switch: A theoretical investigation

Using ab initio spectroscopic tools, we have studied the structural and electronic properties of an hybrid dithienylethene–indolinooxazolidine switch synthesized by Pozzo and coworkers [Photochem. Photobiol. Sci. 9 (2010) 131]. To simulate the electronic absorption spectra of this mixed photochrome, we relied on a PCM-TD-DFT approach. Several functionals have been considered, namely the PBE0 global hybrid as well as four range-separated hybrids (CAM-B3LYP, LC-ωPBE, ωB97X and ωB97XD). On average, considering all four closed/open structures, ωB97XD provides the best compromise for estimating the transition wavelengths. It is shown that the TD-DFT procedure combined with an analysis of the molecular orbitals implied in the absorption bands provide insights into the observed photochromic pathways.     

Influenza Virus RNA Synthesis and the Innate Immune Response

Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In this review, we will focus on the interplay between influenza virus RNA synthesis and the detection of influenza virus RNA by our innate immune system. Specifically, we will discuss the generation of various RNA species, host pathogen receptors, and host shut-off. In addition, we will also address outstanding questions that currently limit our knowledge of influenza virus replication and host adaption. Understanding the molecular mechanisms underlying these factors is essential for assessing the pandemic potential of future influenza virus outbreaks.     

alpha-Bromoisovalerylurea as model substrate for studies on pharmacokinetics of glutathione conjugation in the rat. I. (Bio-) synthesis, analysis and identification of diastereomeric glutathione conjugates and mercapturates

In order to find a model substrate for kinetic characterization of glutathione conjugation in vivo alpha-bromoisovalerylurea (BIU) was studied. After administration of racemic [14C]urea BIU to rats, two radioactive metabolites were found in bile by high-performance liquid chromatography. The identity of these metabolites was established by various methods. Based on the hydrolytic activity of gamma-glutamyltranspeptidase (presence of the gamma-glutamyl moiety), high resolution nuclear magnetic resonance (isovaleryl and glutathionyl moieties) and fast atom bombardment mass spectrometry (molecular weight and fragmentation pattern), they were identified as glutathione conjugates of BIU. Because both conjugates in bile had these characteristics in common they must be diastereomers. Incubation of BIU with glutathione in the presence of rat liver cytosol resulted in formation of the same diastereomeric glutathione conjugates. Chemical synthesis of the diastereomers confirmed their identity. The major urinary excretion products of [14C]urea BIU in the rat were identified as diastereomeric mercapturates. A convenient chromatographic separation of the diastereomeric glutathione conjugates and the mercapturic acids is described. Electrochemical detection was used to determine the presence of the thioethers in both urine and bile. Pharmacokinetic results on BIU conjugation are described in the accompanying paper.     

Modeling the His-Purkinje Effect in Non-invasive Estimation of Endocardial and Epicardial Ventricular Activation

Inverse electrocardiography (iECG) estimates epi- and endocardial electrical activity from body surface potentials maps (BSPM). In individuals at risk for cardiomyopathy, non-invasive estimation of normal ventricular activation may provide valuable information to aid risk stratification to prevent sudden cardiac death. However, multiple simultaneous activation wavefronts initiated by the His-Purkinje system, severely complicate iECG. To improve the estimation of normal ventricular activation, the iECG method should accurately mimic the effect of the His-Purkinje system, which is not taken into account in the previously published multi-focal iECG. Therefore, we introduce the novel multi-wave iECG method and report on its performance. Multi-wave iECG and multi-focal iECG were tested in four patients undergoing invasive electro-anatomical mapping during normal ventricular activation. In each subject, 67-electrode BSPM were recorded and used as input for both iECG methods. The iECG and invasive local activation timing (LAT) maps were compared. Median epicardial inter-map correlation coefficient (CC) between invasive LAT maps and estimated multi-wave iECG versus multi-focal iECG was 0.61 versus 0.31. Endocardial inter-map CC was 0.54 respectively 0.22. Modeling the His-Purkinje system resulted in a physiologically realistic and robust non-invasive estimation of normal ventricular activation, which might enable the early detection of cardiac disease during normal sinus rhythm.

     

Inhibition of thromboxane synthetase potentiates the antihypertensive action of an angiotensin-converting enzyme inhibitor by a prostaglandin-dependent but kinin-independent mechanism

Mean arterial pressure (BP) was measured in conscious, spontaneously hypertensive rats (SHR). Oral administration of the angiotensin I-converting enzyme inhibitor (ACEI) CGS 16617 significantly lowered BP. In contrast, the thromboxane synthetase inhibitor (TxSI) CGS 12970 lacked an antihypertensive action in SHR. When administered concurrently, the TxSI significantly potentiated the antihypertensive actions of the ACEI. Inhibition of thromboxane synthetase did not potentiate the antihypertensive actions of metoprolol or verapamil, indicating that a specific interaction exists between a TxSI and an ACEI. The antihypertensive actions of CGS 16617 also were potentiated by the cyclooxygenase inhibitor indomethacin, a result suggesting that CGS 12970 may enhance the action of CGS 16617 by inhibiting the action of vasoconstrictor prostaglandins produced after administration of an ACEI. The potentiation of the antihypertensive actions of CGS 16617 by CGS 12970 remained unaffected by either the kallikrein inhibitor aprotinin or a bradykinin receptor antagonist. Thus, although the interaction between an ACEI and a TxSI is a prostaglandin-dependent mechanism, it is not mediated by endogenous kinins. Inhibition of thromboxane synthetase significantly stimulated renin release and significantly attenuated the pressor response to exogenously administered angiotensin II. An increase in the dependency of BP upon the renin-angiotensin system and attenuation of the vascular actions of angiotensin II may serve to explain the potentiation of the antihypertensive action of ACEI after inhibition of thromboxane synthetase. The interaction between ACEI and TxSI was not restricted to SHR, because a TxSI potentiated the actions of an ACEI in both normotensive and deoxycorticosterone acetate/Na hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recurrent craniopharyngiomas in children and adults: long-term recurrence rate and management

Background

The significance of the majority of the factors influencing the recurrence rate (RR) of craniopharyngiomas remains unclear, and the management of this significance is controversial. The present study aimed to evaluate the influence of patient age and tumor topography on the RR, the efficacy of radiotherapy, and the safety of surgery for recurrences.

Methods

The RR was analyzed in 38 children (follow-up, 2–256 months [mean, 147.6]) and 63 adults (follow-up, 2–221 months [mean, 100.2]. The efficacy of 18 sessions of radiotherapy (13 patients) and the outcome of 52 secondary surgeries (37 patients) were evaluated.

Results

The RR reached 39.5 % in children and 22.2 % in adults (p?=?0.053). After radical tumor removal, the RR in children (36.7 %) was significantly higher (p?=?0.024) than that in adults (14 %). In children after radical removal of intraventricular and extraventricular craniopharyngiomas (IECs), the RR was higher (60 %; p?=?0.071) than in extraventricular (intrasellar and suprasellar; purely suprasellar extraventricular) tumors (25 %). Radical removal of 50 % of tumors was achieved (73.1 % in children; 26.9 % in adults; p?=?0.002) in 56.7 % of the first and 40.9 % of further recurrences. There was no early mortality after 52 surgeries; functional worsening (endocrine, 2; obesity, 2; visual, 3) occurred after 7/52 secondary surgeries. Recurrence occurred after 9/18 sessions of radiotherapy.

Conclusions

The RR was higher in children than in adults and in IECs relative to other topographic groups. Children with IECs represent a risk group. The efficacy of radiotherapy was inconclusive. Early detection of recurrences enabled safe excision with low morbidity.     

Parkinson's patients cope with daylight saving time

Disturbances of the circadian timing system following daylight saving time (DST) may influence the symptoms of Parkinson's disease (PD). To address this question, we compared the severity of motor fluctuations and non-motor symptoms both before and after the time change. Total daily “off-time” based on diaries, excessive daytime sleepiness (Epworth Sleepiness Scale), depressive symptoms (Beck Depression Inventory), and psychosis associated with PD were assessed both before and after the DST. Eighty-three PD patients (mean age, 67 ± 7.7 years; mean disease duration, 10.4 ± 6.4 years) were included. Thirty-six patients had motor fluctuations (mean daily “off-time”, 4.8 ± 2.4 h/day). There was no significant variation of the total daily “off-time” (2.5 ± 2.6 h/day versus 2.5 ± 2.7 h/day), ESS (8.3 ± 4.8 versus 8.1 ± 4.9), BDI (10.4 ± 6.2 versus 10.0 ± 6.9), or PAPD (1.4 ± 1.6 versus 1.1 ± 1.6) scores (P > 0.05) after DST. Our results suggest that PD patients cope relatively well with DST.     

农科大学生的自我和谐与自测健康:自尊的调节作用

目的探讨农科大学生的自尊、自我和谐与自测健康状况的关系,研究自尊在自我和谐与自测健康关系中的调节效应。方法采用自尊量表、自我和谐量表及自测健康评定量表对国内9所农业高校1677名大学生进行施测,利用阶层回归对变量间的效应关系进行分析。结果①自尊与自我和谐及自测健康存在显著性相关(r=0.63,-0.47;P<0.01);②自尊、自我和谐及各因子得分随自测健康总分的升高而逐步降低(F=182.25,182.99,72.01,83.14,243.73;P<0.05);③自尊在自我和谐与自测健康的关系中起着显著的调节作用(β=1.54,P<0.001)。结论自尊能够调整自我和谐对自测健康的影响。