Items 1-20 of 4007

    • Journal Article

      The human box C/D snoRNA U3 is a miRNA source and miR-U3 regulates expression of sortin nexin 27 

      Lemus-Diaz, Nicolas; Ferreira, Rafael Rinaldi; Bohnsack, Katherine E; Gruber, Jens; Bohnsack, Markus T
      Nucleic Acids Research p.1-16
      MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression and their dysfunction is often associated with cancer. Alongside the canonical miRNA biogenesis pathway involving stepwise processing and export of pri- and pre-miRNA transcripts by the microprocessor complex, Exportin 5 and Dicer, several alternative mechanisms of miRNA production have been described. Here, we reveal that the atypical box C/D snoRNA U3, which functions as a scaffold during early ribosome assembly, is a miRNA source. We show that a unique stem–loop structure in the 5′ domain of U3 is processed to form short RNA fragments that associate with Argonaute. miR-U3 production is independent of Drosha, and an increased amount of U3 in the cytoplasm in the absence of Dicer suggests that a portion of the full length snoRNA is exported to the cytoplasm where it is efficiently processed into miRNAs. Using reporter assays, we demonstrate that miR-U3 can act as a low proficiency miRNA in vivo and our data support the 3′ UTR of the sortin nexin SNX27 mRNA as an endogenous U3-derived miRNA target. We further reveal that perturbation of U3 snoRNP assembly induces miR-U3 production, highlighting potential cross-regulation of target mRNA expression and ribosome production.
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    • Journal Article

      Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity 

      Lazarov, Elinor; Hillebrand, Merle; Schröder, Simone; Ternka, Katharina; Hofhuis, Julia; Ohlenbusch, Andreas; Barrantes-Freer, Alonso; Pardo, Luis A.; Fruergaard, Marlene U.; Nissen, Poul; et al.
      Brockmann, KnutGärtner, JuttaRosewich, Hendrik
      Neurobiology of Disease 2020; 143 p.1-9: Art. 105012
      Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na$^+$/K$^+$-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP. Currently, it is largely unknown what determines the disease severity, and whether severity is linked to the degree of functional impairment of the α3 subunit. Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the α3 Na$^+$/K$^+$-ATPase in transfected HEK cells and oocytes. All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current. No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes, suggesting that these measures of pump dysfunction do not exclusively determine the disease severity.
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    • Journal Article

      Reference Values of the QOLIBRI from General Population Samples in the United Kingdom and The Netherlands 

      Gorbunova, Anastasia; Zeldovich, Marina; Voormolen, Daphne; Krenz, Ugne; Polinder, Suzanne; Haagsma, Juanita; Hagmayer, York; Covic, Amra; Real, Ruben; Asendorf, Thomas; et al.
      von Steinbuechel, Nicole
      Journal of Clinical Medicine 2020; 9(7) p.1-29: Art. 2100
      The Quality of Life after Traumatic Brain Injury (QOLIBRI) instrument is an internationally validated patient-reported outcome measure for assessing disease-specific health-related quality of life (HRQoL) in individuals after traumatic brain injury (TBI). However, no reference values for general populations are available yet for use in clinical practice and research in the field of TBI. The aim of the present study was, therefore, to establish these reference values for the United Kingdom (UK) and the Netherlands (NL). For this purpose, an online survey with a reworded version of the QOLIBRI for general populations was used to collect data on 4403 individuals in the UK and 3399 in the NL. This QOLIBRI version was validated by inspecting descriptive statistics, psychometric criteria, and comparability of the translations to the original version. In particular, measurement invariance (MI) was tested to examine whether the items of the instrument were understood in the same way by different individuals in the general population samples and in the TBI sample across the two countries, which is necessary in order to establish reference values. In the general population samples, the reworded QOLIBRI displayed good psychometric properties, including MI across countries and in the non-TBI and TBI samples. Therefore, differences in the QOLIBRI scores can be attributed to real differences in HRQoL. Individuals with and without a chronic health condition did differ significantly, with the latter reporting lower HRQoL. In conclusion, we provided reference values for healthy individuals and individuals with at least one chronic condition from general population samples in the UK and the NL. These can be used in the interpretation of disease-specific HRQoL assessments after TBI applying the QOLIBRI on the individual level in clinical as well as research contexts.
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    • Journal Article

      Phytotherapy for Cachexia: Where Do We Stand? 

      Kuchta, Kenny; Cameron, Silke
      Frontiers in Pharmacology 2020; 11 p.1-9: Art. 917
      Background: In contrast to Western medicine which currently offers no approved pharmacotherapy options for cachexia, in Japan multi-component extracts of medicinal plants are used with coverage by the national health insurance. This so called “Kampo” medicine is an example of the modern concept of multi-component/multi-target therapy. For the three traditional preparations Hochuekkito (補中益気湯), Juzentaihoto (十全大補湯), and Rikkunshito (六君子湯), a multitude of clinical research data relating to cachexia has been published. These preparations are also referred to as “Hozai” (補剤). A similar concept is found in Russian herbal medicine, where the term “Adaptogen” was coined for pharmacologically active substances which enhance adaptive stress repose. Methods: Scientific literature—including original Japanese articles—was reviewed regarding the effects of these herbal preparations on cachexia. Cachexia is a complex set of symptoms including muscle atrophy with loss of weight, fatigue, and weakness. Results: In a 1985 study by Kuroda et al., Hochuekkito showed efficacy in involuntary weight loss and fatigue in 63% of 162 patients with genitourinary cancer. For cancer-related fatigue, a significant improvement was reported within 2 weeks by Jeong et al. in 2010. In patients with chronic fatigue syndrome, Hochuekkito showed an overall improvement with 8–12 weeks of therapy in a 1997 study by Kuratsune et al. In a 2005 randomized placebo-controlled trial by Satoh et al. on 13 geriatric Q1 patients in a 16-week treatment protocol, Hochuekkito showed significant improvement of general health, physical functioning and the Profile of Mood States (POMS). In 71 geriatric COPD patients in a 2009 placebo-controlled randomized study, Tatsumi et al. found a significant body weight increase and a CRP, TNF-α, IL-6 decrease over 6 months of therapy. For Juzentaihoto in 48 hepatocellular carcinoma patients, Tsuchiya et al. 2008 documented a significantly longer recurrence-free survival (49 vs. 24 months) as compared to the control group (p=0.023). For the much simpler Rikkunshito prescription, a 2011 retrospective study by Fujitsuka et al. on 39 Stage III/IV pancreatic cancer patients treated with Gemcitabine (n=33) or Gemcitabine/Rikkunshito (n=6) showed a significantly prolonged median survival with 224 vs. 378.5 days (p < 0.05). In a 2011 open-label clinical study by Utumi et al. on geriatric cachexia in 6 dementia patients, treatment with Rikkunshito for 4 weeks resulted in a significant body weight increase. In all the above studies, the standardized dosage of 3x2.5 g/d extract granules for most Japanese health insurance-covered Kampo extract-preparations was applied. Conclusion: As there is currently no accepted pharmacotherapy option for cachexia available in the West, a transfer of these East Asian gold standard prescriptions into the European market would be desirable. We were further able to demonstrate that the mTOR, interleucin, and melatonin pathways are modified by herbal compounds which thus counteract cachexia. More research in this field is urgently needed in order to provide new, effective treatments for cachexia patients.
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    • Journal Article

      Influence of Sociodemographic, Premorbid, and Injury-Related Factors on Post-Concussion Symptoms after Traumatic Brain Injury 

      Zeldovich, Marina; Wu, Yi-Jhen; Gorbunova, Anastasia; Mikolic, Ana; Polinder, Suzanne; Plass, Anne; Covic, Amra; Asendorf, Thomas; Andelic, Nada; Voormolen, Daphne; et al.
      von Steinbüchel, Nicole
      Journal of Clinical Medicine 2020; 9(6) p.1-22: Art. 1931
      Background: Post-concussion symptoms (PCS) are often reported as consequences of mild and moderate traumatic brain injury (TBI), but these symptoms are not well documented in severe TBI. There is a lack of agreement as to which factors and covariates affect the occurrence, frequency, and intensity of PCS among TBI severity groups. The present study therefore aims to examine the association between sociodemographic, premorbid, and injury-related factors and PCS. Methods: A total of 1391 individuals (65% male) from the CENTER-TBI study were included in the analyses. The occurrence, frequency (number of PCS), and intensity (severity) of PCS were assessed using the Rivermead Post-concussion Symptoms Questionnaire (RPQ) at six months after TBI. To examine the association between selected factors (age, sex, living situation, employment status, educational background, injury and TBI severity, and premorbid problems) and PCS, a zero-inflated negative binomial model (ZINB) for occurrence and frequency of PCS and a standard negative binomial regression (NB) for intensity were applied. Results: Of the total sample, 72% of individuals after TBI reported suffering from some form of PCS, with fatigue being the most frequent among all TBI severity groups, followed by forgetfulness, and poor concentration. Different factors contributed to the probability of occurrence, frequency, and intensity of PCS. While the occurrence of PCS seemed to be independent of the age and sex of the individuals, both the frequency and intensity of PCS are associated with them. Both injury and TBI severity influence the occurrence and frequency of PCS, but are associated less with its intensity (except “acute” symptoms such as nausea, vomiting, and headaches). Analyses focusing on the mTBI subgroup only yielded results comparable to those of the total sample. Discussion: In line with previous studies, the results support a multifactorial etiology of PCS and show the importance of differentiating between their occurrence, frequency, and intensity to better provide appropriate treatment for individual subgroups with different symptoms (e.g., multiple PCS or more intense PCS). Although PCS often occur in mild to moderate TBI, individuals after severe TBI also suffer from PCS or post-concussion-like symptoms that require appropriate treatment. The chosen statistical approaches (i.e., ZINB and NB models) permit an ameliorated differentiation between outcomes (occurrence, frequency, and intensity of PCS) and should be used more widely in TBI research.
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    • Journal Article

      The integrated stress response induces R-loops and hinders replication fork progression 

      Choo, Josephine Ann Mun Yee; Schlösser, Denise; Manzini, Valentina; Magerhans, Anna; Dobbelstein, Matthias
      Cell Death & Disease 2020; 11(7) p.1-16: Art. 538
      The integrated stress response (ISR) allows cells to rapidly shutdown most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within 1 h, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis. DNA replication is restored by compounds that inhibit eIF2alpha kinases or re-activate eIF2alpha. Mechanistically, the translational shutdown blocks histone synthesis, promoting the formation of DNA:RNA hybrids (R-loops), which interfere with DNA replication. R-loops accumulate upon histone depletion. Conversely, histone overexpression or R-loop removal by RNaseH1 each restores DNA replication in the context of ISR and histone depletion. In conclusion, the ISR rapidly stalls DNA synthesis through histone deficiency and R-loop formation. We propose that this shutdown mechanism prevents potentially detrimental DNA replication in the face of cellular stresses.
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    • Journal Article

      Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis 

      Reinert, Marie-Christine; Benkert, Pascal; Wuerfel, Jens; Michalak, Zuzanna; Ruberte, Esther; Barro, Christian; Huppke, Peter; Stark, Wiebke; Kropshofer, Harald; Tomic, Davorka; et al.
      Leppert, DavidKuhle, JensBrück, WolfgangGärtner, Jutta
      Neurology - Neuroimmunology Neuroinflammation 2020; 7(4) p.1-11: Art. e749
      Objective To investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS). Methods In this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated. Results Untreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001). Conclusions sNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.
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    • Journal Article

      Impact of Case Definitions on Efficacy Estimation in Clinical Trials—A Proof-of-Principle Based on Historical Examples 

      Hahn, Andreas; Frickmann, Hagen; Zautner, Andreas E.
      Antibiotics 2020; 9(7) p.1-11: Art. 379
      Efficacy estimations in clinical trials are based on case definitions. Commonly, they are a more or less complex set of conditions that have to be fulfilled in order to define a clinical case. In the simplest variant, such a case is identical with a single positive diagnostic test result. Frequently, however, case definitions are more complex. Further, their conditions often ignore the inherent logical structure of symptoms and disease: A symptom or a set of symptoms may be necessary but not sufficient for the unambiguous identification of a case. After describing the structure of case definitions and its impact on efficacy estimations, we exemplify this impact using data from two clinical trials dealing with the effectiveness of the vaginal application of tenofovir gel for the prevention of HIV infections and with the therapeutic effects of fecal transplantation on recurrent Clostridium difficile infections. We demonstrate that the diagnostic performance of case definitions affects efficacy estimations for interventions in clinical trials. The potential risk of bias and uncertainty is high, irrespective of the complexity of the case definition. Accordingly, case definitions in clinical trials should focus on specificity in order to avoid the risk of bias.
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    • Journal Article

      Early Predictors of Employment Status One Year Post Injury in Individuals with Traumatic Brain Injury in Europe 

      Arango-Lasprilla, Juan; Zeldovich, Marina; Olabarrieta-Landa, Laiene; Forslund, Marit; Núñez-Fernández, Silvia; von Steinbuechel, Nicole; Howe, Emilie; Røe, Cecilie; Andelic, Nada
      Journal of Clinical Medicine 2020; 9(6) p.1-16: Art. 2007
      Sustaining a traumatic brain injury (TBI) often affects the individual’s ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI at one-year post-injury in European countries. Using a prospective longitudinal non-randomized observational cohort (The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project), data was collected between December 2014–2019 from 63 trauma centers in 18 European countries. The 1015 individuals who took part in this study were potential labor market participants, admitted to a hospital and enrolled within 24 h of injury with a clinical TBI diagnosis and indication for a computed tomography (CT) scan, and followed up at one year. Results from a binomial logistic regression showed that older age, status of part-time employment or unemployment at time of injury, premorbid psychiatric problems, and higher injury severity (as measured with higher Injury severity score (ISS), lower Glasgow Coma Scale (GCS), and longer length of stay (LOS) in hospital) were associated with higher unemployment probability at one-year after injury. The study strengthens evidence for age, employment at time of injury, premorbid psychiatric problems, ISS, GCS, and LOS as important predictors for employment status one-year post-TBI across Europe.
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    • Journal Article

      Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids 

      Zafeiriou, Maria-Patapia; Bao, Guobin; Hudson, James; Halder, Rashi; Blenkle, Alica; Schreiber, Marie-Kristin; Fischer, Andre; Schild, Detlev; Zimmermann, Wolfram-Hubertus
      Nature Communications 2020; 11(1) p.1-12: Art. 3791
      Brain organoids are promising tools for disease modeling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here, we report the directed self-organization of human induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network at a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons with supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed GABA polarity switch and reduced GDPs in >40 day BENO indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months and evidence for long-term potentiation. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modeling of disease.
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    • Journal Article

      Weak rTMS-induced electric fields produce neural entrainment in humans 

      Zmeykina, Elina; Mittner, Matthias; Paulus, Walter; Turi, Zsolt
      Scientific Reports 2020; 10(1) p.1-16: Art. 11994
      Repetitive transcranial magnetic stimulation (rTMS) is a potent tool for modulating endogenous oscillations in humans. The current standard method for rTMS defines the stimulation intensity based on the evoked liminal response in the visual or motor system (e.g., resting motor threshold). The key limitation of the current approach is that the magnitude of the resulting electric field remains elusive. A better characterization of the electric field strength induced by a given rTMS protocol is necessary in order to improve the understanding of the neural mechanisms of rTMS. In this study we used a novel approach, in which individualized prospective computational modeling of the induced electric field guided the choice of stimulation intensity. We consistently found that rhythmic rTMS protocols increased neural synchronization in the posterior alpha frequency band when measured simultaneously with scalp electroencephalography. We observed this effect already at electric field strengths of roughly half the lowest conventional field strength, which is 80% of the resting motor threshold. We conclude that rTMS can induce immediate electrophysiological effects at much weaker electric field strengths than previously thought.
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    • Journal Article

      Novel Secondary Ion Mass Spectrometry Methods for the Examination of Metabolic Effects at the Cellular and Subcellular Levels 

      Bonnin, Elisa A.; Rizzoli, Silvio O.
      Frontiers in Behavioral Neuroscience 2020; 14 p.1-13: Art. 124
      The behavior of an animal has substantial effects on its metabolism. Such effects, including changes in the lipid composition of different organs, or changes in the turnover of the proteins, have typically been observed using liquid mass spectrometry methods, averaging the effect of animal behavior across tissue samples containing multiple cells. These methods have provided the scientific community with valuable information, but have limited resolution, making it difficult if not impossible to examine metabolic effects at the cellular and subcellular levels. Recent advances in the field of secondary ion mass spectrometry (SIMS) have made it possible to examine the metabolic effects of animal behavior with high resolution at the nanoscale, enabling the analysis of the metabolic effects of behavior on individual cells. In this review we summarize and present these emerging methods, beginning with an overview of the SIMS technique. We then discuss the specific application of nanoscale SIMS (NanoSIMS) to examine cell behavior. This often requires the use of isotope labeling to highlight specific sections of the cell for analysis, an approach that is presented at length in this review article. We also present SIMS applications concerning animal and cell behavior, from development and aging to changes in the cellular activity programs. We conclude that the emerging group of SIMS technologies represents an exciting set of tools for the study of animal behavior and of its effects on internal metabolism at the smallest possible scales.
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    • Journal Article

      Preemptive veno-venous ECMO support in a patient with anticipated difficult airway: A case report 

      Chakalov, I.; Harnisch, L.O.; Meyer, A.C.; Moerer, O.
      Respiratory Medicine Case Reports 2020; 30 p.1-6: Art. 101130
      This report presents a case of endotracheal metastasis in which elective veno–venous extracorporeal membrane oxygenation (VV ECMO) was used to undergo tracheal laser-surgery prior to establishment of a definitive airway. Specifically, we describe the respiratory and airway management in an adult patient from the preclinical phase throughout elective preoperative ECMO implantation to postoperative ECMO weaning and decannulation in the Intensive Care Unit. This case report lends further supports to the idea that the extracorporeal membrane oxygenation could be electively used to provide safe environment for surgery in situations where the standard maneuvers of sustaining adequate gas exchange are anticipated to fail.
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    • Journal Article

      Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification 

      Schlotawa, Lars; Adang, Laura A.; Radhakrishnan, Karthikeyan; Ahrens-Nicklas, Rebecca C.
      International Journal of Molecular Sciences 2020; 21(10) p.1-15: Art. 3448
      Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.
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    • Journal Article

      Increased alpha-synuclein tear fluid levels in patients with Parkinson’s disease 

      Maass, Fabian; Rikker, Sebastian; Dambeck, Vivian; Warth, Carmina; Tatenhorst, Lars; Csoti, Ilona; Schmitz, Matthias; Zerr, Inga; Leha, Andreas; Bähr, Mathias; et al.
      Lingor, Paul
      Scientific Reports 2020; 10(1) p.1-5: Art. 8507
      The objective of the study was to estimate if altered levels of alpha-synuclein can be detected in tear fluid of patients with Parkinson’s disease (PD). Therefore, tear fluid samples of 75 PD patients, 75 control subjects and 31 atypical Parkinsonian patients were collected and analyzed in triplicates using an ultra-sensitive single molecule array (SIMOA) system and applying a human alpha-synuclein immunoassay. In PD, levels of total soluble alpha-synuclein were significantly increased compared to control subjects (p = 0.03; AUC PD vs. controls 0.60). There was no difference comparing PD patients stratified by Hoehn & Yahr stages and atypical Parkinsonian syndromes stratified by tauopathies and non-PD-synucleinopathies against each other (p > 0.05). In conclusion, alpha-synuclein can be detected and quantified in tear fluid, revealing small but significant differences in total alpha-synuclein levels between PD and control subjects. Tear fluid can be collected non-invasively and risk-free, therefore presenting a promising source for further biomarker research.
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      Hypokalaemia and outcomes in older patients hospitalized for heart failure 

      Valentova, Miroslava; Patel, Samir; Lam, Phillip H.; Faselis, Charles; Arundel, Cherinne; Fonarow, Gregg C.; Cheng, Yan; Allman, Richard M.; Haehling, Stephan; Anker, Stefan D.; et al.
      Ahmed, Ali
      ESC Heart Failure 2020; 7(3) p.794-803
      Aims: Hypokalaemia is a risk factor for ventricular arrhythmias and sudden death in ambulatory patients with chronic heart failure (HF). The objective of this study was to examine the association between hypokalaemia and outcomes in hospitalized patients with decompensated HF in whom sudden death is less common. Methods and results: Of the 5881 hospitalized patients with HF, 1052 had consistent hypokalaemia (both admission and discharge serum potassium <4.0 mmol/L), and 2538 had consistent normokalaemia (both admission and discharge serum potassium 4.0–5.0 mmol/L). Propensity scores for consistent hypokalaemia, estimated for each of 3590 (1052 + 2538) patients, were used to assemble a matched cohort of 971 pairs of patients with consistent hypokalaemia vs. consistent normokalaemia, balanced on 54 baseline characteristics (mean age, 75 years; 60% women; 28% African American). We repeated the above process to assemble 2327 pairs of patients with discharge potassium <4.0 vs. 4.0–5.0 mmol/L and 449 pairs of patients with discharge serum potassium <3.5 vs. 4.0–5.0 mmol/L. Hazard ratios (HR) and 95% confidence intervals (CIs) associated with hypokalaemia were estimated in matched cohorts. 30 day all‐cause mortality occurred in 5% and 4% of patients with consistent normokalaemia vs. consistent hypokalaemia, respectively (HR, 0.78; 95% CI, 0.52–1.18; P = 0.241). HRs (95% CI) for 30 day mortality associated with discharge serum potassium <4.0 and <3.5 mmol/L were 0.90 (0.70–1.16; P = 0.419) and 1.69 (0.94–3.04; P = 0.078), respectively. Hypokalaemia (<4.0 or <3.5 mmol/L) had no association with long‐term mortality or other outcomes. Conclusions: In hospitalized older patients with HF, compared with normokalaemia (serum potassium 4.0–5.0 mmol/L), hypokalaemia (<4.0 or <3.5 mmol/L) had no significant associations with outcomes.
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      Osteoidosis leads to altered differentiation and function of osteoclasts 

      Grünherz, Lisanne; Prein, Carina; Winkler, Thomas; Kirsch, Manuela; Hopfner, Ursula; Streichert, Thomas; Clausen‐Schaumann, Hauke; Zustin, Jozef; Kirchhof, Kristin; Morlock, Michael M.; et al.
      Machens, Hans‐GünterSchilling, Arndt Friedrich
      Journal of Cellular and Molecular Medicine 2020; 24(10) p.5665-5674
      In patients with osteomalacia, a defect in bone mineralization leads to changed char- acteristics of the bone surface. Considering that the properties of the surrounding matrix influence function and differentiation of cells, we aimed to investigate the ef- fect of osteoidosis on differentiation and function of osteoclasts. Based on osteoma- lacic bone biopsies, a model for osteoidosis in vitro (OIV) was established. Peripheral blood mononuclear cells were differentiated to osteoclasts on mineralized surfaces (MS) as internal control and on OIV. We observed a significantly reduced number of osteoclasts and surface resorption on OIV. Atomic force microscopy revealed a significant effect of the altered degree of mineralization on surface mechanics and an unmasking of collagen fibres on the surface. Indeed, coating of MS with RGD peptides mimicked the resorption phenotype observed in OIV, suggesting that the altered differentiation of osteoclasts on OIV might be associated with an interaction of the cells with amino acid sequences of unmasked extracellular matrix proteins containing RGD sequences. Transcriptome analysis uncovered a strong significant up-regulation of transmembrane glycoprotein TROP2 in osteoclastic cultures on OIV. TROP2 expression on OIV was also confirmed on the protein level and found on the bone surface of patients with osteomalacia. Taken together, our results show a direct influence of the mineralization state of the extracellular matrix surface on dif- ferentiation and function of osteoclasts on this surface which may be important for the pathophysiology of osteomalacia and other bone disorders with changed ratio of osteoid to bone.
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      Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient 

      Schlotawa, Lars; Dierks, Thomas; Christoph, Sophie; Cloppenburg, Eva; Ohlenbusch, Andreas; Korenke, G. Christoph; Gärtner, Jutta
      JIMD Reports 2019; 49(1) p.48-52
      Multiple sulfatase deficiency (MSD) is an ultra‐rare lysosomal storage disorder (LSD). Mutations in the SUMF1 gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi‐organ failure. MSD was caused by a homozygous SUMF1 stop mutation (c.191C>A, p.Ser64Ter). FGE protein and sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two sulfatases, and molecular confirmation.
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      Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer 

      Elakad, Omar; Lois, Anna‐Maria; Schmitz, Katja; Yao, Sha; Hugo, Sara; Lukat, Laura; Hinterthaner, Marc; Danner, Bernhard C.; Hammerstein‐Equord, Alexander; Reuter‐Jessen, Kirsten; et al.
      Schildhaus, Hans‐UlrichStröbel, PhilippBohnenberger, Hanibal
      Cancer Medicine 2020; 9(10) p.3574-3583
      Background: Targeting fibroblast growth factor receptor 1 (FGFR1 ) is a potential treatment for squamous cell lung cancer (SQCLC). So far, treatment decision in clinical studies is based on gene amplification. However, only a minority of patients have shown durable response. Furthermore, former studies have revealed contrasting results regarding the impact of FGFR1 amplification and expression on patient's prognosis. Aims: Here, we analyzed prevalence and correlation of FGFR1 gene amplification and protein expression in human lung cancer and their impact on overall survival. Materials & Methods: FGFR1 gene amplification and protein expression were analyzed by fluorescence in situ hybridization and immunohistochemistry (IHC) in 208 SQCLC and 45 small cell lung cancers (SCLC). Furthermore, FGFR1 protein expression was analyzed in 121 pulmonary adenocarcinomas (ACs). Amplification and expression were correlated to each other, clinicopathological characteristics, and overall survival. Results: FGFR1 was amplified in 23% of SQCLC and 8% of SCLC. Amplification was correlated to males (P = .027) but not to overall survival. Specificity of immunostaining was verified by cellular CRISPR/Cas9 FGFR1 knockout. FGFR1 was strongly expressed in 9% of SQCLC, 35% of AC, and 4% of SCLC. Expression was correlated to females (P = .0187) and to the absence of lymph node metastasis in SQCLC (P = .018) with no significant correlation to overall survival. Interestingly, no significant correlation between amplification and expression was detected. Discussion: FGFR1 gene amplification does not seem to correlate to protein expression. Conclusion: We believe that patient selection for FGFR1 inhibitors in clinical studies should be reconsidered. Neither FGFR1 amplification nor expression influences patient's prognosis.
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    • Journal Article

      Noninvasive Neurally Adjusted Ventilator Assist Ventilation in the Postoperative Period Produces Better Patient-Ventilator Synchrony but Not Comfort 

      Harnisch, L. O.; Olgemoeller, U.; Mann, J.; Quintel, M.; Moerer, O.
      Pulmonary Medicine 2020; 2020 p.1-8: Art. 4705042
      Background. Noninvasive neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator interaction in many settings. There is still scarce data with regard to postoperative patients indicated for noninvasive ventilation (NIV) which this study elates. The purpose of this trial was to evaluate postoperative patients for synchrony and comfort in noninvasive pressure support ventilation (NIV-PSV) vs. NIV-NAVA. Methods. Twenty-two subjects received either NIV-NAVA or NIV-PSV in an object-blind, prospective, randomized, crossover fashion (observational trial). We evaluated blood gases and ventilator tracings throughout as well as comfort of ventilation at the end of each ventilation phase. Results. There was an effective reduction in ventilator delays (p<0.001) and negative pressure duration in NIV-NAVA as compared to NIV-PSV (p<0.001). Although we used optimized settings in NIV-PSV, explaining the overall low incidence of asynchrony, NIV-NAVA led to reductions in the NeuroSync-index (p<0.001) and all types of asynchrony except for double triggering that was significantly more frequent in NIV-NAVA vs. NIV-PSV (p=0.02); ineffective efforts were reduced to zero by use of NIV-NAVA. In our population of previously lung-healthy subjects, we did not find differences in blood gases and patient comfort between the two modes. Conclusion. In the postoperative setting, NIV-NAVA is well suitable for use and effective in reducing asynchronies as well as a surrogate for work of breathing. Although increased synchrony was not transferred into an increased comfort, there was an advantage with regard to patient-ventilator interaction. The trial was registered at the German clinical Trials Register (DRKS no.: DRKS00005408).
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