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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23779号 / 医博第4825号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 玄, 教授 篠原 隆司, 教授 斎藤 通紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

General movements (GMs) are the spontaneous gross motor movements involving the whole body. GMs progressively develop as an infant ages. Several recent research studies involving the qualitative assessment of the GMs in infants have validated that GMs, or the lack of, are an accurate way diagnosing a neurological dysfunction in the early stages of infancy. One study has shown that definitely abnormal movements occurring between 10-20 weeks post-term accurately predicted cerebral palsy in infants with an accuracy of 85 to 98 percent [1]. The qualitative method of assessing an infant's GMs is an accurate way of predicting a neurological dysfunction, however, requires the review of hours of video footage by a trained physician. This process is not only time consuming and costly but is subjective in the sense that the results cannot be easily transferred among different institutions. It is also difficult to conduct longitudinal studies without first reviewing the entire history of video footage of the infant's GMs. Improvements can be made to the qualitative GMs assessment method by utilizing recent advances in technology that "can make data collection and analysis more efficient, without compromising competency" [2]. In particular, preliminary research has shown that data collected from"wired" micro-electrical-mechanical systems (MEMS) accelerometers attached to the wrist and ankles of an infant is a feasible way of collecting and characterizing the motion patterns that infants display during GMs [3]. The work presented in this thesis is directed towards improving the past research that used "wired" accelerometers to acquire acceleration signals from the limbs of infants. This thesis describes the process of transitioning the "wired" accelerometers to the wireless level, designing a user-friendly interface to graphically interpret the acceleration data, and assessing the designed system through clinical trials on normal and at-risk infants using the design system. / Master of Science

Objective: We sought to determine N-terminal proatrial natriuretic peptide concentrations [Nt-proANP] in plasma from cats with hypertrophic cardiomyopathy (HCM). Secondarily, we wished to evaluate the relationship between [Nt-proANP] and echocardiographic variables. Methods: Venous blood samples were obtained from seventeen cats with HCM and from nineteen healthy cats. Plasma [Nt-proANP] was determined using an ELISA assay. The relationship between plasma [Nt-proANP] and M-mode, 2-dimensional and Doppler echocardiographic variables was evaluated. Cats that were hyperthyroid or had evidence of renal disease were excluded from the study. Results: The mean plasma [Nt-proANP] was higher in cats with HCM (3.81 +/- 1.23 pmol/l) than in control cats (3.08 +/- 1.41 pmol/l); however, this difference was not statistically significant (p=0.17). There was a significant correlation between plasma [Nt-proANP] and left ventricular posterior wall thickness (r = 0.42; p=0.01). Additionally, plasma [Nt-proANP] was correlated with left atrial size (r = 0.35; p=0.03). A linear regression model was developed to further explore these relationships. LAs2D and LVPWd had an interactive effect on plasma [Nt-proANP] (R2 = 0.2737; p= 0.02). There was no correlation between any other echocardiographic variable and plasma [Nt-proANP]. There was no correlation between plasma [Nt-proANP] and heart rate (HR), body-weight, or age. Conclusions: Cats with HCM do not have significantly higher plasma [Nt-proANP] than normal cats. There was a significant linear relationship between [Nt-proANP] and LAs2D, LVPWd and the model that described their interaction. / Master of Science

Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment. The non-competitive NMDA receptor antagonist, phencyclidine (PCP), is a psychomotor stimulant drug that has been shown to induce symptoms characteristic of schizophrenia in humans and animals. The aim of these studies was to use the sub-chronic PCP model in rats to investigate cognitive dysfunction in behavioural tests which have been highlighted as relevance by the MATRICS initiative (MATRICS.ucla.edu). The main tests used were attentional set-shifting, operant reversal learning, and novel object recognition tasks. The pharmacology of antipsychotics was studied in the reversal learning task using receptor selective compounds. Following this, experiments were carried out using in vitro electrophysiology and in vivo microdialysis in an attempt to investigate the mechanisms underpinning the PCP-induced cognitive deficits. The attentional set-shifting task is a test of executive function, the extra-dimensional shift (EDS) phase relates to the ability to shift attention to a different stimulus dimension; this is impaired in patients with schizophrenia. The studies presented in chapter 2 showed that sub-chronic PCP administration impaired attentional set-shifting performance selectively in the EDS phase, a deficit which was significantly attenuated by sub-chronic administration of clozapine and risperidone, but not haloperidol. The effect of PCP was also shown to be more robust in female rats compared to males. A deficit in set-shifting ability was also observed in isolation reared rats. However, the deficits produced by PCP were more robust than the deficit produced by isolation rearing. The reversal learning task is another test of executive function. Chapter 3 reported that sub-chronic PCP administration impairs reversal learning ability in an operant task, as demonstrated by reduced percent correct responding in the reversal phase of the reversal learning task. It was found that a D1 agonist (SKF-38398), a 5-HT1A partial agonist (buspirone), a 5-HT2C antagonist (SB-243213A) and an agonist and positive allosteric modulator of the alpha 7 nACh receptor (PNU-282987 and PheTQS respectively) are able to reverse the sub-chronic PCP-induced deficit in reversal learning. Although many antipsychotics have affinity for muscarinic M1 and histamine H1 receptors, selective agents at these receptors were not able to improve the PCP-induced deficit. In chapter 4, the atypical antipsychotics, clozapine and risperidone, when given alone to naïve rats had no effect on reversal learning. Haloperidol when given to naïve rats impaired performance at the highest dose. Sub-chronic PCP was again found to impair reversal learning performance. Investigative experiments revealed that the 2 min time-out could be important as a cue. Following a double reversal, olanzapine-treated rats lost the ability to switch between the rules, whereas clozapine and risperidone-treated rats could perform the double reversal. Experiments with the extended (15 min) reversal phase could allow the investigation of the time-course effects of antipsychotics or selective compounds. The studies presented in chapter 5 found a reduction in gamma oscillations in the CA3 region of the hippocampus, following sub-chronic PCP treatment (2-5 weeks post treatment) that was paralleled by a deficit in parvalbumin immunoreactive (IR) cell density, at a similar time point (2 weeks post treatment). In contrast, a time-dependent increase in gamma oscillations was observed (6-8 weeks post treatment), at which point parvalbumin IR cell density was unchanged (8 weeks post treatment). Gamma oscillations were unchanged in the prefrontal cortex (PFC) following the PCP treatment regime. Locomotor activity tests were also carried out to ensure that the sub-chronic PCP treatment was successful. In-vivo microdialysis revealed that vehicle-treated rats show an increase in dopamine in the PFC which is selective for the retention trial of the novel object recognition task. PCP-treated rats were unable to distinguish between the novel and familiar objects and the increase in dopamine observed in vehicle rats was absent. As a control experiment it was also shown that sub-chronic PCP did not induce anxiety-like symptoms in the elevated plus maze and open field tests. These studies suggest that sub-chronic PCP induces cognitive deficits in behavioural tasks, and these deficits may be due to GABAergic mediated processes in the hippocampus and dopaminergic dysfunction in the PFC. These behavioural and neurochemical results are concurrent to findings observed in schizophrenia.

No / Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1¿1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.

Yes / Objective: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism. Methods: Knee joints from mice overexpressing bGH or GHa and wild-type (WT) control mice were examined using histology and micro–computed tomography for osteoarthritic (OA) pathologies. Additionally, cartilage from bGH mice was used for metabolomics analysis. Mouse primary chondrocytes from bGH and WT mice, with or without pegvisomant treatment, were used for quantitative polymerase chain reaction and Seahorse respirometry analyses. Results: Both male and female bGH mice at ~13 months of age had increased knee joint degeneration, which was characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher Osteoarthritis Research Society International and Mankin scores in bGH mice compared to WT control mice. Metabolomics analysis revealed changes in a wide range of metabolic pathways in bGH mice, including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes up-regulated fatty acid oxidation and increased expression of Col10a. Joints of GHa mice were remarkably protected from developing age-associated joint degeneration, with smooth articular joint surface. Conclusion: This study showed that an excessive amount of GH promotes joint degeneration in mice, which was associated with chondrocyte metabolic dysfunction and hypertrophic changes, whereas antagonizing GH action through a GHa protects mice from OA development. / Dr. Zhu's work was supported by Ohio University, the Arthritis National Research Foundation (grant 833836), a FIRST award from the American Society for Bone and Mineral Research, the NIH (grant R15-AR-080813), and a Hevolution Foundation AGE grant (AGE-008). Dr. Davis’ work was supported by a medical student seed grant from Ohio University. Dr. Lotz's work was supported by the NIH (grant R37-AG-059418). Dr. Berryman was supported by the NIH (grant R01-AG-059779). Dr. Kopchick was supported by the State of Ohio's Eminent Scholar Program that includes a gift from Milton and Lawrence Goll and the AMVETS, and by the NIH (grant R01-AG-059779).

Cisplatin, a platinum-based drug extensively utilized in chemotherapy, is effective in treating a variety of cancer forms. Clinical studies have shown that cisplatin triggers muscle wasting and dysfunction, which significantly impacts the clinical prognosis of cancer patients. Additionally, recent research revealed that pyroptosis, a highly inflammatory cell-death, mediates muscle wasting. However, its role in cisplatin-induced skeletal muscle toxicity remains unclear. Therefore, we hypothesized that cisplatin induces myotoxicity and causes adverse skeletal muscle remodeling through pyroptosis. In this study, C57BL/6 mice (10±2 weeks old) were divided into two groups: Control(saline) and Cisplatin (cisplatin). Saline and Cisplatin were respectively administered via intraperitoneal injection (i.p.) at 2.3mg/kg body weight (BW) for 5 consecutive days (first cycle), followed by 5 days of rest, and then another 5 consecutive days (second cycle), making it a total of 10 injections and a cumulative dose of 23 mg/kg BW. At day 29 (D29), the muscle function was assessed by subjecting the mice to grip force tests and weight tests. Gastrocnemius muscle tissues from sacrificed mice were collected for histological analysis. Further analysis for protein expression of pyroptosis-associated markers (TLR4, NLRP3, Caspase-1, IL-1β, IL-18, and GSDMD) was performed using immunohistochemistry and western blotting. The stimulation of TLR4 leads to the formation of the NLRP3 inflammasome which initiates the activation of Caspase-1, Il-1β and IL-18, along with the executioner of pyroptosis, GSDMD. Our data revealed that cisplatin-treatment significantly (P