EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line

Background: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes. Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy. Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels. Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process. Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases

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

Türkiye Romatizma Araştırma ve Savaş Derneği ankilozan spondilit ulusal tedavi önerileri

Objectives: To develop Turkish League Against Rheumatism (TLAR) National Recommendations for the management of ankylosing spondylitis (AS). Materials and methods: A scientific committee of 25 experts consisting of six rheumatologists and 19 physical medicine and rehabilitation specialists was formed by TLAR. Recommendations were based on the 2006 ASsessment in Ankylosing Spondylitis International Working Group(ASAS)/European League Against Rheumatism (EULAR) recommendations and a systematic review of associated publications between January 2005 and September 2010. A Delphi process was used to develop the recommendations. Twelve major recommendations were constructed for the management of AS. Voting using a numerical rating scale assessed the strength of each recommendation. Results: The 12 recommendations include patient assessment, patient follow-up along with pharmacological and non-pharmacological methods. Some minor additions and changes have been made to the ASAS/EULAR recommendations. All of the recommendations had sufficient strength. Conclusion: National recommendations for the management of AS were developed based on scientific evidence and consensus expert opinion. These recommendations will be updated regularly in accordance with recent developments.Türkiye Romatizma Araştırma ve Savaş Derneği᾽nin (TRASD) Ankilozan Spondilit (AS) için ulusal tedavi önerilerinin oluşturulmasıdır. Gereç ve yöntemler: TRASD tarafından altı Romatoloji ve 19 Fiziksel Tıp ve Rehabilitasyon uzmanı olmak üzere toplam 25 kişiden oluşan bir bilimsel kurul oluşturuldu. Önerilerde 2006 yılında yayınlanan Ankilozan Spondilit Değerlendirme Uluslararası Çalışma Grubu (ASAS)/Romatizmaya karşı Avrupa Ligi (EULAR) önerileri ve Ocak 2005 - Eylül 2010 arasında yayınlanmış olan ilişkili yayınlar konusundaki sistematik bir inceleme temel alındı. Öneriler oluşturulurken Delphi süreci kullanıldı. Ankilozan spondilit tedavisi ile ilgili 12 ana öneri oluşturuldu. Oylama yapılarak önerilerin güçlülük düzeyi bir nümerik derecelendirme skalası ile belirlendi. Bulgular: On iki öneri hasta değerlendirilmesini, hasta takibini ve farmakolojik ve non-farmakolojik yöntemleri içermektedir. ASAS/EULAR önerilerine bazı ilaveler ve önerilerde bazı küçük değişiklikler yapılmıştır. Tüm öneriler yeterli kuvvete sahipti. Sonuç: Bilimsel kanıtlar ve uzmanların görüş birliği ile AS tedavisine yönelik ulusal öneriler oluşturulmuştur. Bu öneriler, yeni gelişmeler doğrultusunda düzenli olarak güncellenmelidi

The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study

IntroductionElevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia.MethodsThis multi-center, prospective study enrolled patients aged 3–216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed.ResultsOverall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001).DiscussionQuestioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases. Trial RegistrationClinicaltrials.gov NCT04120168

Burkholderia Türlerinin Moleküler Yöntemlerle Tiplendirilmesi, Türler Arasında Biyofilm Oluşumu ve Antibiyotik Direnç Farklılığının Belirlenmesi.

The aim of this study was to identify Burkholderia spp. strains isolated from CF and non-CF patients with routine microbiological methods and multilocus sequence analysis (MLSA), to determine the antibiotic susceptibility and synergies, and to evaluate biofilm formation of these isolates. A total of 38 isolates from 26 patients identified as B. cenocepacia (n=16), B. contaminans (n=11), B. gladioli (n=4), B. dolosa (n=4), B. multivorans (n=2) and B. seminalis (n=1). Correct species-level identification of MALDI-TOF MS was 66%. Biofilm formation in these species was determined as 53% (n=20) and there was no statistical difference in biofilm production among Burkholderia species. Overall rates of susceptibility to ceftazidime, meropenem, TMP-SXT, and levofloxacin of the isolates was 66%, 34%, 50%and 60%, respectively. In antibiotic resistance against Burkholderia spp., isolates obtained from CF patients were more susceptible to ceftazidime, but no significant difference was found for other antibiotics. Synergy has shown between meropenem and TMP-SXT at two isolates. Antagonism has detected at 15 isolates, 12 of them were between meropenem and ceftazidime, three of them were between ceftazidime and TMP-SXT. This study identifies the distinctness of sequence types between Burkholderia spp. isolated from CF and non-CF patients provide a better understanding of the importance of biofilm formation for the infections with these bacteria and emphasize the management of therapy should be driven by the antibiotic test results.Çalışma Hacettepe Üniversitesi BAP Koordinasyon Birimi tarafından desteklenmiştir. Proje Kodu: THD-2016-10613 Öğrenci doktora eğitimi sırasında TÜBİTAK Bilim İnsanı Destek Programları Başkanlığı 2214-A kapsamında desteklenmiştir. Proje Kodu: 1059B141601066İÇİNDEKİLER ONAY SAYFASI iii YAYIMLAMA VE FİKRİ MÜLKİYET HAKLARI BEYANI iv ETİK BEYAN v TEŞEKKÜR vi ÖZET vii ABSTRACT viii İÇİNDEKİLER ix SİMGE VE KISALTMALAR xi ŞEKİLLER xii TABLOLAR xiii 1. GİRİŞ 1 2. GENEL BİLGİLER 3 2.1 Mikrobiyolojik Özellikler 3 2.2 Taksonomi 3 2.3 Epidemiyoloji 7 2.3.1 Tiplendirme 9 2.4 Patogenez 11 2.5 Klinik (KF ve Burkholderia) 15 2.6 Tanı 16 2.7 Antibiyotik Duyarlılık 21 2.7.1 Burkholderia Türlerinde Önerilen Antibiyotik Duyarlılık Yöntemi ve Kullanılan Antibiyotikler 23 2.7.2 Burkholderia Türlerinde Sinerji Testleri 24 2.7.3 Burkholderia Türlerinde Direnç Mekanizmaları 25 2.8 Tedavi 26 3. GEREÇ VE YÖNTEM 28 3.1 Bakteri İzolatları 28 3.2 Bakteri İzolatlarının Rutin Yöntemlerle Tanımlanması 28 3.3 Bakteri İzolatlarının Multilokus Sekans Analizi ile Tanımlanması 29 3.3.1 DNA İzolasyonu 29 3.3.2 Multilokus Sekans Tiplendirmesi (MLST) 30 3.4 Mikroplak Yöntemi ile Biyofilm Üretiminin Değerlendirilmesi 34 3.5 Sıvı Mikrodilüsyon Yöntemi ile Antibiyotik Duyarlılıklarının Değerlendirilmesi 35 3.6 Sinerji Testi ile Antibiyotik Kombinasyonlarının Duyarlılıklarının Değerlendirilmesi 38 3.7. İstatistiksel Analiz 40 4. BULGULAR 41 5. TARTIŞMA 53 6. SONUÇ VE ÖNERİLER 66 7. KAYNAKLAR 68 8. EKLER EK-1 Turnitin Orjinallik Raporu Dijital Makbuz EK-2 Turnitin Orjinallik Raporu Ekran Görüntüsü 9. ÖZGEÇMİŞBu çalışmada, kistik fibrozisli (KF) ve KF olmayan hastalardan izole edilen Burkholderia türlerinin rutin mikrobiyolojik yöntemler ve multilokus sekans analizi (MLSA) ile tanımlanması, biyofilm oluşumunun değerlendirilmesi, antibiyotik duyarlılıkları ve sinerjilerinin belirlenmesi amaçlanmıştır. Yirmialtı farklı hastaya ait 38 izolat B. cenocepacia (n:16), B. contaminans (n:11), B. gladioli (n: 4), B. dolosa (n:4), B. multivorans (n:2) ve B. seminalis (n:1) olarak belirlenmiştir. Tür düzeyinde MALDI-TOF MS ile doğru tanımlama %66 olarak bulunmuştur. Çalışılan izolatlarda biyofilm oluşumu %53 (n = 20) olarak belirlenmiş ve türler arasında anlamlı bir fark bulunmamıştır. İzolatların seftazidim, meropenem, TMP-SXT ve levofloksasine karşı duyarlılıkları sırasıyla %66, %34, %50 ve %60 olarak belirlenmiştir. Burkholderia türlerine karşı antibiyotik direncinde, KF hastalarından elde edilen izolatlar seftazidime daha duyarlı bulunmuş, diğer antibiyotikler için anlamlı fark saptanmamıştır. İki izolatta meropenem ve TMP-SXT arasında sinerji gözlenmiştir. Onbeş izolatta antagonizma tespit edilmiş, bunun 12’si meropenem ile seftazidim, 3’ü seftazidim ile TMP-SXT arasında bulunmuştur. Bu çalışma KF ve KF olmayan hastalarda izole edilen Burkholderia spp. sekans sonuçlarının farkını, biyofilm oluşumunun bu bakteri ile oluşan enfeksiyonlarda önemli olduğunu ve tedavinin in vitro antibiyotik duyarlılık test sonuçlarına göre değerlendirilmesi gerektiğini göstermiştir

Sosyoekonomik Gelişmişlik Sıralaması Araştırmaları (SEGE) Açısından İkinci Düzey Seçilmiş İlçelerin Deprem Sonrası Ekonomik ve Sosyal Analizi

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