Tuberculosis (TB) continues to be a worldwide health problem despite available effective chemotherapy. In the past 2 decades, distribution of new TB cases in the U.S. has shifted to persons over the age of 65, who account for 12% of the U.S. population but 27% of the total TB morbidity. Residents of long-term care facilities are at greater risk of developing TB than are elderly persons living in private homes or in the community at large. Because this older age group continues to be the largest repository for TB and because the geriatric population in this country is growing, TB is an important medical issue.

Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with severe neurological manifestations due to a-N-acetylglucosaminidase (NaGlu) deficiency. The mechanism of neuropathology in MPS IIIB is unclear. This study investigates the role of immune responses in neurological disease of MPS IIIB in mice. By means of gene expression microarrays and realtime quantitative reverse transcriptase-polymerase chain reaction, we demonstrated significant up-regulation of numerous immune-related genes in MPS IIIB mouse brain involving a broad range of immune cells and molecules, including T cells, B cells, microglia/ macrophages, complement, major histocompatibility complex class I, immunoglobulin, Toll-like receptors, and molecules essential for antigen presentation. The significantly enlarged spleen and lymph nodes in MPS IIIB mice were due to an increase in splenocytes/lymphocytes, and functional assays indicated that the T cells were activated. An autoimmune component to the disease was further suggested by the presence of putative autoantigen or autoantigens in brain extracts that reacted specifically with serum IgG from MPS IIIB mice. We also demonstrated for the first time that immunosuppression with prednisolone alone can significantly slow the central nervous system disease progression. Our data indicate that immune responses contribute greatly to the neuropathology of MPS IIIB and should be considered as an adjunct treatment in future therapeutic developments for optimal therapeutic effect.

Magister Public Health - MPH / Chronic non-communicable diseases (NCDs) have not received adequate attention in Eswatini (formerly Swaziland) due to the high burden of HIV/AIDS, tuberculosis and other communicable diseases. However, in 2019, NCDs were estimated to account for 45.86% of all deaths in the country with cardiovascular diseases, diabetes mellitus and chronic respiratory conditions amongst the top ten causes of death. Persistent shortages of medicines in public health facilities in Eswatini have been observed resulting in patients purchasing their medicines from private retail pharmacies.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20583号 / 工博第4363号 / 新制||工||1678(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 浜地 格, 教授 森 泰生, 教授 白川 昌宏 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

INTRODUCTION: HIV/AIDS is a global health problem, with Sub-Saharan Africa the most affected. “Neuro-AIDS” refers to the extensive neuropathological manifestations of the disease. Neuroimaging of the HIV-infected individual plays a fundamental role in their work-up. Limited resources, however, drive the development of imaging protocols based on clinical signs. ‘Confusion’ may or may not represent a significant presenting sign and needs to be investigated, as it is the basis of referral of a significant number of patients for CT scanning. AIM: To determine the frequency of positive findings of head CT in HIV-infected adults presenting with confusion with/without associated neurology, and correlate them with the degree of immunosuppression, presence of CSF abnormality and their ARV therapy status. METHOD: CT brain scans of adult patients, who were HIV-positive and presented with confusion in Johannesburg, Gauteng, were retrospectively reviewed. The neurological status, CD4 counts, LP results and their ARV therapy status were documented. RESULTS: 30% of our HIV-infected patients presented with confusion. There were 156 patients who were included. CT scans were abnormal in 81%. We found that ‘associated neurology’ was a weak predictor for abnormal CT, making it a poor screening tool. A positive LP was predictive of infection (p=0.04 for focal infection, p=0.03 for infected surface collection) and infarction (p<0.01) on CT. CD4 count, LP results and ARV therapy were found to be abnormal in the majority of patients. CONCLUSIONS: CT was abnormal in the majority of HIV-infected patients presenting with confusion. Neurology was an unreliable clinical indicator. A positive LP was a good predictor for CT evidence of infection and infarction. The clinical parameters such as CD4 counts, LP results and ARV therapy, were abnormal in the majority of patients. If any of these parameters are abnormal in a patient with a normal CT, we believe this should motivate for further imaging with MRI.

<p>Epilepsies are the results of abnormal brain hyperactivities caused by brain injury, drug intoxication, and genetic perturbations. In the group of genetic-related epilepsies, the ion channel mutations contribute 25% of total epilepsy cases. Many studies suggest some forms of severe epilepsies can start early in patients’ lives, with epilepsy starting during infancy and childhood. With the wide adoption of genomic sequencing in children having seizures, an increasing number of <em>SCN2A</em> genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A, is predominantly expressed in the pyramidal excitatory neurons and supports action potential (AP) firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To probe the potential hypothesized biophysical property changes, we used a heterologous expression system expressing the Nav1.2-L1342P. We observed prominent but quite complex gating kinetics without significant changes in window current. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human-induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9-mediated genome editing. Using patch-clamping and microelectrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have significantly increased intrinsic excitability, higher sodium current density, and enhanced bursting and synchronous network firing, suggesting hyperexcitability phenotypes. Interestingly, L1342P neuronal culture displayed a degree of resistance to the anticonvulsant medication phenytoin, which recapitulated aspects of clinical observation of patients carrying the L1342P variant. In contrast, phrixotoxin-3 (PTx3), a compound showing greater specificity on Nav1.2 over other sodium channel subtypes, can potently alleviate spontaneous and chemically induced hyperexcitability of neurons carrying the L1342P variant. Our results reveal a possible pathogenic underpinning of Nav1.2-L1342P mediated epileptic seizures and demonstrate the utility of genome-edited hiPSCs as an in vitro platform to advance personalized phenotyping and drug discovery.</p>

Stress plays a significant role in neural development and brain function. To better understand the mechanisms underlying the impact of stress on brain development and neuroendocrine function, this study focuses on the phenylethanolamine-N-methyltransferase (Pnmt) enzyme as a key mediator of stress hormone signaling. Pnmt is activated as part of a positive feedback mechanism during stress to convert norepinephrine to epinephrine and amplify the sympathetic response. Most of our knowledge about Pnmt is derived from its role in the systemic production of epinephrine from adrenal chromaffin cells, but it is also known to be expressed in the central nervous system, including the brainstem, retina, hypothalamus, and cerebellum. Given the importance of the central nervous system in modulating stress responses, this project sought to investigate cellular Pnmt expression in the central nervous system using a genetic-marking strategy with a Pnmt-Cre-recombinase knock-in driver strain (Pnmt+/Cre) and a β-galactosidase (βGal) reporter strain (R26R+/βGal) in parallel with Pnmt-specific immunofluorescent histochemical staining to identify Pnmt+ cells in the adult mouse cerebellum, hypothalamus, and cerebral cortex. The results show extensive patterns of active and historical Pnmt protein expression throughout the cerebellum and hypothalamus, with significant neuropeptide Y co-expression in the hypothalamus and considerable historical Pnmt expression throughout the cerebral cortex. To quantify baseline Pnmt mRNA levels across embryonic and postnatal neural development and elucidate differential Pnmt isoform expression through tissue-specific regulation in the developing brain, quantitative polymerase chain reaction (qPCR) was performed in the brainstem, cerebellum, and cerebral cortex with isoform-specific primers. Initial results show a developmental, tissue-specific Pnmt isoform shift between embryonic and postnatal neural development by an intron-retention alternative splicing mechanism. Ultimately, these findings provide an anatomical "blueprint" for investigating the role of central nervous system Pnmt expression in health and disease, and emphasize the role of Pnmt in early neural development, illustrating how stress impacts the formation of neural connections during formative periods of brain maturation.

No description available.

Nitric oxide (NO) has been implicated in large number of pathologies and in normal physiological function of the brain. The aim of this study was to recognize the effect of Nitro-L-Arginine Methyl Ester ·HCl (NAME) and L-Arginine Ethyl Ester.HCl (ARGININE) on reactivity of the central DA D3 receptor to agonist (Quinpirole) in rats. For this reason we have been used specific behavioural procedure such yawning behaviour which is mediated via central DA D3 receptors. Experiments were perform in adult male Wistar rats treated daily with quinpirole (0.05 mg/kg IP) or vehicle (0.9% NaCl) for the first 11 days from birth to obtain of the central D3 receptor supersensitivity. NAME and ARGININE in different way modified response of the central DA receptor to quinpirole estimated by means yawning behavioural procedure.

No description available.