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White, Helen ; Deprez, Liesbet ; Corbisier, Philippe ; Hall, Victoria ; Lin, Feng ; Mazoua, Stéphane ; Trapmann, Stefanie ; Aggerholm, Anni ; Andrikovics, Hajnalka ; Akiki, Susanna ; Barbany, Gisela ; Boeckx, Nancy ; Bench, Anthony ; Catherwood, Mark ; Cayuela, Jean-Michel ; Chudleigh, Sandra ; Clench, Tim ; Colomer, Dolors ; Daraio, Filomena ; Dulucq, Stephanie ; Farrugia, Joanna ; Fletcher, Linda ; Foroni, Letizia ; Ganderton, Ros ; Gerrard, Gareth ; Gineikienė, Eglė ; Hayette, Sandrine ; El Housni, Hakim ; Izzo, Barbara ; Jansson, Mattias ; Johnels, Petra ; Jurcek, Tomas ; Kairisto, Veli ; Kizilors, Aytug ; Kim, Dong-Wook ; Lange, Thoralf ; Lion, Thomas ; Polakova, Katerina Machova ; Martinelli, Giovanni ; McCarron, Sarah ; Merle, Pauline A. ; Milner, Ben ; Mitterbauer-Hohendanner, Gerlinde ; Nagar, Meital ; Nickless, Guillermina ; Nomdedéu, Josep F. ; Nymoen, Dag A. ; Leibundgut, Elisabeth Oppliger ; Ozbek, Ugur ; Pajič, Tadej ; Pfeifer, Heike ; Preudhomme, Claude ; Raudsepp, Kadri ; Romeo, Giuliana ; Sacha, Tomasz ; Talmaci, Rodica ; Touloumenidou, Tasoula ; Van der Velden, Vincent H. J. ; Waits, Paula ; Wang, Lihui ; Wilkinson, Elizabeth ; Wilson, Gill ; Wren, Dörte ; Zadro, Renata ; Ziermann, Janine ; Zoi, Katerina ; Müller, Martin C. ; Hochhaus, Andreas ; Schimmel, Heinz ; Cross, Nicholas C. P. ; Emons, Hendrik
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
Sex differences in psychiatric comorbidity and clinical presentation in youths with conduct disorder
(2021)
Konrad, Kerstin ; Kohls, Gregor ; Baumann, Sarah ; Bernhard, Anka ; Martinelli, Anne ; Ackermann, Katharina ; Smaragdi, Areti ; Gonzalez-Madruga, Karen ; Wells, Amy ; Rogers, Jack C. ; Pauli, Ruth ; Clanton, Roberta ; Baker, Rosalind ; Kersten, Linda ; Prätzlich, Martin ; Oldenhof, Helena ; Jansen, Lucres ; Kleeven, Anneke ; Bigorra, Aitana ; Hervás, Amaia ; Kerexeta-Lizeaga, Iñaki ; Sesma-Pardo, Eva ; Gonzalez-Torres, Miguel Angel ; Siklósi, Réka ; Dochnal, Roberta ; Kalogerakis, Zacharias ; Pirlympou, Mara ; Papadakos, Leonidas ; Cornwell, Harriet ; Scharke, Wolfgang ; Dikeos, Dimitris ; Fernández-Rivas, Aranzazu ; Popma, Arne ; Stadler, Christina ; Herpertz-Dahlmann, Beate ; De Brito, Stephane A. ; Fairchild, Graeme ; Freitag, Christine M.
Background: Conduct disorder (CD) rarely occurs alone but is typically accompanied by comorbid psychiatric disorders, which complicates the clinical presentation and treatment of affected youths. The aim of this study was to investigate sex differences in comorbidity pattern in CD and to systematically explore the ‘gender paradox’ and ‘delayed-onset pathway’ hypotheses of female CD.
Methods: As part of the FemNAT-CD multisite study, semistructured clinical interviews and rating scales were used to perform a comprehensive phenotypic characterization of 454 girls and 295 boys with CD (9–18 years), compared to 864 sex- and age-matched typically developing controls.
Results: Girls with CD exhibited higher rates of current major depression, anxiety disorders, post-traumatic stress disorder and borderline personality disorder, whereas boys with CD had higher rates of current attention-deficit/hyperactivity disorder. In line with the ‘gender paradox’ hypothesis, relative to boys, girls with CD showed significantly more lifetime psychiatric comorbidities (incl. Alcohol Use Disorder), which were accompanied by more severe CD symptoms. Female and male youths with CD also differed significantly in their CD symptom profiles and distribution of age-of-onset subtypes of CD (i.e. fewer girls with childhood-onset CD). In line with the ‘delayed-onset pathway’ hypothesis, girls with adolescent-onset CD showed similar levels of dimensional psychopathology like boys with childhood-onset CD, while boys with adolescent-onset CD had the lowest levels of internalizing psychopathology.
Conclusions: Within the largest study of CD in girls performed to date, we found compelling evidence for sex differences in comorbidity patterns and clinical presentation of CD. Our findings further support aspects of the ‘gender paradox’ and ‘delayed-onset pathway’ hypotheses by showing that girls with CD had higher rates of comorbid lifetime mental disorders and functional impairments, and they usually developed CD during adolescence. These novel data on sex-specific clinical profiles of CD will be critical in informing intervention and prevention programmes.
Schrade, Katharina ; Tröger, Jessica ; Eldahshan, Adeeb ; Zühlke, Kerstin ; Abdul Azeez, Kamal R. ; Elkins, Jonathan M. ; Neuenschwander, Martin ; Oder, Andreas ; Elkewedi, Mohamed ; Jaksch, Sarah ; Andrae, Karsten ; Li, Jinliang ; Fernandes, Joao ; Müller, Paul Markus ; Grunwald, Stephan ; Marino, Stephen A. ; Vukićević, Tanja ; Eichhorst, Jenny ; Wiesner, Burkhard ; Weber, Marcus ; Kapiloff, Michael ; Rocks, Oliver ; Daumke, Oliver ; Wieland, Thomas ; Knapp, Stefan ; Kries, Jens Peter von ; Klussmann, Enno
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Smaragdi, Areti ; Cornwell, Harriet ; Toschi, Nicola ; Riccelli, Roberta ; Gonzalez-Madruga, Karen ; Wells, Amy ; Clanton, Roberta ; Baker, Rosalind ; Rogers, Jack C. ; Martin-Key, Nayra ; Puzzo, Ignazio ; Batchelor, Molly ; Sidlauskaite, Justina ; Bernhard, Anka ; Martinelli, Anne ; Kohls, Gregor ; Konrad, Kerstin ; Baumann, Sarah ; Raschle, Nora Maria ; Stadler, Christina ; Freitag, Christine M. ; Sonuga-Barke, Edmund ; De Brito, Stéphane A. ; Fairchild, Graeme
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Sylvester, Francisco ; Weichert, Fabian G. ; Lozano, Verónica L. ; Groh, Ksenia J. ; Bálint, Miklós ; Baumann, Lisa ; Bässler, Claus ; Brack, Werner ; Brandl, Barbara ; Curtius, Joachim ; Dierkes, Paul ; Döll, Petra ; Ebersberger, Ingo ; Fragkostefanakis, Sotirios ; Helfrich, Eric J. N. ; Hickler, Thomas ; Johann, Sarah ; Jourdan, Jonas ; Klimpel, Sven ; Kminek, Helge ; Liquin, Florencia ; Möllendorf, Darrel ; Mueller, Thomas ; Oehlmann, Jörg ; Ottermanns, Richard ; Pauls, Steffen U. ; Piepenbring, Meike ; Pfefferle, Jakob ; Schenk, Gerrit Jasper ; Scheepens, Johannes Fredericus ; Scheringer, Martin ; Schiwy, Sabrina ; Schlottmann, Antje ; Schneider, Flurina ; Schulte, Lisa Maria ; Schulze-Sylvester, Maria ; Stelzer, Ernst H. K. ; Strobl, Frederic ; Sundermann, Andrea ; Tockner, Klement ; Tröger, Tobias ; Vilcinskas, Andreas ; Völker, Carolin ; Winkelmann, Ricarda ; Hollert, Henner
Rico-Sánchez, Axel Eduardo ; Sundermann, Andrea ; López-López, Eugenia ; Torres-Olvera, Martin Jonatan ; Mueller, Sarah Ashley ; Haubrock, Phillip Joschka
Maintaining biodiversity and ecosystem function is critical on national and global scales. However, while only a fraction of the global biodiversity is known, its current decline is unprecedented, making biodiversity hotspots a conservation priority. The Sierra Gorda Biodiversity Reserve (SGBR) in Central Mexico is known for its rich biodiversity. It is an example of the juxtaposition between species discovery and extinction: aquatic species richness is mostly unknown as no efforts have investigated aquatic communities so far, but are already anthropogenically stressed. We hypothesized that invasive species are already well established in various protected areas and investigated this by assessing the threat of invasive species that are already established within the SGBR on the native biodiversity. By combining field sampling with peer-reviewed literature and local reports, we identify the presence of various non-native species in SGBR. Among these non-native species identified were opportunistic predatory fish and potentially-pathogen transmitting molluscs, but also, a habitat engineer capable of modifying ecosystem functions. Moreover, we highlight that these species were introduced despite legislation and without any knowledge among authorities. As a result, we underline the necessity to describe native species, control invasive and prevent the introduction of further non-native species. If accelerated action is not taken, we risk losing a considerable amount of described and unknown freshwater biota. Keywords: Anthropocene, Biodiversity loss, Freshwater, Invasive species, Mexico, Nature reserve.
Strzelczyk, Adam ; Kalski, Malin ; Bast, Thomas ; Wiemer-Kruel, Adelheid ; Bettendorf, Ulrich ; Kay, Lara ; Kieslich, Matthias ; Kluger, Gerhard ; Kurlemann, Gerhard ; Mayer, Thomas ; Neubauer, Bernd Axel ; Polster, Tilman ; Herting, Arne ; Spiczak Brzezinski, Sarah von ; Trollmann, Regina ; Wolff, Markus ; Irwin, John ; Carroll, Joe ; Macdonald, Daniel ; Pritchard, Clive ; Klein, Karl Martin ; Rosenow, Felix ; Schubert-Bast, Susanne
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.
Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.
Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.
Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
Strzelczyk, Adam ; Knake, Susanne ; Holtkamp, Martin ; Schulze-Bonhage, Andreas ; Lemke, Johannes ; Spiczak Brzezinski, Sarah von ; Berkenfeld, Ralf ; Rosenow, Felix ; Brandt, Christian ; Schmitt, Friedhelm C.
The Board of Directors of the German Society of Epileptology and the committee on epilepsy and syncope of the German Society of Neurology have reviewed the current data on vaccination to prevent coronavirus disease 2019 (COVID-19) and vaccination prioritization in people with epilepsy and provide a summary and recommendations.
Reitz, Sarah ; Behrens, Marion ; Lortz, Irina ; Conradi, Nadine Caroline ; Rauch, Maximilian ; Filipski, Katharina Johanna ; Voß, Martin ; Kell, Christian Alexander ; Czabanka, Marcus Alexander ; Forster, Marie-Thérèse
Objectives: Gliomas are often diagnosed due to epileptic seizures as well as neurocognitive deficits. First treatment choice for patients with gliomas in speech-related areas is awake surgery, which aims at maximizing tumor resection while preserving or improving patient’s neurological status. The present study aimed at evaluating neurocognitive functioning and occurrence of epileptic seizures in patients suffering from gliomas located in language-related areas before and after awake surgery as well as during their follow up course of disease.
Materials and Methods: In this prospective study we included patients who underwent awake surgery for glioma in the inferior frontal gyrus, superior temporal gyrus, or anterior temporal lobe. Preoperatively, as well as in the short-term (median 4.1 months, IQR 2.1-6.0) and long-term (median 18.3 months, IQR 12.3-36.6) postoperative course, neurocognitive functioning, neurologic status, the occurrence of epileptic seizures and number of antiepileptic drugs were recorded.
Results: Between 09/2012 and 09/2019, a total of 27 glioma patients, aged 36.1 ± 11.8 years, were included. Tumor resection was complete in 15, subtotal in 6 and partial in 6 patients, respectively. While preoperatively impairment in at least one neurocognitive domain was found in 37.0% of patients, postoperatively, in the short-term, 36.4% of patients presented a significant deterioration in word fluency (p=0.009) and 34.8% of patients in executive functions (p=0.049). Over the long-term, scores improved to preoperative baseline levels. The number of patients with mood disturbances significantly declined from 66.7% to 34.8% after surgery (p=0.03). Regarding seizures, these were present in 18 (66.7%) patients prior to surgery. Postoperatively, 22 (81.5%) patients were treated with antiepileptic drugs with all patients presenting seizure-freedom.
Conclusions: In patients suffering from gliomas in eloquent areas, the combination of awake surgery, regular neurocognitive assessment - considering individual patients´ functional outcome and rehabilitation needs – and the individual adjustment of antiepileptic therapy results in excellent patient outcome in the long-term course.