49 results on '"Cetin, Hakan"'
Search Results
2. Clinical heterogeneity within the ALS‐FTD spectrum in a family with a homozygous optineurin mutation.
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Parvizi, Tandis, Klotz, Sigrid, Keritam, Omar, Caliskan, Haluk, Imhof, Sophie, König, Theresa, Haider, Lukas, Traub‐Weidinger, Tatjana, Wagner, Matias, Brunet, Theresa, Brugger, Melanie, Zimprich, Alexander, Rath, Jakob, Stögmann, Elisabeth, Gelpi, Ellen, and Cetin, Hakan
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FRAMESHIFT mutation ,AUTOPSY ,AMYOTROPHIC lateral sclerosis ,DNA-binding proteins ,MOTOR neurons ,CHRONIC traumatic encephalopathy ,FRONTOTEMPORAL lobar degeneration - Abstract
Objective: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA‐binding protein 43 kDa (TDP‐43) pathology, in addition to accumulations of tau and alpha‐synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. Methods: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole‐exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. Results: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS‐FTLD pattern associated with prominent neuronal and oligodendroglial TDP‐43 pathology, and an atypical limbic 4‐repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). Interpretation: OPTN mutations can be associated with extensive TDP‐43 pathology and limbic‐predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS‐FTD spectrum within the same family. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.
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Krenn, Martin, Wagner, Matias, Zulehner, Gudrun, Weng, Rosa, Jäger, Fiona, Keritam, Omar, Sener, Merve, Brücke, Christof, Milenkovic, Ivan, Langer, Agnes, Buchinger, Dominic, Habersam, Richard, Mayerhanser, Katharina, Brugger, Melanie, Brunet, Theresa, Jacob, Maureen, Graf, Elisabeth, Berutti, Riccardo, Cetin, Hakan, and Hoefele, Julia
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NEUROMUSCULAR diseases ,MOLECULAR diagnosis ,NUCLEOTIDE sequencing ,GENETIC testing ,GENETIC disorder diagnosis - Abstract
Background: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes. Methods: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis. Results: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21–0.82), while a positive family history (OR 5.46; 95%CI 2.60–11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11–7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies. Conclusion: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Comparison of five different fluoroscopic methods for identifying the MPFL femoral footprint.
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Emre, Tuluhan Yunus, Cetin, Hakan, Selcuk, Huseyin, Kilic, Koray Kaya, Aykanat, Faruk, Sarikcioglu, Levent, and Kose, Ozkan
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FLUOROSCOPY ,LIGAMENTS ,FEMUR - Abstract
Purpose: The success of medial patellofemoral ligament (MPFL) reconstruction is closely linked to the precise positioning of the femoral tunnel. Intraoperative fluoroscopy is commonly utilized to identify the MPFL footprint. This study aimed to ascertain the most accurate fluoroscopic method among the five previously described methods used to determine the MPFL femoral footprint. Materials and methods: Using 44 well-preserved dry femur bones, the MPFL femoral insertion site was demarcated using anatomical bony landmarks, namely the center of the saddle sulcus between the medial epicondyle, adductor tubercle and gastrocnemius tubercle. Fluoroscopic true lateral knee images were acquired and measurements taken, referencing established methods by Schottle et al., Redfern et al., Wijdicks et al., Barnett et al., and Kaipel et al. The distance between anatomic and fluoroscopic MPFL footprints was then measured on digital fluoroscopic images. The accuracy of the locations was compared using a margin of error of 5 and 7 mm. Results: The Schottle method consistently emerged superior, showcasing the smallest mean distance (3.2 ± 1.2 mm) between the anatomic and radiographic MPFL footprints and a high in-point detection rate of 90.9% under 5 mm criteria. While the Redfern method displayed perfect accuracy (100%) within the 7 mm criteria, the Schottle method also performed 97.7% accuracy. Conclusions: For intraoperative identification of the MPFL footprint using fluoroscopy, the Schottle method is the most consistent and accurate among the assessed methods. Thus, its accuracy in detecting the MPFL footprint makes it recommended for MPFLR to ensure optimal outcomes. Level of evidence: Level IV, cadaveric study. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Multifocal motor neuropathy as a mimic of amyotrophic lateral sclerosis: Serum neurofilament light chain as a reliable diagnostic biomarker.
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Kleinveld, Vera E. A., Keritam, Omar, Horlings, Corinne G. C., Cetin, Hakan, Wanschitz, Julia, Hotter, Anna, Zirch, Laura S., Zimprich, Fritz, Topakian, Raffi, Müller, Petra, Oel, Dierk, Quasthoff, Stefan, Erdler, Marcus, Rauschka, Helmut, Grinzinger, Susanne, Jecel, Julia, Gaulhofer, Petra, Castek, Barbara, Stadler, Klaus, and Löscher, Wolfgang N.
- Abstract
Introduction/Aims: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS. Methods: NfL was measured in serum in n = 37 patients with MMN and n = 37 age‐ and sex‐matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling. Results: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p <.01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963–1.000], sensitivity 94.6%, specificity 100%, cut‐off 44.00 pg/mL). Discussion: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Anti-Inflammatory and Antipruritic Effects of Remote Ischaemic Postconditioning in a Mouse Model of Experimental Allergic Contact Dermatitis.
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Gunduz, Ozgur, Sapmaz-Metin, Melike, Topuz, Ruhan Deniz, Kaya, Oktay, Karadag, Cetin Hakan, and Ulugol, Ahmet
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CONTACT dermatitis ,ISCHEMIC postconditioning ,LABORATORY mice ,ISCHEMIC preconditioning ,T cells ,ALLERGIC conjunctivitis - Abstract
Background and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4
+ and CD8+ T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8+ T lymphocyte and neutrophil infiltration and reducing IL-17 secretion. [ABSTRACT FROM AUTHOR]- Published
- 2023
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7. A homozygous AP3D1 missense variant in patients with sensorineural hearing loss as the leading manifestation.
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Frohne, Alexandra, Koenighofer, Martin, Cetin, Hakan, Nieratschker, Michael, Liu, David T., Laccone, Franco, Neesen, Juergen, Nemec, Stefan F., Schwarz-Nemec, Ursula, Schoefer, Christian, Avraham, Karen B., Frei, Klemens, Grabmeier-Pfistershammer, Katharina, Kratzer, Bernhard, Schmetterer, Klaus, Pickl, Winfried F., and Parzefall, Thomas
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MISSENSE mutation ,SENSORINEURAL hearing loss ,PREMATURE ovarian failure ,HEARING disorders ,PROTEIN-protein interactions - Abstract
Loss-of-function variants in AP3D1 have been linked to Hermansky–Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein–protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Analysis of co‐medication in people with dementia.
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Wurm, Raphael, Parvizi, Tandis, Goeschl, Stella, Untersteiner, Helena, Silvaieh, Sara, Stamm, Tanja, Cetin, Hakan, Reichardt, Berthold, and Stögmann, Elisabeth
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DEMENTIA ,DEMENTIA patients ,DATABASES ,HYPERLIPIDEMIA ,CASE-control method ,VASCULAR dementia - Abstract
Background and purpose: Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case–control study, we analysed a large population‐based prescription database to explore the patterns of co‐medication in patients with dementia. Methods: Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co‐medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow‐up duration as a control. Results: We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co‐medications while control patients were treated with a total of 5.2 co‐medications (p < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; p < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co‐medications was associated with markers of more intensive antidementia treatment. Conclusion: Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life. [ABSTRACT FROM AUTHOR]
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- 2023
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9. The diagnostic and prognostic utility of repetitive nerve stimulation in patients with myasthenia gravis.
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Tomschik, Matthias, Renaud, Eva, Jäger, Fiona, Paternostro, Chiara, Rath, Jakob, Rinner, Walter, Zulehner, Gudrun, Zimprich, Fritz, and Cetin, Hakan
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MYASTHENIA gravis ,NEURAL stimulation ,ACTION potentials ,CHOLINERGIC receptors ,MEDICAL records ,NURSES - Abstract
Repetitive nerve stimulation (RNS) is a standard test for the diagnosis of myasthenia gravis (MG), where decrement of compound muscle action potentials (CMAP) corresponds to clinical muscle fatigability. Our aim was to ascertain the diagnostic and prognostic utility of RNS in MG patients. This study included MG patients treated between 01/2000 and 12/2016, with an observational period of at least one year and a minimum of two neurological examinations. Clinical and electrophysiological data were retrospectively gathered from patient records, and CMAP decrement was correlated with autoantibody titers and clinical disease severity at different time points. Ninety-four patients were included, with 88.3% of the cohort testing positive for acetylcholine receptor autoantibodies (AChR-Abs). RNS sensitivity was higher in patients with generalized disease (71.6%) than in purely ocular MG (38.5%). CMAP decrement did not significantly correlate with AChR-Ab titers, nor with clinical symptom severity at the time of testing or last follow up. However, there was a significant correlation between CMAP decrement and the worst recorded clinical status on a group level. RNS testing is more sensitive in generalized disease and AChR-Ab positive patients, but our data do not support RNS as a tool for long-term outcome prediction. Future studies with a prospective study design could help to overcome a number of limiting factors discussed in our study. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Noise analysis of mode matched vibratory gyroscopes.
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Cetin, Hakan and Yaralioglu, Goksenin
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GYROSCOPES ,SMART devices ,NOISE ,SMARTPHONES ,RANDOM walks ,ROTATIONAL motion ,CORIOLIS force - Abstract
MEMS (micro-electromechanical system) vibratory gyroscopes have attracted a lot of interest recently and these gyroscopes made their way through portable devices and smart phones. However, their performance is not enough to cope with the demanding requirements of applications such as dead reckoning. Mode-matched gyroscopes can be a solution for this problem. Various mode-matched gyroscope architectures have been proposed and their noise performances have been analyzed in detail. However, in most of these analyses zero-rate output was considered and the noise analysis for dynamic cases were ignored. In this paper, we demonstrate the noise analysis of mode-matched vibratory gyroscope using the power spectral density (PSD) and the Allan deviation methods while in rotation. We show that for mode-matched gyros the noise performance of a rotating gyro can be significantly different from that of a gyro that does not experience any rotation. We also show that this difference is due to the coupling between the drive and sense systems via Coriolis force. This sets a fundamental limit for the noise performance of mode-matched vibratory gyroscopes where ARW (angle random walk) increases proportionally with the rotation rate for the open loop and the force to rebalance operation modes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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11. A case of primary optic pathway demyelination caused by oncocytic oligodendrogliopathy of unknown origin.
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Hametner, Simon, Silvaieh, Sara, Thurnher, Majda, Dal-Bianco, Assunta, Cetin, Hakan, Ponleitner, Markus, Zebenholzer, Karin, Pemp, Berthold, Trattnig, Siegfried, Rössler, Karl, Berger, Thomas, Lassmann, Hans, Hainfellner, Johannes A., and Bsteh, Gabriel
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VISUAL evoked potentials ,DEMYELINATION ,MAGNETIC resonance imaging ,WHITE matter (Nerve tissue) ,MULTIPLE sclerosis ,OLIGODENDROGLIA - Abstract
We report the case of a 22-year-old woman presenting with an acute onset of dizziness, gait dysbalance and blurred vision. Magnetic resonance imaging included 3 Tesla and 7 Tesla imaging and revealed a T2-hyperintense, T1-hypointense, non-contrast-enhancing lesion strictly confined to the white matter affecting the right optic radiation. An extensive ophthalmologic examination yielded mild quadrantanopia but no signs of optic neuropathy. The lesion was biopsied. The neuropathological evaluation revealed a demyelinating lesion with marked tissue vacuolization and granular myelin disintegration accompanied by mild T cell infiltration and a notable absence of myelin uptake by macrophages. Oligodendrocytes were strikingly enlarged, displaying oncocytic characteristics and showed cytoplasmic accumulation of mitochondria, which had mildly abnormal morphology on electron microscopy. The diagnosis of multiple sclerosis was excluded. Harding's disease, a variant of Leber's hereditary optic neuropathy, was then suspected. However, neither PCR for relevant mutations nor whole exome sequencing yielded known pathogenetic mutations in the patient's genome. We present a pattern of demyelinating tissue injury of unknown etiology with an oncocytic change of oligodendrocytes and a lack of adequate phagocytic response by macrophages, which to the best of our knowledge, has not been described before. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Clinical trials in pediatric ALS: a TRICALS feasibility study.
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Kliest, Tessa, Van Eijk, Ruben P.A., Al-Chalabi, Ammar, Albanese, Alberto, Andersen, Peter M., Amador, Maria Del Mar, BrÅthen, Geir, Brunaud-Danel, Veronique, Brylev, Lev, Camu, William, De Carvalho, Mamede, Cereda, Cristina, Cetin, Hakan, Chaverri, Delia, Chiò, Adriano, Corcia, Philippe, Couratier, Philippe, De Marchi, Fabiola, Desnuelle, Claude, and Van Es, Michael A.
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CLINICAL trials ,AMYOTROPHIC lateral sclerosis ,FEASIBILITY studies ,CHILD patients ,PEDIATRIC therapy - Abstract
Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Muscle involvement in T-cell large granular lymphocytic leukemia presenting with asymmetric limb-girdle weakness and scapular winging.
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Krenn, Martin, Gelpi, Ellen, Simonitsch‐Klupp, Ingrid, Kasprian, Gregor, Zulehner, Gudun, Grisold, Anna, Zimprich, Fritz, Cetin, Hakan, Hülsmann, Martin, Wohlfarth, Philipp, and Simonitsch-Klupp, Ingrid
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- 2022
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14. Three novel FHL1 variants cause a mild phenotype of Emery‐Dreifuss muscular dystrophy.
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Borch, Josefine d. S., Krag, Thomas, Holm‐Yildiz, Sonja D., Cetin, Hakan, Solheim, Tuva A., Fornander, Freja, Straub, Volker, Duno, Morten, and Vissing, John
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Emery‐Dreifuss muscular dystrophy (EDMD) is a hereditary muscle disease, characterized by the clinical triade of early‐onset joint contractures, progressive muscle weakness, and cardiac involvement. Pathogenic variants in FHL1 can cause a rare X‐linked recessive form of EDMD, type 6. We report three men with novel variants in FHL1 leading to EDMD6. The onset of muscle symptoms was in late adulthood and muscle weakness was not prominent in either of the patients. All patients had hypertrophic cardiomyopathy and one of them also had cardiac arrhythmias. Western blot performed on muscle biopsies from two of the patients showed no FHL1 protein expression. We predict that the variant in the third patient also leads to the absence of FHL1 protein. Complete loss of all FHL1 isoforms combined with mild muscle involvement supports the hypothesis that loss of all FHL1 isoforms is more benign than the cytotoxic effects of expressed FHL1 protein with pathogenic missense variants. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Short‐term and sustained clinical response following thymectomy in patients with myasthenia gravis.
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Rath, Jakob, Taborsky, Manuela, Moser, Bernhard, Zulehner, Gudrun, Weng, Rosa, Krenn, Martin, Cetin, Hakan, Matilla, José Ramon, Müllauer, Leonhard, and Zimprich, Fritz
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THYMECTOMY ,MYASTHENIA gravis ,PROPORTIONAL hazards models ,CHOLINERGIC receptors ,PATIENT selection - Abstract
Background and purpose: This study was undertaken to investigate short‐ and long‐term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR‐Ab)‐positive myasthenia gravis (MG). Methods: Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow‐up. Clinical factors associated with achieving an initial or a sustained response were analyzed. Results: Ninety‐four patients with a median age of 33 years (interquartile range [IQR] = 22–51), 68% with nonthymomatous MG and 32% with thymoma‐associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long‐term follow‐up (median = 89.5 months, IQR = 46–189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy (n = 24), a high AChR‐Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response (p = 0.03). Conclusions: Sustained long‐term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR‐Abs after surgery appears to be a promising prognostic marker. [ABSTRACT FROM AUTHOR]
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- 2022
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16. A systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmunity.
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Panhuber, Anja, Lamorte, Giovanni, Bruno, Veronica, Cetin, Hakan, Bauer, Wolfgang, Höftberger, Romana, Erber, Astrid C., Frommlet, Florian, and Koneczny, Inga
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THROMBOTIC thrombocytopenic purpura ,AUTOIMMUNITY ,HLA histocompatibility antigens ,HAPLOTYPES ,PEMPHIGUS vulgaris - Abstract
Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case–control studies on IgG4-AID based on MOOSE/ HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44–5.9; p < 0.00001; A: OR 2.54; 95% CI 1.82–3.55; p < 0.00001) and HLA-DRB1*14 (G: OR 4.31; 95% CI 2.82–6.59; p < 0.00001; A: OR 4.78; 95% CI 3.52–6.49; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (OR 6.3; 95% CI 3.28–12.09; p < 0.00001/OR 4.98; 95% CI 3.8–6.53; p < 0.00001) were increased while HLA-DRB1*13 (G: OR 0.48; 95% CI 0.34–0.68; p < 0.0001; A: OR 0.46; 95% CI 0.34–0.62; p < 0.00001) was decreased in IgG4-AID patients. In conclusion, the HLA-DQB1*05, HLA-DRB1*14 alleles and the HLA-DQB1*05-DRB1*14 haplotype could be genetic risk factors that predispose for the production of pathogenic IgG4 autoantibodies and the HLA-DRB1*13 allele may protect from IgG4 autoimmunity. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Real-world treatment of adult patients with Guillain-Barré syndrome over the last two decades.
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Rath, Jakob, Zulehner, Gudrun, Schober, Bernadette, Grisold, Anna, Krenn, Martin, Cetin, Hakan, and Zimprich, Fritz
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ADULTS ,GUILLAIN-Barre syndrome ,INTRAVENOUS immunoglobulins ,DIAGNOSIS ,DISABILITIES - Abstract
This study investigated treatment characteristics of Guillain-Barré syndrome (GBS) in a real-world setting between 2000 and 2019. We analyzed clinical improvement between nadir and last follow-up in patients with severe GBS (defined as having a GBS disability scale > 2 at nadir) and aimed to detect clinical factors associated with multiple treatments. We included 121 patients (74 male; median age 48 [IQR 35–60]) with sensorimotor (63%), pure motor (15%), pure sensory (10%) and localized GBS (6%) as well as Miller Fisher syndrome (6%). 44% of patients were severely affected. All but one patient received at least one immunomodulatory treatment with initially either intravenous immunoglobulins (88%), plasma exchange (10%) or corticosteroids (1%), and 25% of patients received more than one treatment. Severe GBS but not age, sex, GBS subtype or date of diagnosis was associated with higher odds to receive more than one treatment (OR 4.22; 95%CI 1.36–13.10; p = 0.01). Receiving multiple treatments had no adjusted effect (OR 1.30, 95%CI 0.31–5.40, p = 0.72) on clinical improvement between nadir and last follow-up in patients with severe GBS. This treatment practice did not change over the last 20 years. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Cerebrospinal fluid analysis in Guillain–Barré syndrome: value of albumin quotients.
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Rath, Jakob, Zulehner, Gudrun, Schober, Bernadette, Grisold, Anna, Krenn, Martin, Cetin, Hakan, and Zimprich, Fritz
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CEREBROSPINAL fluid examination ,GUILLAIN-Barre syndrome ,ALBUMINS ,CEREBROSPINAL fluid ,LOGISTIC regression analysis - Abstract
Background: Albuminocytologic dissociation in cerebrospinal fluid (CSF) is a diagnostic hallmark of Guillain–Barré syndrome (GBS). Compared to CSF total protein (TP), the CSF/serum albumin quotient (Qalb) has the advantage of method-independent reference ranges. Whether the diagnostic yield differs between Qalb and CSF-TP is currently unknown. Methods: We retrospectively analyzed the diagnostic yield (i.e., a value above the URL indicating blood–nerve barrier dysfunction) of Qalb and CSF-TP levels in patients with GBS. We evaluated two different equations (Reiber's and Hegen's) for age-adjusted URLs of Qalb and compared results to CSF-TP using the standard URL of 0.45 g/L as well as age-adjusted URLs (by decade of age). Additionally, multivariable logistic regression analysis was used to assess the effect of clinical factors on the diagnostic yield. Results: We analyzed 110 patients [62% males; median age 48 (IQR 35–58)] with sensorimotor (68), motor (16), sensory (12) and localized (8) GBS as well as Miller Fisher syndrome (6). Qalb and CSF-TP were highly correlated (r = 0.95, p < 0.001). The diagnostic yield of Qalb was 65% with Reiber's and 47% with Hegen's age-adjusted URLs compared to 66% with the fixed CSF-TP URL of 0.45 g/L and 49% with age-adjusted CSF-TP URLs. A longer duration from clinical onset to lumbar puncture was associated with a higher diagnostic yield. Conclusion: Qalb strongly correlates with CSF-TP in patients with GBS with a similar diagnostic yield for the detection of a blood–nerve barrier dysfunction. However, the diagnostic yield of both values is lower when using more recent age-adjusted URLs and at earlier timepoints. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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19. Flexural wave-based soft attractor walls for trapping microparticles and cells.
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Aghakhani, Amirreza, Cetin, Hakan, Erkoc, Pelin, Tombak, Guney Isik, and Sitti, Metin
- Abstract
Acoustic manipulation of microparticles and cells, called acoustophoresis, inside microfluidic systems has significant potential in biomedical applications. In particular, using acoustic radiation force to push microscopic objects toward the wall surfaces has an important role in enhancing immunoassays, particle sensors, and recently microrobotics. In this paper, we report a flexural-wave based acoustofluidic system for trapping micron-sized particles and cells at the soft wall boundaries. By exciting a standard microscope glass slide (1 mm thick) at its resonance frequencies <200 kHz, we show the wall-trapping action in sub-millimeter-size rectangular and circular cross-sectional channels. For such low-frequency excitation, the acoustic wavelength can range from 10–150 times the microchannel width, enabling a wide design space for choosing the channel width and position on the substrate. Using the system-level acousto-structural simulations, we confirm the acoustophoretic motion of particles near the walls, which is governed by the competing acoustic radiation and streaming forces. Finally, we investigate the performance of the wall-trapping acoustofluidic setup in attracting the motile cells, such as Chlamydomonas reinhardtii microalgae, toward the soft boundaries. Furthermore, the rotation of microalgae at the sidewalls and trap-escape events under pulsed ultrasound are demonstrated. The flexural-wave driven acoustofluidic system described here provides a biocompatible, versatile, and label-free approach to attract particles and cells toward the soft walls. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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20. BIM Dimensions and Application Areas for Enhancing Sustainability and Affordability of Affordable Housing: As a Key for Effective Housing Policies.
- Author
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Sertyesilisik, Begum, Sertyesilisik, Egemen, Cetin, Hakan Taha, and Ocakoglu, Emre
- Subjects
SUSTAINABILITY ,HOUSING policy ,LIFE cycle costing ,HOUSING ,ECOLOGICAL houses ,BUILDING information modeling ,FACILITY management - Abstract
Affordable housing plays a key role in well-being and sustainable development. The energy efficiency and sustainability performance of these houses support environmental sustainability and reduce their operational cost and energy consumption. Furthermore, enhanced energy efficiency is a significant factor in affordable houses in the fight against fuel poverty. This paper underlines the importance of sustainable affordable houses for reduced life cycle costs and enhanced welfare and well-being of its residents. Based on an in-depth literature review, considering the entire life cycle of affordable houses, this paper aims to investigate usage of all BIM dimensions and their application areas for enhancing sustainability and affordability of affordable housing as a key for effective housing policies. The integrated usage of Building Information Modelling (BIM) and energy simulation software has the potential to add value to the affordable houses as this integration supports energy savings and enhanced sustainability performance throughout the building's life-cycle. This paper highlights BIM's usage for energy and facility management. Furthermore, this paper emphasises the importance of the policies for effective solutions to the housing problem and recommends holistic policies based on a systematic and interdisciplinary approach to the housing problem. This paper highlights the political economy of affordable housing policies and suggests affordable housing policies request usage of BIM throughout the entire life cycle of affordable houses. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. Subgroup stratification and outcome in recently diagnosed generalized myasthenia gravis.
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Tomschik, Matthias, Hilger, Eva, Rath, Jakob, Mayer, Eva-Maria, Fahrner, Michael, Cetin, Hakan, Löscher, Wolfgang N., and Zimprich, Fritz
- Published
- 2020
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22. The Structure, Function, and Physiology of the Fetal and Adult Acetylcholine Receptor in Muscle.
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Cetin, Hakan, Beeson, David, Vincent, Angela, and Webster, Richard
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CHOLINERGIC receptors ,FETAL physiology ,CONGENITAL myasthenic syndromes ,NICOTINIC acetylcholine receptors ,MYONEURAL junction - Abstract
The neuromuscular junction (NMJ) is a highly developed synapse linking motor neuron activity with muscle contraction. A complex of molecular cascades together with the specialized NMJ architecture ensures that each action potential arriving at the motor nerve terminal is translated into an action potential in the muscle fiber. The muscle-type nicotinic acetylcholine receptor (AChR) is a key molecular component located at the postsynaptic muscle membrane responsible for the generation of the endplate potential (EPP), which usually exceeds the threshold potential necessary to activate voltage-gated sodium channels and triggers a muscle action potential. Two AChR isoforms are found in mammalian muscle. The fetal isoform is present in prenatal stages and is involved in the development of the neuromuscular system whereas the adult isoform prevails thereafter, except after denervation when the fetal form is re-expressed throughout the muscle. This review will summarize the structural and functional differences between the two isoforms and outline congenital and autoimmune myasthenic syndromes that involve the isoform specific AChR subunits. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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23. Pathomechanisms and Clinical Implications of Myasthenic Syndromes Exacerbated and Induced by Medical Treatments.
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Krenn, Martin, Grisold, Anna, Wohlfarth, Philipp, Rath, Jakob, Cetin, Hakan, Koneczny, Inga, and Zimprich, Fritz
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MYASTHENIA gravis ,THERAPEUTICS ,IMMUNE checkpoint inhibitors ,MUSCLE weakness ,TREATMENT effectiveness ,MYONEURAL junction - Abstract
Myasthenic syndromes are typically characterized by muscle weakness and increased fatigability due to an impaired transmission at the neuromuscular junction (NMJ). Most cases are caused by acquired autoimmune conditions such as myasthenia gravis (MG), typically with antibodies against the acetylcholine receptor (AChR). Different drugs are among the major factors that may complicate pre-existing autoimmune myasthenic conditions by further impairing transmission at the NMJ. Some clinical observations are substantiated by experimental data, indicating that presynaptic, postsynaptic or more complex pathomechanisms at the NMJ may be involved, depending on the individual compound. Most robust data exist for the risks associated with some antibiotics (e.g., aminoglycosides, ketolides, fluoroquinolones) and cardiovascular medications (e.g., class Ia antiarrhythmics, beta blockers). Apart from primarily autoimmune-mediated disorders of the NMJ, de novo myasthenic manifestations may also be triggered by medical treatments that induce an autoimmune reaction. Most notably, there is growing evidence that the immune checkpoint inhibitors (ICI), a modern class of drugs to treat various malignancies, represent a relevant risk factor to develop severe and progressive medication-induced myasthenia via an immune-mediated mechanism. From a clinical perspective, it is of utmost importance for the treating physicians to be aware of such adverse treatment effects and their consequences. In this article, we aim to summarize existing evidence regarding the key molecular and immunological mechanisms as well as the clinical implications of medication-aggravated and medication-induced myasthenic syndromes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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24. No association between proton pump inhibitor use and ALS risk: a nationwide nested case–control study.
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Cetin, Hakan, Sun, Jiangwei, Almqvist, Catarina, Reichardt, Berthold, Tomschik, Matthias, Zimprich, Fritz, Fang, Fang, and Ingre, Caroline
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PROTON pump inhibitors ,NEURODEGENERATION ,AMYOTROPHIC lateral sclerosis ,GENE expression ,LOGISTIC regression analysis - Abstract
The use of proton pump inhibitors (PPIs) has been proposed as a potential risk factor for neurodegenerative diseases, but little is known regarding its role in amyotrophic lateral sclerosis (ALS). We therefore aimed to assess the association of PPI use with the subsequent risk of ALS, and performed a register-based nationwide nested case–control study, including 2,484 ALS cases diagnosed during July 2006–December 2013 in Sweden and 10 population controls per case that were individually matched to the case by sex, age, and area of residence. Dispenses and cumulative defined daily doses (cDDDs) of PPIs were extracted from the Swedish Prescribed Drug Register. The association of PPI use with the risk of ALS was assessed using conditional logistic regression, after applying different lag windows to avoid reverse causation. ALS patients were more likely to be dispensed with PPIs before diagnosis than controls. However, previous PPI use was not associated with an increased risk of ALS (OR = 1.08, 95% CI 0.97–1.19), and there was no dose–response relationship between cDDDs of PPIs and ALS risk (p = 0.0874), after excluding dispenses during the year before ALS diagnosis. The results were similar after excluding dispenses during the 2 or 3 years before ALS diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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25. The role of gut microbiota, butyrate and proton pump inhibitors in amyotrophic lateral sclerosis: a systematic review.
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Erber, Astrid C., Cetin, Hakan, Berry, David, and Schernhammer, Eva S.
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AMYOTROPHIC lateral sclerosis ,PROTON pump inhibitors ,GUT microbiome ,META-analysis ,BUTYRATES - Abstract
Aim of the study: We conducted a systematic review on existing literature in humans and animals, linking the gut microbiome with amyotrophic lateral sclerosis (ALS). Additionally, we sought to explore the role of the bacterially produced metabolite butyrate as well as of proton pump inhibitors (PPIs) in these associations. Materials and methods: Following PRISMA guidelines for systematic literature reviews, four databases (Medline, Scopus, Embase and Web of Science) were searched and screened by two independent reviewers against defined inclusion criteria. Six studies in humans and six animal studies were identified, summarized and reviewed. Results: Overall, the evidence accrued to date is supportive of changes in the gut microbiome being associated with ALS risk, and potentially progression, though observational studies are small (describing a total of 145 patients with ALS across all published studies), and not entirely conclusive. Conclusions: With emerging studies beginning to apply metagenome sequencing, more clarity regarding the importance and promise of the gut microbiome in ALS can be expected. Future studies may also help establish the therapeutic potential of butyrate, and the role of PPIs in these associations. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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26. Myasthenia gravis AChR antibodies inhibit function of rapsyn-clustered AChRs.
- Author
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Cetin, Hakan, Webster, Richard, Wei Wei Liu, Akiko Nagaishi, Koneczny, Inga, Zimprich, Fritz, Maxwell, Susan, Cossins, Judith, Beeson, David, Vincent, Angela, Liu, Wei Wei, and Nagaishi, Akiko
- Subjects
MYASTHENIA gravis ,CHOLINERGIC receptors ,SCAFFOLD proteins ,MYONEURAL junction ,IMMUNOGLOBULINS ,CELL physiology ,AUTOANTIBODIES ,SNAKE venom ,FLUOXETINE ,MUSCLE proteins ,MICROSCOPY ,ELECTROPHYSIOLOGY ,CYTOLOGY ,CELL lines ,PHARMACODYNAMICS - Abstract
Objective: Direct inhibition of acetylcholine receptor (AChR) function by autoantibodies (Abs) is considered a rare pathogenic mechanism in myasthenia gravis (MG), but is usually studied on AChRs expressed in cell lines, rather than tightly clustered by the intracellular scaffolding protein, rapsyn, as at the intact neuromuscular junction. We hypothesised that clustered AChRs would provide a better target for investigating the functional effects of AChR-Abs.Methods: Acetylcholine-induced currents were measured using whole-cell patch clamping and a fast perfusion system to assess fast (<2 min) functional effects of the serum samples. The sensitivity, specificity and rapidity of the system were first demonstrated by applying maternal AChR-Ab positive plasmas known to inhibit fetal AChR function in TE671 cells. Eleven previously untested AChR-Ab positive MG sera, 10 AChR-Ab negative MG sera and 5 healthy control sera were then applied to unclustered and rapsyn-clustered human adult AChRs in CN21 cells.Results: The maternal AChR-Ab positive plasmas reduced fetal AChR currents, but not adult AChR currents, by >80% within 100 s. Only 2/11 AChR-Ab positive sera inhibited AChR currents in unclustered AChRs, but 6/11 AChR-Ab positive sera compared with none of the 10 AChR-Ab negative sera (p=0.0020) inhibited rapsyn-clustered AChR currents, and current inhibition by the AChR-Ab positive sera was greater when the AChRs were clustered (p=0.0385). None of the sera had detectable effects on desensitisation or recovery from desensitisation.Conclusion: These results show that antibodies can inhibit AChR function rapidly and demonstrate the importance of clustering in exploring pathogenic disease mechanisms of MG Abs. [ABSTRACT FROM AUTHOR]- Published
- 2020
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27. Frequency and clinical features of treatment-refractory myasthenia gravis.
- Author
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Rath, Jakob, Brunner, Ines, Tomschik, Matthias, Zulehner, Gudrun, Hilger, Eva, Krenn, Martin, Paul, Anna, Cetin, Hakan, and Zimprich, Fritz
- Subjects
MYASTHENIA gravis ,MEDICAL personnel ,IMMUNOSUPPRESSIVE agents - Abstract
Background: To investigate the frequency and characterize the clinical features of treatment-refractory myasthenia gravis in an Austrian cohort. Methods: Patient charts of 126 patients with generalized myasthenia gravis and onset between 2000 and 2016 were analyzed retrospectively. Patients were classified as treatment-refractory according to strict, predefined criteria. These mandated patients being at least moderately symptomatic (i.e., MGFA class III) or needing either maintenance immunoglobulins or plasma exchange therapy for at least 1 year in spite of two adequately dosed immunosuppressive drugs. Clinical features and outcome at last follow-up were compared to treatment-responsive patients. Results: 14 out of 126 patients (11.1%) met these criteria of treatment-refractory myasthenia gravis. Treatment-refractory patients had more frequent clinical exacerbations and more often received rescue treatments or a further escalation of immunosuppressive therapies. They also remained more severely affected at last follow-up. An early onset of myasthenia gravis was associated with a higher risk for a refractory course. Conclusion: A small subgroup of patients with generalized myasthenia gravis do not respond sufficiently to standard therapies. Refractory disease has considerable implications for both patients and health care providers and highlights an unmet need for new treatment options. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. Effects of hippocampal histone acetylation and HDAC inhibition on spatial learning and memory in the Morris water maze in rats.
- Author
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Topuz, Ruhan Deniz, Gunduz, Ozgur, Tastekin, Ebru, and Karadag, Cetin Hakan
- Subjects
THETA rhythm ,BUTYRATES ,HISTONE acetylation ,DEACETYLATION ,SPATIAL memory ,SPRAGUE Dawley rats ,HISTONE deacetylase inhibitors ,SODIUM butyrate - Abstract
In recent years, it has been pointed out that epigenetic changes affect learning and memory formation. Particularly, it has been shown that histone acetylation and DNA methylation work in concert to regulate learning and memory formation. We aimed to examine whether acetylation of H2B within the rat hippocampus alters by trainings in the Morris water maze test. Male, 2–3 months old, Sprague Dawley rats were trained in Morris water maze task. Animals were given four trials per day for five consecutive days to locate a hidden platform. On the sixth day, the platform was removed and the animals were swum for 60 s. The effects of sodium butyrate, histone deacetylase inhibitor, were tested on normal and scopolamine‐induced memory‐impaired rats. The histone deacetylase inhibitor, sodium butyrate, increased histone H2B acetylation in normal rats. Sodium butyrate had no effect on learning and memory performance of normal rats; however, it partially ameliorated learning and memory disruption induced by scopolamine. So, the histone deacetylase inhibitors can be new treatment agent for cognitive disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure.
- Author
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Vanhaesebrouck, An E, Webster, Richard, Maxwell, Susan, Cruz, Pedro M Rodriguez, Cossins, Judith, Wickens, James, Liu, Wei-wei, Cetin, Hakan, Cheung, Jonathan, Ramjattan, Hayley, Palace, Jacqueline, Beeson, David, and Rodriguez Cruz, Pedro M
- Subjects
MYONEURAL junction ,CONGENITAL myasthenic syndromes ,CHOLINERGIC receptors ,MUSCLE fatigue ,ACETYLCHOLINESTERASE inhibitors ,MYASTHENIA gravis - Abstract
Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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30. Endocannabinoid and N-acylethanolamide levels in rat brain and spinal cord following systemic dipyrone and paracetamol administration.
- Author
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Topuz, Ruhan Deniz, Gunduz, Ozgur, Karadag, Cetin Hakan, Dokmeci, Dikmen, and Ulugol, Ahmet
- Subjects
SPINAL cord ,DIPYRONE ,TANDEM mass spectrometry ,RATS - Abstract
Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2019
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31. Muscle acetylcholine receptor conversion into chloride conductance at positive potentials by a single mutation.
- Author
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Cetin, Hakan, Epstein, Max, Wei W. Liu, Maxwell, Susan, Rodriguez Cruz, Pedro M., Cossins, Judith, Vincent, Angela, Webster, Richard, Biggin, Philip C., and Beeson, David
- Subjects
CHOLINERGIC receptors ,LIGAND-gated ion channels ,CONGENITAL myasthenic syndromes ,MUSCLES ,CHLORIDES - Abstract
Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we report on a CHRNA1 mutation (α1Leu251Arg) in a patient with congenital myasthenic syndrome associated with transformation of the muscle acetylcholine receptor (AChR) into an inhibitory channel. Performing patch-clamp experiments, the AChR was found to be converted into chloride conductance at positive potentials, whereas whole-cell currents at negative potentials, although markedly reduced, were still carried by sodium. Umbrella sampling molecular dynamics simulations revealed constriction of the channel pore radius to 2.4 Å as a result of the mutation, which required partial desolvation of the ions in order to permeate the pore. Ion desolvation was associated with an energetic penalty that was compensated for by the favorable electrostatic interaction of the positively charged arginines with chloride. These findings reveal a mechanism for the transformation of the muscle AChR into an inhibitory channel in a clinical context. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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32. Rapsyn facilitates recovery from desensitization in fetal and adult acetylcholine receptors expressed in a muscle cell line.
- Author
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Cetin, Hakan, Liu, Wei, Cheung, Jonathan, Cossins, Judith, Vanhaesebrouck, An, Maxwell, Susan, Vincent, Angela, Beeson, David, and Webster, Richard
- Subjects
CHOLINERGIC receptors ,MUSCARINIC acetylcholine receptors ,MUSCLE cells ,NICOTINIC acetylcholine receptors ,CELL lines ,MYONEURAL junction - Abstract
Key points: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied.Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform.Recovery from desensitization is determined by the AChR isoform‐specific cytoplasmic M3–M4 domain.The co‐expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering.These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. The neuromuscular junction (NMJ) is the site of a number of autoimmune and genetic disorders, many involving the muscle‐type nicotinic acetylcholine receptor (AChR), although there are aspects of normal NMJ development and function that need to be better understood. In particular, there are still questions regarding the implications of the developmental switch from fetal to adult AChRs, as well as how their functions might be modified by rapsyn that clusters the AChRs. Desensitization of human muscle AChRs was investigated using the patch clamp technique to measure whole‐cell currents in muscle‐type (TE671/CN21) and non‐muscle (HEK293) cell lines expressing either fetal or adult AChRs. Desensitization time constants were similar with both AChR isoforms but recovery time constants were shorter in cells expressing adult compared to fetal AChRs (P < 0.0001). Chimeric experiments showed that recovery from desensitization was determined by the M3–M4 cytoplasmic loops of the γ‐ and ε‐subunits. Expression of rapsyn in TE671/CN21 cells induced AChR aggregation and also, surprisingly, shortened recovery time constants in both fetal and adult AChRs. However, this was not dependent on clustering because rapsyn also facilitated recovery from desensitization in HEK293 cells expressing a δ‐R375H AChR mutant that did not form clusters in C2C12 myotubes. Thus, rapsyn interactions with AChRs lead not only to clustering, but also to a clustering independent faster recovery from desensitization. Both effects of rapsyn could be a necessary adjustment to the motor neuron firing rates that increase around the time of birth. Key points: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied.Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform.Recovery from desensitization is determined by the AChR isoform‐specific cytoplasmic M3–M4 domain.The co‐expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering.These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. Effects of in vitro Amitriptyline, Fluoxetine, Tranylcypromine and Venlafaxine on Saphenous Vein Grafts.
- Author
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Akinci, Melek, Karadag, Cetin Hakan, Huseyin, Serhat, Oltulu, Cagatay, Canbaz, Suat, Gunduz, Ozgur, and Topuz, Ruhan Deniz
- Subjects
SAPHENOUS vein ,FLUOXETINE ,AMITRIPTYLINE ,CORONARY artery bypass ,VENLAFAXINE - Abstract
Objective: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. Methods: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3×10-6M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10-11-3x10-5M, while venlafaxine was added in the range of 10-9-3×10-5M. Then, the antidepressant-induced relaxation responses were recorded isometrically. Results: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. Conclusion: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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34. Multifocal motor neuropathy in Austria: a nationwide survey of clinical features and response to treatment.
- Author
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Löscher, Wolfgang N., Oberreiter, Eva-Maria, Horlings, Corinne G. C., Wanschitz, Julia, Jecel, Julia, Laich, Eva, Müller, Petra, Oel, Dierk, Stadler, Klaus, Topakian, Raffi, Örtl, Wolfgang, Lenzenweger, Eva, Rath, Jakob, Zimprich, Fritz, Cetin, Hakan, Stieglbauer, Karl, Thaler-Wolf, Claudia, Erdler, Marcus, Quasthoff, Stefan, and Culea, Valeriu
- Subjects
ANTIBODY formation ,NEUROPATHY ,INTRAVENOUS immunoglobulins ,MUSCLE strength - Abstract
Background and objectives: Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature.Methods: Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed.Results: 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment.Discussion: The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. Frequency of comedication in patients with dementia: Epidemiology / Prevalence, incidence, and outcomes of MCI and dementia.
- Author
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Wurm, Raphael, Stamm, Tanja, Reichardt, Berthold, Parvizi, Tandis, Silvaieh, Sara, König, Theresa, Cetin, Hakan, and Stögmann, Elisabeth
- Published
- 2020
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36. Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes.
- Author
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Cetin, Hakan and Vincent, Angela
- Subjects
AUTOIMMUNE diseases ,MUSCLE weakness ,LAMBERT-Eaton myasthenic syndrome ,LIPOPROTEIN receptors ,PROTEIN-protein interactions - Abstract
Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein-protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
37. Serological and experimental studies in different forms of myasthenia gravis.
- Author
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Vincent, Angela, Huda, Saif, Cao, Michelangelo, Cetin, Hakan, Koneczny, Inga, Rodriguez‐Cruz, Pedro, Jacobson, Leslie, Viegas, Stuart, Jacob, Saiju, Woodhall, Mark, Nagaishi, Akiko, Maniaol, Angelina, Damato, Valentina, Leite, M. Isabel, Cossins, Judith, Webster, Richard, Palace, Jacqueline, and Beeson, David
- Subjects
MYASTHENIA gravis ,SEROLOGY ,CLINICAL trials ,CHOLINERGIC receptors ,LOW density lipoproteins - Abstract
Abstract: Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10–20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle‐specific kinase (MuSK). The use of cell‐based assays has extended the repertoire of antibody tests to clustered AChRs, low‐density lipoprotein receptor–related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the
in vitro andin vivo pathogenic roles of MuSK antibodies are discussed. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
38. Epidemiology of Multiple Sclerosis in Austria.
- Author
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Salhofer-Polanyi, Sabine, Cetin, Hakan, Leutmezer, Fritz, Baumgartner, anna, Blechinger, Stephan, Dal-Bianco, assunta, altmann, Patrick, Bajer-Kornek, Barbara, Rommer, Paulus, Guger, Michael, Leitner-Bohn, Doris, Reichardt, Berthold, alasti, Farideh, Temsch, Wilhelm, and Stamm, Tanja
- Abstract
Background: To assess the incidence rate and prevalence ratio of multiple sclerosis (MS) in Austria. Methods: Hospital discharge diagnosis and MS-specific immunomodulatory treatment prescriptions from public health insurances, covering 98% of Austrian citizens with health insurance were used to extrapolate incidence and prevalence numbers based on the capture-recapture method. Results: A total of 1,392,629 medication prescriptions and 40,956 hospitalizations were extracted from 2 data sources, leading to a total of 13,205 patients. The incidence rate and prevalence ratio of MS in Austria based on the capture-recapture method were 19.5/100,000 person-years (95% CI 14.3-24.7) and 158.9/100,000 (95% CI 141.2-175.9), respectively. Female to male ratio was 1.6 for incidence and 2.2 for prevalence. Conclusions: Incidence rates and prevalence ratios of MS in our study are within the upper range of comparable studies across many European countries as well as the United States. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
39. Iodinated contrast agents in patients with myasthenia gravis: a retrospective cohort study.
- Author
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Rath, Jakob, Mauritz, Matthias, Zulehner, Gudrun, Hilger, Eva, Cetin, Hakan, Kasprian, Gregor, Auff, Eduard, and Zimprich, Fritz
- Subjects
CONTRAST media ,MYASTHENIA gravis ,COMPUTED tomography ,DISEASE exacerbation ,SYMPTOMS ,PATIENTS - Abstract
Currently, it has not been satisfactorily established, whether modern low-osmolality iodinated contrast agents (ICAs) used in computed tomography (CT) studies are a risk factor for exacerbation of myasthenic symptoms. The rate of acute adverse events as well as delayed clinical worsening up to 30 days were analyzed in 73 patients with confirmed myasthenia gravis (MG) who underwent contrast-enhanced CT studies and compared to 52 patients who underwent unenhanced CT studies. One acute adverse event was documented. 12.3% of MG patients experienced a delayed exacerbation of symptoms after ICA administration. The rate of delayed severe exacerbation was higher in the contrast-enhanced group. Alternative causes for the exacerbation of MG-related symptoms were more likely than ICA administration in all cases. ICA administration for CT studies in MG patients should not be withheld if indicated, but patients particularly those with concomitant acute diseases should be carefully monitored for exacerbation of symptoms. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
40. Analysis of Vibratory Gyroscopes: Drive and Sense Mode Resonance Shift by Coriolis Force.
- Author
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Cetin, Hakan and Yaralioglu, Goksen G.
- Abstract
In this paper, we demonstrate the analysis of coupling between drive and sense systems of vibratory gyroscopes. Vibratory gyroscopes have attracted a lot of interest recently with the development of MEMS gyroscopes. These gyroscopes made their way through portable devices and smart phones. Novel gyroscope architectures have been proposed and analyzed in detail. However, in most of these analyses, coupling between the sense and drive systems was ignored. We analytically show that drive and sense systems are coupled together via Coriolis and centrifugal force. As a result, system resonances shift as the rotation rate increase for linear and torsional gyroscope systems. Starting from a simple gyro system, we calculated the sense and drive resonant frequency shifts in various configurations. Then, for more complex systems where analytical solution is difficult to obtain, we used commercially available FEM tools to determine corresponding frequency shift. In general, we found that the shift is small and can be ignored for linear vibratory gyroscopes where $Q$ of the sense system is less than 2500 for mode matched gyros. But for higher $Q$ systems, the frequency shift may affect the linearity of these gyroscopes. This sets a fundamental limit for the linearity of vibratory gyroscopes. Based on our calculations the non-linearity is above 1% for linear 2-DOF mode-matched vibratory gyroscopes where $Q$ is above 3000 and for torsional 2-DOF vibratory gyroscopes where $Q$ is above 600. Multi-DOF and ring vibratory gyroscopes are also examined. We find that the effect is less pronounced for Multi-DOF gyros, whereas there is a large effect on the linearity of ring gyroscopes. [ABSTRACT FROM PUBLISHER]
- Published
- 2017
- Full Text
- View/download PDF
41. Descending serotonergic and noradrenergic systems do not regulate the antipruritic effects of cannabinoids.
- Author
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Todurga, Zeynep Gizem, Gunduz, Ozgur, Karadag, Cetin Hakan, and Ulugol, Ahmet
- Subjects
CANNABINOIDS ,SEROTONINERGIC mechanisms ,NORADRENERGIC mechanisms ,ANTIPRURITICS ,PAIN management ,INTRADERMAL injections ,THERAPEUTICS - Abstract
BackgroundFor centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.ObjectiveThe goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.Material and methodsScratching behaviour was induced by intradermal injection of serotonin (50 µg/50 µl/mouse) to Balb/c mice. The neurotoxins 5,7-dihydroxytryptamine (5,7-DHT, 50 μg/mouse) and 6-hydroxydopamine (6-OHDA, 20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. WIN 55,212-2 (1, 3, 10 mg/kg, i.p.) dose-dependently attenuated serotonin-induced scratches. Neurotoxic destruction of neither the serotonergic nor the noradrenergic systems by 5,7-DHT and 6-OHDA, respectively, had any effect on the antipruritic action of WIN 55,212-2.ConclusionOur findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
42. Associations between co-medications and survival in ALS-a cohort study from Austria.
- Author
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Cetin, Hakan, Klickovic, Uros, Rath, Jakob, Zulehner, Gudrun, Füzi, Judith, Reichardt, Berthold, Hagmann, Michael, Wanschitz, Julia, Löscher, Wolfgang, Auff, Eduard, and Zimprich, Fritz
- Subjects
AMYOTROPHIC lateral sclerosis ,MUSCLE relaxants ,PROTON pumps (Biology) ,ANTICONVULSANTS ,CATION pumps (Biology) - Abstract
The aim of this study was to evaluate associations between co-medications and survival of patients with amyotrophic lateral sclerosis (ALS). Prescription databases of the Austrian sickness funds covering more than 5 million people formed the basis of this study. ALS cases were deduced from riluzole prescriptions during the study period from January 1, 2008, to June 30, 2012. After adjusting for potential confounding factors associations between co-medications and ALS survival were analyzed. A total of 522 ALS patients could be identified during the study period. Sixteen of the most frequently used drug classes were considered for the survival analyses of which two were nominally associated with ALS survival. Proton pump inhibitors (PPI) were negatively correlated with survival (HR 1.34, 95 % CI 1.04-1.73) and centrally acting muscle relaxants (CAMR) showed a positive association (HR 0.56, 95 % CI 0.39-0.81). After correcting for multiple testing, the association between CAMR and ALS survival remained significant ( p = 0.03). In conclusion, this is the first study systematically evaluating potential associations between commonly used drugs and ALS disease course. We report a positive association between CAMR use and survival, which may have derived from an indication bias representing the better prognosis of the upper motor neuron predominant disease variant. However, this is still interesting since it demonstrates the sensitivity of our study design to pick up survival effects. The use of large prescription registries could thus provide a valuable basis to find clues to underlying pathophysiological mechanisms in ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
43. Epidemiology of Amyotrophic Lateral Sclerosis and Effect of Riluzole on Disease Course.
- Author
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Cetin, Hakan, Rath, Jakob, Füzi, Judith, Reichardt, Berthold, Fülöp, Gerhard, Koppi, Stefan, Erdler, Marcus, Ransmayr, Gerhard, Weber, Jörg, Neumann, Kurt, Hagmann, Michael, Löscher, Wolfgang N., auff, Eduard, and Zimprich, Fritz
- Abstract
Objectives: To assess the epidemiology of ALS in Austria and to evaluate the long-term effect of riluzole treatment on survival. Methods: Hospital discharge and riluzole prescription databases were used to identify ALS cases from January 2008 to June 2012. Using the capture-recapture method we evaluated the incidence and prevalence of ALS and patients' survival in dependence of age, gender and riluzole treatment. Results: The corrected incidence and prevalence of ALS were 3.13/100,000 person-years (95% CI, 2.77 to 3.50) and 9.14/100,000 persons (95% CI, 8.53 to 9.79), respectively. Median survival from diagnosis was 676 days (95% CI, 591 to 761). A younger age at diagnosis was associated with a longer survival. Gender did not appear to affect survival time. Riluzole therapy was associated with a survival advantage only for the initial treatment period. The adjusted hazard ratio of mortality for using riluzole increased continually over time resulting in an apparent reversal of its beneficial effect after 6 months of therapy. Conclusions: We report incidence and prevalence estimates that are on the upper end of the wide range discussed in literature. Riluzole seems to exert a beneficial effect only in the first 6 months of therapy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
44. Evaluation of the Website Content of Hospitality Businesses: The Case of Central Antalya.
- Author
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Ergun, Gözde Seval, Cetin, Hakan, and Yirik, Sevket
- Published
- 2015
- Full Text
- View/download PDF
45. Characteristics of Global Terrorism.
- Author
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Ors, Huseyin and Cetin, Hakan Cem
- Abstract
Global terrorism has become a major threat in the 21st century, thereby becoming the most prominent issue on the agenda of international relations. This study discusses the characteristics of global terrorism and the potential causes; why terror has become an international in the modern world. Although there are numerous sources about terrorism itself or international terrorism, few of them put sufficient arguments about the transformation process of terrorism from domestic level to the to the global level. First, what international terrorism initially reminds us is argued by making some comparisons between domestic and international terrorism. Than, briefly, the definition and its dilemma is noted. Subsequently, the historical perspective and the prevailing causes of internationalization or terror are examined more substantially. And the article ends with some concluding remarks relating the whole argument. [ABSTRACT FROM AUTHOR]
- Published
- 2007
46. Effects of Losartan on Glycerol-induced Myoglobinuric Acute Renal Failure in Rats.
- Author
-
KAYA, Oktay, AYDOGDU, Nurettin, TASTEKIN, Ebru, KARADAG, Cetin Hakan, GUNDUZ, Ozgur, and SUT, Necdet
- Subjects
LOSARTAN ,GLYCERIN ,MYOGLOBINURIA ,TREATMENT of acute kidney failure ,NITRIC oxide ,FREE radicals ,LABORATORY rats - Abstract
Copyright of Kafkas Universitesi Veteriner Fakultesi Dergisi is the property of University of Kafkas, Faculty of Veterinary Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2013
- Full Text
- View/download PDF
47. Epidemiology of myasthenia gravis in Austria: rising prevalence in an ageing society.
- Author
-
Cetin, Hakan, Fülöp, Gerhard, Zach, Heidemarie, Auff, Eduard, and Zimprich, Fritz
- Abstract
Copyright of Wiener Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2012
- Full Text
- View/download PDF
48. Modulatory role of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), in morphine tolerance and dependence in mice.
- Author
-
Gunduz, Ozgur, Karadag, Cetin Hakan, and Ulugol, Ahmet
- Subjects
NITRIC oxide ,OPIOIDS ,MORPHINE ,ARGININE ,LABORATORY mice ,CAROTID artery - Abstract
Elevated plasma asymmetric dimethylarginine (ADMA) levels have been implicated in many cardiovascular and metabolic disorders. In the current work, we investigated the hypothesis that peripheral ADMA is an important contributor to opioid tolerance and dependence, by determining plasma ADMA levels during the development of tolerance and dependence to morphine in mice. Tolerance to and dependence on morphine were induced by repeated injections of morphine (10 mg/kg, s.c.) twice daily to male mice, divided into groups of 3-, 6-, 9- and 10-day injection duration. The loss of antinociceptive effect of morphine in the tail flick test was used for evaluating the degree of tolerance. Physical dependence was assessed following the administration of a 5 mg/kg dose of naloxone, by counting the occurrence of withdrawal jumps and forepaw tremors for 20 min. At the end of each period, animals were anesthetized and blood samples were collected from carotid artery. The plasma levels of ADMA, symmetric dimethylarginine (SDMA), l-homoarginine and l-arginine in morphine-tolerant and -dependent mice were not different from duration-matched control mice. Similarly, no difference was observed in plasma ADMA and the other molecules concentrations between groups of mice with different stages of development of tolerance and dependence. Our results suggest that endogenous plasma ADMA, SDMA, l-homoarginine and l-arginine levels remain unchanged during the development of morphine tolerance and dependence, and are not associated with these phenomena. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
49. Multiple roles of integrin-a3 at the neuromuscular junction.
- Author
-
Ross, Jacob A., Webster, Richard G., Lechertier, Tanguy, Reynolds, Louise E., Turmaine, Mark, Bencze, Maximilien, Jamshidi, Yalda, Cetin, Hakan, Muntoni, Francesco, Beeson, David, Hodilvala-Dilke, Kairbaan, and Conti, Francesco J.
- Subjects
INTEGRINS ,MYONEURAL junction ,NEURAL transmission - Abstract
The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-a3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-a3 also regulates integrity of the synapse - mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre- and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-a3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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