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Investigation of brain CD47 expression and its relation with cognitive functions in diabetic mice models
Diabetes Mellitus is an endocrine disorder resulting in hyperglycaemia that affects many vital organs of the body like the brain. The detailed molecular basis of dementia and cognitive dysfunction resulting from diabetes is not totally known. CD47 is a cell surface protein working in the homeostasis of the immune system. The relation of CD47 is shown in neurodegenerative diseases. Also, CD47 has a role in pancreatic islet cells and their maintenance in T1DM models. In this thesis, CD47 expression and its relation with cognitive functions is investigated in type 1 and type 2 diabetic mice models induced with STZ and high fat diet respectively. Cognition tests were done to evaluate the animals' cognitive functions. Immunofluorescent staining and imaging were done to investigate the expression of CD47 in hippocampus region of brain tissue. As a result, it is found that there is a significant increase in type 1 and type 2 models in the expression of CD47 levels. There is also a significant difference between two cognitive tests out of three between healthy and T1DM models. Unfortunately, there was no correlation found between CD47 expressions and cognitive functions. To conclude, we think that CD47 levels in the brain may be elevated as a way of cells to protect themselves from excess blood glucose independent from cognitive functions.
The quantification of fibrosis in cleared human and mouse liver tissues by light-sheet fluorescence microscope using a slide-free approach
Background & Aim: Liver fibrosis is a common end point of any type of liver injury. Liver biopsy is the only reliable modality for determining the extent of fibrosis and subsequently providing patients with appropriate treatment. However, liver biopsy is not without limitations. Sampling error, observer variability, and semi-quantitative assessment are the significant limitations of the procedure, which may limit the accurate assessment of hepatic fibrosis. Besides, the utility of such small samples increases the staging inaccuracy. Problems in assessment of hepatic fibrosis limit the development of effective biomarkers and therapeutics particularly in NASH clinical trials. A slide-free examination of optically cleared liver biopsy samples may assist in accurate quantification of hepatic fibrosis. To this end, we developed a platform for quantifying hepatic fibrosis in human and mouse liver tissues utilizing a modified-CLARITY and custom-made light sheet fluorescence microscope. Material and Method: A hundred and sixty-eight liver specimens from human subjects were included in this study. The cohort included fifty-seven NAFLD, thirty-eight viral hepatitis patients, and thirteen healthy subjects who underwent hepatic resection due to benign liver diseases. Sirius-red stained mouse and human liver sections were scored by an expert pathologist and Collagen proportionate area (CPA) analysed for 2D quantification of liver fibrosis. Liver specimens were cleared using the modified-CLARITY method and visualized with a custom-made light sheet microscope. To test the applicability of the method in intermediate stages of fibrosis, five animal models of liver disease were employed in C57Bl/6 mice. Collagen type I and Elastin were quantified in cleared human liver tissues using a slide-free approach via custom-made light sheet microscope. Multiple optical sections of whole liver samples were used to calculate collagen proportionate volume (CPV) and elastin proportionate volume (EPV). Results: In this project, we successfully obtained transparent liver tissues for volumetric quantification of hepatic fibrosis. The modified-CLARITY method efficiently cleared human and mouse liver tissues. The major ECM proteins, Collagen type I and Elastin, were quantified in the human NAFLD and viral hepatitis cohort. Cut-off values were determined for CPV and EPV values for each fibrotic stages of human NASH. Further analysis demonstrated substantial sectional variability between optical slices of volumetric imaging data. Coefficient of variation analysis determined the extent of variation and found 84.6% intermediate and high level variation for CPV and EPV sections of F3-4 groups of NAFLD. 3D fibrosis staging of optical sections with established cut-off values for CPV and EPV demonstrated that only 44% and 47% of optical sections would be staged the same for F3 and F4, respectively. Conclusion: We developed a slide-free method for assessing the 3D pathology of hepatic fibrosis using a custom-made light sheet microscope. Volumetric image analysis of whole liver biopsies revealed substantial heterogeneity within the biopsy. Comprehensive profiling of extracellular matrix proteins in hepatic fibrosis and quantification with a slide-free non-destructive platform may improve the staging accuracy. Thus, utilizing this method may advance the treatments for NASH clinical studies.
Primer insan beyni mural hücrelerinin izolasyonu ve karakterizasyonu
Pericytes and smooth muscle cells (SMCs) are mural cells that are located on the abluminal side of the blood vessels. In the central nervous system (CNS), pericytes are implicated to play roles in maintaining the integrity of the blood brain barrier (BBB), and regulation of cerebral blood flow. Recent studies show that pericytes also have immunoregulatory functions. In response to inflammatory stimuli, pericytes have been shown to upregulate expression of cell adhesion molecules such as VCAM-1, ICAM-1 and pro-inflammatory cytokines and chemokines. In genetically engineered animal models, loss of pericytes lead to increased BBB permeability and an increased immune cell infiltration into the CNS. On the other hand, studies investigating the role of pericytes in the tumor microenvironment (TME) showed that tumor associated pericytes could support tumor progression by immunosuppression. Hence, investigating the pathways pericytes use to interact with the immune system can reveal disease mechanisms that could be potential targets for immunomodulatory treatments. However, studying mural cells in vivo and in vitro is difficult as pericytes, SMCs and fibroblasts have a very similar molecular signature. In this study, we aimed to investigate the immunologic properties of brain pericytes by (i) generating primary human brain pericyte cells from tissue obtained during surgery by using two different methods present in the literature, (ii) comparing their molecular characteristics to commercially available human brain pericyte and human brain fibroblast cell lines, (iii) establishing their gene expression pattern changes in response to inflammatory cytokines, (iv) studying human brain pericyte – T lymphocyte interactions in vitro via chemotaxis experiments and (v) generating a CXCL10 knock-out human brain pericyte cell line via CRISPR/Cas9 to study the effect of CXCL10 on human brain pericyte – T lymphocyte chemotaxis. Overall, our data points to a potential pro-inflammatory role for brain pericytes; thus, understanding the specific pathways they are involved in T lymphocyte recruitment into the CNS could help us determine if these pathways can be targeted for interventions in neuroinflammatory conditions.
The role of notch signaling pathway in CD4 + CD25 + FOXP3 + T regulatory cell balance in Chronic Obstructive Pulmonary Disease
Notch signaling is essential for airway development and progenitor/stem cell regeneration, regulation, and controlling the fate of airway epithelial cells during differentiation. This signaling pathway also regulates the Th1/Th2 and Th17/ T regulatory (Treg) cells immune balance and has a substantial influence on disease pathogenesis. The impact of the Notch signaling pathway to the pathogenesis and progression of chronic obstructive pulmonary disease (COPD) is not well understood, despite the fact that studies suggest that its dysregulation may lead to various of respiratory diseases. Our current study demonstrated the increased distribution of the Notch receptor on T regulatory cells in healthy smokers, and patients with stable, and exacerbated COPD, as compared to nonsmokers also the high level of Th1/Th2 cell ratio in exacerbated COPD patients by flow cytometry. We also studied Notch and Treg/Th17 cell balance by analyzing the expression of Foxp3, RORγt, and Notch downstream genes such as Hes5 and Hey1, in CD4+T-helper cells using RT-PCR; At the gene level, no significant differences between study groups were observed. By using the Multiplex Cytokine Assay, we measured the levels of pro- and anti-inflammatory cytokines in COPD patients and found high levels of pro-inflammatory cytokines, as well as a negative correlation between Notch expression and anti-inflammatory cytokines. Together, these data showed that the Notch signaling pathway may deteriorate the Treg cell function as well as may be one of the major drivers in COPD inflammation. Free Keywords: Notch signaling pathway, T regulatory cells, T cell imbalance, Chronic obstructive pulmonary disease, pathogenesis, inflammation, stable, exacerbated.
Investigation of anti-neurofascin and anti-myelin oligodendrocyte glycoprotein antibodies in patients with chronic inflammatory demyelinating polyneuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic immune-mediated peripheral neuropathy that can affect people of all ages. Walking difficulty, arm and leg weakness, numbness and tingling and tremor can be seen in CIDP. In around 2-18% of patients diagnosed with CIDP, antibodies against paranodal antigens, including Neurofascin 155 (NF155), Neurofascin 186 (NF186), Contactin1 and Caspr1 can be detected in the serum, identifying this subgroup as seropositive CIDP. Treatment approach can be different is this subgroup compared to common CIDP, therefore, it is important to identify these patients. However, antibody tests against the paranodal antigens are not available in Turkey. In this study, we first aimed to establish a live cell-based assay to test the presence of antibodies against NF-155, NF-186 in the serum and cerebrospinal fluid of patients. Then we aimed to test the sera obtained from a nationwide cohort of CIDP patients for these antibodies, as well as anti-MOG antibodies to identify the frequency and characteristics of anti-NF155 antibody positive CIDP in Turkey. The live cell base assay method was applied to live, unfixed cells to preserve the structural integrity of the NF protein. Initially, plasmids containing NF155-EGFP, NF186-EGFP or EGFP (as control) gene was transfected into HeLA cells using a transfection reagent. Then, patient serum or CSF was incubated the transfected cells followed by incubation with a biotin-conjugated secondary antibody. Finally, Alexa fluor-647 conjugated streptavidin was added to detect antibody binding by flow cytometry. Delta and ratio of mean fluorescent intensity (MFI) was calculated by using the data from protein and GFP-only expressing cells. A cut-off value was determined by using sera from healthy controls. We tested sera from 182 CIDP patients. The patients were 41 (21.8) years old on average, with a F:M of 70/104. 147 patients were adult, and 35 patients were pediatric. A total of 11 samples were positive for NF-155-IgG. Among these samples, 6/11 had IgG4 as the dominant isotype, verifying anti-NF155 antibody positivity. Detailed clinical information was present in five patients, that was compatible with the clinical characteristics of seropositive CIDP patients previously reported in the literature. Among seven NF155-IgG4+ patients six were adults and one was a pediatric patient. IgG2 and IgG3 antibodies were also present in addition to IgG4 subtype in three patients. The frequency of anti-NF155 antibody positivity in the Turkish cohort was found to be 3.5%. In the rest of the four patients no IgG positivity was detected and low IgM positivity was detected in three samples. CSF from one NF155 IgG4 positive patient was also analysed and showed the presence of antibodies in the CSF, as well. In another 13 CSF samples tested from CIDP patients one samples had low titers of NF155-IgG, NF186-IgG and MOG-IgG. This patient's serum was negative for these antibodies. Among 12 Guillain-Barre Syndrome (GBS) CSF samples tested, two patients had low titers of NF155-IgG. Among eight MS patients and 22 patients with other neurological disorders, none of the CSF samples tested positive for NF155-IgG or NF186-IgG. In addition, we analysed the presence MOG antibodies in CIDP patients. Serum tests were positive for MOG antibodies in nine patients. Two of the patients were children. Pediatric patients were diagnosed with CIDP and combined central and peripheral demyelination syndrome (CCPD). Adult patients comprised the remaining seven cases, of which two were diagnosed with CCPD and the remaining five with CIDP. In the nine patients with positive serum MOG-IgG, NF155 and NF186 antibodies were negative. Analysis of 16 CSF samples obtained from CIDP and GBS patients revealed that, five patients had low titers of MOG-IgG. Serum MOG-IgG was found to be borderline positive in two of these patients. In the other three patients, serum positivity was not detected. Among patients with both serum and CSF MOG-IgG positivity, one patient had CCPD and the other had CIDP. In conclusion, we have established a live cell-based assay to test anti-NF155 and anti-NF186 antibodies from serum and CSF. We further identified the frequency of these antibodies in a large cohort of Turkish CIDP patients containing adult and pediatric patients, together with their immunological and clinical characteristics. Additionally, we found that MOG-IgG can also be present in the serum and CSF of CIDP patients as well as CCPD patients. Key words: Chronic inflammatory demyelinating polyneuropathy, combined central and peripheral demyelination syndrome, autoantibody, neurofascin, myelin oligodendrocyte glycoprotein
Effects of diesel exhaust particles and engineered nanoparticles on DNA methylation of genes associated with pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) in bronchial epithelial cells
Inhaled particles such as diesel exhaust particles (DEP) and engineered nanoparticles (NP) create an important risk for respiratory health. Studies suggest that DEP and NP induce oxidative stress, cellular toxicity, and inflammation, which can lead to airway diseases. These particles are also shown to cause DNA methylation in various cellular systems. However, their effects on genes involved in chronic obstructive pulmonary disease (COPD) are not clear. We aimed to investigate the effects of DEP and NP on mRNA expression and DNA methylation of genes associated with the pathogenesis of COPD. BEAS-2B cells were incubated with DEP, Titanium Dioxide (TiO2), and Multi-walled Carbon Nanotubes (MWCNT) at concentrations of 0-100 µg/mL for 6, 24 and 48 hours, and viability of the cells was assessed using MTT assay. mRNA expression of COPD-associated genes (GCLC, CYP1B1, MUC5B, MUC5AC, FAM13A, SERPINA1) was analysed by qRT-PCR. CpG-targeted pyrosequencing was performed to understand DNA methylation status of differentially expressed genes. Particles did not cause a reduction in cell viability greater than 50%, except 100 µg/mL DEP at T48 hours of incubation. DEP and NP altered mRNA expression of GCLC and CYP1B1 genes, which are both involved in oxidative stress mechanisms. There were no significant DNA methylation changes in the promoter regions of the genes. However, DNA methylation changes were observed at CpG sites in exon 1 and intron 1. Although 50 µg/mL DEP increased DNA methylation of GCLC gene following 24 hours of incubation, this was decreased by MWCNT as the exposure time increased. TiO2 did not cause significant DNA methylation changes in GCLC gene. MWCNT (100 µg/mL)increased DNA methylation of CYP1B1 gene at T6 and T48 hours, whereas neither DEP nor TiO2 caused a significant change in DNA methylation of CYP1B1 gene. Our findings suggest that DEP and engineered NP may play a role in the pathogenesis of COPD by altering mRNA expression and DNA methylation of GCLC and CYP1B1 genes. Keywords: Bronchial Epithelial Cells, Diesel Exhaust Particles, Engineered Nanoparticles, DNA Methylation, COPD.
Decision making in OCD and its interaction with metacognition and genetics: A proposal towards expected value of control theory
Obsessive – Compulsive Disorder is a neurocognitive disorder which affects approximately 3% of the general population. Almost 33% of patients with OCD diagnosis remain treatment refractory even after the prescription of pharmacological options we have. Thus, we need more comprehensive understanding of the neurobiological basis of OCD to propose more effective treatment options. One of the remarkable characteristics of OCD is the accompanying insight about the symptoms. The patients with OCD diagnosis acknowledge that there is no need to wash their hands repeatedly in the case of contamination obsession, however they can not abstain from performing this compulsive behavior. In this dissertation, the mechanism behind this discrepancy was tried to be understood. The perceptual decision making characteristics of the patients with OCD diagnosis is scarcely studied area of research. This dissertation focused on perceptual decision making in healthy participants with varying degrees of propensity to OCD. In the first study, the relation between dopamine gene related gene polymorphisms (COMT, DRD2 and DARPP-32) and latent decision making variables in addition to obsessivecompulsive factors. The results of this study suggest that having Met/Met allele of COMT gene is associated with lower decision threshold, higher drift rate and higher obsessivecompulsive factor scores. In the second study, metacognitive assessments of participants, in addition to perceptual decision making task, were collected. This study showed that participants with high propensity to OCD have more efficient metacognitive assessments, however they can not use this metacognitive information to modulate the strategy used in their subsequent action in decision making task. Lastly, current literature about cognitive alterations observed in OCD was reviewed in the framework of Expected Value of Control (EVC) Theory which proposes a computational model and neuronal allocations for the adjustment of cognitive control. Overall, these results suggest that participants with high propensity to OCD struggles in behavioral adaptation and this might be the result of a dysfunction in different parts of EVC. Keywords: OCD, decision making, COMT gene, metacognition, Expected Value of Control Theory
Selective and sensitive determination of real-time Butyrylcholinesterase activity via Phenoxy 1,2-dioxetane-based chemiluminescent probe
Butyrylcholinesterase (BChE), or pseudo-cholinesterase, is one of the significant cholinesterases in the human body with a diverse substrate range and function area. It plays crucial roles in numerous physiological and pathological processes, including regulation of acetylcholine, detoxification of poisons, metabolism of drugs, regulation of fat metabolism, and beyond. Accordingly, it is an essential yet challenging target for bioimaging studies. Several methods and small molecule probes have been proposed for BChE activity detection and measurement so far. However, they suffered from either low detection limits, inadequate selectivity or method-intrinsic drawbacks. Herein, we have presented a BChE-responsive chemiluminescent probe, BCC, based on a phenoxy 1,2-dioxetane core with an electron-withdrawing acrylic group for monitoring BChE activity in native biological contexts; thus, we have introduced the first-ever example of a chemiluminescence-based bioimaging technic for the visualization of BChE activity. BCC generated a selective and sensitive turn-on response with BChE but not with competitive analytes in aqueous solutions. BCC was successfully utilized to measure and visualize endogenous BChE activity in normal and cancerous cell lines without showing any toxicity. Inhibition studies have proven that BCC can detect fluctuations in BChE levels precisely. BChE in healthy mice models has been visualized in distinct body regions, from the liver to the brain, as BCC could pass through the blood-brain barrier. Likewise, tumours grown on mouse models derived from neuroblastoma cells have been pictured with a very high signal-to-noise ratio. Hence, BCC stood out as a promising chemiluminescent probe for selective and sensitive detection of BChE, which can be used to further understand its contribution to regular biological processes and the formation of diseases.
Adaptive response to fluconazole in candida parapsilosis: Ergosterol pathway mutations, gene expressions, and metabolomic shifts
Candida parapsilosis complex is the second most common cause of bloodstream infection among Candida species both in our country and in many centers in Southern Europe and become a major health-care problem due to the increasing antifungal resistance. Azoles, an important group of antifungal drugs are bind to lanosterol demethylase and inhibit the enzyme. Resistance is usually associated with point mutations in the ERG11 gene and ERG3 genes which play role in ergosterol biosynthesis. This study aims to analyze the effects of fluconazole on C. parapsilosis cells in metabolomic, transcriptomic and genomic level especially focusing on the critical steps in ergosterol synthesis pathway. In this study, 15 fluconazole non-susceptible C. parapsilosis isolates are included. Analysis of the resistance profile is performed with broth microdilution test according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Fluconazole non-susceptible isolates are treated with the 0.5 Minimum Inhibitory Concentration (MIC) and 1 MIC of fluconazole and the mRNA expression level changes are measured with quantitative real-time polymerase chain reaction (qRT-PCR) method. Effects of fluconazole on the metabolomic profiles of C. parapsilosis cells are examined with Nucleic Magnetic Resonance Spectroscopy (NMR). Sanger sequence analysis showed that 10/15 (66%) of the isolates were harboring Y132F mutations in ERG11 gene and all of them were carrying missense mutation (C825T) in ERG3 gene. Although, an increase in ERG11 mRNA expression levels is observed regardless of the mutation type, some of the selected isolates behaved controversial under fluconazole exposure. Together with all isolates, especially K478 had a decreasing ERG11 mRNA expression level trend under higher fluconazole concentration. Even if the highest ERG3 and UPC2 mRNA expression levels were observed in K478, the same decreasing trend were also detected under higher fluconazole concentrations in these genes. According to metabolomic analysis results, under the fluconazole exposure, the metabolic pathways most significantly altered are: 1) alanine, aspartate, and glutamate metabolism, 2) arginine and proline metabolism, 3) homocysteine, methionine metabolism, and 4) arabinitol metabolism. We assumed that the metabolomic changes observed in our study might be related with two important biochemical processes which are nitrogen assimilation and oxidative stress responses. In conclusion, in drug-resistant C. parapsilosis isolates, the response to fluconazole exposure in terms of mRNA expression of ergosterol biosynthesis enzyme genes is strain-specific, clearly indicating that there are numerous different regulations besides point mutations in the enzyme genes of ergosterol synthesis and control. These regulations lead to a wide range of metabolomic changes within the cell, while a common metabolic response is formed in almost all isolates to neutralize the toxic effect of fluconazole and ensure survival. A detailed in-depth investigation of this survival response will uncover new drug targets in the future. Keywords: Candida parapsilosis, azole resistance, ERG11 gene, ERG3 gene, UPC2 gene, quantitative real-time PCR (qRT-PCR), Sanger sequencing, NMR spectroscopy
Functional genetic screens of chromosome 1q in breast cancer via 2D and 3D in vitro models
Breast cancer, with an incidence rate affecting approximately 2.3 million women globally, poses significant health challenges due to high recurrence rates and resistance to therapy. The diversity of molecular subtypes further complicates targeted treatment. Genetic abnormalities, particularly chromosomal alterations, play a critical role in tumour initiation and progression. Specifically, chromosome 1q (Chr1q) copy number alterations (CNA) are linked to poor patient prognosis and survival. This study hypotheses that Chr1q CNAs induce a genomic disorder/catastrophe, activating oncogenic drivers or causing gene expression loss. To investigate, we performed functional CRISPR screening targeting Chr1q genes in breast cancer. We utilised both 2D and 3D cultures in two breast cancer cell lines and one normal breast cell line to capture cancer-specific phenotypes influencing proliferation. We identified cancer-specific dropout genes negatively impacting proliferation in breast cancer cells but not in non-tumorigenic controls. Among 14 shared candidates, RPRD2 and GON4L were selected for further validation due to their significant effects on breast cancer proliferation in both 2D and 3D models. RPRD2 showed cancer-specific activity, while GON4L also impacted normal breast cells. For enriched candidates with positive phenotypes, we normalised 3D screening results by 2D (3D/2D). ARL8A and ARNT emerged as significant in at least one breast cancer cell line. Validation experiments revealed that blocking ARL8A and ARNT decreased proliferation in 2D models but increased 3D spheroid growth, indicating differential phenotypic impacts. Additionally, ARNT knockout in normal breast cells led to increased proliferation. This study highlights the necessity of transitioning from 2D to 3D models in functional screening for more accurate phenotypic evaluations. It also underscores the importance of Chr1q in breast cancer carcinogenesis and identifies potential cancer driver genes.
Sağlık çalışanlarında göz sağlığı okuryazarlığı ve sağlık okuryazarlığı arasındaki ilişkinin incelenmesi
Sağlık tanımı tarihsel süreç içinde ele alındığı döneme ve kültüre göre farklılıklar göstermiştir. Çevre koşulları ve sosyo ekonomik şartların değişmesi ile sağlık kavramı önem kazanmıştır. Sağlığın korunması, geliştirilmesi ve sürekliliğinin sağlanması öncelikli hal almıştır. Tarihsel süreç içinde sosyo ekonomik ve kültürel değişimler hızla gerçekleşmiş insanlar çevreye uyum sağlamışlardır. İşte bu noktada uyum sağlayabilme becerisi, yaşam boyu öğrenme ile birleşerek insan içindeki potansiyeli ortaya çıkartmıştır. Yaşam boyu öğrenmeye bağlı olarak okuryazarlık kavramı önem kazanmıştır. Okuryazarlık tanımı en sade haliyle, okuma yazma becerisine sahip olmak olarak tanımlansa da zamanla yeterli görülmemiş, okuduğunu anlamak, yorumlayabilmek okuryazarlık şartlarını oluşturmuştur. Sağlık konusunda doğru karar vermek bilgiye erişimin hızlı gerçekleştiği bir dönemde oldukça zor olmaktadır. Yazılı ve sözlü bilginin anlaşılması sağlık personeli ve hasta arasındaki sağlık iletişiminin ve sağlık okuryazarlığının önemini vurgulamaktadır. Gözlerimiz etrafımızda olanları algıladığımız duyu organımızdır. Sıklıkla rastlanılan bozuklukların, ani görme kaybı oluşturacak hastalıkların önlenebilir, tedavi edilebilir olması göz taraması ve kontrollerde görme kayıplarının en aza indirilmesi göz sağlığı okuryazarlığının önemini artırmaktadır. Bu çalışmanın amacı sağlık çalışanlarında göz sağlığı okuryazarlığı ve sağlık okuryazarlığı düzeyini belirlemektir. Çalışmada göz sağlığı okuryazarlığı ve sağlık okuryazarlığı düzeyini belirlemede 5'li Likert ölçeği kullanılmıştır. Veri analizleri SSPS 24.0 paket programı kullanılmıştır. Göz sağlığı okuryazarlığı ve sağlık okuryazarlığı arasındaki ilişkinin saptanmasında Pearson korelasyon analizi yapılmış ve sonucunda beklendik şekilde göz sağlığı okuryazarlığı arttıkça sağlık okuryazarlığında arttığı saptanmıştır.
Clinical and functional characterization of a new muscular dystrophy caused by novel recessive SNUPN pathogenic variants
Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive muscle weakness and degeneration. This study presents a comprehensive investigation of a novel muscular dystrophy phenotype associated to germline recessive mutations in the SNUPN gene, identified in 21 patients from 18 unrelated families. Clinically, the affected individuals exhibited progressive muscle weakness with a broad spectrum of severity, ranging from mild symptoms and retained ambulation to severe early-onset muscular dystrophy leading to premature death from respiratory complications. Beyond muscular dystrophy, several patients displayed extra-muscular manifestations, notably neurological deficits, including cerebellar atrophy and congenital cataracts, reflecting broader systemic implications of SNUPN mutations. SNUPN encodes the SNURPORTIN-1 (SPN1) protein, which plays a critical role in the nuclear import of uridine-rich small nuclear ribonucleoproteins (UsnRNPs), crucial components of the spliceosome machinery. Most identified mutations clustered at the C-terminus of the SPN1 protein, highlighting its critical functional role and suggesting it as a potential mutational hotspot. Functional analyses demonstrated that defective SPN1 impairs the nuclear import of UsnRNPs, causing aberrant alternative splicing of numerous genes implicated in muscle structure and function. This aberrant splicing affected critical muscle-related proteins, including extracellular matrix components, sarcolemmal proteins, and cytoskeletal elements, likely contributing to muscle fiber degeneration, fibrosis, and functional impairment. Furthermore, this study uncovered novel insights into SPN1 protein biology, particularly its self-oligomerization and interaction with the survival motor neuron (SMN) protein complex. Disrupted SPN1-SMN interaction and autophagic dysregulation were observed, potentially suggesting these pathways may play a key role in the muscular dystrophy pathogenesis. Aberrant accumulation of autophagy markers (LC3-II and p62) in patient muscle tissues and cell lines further underscored this dysregulation. Comparative analysis with concurrently published data from independent cohorts supported our findings, reinforcing the genotype-phenotype correlations and highlighting novel disease mechanisms. Collectively, this research significantly expands the genetic landscape of muscular dystrophies by characterizing SNUPN-related muscular dystrophy at clinical, molecular, and functional levels. Future studies employing animal models and extended patient cohorts are essential to further deepen the understanding of SNUPN pathology, unravel the intricate molecular mechanisms, and facilitate the development of targeted therapeutic strategies.
Kronik bel ağrısı olan sporcularda pliometrik egzersiz eğitiminin etkinliği: Randomize kontrollü çalışma
Bulut, M. (2024). Kronik Bel Ağrısı Olan Sporcularda Pliotmetrik Egzersiz Eğitiminin Etkisi: Randomize Kontrollü Çalışma, Yüksek Lisans Tezi, Biruni Üniversitesi Lisansüstü Eğitim Enstitüsü, İstanbul. Bu çalışmanın amacı, kronik bel ağrısı olan sporcularda pliometrik egzersiz eğitiminin etkilerini incelemektir. Çalışmaya toplam 32 kişi (15 erkek, 17 kadın) katılmıştır. 18-25 yaş aralığında olan katılımcıların yaş ortalaması 20.59±1.91 yıldır. 32 sporcu randomizasyon yöntemi ile iki gruba ayrılmıştır: Çalışma grubu(n:16) ve kontrol grubu (n:16). Katılımcıların ağrı şiddetini değerlendirmek için Vizüel Analog Skala (VAS), özürlülük durumlarını değerlendirmek için Oswestry Özürlülük İndeksi(OÖİ), statik denge düzeyini değerlendirmek için Flamingo Denge Testi (FDT), Kas kuvvetini ölçmek için Manuel Kas Testi, Kas kısalığını değerlendirmek için Manuel Kısalık Testleri, esnekliği ölçmek için Otur &Uzan Testi, fonksiyonelliği değerlendirmek için Vertikal Sıçrama Testi ve Mekik Koşu Testleri kullanılmıştır. Her iki grup katılımcıları 6 haftalık (haftada 3 gün) fizyoterapi programına alınmıştır. Çalışma grubu fizyoterapi programına ilave olarak pliometrik egzersiz programına alınmıştır (6 hafta, haftada 3 gün). Tedavi programı sonrasında her iki grupta tüm parametrelerde iyileşme olduğu belirlenmiştir (p ≤0,05). Gruplar birbiriyle karşılaştırıldığında; tüm parametrelerde pliometrik egzersiz programına alınan çalışma grubuna katılan bireylerin kontrol grubuna kıyasla daha anlamlı gelişmeler gösterdiği saptanmıştır (p ≤0,05). Kronik bel ağrılı sporcularda standart fizyoterapi programına ilave edilen pliometrik egzersiz eğitiminin tedavi etkinliğini arttırdığına karar verilmiştir. Sporcularda kronil bel ağrısı nedeniyle azalan performansı arttırmak amacıyla pliometrik egzersizlerin tedavi programına eklenmesini önermekteyiz.
İnfertil çiftlerin uyguladıkları geleneksel yöntemler
Bu araştırma, infertilite tedavisi gören bireylerin geleneksel yöntem kullanımlarını ve geleneksel tamamlayıcı tıbba karşı tutumlarını belirlemek amacıyla tanımlayıcı ve ilişki arayıcı şekilde yapıldı. Araştırma, İstanbul'da bir özel hastanenin tüp bebek merkezinde, Şubat 2023- Haziran 2023 tarihleri arasında gerçekleştirildi. Araştırmaya 233 infertil kadın ve 108 erkek olmak üzere toplam 341 birey alındı. Araştırmanın verileri, tanıtıcı bilgi formu ve Geleneksel Tamamlayıcı Tıp Tutum Ölçeği ile toplandı. İnfertil hastaların gebelik için geleneksel bir yöntem kullanma oranın %56.9 olduğu görüldü. Geleneksel yöntemleri kullanan bireylerin oranının %63.9'u bu yöntemleri kullanırken doktora bildirmedikleri belirlendi. En yaygın kullanılan geleneksel yöntemler arasında manevi dualar (%51.5), soğan kürü (%17.0), fitoterapi (%16.0), hacamat (%16.5) ve incir kürü (%16.0) yer aldığı görüldü. Ayrıca, bal (%14.9), keçiboynuzu pekmezi (%12.4), avokado (%11.3) gibi doğal besin ürünlerinin de sıklıkla kullanıldığı saptandı. Gebelik için geleneksel bir yöntem kullananlar, kullanmayanlara göre anlamlı derecede daha yüksek GTT tutum puanlarına sahip olduğu belirlendi. Ortaokul mezunu olan katılımcıların ölçek toplam puanları, üniversite ve lisansüstü mezunlarına kıyasla daha fazlaydı. Ayrıca geniş aileye sahip olan ve akraba evliliği olan katılımcıların ölçek toplam puanları daha fazlaydı. Geliri giderinden az olan katılımcıların ölçek toplam puanları da benzer şekilde geliri giderine eşit ya da geliri giderinden fazla olanlara kıyasla daha yüksekti. Sonuç olarak, katılımcıların yaklaşık olarak yarıdan fazlasının geleneksel yöntem kullandıkları ve bu yöntemleri kullanan katılımcıların Geleneksel Tamamlayıcı Tıp Tutum Ölçeği toplam puanlarının da daha yüksek olduğu belirlendi. Geleneksel Tamamlayıcı Tıp Tutum Ölçeği toplam puanını eğitim, aile yapısı, gelir durumu ve akraba evliliği etkileyen faktörlerdendi.
Bariatrik cerrahi planlanan hastaların yeme bağımlılığı, depresyon ve beslenme durumunun değerlendirilmesi
Bu araştırma, bariatrik cerrahi planlanan hastalarda yeme bağımlılığı, depresyon ve beslenme durumunun değerlendirilmesi amacıyla planlanıp yürütülmüştür. Çalışmaya, özel bir hekim muayenehanesine bariatrik cerrahi için başvurmuş, hekim tarafından genel sağlık muayenesi yapılmış, çalışmaya katılmayı gönüllü olarak kabul eden, Ankara'da yaşayan 127 yetişkin birey katılmıştır. Bireylere, demografik özellikleri, sağlık durumları ve beslenme alışkanlıkları ile ilgili sorular içeren anket formu yüz yüze görüşme yöntemi ile uygulanmıştır. Bireylerin beslenme durumunun saptanması için üç günlük besin tüketim kaydı alınmıştır. Bireylerin antropometrik ölçümleri yapılıp bazal metabolizma hızı, bel/boy ve bel/kalça oranı hesaplanmıştır. Bireylerin, yeme bağımlılığı Yale Yeme Bağımlılığı Ölçeği ve depresyon durumları ise Beck Depresyon Ölçeği (BDÖ) ile değerlendirilmiştir. Bireylerin 49'u erkek (% 38.6) ve 78'i kadın (% 61.4), yaş ortalaması 38.7±11.24 yıldır. Kadınların %96.2'sı, erkeklerin ise %93.0'ı daha önce diyet yapmıştır. Kadınların %53.8'inin, erkeklerin ise %20.4'ünün öğün atladıkları belirlenmiştir. Bireylerin günlük diyetle aldıkları; enerji, karbonhidrat, protein, yağ ve kolesterol yüzdeleri "önerilen günlük alım miktarlarını" (Recommended Dietary Allowances-RDA) karşılamaktadır. RDA önerilerine göre, bireylerin günlük diyetle aldıkları potasyum minerali tüm bireylerde yetersiz, ayrıca E vitamini, pantotenik asit, kalsiyum ve demirin kadınlarda yetersiz olduğu saptanmıştır. BDÖ puan ortalaması erkeklerde 15.2±8.21, kadınlarda ise 16.8±7.30 olduğu saptanmıştır. Kadınlarda, minimal depresyon aralığında olan bireylerin BKİ ortalaması 41.0±7.38 kg/m2, hafif depresyon aralığında olan bireylerin BKİ ortalaması 39.9±4.16 kg/m2, orta depresyonu olanların BKİ ortalaması 42.9±7.27 kg/m2 ve şiddetli depresyon aralığında olan bireylerin BKİ ortalaması 46.7±1.35 kg/m2 olarak saptanmıştır ve kadınlarda depresyon şiddeti ile BKİ arasındaki ilişki istatistiksel olarak anlamlıdır. Yeme bağımlılığı olan bireylerin bel çevresi ortalaması (129.8±14.20 cm), yeme bağımlılığı olmayan bireylerin ortalamasından (126.4±16.20 cm) istatistiksel olarak anlamlı şekilde daha yüksek olduğu tespit edilmiştir. Bireylerin BKİ değerleri ile karbonhidrat alım değerleri arasında istatistiksel olarak anlamlı pozitif yönde, protein yüzde değerleri arasında ise istatistiksel olarak anlamlı negatif yönde zayıf bir ilişki belirlenmiştir. Sonuç olarak, obezitenin önlenmesine katkı sağlayabilmek için yeme bağımlılığı, depresyon ve beslenme durumlarının daha fazla incelenmesi ve bu konularla ilgili daha fazla çalışma yapılması gerekmektedir.
Alanya'da kamu hastanesinde çalışan sağlık profesyonellerinin sağlık turizmine ilişkin bilgi ve tutumlarının değerlendirilmesi
Bu çalışma Antalya ili Alanya ilçesinde bir kamu hastanesinde çalışan sağlık profesyonellerinin sağlık turizmine yönelik bilgi ve tutumlarının değerlendirilmesi amacıyla yapılmıştır. Çalışmanın bu bölümünde elde edilen bulguların yorumlanması ve konuya ilişkin diğer çalışmalarla kıyaslanması sağlanmıştır. Araştırmanın evrenini, araştırmanın yapıldığı hastanede çalışan 1500 sağlık profesyoneli oluşturmuştur. Araştırmanın örneklemini %5 anlamlılık düzeyinde, %5 örneklem hatası ile yapılan örneklem hesabı ile belirlenen 306 kişi oluşturmuştur. Araştırmanın verileri araştırmacı tarafından oluşturulan tanıtıcı bilgiler formu ve Sağlık Turizminin Gelişimine Karşı Halkın Tutum Ölçeği ile toplanmıştır. İstatistiksel analizlerde bireylerin tanıtıcı özelliklerin analizinde sayı, yüzde, ortalama, standart sapma, minimum - maksimum değerleri kullanılmıştır. Katılımcıların tanımlayıcı özelliklerine göre ölçek düzeylerindeki farklılaşmaların incelenmesinde bağımsız gruplar t-testi, tek yönlü varyans analizi (Anova) ve post hoc (Tukey, LSD) analizlerinden faydalanılmıştır. Araştırmaya katılan bireylerin %44,4'ü (136),30 ve altı yaş grubunda, %52,9'u (162) kadın, %50,7'si (155) bekar, %95,4'ü (144) çekirdek aile yapısına sahiptir. Araştırmaya katılanların %69,0'ının Alanya'da yaşayanların sağlık turizmi bilgisine sahip olmadıklarını düşündükleri, %36,6'sının sağlık profesyonellerinin de sağlık turizmi bilgisine sahip olmadıklarını düşündükleri saptanmıştır. Sağlık profesyonellerinin "Sağlık Turizminin Gelişimine Karşı Halkın Tutum Ölçeği" puanları incelendiğinde ise ölçek toplam puan ortalamasının 81,59±12,30, "ülkeye katkı" ortalaması 37,63±4,62, "hizmet adaleti" ortalaması 24,29±5,66, "kaliteli hizmet alma" ortalaması 19,670±4,243 olduğu görülmüştür. Araştırma sonucunda sağlık profesyonellerinin sağlık turizmine yönelik bilgi sahibi oldukları ancak istendik düzeyde olmadığı saptanırken, sağlık turizminin gelişimine yönelik puanlarının yüksek olduğu ancak yetersiz olduğu saptanmıştır. Bu araştırmadan yola çıkarak turizm bölgesinde çalışan sağlık profesyonellerine yönelik bilgilendirmelerin kurumlar bünyesinde verilecek olan hizmet içi eğitimler kapsamında sunulması önerilmektedir.
Erbil şehri genç spor merkezlerinde spor kriz yönetimi çalışması
The purpose of our research is to know what the crisis means and where it came from and how it is defined? And what are the characteristics, types, qualities, stages, and solutions of the crisis? And what is the purpose of managing the crisis? While presenting a number of important and necessary issues about the crisis, which are based on a number of scientific sources, we can understand the meaning of the word crisis, which has an impact on all aspects of life, and there are other terms that are similar to crises such as "problems, shocks, disasters, events... Etc." at the same time, the crisis will be divided into several parts and branches, what are the characteristics? It has been discussed and revealed that when we face a crisis, we must be able to manage the crisis to solve it with the least time and harm and gain a good experience to benefit us if we facing another crisis, or to prevent other crises. Every institution that consists of a management system faces many different crises, institutions, clubs, centers and sports centers, like any administrative institution, but what makes it self-sufficient in the face of the crisis is that the institution's administrative system is able to withstand and solve the crisis, which makes the institution better and stronger, so in this research I've put my doubts on managing sports crises. The researcher here, apart from the theoretical aspect of a detailed study of the crisis, has been field-based through a survey considering the scientific criteria conducted among youth sports centers in Erbil, with the participation of 169 leaders and employers at the management, administration and members of these sports centers, All the data has been passed through a number of important and necessary analysis to ensure the correct answers and be able to get the results correctly, like (Reliability statistics), (frequency table) and (factor analysis). The results showed that youth sports centers in Erbil city faced severe financial and technical crises, and considering the results of the data analysis, the study concluded: 1- The specified budget should be added to youth sports centers, and other financial resources should be provided to them. 2- Opening development courses and strengthening for president, members and employees of sports centers in the field of management and administration. 3- Improving the capabilities and equipment of the youth sports centers in Erbil city.
Yeni Tiyazol türevleri ve biyolojik etkilerinin araştırılması
In this thesis, it was aimed to design and synthesize a total of 12 compounds (5a-5l) containing the thiazole ring, which is a potential structure that can be used in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. N-[4-(4-Acetamidophenyl)thiazol-2-yl)-]2-((heteroaryl)thio)propanamide (5a-5l) derivative compounds were analyzed using various techniques such as IR, NMR, and HRMS, and their physical properties were determined. The synthesized compounds were then tested for their potential inhibitory activity on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO-A and MAO-B) enzymes. The compounds showed remarkable activity as AChE inhibitors, of which compounds 5d, 5e and 5j exhibited the highest AChE inhibitory activity. However, the inhibitory activities of the compounds against both the BChE and the MAOs were weak. The three most effective compounds, the way they bind to protein sites, the bonds they make, and the effects of time-environmental variables on these interactions were investigated by molecular docking and dynamic simulation docking analyses. This study highlights that thiazole compounds are a good framework for the treatment of neurodegenerative disorders in drug development studies.
Nazal yol yoluyla in situ jel yüklenen metoklopramid nano yapılı lipid taşıyıcı: Hazırlama, karakterizasyon ve in vitro değerlendirme
This study is done to overcome the limitations of MTC occurred when taken by different routes of administration in order to improve its bioavailability and to increase patient compliance, also in an attempt to prolong their nasal cavity residence time when it is taken intranasally, and for the achievement of a prolong drug permanence into the site of administration. An innovator composite formulates, by associating the liposome (soybean and cholesterol) and in situ gel (gellan gum) delivery systems, has been created. Thin film hydration method, also called bangham method was used to prepare MTC loaded liposomes. The optimal liposomal formulation was determined using D-optimal mixture experimental design. All of the prepared formulations, there values of polydispersity index were lower than 0.6, which indicates monomodal size distributions. Also, the particle size of the MTC loaded liposomes were small, the formulation's mean particle was smaller than 150 nm. The encapsulation efficiency of MTC in liposomal formulation was between 71% and 94%. Furthermore, in this work, zeta potential values were negative for all our API-Lip formulations. In the present study, MTC loaded liposome were prepared and incorporated with gellan gum solution. Furthermore, MTC loaded in situ gel preparation and characterization studies were performed, in addition to liposomal morphology, determination of mechanical properties, rheological behavior, ex vivo and in vitro release study. Based on observed data the MTC loaded liposome formulation incorporated with gellan gum was showing significant results. Cumulative drug release from the MTC loaded liposome incorporated with gellan gum formulations after 5 h was found to be more than 80%. This study might point to the potential of an intranasal innovative composite formulation taken together, liposomes included the nasal in situ gel in terms ease of administration, drug dosing accuracy, good capability for reduction of the nasal mucociliary transport time with prolongation of residence time at the site of absorption, the avoidance of antiemetic drug's bitter taste and improved drug bioavailability. Therefore, it could be taken into consideration in pharmaceutical industries in the future. Keywords: In-situ gel, Liposomes, MTC loded liposomes, Mucoadhesion, Residence time.
Akut ve kronik non-spesifik boyun ağrısı olan bireylerde ağrı, propriosepsiyon ve kinezyofobi arasındaki ilişkinin incelenmesi
In this study, kinesiophobia, proprioception, pain, and quality of life were evaluated in patients with non-specific acute and chronic neck pain. 52 patients, 26 with acute (mean age: 35.08±10.877) and 26 with chronic (mean age: 35.58±10.238) non-specific neck pain, who applied to Yeditepe University Hospital in Istanbul participated in this study. Joint range of motion and joint position sense were measured using the Goniometer-Pro (G-Pro), an iPhone application. Endurance was measured with the deep flexor muscle endurance test. The Neck Disability Index (BDI), the Tampa Kinesiophobia Scale (TKS), the Visual Analog Scale (VAS), and the International Physical Activity Questionnaire were used to determine the intensity of the pain, the fear of movement, the level of disability, and the level of physical activity (IPAQ). The study's data were statistically analyzed using the SPSS 20.0 program. Individuals with acute and chronic neck pain showed no significant difference in their sense of joint position or fear of movement. Deep neck flexor muscle endurance was found to be higher in those with chronic neck pain than in people with acute neck pain (p<0.05). The degree of neck disability in both groups, as well as the fear of movement, were found to be significantly correlated. In neither group was there a correlation between sense of joint position and fear of movement. In those with chronic neck pain, there was a significant correlation between the intensity (VAS rest and VAS night) and fear of movement (p<0.01), but not in people with acute neck pain. Joint position sense and pain intensity did not significantly correlate in either group. In conclusion, it was found that there was a significant relationship between fear of movement and intensity of pain and neck disability in people with chronic neck pain, despite the fact that there was no correlation between fear of movement and sense of joint position in individuals with acute and chronic neck pain. Studies on individuals who suffer from non-specific acute and chronic neck pain have been reported to be limited, and additional research is required in this area. Key words: Acute Neck Pain, Chronic Neck Pain, Proprioception, Kinesiophobia
Şizofreni hastalarında fiziksel aktivite ve sanal gerçeklik eğitiminin fiziksel fonksiyon, biliş ve yaşam kalitesi üzerine etkilerinin karşılaştırılması
This thesis aims to compare the effects of Physical Activity (PA) and Virtual Reality (VR) training on physical function, cognition, and quality of life in patients with schizophrenia (PwS). The study was conducted over 12 Weeks and included three groups: a VR group (n=15), a PA group (n=12), and a Control group. The primary outcome measures focused on physical function, cognition, and quality of life using the SF-36 questionnaire. The results revealed significant differences in several areas. The PA group experienced a significant decrease in sedentary time compared to their baseline measurements (p<0.05) and exhibited a significant increase in exercise time compared to their baseline measurements (p<0.05). The VR intervention had a positive impact on the physical health of the participants, as indicated by improved Physical Component Summary (PCS) scores (p<0.05). Furthermore, the VR group showed statistically higher average post-test right-hand dynamometer scores than pre-test scores (p<0.05). Both the VR and PA groups showed statistically higher mean Sit-to-Stand (SST) measurements in the post-test compared to the other groups (p<0.05). In addition, in the VR and PA groups, the Timed Up and Go (TUG) averages obtained in the post-test were statistically lower than the pre-test time (p<0.05). Moreover, in the VR and Control groups, the 6-Minute Walk Test (6MWT) Rounds mean was statistically higher than the pre-test time (p<0.05). Within the PA group, the average Calgary Depression Scale for Schizophrenia (CDSS) scores significantly decreased after 12 weeks (p<0.05). Additionally, in the PA group, the average Mini-Mental State Examination (MMSE) score in the post-test was statistically higher than in the pre-test (p<0.05). These findings suggest that both PA and VR interventions have beneficial effects on physical function, cognition, and quality of life in PwS. Specifically, the PA intervention reduced sedentary behavior and increased exercise time (p<0.05), while the VR intervention positively impacted physical health (p<0.05). The results highlight the importance of incorporating PA and VR interventions to enhance the well-being of individuals with schizophrenia. Further research and implementation of these interventions could contribute to improving the overall care and management of PwS. Keywords: schizophrenia, Nintendo Wii Fit, interactive gaming, physical engagement, immersion, balance, Quality of Life, therapeutic intervention.
Yeni nesil dizileme tekniği kullanılarak karaciğer kanserinin sistem biyolojisi analizi
The underlying mechanism for the development of Hepatocellular Carcinoma (HCC) is highly complex due to tissue heterogeneity. Although the traditional approaches mainly focus on a single gene or locus, understanding the variations in the signaling pathways of cancerogenic cells during hepatocarcinogenesis may help to develop novel strategies for treatment and drug development to prevent cancer progression in the patients. This thesis study primarily focuses on unveiling the transcriptome sequencing of differentially expressed genes in HCC, which mainly concentrate on known disease signaling pathways. For this purpose, RNA-seq data of two HCC cell lines were targeted by three different kinase inhibitors and two of their combinations with Sorafenib. The functional pathways enriched with differentially expressed genes were identified by solving a graph problem called as Prize Collecting Steiner Tree (PCST) on human interactome generating inhibitor specific networks. As a result of this study, we found that combinatory treatment of Sorafenib with PIK-75 to HCC cell lines Huh7 and Mahlavu stimulates apoptosis, while TGX-221 with Sorafenib strikingly promotes cell growth antagonizing cellular death, especially for Mahlavu cell line. The states of transcriptomes for different kinase inhibitors were visualized using Cytoscape and molecular interactions were scanned deeply to understand synergistic or antagonistic effects of these kinase inhibitory treatments. Hence, this study provides comprehensive pathways analysis for differential kinase inhibitor reactions of HCC. Using these data, novel HCC drug targets were identified which may lead to more cost-effective and diverse treatment options available for the treatment of liver cancer.
Fiziksel aktivite müdahaleleri: Dijital Uygulamaların etkinliği
Amaç: Bu araştırmanın amacı fiziksel aktivite düzeyinin artırılmasında dijital müdahalelerin etkilerinin incelenmesi ve gelecek çalışmalara katkı sağlamaktır. Gereç ve yöntem: Literatürdeki dijital müdahalelerin fiziksel aktivite düzeyine etkisini konu alan çalışmalar incelenmiş ve "Kapsamlı Dijital Müdahale Modeli" tasarlanmıştır. Oluşturulan modelin etkilerinin incelenmesi için "Daha Aktif Daha Sağlıklı" kod adıyla proje oluşturulmuştur. Deneyin uygulanması için "Pacer" adlı mobil uygulama aracılığıyla, modelimize dayanarak üretilen müdahaleler katılımcılara bildirim veya uygulama içi mesaj olarak ulaştırılmıştır. Deney grubu 190 kişi (31.28±10.47 yaş ortalaması ile 129 kadın, 31.64±12.10 yaş ortalaması ile 61 erkek), kontrol grubu 192 kişi (24±8.55 yaş ile 137 kadın, 36.29±9.11 yaş ile 55 erkek) olarak 12 haftalık günlük adım sayıları özel bir vekil sunucu kullanılarak mobil uygulama aracılığıyla toplanmıştır. Java Script alt yapısı üzerine kurulmuş bir veri aktarım formatında elde edilen deney ve kontrol gurubu adım sayıları, proje ekibi tarafından geliştirilen özel bir yazılım aracılığıyla hazırlanmsıştır. Analizinde; t-testi ve tek yönlü ANOVA testi kullanılmış ve aritmetik ortalama (x̄), standart sapma (s.s), frekans (f), yüzde (%) değerleri hesaplanmıştır. Bulgular: Kapsamlı dijital müdahale modelini baz alarak oluşturulan girişimlerin deney (15,351.81) ve kontrol grubunun (12,154.69) haftalık kişi başı ortalama adım sayısı sonuçlarina göre, deney grubu katılımcılarının fiziksel aktivite düzeyine katkı sağladığı gözlemlenmiştir. Ancak istatiksel analiz açısından (p < 0.05) düzeyinde anlamlı bir farklılık görülmemiştir (𝑡0,05 ∶ 353=1304). Korona salgını adım sayılarının dramatik şekilde azalmasına neden olduğu gözlenmiştir. Sonuç: Bu çalışma kapsamında tasarlanan modeli kullanılarak yapılan dijital müdahalelerin günlük adım sayılarını artırmak için verimli olduğu tespit edilmiştir. Anahtar kelimeler: Dijital müdahaleler, Fiziksel aktivite, Öz belirleme, Sosyal medya, Oyunlaştırma
Premalign özellikli prostat dokularında epigenetik değişikliklerin karakterizasyonu
Prostate cancer (PCa) is one of the most commonly diagnosed, non-cutaneous malignancy and a leading cause of cancer-related death worldwide. Conventional methods of diagnosis include prostate specific antigen testing, digital rectal examination, and transrectal ultrasound guided prostate biopsies. The limitation of these approaches has led to the development of multiparametric MRI (mpMRI) guided biopsies. Significantly more sensitive, mpMRI can accurately identify radiographically suspicious lesions that are likely to be malignant and guide biopsy collection. However, even with this approach, ~10% of suspicious biopsies are found to be histopathologically benign. Given the sensitivity of mpMRI, it is unclear if these lesions harbor premalignant features or are technical artifacts. Epigenetic alterations, including DNA hypermethylation, are commonly found early in the development of PCa. Therefore, using these as premalignant markers, we characterized the epigenetic signatures of those radiographically suspicious lesions that were deemed to be benign by histology. Focusing on three well-characterized tumor suppressors, APC, GSTP1 and RARβ2 we developed a highly sensitive quantitative methylation specific PCR method to quantify promoter methylation. This method could robustly identify malignant and benign samples with the limited genetic material from FFPE biopsies. With this we quantified the promoter methylation of radiographically suspicious lesions from patients with either histopathology positive ("malignant"; n=28, 82 biopsies) or negative ("MRI"; n=18, 56 biopsies) biopsies. We found that the observed methylation levels of MRI cohort were markedly higher than benign samples yet lower than malignant tumors. This difference was highly gene specific. In our MRI cohort we did not observe any methylation positive cores at the APC promoter while almost all samples were positive for GSTP1 methylation. Even in the malignant cohort, only 37% of biopsies were methylation positive with the APC gene. Further, the relative methylation of the MRI cohort was heterogeneous with several cores biopsied from the same patient being positive for different markers. Intriguingly, when we investigated the clinical outcome of this cohort, almost none of the lesions in the MRI cohort had progressed into a neoplastic lesion. Overall, our results demonstrate that radiographically suspicious non-malignant lesions carry premalignant epigenetic alterations.
Yöneticilerin etik liderlik davranışları ile çalışanların performansı ve örgütsel bağlılıkları arasındaki ilişki: Sağlık sektörü örneği
Etik liderler dürüstlükleri ile ön plana çıkarlar. Söylediklerini uygularlar ve değerleri, sözleri ve eylemleri bir bütündür. Başkaları için söylediklerine kendileri de uyarlar aksi takdirde güvenilirlikleri ve itibarları da zarar görecektir. Etik liderler tarafından yönetilen kuruluşlar, diğer şirketler için de iyi bir örnek teşkil ederler ve şirketlerin saygınlığı artar, marka değeri yükselir. Aday çalışanların çalışmak, tedarikçilerin ortak iş yapmak ve rakiplerin taklit etmek isteyeceği özellikler etik liderlik ile artacaktır. Bu çalışmamızda etik liderlik davranışları ile örgütsel bağlılık ve performans arasındaki ilişki incelenmiş olup, 300 kişinin katılımı ile anketler gerçekleştirilmiştir. Örgütsel Bağlılık Ölçeği, Etik Liderlik Ölçeği ve Performans Değerlendirme Ölçeği arasındaki ilişkiler Spearman korelasyon katsayısı ile incelenmiştir. Örgütsel Bağlılık Ölçeği, Etik Liderlik Ölçeği ve Performans Değerlendirme Ölçeği güvenilirliği Cronbach Alfa ile hesaplanmıştır. İstatistiksel analizler için SPSS programı kullanılmıştır. Örgütsel bağlılık ölçeği toplam puan ile performans değerlendirme ölçeği arasında aynı yönde anlamlı ilişki bulunmuştur. Örgütsel bağlılık ölçeği alt boyutu olan duygusal bağlılık ile performans değerlendirme ölçeği arasında aynı yönde anlamlı ilişki bulunurken, ölçeğin alt boyutları olan devam ve normatif bağlılık ile performans değerlendirme ölçeği aralarında anlamlı ilişki bulunmamaktadır. Örgütsel bağlılık ölçeği toplam puanının ve duygusal bağlılık puanının artması performans değerlendirme puanının da artmasını sağlamaktadır. Etik liderlik ölçeği ile performans değerlendirme ölçeği puanı arasında aynı yönde anlamlı ilişki belirlenmiştir. Araştırmamızın sonuçları göstermektedir ki, sağlık sektörü çalışanları için, etik liderlik davranışları ile çalışanların performansları arasında anlamlı bir ilişki varken, örgütsel bağlılık ve etik liderlik arasında anlamlı bir ilişki bulunmamaktadır. Anahtar Kelimeler: Performans, Örgütsel Bağlılık, Liderlik, Etik Liderlik
Afrika Çad N'djamena Al-Nahda hastanesi'nde görev yapan sağlık yöneticilerinin liderlik davranışları ve kriz yönetimi üzerine bir araştırma.
Bu çalışma Afrika ÇCad N'djamena Al-Nahda Hastanesi'nde gőrev yapan sağlık yöneticilerinin liderlik davranışlarını ve kriz yönetimini değerlendirmek amacıyla planlanmıștır. Kesitsel ve tanımlayicı tipte olan çalışmanın evrenini Ocak-Mart 2025 tarihlerinde Afrika Çad N'djamena Al-Nahda Hastanesi 'nde görev yapan sağlık yöneticileri (n=200 kişi) oluşturmuştur. Herhangi bir örneklem yöntemi seçilmeden evrenin tamamına ulaşılmas planlanmıș ve izinliler dișinda 167 sağlık yöneticisi ile araștrma tamamlanmıştır. Araştırmanın verileri; araștırmacılar tarafindan literatür incelenerek olușturulan sağlık yöneticilerinin sosyodemografik özelliklerini, çalıșma ortamını, çalışma şekillerini, liderlik davranışlarını, iş stresi ve kriz yönetimi düzeylerini değerlendirmeye yönelik sorular sorular ile Liderlik Davranışları Olçeği ve Kriz Yönetimi Olçeğinden olușan anket yaklașık 20 dakika süre içinde uygulanmıstr. Verilerin analizinde frekans, ortalama, standart sapma, t testi, Mann Whitney U testi, ANOVA, Kruskal Wallisve korelasyon ve regresyon testleri kullanılmıştır. Tüm testlerde istatistiksel önem düzeyi 0.05 olarak alımıștır. 40 yaș ve üzeri, kadın, lisansüstü mezun, $ yildan daha fazla sūre yöneticilik yapan sağlıik yöneticilerinin destekleyici liderlik boyutu daha yüksek bulunmuştur. Mesleki deneyimi 5 yldan fazla olan sağhık yöneticilerinin kriz yönetimi uygulamaları daha yüksek saptanmıștır. Her iki ölçek arasındaki ilişki incelendiğinde; liderlik davranışları ölçeği araçsal liderlik alt boyutu ile kriz yönetimi ölçeği kriz sırası alt boyutu puanları arasinda zayıf düzeyde pozitif yönde anlamlı bir ilişki, bașarı yönelimli liderlik davranıșları ölçeği ile kriz yönetimi ölçeği kriz öncesi alt boyutu puanları arasında zayif důzeyde pozitif yönde anlamlı bir lişk bulunmuștur. Basit doğrusal regresyon analizinin sonuçlarina göre kriz yÖnetimini etkileyen tek liderlik davranıșı araçsal liderlik olarak saptanmıştır. Bu çalışmada Afrika Çad N'djamena Al-Nahda Hastanesi 'nde görev yapan sağlık yöneticilerinin liderlik davranışları ve kriz yönetimi uygulamaları yüksek düzeyde bulunmuştur.
Sportif faaliyetlerde görev alan afet profesyonellerinin iş stresi, iletişim becerisi ve empati düzeylerinin çeşitli değişkenlere göre incelenmesi
Amaç: Bu çalışma, sportif faaliyetlerde görev alan afet profesyonellerinin iş stresleri, iletişim becerileri ve empati düzeylerinin çeşitli değişkenlere göre incelenmesini amaçlamıştır. Yöntem: Çalışmaya 199'u erkek 23'ü kadın olmak üzere toplam 222 arama gönüllü kurtarma personeli dâhil edilmiştir. Katılımcıların demografik durumlarını saptamak için frekans analizi, yaş, cinsiyet, medeni durum ve eğitim durumu değişkenlerine göre iş streslerinin iletişim becerilerinin ve empati düzeylerinin karşılaştırılmasında Bağımsız Örneklem T-Testi uygulanmış olup; yaş değişkenine göre karşılaştırılmasında Tek Yönlü ANOVA analizi; farkın hangi gruplardan kaynaklandığını bulmak için de Tukey Testi uygulanmış aynı zamanda değişkenler arasında ki ilişkinin tespit edilesi için Pearson Korelasyon Testi uygulanmış ve anlamlılık düzeyi (p<0.05) alınmıştır. Bulgular: Katılımcıların iş stresleri, iletişim becerileri ve empati düzeyleri medeni durum göre incelendiğinde benmerkezci eğilim alt boyutunda istatistiksel olarak anlamlı farka rastlanılmıştır. Katılımcıların iş stresleri, iletişim becerileri ve empati düzeyleri eğitim durumlarına göre incelendiğinde stres ve iletişim becerileri alt boyutları toplam puanında istatiksel olarak anlamlı farklılık tespit edilmiştir. Katılımcıların cinsiyet ve yaş durumlarına göre iş stresleri, iletişim becerileri ve empati düzeyleri incelendiğinde ise istatistiksel olarak anlamlı farklılığa rastlanılmamıştır, stres ile empati düzeyleri arasında anlamlı ilişki yokken, iletişim becerileri ile stres arasında anlamlı ilişki tespit edilmiştir. Sonuç: Çalışmada bekar katılımcıların evli katılımcılara göre daha ben merkeziyetçi oldukları aynı zamanda katılımcıların eğitim durumlarına göre stres toplam puanlarının üniversite olan katılımcıların lehine anlamlı fark olduğu, iletişim toplam puanlarında ise lise mezunu katılımcıların üniversite mezunu katılımcılara göre anlamlı düzeyde daha fazla ortalamaya sahip oldukları görülmüştür. Sonuç olarak; sportif faaliyetlerde görev alan arama ve kurtarma personellerinin stresle başa çıkmaları, iletişim becerilerini etkin kullanmaları ve empati düzeylerinin yüksek olması başarıya ulaşmada kritik rol oynayabileceği söylenebilir. Anahtar Kelimeler: Arama Kurtarma, Empati Düzeyi, İletişim Becerisi, İş Stresi
Possible roles of histamine receptors and RhoA signalling pathways in blood-brain barrier
Blood-brain barrier (BBB) which creates a major obstacle for the transport of molecules into the brain can be opened by various treatments for effective drug delivery into the brain parenchyma, however its subsequent closure is also crucial to limit the detrimental alterations that can potentially occur in neuronal microenvironment by circulatory substances. In this study, we tested the efficacy of blocking histamine receptors (HRs) and RhoA in reversing histamine-induced BBB opening. Following intravenous histamine injection (10 mg/kg), mice were treated with HR antagonists, hydroxyzine (H1R, 3 mg/kg), cimetidine (H2R, 10 mg/kg), ciproxifan (H3R, 3 mg/kg) and JNJ-7777120 (H4R, 20 mg/kg), and Rho A inhibitor fasudil (10 mg/kg). Blood-brain barrier permeability to molecules with large and small molecular weights was evaluated by fluorescent detection of intravenously administered albumin-Alexa Fluor-594 (1%) and cadaverine Alexa-Flour-488 (1%), respectively in brain parenchyma. To analyze changes in the immunoreactivity of claudin-5 and caveolin-1 proteins, immunofluorescence staining was performed. The alterations in HR expression were detected by RT-PCR. Treatment with hydroxyzine significantly decreased fluorescence intensity of albumin-Alexa Fluor-594 in brain parenchyma following histamine-induced BBB opening (p<0.01), while there were no significant changes in the fluorescence intensity of cadaverine Alexa-Flour-488 by HR antagonists and fasudil in this setting. No significant changes were noted in HR mRNA and protein levels following administration of HR antagonists and fasudil to histamine-treated mice. Our results suggest that treatment with H1R antagonist hydroxyzine restores histamine-induced BBB disruption which emphasizes its potential use as a novel means of closing transiently opened BBB to protect the neuronal microenvironment against potentially toxic blood-borne substances in brain drug delivery applications.