京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13207号 / 論医博第2161号 / 新制||医||1031(附属図書館) / (主査)教授 福原 俊一, 教授 湊谷 謙司, 教授 小池 薫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Transplants of fetal neural tissue survive and develop in lesion cavities produced in adult rats. The present experiment tested the effect of grafting fetal hippocampal or brainstem tissue on the ability of rats with hippocampal lesions to perform on a differential reinforcement of low response rate (DRL) operant schedule. The DRL interval was 20 s. Eighty-six percent of the hippocampal grafts and 69% of the brainstem grafts developed to maturity. Inspection of sections stained using a silver technique for axis cylinders or taken from rats in which the mature transplant had been injected with Fast blue, indicated that these grafts formed connections with the host brain. Consistent with previous reports, rats with hippocampal lesions were impaired in performance of the DRL task. Rats given fetal grafts of hippocampal tissue into the hippocampal lesion site on the day of lesion production were significantly better in performance of the DRL requirement than were lesion-only rats or rats receiving grafts of fetal brainstem tissue. The results of this study confirm that grafts of fetal brain tissue can both develop in a lesion site in an adult brain and ameliorate lesion-induced behavioral deficits.

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A 3 year old Hispanic male presented with fevers, skin rash, left neck swelling and refusal to walk of several days duration. Physical exam revealed a febrile, fussy toddler with a tender, cystic lesion in the left submandibular region. Both ankles had tender cystic lesions on the lateral malleolar regions. Labs: WBC 33,000 with neutrophilia, bandemia, thrombocytosis, and increased ESR and CRP. MRI of the neck and ankles revealed cystic lymphatic malformations with no communication with the joints.ENT specialist was consulted and neck cystic lesion was aspirated to rule out a septic focus. Bone scan of the lower extremities ruled out infectious or malignant etiology. He was started on multiple antibiotics with a presumed diagnosis of sepsis. An ECHO on the 4th hospital day showed a pericardial effusion which required a pericardial window. He also developed bilateral pleural effusions which resolved with supportive treatment. Aspirates from the cystic lesions, pericardial fluid, blood and urine cultures were sterile. Even in the second week of hospital stay, he continued to spike high fevers (Tmax 107) with high white counts and left shift inspite of treatment with antibiotics. A diagnosis of systemic onset juvenile idiopathic arthritis (SOJIA) was made with input from rheumatologist. Antibiotics were discontinued and steroids were started with good response. Cystic lesions were treated with percutaneous sclerotherapy with doxycycline. He was discharged home on oral steroids, NSAID’s and weekly methotrexate. Etanercept was added to decrease dependence on oral steroids. He remains in good health 2 years since initial presentation. Discussion: A febrile toddler who refuses to walk is a common clinical presentation in pediatrics. Differential diagnosis of such a patient includes osteomyelitis, septic arthritis, acute rheumatic fever, leukemia and non-accidental trauma. The presence of systemic extra-articular symptoms as in our patient must alert the pediatrician to systemic onset juvenile rheumatoid arthritis (SOJIA). It accounts for 10-20% of all juvenile idiopathic arthritis (JIA) patients with an incidence of 0.4-0.8 per 100,000. SOJIA differs from other conditions in its multisystem involvement. Clinical features like pleurisy, pericarditis, spiking fevers, hepatosplenomegaly and lymphadenopathy overshadow the joint symptoms. The joint involvement may be completely absent or may be a late clinical feature. These patients have leukocytosis, thrombocytosis and high inflammatory markers simulating a septic focus. In our patient, the accurate diagnosis was complicated by the confounding presence of multiple cystic lymphatic lesions. Treatment of SOJIA is challenging. Oral steroids, NSAID’s, methotrexate, etanercept and the newer anakinra have been used with varying success. Our case underlines the importance of considering a diagnosis of systemic onset JIA in a febrile toddler even in the absence of overt joint involvement.

The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.

Malignant melanoma (MM) is a type of skin cancer that is associated with a very poor prognosis and can often lead to death. Early detection is crucial in order to administer the right treatment successfully but currently requires the expertise of a dermatologist. In the past years, studies have shown that automatic detection of MM is possible through computer vision and machine learning methods. Skin lesion segmentation and classification are the key methods in supporting automatic detection of different skin lesions. Compared with traditional computer vision as well as other machine learning methods, deep neural networks currently show the greatest promise both in segmentation and classification. In our work, we have implemented several deep neural networks to achieve the goals of skin lesion segmentation and classification. We have also applied different training schemes. Our best segmentation model achieves pixel-wise accuracy of \textbf{0.940}, Dice index of \textbf{0.867} and Jaccard index of \textbf{0.765} on the ISIC 2017 challenge dataset. This surpassed the official state of the art model whose pixel-wise accuracy was 0.934, Dice index 0.849 and Jaccard Index 0.765. We have also trained a segmentation model with the help of adversarial loss which improved the baseline model slightly. Our experiments with several neural network models for skin lesion classification achieved varying results. We also combined both segmentation and classification in one pipeline meaning that we were able to train the most promising classification model on pre-segmented images. This resulted in improved classification performance. The binary (melanoma or not) classification from this single model trained without extra data and clinical information reaches an area under the curve (AUC) of 0.684 on the official ISIC test dataset. Our results suggest that automatic detection of skin cancers through image analysis shows significant promise in early detection of malignant melanoma.

Active disease resistance in plants is induced during the pathogen infection process that triggers multiple defense-related genes to establish broad-spectrum resistance. Several biotic and abiotic agents can mimic natural induced resistance (IR), categorized as systemic acquired (SAR) or induced systemic resistance (ISR). IR, triggered by acibenzolar-S-methyl (ASM) or plant growth-promoting rhizobacteria (PGPR), was evaluated on two-to-three types of tobacco in greenhouse and field studies. Tobacco mosaic virus (TMV) local lesion assays monitored induction and maintenance of ASM-induced SAR over a 21 day period via proportional reduction in the number of TMV local lesions between an untreated control and ASM-treated plants. Intraspecific variation in SAR was found among tobacco types; burley and flue-cured tobaccos responded by day 3, while oriental tobacco responded between day 3 and 6. The SAR signal was greatest between 6 and 15 days following ASM application, but IR was slightly evident even at 21 days after ASM application in all three tobacco types. Bottom and middle leaves responded similarly on all sample dates, but top leaves showed the weakest SAR response. Tobacco cyst nematode (TCN; Globodera tabacum solanacearum) is one of the most destructive pathogens of tobacco in Virginia. Among four PGPR combinations tested, a mixture of Bacillus amyloliquefaciens IN937a (GB99) and B. subtilis A13 (GB122) most consistently suppressed TCN reproduction in flue-cured and oriental tobacco. Application of ASM similarly reduced final numbers of TCN cysts, but also resulted in chlorosis, stunting, and lower plant fresh weight. GB99+GB122 also suppressed TCN development and reproduction in susceptible and resistant flue-cured cultivars, but reductions by ASM were less consistent. In a split-root trial, soil amendment with GB99+GB122 in one half of an oriental tobacco root system lowered final numbers of TCN more than did ASM. ASM exhibited undesirable effects in phytotoxicity trials in flue-cured and oriental tobacco, but GB99+GB122 was not phytotoxic. When oriental tobacco seedlings were grown in a GB99+GB122-treated soil-less media, a single application of 200 mg ASM/L one week after transplanting significantly suppressed TCN reproduction in the field without phytotoxicity. Further field research is needed to confirm this effect in flue-cured tobacco. / Ph. D.

Paroxysmal Atrial fibrillation (AF) is often clinically silent and may be missed by the usual diagnostic workup after ischemic stroke. We aimed to determine whether shape characteristics of ischemic stroke lesions can be used to predict AF in stroke patients without known AF at baseline. Lesion shape quantification on brain MRI was performed in selected patients from the intervention arm of the Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS) study, which included patients with ischemic stroke or TIA without prior AF. Multiple morphologic parameters were calculated based on lesion segmentation in acute brain MRI data. Multivariate logistic models were used to test the association of lesion morphology, clinical parameters, and AF. A stepwise elimination regression was conducted to identify the most important variables. A total of 755 patients were included. Patients with AF detected within 2 years after stroke (n=86) had a larger overall oriented bounding box (OBB) volume (p=0.003) and a higher number of brain lesion components (p=0.008) than patients without AF. In the multivariate model, OBB volume (OR 1.72, 95%CI 1.29–2.35, p<0.001), age (OR 2.13, 95%CI 1.52–3.06, p<0.001), and female sex (OR 2.45, 95%CI 1.41–4.31, p=0.002) were independently associated with detected AF. Ischemic lesions in patients with detected AF after stroke presented with a more dispersed infarct pattern and a higher number of lesion components. Together with clinical characteristics, these lesion shape characteristics may help in guiding prolonged cardiac monitoring after stroke.

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