Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

一氧化氮合酶对大黄游离蒽醌提取物致小鼠腹泻的影响

目的研究大黄游离蒽醌的致泻作用及与NO的相关性。方法分别测定小鼠在给药后的排稀便时间和次数;在给小鼠预防性ip 40 mg.kg-1NO合酶抑制剂NAME后30 min,分别ig不同剂量的大黄游离蒽醌或等容量蒸馏水,30 min后处死小鼠,分别测定其胃、小肠及结肠内容物的重量和总蛋白,以及小肠和结肠内容物中K 、Na 、Cl-的含量。结果100、200 mg.kg-1游离蒽醌均可引起小鼠腹泻。L-NAME可显著对抗游离蒽醌致小鼠腹泻及增加小鼠胃、小肠及结肠的内容物、蛋白质浓度,调节电解质水平。结论大黄游离蒽醌的致泻作用与NO合酶通路的活性改变有关。     

The age‐related changes in 40 Hz Auditory Steady‐State Response and sustained Event‐Related Fields to the same amplitude‐modulated tones in typically developing children: A magnetoencephalography study

Recent studies have revealed that gamma‐band oscillatory and transient evoked potentials may change with age during childhood. It is hypothesized that these changes can be associated with a maturation of GABAergic neurotransmission and, subsequently, the age‐related changes of excitation–inhibition balance in the neural circuits. One of the reliable paradigms for investigating these effects in the auditory cortex is 40 Hz Auditory Steady‐State Response (ASSR), where participants are presented with the periodic auditory stimuli. It is known that such stimuli evoke two types of responses in magnetoencephalography (MEG)—40 Hz steady‐state gamma response (or 40 Hz ASSR) and auditory evoked response called sustained Event‐Related Field (ERF). Although several studies have been conducted in children, focusing on the changes of 40 Hz ASSR with age, almost nothing is known about the age‐related changes of the sustained ERF to the same periodic stimuli and their relationships with changes in the gamma strength. Using MEG, we investigated the association between 40 Hz steady‐state gamma response and sustained ERF response to the same stimuli and also their age‐related changes in the group of 30 typically developing 7‐to‐12‐year‐old children. The results revealed a tight relationship between 40 Hz ASSR and ERF, indicating that the age‐related increase in strength of 40 Hz ASSR was associated with the age‐related decrease of the amplitude of ERF. These effects were discussed in the light of the maturation of the GABAergic system and excitation–inhibition balance development, which may contribute to the changes in ASSR and ERF.     

Evaluation of 5‐Year Risk of Cardiovascular Events in Patients after Acute Myocardial Infarction Using Synchronization of 0.1‐Hz Rhythms in Cardiovascular System

Background: Synchronization between 0.1‐Hz rhythms in cardiovascular system is deteriorated at acute myocardial infarction (AMI) leading to a disruption of natural functional couplings within the system of autonomic regulation. Objective: This study evaluates the prognostic value of autonomic regulation indices for the 5‐year risk of fatal and nonfatal cardiovascular events in patients after AMI. Methods and Results: We studied 125 patients (53 [42%] female) after AMI aged between 30 and 83 years. The period of observation was 5 years with checkpoints at the first week after AMI and after each year after AMI. We compared the prognostic value of established clinical characteristics and degree S of synchronization between 0.1‐Hz rhythms in heart rate and microcirculation for evaluation of the 5‐year risk of mortality and recurrent myocardial infarction (MI) in patients after AMI. Acute heart failure Killip 2–4 at AMI and S < 20% at the first week after AMI were identified as the most important factors for evaluation of the risk of 5‐year mortality in patients after AMI (χ²= 14.2, P = 0.003). Sensitivity and specificity of low S (<20%) at the first week after AMI were 76% and 43%, respectively. For evaluation of the 5‐year risk of recurrent MI index S had no advantage over established clinical characteristics. Conclusion: The value of S below 20% in patients with AMI is a sensitive marker of high risk of mortality during the subsequent five years. It is characterized by better prognostic value than most of established clinical characteristics.     

Surfactant protein-A in bronchoalveolar lavage fluid from neonates with RDS on conventional and high-frequency oscillatory ventilation

Surfactant protein-A (SP-A) was measured in bronchoalveolar lavage (BAL) samples from ventilated neonates in order to study the concentration of SP-A with regard to: 1) high-frequency oscillatory ventilation (HFOV) vs. conventional mechanical ventilation (CMV); 2) the postnatal course and ontogeny of SP-A; and 3) the correlation with measurements of pulmonary function. Patients on HFOV had markedly lower BAL SP-A concentrations on days 1 and 2 compared to those on CMV, which may indicate influence of mode of ventilation on surfactant metabolism. The SP-A concentrations increased postnatally concurrent with resolution of acute respiratory distress syndrome. Finally, there were only weak correlations between BAL SP-A concentration and dynamic lung compliance and oxygen requirement.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Modulatory effects of 1 Hz rTMS over the cerebellum on motor cortex excitability

Clinical observations and data from animal experiments point to a physiological facilitatory influence of the deep cerebellar structures on the motor system through the cerebello-thalamo-cortical pathways. The aim of the present study was to explore the long-term effects of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the cerebellum on short intracortical inhibition (SICI) and facilitation (ICF) of the motor cortex in normal subjects. Eight healthy subjects (mean age 26.9 ± 3.1) underwent 1 Hz frequency rTMS delivered on the right cerebellar hemisphere. Before and after cerebellar rTMS, SICI and ICF were assessed in the motor cortex contralateral to the stimulated cerebellar hemisphere by means of a paired pulse paradigm with a conditioning subthreshold stimulus set to 80% of the motor threshold (MT) followed by a testing stimulus at 120% of MT intensity. Five different interstimulus intervals (ISIs) were used to assess SICI (2 and 4 ms) and ICF (7, 10 and 15 ms). Amplitude of the responses was expressed as the percentage of motor evoked potential (MEP) to test stimulus alone. Results showed a significant decrease of ICF at 10 ms ISI that persisted up to 20 min after cerebellar rTMS. This was the only significant modulatory effect of cerebellar stimulation on intracortical motor excitability A suppressive effect of the low-frequency TMS on Purkinje cells could be supposed, even if, the lack of effects on other facilitatory ISIs, stands for more complex modulatory effects of rTMS over cerebellum. The study is a further demonstration that rTMS over the cerebellum induces a long-lasting modulatory effect on the excitability of the interconnected motor area.     

Mirroring and mu rhythm involvement in social cognition: Are there dissociable subcomponents of theory of mind?

Tager-Flusberg and Sullivan [Tager-Flusberg, H., Sullivan, K., 2000. A componential view of theory of mind: evidence from Williams syndrome. Cognition 76, 59–90] have argued for a distinction between the social-perceptive component of theory of mind (ToM), involving judgment of mental state from facial and body expressions, and the social-cognitive component, which is representation-based and linked to language and theory-building. This is analogous to the distinction made by others [Gallese, V., Keysers, C., Rizzolatti, G., 2004. A unifying view of the basis of social cognition. Trends in Cognitive Science 8, 396–403] between representing the mental state of another as if it was one's own (simulation theory), which requires involvement of the mirror neuron system, and explicit or declarative reasoning about mental states (theory theory), which does not. This componential view of ToM was tested by examining mirroring, as indexed by EEG mu rhythm suppression, in subjects performing tasks assumed to tap both dimensions. Mu suppression was positively correlated with accuracy on the social-perceptual task but not in the social-cognitive task. In a ToM control task requiring judgments about person–object interactions accuracy was correlated with mu suppression. This implies that mirroring is involved in making judgments about emotions and person–object interactions. However, mirroring is insensitive to the distinction between correct and incorrect inferences in the social-cognitive task suggesting that additional mechanisms are needed to make mental attributions of beliefs and intentions. These results are consistent with a refined componential view of ToM.     

基于MATLAB的工频干扰陷波器设计

50Hz的工频干扰是心电信号的主要干扰源,尤其在供电系统不稳定、外界环境适应性差时严重影响心电信号正确判断。本文通过MATLAB提供的信号处理工具箱,简便高效地设计出了高性能50Hz陷波器,该设计省却了其它设计方法的繁琐过程,经滤波实地应用证明了该陷波器的有效性。