Possible involvement of iron-induced oxidative insults in neurodegeneration.

Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research

iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer’s Disease

In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer’s disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development

Face Image Enhancement Using 3D and Spectral Information

This paper presents a novel method of enhancing image quality of face pictures using 3D and spectral information. Most conventional techniques directly work on the image data, shifting the skin color to a predefined skin tone, and so do not take into account the effects of shape and lighting. The proposed method first recovers the 3D shape of a face in an input image using a 3D morphable model. Then, using color constancy and inverse rendering techniques, specularities and the true skin color, i.e., its spectral reflectance, are recovered. The quality of the input image is improved by matching the skin reflectance to a predefined reference and reducing the amount of specularities. The method realizes the enhancement in a more physically accurate manner compared to previous ones. Subjective experiments on image quality demonstrates the validity of the proposed method

Fatal intra-abdominal hemorrhage as a result of avulsion of the gallbladder: A postmortem case report

Gallbladder injuries are extremely rare in blunt trauma, with a reported incidence of <2%. We report an autopsy case of fatal hemorrhagic shock due to intra-abdominal bleeding resulting from complete avulsion of the gallbladder associated with liver cirrhosis. Multiplanar images derived from multislice computed tomography (MSCT) performed as part of pre-autopsy screening showed complete avulsion of the gallbladder without any other associated intra-abdominal injuries, facilitating forensic autopsy planning. In this report, we discuss the role of MSCT in cases of fatal intra-abdominal bleeding caused by avulsion of the gallbladder and discuss the mechanism of this injury

A case report of forensic personal identification by transposed teeth and dental treatment marks using multidetector row computed tomography

Using postmortem computed tomography (CT) images, we achieved personal identification of a body using transposed teeth and dental treatment marks. Transposition of teeth is a rare malpositioning anomaly. CT images can clarify the malpositioning of the teeth's roots, which is difficult to discern from gross observation of the dentition. Because dental hygiene has reduced the incidence of caries in recent years, it might be difficult to use treatment marks for personal identification in the future. Transposed teeth, although rare, provide an important clue to personal identification

iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer’s Disease

アルツハイマー病病因物質を低減させる既存薬カクテルの同定 --患者由来iPS細胞を用いた化合物スクリーニングとin vitroトライアル--. 京都大学プレスリリース. 2017-11-28.In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer’s disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development

Impact of linked color imaging and blue laser imaging on the diagnosis of esophageal squamous cell carcinoma in iodine unstained areas

Abstract The pink color sign in iodine unstained areas is useful to differentiate esophageal squamous cell carcinoma (ESCC) from other lesions. However, some ESCCs have obscure color findings which affect the ability of endoscopists to differentiate these lesions and determine the resection line. Using white light imaging (WLI), linked color imaging (LCI) and blue laser imaging (BLI), 40 early ESCCs were retrospectively evaluated using images before and after iodine staining. Visibility scores for ESCC by expert and non‐expert endoscopists were compared using these three modalities and color differences measured for malignant lesions and surrounding mucosa. BLI had the highest score and color difference without iodine staining. Each determination with iodine was much higher than without iodine regardless of the modality. With iodine, ESCC mainly appeared pink, purple and green using WLI, LCI and BLI, respectively and visibility scores determined by non‐experts and experts were significantly higher for LCI (both p < 0.001) and BLI (p = 0.018 and p < 0.001) than for WLI. The score with LCI was significantly higher than with BLI among non‐experts (p = 0.035). With iodine, the color difference using LCI was twice that with WLI and one with BLI was significantly larger than with WLI (p < 0.001). These greater tendencies were found regardless of location, depth of cancer or intensity of pink color using WLI. In conclusion, areas of ESCC unstained by iodine were easily recognized using LCI and BLI. Visibility of these lesions is excellent even by non‐expert endoscopists, suggesting that this method is useful to diagnose ESCC and determine the resection line

Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. Results Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. Conclusions Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.</p