George Canning and the Concert of Europe, September 1822-July 1824.

This thesis is a study of the diplomacy of George Canning between September 1822 and July 1824. It offers a detailed analysis of Canning's diplomacy on all the major international questions of the period in which his country's vital interests were involved. Those questions were: (1) the Franco-Spanish crisis in 1822-3 and the French intervention in Spain in 1823; (2) the affairs of Spanish America including the question of the independence of Spain's former colonies and that of the future of Cuba; (3) political instability in European Portugal; (4) the question of Brazilian independence; (5) the Greek War of Independence and the Russo-Turkish crisis. This study challenges and revises the existing accounts of Canning's diplomacy on these questions in many important points. However, it is not merely a narrative account of Canning's diplomacy, but also an attempt to present a clear and comprehensive picture of the system of his diplomacy and some general principles which guided it. It pays particular attention to the relations between Canning's diplomacy and the Concert of Europe-the post-1815 system of great-power co-operation in Europe. It has been generally believed that Canning was an isolationist whose principal aim in foreign policy was to destroy this system of great-power co-operation - which he believed was ideologically unacceptable to Britain and was unduly restraining her freedom of action-and replace it with a more fluid eighteenth-century-style balance-of-power system - which he believed would give Britain greater freedom of action and would be more beneficial to her interests and influence in and outside Europe. This study challenges this widely accepted view, and argues that Canning's aim was not to break up the system of great-power concert entirely but to transform it into such a shape that would be acceptable both to Britain and to the powers of the continent

An experimental study on the relation of T2-signal high intensity in MRI to histopathological changes in the kainic acid model of temporal lobe epilepsy in rats.

側頭葉てんかんでは，てんかん焦点に一致してMRI T2高信号領域が見られ，FLAIR法でこれがより明瞭になるが，このMRI所見と病理組織学的変化との関係は必ずしもはっきりしていない。そこで，Sprague－Dawleyラットにカイニン酸（KA）でけいれん発作重積状態を起こし，経時的にMRIを記録するとともに，ニッスル染色，GFAP免疫染色での病理組織学的変化を調べて両者の関係について検討した。KA群では，MRIで1～8週間後のいずれにおいてもpiriform cortexからentorhinal cortexにかけて不整形のT2高信号領域がみられたが，stage3のけいれん発作しか出現しなかったラットではstage4，5が出現したラットに比べて程度が弱かった。組織学的には，CA1，subiculum，piriform cortex，entorhinal cortexで神経細胞の消失，濃染細胞の増加と萎縮，GFAP免疫反応の増強が見られたが，piriform cortex，entorhinal cortexでの神経細胞消失の程度はT2信 号の程度と相関せず，GFAP免疫反応が増強した領域に一致して高信号がみられた。しかし，海馬のGFAP免疫反応増強はMRI所見に反映されず，これはMRIの解像度の限界にもよると考えられた。The relation of T2-signal high intensity areas observed in temporal lobe epilepsy to histopathological changes in limbic structures was examined in the rat kainic acid (KA) model of epilepsy. Male 8-week-old Sprague-Dawley rats were injected with 10mg/kg(i.p.) of KA or saline (control). Repetitive generalized convulsions (stage 3, or stage 4,5 seizures of amygdala kindled seizures) lasted for 3 to 4 hrs. were induced by KA injection in all rats. MRI was recorded on the day before the KA injection and 1, 2, 4, 8 weeks after the injection by fluid-attenuated inversion recovery method under deep pentobarbital anesthesia. Following the last MRI recording, rats were perfused with 4% paraformaldehyde (PFA) from left cardiac ventricle, post-fixed overnight in 4% PFA and brains were embedded in parafin. Coronal brain sections (6μm) were stained with cresyl violet, or mouse anti-GFAP antibody followed by biotinylated goat anti-mouse IgG and avidin-biotin-peroxidase (vectastain ABC kit). Irregularshaped moderate to severe high T2-signal areas were observed in bilateral piriform and entorhinal cortex in MRI. These high T2-signal areas were ovserved from 1 week after the KA injection to 8 weeks after the injection, and were more prominent in rats elicited stage 4 or 5 seizures than in rats elicited stage 3 seizures. Loss of pyramidal neurons and increased GFAP immunoreactivity were observed in piriform cortex, entorhinal cortex, CA1, subiculum, and hilus of dentate gyrus. The increase of GFAP immunoreactivity, but not the intensity of neuronal loss, in piriform and entorhinal cortex was almost correponded to the size and intensity of T2-signal. However, the increase of GFAP immunoreactivity in hippocampus was not detected as the increase of T2-signal in MRI. These findings indicate that astroglial reactions in piriform and entorhinal cortex are more sensitive to T2-weighted MRI than those in hippocampus

Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: an experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats.

A new model of status epilepticus (SE), which was induced by intermittent electrical stimulation (20 Hz for 20 sec every min for 180 min) of the deep prepyriform cortex, has been developed in the conscious rat. SE was induced in 9 of 16 rats in the drug-free group. The number of stimulation trains required to induce SE in this status subgroup was 125.6 +/- 12.7 (mean +/- SEM) and the mean duration of self-sustained seizure activity (SSSA) occurring after cessation of the stimulation session was 295.4 +/- 111.4 min. Some animals showed secondary generalized seizures. Significant cell loss was observed in the hippocampal CA3 pyramidal cell layer ipsilateral to the stimulation site and bilateral CA1 areas in the status subgroup compared with the group subjected to sham operation. In addition, there was a significant negative correlation between the duration of SSSA subsequent to the stimulation session and the total number of intact pyramidal neurons observed in the bilateral CA1 and ipsilateral CA3 subfields of the status subgroup. There were significant differences between the status and non-status subgroups with respect to the number of afterdischarges (ADs) and the total AD duration during the stimulation session. Pretreatment with phenobarbital (30 mg/kg) prevented the development of SE and hippocampal cell loss completely. Pretreatment with MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (0.25 or 1 mg/kg), also prevented hippocampal cell loss, although it did not block SE generation completely, which suggests dissociation of the mechanisms underlying the development of SE and hippocampal damage. These results indicate that prolonged SSSA actually causes hippocampal damage and it is critically dependent upon NMDA receptor participation.</p

Medial prefrontal cortex and anterior cingulate cortex in the generation of alpha activity induced by transcendental meditation: a magnetoencephalographic study.

Previous EEG studies have shown that transcendental meditation (TM) increases frontal and central alpha activity. The present study was aimed at identifying the source of this alpha activity using magnetoencephalography (MEG) and electroencephalography (EEG) simultaneously on eight TM practitioners before, during, and after TM. The magnetic field potentials corresponding to TM-induced alpha activities on EEG recordings were extracted, and we attempted to localize the dipole sources using the multiple signal classification (MUSIC) algorithm, equivalent current dipole source analysis, and the multiple spatio-temporal dipole model. Since the dipoles were mapped to both the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), it is suggested that the mPFC and ACC play an important role in brain activity induced by TM.</p

ハプスブルク領ネーデルラントの防衛とフェリペとイングランド女王メアリー1 世の結婚 ―1550 年代の西ヨーロッパ国際関係―

The 1550s was a period of great transition in western European international relations, during which the “Habsburg Empire” of Emperor Charles V was divided into two parts. This article examines the motives and strategies of Habsburg leaders behind this division of the empire and considers the attempt of Charles and his son Philip to enhance the defence of the Habsburg Netherlands through the latter’s marriage with Mary I of England in 1554

フランス宗教戦争の勃発

In April 1559 the long series of Habsburg-Valois wars was brought to an end in the peace treaty of Cateau- Cambrésis. For the next few decades, western European international relations were dominated by civil wars in France and the Habsburg Netherlands. This article examines how political and religious factors led to the outbreak of a series of religious civil wars in France, commonly known as the French Wars of Religion. The first chapter describes the religious policies of Francis I and Henry II and the growth of Protestantism in France under their reign. Despite mounting persecution after the mid-1530s, Protestantism spread to many parts of France especially after the mid-1550s. Henry II was particularly alarmed by the spread of Calvinism among the nobility. At the end of the war in 1559, Henry was determined to give more attention to the religious problem in France. Instead, his premature death in July 1559 put the country into political and religious turmoil. The second chapter examines events leading to the outbreak of the first religious war in April 1562. After Henry’s death, the religious tension was exacerbated by a power struggle among noble families – such as the Guises, the militant defenders of the Catholic faith, and the Bourbons, who were sympathetic to the Protestant cause – to dominate Henry’s young sons, Francis II（ 1559-60） and Charles IX（ 1560-74）. Their mother, Catherine de Medici, tried hard to maintain a religious peace in France by means of a compromise between the two faiths, but in vain. The‘ massacre of Vassy’ in March 1562 provoked a Huguenot army to capture Orléans. The third chapter provides a brief description of the war itself and explains how the absence of a large standing army and the crown’s inability to fund military efforts for any protracted period of time prevented it from defeating the Huguenots. To sum up, this article shows that the war defies a simple explanation and was caused by various political and religious factors including the untimely death of Henry II, the power struggle among noble factions, the desire of many noblemen to display their military virtue, the belief of many Catholics that Protestantism was a serious threat to the peace and stability of their community, and the impossibility of achieving doctrinal compromise

Changes in Plasma Clozapine Levels after Smoking Cessation in Japanese Inpatients with Schizophrenia: A Retrospective Cohort Study

Although reported for Caucasians, changes in plasma clozapine levels after smoking cessation in East Asians remain unclear. We here investigated plasma clozapine levels before and after smoking cessation in Japanese inpatients with schizophrenia. We conducted a retrospective chart review of 14 inpatients with schizophrenia who were being treated with clozapine between June 1, 2019, and July 31, 2019 and who were smokers as of July 1, 2019, the day on which a smoking ban was instituted in the tertiary public psychiatric hospital. The primary outcome was individual differences in plasma clozapine levels between before and after the smoking ban, which were compared using paired t-tests. The mean plasma clozapine level was significantly increased, by 213.4 ng/mL (95% CI 119.9-306.8; p<0.01) or 53.2%. Four of the 14 inpatients experienced clinically significant side effects, such as myoclonus, drooling, and amnesia, due to the development of high plasma clozapine levels. Our findings indicated that close monitoring of plasma clozapine levels before and after smoking cessation and prior dose adjustment of clozapine may be necessary, to prevent a significant risk of developing high plasma clozapine levels, even in Japanese patients

Safety and Effectiveness of Perospirone in Comparison to Risperidone for Treatment of Delirium in Patients with Advanced Cancer: A Multicenter Prospective Observational Study in Real-World Psycho-Oncology Settings

The clinical benefit of perospirone for treatment of delirium in patients with advanced cancer is not sufficiently clear. The objective of this study was to compare the safety and effectiveness of perospirone to those of risperidone for the treatment of delirium in patients with advanced cancer. This is a secondary analysis of a multicenter prospective observational study in nine psycho-oncology consultation services in Japan. The study used the Delirium Rating Scale (DRS) Revised-98 to measure effectiveness and the CTCAE (Common Terminology Criteria for Adverse Events) version 4 to assess safety. Data from 16 patients who received perospirone and 53 patients who received risperidone were analyzed. The mean age was 70 years in the perospirone group and 73 years in the risperidone group. Both groups showed a significant decrease in the total score of DRS-R-98 after three days of treatment (perospirone: 11.7 (7.9-15.4) to 7.0 (3.3-10.7), difference −4.7, effect size=0.72, p=0.003; risperidone: 15.5 (13.6-17.4) to 12.2 (10.1-14.2), difference −3.3, effect size=0.55, p=0.00). The risperidone group showed significant improvements in sleep-wake cycle disturbance, orientation, attention, and visuospatial ability. In the perospirone group, there was a significant improvement of sleep-wake cycle disturbance. The median daily dose of perospirone was 4 mg/day. There were fewer episodes of somnolence as an adverse event in the perospirone group. Low-dose perospirone was thus found to be effective for the treatment of delirium in patients with advanced cancer and may be associated with fewer episodes of over-sedation as an adverse event

Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus

The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes' functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field