The case for allele‐specific recognition by the TCR

There is a sharp difference in how one views TCR structure–function–behaviour dependent on whether its recognition of major histocompatibility complex‐encoded restriction elements (R) is germline selected or somatically generated. The generally accepted or Standard model is built on the assumption that recognition of R is by the V regions of the αβ TCR, which is not driven by allele specificity, whereas the competing model posits that recognition of R is allele‐specific. The establishing of allele‐specific recognition of R by the TCR would rule out the Standard model and clear the road to a consideration of a competing construct, the Tritope model. Here, the case for allele‐specific recognition (germline selected) is detailed making it obvious that the Standard model is untenable.     

A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study

ObjectiveWe aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.MethodsIn order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.ResultsWe found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.ConclusionIn this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.SignificanceEstablished and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.     

Daily skin-to-skin contact in full-term infants and breastfeeding: Secondary outcomes from a randomized controlled trial

This randomized controlled trial evaluated the effect of a 5-week daily skin-to-skin contact (SSC) intervention between mothers and their full-term infants, compared with care-as-usual, on exclusive and continued breastfeeding duration during the first post-natal year. Healthy pregnant women (n = 116) from a community sample were enrolled and randomly allocated to the SSC or care-as-usual condition. SSC mothers were requested to provide one daily hour of SSC for the first five post-natal weeks. Twelve months post-partum, mothers indicated the number of exclusive and continued breastfeeding months. Multiple regression analyses were conducted using intention-to-treat, per-protocol and exploratory dose–response frameworks. In intention-to-treat analyses, exclusive and continued breastfeeding duration was not different between groups (exclusive: 3.61 ± 1.99 vs. 3.16 ± 1.77 months; adjusted mean difference 0.28, 95% confidence interval [CI] ?0.33 to 0.89; p = 0.36; continued: 7.98 ± 4.20 vs. 6.75 ± 4.06 months; adjusted mean difference 0.81, 95% CI ?0.46 to 2.08; p = 0.21). In per-protocol analyses, exclusive and continued breastfeeding duration was longer for SSC than care-as-usual dyads (exclusive: 4.89 ± 1.26 vs. 3.25 ± 1.80 months; adjusted mean difference 1.28, 95% CI 0.31–2.24; p = 0.01; continued: 10.81 ± 1.97 vs. 6.98 ± 4.08 months; adjusted mean difference 2.33, 95% CI 0.13–4.54; p = 0.04). Exploratory dose–response effects indicated that more SSC hours predicted longer exclusive and continued breastfeeding duration. This study demonstrates that for the total group, the 5-week daily SSC intervention did not extend exclusive and continued breastfeeding duration. However, for mothers performing a regular daily hour of SSC, this simple and accessible intervention may extend exclusive and continued breastfeeding duration by months. Future studies are required to confirm these promising findings. Trial registration: Netherlands Trial Register (NTR5697).     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

Sex differences in neural mechanisms of social and non-social threat monitoring

Adolescent males and females differ in their responses to social threat. Yet, threat processing is often probed in non-social contexts using the error-related negativity (ERN; Flanker EEG Task), which does not yield sex-specific outcomes. fMRI studies show inconsistent patterns of sex-specific neural engagement during threat processing. Thus, the relation between threat processing in non-social and social contexts across sexes and the effects perceived level of threat on brain function are unclear. We tested the interactive effect of non-social threat-vigilance (ERN), sex (N = 69; Male=34; 11–14-year-olds), and perceived social threat on brain function while anticipating feedback from ‘unpredictable’, ‘nice’, or ‘mean’ purported peers (fMRI; Virtual School Paradigm). Whole-brain analyses revealed differential engagement of precentral and inferior frontal gyri, putamen, anterior cingulate cortex, and insula. Among males with more threat-vigilant ERNs, greater social threat was associated with increased activation when anticipating unpredictable feedback. Region of interest analyses revealed this same relation in females in the amygdala and anterior hippocampus when anticipating mean feedback. Thus, non-social threat vigilance relates to neural engagement depending on perceived social threat, but peer-based social contexts and brain regions engaged, differ across sexes. This may partially explain divergent psychosocial outcomes in adolescence.     

哮喘患儿血清嗜酸性粒细胞阳离子蛋白改变及其意义

目的：评价变应性哮喘患儿血清嗜酸性粒细胞阳离子蛋白（S-ECP）水平改变及其意义。方法：测定25例哮喘发作期患儿糖皮质激素吸入治疗12周前后，及20例未予糖皮质激素吸入治疗的哮喘缓解期患儿S-ECP水平，并对发作期患儿S-ECP水平变化与血嗜酸性粒细胞计数（B-EOS）、肺功能一秒用力呼气量（FEV1）、一秒用力呼气量比用力肺活量（FEV1/FVC）及症状评分的关系作相关性分析。结果：哮喘发作组治疗后S-ECP水平较治疗前显著降低，与对照组（健康儿童10名）比较差异无显著性；哮喘缓解组S-ECP水平明显高于发作组治疗后，但明显低于发作组治疗前。哮喘发作组治疗前S-ECP水平变化与B-EOS无相关性，与FEV1、FEV1/FVC呈负相关，与症状评分呈正相关。结论：监测S-ECP水平可作为评价哮喘气道炎症程度、病情预后和指导抗炎治疗的有效指标。     

Characteristics of the Nonselective Cation Current （NSCCs） in Rabbit Left Ventricular Epicardial, Midmyocardial and Endocardial Myocytes

Objectives Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. This has been shown to be due to a smaller IKs and a lager sodium-calcium exchange current (INa-Ca) and late INa in M region (deep subepicardial to midmyocardial). Studies from our laboratory have found a new repolarization current-nonselective cation current (NSCCs) existing in rabbit right ventricular myocytes. Methods We examined the characteristics of NSCCs in epicardial, M region, and endocardial cells isolated from the rabbit left ventricle with standard microelectrode and whole-cell patch-clamp techniques. The permeability to Na , K , Li , Cs but not to Cl- indicating that it was a nonselective cation current. Gd3 (0.1 mmol/l) and La3 (0.1 mmol/l) can block the current markedly. Results Further characterization of NSCCs was significantly smaller in M cells than in epicardial and endocardial cells. NSCCs current density was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -80 mV, INs current density was (-0.44±0.05) PA/PF in endocardial cells, (-0.12±0.05) PA/PF in M cells and (-0.28±0.07) PA/PF in epicardial cells; and with repolarization to 30 mV, INs current density was (1.09±0.29) PA/PF in endocardial cells, (0.38±0.09) PA/PF in M cells and (0.91±0.32) PA/PF in epicardial cells. Conclusions Transmural dispersion of repolarization was due to the heterogeneity of NSCCs in rabbit left ventricle epicardial, endocardial myocytes and M cells. These findings may advance our understanding of the ionic basis for our understanding of factors contributing to the development of cardiac arrhythmias.     

计算机辅助手术的发展状况和展望——参加第17届国际计算机辅助放射学及手术大会（CARS 03）后记

计算机辅助手术和治疗(IGST)是一个新兴的多学科交叉的研究领域,近年来取得了飞速的发展.作为该领域顶级会议之一的国际计算机辅助放射学及手术大会(CARS2003)于2003年6月25至28日在英国伦敦伊丽莎白二世国际会议中心隆重举行了第17届会议.本文将对这次大会作一回顾和总结,内容包括科学论文方面的评论和产品展览方面的情况.