5,842 research outputs found

    It doesn't end with closure:Optimizing health care throughout life after esophageal atresia repair

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    The role of the oral microbiome in the immunobullous diseases pemphigus vulgaris and mucous membrane pemphigoid and oral lichen planus

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    Saliva is formed from contributions of salivary glands and the serum exudates principally from gingival margins or damaged mucosa combined with components derived from the environment, including a community of microorganisms - the microbiome. I postulate that changes in microbial diversity and population structure play key roles in the modulation of host- microbial interactions which influence both the hypersensitive autoimmune responses and inflammation seen in these inflammatory mucocutaneous disorders. For my research, a total of 186 participants were recruited: 48 mucous membrane pemphigoid (MMP), 48 pemphigus vulgaris (PV), 50 oral lichen planus (OLP) patients, and 40 healthy controls. Unstimulated whole saliva, subgingival plaque, serum, and plasma samples were collected from 186 participants. In addition, metadata were collected on the following covariates: age, gender, ethnicity, type of the diet, disease history and therapeutic intervention in the preceding six months. Oral disease severity scores (ODSS) were assessed, and periodontal status was examined using a periodontal six pocket chart. To characterise microbiome profiles, saliva and subgingival plaque were processed for sequencing genomic DNA using the NGS Shotgun metagenomics sequencing technique. Inflammatory cytokines and proteases were investigated in saliva and serum using Human Magnetic Luminex Screening Assay (R&D Systems). Selected cytokines were analysed by enzyme-linked immunosorbent assay (ELISA) technique (R&D Systems) to determine host inflammatory responses in saliva and serum samples. Additionally, saliva and plasma samples were analysed for metabolites by nuclear magnetic resonance (NMR). Significant increases in periodontal score (PISA) in all three groups of disease were identified compared to healthy control group with significant positive correlation between oral disease severity (ODSS) and PISA in OLP and PV groups. All three groups of diseases had significantly higher levels of inflammatory Th2/Th17 cytokines (IL-6, IL-13 and IL-17 in saliva samples), as well as higher levels of MMP-3 matrixins in saliva. In addition, there were positive correlations between ODSS and salivary IL-6, IL-13 and MMP-3 in saliva of OLP, salivary and serum levels of IL-6 and MMP-3 in MMP group, and significant association of salivary IL-6, IL-1β and MMP-3 in PV group. Metabolomic data showed that saliva is a better biofluid for correlation of the metabolomic profile with oral disease severity than plasma. Salivary ethanol was corelated with disease severity in the OLP group, whereas in PV was a strong correlation of ODSS with choline. Finally, a unique microbial community was found in each group of diseases. In the MMP group, ODSS was significantly correlated with L. hofstadii, C. sputigena, N. meningitidis, N. cinerea and P. sacchar0lytica. In PV, a positive correlation was found with F. nucleatum, G. morbillorum, and E. corrodens, G. elegans, H. sapiens and T. vincentii. In OLP, the disease tends to worsen when there was reduced abundance of X. cellulosilytica, Actinomyces ICM 47, S. parasanguinis, S. salivarius, L. mirabilis and O. sinus. Lower microbial diversity was correlated with ODSS in saliva and plaque of the OLP group. In conclusion, this study provides strong evidence of the complex interplay between the oral microbiome, immunological factors, and metabolites in the context of immunobullous diseases and OLP. The findings highlight the integral role of oral bacteria in disease progression, the significance of immune dysregulation, and the potential impact of specific microbial species and metabolic pathways. These insights give the way for further research and clinical applications, offering the promise of personalized approaches for diagnosis, and management of OLP, MMP and PV. Future investigations should focus on discovering the mechanistic details underlying these associations and validating the identified biomarkers in larger patient cohorts, ultimately contributing to a deeper understanding of the pathogenesis of these conditions

    Intracranial aneurysms in patients with Kawasaki disease or thoracic aortic aneurysms

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    Saccular intracranial aneurysm (sIA) is the most common type of IAs and characterized by outpoching sac with a neck arising from the cerebral artery wall. Pathophysiology of IAs are still poorly understood. Fusiform IA is a focal circumferential dilatation of the cerebral artery and unlike sIAs, do not have aneurysm neck, which make their treatment more complex compared to sIAs. The primary goal in the study I and II were to evaluate if Kawasaki disease (KD) is associated with increased risk for IAs (I) and white matter hyperintensities (WMH) (II); in the study III if sIAs are related with increased risk for thoracic aortic aneurysms (TAA) or dilatations (TAD); and in the study IV was to evaluate outcomes of flow diverter stent (FD) treatment of the ruptured posterior circulation fusiform IAs. In the study (I and II) 40 adults with a history of KD in a childhood were screened with brain Magnetic Resonance Imaging and Angiography for IAs and brain WMHs. No IAs were found in KD patients, which is significantly under the prevalence of 10% (95% CI 0%-8.8%, p = 0.03) that is the recommended limit for IA screening. In the study (II), we found that Kawasaki disease is related with increased WMH burden compared to age- and sex-matched migraine controls. Our study suggests that KD is not associated with IAs, but instead is associated with increased WMH burden, indicating long-term cerebrovascular involvement of KD. In the study (III) we retrospectively reviewed 411 patients with sIAs and available imaging studies (computed tomography or magnetic resonance imaging) of all thoracic aortic segments for TADs and TAAs. The prevalence of TADs and TAAs were 18% and 8%. Rheumatic disease and alcohol abuse were significant risk factors for TADs/TAAs. Our results suggests that sIAs might be associated with increased risk for TAAs and TADs. In the study (IV) five patients with ruptured posterior circulation fusiform aneurysms and treated with a FD were reviewed rertrospectively. We found that FD is a feasible treatment option for ruptured fusiform posterior circulation IAs, with a high aneurysm occlusion rate (100% at 6-months) and 80% of patients had a good outcome. However, FD treatment carries a significant risk for complications and should be considered only when other treatment options are not available.Aivovaltimoaneurysmien yhteys Kawasakin tautiin ja rinta-aortan laajentumiin. Sakkulaarinen aivovaltimoaneurysma (sIA) on yleisin aivoaneurysmatyyppi. SIA on aivovaltimoiden seinämästä työntyvä paikallinen pullistuma, joka yhdistyy aivovaltimon seinämään kaulalla. Fusiforminen IA on aivovaltimon paikallinen laajentuma ja toisin kuin sIA:ssa, fusiformisessa IA:ssa ei ole erillistä kaulaa, joka tekee hoidosta haastavaa. IA:ien syntymisen patofysiologia tunnetaan huonosti. Tutkimuksien (I) ja (II) tavoitteena oli selvittää, onko lapsuuden Kawasakin taudilla yhteyttä suurentuneeseen riskiin vuotamattomille IA:lle ja aivojen valkean aineen muutoksille. Tutkimuksen (III) tavoitteena oli selvittää ovatko sIA:t yhteydessä suurentuneeseen riskiin torakaaliaortan aneurysmille (TAA) tai dilataatioille (TAD). Tutkimuksen (IV) tarkoituksena oli selvittää flow diverter stenttihoidon (FD) tuloksia vuotaneiden takaverenkierron fusiformisten IA:ien hoidossa. Tutkimuksissa (I ja II) 40:lle lapsuudessa Kawasakin taudin sairastaneelle potilaalle suoritettiin aivojen ja aivoverisuonten magneettikuvaus IA:ien ja WMH muutosten seulomiseksi. Valkean aineen muutosten määrää verrattiin ikä- ja sukupuolivakioituihin verrokkeihin (migreenipotilaat). Kawasakin taudin sairastaneilla potilailla ei todettu IA:a ja prevalenssi oli merkittävästi alle suositellun IA:en seulontarajan 10 % (95 % CI 0 %-8.8 %, p= 0.03). Sen sijaan Kawasakin taudin sairastaneilla henkilöillä oli merkittävästi enemmän valkean aineen muutoksia verrokkeihin nähden, viitaten siihen, että Kawasakin taudilla voi olla myös aivoverisuoniin kohdistuvia vaikutuksia. Tutkimuksessa (III) analysoimme retrospektiivisetsti 411 sIA potilasta, joilla oli kuvannettu rinta-aortta tietokonetomografialla tai magneettikuvauksella. TAD:n ja TAA:n prevalenssi oli 18 % ja 8 %. Reumasairaus ja alkoholin väärinkäyttö lisäsivät merkittävästi riskiä TAD:lle/TAA:lle. SIA:iin saattaa liittyä suurentunut riski TAD:lle/TAA:lle. Tutkimuksessa (IV) analysoimme retrospektiivisesti viisi potilasta, joiden vuotanut aivojen takaverenkierron fusiforminen IA oli hoidettu FD:llä. Aneurysmien hoitotulokset olivat hyviä FD:llä ja 80 % potilaista toipuivat hyvin. FD hoitoon liittyy kuitenkin merkittäviä komplikaatioriskejä ja FD hoitoa tulisi miettiä vuotaneissa aneurysmissa vain, jos muut hoitovaihtoehdot katsotaan mahdottomiksi

    Alzheimer’s And Parkinson’s Disease Classification Using Deep Learning Based On MRI: A Review

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    Neurodegenerative disorders present a current challenge for accurate diagnosis and for providing precise prognostic information. Alzheimer’s disease (AD) and Parkinson's disease (PD), may take several years to obtain a definitive diagnosis. Due to the increased aging population in developed countries, neurodegenerative diseases such as AD and PD have become more prevalent and thus new technologies and more accurate tests are needed to improve and accelerate the diagnostic procedure in the early stages of these diseases. Deep learning has shown significant promise in computer-assisted AD and PD diagnosis based on MRI with the widespread use of artificial intelligence in the medical domain. This article analyses and evaluates the effectiveness of existing Deep learning (DL)-based approaches to identify neurological illnesses using MRI data obtained using various modalities, including functional and structural MRI. Several current research issues are identified toward the conclusion, along with several potential future study directions

    Common Sleep Problems and Management in Older Adults

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    Sleep problems are common among the elderly due to physiological changes and comorbid psychiatric and medical conditions. Sleep architecture changes with age. However, sleep disturbances among older adults should not be seen barely as a result of ageing. Depression and anxiety are important differential diagnoses for elderly patients complaining of sleep disturbance. Dementia and delirium are also common causes of sleep disturbances among older people. Elderly people often carry several medical comorbidities. These medical conditions can both lead to and be exacerbated by sleep problems. Given the frailty, multimorbidity and vulnerability of some of the elderly, the management of sleep problems requires additional considerations compared with younger adult patients. Behavioural modifications and drugs of choice will be discussed

    Dissecting Extracellular Matrix Internalisation Mechanisms using Functional Genomics

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    Breast and ovarian malignancies account for one third of female cancers. The role of the stroma in supporting invasive growth in breast cancer has become clear. Breast cancer cells interact and respond to the cues from the surrounding extracellular matrix (ECM). Integrins are main cell adhesion receptors and key players in invasive migration by linking the ECM to the actin cytoskeleton. In addition, integrins mediate distinctive biochemical and biomechanical signals to support cancer invasion. The role of matrix proteases in promoting ECM degradation and cancer dissemination has been extensively studied; however, cancer cells possess additional means to support those processes, such as integrin-mediated ECM endocytosis and consequent degradation in the lysosomes. Internalisation of the extracellular matrix is upregulated in invasive breast cancer. Nonetheless, the mechanisms by which cancer cells regulate this process are poorly understood. We developed a high throughput pH sensitive system to detect ECM uptake. Here, we show that MDA-MB-231 breast cancer cells converge in macropinocytosis to internalise diverse ECM components and we confirm that this process is modulated by PAK1. To unravel which ECM components breast cancer cells internalise in a complex environment (namely, cell derived matrices), we performed mass spectrometry. Proteomic analysis identified Annexin A6, Collagen VI, Tenascin C and fibronectin, among other matrisome proteins, to be internalised by invasive breast cancer cells. Following ECM endocytosis, ECM is targeted for lysosomal degradation. To unravel the molecular mechanisms behind this process, we performed a trafficking screen and identified the AP3 complex, VAMP7, Arf1 and ARFGEF2. Our results suggest that the AP3 complex may regulate ECM-integrin delivery to lysosomes. To gain more insight on the signalling pathways governing macropinocytosis in breast cancer cells, we performed a kinase and phosphatase screen that unravelled MAP3K1 and PPP2R1A, a subunit of protein phosphatase 2A (PP2A) as relevant regulators of ECM endocytosis. Furthermore, our data suggests that p38 mitogen-activated protein kinase (MAPK) activation upon binding to the ECM is required for ECM macropinocytosis. Outstandingly, inhibiting p38 MAPK led to profound changes in the ability of breast cancer cells to migrate in cell derived matrices. Previous work from the Rainero lab focused on characterising the receptors involved in ECM internalisation; α2β1 integrin was identified as the main regulator of ECM uptake in MDA-MB-231 cells. In particular, α2β1 integrin has been shown to activate p38 MAPK pathway. Taken together, we hypothesise that binding of ECM to α2β1 integrin results in the activation of PAK1 and MAP3K1, which in turn leads to ECM endocytosis. p38 MAPK activity may induce changes in actin polymerisation via PPP2R1A and/or focal adhesion turnover, which consequently promotes ECM macropinocytosis and invasive migration

    Introduction to Psychology

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    Introduction to Psychology is a modified version of Psychology 2e - OpenStax

    Identification of novel biomarkers in critically ill patients

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    This thesis summarizes publications of prospective, non-interventional studies on the identification of novel biomarkers in critical care medicine. Biomarkers in the context of this thesis are laboratory values that are determined from the blood of patients who are treated on an intensive care unit. They are used in clinical routine for diagnosis, prognosticate and monitor treatment. For clinical applicability, biomarkers must have appropriate statistical test characteristics to enable distinction between different states of disease. Beyond that, biomarkers should be easy to obtain, rapidly measurable, and generalizable for instant interpretation in the clinical context and prompt decision making to favourably influence the course of the disease. The aim of this thesis was to evaluate the significance, regulation, diagnostic and prognostic value of novel biomarkers measured in the blood of critical ill patients
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