日本の極低出生体重児における先天異常の疫学

京都大学0048新制・論文博士博士(医学)乙第13379号論医博第2213号新制||医||1047(附属図書館)(主査)教授 川上 浩司, 教授 滝田 順子, 教授 古川 壽亮学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

Current status and legal/ethical problems in the research use of the tissues of aborted human fetuses in Japan

To date, there is no law regulating the research use of human aborted fetuses in Japan. The aim was to review the current status with historical background and legal/ethical problems limiting the research use of the tissues of aborted human fetuses. We reviewed literature via PubMed, Web of Science, Scopus, Japana Centra Revuo Medicina and CiNii, reports from various committees and research groups from Ministry of Health, Labour and Welfare (MHLW), and domestic books. Aborted human fetal tissues used for research purposes were first documented in the 1920s. The first guideline, the Peel Code was released in 1972. Since then, in Western countries, the research use of aborted fetuses has been less restricted compared with that of embryos, due to the following guidelines outlined by expert groups. Currently, aborted fetal tissues are commercially available for research purposes in the United States. In Japan, only four indications are presented in “a public statement permitting research use of deceased fetuses' and ‘neonates’ organs, etc.” (1987). In the 2000s, expert committees of the MHLW concluded that research use of human aborted fetuses should be discontinued, and that comprehensive rules and independent regulations should be implemented. This issue has not been discussed in the Japanese legislature since 2003. Establishment of laws and guidelines for this issue is insufficient not only in Japan but also in other countries. It is important to secure transparency for making laws and guidelines and in obtaining public understanding

Correlation of systolic time interval with abnormal myocardial contraction by coronary occlusion in anesthetized open-chest dogs.

The correlation between the systolic time interval and abnormal contraction in ischemic myocardium was studied in anesthetized open-chest dogs. A strain-gauge was sutured on the surface of the left ventricular wall perfused by the left anterior descending coronary artery (LAD) for measuring segment-length. The left ventricular stroke volume decreased progressively after occlusion of LAD. The left ventricular ejection time (LVET) was progressively shortened in close correlation with the elongation of segment-length at the onset of isometric relaxation in 20 seconds after LAD occlusion when early systolic myocardial contraction and isometric contraction time (ICT) were not affected. ICT was gradually prolonged and closely related with the lengthening of the early systolic segment-length, while LVET recovered toward the control level in spite of further decrease in stroke volume. A close relationship was observed between ICT/LVET and stroke volume (gamma = 0.76, P less than 0.01). The results suggested the possibility that LVET was normalized even when the left ventricular function was impaired, and ICT/LVET ratio was the most sensitive index of LV dysfunction.</p

The association of ectopic craniopharyngioma in the fourth ventricle with familial adenomatous polyposis: illustrative case

[BACKGROUND] Craniopharyngioma (CP) often arises in the sellar and suprasellar areas; ectopic CP in the posterior fossa is rare. Familial adenomatous polyposis (FAP) is a genetic disorder involving the formation of numerous adenomatous polyps in the gastrointestinal tract, and it is associated with other extraintestinal manifestations. [OBSERVATIONS] The authors reported the case of a 63-year-old woman with FAP who presented with headache and harbored a growing mass in the fourth ventricle. Magnetic resonance imaging (MRI) findings revealed a well-circumscribed mass with high intensity on T1-weighted images and low intensity on T2-weighted images and exhibited no contrast enhancement. Gross total resection was performed and histopathology revealed an adamantinomatous CP (aCP). The authors also reviewed the previous reports of ectopic CP in the posterior fossa and found a high percentage of FAP cases among the ectopic CP group, thus suggesting a possible association between the two diseases. [LESSONS] An ectopic CP may be reasonably included in the differential diagnosis in patients with FAP who present with well-circumscribed tumors in the posterior fossa

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function

Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function

Classification of First-Episode Schizophrenia Patients and Healthy Subjects by Automated MRI Measures of Regional Brain Volume and Cortical Thickness

BACKGROUND: Although structural magnetic resonance imaging (MRI) studies have repeatedly demonstrated regional brain structural abnormalities in patients with schizophrenia, relatively few MRI-based studies have attempted to distinguish between patients with first-episode schizophrenia and healthy controls. METHOD: Three-dimensional MR images were acquired from 52 (29 males, 23 females) first-episode schizophrenia patients and 40 (22 males, 18 females) healthy subjects. Multiple brain measures (regional brain volume and cortical thickness) were calculated by a fully automated procedure and were used for group comparison and classification by linear discriminant function analysis. RESULTS: Schizophrenia patients showed gray matter volume reductions and cortical thinning in various brain regions predominantly in prefrontal and temporal cortices compared with controls. The classifiers obtained from 66 subjects of the first group successfully assigned 26 subjects of the second group with accuracy above 80%. CONCLUSION: Our results showed that combinations of automated brain measures successfully differentiated first-episode schizophrenia patients from healthy controls. Such neuroimaging approaches may provide objective biological information adjunct to clinical diagnosis of early schizophrenia

Effect of GBR12909 on affective behavior: Distinguishing motivational behavior from antidepressant-like and addiction-like behavior using the runway model of intracranial self-stimulation

Rationale: It was recently demonstrated that the priming stimulation effect (PSE) in the runway model of intracranial self-stimulation (ICSS) can be used as a model system to study the motivational effects of drugs. However, the characteristics of this navel experimental model have not been fully clarified. Objective: To elucidate the involvement of dopamine uptake inhibition in motivated behavior and the difference in experimental characteristics between closely related experimental models, we investigated the effects of the dopamine uptake inhibitor GBR12909 in the runway ICSS model, in the forced swimming test (FST), and on conditioned place preference (CPP). In addition, the role of dopamine receptor signaling in the runway model was evaluated using dopamine receptor agonists and antagonists. Results: GBR12909 dose-dependently increased running speed on the runway and decreased immobility time in the FST without affecting the time spent in the drug-associated compartment in CPP tests. The effect of GBR12909 in the runway model was inhibited by pre-treatment with the dopamine receptor antagonists haloperidol and raclopride. The dopamine receptor agonists SKF38393 and quinpirole dose-dependently decreased running speed. Conclusions: These results demonstrate that GBR12909 displays motivation-enhancing and antidepressant-like effects without place conditioning effects. In addition, the mechanisms of PSE enhancement in the runway ICSS model are different from those underlying closely associated experimental models and are mediated by increases in dopamine signaling

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer. SIGNIFICANCE: GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic and epigenomic features. This article is highlighted in the In This Issue feature, p. 587