Basal cell carcinoma is an indolent, slow-growing tumor that rarely metastasizes. Approximately 70% of tumors occur in the head and neck regions. If a basal cell tumor metastasizes, it usually spreads to the regional lymph nodes first, followed by the lungs. We describe a patient with basal cell carcinoma of the right lower extremity with skin metastases. Skin biopsy of one tumor revealed fibroepithelioma of Pinkus, a rare variant of basal cell carcinoma.

OBJECTIVE: The close relationship between obesity and type 2 diabetes (T2D) highlights the fact that most diabetes patients are overweight or obese. We propose that elevated glucose and free fatty acid levels in those patients cause beta-cell dysfunction. Chronic exposure to excess nutrients (glucose and free fatty acid) leads to glucolipotoxicity, characterized by basal insulin hypersecretion, a left-shift in the glucose dose-dependent insulin secretion curve, and blunted glucose-stimulated insulin secretion. One of the suggested reasons for this defect is elevated intracellular lipid. In this study, our objective was to investigate whether reducing beta-cell lipid levels can reverse basal insulin hypersecretion. METHODS: INS-1 (823/13) cells were cultured in 4 or 11 mM glucose media. Elevated glucose and KCl doses were added to cells in the insulin secretion experiments. In the KCl-induced insulin secretion experiment, cells were treated with a combination of 12 mM glucose and 250 μM diazoxide, then assigned to different test concentrations with elevated KCl doses. Insulin release and content were measured by the insulin ultra-sensitive homogenous time-resolved fluorescence (HTRF) kit (Cisbio). Following that, we monitored intracellular Ca2+ activity of KCl-induced insulin secretion on a fluorescence spectrophotometer F-2000 (Hitachi). Additionally, we acutely added Adipo C (20 µM) or fatty acid-free BSA to cells to reduce the lipids levels in the ß-cells. We also stained with Nile Red (Sigma) to examine the intrinsic lipid droplets in those cells. RESULTS: ß-cells cultured in excess nutrients (11 mM glucose) exhibited a left shift in the glucose dose-dependent response curve. The hypersecretion at low glucose could be blocked by the KATP channel activator, diazoxide, indicating that Ca2+ influx drives the increase in secretion at glucose concentrations normally considered basal. Here we extend this left shift to include KCl-induced insulin secretion, supporting a role for Ca2+ in the observed hypersensitivity. KCl-induced Ca2+ influx was also left-shifted. Interestingly, we found acute exposure to Adipo C or fatty acid-free BSA reversed the basal hypersecretion in cells cultured in excess nutrients. CONCLUSION: The work presented in this study provided supporting evidence that ß-cells cultured in excess nutrients were hypersensitive to glucose while extending these studies to KCl-induced insulin release. The excess nutrient-induced left shift in both glucose and KCl-stimulated insulin secretion was mediated by increased Ca2+. Thus, we postulate that excess nutrient exposure increases ß-cell plasma membrane lipids that alter Ca2+ handling to allow increased Ca2+ influx at inappropriate low glucose concentrations. Our results demonstrated that cells acutely exposed to the putative long-chain acyl-CoA synthetase inhibitor Adipo C or fatty acid-free BSA reversed basal insulin hypersecretion and supports a role for lipids mediating the adverse effect. T2D patients with obesity have a similar physiologically elevated fasting blood glucose and lipid. Thus, our findings suggest lowering lipid levels in ß-cells may have therapeutic potential in treating hyperinsulinemia leading to T2D.

BAKGRUND Handhygien innebär handtvätt samt användning av handdesinfektionsmedel för att få bort smuts och mikroorganismer från händer. Vidare innebär basal handhygien riktlinjer och rutiner för skötsel av handtvätt och användning av handdesinfektionsmedel inom hälsooch sjukvården. Riktlinjerna och rutinerna ska tillämpas av hälso- och sjukvårdspersonal inom all hälso- och sjukvård världen över. Hälso- och sjukvårdspersonalens förmåga att utföra arbetsuppgifter enligt riktlinjerna är en faktor som påverkar förekomsten av vårdrelaterade infektioner. Vårdrelaterade infektioner är ett problem för patientsäkerheten inom hälso- och sjukvården som kan leda till ökat lidande för patienten. SYFTE Syftet med studien var att beskriva hälso- och sjukvårdspersonalens följsamhet till handhygien inom slutenvård. METOD En allmän litteraturöversikt valdes som metod. Litteratursökningar gjordes i databaserna CINAHL Complete och PubMed. Sökorden som användes till litteraturöversikten var “hand hygiene”, “handwashing”, “compliance”, “nurses”, “nursing staff, hospital”, “professional compliance”, och “guideline adherence”. 15 artiklar har inkluderats i resultatet. RESULTAT Huvudfynden från resultatet innefattade en variation av följsamhet till handhygien samt brist på resurser och faciliteter. Hudproblem relaterat till handhygien samt varierande riktlinjer för handhygien, var ytterligare huvudfynd. Resultaten baserades på observations-, enkät- och intervjustudier. SLUTSATS Det finns ingen entydighet kring hur hälso- och sjukvårdspersonalens följsamhet till handhygien inom slutenvård ser ut. Variationen av följsamhet till handhygien visar att WHO:s globala riktlinjer inte lyckas omsättas i praktiken i den mån det behövs. Riktlinjer behöver anpassas för att gynna alla länder oberoende av landets socioekonomiska ställning. Därmed kan patientsäkerheten öka och vårdlidandet minska. Nyckelord: Basal handhygien, Följsamhet, Handhygien, Slutenvård, Vårdrelaterade infektioner.

Movement is the key to animal behavior. From fighting off predators to reaching for food, our survival relies on movement. Losing the ability to move the body through the world in a purposeful way would be dire. We learn to perform a wide variety of actions, which require exact motor control. How are such skilled actions refined over time? The neural mechanism of motor learning has been posited to arise from integrating neuronal signals about motor commands, environmental context, and outcome through the cortico-basal ganglia-thalamic loop. Here, I investigate the role of two thalamic nuclei — the parafascicular (Pf) and ventroanterior/ventrolateral (VAL) —in the process of motor learning. In an introductory Chapter 1, I introduce some key behavioral signatures of motor learning and the distributed neural circuity for movement through the cortico-basal ganglia-thalamic network. Pf and VAL are at the center of this network. Both receive basal ganglia output but differ in primary projection patterns. Pf sends large excitatory projections directly to the striatum (the main input area of the basal ganglia), while VAL projects back to the cortex. Despite their critical place in the movement system, little is known about their changing roles in motor learning. In Chapter 2, I highlight a novel skilled forelimb joystick target task for mice; the JTT. In the JTT, head-fixed mice learn reaches to spatial targets in 2D space by moving an unrestricted joystick without visual feedback. This task allows for multiple windows of learning and refinement of various reaches in space. Over the learning of targeted reaching movements, mice increase their accuracy and individual trajectories become less variable, showing that they have learned the location of the target in space, and also refine the reaching movements. In Chapter 3, I use 2-photon calcium imaging of the forelimb-related areas of Pf and VAL to investigate how their activity changes over learning of forelimb reaching actions. Both Pf and VAL are highly engaged during movements. Neural population engagement of Pf decreases over time, suggesting a specific role early in learning. Additionally, the underlying neural dynamics of Pf and VAL shift and occupy different state spaces over learning, as shown through principal component analysis. To investigate if neural activity in Pf or VAL encodes behavioral information, we used a ridge regression model to predict the initial direction of movements from neural data. We were able to predict the initial direction from Pf activity on early training days, but not from VAL. In Chapter 4, I performed pre and post-learning lesions to Pf or VAL to investigate if they are needed for learning and/or performance of targeted reaches. Results show that Pf is needed for learning, but not the performance of accurate spatial reaches. VAL, on the other hand, does not affect the learning or performance of target reaches, but does affect the speed of movements. In a discussion-based Chapter 5, I summarize these above experiments, which suggest different roles for PF and VAL over learning of multiple targeted reaches, and reflect on future directions of my findings in the broader context of motor learning research in neuroscience. In particular, my findings highlight a novel and critical role for Pf in learning and processing directional information during early skill learning. This work demonstrates that the thalamus is an essential node of the brain networks involved in motor learning.

We report two cases of combined cutaneous tumors composed of melanoma and carcinoma. The first tumor presented as a 5-mm pink-blue macule over the right zygomatic arch in an 85-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of melanoma (highlighted by SOX10 and MART-1, with high Ki-67 proliferative index) intermixed with nodular basal cell carcinoma (highlighted by pan-cytokeratin and Ber-EP4). The neoplastic melanocytes were confined to the basal cell carcinoma nodules, and a diagnosis of combined melanoma in situ and basal cell carcinoma was rendered. After therapeutic excision, the patient was disease-free at 9 months after the initial diagnosis. The second tumor presented as a 6-mm pink-brown crusted papule on the right forehead in an 89-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of malignant melanoma (MM) (highlighted by S100 and MART-1) intermixed with squamous cell carcinoma (SCC) (highlighted by cytokeratin and p63), and a diagnosis of combined MM-SCC was rendered. These two cases highlight the importance of recognizing these rare types of melanocytic-epithelial cutaneous neoplasms to arrive at an accurate diagnosis that may inform appropriate disease stage and therapy.

Aging and Alzheimer’s disease (AD) are associated with decreased cognitive function and neural degeneration. The basal forebrain is one of the first areas of the brain to degenerate in AD and depends on the neurotrophin brain-derived neurotrophic factor (BDNF) for survival. Loss of BDNF transport from target neurons may contribute to basal forebrain cholinergic neuron (BFCN) vulnerability in AD and aging. Oxidative stress is associated with cholinergic dysfunction and cognitive decline in aging and AD, and it is possible that oxidative stress may contribute to BDNF transport deficits in BFCNs. BFCNs are grown in microfluidic chambers that allow isolation of BFCN soma and axon terminals so transport of biotinylated and fluorescently labelled BDNF can be quantified. The objective of my research was to determine if oxidative stress induces BDNF retrograde transport deficits in BFCNs, and the mechanism behind this effect. I found that oxidative stress does reduce BDNF retrograde transport in BFCNs. Because it has previously been shown that aged BFCNs have decreased BDNF transport and downregulate the BDNF receptor TrkB, expression of both TrkB and p75NTR receptors was tested following oxidative stress using immunocytochemistry (ICC) and western blotting. This experiment showed that oxidative stress does not affect p75NTR or TrkB receptor levels. A likely alternative is that oxidative stress may lead to alterations in the transport machinery responsible for retrograde BDNF transport. I hypothesized that oxidative stress decreases retrograde axonal transport of BDNF via increased insulin-like growth factor 1 receptor (IGF1R) activity, which decreases the protein expression of the adaptor proteins BICD1 and Hook1 by inhibiting GSK3β activity via the PI3K-Akt pathway. ICC and western blotting showed that oxidative stress has no effect on either BICD1 or Hook1 levels. Future directions of this work involve further studying the involvement of the IGF1R pathway in oxidative stress, and the effect on other proteins involved in BDNF transport, including htt and DISC1. / Thesis / Master of Science (MSc)

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13570号 / 論医博第2296号 / 新制||医||1069(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 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 Science / Kyoto University / DFAM

No description available.

No description available.

No description available.