Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.PoLiMeR Innovative Training Network ; SNIC ; ScandiBio Therapeutics ; ScandiBio Therapeutics and Knut ; Knut och Alice Wallenbergs Stiftels

Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial

Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered\ua0combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35\ua0g L-serine (61.75%), 1\ua0g nicotinamide riboside (5%), 2.55\ua0g\ua0N-acetyl-L-cysteine (12.75%), and 3.73\ua0g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28\ua0days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the\ua0CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration\ua0ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Exploring the predictors of doctoral students academic satisfaction

During last decade, doctoral education has been an issue of investigation and reform in response to several challenges. In United States, drop-out rates have been reported to be really high; i.e., about half does not persist to graduation (Bair & Haworth, 2004). The European Union changed the higher education agenda “to make Europe the most competitive and dynamic knowledge-based economy in the world” (Kehm, 2006, p. 67). In addition, the number of doctoral students has been observed to increase significantly within the last 10-15 years. Considering these issues and relationship between student satisfaction and completion of doctoral degree (Lovitts, 1996), investigating factors associated with academic satisfaction of doctoral students seems crucial to keep those students in the program. In contrast to widespread use of “master-apprentice model” in Europe (Kehm, 2006), more structured doctoral programs are present in Turkey. The current study investigated the contribution of different components of doctoral education to academic satisfaction. The findings regarding “what makes a difference” would provide implications for stakeholders to design and employ best practices of doctoral education. There is some evidence in the literature indicating that several personal and institutional factors contribute to the academic satisfaction (Bair & Haworth, 2004; Danielson, 1998). For example, the coursework is a common feature of structured doctoral programs. The more students perceive the coursework to be of high quality and value, the more satisfied they are with the program (Valentine, 1987). Meyers et al. (2000) found that coursework provided good foundation for students’ postdoctoral careers, as well. The advisor-advisee relationship is another important aspect of graduate education. The answer to the question of what makes a good advisor varies greatly in the literature. Bloom et al. (2007) found that effective advisor characteristics are care for students, accessibility, being role models both professionally and personally, individually tailored guidance, and engagement of students into the profession. Cronan-Hillix et al. (1986) reported the characteristics as interested, supportive, knowledgeable, and competent. Moreover, Offstein et al. (2004) found that supporter role of advisor results in satisfaction of graduate students and also were associated with positive consequences. There are some early studies showing contribution of the faculty-student relationship to job satisfaction (Levine & Weitz, 1968) and academic satisfaction (Gregg, 1972). Furthermore, Cropanzano et al. (1997) stated that administrator’s help in organizations to fulfill the needs of graduate students leads to improve their performance. In that sense, participative policy is considered to enhance communication among faculty and administrators resulting in better quality of education (Conway, 1984). Financial problems play an important role in satisfaction, as well. Working at a job outside of the school creates a disadvantage for students by limiting the time for studies. Most of the doctoral students complain about the lack of time to make research. Accordingly, Güven and Tunç (2007) found that financial problems affect the research productivity of the doctoral students. Graduate students are expected to conduct research studies and attend academic meetings in their field (Ku et al., 2008). However, these necessitate enough time, money, and technological resources

Ramazan Güvenlioğlu ve ailesinin Yugoslavya'dan Türkiye'ye göçü

Ankara : İhsan Doğramacı Bilkent Üniversitesi İktisadi, İdari ve Sosyal Bilimler Fakültesi, Tarih Bölümü, 2015.This work is a student project of the The Department of History, Faculty of Economics, Administrative and Social Sciences, İhsan Doğramacı Bilkent University.by Öztürk, İbrahim Mert

Dersim’den Çorum’a yapılan göçler

Ankara : İhsan Doğramacı Bilkent Üniversitesi İktisadi, İdari ve Sosyal Bilimler Fakültesi, Tarih Bölümü, 2015.This work is a student project of the The Department of History, Faculty of Economics, Administrative and Social Sciences, İhsan Doğramacı Bilkent University.by Ünsal, Mehmet Süha

Sjögren sendromu ile birlikteliği olan eritem annüler santrifüj tanılı bir olgu

Erythema annulare centrifigum is a dermatose which is frequently seen in adults. It is characterized by erythematous lesions which spread asymmetrically to periphery and have a collarette desquamation. Although infection, tumor, food allergy, drug reaction can play a role in the aetiology, most of the cases are idiopathic. A forty-nine years old, female patient presented to our clinic with erythematous lesions on both of her lower extremities. Six weeks prior to her referral, she treated with quinine for Sjogren syndrome. She had a diagnosis of granuloma annulare in her personal history. There was no significance in her family history. in dermatologic examination; annular erythematous plaques and collarette desquamation were detected on lower extremities. Histopathologic examination of the lesional biopsy specimen revealed focal spongiosis in the epidermis, dermal oedema, vascular proliferation and perivascular infiltration of lymphocytes, eosinophils and histiocytes. in the laboratory examination; blood count, liver and kidney function tests, sedimentation, C-reactive protein was normal. Rheumatoid factor was 30. Antinuclear antibody was 1/640 granular pattern. A case of erythema annulare centrifigum with Sjögren Syndrome is discussed with the other skin findings of the disease.Eritem anüler santrifüj sıklıkla yetişkinlerde görülen eritemli bir dermatozdur. Perifere doğru asimetrik genişleyen ve pitriyazik skuamın eşlik ettiği eritematöz lezyonlar şeklinde görülür. Etyolojide infeksiyon, tümör, besin alerjisi, ilaç reaksiyonu olabilmekle birlikte, çoğu olgu idyopatiktir. Kırk dokuz yaşında kadın hasta, her iki bacak ve kollarda on beş gün önce oluşan kızarıklık şikayeti ile başvurdu. Özgeçmişinde bir buçuk ay önce tanı konan Sjögren Sendromu ve kinin tablet kullanma öyküsü yanı sıra geçirilmiş granulom anüler tanısı vardı. Soygeçmişinde özellik yoktu. Dermatolojik muayenesinde, her iki bacakta ve kolda ortası daha soluk, periferinde yakalık tarzında deskuamasyon gözlenen eritemli plakları mevcuttu. Lezyonlardan alınan biyopsinin histopatolojik incelemesinde, epidermiste fokal spongiyoz, yüzeyel dermada ödem, damar proliferasyonu ve perivasküler lenfosit ve histiyositlerden zengin eozinofillerin eşlik ettiği manşon tarzında yangısal hücre infiltrasyonu gözlendi. Yapılan tetkiklerinde hemogram, karaciğer fonksiyon testleri, böbrek fonksiyon testleri, sedimentasyon, C-reaktif protein normal değerlerde idi. Romatoid faktör 30, antinükleer antikor 1/640 granüler olarak saptandı. Sjögren Sendromu ile birlikteliği olan eritem anüler santrifüj tanılı olgu, sendromun diğer deri bulguları ile birlikte tartışılmaktadır