パーキンソン病における線条体ドパミン欠乏による機能的結合性の変化

京都大学新制・論文博士博士(医学)乙第13570号論医博第2296号京都大学大学院医学研究科医学専攻(主査)教授 花川 隆, 教授 渡邉 大, 教授 高橋 淳学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

High expression of a novel carnitine palmitoyltransferase I like protein in rat brown adipose tissue and heart: isolation and characterization of its cDNA clone

AbstractTo characterize energy metabolism in rat brown adipose tissue (BAT), we carried out differential screening of a cDNA library of BAT with a cDNA probe of white adipose tissue (WAT) and isolated one cDNA clone. It contained a single open reading frame of 2,316 bases which encodes a protein of 88.2 kDa. The predicted amino acid sequence showed the highest homology (62.6%) with that of rat carnitine palmitoyltransferase I (CPTI). The transcript corresponding to this cDNA was found to be abundantly expressed in BAT and heart. Therefore, the isolated clone is concluded to encode a CPTI like protein expressed in BAT and heart

High-mass star formation in Orion triggered by cloud-cloud collision II, Two merging molecular clouds in NGC2024

We analyzed the NANTEN2 13CO (J=2-1 and 1-0) datasets in NGC 2024. We found that the cloud consists of two velocity components, whereas the cloud shows mostly single-peaked CO profiles. The two components are physically connected to the HII region as evidenced by their close correlation with the dark lanes and the emission nebulosity. The two components show complementary distribution with a displacement of 0.4 pc. Such complementary distribution is typical to colliding clouds discovered in regions of high-mass star formation. We hypothesize that cloud-cloud collision between the two components triggered the formation of the late O stars and early B stars localized within 0.3 pc of the cloud peak. The collision timescale is estimated to be ~ 10^5 yrs from a ratio of the displacement and the relative velocity 3-4 km s-1 corrected for probable projection. The high column density of the colliding cloud 1023 cm-2 is similar to those in the other massive star clusters in RCW 38, Westerlund 2, NGC 3603, and M42, which are likely formed under trigger by cloud-cloud collision. The present results provide an additional piece of evidence favorable to high-mass star formation by a major cloud-cloud collision in Orion.Comment: 24 pages, 10 figures, submitted for publication in PASJ (cloud-cloud collision special issue

A case of reversible cerebral vasoconstriction syndrome associated with anti-phospholipid antibody syndrome and systemic lupus erythematosus

The pathomechanisms and treatment strategy for rare presentations of reversible cerebral vasoconstriction syndrome (RCVS) with anti-phospholipid syndrome (APS) remain to be determined. We report a 67-year-old woman with APS who presented with ischemic stroke due to RCVS. She was treated with low-dose cilostazol and lomerizine hydrochloride, which resulted in functional improvement and recovery of vasoconstriction within 12 weeks. Her plasma endothelin-1 level was decreased after relief of vasoconstriction, compared with the pre-treatment condition. Increased plasma endothelin-1 may be related to the underlying pathomechanism of RCVS with APS, against which cilostazol and lomerizine hydrochloride could be effective

Association between acetylcholine receptor characteristics in biceps motor endplates and the epidemiological predictors for conversion from ocular to generalized myasthenia gravis

Objective: Epidemiological studies have identified various predictors of conversion from ocular myasthenia gravis (OMG) to secondary generalized myasthenia gravis (SGMG), but none have been confirmed. We investigated the effects of the epidemiological conversion predictors on the destruction of motor endplates in the biceps of patients with OMG and attempted to identify predictors of conversion to SGMG histologically.Methods: Patients with clinically diagnosed OMG who requested immunohistological diagnosis and who underwent muscle biopsy were included in this study. We immunostained the biceps motor endplate and semi-quantitatively measured the density and number of AChRs to determine their association with the epidemiological predictors of conversion from OMG to SGMG.Results: Thirteen patients with OMG were included, of which two patients with positive AChR antibody and concomitant thymoma converted to SGMG. In the classification according to the presence of AChR antibody, the AChR densities tended to be lower in the antibody-positive group than in the negative group (p=0.079), and the AChR numbers were significantly lesser in the AChR antibody-positive group than in the negative group (p=0.019). There were no differences in AChR densities or numbers according to sex, presence of thymic abnormalities, or presence of comorbid autoimmune diseases.Conclusion: In OMG, the AChR numbers in motor endplates of the biceps were significantly lesser in the AChR antibodypositive group than in the negative group. Since the muscle strength tends to decrease as the number of AChRs decreases, AChR antibody positivity may be a predictor of OMG to SGMG conversion, but further studies are needed to confirm

Neuromelanin‐Sensitive Magnetic Resonance Imaging Using DANTE Pulse

BACKGROUND: Neuromelanin-sensitive magnetic resonance imaging techniques have been developed but currently require relatively long scan times. The aim of this study was to assess the ability of black-blood delay alternating with nutation for tailored excitation-prepared T1-weighted variable flip angle turbo spin echo (DANTE T1-SPACE), which provides relatively high resolution with a short scan time, to visualize neuromelanin in the substantia nigra pars compacta (SNpc). METHODS: Participants comprised 49 healthy controls and 25 patients with Parkinson's disease (PD). Contrast ratios of SNpc and hyperintense SNpc areas, which show pixels brighter than thresholds, were assessed between DANTE T1-SPACE and T1-SPACE in healthy controls. To evaluate the diagnostic ability of DANTE T1-SPACE, the contrast ratios and hyperintense areas were compared between healthy and PD groups, and receiver operating characteristic analyses were performed. We also compared areas under the curve (AUCs) between DANTE T1-SPACE and the previously reported gradient echo neuromelanin (GRE-NM) imaging. Each analysis was performed using original images in native space and images transformed into Montreal Neurological Institute space. Values of P < 0.05 were considered significant. RESULTS: DANTE T1-SPACE showed significantly higher contrast ratios and larger hyperintense areas than T1-SPACE. On DANTE T1-SPACE, healthy controls showed significantly higher contrast ratios and larger hyperintense areas than patients with PD. Hyperintense areas in native space analysis achieved the best AUC (0.94). DANTE T1-SPACE showed AUCs as high as those of GRE-NM. CONCLUSIONS: DANTE T1-SPACE successfully visualized neuromelanin of the SNpc and showed potential for evaluating PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Two-Minute Quantitative Susceptibility Mapping From Three-Dimensional Echo-Planar Imaging: Accuracy, Reliability, and Detection Performance in Patients With Cerebral Microbleeds

Objectives: The aim of this study was to assess the accuracy, reliability, and cerebral microbleed (CMB) detection performance of 2-minute quantitative susceptibility mapping (QSM) from 3-dimensional echo-planar imaging (3D-EPI). Materials and Methods: Gadolinium phantom study was conducted using 3D-EPI, single–echo time (TE), and multi-TE gradient-recalled echo (GRE) sequences on two 3-T magnetic resonance (MR) scanners to assess the accuracy between measured and theoretical susceptibility values. The institutional review board approved this prospective study, and 40 healthy volunteers were enrolled with written consent between April 2018 and October 2019. Each underwent 3D-EPI, single-TE, and multi-TE GRE sequences consecutively on one 3-T MR scanner, and QSMs were calculated to assess the reliability of 3D-EPI QSM. Intraclass correlation coefficient (ICC), linear regression, and Bland-Altman plots were calculated. Patients with CMB who underwent both 3D-EPI and GRE QSM scans were retrospectively enrolled. Two radiologists evaluated images independently, and Cohen κ coefficients were calculated to compare CMB detection performance. Results: Phantom study showed excellent validity of 3D-EPI QSM on both MR scanners: Skyra, R2 = 0.996, P < 0.001, ICC = 0.997, mean difference, −2 ppb (95% confidence interval [CI], −45 to 40 ppb); Prisma, R2 = 0.992, P < 0.001, ICC = 0.988, mean difference, 15 ppb (95% CI, −67 to 97 ppb). A human study of 40 healthy volunteers (59 ± 13 years, 25 women) showed excellent reliability with 3D-EPI QSM for both single-TE and multi-TE GRE (R2 = 0.981, P < 0.001, ICC = 0.988; R2 = 0.983, P < 0.001, ICC = 0.990, respectively), supported by a Bland-Altman mean difference of 4 ppb (95% CI, −15 to 23 ppb) for single-TE GRE and 3 ppb (95% CI, −15 to 20 ppb) for multi-TE GRE. The CMB detection performance evaluation from 38 patients (51 ± 20 years, 20 women) showed almost perfect agreement between 3D-EPI and GRE QSM for both raters (κ = 0.923 and 0.942, P < 0.001). Conclusions: Faster QSM from 3D-EPI demonstrated excellent accuracy, reliability, and CMB detection performance

Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells

Development of factor VIII (fVIII)-neutralizing antibodies, called inhibitors, is a challenging problem in the management of hemophilia A patients. We explored the possibility of pretreatment with apoptotic fVIII-expressing embryonic stem (ES) cells to prevent the development of fVIII inhibitors. Murine ES cells integrated with the human F8 gene were differentiated into embryoid bodies, dissociated to a single cell suspension, subjected to hypo-osmotic shock to induce apoptosis, and intraperitoneally injected into hemophilia A mice. Inhibitors were induced by periodic intraperitoneal injections of recombinant human fVIII (rhfVIII). In the groups in which intraperitoneal injections of rhfVIII began at 1-3 weeks after pretreatment, the titers of inhibitors were significantly lower after the third administration of rhfVIII compared with that in the control group in which apoptotic Ainv18 ES cells (without the human F8 gene) were used for pretreatment, and continued to show lower levels until the sixth administration of rhfVIII. These results suggest that pretreatment with apoptotic hfVIII-expressing ES cells might be promising for the prevention of fVIII inhibitor development in hemophilia A patients

Insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system

PURPOSE: To demonstrate the capability of insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system. METHODS: Insertable inductively coupled volume coils with diameters of 26 and 64 mm (D26 and D64 coils) targeted for monkey and mouse brain specimen sizes were designed and fabricated. These coils were placed inside the imaging volume of a transmit/receive knee coil without wired connections to the main system. Signal-to-noise ratio (SNR) evaluations were conducted with and without the insertable coils, and the g-factor maps of parallel imaging (PI) were also calculated for the D64 coil. Brain specimens were imaged using 3D T 2 ∗ -weighted images with spatial resolution of isotropic 50 and 160 μm using D26 and D64 coils, respectively. RESULTS: Relative average (SD) SNRs compared with knee coil alone were 12.54 (0.30) and 2.37 (0.05) at the center for the D26 and D64 coils, respectively. The mean g-factors of PI with the D64 coil for the factor of 2 were less than 1.1 in the left-right and anterior-posterior directions, and around 1.5 in the superior-inferior direction or when the PI factor of 3 was used. Acceleration in two directions showed lower g-factors but suffered from intrinsic low SNR. Representative T 2 ∗ -weighted images of the specimen showed structural details. CONCLUSION: Inductively coupled small diameter coils insertable to the knee coil demonstrated high SNR and modest PI capability. The concept was successfully used to visualize fine structures of the brain specimen. The insertable coils are easy to handle and enable MR microscopy in a human whole-body 7T MRI system