Corticospinal tract-sparing intensity-modulated radiotherapy treatment planning

Aim

To establish intensity-modulated radiotherapy (IMRT) planning procedures that spare the corticospinal tract by integrating diffusion tensor tractography into the treatment planning software.

Background

Organs at risk are generally contoured according to the outline of the organ as demonstrated by CT or MRI. But a part of the organ with specific function is difficult to protect, because such functional part of the organ cannot be delineated on CT or conventional sequence of MRI.

Methods

Diagnostic and treatment planning images of glioblastoma patients who had been treated by conventional 3-dimensional conformal radiotherapy were used for re-planning of IMRT. Three-dimensional fiber maps of the corticospinal tracts were created from the diffusion tensors obtained from the patients before the surgery, and were blended with the anatomical MR images (i.e. gadolinium-enhanced T1-weighted images or T2-weighted images). DICOM-formatted blended images were transferred and fused to the planning CT images. Then, IMRT plans were attempted.

Results

The corticospinal tracts could be contoured as organs at risk (OARs), because the blended images contained both anatomical information and fiber-tract maps. Other OARs were contoured in a way similar to that of ordinary IMRT planning. Gross tumor volumes, clinical target volumes, planning target volumes, and other OARs were contoured on the treatment planning software, and IMRT plans were made.

Conclusions

IMRT plans with diminished doses to the corticospinal tract were attained. This technique enabled us to spare specific neuron fibers as OARs which were formerly “invisible” and to reduce the probability of late morbidities.     

Substrate tRNA recognition mechanism of a multisite-specific tRNA methyltransferase, Aquifex aeolicus Trm1, based on the X-ray crystal structure

Archaeal and eukaryotic tRNA (N(2),N(2)-guanine)-dimethyltransferase (Trm1) produces N(2),N(2)-dimethylguanine at position 26 in tRNA. In contrast, Trm1 from Aquifex aeolicus, a hyper-thermophilic eubacterium, modifies G27 as well as G26. Here, a gel mobility shift assay revealed that the T-arm in tRNA is the binding site of A. aeolicus Trm1. To address the multisite specificity, we performed an x-ray crystal structure study. The overall structure of A. aeolicus Trm1 is similar to that of archaeal Trm1, although there is a zinc-cysteine cluster in the C-terminal domain of A. aeolicus Trm1. The N-terminal domain is a typical catalytic domain of S-adenosyl-l-methionine-dependent methyltransferases. On the basis of the crystal structure and amino acid sequence alignment, we prepared 30 mutant Trm1 proteins. These mutant proteins clarified residues important for S-adenosyl-l-methionine binding and enabled us to propose a hypothetical reaction mechanism. Furthermore, the tRNA-binding site was also elucidated by methyl transfer assay and gel mobility shift assay. The electrostatic potential surface models of A. aeolicus and archaeal Trm1 proteins demonstrated that the distribution of positive charges differs between the two proteins. We constructed a tRNA-docking model, in which the T-arm structure was placed onto the large area of positive charge, which is the expected tRNA-binding site, of A. aeolicus Trm1. In this model, the target G26 base can be placed near the catalytic pocket; however, the nucleotide at position 27 gains closer access to the pocket. Thus, this docking model introduces a rational explanation of the multisite specificity of A. aeolicus Trm1.     

N-acetylglucosaminyltransferase V-deficiency increases susceptibility to murine malaria

It is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. To elucidate the role of N-glycans on malaria parasite infection, we induced experimental murine malaria infection (using Plasmodium berghei ANKA) in mice deficient in N-acetylglucosaminyltransferase V (Mgat5), which is one of the enzymes involved in β1,6-GlcNAc N-glycan biosynthesis. After infection, Mgat5^-/- mice showed severe body weight loss and parasitemia compared with wild-type mice. The Mgat5^-/- mice, but not wild-type mice, also showed severe pathology accompanied by marked infiltration of plasma cells into the lungs and liver. These results suggest that β1,6-GlcNAc N-glycans on/in host erythrocytes may interfere with invasion of the parasites and progression to severe malaria.     

Modulation of endoplasmic reticulum (ER) stress-induced autophagy by C/EBP homologous protein (CHOP) and inositol-requiring enzyme 1α (IRE1α) in human colon cancer cells

To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1α (IRE1α) and C/EBP homologous protein (CHOP) were involved in the ER stress–autophagy pathway, and CHOP was a regulator of IRE1α protein expression. Our findings suggest that CHOP promotes IRE1α and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress–autophagy pathway.     

Did Parents and Teachers Struggle with Child Survivors 20 Months after the 2011 Earthquake and Tsunami in Japan? A Retrospective Observational Study

Background

On March 11, 2011, Japan was struck by the earthquake and tsunami. Twenty months after the disaster, we collected information on the difficulties faced by parents and teachers in dealing with the post-traumatic symptoms of child survivors. The aim of this study was to evaluate the relationship between post-traumatic symptoms in children and parents’ and teachers’ difficulties in dealing with children who survived the huge disaster.

Methods

The subjects included 12,524 children from elementary, middle, and junior high schools in Ishinomaki City. The Post Traumatic Stress Symptoms for Children 15 items (PTSSC-15), a self-rating questionnaire on post-traumatic symptoms, was distributed among the children, and Strength and Difficulties Questionnaire (SDQ), a self-rating questionnaire on difficulties in dealing with children, was given to their parents and teachers. With PTSSC-15, a valid response was obtained from 10,909 (89.5%) participants. With SDQ for teachers and parents, valid responses were obtained from 10,577 (86.7%) and 7052 (83.9%) participants, respectively.

Results

PTSSC-15 scores were significantly higher (P<0.001) in girls than in boys from the junior high school. These effect sizes were less than 0.30. Correlations of teachers’ SDQ scores and PTSSC-15 scores were significantly low (r<0.21, P<0.001) for both genders and all children. Likewise, correlations between SDQ scores assigned by parents (excluding “prosocial behavior”) and PTSSC-15 scores were significantly low (r<0.21, P<0.001) for both genders and at all school levels.

Conclusion

This study elucidated that the difficulties faced by parents and teachers while dealing with child survivors significantly low correlate with the child’s post-traumatic symptoms caused by the 2011 earthquake and tsunami. Thus, it is important that clinicians should not only evaluate post-traumatic symptoms with a self-rating questionnaire but also try to objectively evaluate whether there were day-to-day difficulties caused by the post-traumatic symptoms.     

Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation

It is known that obese adipose tissues are hypoxic and express hypoxia-inducible factor (HIF)-1α. Although some studies have shown that the expression of HIF-1α in adipocytes induces glucose intolerance, the mechanisms are still not clear. In this study, we examined its effects on the development of type 2 diabetes by using adipocyte-specific HIF-1α knockout (ahKO) mice. ahKO mice showed improved glucose tolerance compared with wild type (WT) mice. Macrophage infiltration and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor α (TNFα) were decreased in the epididymal adipose tissues of high fat diet induced obese ahKO mice. The results indicated that the obesity-induced adipose tissue inflammation was suppressed in ahKO mice. In addition, in the ahKO mice, serum insulin levels were increased under the free-feeding but not the fasting condition, indicating that postprandial insulin secretion was enhanced. Serum glucagon-like peptide-1 (GLP-1) levels were also increased in the ahKO mice. Interestingly, adiponectin, whose serum levels were increased in the obese ahKO mice compared with the obese WT mice, stimulated GLP-1 secretion from cultured intestinal L cells. Therefore, insulin secretion may have been enhanced through the adiponectin-GLP-1 pathway in the ahKO mice. Our results suggest that the deletion of HIF-1α in adipocytes improves glucose tolerance by enhancing insulin secretion through the GLP-1 pathway and by reducing macrophage infiltration and inflammation in adipose tissue.     

Factors Affecting Unhappiness at School among Japanese Adolescents: An Epidemiological Study

Background

Unhappiness at school is one of the main reasons for truancy among adolescents. In order to assess this problem more thoroughly in the context of Japanese adolescents, the present study examined the associations between feelings of unhappiness at school and lifestyle habits, school life realities, and mental health status.

Method

This study was designed as a cross-sectional survey. A self-administered questionnaire was provided to students enrolled in randomly selected junior and senior high schools throughout Japan. We calculated the percentages of both junior and senior high school students who felt unhappy at school based on factors related to school life, lifestyle habits, and mental health status. Multiple logistic regression analyses were performed in order to examine the associations between those factors and students'' feelings of unhappiness at school.

Results

A total of 98,867 valid responses were analysed, 7.9% (Boys: 8.4%, Girls: 7.4%) of which came from students who responded that they felt unhappy at school. For both junior and senior high school students, the percentages of those who felt unhappy at school were significantly higher among those who had not yet decided on their future life course, who did not participate in extracurricular activities, did not eat breakfast every day, went to bed late, had used tobacco or alcohol in the previous 30 days, and had poor mental health compared with others. The results of multiple logistic regression analyses indicated that the adjusted odds ratios for feeling unhappy at school with regard to the above-mentioned factors were significantly high for both junior and senior high school students.

Conclusions

The present results suggest that school employees and administrators must provide health guidance to students, considering that irregular lifestyle habits, lower school engagement, smoking, drinking alcohol, and poor mental health status are all associated with maladaptation to school among adolescents.     

Effectiveness of imaging modalities for screening IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) and for differentiating it from Sj?gren’s syndrome (SS), with an emphasis on sonography

IntroductionThe aim of this study was to clarify the effectiveness of various imaging modalities and characteristic imaging features in the screening of IgG4-related dacryoadenitis and sialadenitis (IgG4-DS), and to show the differences in the imaging features between IgG4-DS and Sjögren’s syndrome (SS).MethodsThirty-nine patients with IgG4-DS, 51 with SS and 36 with normal salivary glands were enrolled. Images of the parotid and submandibular glands obtained using sonography, 2-[¹⁸F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT), computed tomography (CT) and magnetic resonance imaging (MRI) were retrospectively analyzed. Six oral and maxillofacial radiologists randomly reviewed the arranged image sets under blinded conditions. Each observer scored the confidence rating regarding the presence of the characteristic imaging findings using a 5-grade rating system. After scoring various findings, diagnosis was made as normal, IgG4-DS or SS, considering all findings for each case.ResultsOn sonography, multiple hypoechoic areas and hyperechoic lines and/or spots in the parotid glands and obscuration of submandibular gland configuration were detected mainly in patients with SS (median scores 4, 4 and 3, respectively). Reticular and nodal patterns were observed primarily in patients with IgG4-DS (median score 5). FDG-PET/CT revealed a tendency for abnormal ¹⁸F-FDG accumulation and swelling of both the parotid and submandibular glands in patients with IgG4-DS, particularly in the submandibular glands. On MRI, SS had a high score regarding the findings of a salt-and-pepper appearance and/or multiple cystic areas in the parotid glands (median score 4.5). Sonography showed the highest values among the four imaging modalities for sensitivity, specificity and accuracy. There were significant differences between sonography and CT (p = 0.0001) and between sonography and FDG-PET/CT (p = 0.0058) concerning accuracy.ConclusionsChanges in the submandibular glands affected by IgG4-DS could be easily detected using sonography (characteristic bilateral nodal/reticular change) and FDG-PET/CT (abnormal ¹⁸F-FDG accumulation). Even inexperienced observers could detect these findings. In addition, sonography could also differentiate SS. Consequently, we recommend sonography as a modality for the screening of IgG4-DS, because it is easy to use, involves no radiation exposure and is an effective imaging modality.