Publications by authors named "Junko Ito"

78 Publications

The first survey about women doctors in the Japanese Society for Pediatric Endocrinology (JSPE).

Clin Pediatr Endocrinol 2021 10;30(3):121-126. Epub 2021 Jul 10.

Support Team for Women Doctors in Education and Training Committee.

The Career Development for Women Pediatric Endocrinologists and Work-Life Balance Committee and Support Team for Women Doctors in Education and Training Committee investigated the current situation of women doctors in the Japanese Society for Pediatric Endocrinology (JSPE). The proportion of women doctors (PWD) was as follows. 1) Members of JSPE: 40.2% in fiscal 2018, versus 33.3% in fiscal 2010; 2) councilors: 21.6% from fiscal 2014 to 2017, versus 6.3% from fiscal 2008 to 2010; 3) board members: 13.6% from fiscal 2014 to 2017, versus 0% from fiscal 2008 to 2010; 4) board-certified endocrinologists (Pediatrics) and certified endocrine educators (Pediatrics): 31.7% and 25.4% in fiscal 2018, versus 22.4% and 15.3% in fiscal 2010, respectively; and 5) average value of first presenters and chairpersons in the Annual Scientific Meeting of JSPE was 41.4% and 22.3% from 2010 to 2019. These PWD figures for JSPE were higher than those of the Japan Pediatric Society and the Japan Endocrine Society, indicating a reducing gender gap in JSPE, although increases in the PWD of decision-making posts remains insufficient.
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http://dx.doi.org/10.1297/cpe.30.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267557PMC
July 2021

Clarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient.

Am J Case Rep 2021 Jun 15;22:e931731. Epub 2021 Jun 15.

Medical Mycology Research Center, Chiba University, Chiba, Japan.

BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.
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http://dx.doi.org/10.12659/AJCR.931731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216568PMC
June 2021

Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.

Nat Commun 2021 05 25;12(1):3101. Epub 2021 May 25.

Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.

Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson's disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis.
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http://dx.doi.org/10.1038/s41467-021-23452-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149644PMC
May 2021

Renal morphology and function from childhood to adulthood in Turner syndrome.

Clin Exp Nephrol 2021 Jun 22;25(6):633-640. Epub 2021 Feb 22.

Department of Pediatrics, Toranomon hospital, 2-2-2 Tranomon, Minato-ku, Tokyo, 1058470, Japan.

Background: Turner syndrome (TS) is a chromosomal disorder with various complications, including congenital anomaly of the kidney and urinary tract (CAKUT). However, its renal function remains poorly known. Therefore, this study aimed to evaluate renal function in TS of various ages from childhood to adulthood.

Methods: We retrospectively analyzed 63 patients with TS who visited our hospital between 1989 and 2020, examined their renal morphology, and analyzed renal function by calculating the estimated glomerular filtration rate (eGFR) using formulas applicable for Japanese populations.

Results: Renal morphological abnormality was observed in 22 cases (35.0%) (horseshoe kidney, 7 [11.1%]; hydronephrosis, 11 [17.5%]; duplex collecting system, 3 [4.8%]; and single unilateral kidney, 1 [1.6%]). We evaluated the eGFR of 47 subjects aged 2.8-39.3 years and classified them into Group 1 (with CAKUT, n = 15) and Group 2 (without CAKUT, n = 32). The eGFR at the first visit and the final follow-up was not statistically different between these groups. In Group 1 with CAKUT, the eGFR was not significantly different between that at the first visit and that at the final follow-up (p = 0.21). During the observation period (median, 7.9 years), the eGFR of all individuals in both groups gradually decreased with age, but did not fall < 60 mL/min/1.73 m, which defines chronic kidney disease (CKD).

Conclusions: The renal function of TS remained normal in all cases during our investigation period, and no one developed CKD by the age of 40 years.
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http://dx.doi.org/10.1007/s10157-021-02031-wDOI Listing
June 2021

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

J Neuropathol Exp Neurol 2021 01;80(2):129-136

Department of Pathology, Brain Research Institute, Niigata University.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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http://dx.doi.org/10.1093/jnen/nlaa141DOI Listing
January 2021

Communities of mycorrhizal fungi in different trophic types of Asiatic Pyrola japonica sensu lato (Ericaceae).

J Plant Res 2020 Nov 24;133(6):841-853. Epub 2020 Oct 24.

Agro-Environmental Science, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.

Mixotrophic plants obtain carbon by their own photosynthetic activity and from their root-associated mycorrhizal fungi. Mixotrophy is deemed a pre-adaptation for evolution of mycoheterotrophic nutrition, where plants fully depend on fungi and lose their photosynthetic activity. The aim of this study was to clarify mycorrhizal dependency and heterotrophy level in various phenotypes of mixotrophic Pyrola japonica (Ericaceae), encompassing green individuals, rare achlorophyllous variants (albinos) and a form with minute leaves, P. japonica f. subaphylla. These three phenotypes were collected in two Japanese forests. Phylogenetic analysis of both plants and mycorrhizal fungi was conducted based on DNA barcoding. Enrichment in C among organs (leaves, stems and roots) of the phenotypes with reference plants and fungal fruitbodies were compared by measuring stable carbon isotopic ratio. All plants were placed in the same clade, with f. subaphylla as a separate subclade. Leaf C abundances of albinos were congruent with a fully mycoheterotrophic nutrition, suggesting that green P. japonica leaves are 36.8% heterotrophic, while rhizomes are 74.0% heterotrophic. There were no significant differences in δC values among organs in both albino P. japonica and P. japonica f. subaphylla, suggesting full and high mycoheterotrophic nutrition, respectively. Among 55 molecular operational taxonomic units (OTUs) detected as symbionts, the genus Russula was the most abundant in each phenotype and its dominance was significantly higher in albino P. japonica and P. japonica f. subaphylla. Russula spp. detected in P. japonica f. subaphylla showed higher dissimilarity with other phenotypes. These results suggest that P. japonica sensu lato is prone to evolve mycoheterotrophic variants, in a process that changes its mycorrhizal preferences, especially towards the genus Russula for which this species has a marked preference.
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http://dx.doi.org/10.1007/s10265-020-01233-9DOI Listing
November 2020

Immunohistochemistry or Molecular Analysis: Which Method Is Better for Subtyping Craniopharyngioma?

Endocr Pathol 2021 Jun 23;32(2):262-268. Epub 2020 Sep 23.

Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo, Japan.

Craniopharyngioma (CP) is mainly classified into two pathological subtypes: adamantinomatous (ACP) and papillary (PCP). CTNNB1 (β-catenin) mutations are detected in ACPs, and the BRAF V600E mutation is detected in PCPs. However, genetic analysis is not always possible in general medical practice. In this study, we investigated whether immunohistochemistry could replace genetic analysis as an aid in subtype diagnosis. Here, 38 CP patients who had undergone their first tumor resection were included. Among the 38 cases, 22 were morphologically diagnosed as ACP, 10 cases were diagnosed as PCP, and six cases were diagnosed as undetermined CP that were morphologically difficult to classify as either ACP or PCP. Results of immunohistochemistry and genetic analysis and clinical features were compared. Based on the immunohistochemistry, 26 (22 ACPs and four undetermined CPs) showed nuclear β-catenin expression, 11 (nine PCPs and two undetermined CPs) exhibited positive BRAF V600E immunostaining, and one PCP showed membranous β-catenin expression and negative BRAF V600E immunostaining. Among the 26 nuclear β-catenin expression cases, 11 had CTNNB1 mutations; however, 15 cases had mutations of neither CTNNB1 nor BRAF V600E. All 11 BRAF V600E immunopositive cases had BRAF V600E mutations. When comparing clinical features, pediatric patients and those with tumor calcification and less solid components on MRI more commonly had nuclear β-catenin expression tumors than BRAF V600E immunopositive tumors, reflecting the differences in clinical features between ACP and PCP. Accordingly, immunohistochemistry can replace genetic analysis as an aid to determine the subtype diagnosis of CP in general medical practice.
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http://dx.doi.org/10.1007/s12022-020-09644-zDOI Listing
June 2021

Exploring the factors underlying remyelination arrest by studying the post-transcriptional regulatory mechanisms of cystatin F gene.

J Neurochem 2021 Jun 1;157(6):2070-2090. Epub 2020 Oct 1.

Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.

Remyelination plays an important role in determining the fate of demyelinating disorders. However, it is arrested during chronic disease states. Cystatin F, a papain-like lysosomal cysteine proteinase inhibitor, is a crucial regulator of demyelination and remyelination. Using hemizygous proteolipid protein transgenic 4e (PLP ) mice, an animal model of chronic demyelination, we found that cystatin F mRNA expression was induced at 2.5 months of age and up-regulated in the early phase of demyelination, but significantly decreased in the chronic phase. We next investigated cystatin F regulatory factors as potential mechanisms of remyelination arrest in chronic demyelinating disorders. We used the CysF-STOP-tetO::Iba-mtTA mouse model, in which cystatin F gene expression is driven by the tetracycline operator. Interestingly, we found that forced cystatin F mRNA over-expression was eventually decreased. Our findings show that cystatin F expression is modulated post-transcriptionally. We next identified embryonic lethal, abnormal vision, drosophila like RNA-binding protein 1 (ELAVL-1), and miR29a as cystatin F mRNA stabilizing and destabilizing factors, respectively. These roles were confirmed in vitro in NIH3T3 cells. Using postmortem plaque samples from human multiple sclerosis patients, we also confirmed that ELAVL-1 expression was highly correlated with the previously reported expression pattern of cystatin F. These data indicate the important roles of ELAVL-1 and miR29a in regulating cystatin F expression. Furthermore, they provide new insights into potential therapeutic targets for demyelinating disorders.
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http://dx.doi.org/10.1111/jnc.15190DOI Listing
June 2021

Characteristic terahertz absorption spectra of paramylon and paramylon-ester compounds.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Jan 13;244:118828. Epub 2020 Aug 13.

Division of Materials Science, Faculty of Pure & Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan; Algae Biomass and Energy System (ABES) Research and Development Center, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address:

Paramylon is a long-chain polysaccharide, composed of glucose units connected via β-(1,3) glycosidic bonds, that spontaneously forms a three-strand helical bundle. Paramylon-esters can be made by partially or fully replacing saccharide chain hydroxide groups with carboxylic functional groups, such as stearoyl (CH(CH)CO) and palmitoyl (CH(CH)CO). The paramylon-ester with carboxylic acids has superior characteristics, including high thermal resistance, stability and transparency under visible light, which are necessary for thermoplastic applications. In this study, the absorption coefficient α(ν) and absorbance spectra of paramylons and paramylon-esters were measured in the 0.3-8.0 THz range and compared with the corresponding spectra of glucose and cellulose. Paramylon and paramylon-ester molecules were found to exhibit unique, so-called fingerprint, α(ν)peaks at 4.0, 6.0 and 8.0 THz, and 2.5 and 5.0 THz, respectively. We speculate that the spectral features observed are owing to intermolecular interaction modes of the weakly coupled polysaccharide chains. The paramylons with different molecular weights show very similar absorption features in the low-frequency side, both in spectral shapes and intensities, indicating that absorption is independent of molecular size. The paramylon-esters with varying degrees of substitution (DS) are similar spectral shapes but different intensities. A linear correlation between α(ν) peak intensity and the DS of paramylon-esters was established with the R value above 0.99. This behavior can be used for the detection and identification of novel paramylon-ester molecules.
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http://dx.doi.org/10.1016/j.saa.2020.118828DOI Listing
January 2021

Insight from an autopsy in a patient with rapidly worsening heart failure due to amyloid light-chain cardiac amyloidosis: A case report.

J Cardiol Cases 2020 Aug 13;22(2):48-51. Epub 2020 May 13.

Department of Cardiology and Catheterization Laboratories, Shonan Kamakura General Hospital, Kamakura, Japan.

Amyloid light-chain (AL) amyloidosis is a systemic disease characterized by the deposition of misfolded immunoglobulin light chain, causing organ failure, and in particular cardiac involvement is a leading cause of morbidity and mortality. We report the case of a 47-year-old man without prior cardiovascular events who presented with shortness of breath. He was diagnosed with primary AL cardiac amyloidosis (CA) from the laboratory test, the endomyocardial biopsy, the bone marrow examination, and the cardiovascular imaging. Only a week after discharge of the first heart failure (HF) admission, he was readmitted for the exacerbation of HF. Finally, he died 2 weeks after the second admission, that is 3 months after the onset of HF. Autopsy, which was performed to investigate the causes of rapid worsening HF, implied the impairment of ventricular function and coronary microcirculation dysfunction. We could diagnose CA immediately by using diagnostic tools, however, we recognized that there was the fulminant type in CA, and considered the insight from autopsy. 〈 This case demonstrates a young patient with cardiac amyloidosis (CA) developed rapid worsening heart failure (RWHF), and then he died 1 month after diagnosis, that is 3 months after the onset of heart failure. This case deems to be a fulminant type in amyloid light-chain CA, and autopsy suggested the mechanisms of RWHF, which are the impairment of ventricular function and coronary microcirculation dysfunction.〉.
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http://dx.doi.org/10.1016/j.jccase.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403536PMC
August 2020

A nationwide questionnaire survey targeting Japanese pediatric endocrinologists regarding transitional care in childhood, adolescent, and young adult cancer survivors.

Clin Pediatr Endocrinol 2020 16;29(2):55-62. Epub 2020 Apr 16.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.
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http://dx.doi.org/10.1297/cpe.29.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160455PMC
April 2020

Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity.

Schizophr Bull 2020 12;46(6):1619-1628

Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.
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http://dx.doi.org/10.1093/schbul/sbaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846078PMC
December 2020

Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression change in patients with amyotrophic lateral sclerosis.

Int J Med Sci 2020 4;17(4):480-489. Epub 2020 Feb 4.

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.

Amyotrophic lateral sclerosis (ALS) is a serious disease characterized by the degeneration of motor neurons resulting in muscle weakness and paralysis. The neuroendocrine polypeptide VGF is localized in the central nervous system and peripheral endocrine neurons and is cleaved into several polypeptides with multiple functions. Previous studies revealed that VGF was decreased in the cerebrospinal fluid of ALS model mice and sporadic ALS patients. However, it is unknown which cells supply VGF in the spinal cord and a detailed localization is lacking. In this study, we evaluated the VGF-producing cells and protein localization using hybridization and immunostaining in the spinal cords of ALS and control patients. mRNA was localized both in the dorsal and anterior horns of the spinal cords. Moreover, in the anterior horn, mRNA co-localized with a neurofilament heavy chain, which is a motor neuron marker, and mRNA-positive motor neurons were decreased in the spinal cords of ALS patients. We revealed that VGF protein level was decreased in the anterior horn of ALS patients; however, the expression level of VGF protein was not changed in the posterior horn or white matter. Furthermore, the expression level of VGF protein was conserved in ALS patients with long-term survival. These results reveal that VGF is mainly supplied by human motor neurons, and suggest that VGF expression changes may be involved in ALS pathology.
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http://dx.doi.org/10.7150/ijms.39101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053308PMC
January 2021

Molecular vibration and Boson peak analysis of glucose polymers and ester via terahertz spectroscopy.

Carbohydr Polym 2020 Mar 28;232:115789. Epub 2019 Dec 28.

Division of Materials Science, Faculty of Pure and Applied Sciences, University of Tsukuba, Japan; Algae Biomass and Energy System (ABES) Research and Development Center, University of Tsukuba, Japan.

Complex permittivity spectra were obtained herein by performing broadband terahertz (THz) spectroscopy on cellulose, paramylon, and paramylon ester. Absorption peaks observed for cellulose and paramylon at approximately 3 THz are attributed to hydrogen bonds. In addition, a broad absorption peak around 2 THz was observed for all the polymers, demonstrating a general feature of polymer glasses derived from weak interatomic van der Waals forces. The boson peak was observed for cellulose and paramylon ester. The boson peak frequency for cellulose nearly equaled that for glassy glucose-a unit structure of the cellulose polymer. Additionally, the insensitivity of cellulose to the polymerization degree was consistent with recent results obtained via molecular dynamics simulations. In contrast, the boson peak frequency of paramylon ester was markedly smaller than that of cellulose. These results demonstrate the importance of hydrogen bonds as determinants of the boson peak frequency.
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http://dx.doi.org/10.1016/j.carbpol.2019.115789DOI Listing
March 2020

Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study.

Ann Neurol 2020 02 10;87(2):302-312. Epub 2019 Dec 10.

Department of Pathology, Brain Research Institute, Niigata University, Niigata.

Objective: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype.

Methods: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features.

Results: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra.

Interpretation: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.
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http://dx.doi.org/10.1002/ana.25652DOI Listing
February 2020

Minimal amount of tissue-based pH measurement to improve quality control in neuropsychiatric post-mortem brain studies.

Psychiatry Clin Neurosci 2019 Sep 17;73(9):566-573. Epub 2019 Jun 17.

Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan.

Aim: Tissue pH and RNA integrity are crucial quality-control indicators of human post-mortem brain tissues in the identification of the pathogeneses of neuropsychiatric disorders, but pH has not been measured as often due to limitations in the amount of tissue available. This study was designed to develop and validate a protocol for tissue pH evaluation using a minimal amount of human post-mortem tissues.

Methods: A procedure that included a proper ratio of brain tissue weight to water for homogenization and the duration of homogenization was designed based on preliminary experiments using mouse brain tissues. The minimal (10 mg) and typical (100 mg) amounts of post-mortem brain tissue from 52 subjects were homogenized in 5 volumes (50 μL/10 mg tissue) and 10 volumes (1000 μL/100 mg tissue) of nuclease-free water and subjected to pH measurements using an InLab Ultra micro pH electrode.

Results: The pH values based on the new protocol using a minimal amount of tissue significantly correlated with measurements of the standard protocol (r = 0.86). The correlation coefficients of the pH values between gray and white matter of the same brain region, and the values between different brain regions were 0.73 and 0.54, respectively.

Conclusion: The proposed protocol used one-tenth of the tissue amount of current standard protocol and enabled us to evaluate the exact quality of post-mortem brain tissue subjected to subsequent analyses. The application of this protocol may improve the detection of biological phenomena of interest in post-mortem brain studies by diminishing confounding factors.
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http://dx.doi.org/10.1111/pcn.12863DOI Listing
September 2019

Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors.

J Neurooncol 2019 May 1;143(1):27-33. Epub 2019 Mar 1.

Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Purpose: Dysembryoplastic neuroepithelial tumors (DNTs) are slow-growing glioneuronal tumors, and their genetic backgrounds are getting unveiled. Recently, fibroblast growth factor receptor 1 internal tandem duplication (FGFR1-ITD) of the tyrosine kinase domain (TKD) has been demonstrated by whole-genome sequencing.

Methods And Results: Here, we analyzed 22 DNTs using multiplex ligation-dependent probe amplification (MLPA) with formalin-fixed paraffin-embedded specimens and found a copy number gain in TKD of FGFR1 (13 cases, 59%), which suggested the presence of FGFR1-ITD. Another 5 DNTs harbored FGFR1 hot spot mutations including a double mutant case, and FGFR1 alterations were detected in 18 DNTs (82%). The BRAF V600E mutation, another important mutation in DNTs, was not observed.

Conclusions: With recent findings of less frequent or absent FGFR1-ITD in pilocytic astrocytomas or rosette-forming glioneuronal tumors, the analysis of FGFR1 aberrations, especially FGFR1-ITD, was suggested to be helpful to discriminate DNTs from their histological mimics.
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http://dx.doi.org/10.1007/s11060-019-03138-7DOI Listing
May 2019

Outcomes of three-Tesla magnetic resonance imaging for the identification of pituitary adenoma in patients with Cushing's disease.

Endocr J 2019 Mar 14;66(3):259-264. Epub 2019 Feb 14.

Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan.

Pituitary adenoma has been reported to be detectable in only 36-63% of Cushing's disease (CD) patients by magnetic resonance imaging (MRI). In this study, we investigate the outcomes and problems associated with tumor identification using 3-Tesla (3-T) MRI, which provides clearer images than ≤1.5-T MRI, in 115 patients who were initially diagnosed with CD. Before surgery, 31 macroadenomas (27%) and 54 microadenomas (47%) were identified by 3-T MRI, but pituitary adenoma was invisible on MRI in the remaining 30 cases (26%). The smallest tumor diameter amenable to a definitive diagnosis was 2 mm, and spoiled gradient-echo was the best sequence for diagnosing microadenomas. In 14 of 30 cases of MRI-invisible CD, the pituitary adenoma was identified during surgery. Nine of these 14 tumors that developed from outside the pituitary gland were retrospectively identified on MRI by comparison with surgical findings. The remaining 16 cases of MRI-invisible CD in which the pituitary adenoma was not identified during surgery involved partial hypophysectomy. Seven cases were hormonally remitted, but another nine cases experienced persistent disease after surgery. The sensitivity and specificity of the pituitary adenoma diagnosis in CD patients after the introduction of 3-T MRI were 80% and 100%, respectively. However, the sensitivity decreased to 72% when macroadenomas were excluded. Some adenomas associated with CD are still undetectable on 3-T MRI due to tumor size, location and intensity. However, sensitivity can be improved by monitoring tumors that develop outside the pituitary gland.
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http://dx.doi.org/10.1507/endocrj.EJ18-0458DOI Listing
March 2019

Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years.

J Neuropathol Exp Neurol 2018 11;77(11):981-986

Departments of Pathology.

We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.
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http://dx.doi.org/10.1093/jnen/nly082DOI Listing
November 2018

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation.

Neuropathology 2018 May 25. Epub 2018 May 25.

Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.
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http://dx.doi.org/10.1111/neup.12473DOI Listing
May 2018

Therapeutic outcomes of transsphenoidal surgery in pediatric patients with craniopharyngiomas: a single-center study.

J Neurosurg Pediatr 2018 06 30;21(6):549-562. Epub 2018 Mar 30.

3Pediatrics, and.

OBJECTIVE The aim of this study was to analyze the outcomes of transsphenoidal surgery (TSS) in a single-center clinical series of pediatric craniopharyngioma patients treated with gross-total resection (GTR). METHODS The authors retrospectively reviewed the surgical outcomes for 65 consecutive patients with childhood craniopharyngiomas (28 girls and 37 boys, mean age 9.6 years) treated with TSS (45 primary and 20 repeat surgeries) between 1990 and 2015. Tumors were classified as subdiaphragmatic or supradiaphragmatic. Demographic and clinical characteristics, including extent of resection, complications, incidence of recurrence, pre- and postoperative visual disturbance, pituitary function, and incidence of diabetes insipidus (DI), as well as new-onset obesity, were analyzed and compared between the primary surgery and repeat surgery groups. RESULTS Of the 45 patients in the primary surgery group, 26 (58%) had subdiaphragmatic tumors and 19 had supradiaphragmatic tumors. Of the 20 patients in the repeat surgery group, 9 (45%) had subdiaphragmatic tumors and 11 had supradiaphragmatic tumors. The only statistically significant difference between the 2 surgical groups was in tumor size; tumors were larger (mean maximum diameter 30 mm) in the primary surgery group than in the repeat surgery group (25 mm) (p = 0.008). GTR was accomplished in 59 (91%) of the 65 cases; the GTR rate was higher in the primary surgery group than in the repeat surgery group (98% vs 75%, p = 0.009). Among the patients who underwent GTR, 12% experienced tumor recurrence, with a median follow-up of 7.8 years, and recurrence tended to occur less frequently in primary than in repeat surgery patients (7% vs 27%, p = 0.06). Of the 45 primary surgery patients, 80% had deteriorated pituitary function and 83% developed DI, whereas 100% of the repeat surgery patients developed these conditions. Among patients with preoperative visual disturbance, vision improved in 62% but worsened in 11%. Visual improvement was more frequent in primary than in repeat surgery patients (71% vs 47%, p < 0.001), whereas visual deterioration was less frequent following primary surgery than repeat surgery (4% vs 24%, p = 0.04). Among the 57 patients without preoperative obesity, new-onset postoperative obesity was found in 9% of primary surgery patients and 21% of repeat surgery patients (p = 0.34) despite aggressive resection, suggesting that hypothalamic dysfunction was rarely associated with GTR by TSS in this series. However, obesity was found in 25% of the repeat surgery patients preoperatively due to prior transcranial surgery. Although there were no perioperative deaths, there were complications in 12 cases (18%) (6 cases of CSF leaks, 3 cases of meningitis, 2 cases of transient memory disturbance, and 1 case of hydrocephalus). Postoperative CSF leakage appeared to be more common in repeat than in primary surgery patients (20% vs 4.4%, p = 0.2). CONCLUSIONS The results of TSS for pediatric craniopharyngioma in this case series suggest that GTR should be the goal for the first surgical attempt. GTR should be achievable without serious complications, although most patients require postoperative hormonal replacement. When GTR is not possible or tumor recurrence occurs after GTR, radiosurgery is recommended to prevent tumor regrowth or progression.
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http://dx.doi.org/10.3171/2017.10.PEDS17254DOI Listing
June 2018

meningitis in a diffuse large B-cell lymphoma patient with CD4-positive lymphocytopenia and persistent oligoclonal CD8-positive lymphocytes in the peripheral blood.

Int J Clin Exp Pathol 2018 1;11(1):455-461. Epub 2018 Jan 1.

Medical Mycology Research Center, Chiba University Chuo-Ku, Chiba, Japan.

Nocardiosis, sometimes presenting with multiple granulomatous lesions, is a rare opportunistic infection occurring in immunocompromised patients. However, its immunological features remain largely unaddressed. We investigated the immunological characteristics of human nocardiosis and examined the component cells of the granulomatous lesions. A 66-year-old man with diffuse large B-cell lymphoma presented with fever and multiple nodules in the lung during chemotherapy. The blood culture formed white colonies, but their characterization was difficult by routine microbiological laboratory methods. Matrix-assisted laser desorption ionization-time of flight mass spectrometry identified the colonies as . Meanwhile, the patient suddenly experienced an epileptic seizure without a brain abscess. His cerebrospinal fluid (CSF) showed neutrophilic pleocytosis (108/mm). The conventional agar culturing failed to isolate colonies, but culturing with brain-heart infusion agar generated colonies. These colonies were completely concordant with those from the blood, as confirmed by 16S rRNA gene sequencing. Therefore, the patient had developed meningitis through sepsis induced by . His CD4-positive T-lymphocyte counts were low, and oligoclonal CD8-positive αβ T-lymphocytes were present in the blood prior to the first and after three cycles of chemotherapy. He had bone marrow granulomatous lesions comprising lymphoma and CD8-positive αβ T-cells. Treatment with sulfamethoxazole/trimethoprim relieved all of his symptoms. The combined analysis by microbiological and molecular methods determined the cause of his epileptic seizure. His immunological characteristics, including low CD4-positive or CD8-positive αβ T-lymphocytes, may have contributed to the unusual clinical presentations by , which rarely involves the central nervous system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957946PMC
January 2018

Childbirth and fertility preservation in childhood and adolescent cancer patients: a second national survey of Japanese pediatric endocrinologists.

Clin Pediatr Endocrinol 2017 22;26(2):81-88. Epub 2017 Apr 22.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Although existing guidelines recommend long-term follow-up of childhood cancer survivors (CCSs), their fertility has not been fully investigated in Japan. To address this issue, we organized a working panel consisting of medical specialists in foundation hospitals. We conducted questionnaire surveys targeting pediatric endocrinologists regarding reproduction in pediatric and adolescent cancer patients in collaboration with the CCS committee of the Japanese Society for Pediatric Endocrinology (JSPE). The first questionnaire was sent to 178 directors or councilors of the JSPE, and the second was sent to those who had provided answers on their experience with childbirth or fertility preservation. A total of 151 responses (84.8%) were obtained in the first survey. In the second survey, the response rate was 100% (39 respondents). There were 27 answers describing experiences with childbirth (16 from partners of male CCSs, 22 from female CCSs). A few cases of premature birth and low birth weight were reported. There were 25 answers describing experiences with fertility preservation; 21 were from male and 17 from female CCSs. It was mainly physicians who recommended fertility preservation. This nationwide questionnaire survey revealed that a limited number of Japanese pediatric endocrinologists had experience with childbirth and fertility preservation in CCSs. A further long-term follow-up study of their fertility is needed.
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http://dx.doi.org/10.1297/cpe.26.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402309PMC
April 2017

First case report of pulmonary nocardiosis caused by .

JMM Case Rep 2016 Aug 30;3(4):e005054. Epub 2016 Aug 30.

Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuoku, Chiba City, Chiba, 260-8673, Japan.

Introduction: species usually cause opportunistic infections, and the frequency of these infections is increasing owing to the growing population of immunocompromised hosts. However, species may sometimes cause an infection disease in immunocompetent hosts. infections are the least common and are very rare.

Case Presentation: Herein, we report the first case of a pulmonary infection with in a 61-year-old Japanese woman with a history of hyperlipidaemia and bronchiectasis and a 6-month history of non-productive hacking cough. A sample of bronchial lavage fluid obtained by bronchofiberscopy showed filamentous branching gram-positive rods and acid-fast filamentous branching rods, and a colony of suspected was cultured. Based on 16S rRNA, , and gene sequence analyses and biochemical and physiological properties, the strain was identified as The strain was resistant to the antimicrobial agents amoxicillin-clavulanic acid, clarithromycin, minocycline, gentamycin, tobramycin, ciprofloxacin and trimethoprim-sulfamethoxazole. The patient was treated with biapenem followed by intravenous amikacin and oral linezolid.

Conclusion: Despite its rarity, the species require attention owing to the existence of multidrug-resistant strains.
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http://dx.doi.org/10.1099/jmmcr.0.005054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330244PMC
August 2016

GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

J Neurosci Res 2017 08 9;95(8):1647-1665. Epub 2016 Dec 9.

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.

Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23999DOI Listing
August 2017

Effects of financial support on treatment of adolescents with growth hormone deficiency: a retrospective study in Japan.

BMC Health Serv Res 2016 10 21;16(1):602. Epub 2016 Oct 21.

GH Treatment Study Committee, The Foundation for Growth Science, 5-1-16 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Treatment costs for children with growth hormone (GH) deficiency are subsidized by the government in Japan if the children meet clinical criteria, including height limits (boys: 156.4 cm; girls: 145.4 cm). However, several funding programs, such as a subsidy provided by local governments, can be used by those who exceed the height limits. In this study, we explored the impacts of financial support on GH treatment using this natural allocation.

Methods: A retrospective analysis of 696 adolescent patients (451 boys and 245 girls) who reached the height limits was conducted. Associations between financial support and continuing treatment were assessed using multiple logistic regression analyses adjusting for age, sex, height, growth velocity, bone age, and adverse effects.

Results: Of the 696 children in the analysis, 108 (15.5 %) were still eligible for financial support. The proportion of children who continued GH treatment was higher among those who were eligible for support than among those who were not (75.9 % vs. 52.0 %, P < 0.001). The odds ratios of financial support to continuing treatment were 4.04 (95 % confidence interval [CI]: 1.86-8.78) in boys and 1.72 (95 % CI: 0.80-3.70) in girls, after adjusting for demographic characteristics and clinical factors.

Conclusions: Financial support affected decisions on treatment continuation for children with GH deficiency. Geographic variations in eligibility for financial support pose an ethical problem that needs policy attention. An appropriate balance between public spending on continuation of therapy and improved quality of life derived from it should be explored.
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http://dx.doi.org/10.1186/s12913-016-1854-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073827PMC
October 2016

Gonadal function, fertility, and reproductive medicine in childhood and adolescent cancer patients: a national survey of Japanese pediatric endocrinologists.

Clin Pediatr Endocrinol 2016 Apr 28;25(2):45-57. Epub 2016 Apr 28.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

An increasing number of pediatric cancer patients survive, and treatment-related infertility represents one of the most important issues for these patients. While official guidelines in Japan recommend long-term follow-up of childhood cancer survivors (CCSs), their gonadal function and fertility have not been clarified. To address this issue, we organized a working panel to compile evidence from long-term survivors who received treatments for cancer during childhood or adolescence. In collaboration with members of the CCS Committee of the Japanese Society for Pediatric Endocrinology (JSPE), we conducted a questionnaire survey regarding reproductive function in pediatric cancer patients. A cross-sectional survey was sent to 178 JSPE-certified councilors who were asked to self-evaluate the medical examinations they had performed. A total of 151 responses were obtained, revealing that 143 endocrinologists were involved in the care of CCSs. A quarter of the respondents reported having experienced issues during gonadal or reproductive examinations. Several survivors did not remember or fully understand the explanation regarding gonadal damage, and faced physical and psychological distress when discussing the risk of becoming infertile. Pediatric endocrinologists had anxieties regarding their patients' infertility and the risk of miscarriage, premature birth, and delivery problems. Only a limited number of endocrinologists had experience with managing childbirth and fertility preservation. Many councilors mentioned the necessity for inter-disciplinary communication among healthcare providers. Both endocrinologists and oncologists should set and follow a uniform clinical guideline that includes management of fertility of CCSs.
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http://dx.doi.org/10.1297/cpe.25.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860515PMC
April 2016

The diagnostic utility of reduced immunohistochemical expression of SMARCB1 in synovial sarcomas: a validation study.

Hum Pathol 2016 Jan 25;47(1):32-7. Epub 2015 Sep 25.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, 104-0045 Japan; Rare Cancer Center, National Cancer Center Hospital, Tokyo, 104-0045 Japan. Electronic address:

Synovial sarcoma is a malignant mesenchymal neoplasm of uncertain histogenesis, characterized by a specific SS18-SSX fusion. The diagnosis of synovial sarcoma can be challenging based on morphology and conventional immunohistochemistry alone, and identification of the fusion gene by molecular genetics may be necessary for diagnosis. Several recent studies have demonstrated the diagnostic utility of the reduced expression of SMARCB1 in synovial sarcomas as measured using immunohistochemistry. Therefore, we undertook a validation study using synovial sarcomas and other spindle or round cell tumors that could enter differential diagnosis of monophasic or poorly differentiated synovial sarcomas. Among 36 synovial sarcomas that were successfully evaluated, the expression of SMARCB1 was diffusely reduced in 33 cases (92%) at variable degrees. In contrast, the expression of SMARCB1 was not reduced in any of the 93 evaluable non-synovial sarcoma tumors (5 thymomas, 5 sarcomatoid mesotheliomas, 10 schwannomas, 9 mesenchymal chondrosarcomas, 20 solitary fibrous tumors, 19 Ewing sarcomas, and 25 malignant peripheral nerve sheath tumors). A few schwannomas and malignant peripheral nerve sheath tumors showed mosaic or complete loss of SMARCB1 expression. Reduced expression of SMARCB1 immunoreactivity was therefore found to be highly sensitive and specific for synovial sarcoma, and can be useful for rapidly and accurately confirming the diagnosis of synovial sarcoma. This reduction in SMARCB1 expression likely reflects the BAF47 ejection mechanism of the SS18-SSX fusion product and can therefore be viewed as an indirect visualization of this fusion product.
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http://dx.doi.org/10.1016/j.humpath.2015.09.010DOI Listing
January 2016

Therapeutic outcomes in patients undergoing surgery after diagnosis of Cushing's disease: A single-center study.

Endocr J 2015 17;62(12):1115-25. Epub 2015 Oct 17.

Department of Hypothalamic & Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan.

This study aimed to investigate early and late outcomes of patients who underwent neurosurgical procedures for the preoperative diagnosis of Cushing's disease (CD). Clinical, endocrine, imaging, and histologic data from 252 patients undergoing pituitary surgery at Toranomon Hospital through the end of 2012 were entered into a database and statistically analyzed. In 22 of these patients (8.7%; positive venous sampling in 15 and negative venous sampling in 7 patients), tumors were invisible on magnetic resonance imaging (MRI) and 42.9% of them achieved remission. In the remaining 230 patients, 93.5% of those with microadenomas (n=154) and 71.1% of those with macroadenomas (n=76) achieved early postoperative remission, with recurrence rates of 2.7% and 14.8%, respectively, during a 72.5-month median follow-up. In multivariate analyses, cavernous sinus invasion (CSI; odds ratio [OR], 13.0), type of surgery (OR, 4.0), and tumor size (OR, 2.7) were significant preoperative factors affecting early postoperative results, whereas peak cortisol levels ≥9.4 μg/dL in response to corticotropin-releasing hormone (CRH) and CSI were significant factors predicting recurrence. Tumor recurrence was more common in patients with non-densely granulated adenomas than in patients with densely granulated adenomas. We propose that the higher remission and lower recurrence rates in this series are due to our surgical strategies, including extracapsular tumor removal, aggressive resection of tumors with CSI, extended transsphenoidal surgery (TSS), or a combined approach for large/giant adenomas. Appropriate multimodal treatments, including radiotherapy, medication, and repeated surgery in patients with persistent or recurrent CD, could result in better overall outcomes than previously achieved.
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http://dx.doi.org/10.1507/endocrj.15-0463DOI Listing
October 2016
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