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ADHS im Erwachsenenalter ist eine komplexe Erkrankung, die durch verschiedene diagnostische Instrumente erfasst wird. Aktuell spielen dabei vor allem die klinische Exploration, Interview- und Fragebogendaten eine Rolle.
Obwohl bei Patient*innen vielfältige kognitive Einschränkungen bestehen, wird die Verwendung neuropsychologischer Daueraufmerksamkeitstests (CPTs) in den klinischen Leitlinien nur ergänzend erwähnt. Validität und Nützlichkeit von CPTs bei ADHS Patient*innen wird aufgrund der mangelnden Sensitivität und
Spezifität immer wieder kritisch diskutiert. Multidimensionale Ansätze, in denen verschiedene neuropsychologische Beurteilungen mit klinischen Parametern kombiniert werden, sollen das Aufstellen einer ADHS Diagnose im Erwachsenenalter verbessern. Die vorliegende Studie untersucht zwei verschiedene CPTs bezüglich deren Vergleichbarkeit und deren Verknüpfung mit klinischen Parametern. Ein direkter Vergleich innerhalb derselben Stichprobe ist bisher nicht durchgeführt worden, könnte jedoch wichtige Implikationen für die Testauswahl und darauffolgende klinische Interventionen haben. Die klinische Stichprobe besteht aus zufällig ausgewählten erwachsenen Patient*innen, die sich in der ADHS Ambulanz der Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Universitätsklinikums Frankfurt zur diagnostischen ADHS Beurteilung zwischen Mai und November 2019 vorstellten. Die Patient*innen wurden von erfahrenen Ärzt*innen mithilfe des strukturierten diagnostischen Interviews für ADHS bei Erwachsenen (DIVA 2.0) befragt. Au§erdem wurden Schulzeugnisse bewertet und die medizinische Vorgeschichte erhoben. Anschließend wurden die Patient*innen mit dem Wender-Reimherr Interview (WRI) von einer unabhängigen Interviewerin befragt und füllten die folgenden Selbstbeurteilungsfragebögen aus: Kurzform der Wender-Utah Rating Scale (WURS-k), Impulsive Behavior Scale (UPPS) und General Health Questionnaire (GHQ-28). Alle Patient*innen nahmen anschließend an der Testung mit zwei CPTs teil: dem Quantified Behavior Test (Qb-Test) und Nesplora Aquarium [9]. Der Qb-Test misst neben Unaufmerksamkeit und Impulsivität auch Hyperaktivität mithilfe einer Infrarot Kamera und eines Reflektors, welche das Bewegungsmuster während der Testung aufzeichnen. In Nesplora Aquarium wird virtuelle Realität genutzt, um das Bewegungsmuster mithilfe eines optischen Gerätes, das mit Sensoren und Lautsprechern ausgestattet ist, aufzuzeichnen. Es zeigte sich, dass die übergreifende Vergleichbarkeit beider Tests begrenzt ist. Trotz der kongruenten Messung von Unaufmerksamkeit in beiden Tests konnten keine Korrelationen mit den klinischen Parametern festgestellt werden. Hyperaktivität ist in beiden Tests positiv mit aktuellen ADHS Symptomen assoziiert, wobei der Qb-Test darüber hinaus noch Korrelationen mit ADHS Symptomen aus der Kindheit aufweist. Impulsivität stellte sich als ein unabhängiges Konstrukt heraus, sowohl die Korrelation zwischen beiden Tests als auch die Assoziation mit klinischen Parametern betreffend. Dies stellt in Frage, ob ein homogenes mpulsivitätskonstrukt existiert, welches sich in neuropsychologischen Tests und klinischen Symptomen abbildet. Insgesamt ermöglicht die Studie einen guten Vergleich beider CPTs und zeigt detaillierte Informationen über die
Kompatibilität mit klinischen Symptomen auf. Unaufmerksamkeit stellte sich als ein basaler Faktor heraus, der zwischen beiden Tests über alle Patient*innen hinweg überlappt. Da dieser Faktor jedoch nicht mit klinischen Parametern korreliert, unterstreicht dies die Problematik, subjektive mit objektiven Methoden in der ADHS Diagnostik zu verbinden. Die aktuellen Ergebnisse bezweifeln die einfache Anwendung sogenannter objektiver Messverfahren in der klinischen ADHS Diagnostik aufgrund ihrer fragwürdigen Validität. Die Ergebnisse der Studie verdeutlichen die Notwendigkeit eines neuen diagnostischen Ansatzes im Sinne der Präzisionsmedizin, welcher über die konventionellen Klassifikationssysteme hinaus passende individuelle Lösungen für Diagnostik und Behandlung ermöglicht.
In der vorliegenden Dissertation wird auf diesen Ergebnissen basierend der Goldstandard der aktuellen ADHS-Diagnostik unter Beachtung der Leitlinien diskutiert. Die untersuchten CPTs werden unter Berücksichtigung der Gütekriterien guter diagnostischer Verfahren überprüft. Das Potenzial neuropsychologischer Testverfahren im Hinblick auf die Steigerung von Objektivität, Validität und Differenziertheit der Diagnosen wird untersucht und Empfehlungen für die klinische Anwendung formuliert.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
Kumral, Deniz ; Cesnaite, Elena ; Beyer, Frauke ; Hofmann, Simon M. ; Hensch, Tilman ; Sander, Christian ; Hegerl, Ulrich ; Haufe, Stefan ; Villringer, Arno ; Witte, A. Veronica ; Nikulin, Vadim
Objective: To investigate whether regional white matter hyperintensities (WMHs) relate to alpha oscillations (AO) in a large population-based sample of elderly individuals.
Methods: We associated voxel-wise WMHs from high-resolution 3-Tesla MRI with neuronal alpha oscillations (AO) from resting-state multichannel EEG at sensor (N=907) and source space (N=855) in older participants of the LIFE-Adult study (60–80 years). In EEG, we computed relative alpha power (AP), individual alpha peak frequency (IAPF), as well as long-range temporal correlations (LRTC) that represent dynamic properties of the signal. We implemented whole-brain voxel-wise regression models to identify regions where parameters of AO were linked to probability of WMH occurrence. We further used mediation analyses to examine whether WMH volume mediated the relationship between age and AO.
Results: Higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. The age-related increase of relative AP in the right temporal brain region was shown to be mediated by total WMH volume.
Conclusion: A high relative AP corresponding to increased regional WMHs was not associated with age per se, in fact, this relationship was mediated by WMHs. We argue that the WMH-associated increase of AP reflects a generalized and likely compensatory spread of AO leading to a larger number of synchronously recruited neurons. Our findings thus suggest that longitudinal EEG recordings might be sensitive to detect functional changes due to WMHs.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2021)
Kumral, Deniz ; Cesnaite, Elena ; Beyer, Frauke ; Hofmann, Simon M. ; Hensch, Tilman ; Sander, Christian ; Hegerl, Ulrich ; Haufe, Stefan ; Villringer, Arno ; Witte, A. Veronica ; Nikulin, Vadim
Aging is associated with increased white matter hyperintensities (WMHs) and with the alterations of alpha oscillations (7–13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N=907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and LRTC. Finally, higher age was associated with elevated alpha power via total WMH volume. Although an increase in alpha oscillations due to WMH can have a compensatory nature, we rather suggest that an elevated alpha power is a consequence of WMH affecting a spatial organization of alpha sources.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
Kumral, Deniz ; Cesnaite, Elena ; Beyer, Frauke ; Hofmann, Simon M. ; Hensch, Tilman ; Sander, Christian ; Hegerl, Ulrich ; Haufe, Stefan ; Villringer, Arno ; Witte, A. Veronica ; Nikulin, Vadim
White matter hyperintensities (WMHs) in the cerebral white matter and attenuation of alpha oscillations (AO; 7–13 Hz) occur with the advancing age. However, a crucial question remains, whether changes in AO relate to aging per se or they rather reflect the impact of age-related neuropathology like WMHs. In this study, using a large cohort (N=907) of elderly participants (60-80 years), we assessed relative alpha power (AP), individual alpha peak frequency (IAPF) and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. In contrast, we observed no significant relation of probability of WMH occurrence with IAPF and LRTC. We argue that the WMH-associated increase of AP reflects generalized and likely compensatory changes of AO leading to a larger number of synchronously recruited neurons.
Aichholzer, Mareike ; Schiweck, Carmen ; Uckermark, Carmen ; Hamzehloiya, Tirage ; Reif-Leonhard, Christine ; Golbach, Rejane ; Reif, Andreas ; Edwin Thanarajah, Sharmili
Background: The COVID-19 pandemic led to a higher incidence of depression and a worsening of psychiatric conditions, while pre-existing constraints of the healthcare system and safety regulations limited psychiatric care.
Aims: We investigated the impact of the pandemic on the clinical care of patients with a single episode (SE-MDD) or major depressive disorder (MDD) in Germany.
Methods: Nationwide inpatient data were extracted from the German Institute for Hospital Remuneration System for 2020 and 2021 (depression data) and the Robert Koch Institute (COVID-19 incidence). Changes in inpatients were tested with linear regression models. Local cases of depression in our department compared to 2019 were explored with one-way ANOVA and Dunnett's test.
Results: Across Germany, the inpatient numbers with both SE-MDD and MDD declined by more than 50% during three out of four COVID-19 waves. Higher COVID-19 incidence correlated with decreased inpatient numbers. In our department, fewer MDD inpatients were treated in 2020 (adj. p < 0.001) and 2021 (adj. p < 0.001) compared to 2019, while the number of SE-MDD inpatients remained stable. During this period fewer elective and more emergency inpatients were admitted. In parallel, MDD outpatient admissions increased in 2021 compared to 2019 (adj. p = 0.002) and 2020 (adj. p = 0.003).
Conclusion: During high COVID-19 infection rates, MDD patients received less inpatient care, which might cause poor outcomes in the near future. These data highlight the necessity for improved infrastructure in the in- and outpatient domains to facilitate accessibility to adequate care.
Freudenberg, Florian ; Candemir, Esin ; Chen, Xufeng ; Li, Li-Li ; Esen-Sehir, Dilhan ; Schenk, Nicole ; Kinoshita, Makoto ; Grünewald, Lena ; Frerichs, Veronika ; Fattakhov, Nikolai ; Manchen, Jessica ; Bikas, Solmaz ; Kumar, Anita ; O'Leary, Aet ; Slattery, David A. ; Engelhardt, Jakob von ; Courtney, Michael J. ; Reif, Andreas
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet.
Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes.
Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity.
Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.
Qubad, Mishal ; Barnes-Scheufler, Catherine ; Schaum, Michael ; Raspor, Eva ; Rösler, Lara ; Peters, Benjamin ; Schiweck, Carmen ; Goebel, Rainer ; Reif, Andreas ; Bittner, Robert Arthur
Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.
Qubad, Mishal ; Seeger, Amelie ; Peters, Benjamin ; Roebroeck, Alard ; Reif, Andreas ; Bittner, Robert Arthur
Why do humans cooperate and often punish norm violations of others? In the present study, we sought to investigate the genetic bases of altruistic punishment (AP), which refers to the costly punishment of norm violations with potential benefit for other individuals. Recent evidence suggests that norm violations and unfairness are indexed by the feedback-related negativity (FRN), an anterior cingulate cortex (ACC) generated neural response to expectancy violations. Given evidence on the role of serotonin and dopamine in AP as well as in FRN-generation, we explored the impact of genetic variation of serotonin and dopamine function on FRN and AP behavior in response to unfair vs. fair monetary offers in a Dictator Game (DG) with punishment option. In a sample of 45 healthy participants we observed larger FRN amplitudes to unfair DG assignments both for 7-repeat allele carriers of the dopamine D4 receptor (DRD4) exon III polymorphism and for l/l-genotype carriers of the serotonin transporter gene-linked polymorphic region (5-HTTLRP). Moreover, 5-HTTLPR l/l-genotype carriers punished unfair offers more strongly. These findings support the role of serotonin and dopamine in AP, potentially via their influence on neural mechanisms implicated in the monitoring of expectancy violations and their relation to impulsive and punishment behavior.
Haenisch, Frieder ; Cooper, Jason D. ; Reif, Andreas ; Kittel-Schneider, Sarah ; Steiner, Johann ; Leweke, F. Markus ; Rothermundt, Matthias ; Beveren, Nico J. M. van ; Crespo-Facorro, Benedicto ; Niebuhr, David W. ; Cowan, David N. ; Weber, Natalya S. ; Yolken, Robert H. ; Penninx, Brenda W. J. H. ; Bahn, Sabine
Highlights
• A panel of 20 biomarkers was identified capable of differentiating BD patients from controls.
• Excellent discrimination between established BD patients and controls.
• Good to excellent discrimination between misdiagnosed BD patients and first onset MDD patients.
• Fair to good discrimination between pre-diagnostic BD patients and controls.
• Study demonstrates the potential utility of a protein biomarker panel as a diagnostic test for BD.
Abstract
Background: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD.
Methods and findings: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies.
We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC) ⩾ 0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel.
Conclusions: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.
Migueles, Jairo H. ; Molina-Garcia, Pablo ; Torres-Lopez, Lucia V. ; Cadenas-Sanchez, Cristina ; Rowlands, Alex V. ; Ebner-Priemer, Ulrich ; Koch, Elena ; Reif, Andreas ; Ortega, Francisco B.
the benefits of physical activity (PA) and sleep for health, accurate and objective population-based surveillance is important. Monitor-based surveillance has potential, but the main challenge is the need for replicable outcomes from different monitors. This study investigated the agreement of movement behavior outcomes assessed with four research-grade activity monitors (i.e., Movisens Move4, ActiGraph GT3X+, GENEActiv, and Axivity AX3) in adults. Twenty-three participants wore four monitors on the non-dominant wrist simultaneously for seven days. Open-source software (GGIR) was used to estimate the daily time in sedentary, light, moderate-to-vigorous PA (MVPA), and sleep (movement behaviors). The prevalence of participants meeting the PA and sleep recommendations were calculated from each monitor’s data. Outcomes were deemed equivalent between monitors if the absolute standardized difference and its 95% confidence intervals (CI95%) fell within ± 0.2 standard deviations (SD) of the mean of the differences. The participants were mostly men (n = 14, 61%) and aged 36 (SD = 14) years. Pairwise confusion matrices showed that 83–87% of the daily time was equally classified into the movement categories by the different pairs of monitors. The between-monitor difference in MVPA ranged from 1 (CI95%: − 6, 7) to 8 (CI95%: 1, 15) min/day. Most of the PA and sleep metrics could be considered equivalent. The prevalence of participants meeting the PA and the sleep guidelines was 100% consistent across monitors (22 and 5 participants out of the 23, respectively). Our findings indicate that the various research-grade activity monitors investigated show high inter-instrument reliability with respect to sedentary, PA and sleep-related estimates when their raw data are processed in an identical manner. These findings may have important implications for advancement towards monitor-based PA and sleep surveillance systems.
Franke, Barbara ; Michelini, Giorgia ; Asherson, Philip ; Banaschewski, Tobias ; Bilbow, Andrea ; Buitelaar, Jan K. ; Cormand, Bru ; Faraone, Stephen V. ; Ginsberg, Ylva ; Haavik, Jan ; Kuntsi, Jonna ; Larsson, Henrik ; Lesch, Klaus-Peter J. ; Ramos-Quiroga, J. Antoni ; Réthelyi, János M. ; Ribases, Marta ; Reif, Andreas
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
Highlights
• Up-to-date overview on developing new medications including candidates with novel bioloigical targets for the treatment of anxiety disorders and PTSD.
• Targeting glutamatergic, cholinergic and neurosteroid mechanisms can produce acute anxiolytic effects.
• Drugs, including psychedelics, are hypothesized to produce neuroplasticity to cause enduring clinical effects.
• Combining medication with psychological approaches may augment therapeutic efficacy.
• Advances in circuit neuroscience can be leveraged to inform the design of rationale drug targets.
Abstract
Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent and increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, are effective in alleviating symptoms of anxiety disorders and posttraumatic stress disorder (PTSD), at least in some individuals, but have unwanted side-effects and do not resolve underlying pathophysiology. After a period of stagnation, there is renewed enthusiasm from public, academic and commercial parties in designing and developing drug treatments for these disorders. Here, we aim to provide a snapshot of the current state of this field that is written for neuropharmacologists, but also practicing clinicians and the interested lay-reader. After introducing currently available drug treatments, we summarize recent/ongoing clinical assessment of novel medicines for anxiety and PTSD, grouped according to primary neurochemical targets and their potential to produce acute and/or enduring therapeutic effects. The evaluation of putative treatments targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic and neuropeptide systems, amongst others, are discussed. We emphasize the importance of designing and clinically assessing new medications based on a firm understanding of the underlying neurobiology stemming from the rapid advances being made in neuroscience. This includes harnessing neuroplasticity to bring about lasting beneficial changes in the brain rather than – as many current medications do – produce a transient attenuation of symptoms, as exemplified by combining psychotropic/cognitive enhancing drugs with psychotherapeutic approaches. We conclude by noting some of the other emerging trends in this promising new phase of drug development.
Bruckner, Franz ; Gruber, Judith R. ; Ruf, Alea ; Edwin Thanarajah, Sharmili ; Reif, Andreas ; Matura, Silke
Lifestyle factors—such as diet, physical activity (PA), smoking, and alcohol consumption—have a significant impact on mortality as well as healthcare costs. Moreover, they play a crucial role in the development of type 2 diabetes mellitus (DM2). There also seems to be a link between lifestyle behaviours and insulin resistance, which is often a precursor of DM2. This study uses an enhanced Healthy Living Index (HLI) integrating accelerometric data and an Ecological Momentary Assessment (EMA) to explore differences in lifestyle between insulin-sensitive (IS) and insulin-resistant (IR) individuals. Moreover, it explores the association between lifestyle behaviours and inflammation. Analysing data from 99 participants of the mPRIME study (57 women and 42 men; mean age 49.8 years), we calculated HLI scores—ranging from 0 to 4— based on adherence to specific low-risk lifestyle behaviours, including non-smoking, adhering to a healthy diet, maximally moderate alcohol consumption, and meeting World Health Organization (WHO) PA guidelines. Insulin sensitivity was assessed using a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) levels were used as a proxy for inflammation. Lifestyle behaviours, represented by HLI scores, were significantly different between IS and IR individuals (U = 1529.0; p = 0.023). The difference in the HLI score between IR and IS individuals was mainly driven by lower adherence to PA recommendations in the IR group. Moreover, reduced PA was linked to increased CRP levels in the IR group (r = −0.368, p = 0.014). Our findings suggest that enhancing PA, especially among individuals with impaired insulin resistance, holds significant promise as a preventive strategy.
Insulin resistance and working memory exploring the role of blood glucose levels and lifestyle
(2023)
vIntroduction: Type 2 diabetes mellitus and dementia are among the leading causes for reduced quality of life and life expectancy worldwide and often occur comorbidly. Both diseases are linked by altered insulin signaling. Lifestyle factors and blood glucose monitoring play an essential role in the prevention and treatment of type 2 diabetes. So far, a relationship between blood glucose levels, lifestyle, and cognitive performance – a main symptom of dementia - has mainly been established in laboratory settings which reduces its ecological validity.
Objectives: This study uses ambulatory assessment and continuous glucose monitoring to explore the link between blood glucose levels, lifestyle and working memory in an ecological setting. We hypothesize that glycemic variations affect working memory performance in daily life. Second, we hypothesize that a high variance in blood glucose levels has a higher impact on working memory in insulin resistant participants. With this study, we aim to expand the knowledge on the relationship of insulin resistance and cognitive performance from the laboratory setting to everyday life.
Methods: This prospective, exploratory study will include 80 subjects with insulin resistance and 80 healthy controls. At baseline, blood indicators of insulin resistance will be measured to determine group assignment. Our ambulatory assessment includes smartphone-based sampling and sensor-based assessment. Therefore, cognitive performance will be recorded over three consecutive days using a smartphone. Four times a day, a numerical working memory task is prompted by signal-based alarms on the smartphone. Blood glucose levels are recorded in parallel by continuous glucose monitoring. In addition, lifestyle factors such as diet ad physical activity are examined. Diet is assessed by 24-h dietary protocols and movement acceleration by accelerometery.
Multilevel modelling will be used to map the relationship between blood glucose levels and working memory at the within- and between-person level. Diet and exercise are included in the analyses as additional predictors.
Results: Data collection started in March 2021 and is ongoing. Up to now, 40 insulin resistant participants and 36 healthy controls have been measured. Our preliminary results indicate a positive association between blood glucose levels and working memory performance at the within-person level (estimate = .48, 95% CI [.07, .89], p =0.022). At the between-person level the analysis revealed an inverse association between blood glucose levels and working memory performance (estimate = -.45, 95 % CI [-.86 - -.05], p = 0.029).
Conclusion: Our preliminary results are in line with studies showing that an acute rise in blood glucose levels leads to short-term improvements, while stable glucose profiles are beneficial in the long term. This might expand the understanding of the impact of insulin resistance on working memory and represent a target for early interventions. Our preliminary analysis needs to be repeated in our final dataset to confirm our results.
Die Zöliakie ist eine immunvermittelte Systemerkrankung, die durch den Konsum glutenhaltiger Nahrung ausgelöst werden kann. Hierbei spielen sowohl eine genetische Prädisposition als auch verschiedene Umweltfaktoren eine Rolle. Die wissenschaftliche und gesellschaftliche Relevanz der Zöliakie hat in den letzten 25 Jahren zunehmend an Bedeutung gewonnen. Was man heute über die Erkrankung weiß, ist Ergebnis einer Vielzahl von Studien und Veröffentlichungen.
Ziel dieser Arbeit war anhand von szientometrischen Analysen ein umfassendes Bild über diese Forschungslandschaft zu erstellen. Es wurden dabei sowohl quantitative als auch qualitative Analyseverfahren zur Anwendung gebracht.
Getty, Patricia ; Kögler, Marie ; Pineda Cirera, Laura ; Fernàndez-Castillo, Noèlia ; Yotova, Anna Y. ; Slattery, David A. ; O'Leary, Aet ; Reif, Andreas
Esen-Sehir, Dilhan ; Yotova, Anna Y. ; Li, Li-Li ; Reif, Andreas ; Courtney, Michael J. ; Freudenberg, Florian
Tsengenbayar, Tsendmaa ; Yotova, Anna Y. ; Esen-Sehir, Dilhan ; Puspathasan, Melosha ; Reif, Andreas ; Slattery, David A. ; Freudenberg, Florian
Marishi, Aayush ; Esen-Sehir, Dilhan ; Tsengenbayar, Tsendmaa ; Reif, Andreas ; Freudenberg, Florian
Misiak, Błażej ; Wójta-Kempa, Monika ; Samochowiec, Jerzy ; Schiweck, Carmen ; Aichholzer, Mareike ; Reif, Andreas ; Samochowiec, Agnieszka ; Stańczykiewicz, Bartłomiej
Highligths
• Immune-inflammatory alterations might appear in subjects with ADHD.
• Blood levels of tumor necrosis factor-α might be reduced in individuals with ADHD.
• Individuals with ADHD might show elevated blood levels of interleukin-6.
Abstract
It has been observed that subclinical inflammation might be involved in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, studies investigating peripheral blood levels of immune-inflammatory markers have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing unstimulated serum or plasma levels of C-reactive protein (CRP) and cytokines in subjects with ADHD and healthy controls (the PROSPERO registration number: CRD 42021276869). Online searches covered the publication period until 30th Sep 2021 and random-effects meta-analyses were carried out. Out of 1844 publication records identified, 10 studies were included. The levels of interleukin (IL)-6 were significantly higher in studies of participants up to the age of 18 years (k = 10, g = 0.70, 95%CI: 0.10–1.30, p = 0.023) and after including those above the age of 18 years (k = 10, g = 0.71, 95%CI: 0.12–1.31, p = 0.019). In turn, the levels of tumor necrosis factor-α (TNF-α) were significantly lower in subjects with ADHD compared to healthy controls (k = 7, g = −0.16, 95%CI: −0.30 - -0.03, p = 0.020). Individual studies had a high contribution to the overall effect, since the overall effect was no longer significant after removing single studies. No significant differences were found with respect to the levels of CRP, IL-1β, IL-10 and interferon-γ. The present findings indicate that individuals with ADHD tend to show elevated levels of IL-6 and reduced levels of TNF-α. Larger and longitudinal studies recording potential confounding factors and comorbid psychopathology are needed to confirm our findings.
Aichholzer, Mareike ; Gangadin, Shiral S. ; Sommer, Iris ; Wijkhuis, Annemarie ; De Witte, Lotje D. ; Kahn, René S. ; Bahn, Sabine ; Drexhage, Hemmo A. ; Schiweck, Carmen
Highlights
• Inflammatory monocyte genes were used to stratify patients in a RCT with statins.
• One group (∼30% SSD patients) showed a distinct inflammatory monocyte signature.
• Within this “inflammatory” group, statins improved PANSS scores.
• Such changes were not observed for “inflammatory” patients receiving placebo.
• Depression scores in the “inflammatory” group improved during treatment as usual.
Abstract
Immune dysregulation has been reported in schizophrenia spectrum disorders (SSD). In the past decade, several trials using anti-inflammatory agents for treatment of SSD have been completed, with so far limited success. One such anti-inflammatory agent used is simvastatin. A recent, large-scale, randomized controlled trial with simvastatin augmentation failed to show improvement in the predefined primary outcome. However, baseline inflammatory profiles were not taken into account. Here we employed a data-driven clustering approach to investigate whether patients with an inflammatory monocyte gene signature respond better to add-on simvastatin treatment than those without such a signature, over a treatment period of 2 years. In 61 patients (60 randomized, 1:1 placebo:simvastatin) and healthy controls, a previously validated monocyte gene expression signature was assessed using quantitative polymerase chain reaction. Resulting delta cycle threshold values were used to identify patient clusters. Two major patient clusters with either up- or downregulated pro-inflammatory factors were detected. Linear mixed models showed a significant three-way interaction between the inflammatory cluster, treatment, and time for psychotic symptoms. Only patients treated with simvastatin who were in the inflammatory group, showed a consistent improvement: symptom severity gradually decreased after 3 months and reached significance after 12 and 24 months compared to baseline (p.adj<0.05). The effects were small, and overall between-group effects were not significant. Here, we show that patient stratification based on inflammatory gene expression might be useful to select appropriate treatment augmentation for patients with SSD, highlighting the need for precision medicine approaches. Our findings corroborate the results of the primary analyses, showing that in the overall group, simvastatin was not effective; however, at the individual level the treatment might make a difference.
Schiweck, Carmen ; Aichholzer, Mareike ; Gangadin, Shiral S. ; De Witte, Lotje D. ; Kahn, René S. ; Sommer, Iris ; Drexhage, Hemmo A.
Koch, Elena ; Freitag, Christine M. ; Mayer, Jutta ; Medda, Juliane ; Reif, Andreas ; Grimm, Oliver ; Ramos-Quiroga, Josep Antoni ; Palacio Sanchez, Judit ; Asherson, Philip ; Kuntsi, Jonna ; Pawley, Adam D. ; Buitelaar, Jan K. ; Bergsma, Douwe ; Ortega, Francisco B. ; Muntaner-Mas, Adrià ; Reinhard, Iris ; Reichert, Markus ; Giurgiu, Marco ; Ebner-Priemer, Ulrich
Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e-diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and controls aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within-subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive (n = 48), 2. individuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls (n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072)=5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Individuals with a combined presentation significantly showed the steepest slope of physical activity on positive affect (slope_inattentive=0.005, p<0.001; slope_combined=0.009, p<0.001; slope_controls=0.004, p = 0.008). Our analyses on negative affect revealed a negative association only in the individuals with a combined presentation (slope=-0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mechanism reinforcing hyperactivity needs to be empirically clarified in future studies.
Highlights
• Suicides which occurred in a biologics trial targeting the IL-17R are revisited.
• High IL-17 levels are found in depression by the majority of reports.
• Results from studies regarding IL-17 and psychosis are mixed.
• Very few psychiatric studies investigated IL-17 signalling in suicidality.
• Potential mechanisms how IL-17 influences neuro-inflammation are described.
Abstract:
Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine which plays a role in autoimmune disorders, such as psoriasis and multiple sclerosis, and is important for the defense against pathogens, particularly in the gut. However, IL-17 has recently also gained attention in association with suicidal behavior. In this review, we review the literature regarding IL-17 in psychiatric disorders and suicidality. We also take a closer look at the suicides which occurred in the clinical trial for psoriasis with brodalumab, a monoclonal antibody targeting the IL-17 receptor. Lastly, we discuss potential working mechanisms relevant to neuroinflammation and the possible involvement of IL-17.
Schiweck, Carmen ; Aichholzer, Mareike ; Reif-Leonhard, Christine ; Reif, Andreas ; Edwin Thanarajah, Sharmili
Pawley, Adam D. ; Mayer, Jutta ; Medda, Juliane ; Brandt, Geva A. ; Agnew-Blais, Jessica C. ; Asherson, Philip ; Rommel, Anna-Sophie ; Ramos-Quiroga, J. Antoni ; Palacio Sanchez, Judit ; Bergsma, Douwe ; Buitelaar, Jan K. ; Ortega, Francisco B. ; Muntaner-Mas, Adrià ; Grimm, Oliver ; Reif, Andreas ; Freitag, Christine M. ; Kuntsi, Jonna
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Introduction: The influence of our diet on mental health is of increasing importance in current research. Study results on the gut-brain axis suggest that the gut microbiome can influence mental processes via neuronal, hormonal and immune signaling pathways [1]. The gut microbiome is largely influenced by our diet. Some studies provide evidence that a "Western diet" rich in saturated fat and sugar may promote mental disorders [2]. There is evidence, that dietary behaviour in individuals with Attention Deficit Hyperactivity Disorder (ADHD) is characterized by an increased intake of sugar and saturated fat [3]. So far, it is unclear whether this dietary pattern contributes to ADHD symptoms such as impulsivity. The aim of this study is to investigate the influence of certain macronutrients such as fats and mono/disaccharides on impulsivity in individuals with ADHD. Using our APPetite-mobile-app [4] enabled us to study dietary behaviour and momentary impulsiveness in everyday life of our participants.
Methods: 43 participants with ADHD (mean age 36.0 ± 12.3 years, 21 females) and 186 healthy controls (mean age 28.5 ± 7.7 years, 133 females) without any psychiatric condition were included into the study. Food intake was recorded over a period of three days using the APPetite-mobile-app via a 6 step process: (1) Selection of meal type, (2) Entry of time of meal, (3) Selection of consumed foods and drinks, (4) Specification of consumed amounts, (5) Presentation of reminder for commonly forgotten foods, and (6) Indication of predominant reason for eating. In addition to entering consumed foods in the APPetite-mobile-app, subjects completed an online food log for the last 24 hours (myfood 24) at the beginning of the study. After the data collection period, a detailed analysis of the ingested nutrients was performed for each subject. Trait impulsivity was assessed using the UPPS-P, a self-assessment questionnaire. Momentary impulsiveness was assessed via the mHealth APP by means of the Momentary Impulsiveness scale (MIS). The MIS consists of 4 questions capturing different aspects of impulsivity. The participants were prompted to answer these questions at 8 semi-random times per day between 8 AM and 10 PM. The minimum time between 2 prompts was 1 hour. Thereby participants could not predict the exact time of the next prompt and the assessed situations are a better reflection of the participant’s real life.
Results: ANOVA revealed higher levels of both, trait and momentary impulsivity in individuals with ADHD compared to controls (p < 0,01). After preprocessing of data that was sampled via the mHealth APP is completed, a regression analysis with different macronutrients as predictors and impulsivity as dependent variable will be computed. To assess the association between momentary impulsiveness and dietary intake, generalized linear multilevel modelling will be used. Results of these analyses will be presented.
Understanding the underlying mechanisms that link psychopathology and physical comorbidities in schizophrenia is crucial since decreased physical fitness and overweight pose major risk factors for cardio-vascular diseases and decrease the patients’ life expectancies. We hypothesize that altered reward anticipation plays an important role in this. We implemented the Monetary Incentive Delay task in a MR scanner and a fitness test battery to compare schizophrenia patients (SZ, n = 43) with sex- and age-matched healthy controls (HC, n = 36) as to reward processing and their physical fitness. We found differences in reward anticipation between SZs and HCs, whereby increased activity in HCs positively correlated with overall physical condition and negatively correlated with psychopathology. On the other handy, SZs revealed stronger activity in the posterior cingulate cortex and in cerebellar regions during reward anticipation, which could be linked to decreased overall physical fitness. These findings demonstrate that a dysregulated reward system is not only responsible for the symptomatology of schizophrenia, but might also be involved in physical comorbidities which could pave the way for future lifestyle therapy interventions.
The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.
Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Fernàndez-Castillo, Noèlia ; Cabana-Domínguez, Judit ; Kappel, Djenifer B. ; Torrico, Bàrbara ; Weber, Heike ; Lesch, Klaus-Peter J. ; Lao, Oscar ; Reif, Andreas ; Cormand, Bru
Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.
Oremek, Gerhard ; Unkelbach, Uwe Maria Ernst ; Solem, Eivind ; Seiffert, Ulrich B. ; Lehmann, Paul ; Röddiger, Ralf
Haas, Sylvia ; Schellong, Sebastian M. ; Tebbe, Ulrich ; Gerlach, Horst-Eberhard ; Bauersachs, Rupert ; Melzer, Nima ; Abletshauser, Claudia ; Sieder, Christian ; Bramlage, Peter ; Riess, Hanno
Background: Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer.
Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer.
Methods: Acutely-ill, non-surgical patients ≥70 years with (n = 274) or without cancer (n = 2,965) received certoparin 3,000 UaXa o.d. or UFH 5,000 IU t.i.d. for 8-20 days.
Results: 1) Thromboembolic events in cancer patients (proximal DVT, symptomatic non-fatal PE and VTE-related death) occurred at 4.50% with certoparin and 6.03% with UFH (OR 0.73; 95% CI 0.23-2.39). Major bleeding was comparable and minor bleedings (0.75 vs. 5.67%) were nominally less frequent. 7.5% of certoparin and 12.8% of UFH treated patients experienced serious adverse events. 2) Thromboembolic event rates were comparable in patients with or without cancer (5.29 vs. 4.13%) as were bleeding complications. All cause death was increased in cancer (OR 2.68; 95%CI 1.22-5.86). 10.2% of patients with and 5.81% of those without cancer experienced serious adverse events (OR 1.85; 95% CI 1.21-2.81).
Conclusions: Certoparin 3,000 UaXa o.d. and 5,000 IU UFH t.i.d. were equally effective and safe with respect to bleeding complications in patients with cancer. There were no statistically significant differences in the risk of thromboembolic events in patients with or without cancer receiving adequate anticoagulation.
Trial Registration: clinicaltrials.gov, NCT00451412
Die Befundung individueller Fallkonstellationen bei geeigneten Parameterkonstellationen und Fragestellungen ist ein zentraler Bestandteil der medizinischen Aufgabenstellung des Fachgebietes Laboratoriumsmedizin.
Um den labormedizinischen Anteil der medizinischen Diagnostik umfassend zu unterstützen, sollte unabhängig vom Einsatz wissensbasierter Systeme die labormedizinische Spezialbefundung generell bei entsprechenden Fragestellungen und Kenngrößenkonstellationen sowie bei Verfügbarkeit der jeweils geeigneten Methodik, bei Vorhandensein der entsprechenden Krankheitsprävalenzen und der entsprechenden labormedizinischen Kenntnisse durchgeführt werden. Dieser Notwendigkeit wird aber oft wegen des Aufwandes der individuellen fallbezogenen Befunderstellung nicht im erforderlichen Umfang entsprochen.
Bei richtigem Einsatz wissensbasierter Systeme kann die labormedizinische Spezialbefundung effizient unterstützt und auf hohem Niveau optimiert und, soweit sinnvoll, standardisiert werden. Dies ist eine der wesentlichen Zielsetzungen der Pro.M.D.-Entwicklung (Prologsystem zur Unterstützung Medizinischer Diagnostik). Weitere zum Teil ebenfalls bereits zu einem großen Teil erreichte Ziele bei der Pro.M.D.-Entwicklung sind die Schaffung einer gemeinsamen Notationsebene für das bei der labormedizinischen Spezialbefundung formalisierbare Wissen und die dadurch erreichbare Verbesserung des fallbezogenen Erfahrungsaustausches.
Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
(2020)
Fuhrmann, Dominik Christian ; Mondorf, Antonia Maria ; Beifuß, Josefine ; Jung, Michaela ; Brüne, Bernhard
Highlights
• Hypoxia decreases NCOA4 transcription in primary human macrophages.
• NCOA4 mRNA is a target of miR-6862-5p.
• Lowering NCOA4 increases FTMT abundance under hypoxia.
• FTMT and FTH protect from ferroptosis.
• Tumor cells lack the hypoxic decrease of NCOA4 and fail to stabilize FTMT.
Abstract
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
Berger, Martin ; Maqua, Hendrik ; Lysaja, Katharina ; Mause, Sebastian Frederik ; Hindle, Mathew S. ; Naseem, Khalid ; Dahl, Edgar ; Speer, Thimoteus ; Marx, Nikolaus ; Schütt, Katharina
Essentials
• The role of platelet IL-1β release in chronic inflammation is currently unclear.
• Platelets from 65 patients with varying degrees of chronic inflammation were studied.
• Chronic inflammation linked to reduced levels of intracellular IL-1β and IL-1β release.
• Chronic inflammation induces a phenotype that indicates chronic IL-1β release from platelets.
Abstract
Background: Chronic inflammation is a cardiovascular risk factor, and interleukin-1β (IL-1β) is central to the inflammatory host response. Platelets contain the NLRP3 inflammasome and are able to translate IL-1β messenger RNA (mRNA) and secrete mature IL-1β upon activation. However, the role of a chronic inflammatory environment in platelet IL-1β mRNA and protein content remains unclear.
Objectives: The aim of the current study was to investigate intracellular platelet IL-1β and IL-1β mRNA in a chronic inflammatory state.
Methods: Sixty-five patients with stable inflammation (ie, high-sensitivity C-reactive protein within predefined margins in 2 separate measurements) were stratified according to high-sensitivity C-reactive protein levels in low (0.0-0.9 mg/L), medium (1.0-2.9 mg/L), and high (3.0-9.9 mg/L) risk groups. Platelet reactivity as well as platelet IL-1β protein synthesis were studied.
Results: The highest risk group was characterized by a distinct cardiovascular risk profile and approximately 20% higher platelet counts. While platelet reactivity was not different, a reduction in intracellular platelet IL-1β mRNA and IL-1β protein levels was observed in the highest risk group and was linked to decreased platelet size and granularity. This signature suggests a phenotype of chronic IL-1β secretion and could be experimentally phenocopied by stimulation of platelets from healthy volunteers with either TRAP-6 or collagen related peptide (CRP-XL).
Conclusion: Our data suggest a phenotype of chronic IL-1β secretion by platelets in patients with chronic sterile inflammation.
Panuccio, Giuseppe ; De Rosa, Salvatore ; Landmesser, Ulf ; Leistner, David M. ; Abdelwahed, Youssef S.
An 80-year-old post–coronary artery bypass graft (CABG) patient had an acute coronary syndrome with non–ST-segment elevation myocardial infarction (ACS-NSTE) with saphenous vein graft (SVG)–obtuse marginal stenosis. High-definition intravascular ultrasound revealed an underexpanded SVG stent with a hyperechoic structure. Optical coherence tomography confirmed surgical clip causing compression, resolved by post-dilation. This case underscores ACS-NSTE complexity post-CABG and the critical role of coronary imaging in optimizing interventions by addressing surgical clip–induced compression.
Chronic kidney disease (CKD) represents an independent risk factor for cardiovascular diseases (CVD). Accordingly, CKD patients show a substantial increased risk of cardiovascular mortality. Inflammation represents an important link between CKD and CVD. The interaction between endothelial cells and effector cells of the innate immune system plays a central role in the development and progression of inflammation. Vascular injury causes endothelial dysfunction, leading to augmented oxidative stress, increased expression of leukocyte adhesion molecules and chronic inflammation. CKD induces numerous metabolic changes, creating a uremic milieu resulting in the accumulation of various uremic toxins. These toxins lead to vascular injury, endothelial dysfunction and activation of the innate immune system. Recent studies describe CKD-dependent changes in monocytes that promote endothelial dysfunction and thus CKD progression and CKD-associated CVD. The NLR family pyrin domain containing 3–interleukin-1β–interleukin-6 (NLRP3–IL-1β–IL-6) signaling pathway plays a pivotal role in the development and progression of CVD and CKD alike. Several clinical trials are investigating targeted inhibition of this pathway indicating that anti-inflammatory therapeutic strategies may emerge as novel approaches in patients at high cardiovascular risk and nonresolving inflammation. CKD patients in particular would benefit from targeted anti-inflammatory therapy, since conventional therapeutic regimens have limited efficacy in this population.
Higuchi, Takahiro ; Serfling, Sebastian E. ; Leistner, David M. ; Speer, Thimoteus ; Werner, Rudolf A.
PET probes targeting fibroblasts are frequently used for varying applications in oncology. In recent years, the clinical spectrum has been expanded towards cardiovascular medicine, e.g., after myocardial infarction, in aortic stenosis or as a non-invasive read-out of atherosclerosis. We herein provide a brief overview of the current status of this PET radiotracer in the context of cardiovascular disease, including translational and clinical evidence. In addition, we will also briefly discuss future applications, e.g., the use of fibroblast-targeting PET to investigate bilateral organ function along the cardiorenal axis.
Highlights
• Currently, China has the most publications, ahead of the USA and European countries.
• Research focuses are strictly separated into ecological and material science topics.
• Russia and Ukraine are among the frontrunners with a clear focus on materials science.
• The focus in PFAS research is shifting toward ecological issues.
• A national imbalance can be observed that leaves the low economies behind.
Abstract
The European Commission's current efforts to launch the largest proposal to restrict per- and polyfluoroalkyl substances (PFAS) in history reflect the dire global plight of PFAS accumulation in the environment and their health impacts. While there are existing studies on PFAS research, there is a lack of comprehensive analysis that both covers the entire research period and provides deep insights into global research patterns, incentives, and barriers based on various parameters. We have been able to demonstrate the increasing interest in PFAS research, although citation numbers are declining prematurely. Policy regulations based on proving and establishing the toxicity of PFASs have stimulated research in developed countries and vice versa, with increasing emphasis on ecological aspects. China, in particular, is investing increasingly in PFAS research, but without defining or implementing regulations - with devastating effects. The separation of industrial and environmental research interests is clear, with little involvement of developing countries, even though their exposure to PFAS is devastating. It, therefore, requires increased globally networked and multidisciplinary approaches to address PFAS contamination challenges.
Highlights
• CD62p + exosomes were significantly increased in septic polytrauma-patients, while CD40+, as well as CD49e + exosomes were diminished.
• Exosomal IL-6 concentration in septic patients reflects the systemic IL-6.
• Exosomal IL-10 concentration seemed to be constant in patients and healthy controls.
• Decrease of miR-21 in exosomes was associated with the development of sepsis, while exosomal miR-93, miR-155 and miR-92a were not specifically altered.
Abstract
Sepsis as a severe systemic inflammation leads oftentimes to organ dysfunction and subsequently to death. In polytrauma patients, septic complications represent with 45% the predominant cause of late death and are responsible for extremely high costs in the healthcare system. Therefore, clinicians have to detect as early as possible the begin of sepsis to improve the patient's outcome. One new promising diagnostic tool to diagnose septic complications in polytraumatized patients are exosomes.
Plasma samples from polytraumatized patients (Injury Severity Score (ISS) ≥16) which developed sepsis (n = 10) and without sepsis (n = 10), were collected at emergency room (ER), 24h and 5 days after trauma. The EVs subpopulations were investigated by a bead-based multiplex flow cytometry measurement of surface epitopes and were compared with plasma EVs from healthy controls (n = 10). Moreover, exosomal cytokine concentrations were measured via high-sensitive ELISA and were correlated with systemic concentrations. For miRNA cargo analysis, we analysed the miRNAs miR-1298-5p, miR-1262, miR-125b-5p, miR-92a-3p, miR-93-5p, miR-155-5p and miR-21-5p and compared their exosomal concentrations by means of RT-qPCR.
CD62p + exosomes were significantly increased in septic polytrauma-patients (p ≤ 0.05), while CD40+exosomes, as well as CD49e + exosomes were diminished (p ≤ 0.05). Furthermore, we observed that the exosomal IL-6 concentration reflects the systemic IL-6 concentration (r2 = 0.63) and did not significantly alter between patients with and without sepsis. The exosomal IL-10 concentration seemed to be constant in all patients and healthy controls. We observed that a decrease of miR-21-5p in exosomes was associated with the development of sepsis (p ≤ 0.05), while exosomal miR-93-5p, miR-155-5p and miR-92a-3p were not specifically altered in septic patients.
Taken together, the present study in polytraumatized patients demonstrated that the development of sepsis is associated with an increase of CD62p + exosomes. Furthermore, the exosomal cargo was changed in septic patients: miR-21-5p was diminished.
Understanding effects of emotional valence and stress on children’s memory is important for educational and legal contexts. This study disentangles the effects of emotional content of to-be-remembered information (i.e., items differing in emotional valence and arousal), stress exposure, and associated cortisol secretion on children’s memory. We also examine whether girls’ memory is more affected by stress induction. 143 6-to-7-year-old children were randomly allocated to the Trier Social Stress Test for Children (n = 103) or a control condition (n = 40). 25 minutes after stressor onset, children incidentally encoded 75 objects varying in emotional valence (crossed with arousal) together with neutral scene backgrounds. We found that response-bias corrected memory was worse for low arousing negative items than neutral and positive items, with the latter two categories not being different from each other. Whilst boys’ memory was largely unaffected by stress, girls in the stress condition showed worse memory for negative items, especially the low arousing ones, than girls in the control condition. Girls, compared to boys, reported higher subjective stress increases following stress exposure, and had higher cortisol stress responses. Whilst a higher cortisol stress response was associated with better emotional memory in girls in the stress condition, boys’ memory was not associated with their cortisol secretion. Taken together, our study suggests that 6-to-7-year-old children, more so girls, show memory suppression for negative information. Girls’ memory for negative information, compared to boys, is also more strongly modulated by stress experience and the associated cortisol response.
Kessel, Johanna ; Göymen, Elif ; Wolf, Timo ; Wetzstein, Nils ; Küpper-Tetzel, Claus Philippe ; Behrens, Pia ; Borgans, Frauke ; Balaban, Ümniye ; Hogardt, Michael ; Wichelhaus, Thomas A. ; Stephan, Christoph
Highlights
• Open pulmonary tuberculosis patient discharge policy was not reviewed for decades.
• After smear-negativity conversion, substantial cultural positivity may remain.
• It remains unclear, whether smear-negative patients still may be infective.
• The clinical relevance of this finding warrants further investigation.
Abstract
Objectives: Patients with open pulmonary tuberculosis (opTB) are subject to strict isolation rules. Sputum smear microscopy is used to determine infectivity, but sensitivity is lower than for culture. This study aimed to investigate the clinical relevance of this mismatch in contemporary settings.
Methods: Differential results between microscopy and culture were determined at the time of microscopic sputum conversion, from all patients with opTB between 01/2013 and 12/2017. In addition, data on HIV, multi/extensive drug-resistant TB status, time to smear- and cultural-negativity conversion were analyzed; and a Kaplan-Meier curve was developed.
Results: Of 118 patients with opTB, 58 had demographic data available for microbiological and clinical follow-up analysis; among these, 26 (44.8%) had still at least one positive culture result. Median time from opTB-treatment initiation to full microscopic sputum- or culture conversion, was 16.5 days (range 2-105), and 20 days (1-105), respectively (median difference: +3.5 days). Sixteen days after de-isolation, >90% had converted culturally. HIV- or multi/extensive drug-resistant TB status did not impact conversion time.
Conclusion: When patients with opTB were de-isolated after 3 negative sputum smear microscopy tests, a substantial part still revealed cultural growth of Mycobacterium tuberculosis complex, but it remains unclear, whether smear-negative and culturally-positive individuals on therapy are really infective. Thus, the clinical relevance of this finding warrants further investigation.
Bauersachs, Rupert ; Wu, Olivia ; Hawkins, Neil ; Bowrin, Kevin ; Wojciechowski, Piotr ; Clay, Emilie ; Huelsebeck, Maria
Background. The guidelines on antithrombotic treatment in patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization of the lower extremities were developed based on heterogeneous trials, assessing various dose regimens and recruiting patients who were subjected to different revascularization procedures. Objective. To compare efficacy and safety of treatments used in patients with PAD undergoing peripheral revascularization accounting for between-trial heterogeneity and large dispersion of the quality of evidence. Methods. A systematic literature review of randomised controlled trials (RCTs) recruiting adult patients with PAD receiving antithrombotics was conducted until January 2020. Hazard ratios (HR) were pooled using Bayesian network meta-analysis. The estimated between-treatment effects were presented as HR together with 95% credible intervals. The base case analysis included studies recruiting patients following recent peripheral revascularization, who received treatment regimens administered within the recommended therapeutic window, while a sensitivity scenario included all identified trials. Results. Thirteen RCTs were identified (8 RCTs enrolled patients following peripheral revascularization and 5 RCTs regardless of the previous revascularization). Five trials, recruiting an overall of 8349 patients, were considered for the base case analysis. Of those, 6564 patients were recruited in the VOYAGER PAD trial comparing rivaroxaban plus aspirin (RIV plus ASA) versus ASA. RIV plus ASA was associated with a lower risk of repeated peripheral revascularization versus ASA monotherapy (HR = 0.88 [0.79, 0.99]), however having a trend towards an increased rate of major bleeding (HR = 1.43 [0.98, 2.11]). There was no evidence for differences between RIV plus ASA and dual antiplatelet therapy and vitamin K antagonists plus ASA. Similar results were observed in sensitivity analyses. Conclusions. RIV plus ASA is associated with reduced risk of revascularization compared with ASA monotherapy, but the evidence for other comparators, in particular antiplatelet regimens, was insufficient to guide treatment decisions and highlights the challenge in establishing the magnitude of comparative efficacy using existing RCTs.
Bauersachs, Rupert ; Wu, Olivia ; Briere, Jean-Baptiste ; Bowrin, Kevin ; Borkowska, Katarzyna ; Jakubowska, Anna ; Taieb, Vanessa ; Toumi, Mondher ; Huelsebeck, Maria
Aims: Acetylsalicylic acid (ASA) is widely used for the prevention of atherothrombotic events in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD), but the risk of vascular events remains high. We aimed at identifying randomised controlled trials (RCTs) on antithrombotic treatments in patients with chronic CAD or PAD.
Methods: Searches were conducted on MEDLINE, EMBASE, and CENTRAL on March 1st, 2018. This systematic review (SR) uses a narrative synthesis to summarize the evidence for the efficacy and safety of antiplatelet and anticoagulant therapies in the population of both chronic CAD or PAD patients.
Results: Four RCTs from 27 publications were included. Study groups included 15,603 to 27,395 patients. ASA alone was the most extensively studied (n = 3); other studies included rivaroxaban with or without ASA (n = 1), vorapaxar alone (n = 1), and clopidogrel with (n = 1) or without ASA (n = 1). Clopidogrel alone and clopidogrel plus ASA compared to ASA presented similar efficacy with comparable safety profile. Rivaroxaban plus ASA significantly reduced the risk of the composite of cardiovascular death, myocardial infarction, and stroke compared to ASA alone, although major bleeding with rivaroxaban plus ASA increased.
Conclusion: There is limited and heterogeneous evidence on the prevention of atherothrombotic events in patients with chronic CAD or PAD. Clopidogrel alone and clopidogrel plus ASA did not demonstrate superiority over ASA alone. A combination of rivaroxaban plus ASA may offer significant additional benefit in reducing cardiovascular outcomes, yet it may increase the risk of bleeding, compared to ASA alone.
Portas, Laura ; Bauersachs, Rupert ; Bowrin, Kevin ; Briere, Jean-Baptiste ; Cohen, Alexander ; Huelsebeck, Maria ; Jones, Schuyler ; Quint, Jennifer K.
Background: Symptoms, severity, and acuteness of peripheral artery disease (PAD) are major determinants of severe limb symptoms, subsequent risk of cardiovascular events, and mortality. Lower-extremity revascularization (LER) is a key option to relieve symptoms and to prevent limb loss in symptomatic patients with PAD. This study aimed to quantify the burden of disease among patients with PAD-LER in England.
Methods: A retrospective population-based study of linked primary and secondary care electronic health records, included 13,869 adult patients (aged ⩾ 18 years) with PAD-LER from 2003 to 2018. The incidence of first ever PAD-LER was estimated both overall and by type of procedure (endovascular/surgical). Health resource utilization associated with PAD-related complications and treatment patterns were assessed.
Results: A high annual incidence of lower-limb revascularization (41.2 per 1000 person years) and a nearly double incidence of endovascular first revascularization compared with open surgery were observed. More than 70% of patients with PAD-LER had a history of hyperlipidemia and hypertension and roughly one-third were diabetic and had a history of coronary artery disease. Cardiovascular mortality accounted for one-third (34.1 per 1000 person years) of all-cause mortality. Over 93% of patients were hospitalized for any reason and the commonest reasons for hospitalization were cardiovascular diseases and PAD with about one-third hospitalized for revascularization reoccurrence.
Conclusion: There is a significant burden of PAD-LER to the individual and society with ongoing healthcare resource utilization, treatment, and increasing mortality.
Bauersachs, Rupert ; Zeymer, Uwe ; Briere, Jean-Baptiste ; Marre, Caroline ; Bowrin, Kevin ; Huelsebeck, Maria
Background. Atherothrombotic disease, including coronary artery disease (CAD) and peripheral artery disease (PAD), can lead to cardiovascular (CV) events, such as myocardial infarction, stroke, limb ischemia, heart failure, and CV death. Aim. Evaluate the humanistic and economic burden of CAD and PAD and identify unmet needs through a comprehensive literature review. Methods. Relevant search terms were applied across online publication databases. Studies published between January 2010 and August 2017 meeting the inclusion/exclusion criteria were selected; guidelines were also included. Two rounds of screening were applied to select studies of relevance. Results. Worldwide data showed approximately 5–8% prevalence of CAD and 10–20% prevalence of PAD, dependent on the study design, average age, gender, and geographical location. Data from the REACH registry indicated that 18–35% of patients with CAD and 46–68% of patients with PAD had disease in one or more vascular beds. Use of medication to control modifiable CV risk factors was variable by country (lower in France than in Canada); statins and aspirin were the most widely used therapies in patients with chronic disease. Survival rates have improved with medical advancements, but there is an additional need to improve the humanistic burden of disease (i.e., associated disability and quality of life). The economic burden of atherothrombotic disease is high and expected to increase with increased survival and the aging population. Conclusion. CAD and PAD represent a substantial humanistic and economic burden worldwide, highlighting a need for new interventions to reduce the incidence of atherothrombotic disease.
Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000–800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.
Christen, Urs ; Pouzol, Laetitia ; Tunis, Mélanie ; Sassi, Anna ; Tondello, Camilla ; Bayer, Monika ; Hintermann, Edith ; Strasser, Daniel S. ; Schuldes, Sabrina ; Mentzel, Ulrich ; Martinic, Marianne M.
Treatment of patients with recent-onset type 1 diabetes with an anti-CD3 antibody leads to the transient stabilization of C-peptide levels in responder patients. Partial efficacy may be explained by the entry of islet-reactive T-cells spared by and/or regenerated after the anti-CD3 therapy. The CXCR3/CXCL10 axis has been proposed as a key player in the infiltration of autoreactive T cells into the pancreatic islets followed by the destruction of β cells. Combining the blockade of this axis using ACT-777991, a novel small-molecule CXCR3 antagonist, with anti-CD3 treatment may prevent further infiltration and β-cell damage and thus, preserve insulin production. The effect of anti-CD3 treatment on circulating T-cell subsets, including CXCR3 expression, in mice was evaluated by flow cytometry. Anti-CD3/ACT-777991 combination treatment was assessed in the virally induced RIP-LCMV-GP and NOD diabetes mouse models. Treatments started at disease onset. The effects on remission rate, blood glucose concentrations, insulitis, and plasma C-peptide were evaluated for the combination treatment and the respective monotherapies. Anti-CD3 treatment induced transient lymphopenia but spared circulating CXCR3+ T cells. Combination therapy in both mouse models synergistically and persistently reduced blood glucose concentrations, resulting in increased disease remission rates compared to each monotherapy. At the study end, mice in disease remission demonstrated reduced insulitis and detectable plasma C-peptide levels. When treatments were initiated in non-severely hyperglycemic NOD mice at diabetes onset, the combination treatment led to persistent disease remission in all mice. These results provide preclinical validation and rationale to investigate the combination of ACT-777991 with anti-CD3 for the treatment of patients with recent-onset diabetes.
Ottomana, Angela Maria ; Presta, Martina ; O'Leary, Aet ; Sullivan, Mairéad ; Pisa, Edoardo ; Laviola, Giovanni ; Glennon, Jeffrey C. ; Zoratto, Francesca ; Slattery, David A. ; Macrì, Simone
Highlights
• Hyperglycaemia, in rodents, is consistently associated with cognitive impairments.
• The strength of this association is supported by the heterogeneity of the studies.
• The study of the role of insulin on cognition is mainly limited to spatial memory.
• Preclinical studies on the role of insulin signalling on cognition are male biased.
Abstract
Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer’s disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia – as a proxy of insulin-related metabolic dysfunctions – and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.
Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice
(2022)
Langer, Florian ; Gerlach, Horst E. ; Schimke, Alexandra ; Heinken, Andreas ; Hoffmann, Ulrich ; Noppeney, Thomas ; Pittrow, David ; Klotsche, Jens ; Rabe, Eberhard ; Bauersachs, Rupert
Highlights
• In acute isolated SVT, the prevalence of cancer is almost 7 %.
• Cancer increases the SVT-associated VTE risk at 3 and 12 months.
• Cancer patients with isolated SVT may benefit from prolonged anticoagulation.
Abstract
Background: Despite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice.
Methods: INSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed.
Results: Of 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant.
Conclusion: Cancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.
ClinicalTrials.gov identifier: NCT02699151.
Bauersachs, Rupert ; Gerlach, Horst E. ; Heinken, Andreas ; Hoffmann, Ulrich ; Langer, Florian ; Noppeney, Thomas ; Pittrow, David ; Klotsche, Jens ; Rabe, Eberhard
Objective: Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions.
Methods: Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding.
Results: A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m2). SVT was below the knee in 54.5%, above the knee in 26.7%, above and below the knee in 18.8%. At baseline, 93.6% received pharmacological treatment (65.7% fondaparinux, 23.2% heparins, 4.3% direct oral anticoagulants [DOACs], 14.5% analgesics), 77.0% compression treatment, and 1.9% surgery; 6.4% did not receive any anticoagulation. The primary outcome occurred in 5.8%; 4.7% had recurrent or extended SVT, 1.7% DVT, and 0.8% PE. Clinically relevant non-major bleeding occurred in 1.2% and major bleeding in 0.3%. Complete clinical recovery of SVT was reported in 708 patients (62.4%). Primary outcome adjusted by propensity score and for treatment duration was lower with fondaparinux compared with low molecular weight heparin (4.4% vs. 9.6%; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.3 - 0.9; p = .017). On multivariable analysis, associated factors for primary outcome included another SVT prior to the present SVT event (HR 2.3), age per year (HR 0.97), duration of drug treatment per week (HR 0.92), and thrombus length (HR 1.03).
Conclusion: At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.
Objectives: Since the introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs), an additional treatment option, apart from VKAs, has become available for stroke prevention in patients with atrial fibrillation (AF). For various reasons, it is important to consider patients’ preferences regarding type of medication, particularly in view of the established relationship between preferences towards treatment, associated burden of treatment, and treatment adherence. This review aimed to systematically analyse the scientific literature assessing the preferences of AF patients with regard to long-term oral anticoagulant (OAC) treatment.
Methods: We searched the MEDLINE, Scopus and EMBASE databases (from 1980 to 2015), added records from reference lists of publications found, and conducted a systematic review based on all identified publications. Outcomes of interest included any quantitative information regarding the opinions or preferences of AF patients towards OAC treatment, ideally specified according to different clinical or convenience attributes describing different OAC treatment options.
Results: Overall, 27 publications describing the results of studies conducted in 12 different countries were included in our review. Among these, 16 studies analysed patient preferences towards OACs in general. These studies predominantly assessed which benefits (mainly lower stroke risk) AF patients would require to tolerate harms (mainly higher bleeding risk) associated with an OAC. Most studies showed that patients were willing to accept higher bleeding risks if a certain threshold in stroke risk reduction could be reached. Nevertheless, most of the publications also showed that the preferences of AF patients towards OACs may differ from the perspective of clinical guidelines or the perspective of physicians. The remaining 11 studies included in our review assessed the preferences of AF patients towards specific OAC medication options, namely NOACs versus VKAs. Our review showed that AF patients prefer easy-to-administer treatments, such as treatments that are applied once daily without any food/drug interactions and without the need for bridging and frequent blood controls.
Conclusion: Stroke risk reduction and a moderate increase in the risk of bleeding are the most important attributes for an AF patient when deciding whether they are for or against OAC treatment. If different anticoagulation options have similar clinical characteristics, convenience attributes matter to patients. In this review, AF patients favour attribute levels that describe NOAC treatment.
Klingelhöfer, Doris ; Braun, Markus ; Oremek, Gerhard ; Brüggmann, Dörthe ; Groneberg, Jan David Alexander
The question of whether nuclear energy—as a source with relatively low carbon dioxide emissions—can be classified as a sustainable energy source has come into focus in connection with climate change. There is a controversy over securing independence from fossil fuels and gas supplies from other countries through a revival of nuclear energy. On the other hand, some viewpoints are critical: the handling of nuclear waste and the still unclear risks to human health and the environment, especially in light of recent perils from Russian military attacks on Ukrainian nuclear plants. To evaluate the worldwide publications on nuclear energy under health and environmental aspects, socio-economic parameters were included to provide an informed background for all stakeholders, from scientists to decision-makers. The correlation between the number of nuclear power plants and the publication output of the countries is proven to be highly significant. Thus, the operating countries publish the most. It has been shown that the development and economic use of nuclear energy are major stimuli for scientific endeavors. Reactor accidents have also spurred research. Mathematical risk modeling has been the area with the highest citation rate to date, but environmental and health aspects have become more important, especially after major accidents. The results show the importance of economic interests in research on nuclear energy from health and environmental aspects. Against the background of transnational hazards, global research participation should be encouraged. Moreover, the international debate should not ignore the reality of threats and their possible impacts.
Highlights
• Forensic experts should be questioned about their education and experience.
• Reliability of methods used to estimate the PMI should be evident when exposed in court.
• Judges should question if the right method was used in the right manner.
• The PMI is an estimate and cannot be interpreted as the actual time of death.
Abstract
When a capital crime is committed the post-mortem interval (PMI) is of particular importance in investigating a suspect’s alibi in court. A forensic expert can use different methods to estimate the PMI. This research focuses on who is considered an expert in court and whether the methods used to estimate the PMI are reliable. In this study, the methods used to estimate the PMI and the experts consulted, available in Dutch jurisprudence, in the period 2010–2019 were investigated. Ninety-four judicial cases were included and multiple experts and methods of estimating the PMI were found. As part of this study, the methods that were used to estimate the PMI in court were subjected to the Daubert criteria. Of these methods, only the Henssge nomogram and entomological methods met the Daubert criteria. However, the methods are only useful when applied by the right forensic expert and in the right manner. Unfortunately, this was not always the case.
[Posterabstract] Aussagekraft von Pyruvatkinase Typ Tumor M 2 bei Patienten mit einem Seminom
(1994)
Die Einteilung der Pneumonien richtet sich neben klinischen und pathologischen vor allem nach ätiologischen Gesichtspunkten. Es werden diesbezüglich die respirato- bzw. pneumotropen Viren vorgestellt, daneben differentialdiagnostisch wichtige andere Infektionserreger der "Viruspneumonie" (M. pneumoniae, Chlamydia psittaci, Coxiella burnetii) beschrieben und ihre klinischen Aspekte, labordiagnostischen Möglichkeiten sowie die Aussagekraft der verschiedenen Nachweisverfahren diskutiert. Die Letalität der primär virusbedingten Pneumonien ist zwar niedrig, der respiratotrope Virusbefall kann aber Schrittmacher für schwerebakterielle Superinfektionen sein.
Determination of a minimal postmortem interval via age estimation of necrophagous diptera has been restricted to the juvenile stages and the time until emergence of the adult fly, i.e. up until 2–6 weeks depending on species and temperature. Age estimation of adult flies could extend this period by adding the age of the fly to the time needed for complete development. In this context pteridines are promising metabolites, as they accumulate in the eyes of flies with increasing age. We studied adults of the blow fly Lucilia sericata at constant temperatures of 16 °C and 25 °C up to an age of 25 days and estimated their pteridine levels by fluorescence spectroscopy. Age was given in accumulated degree days (ADD) across temperatures. Additionally, a mock case was set up to test the applicability of the method. Pteridine increases logarithmically with increasing ADD, but after 70–80 ADD the increase slows down and the curve approaches a maximum. Sex had a significant impact (p < 4.09 × 10−6) on pteridine fluorescence level, while body-size and head-width did not. The mock case demonstrated that a slight overestimation of the real age (in ADD) only occurred in two out of 30 samples. Age determination of L. sericata on the basis of pteridine levels seems to be limited to an age of about 70 ADD, but depending on the ambient temperature this could cover an extra amount of time of about 5–7 days after completion of the metamorphosis.
Cabozantinib (Cabometyx®) is a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymal-epithelial transition factor (MET) receptor, and the “anexelekto” (AXL) receptor tyrosine kinase. It is approved for the treatment of advanced hepatocellular carcinoma (HCC) after failure of sorafenib in Europe (since November 2018) and in the USA (since January 2019). The approval of cabozantinib was based on results of the randomized, placebo-controlled, phase 3 CELESTIAL trial in patients with unresectable HCC, who received one or two prior lines of treatment including sorafenib. At the second planned interim analysis, the trial was stopped, because the primary end point overall survival was clearly in favor for cabozantinib. Additionally, median progression-free survival was superior to placebo. The most common ≥ grade 3 relevant adverse events in patients with HCC treated with cabozantinib were palmar–plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. In this review, current data on cabozantinib for the treatment of patients with advanced HCC, with a focus on the management of common adverse events and ongoing clinical trials, are discussed.
Die Gattungen Nicotiana tabacum und Nicotiana rustica der Tabakpflanze sind von großer wirtschaftlicher Bedeutung. Aus ihnen wird Tabak hergestellt, der mit Alkohol zur weltweit am häufigsten konsumierten Genussdroge zählt. Aufgrund seiner Legalität wird die Toxizität trotz steigender Warnung und Aufklärung immer noch unterschätzt. Die Toxizität der Tabakpflanze ist vor allem auf das Alkaloid Nikotin zurückzuführen. Dass es selten zu einer Vergiftung durch die reine Pflanze kommt, liegt daran, dass sie optisch kaum zum Verzehr anregt. Häufiger dagegen ist eine Vergiftung durch z. B. verschluckte Zigarettenstummel, die vor allem für Kinder sehr gefährlich sein kann. Eine weitere Gefahr der Vergiftung entsteht bei der Tabakernte. Nikotin wird auch über die Haut aufgenommen und kann so zu der Green Tobacco Sickness bei Tabakplantagenarbeitern führen. Im Ernstfall existiert kein Antidot. Aktivkohle sollte so schnell wie möglich gegeben werden, um die Resorption zu vermindern. Ansonsten muss das Nikotin mit einer Magenwäsche aus dem Körper gefiltert werden. Präventiv sollten deshalb verstärkt auf die Gefahren des Tabaks aufmerksam gemacht werden.
Purpose: The role of hypoalbuminemia and raised C-reactive protein (CRP) levels in predicting critical prognosis has been described extensively in adult literature. However, there are limited studies in pediatrics, particularly neonates. The CRP/albumin (CRP/ALB) ratio is often associated with higher mortality, organ failure and prolonged hospital stay. We hypothesized that the serum CRP/ALB ratio has a prognostic value in predicting surgery and mortality in neonates with necrotizing enterocolitis (NEC).
Methods: Retrospective review of all neonates with clinical and radiological evidence of non-perforated NEC that were treated in a tertiary-level referral hospital between 2009 and 2018. General patient demographics, laboratory parameters and outcomes were recorded. Receiver operating characteristics analysis was performed to evaluated optimal cut-offs and area under the curve (AUC) with 95% confidence intervals (CI).
Results: A total of 191 neonates were identified. Of these, 103 (53.9%) were born at ≤ 28 weeks of gestation and 101 (52.9%) had a birth weight of ≤ 1000 g. Eighty-four (44.0%) patients underwent surgical intervention for NEC. The overall survival rate was 161/191 (84.3%). A CRP/ALB ratio of ≥ 3 on day 2 of NEC diagnosis was associated with a statistically significant higher likelihood for surgery [AUC 0.71 (95% CI 0.63–0.79); p < 0.0001] and mortality [AUC 0.66 (95% CI 0.54–0.77); p = 0.0150], respectively.
Conclusions : A CRP/ALB ratio of ≥ 3 on day 2 is indicative of a critical pathway in neonates with radiologically confirmed, non-perforated NEC. This could be used as an additional criterion to guide parental counselling in NEC for surgical intervention and mortality.
Wir haben einen kommerziell verfügbaren Test zur Bestimmung von Thyroxin (T4) am Analysensystem RA1000 auf seine Eignung in unserem Labor untersucht. Das Prinzip des Tests beruht auf einer immunturbidimetrischen Inhibitionstechnik, die besonders zur Messung niedriger T4-Konzentrationen geeignet ist Es wurde eine Präzision (in Serie, von Tag zu Tag) zwischen 2,6 und 4,6% (VK) ermittelt. Die Richtigkeit wurde untersucht an Patientenproben mit 2 Vergleichsmethoden und vergleichend zu den Sollwerten kommerziell verfügbarer Richtigkeitskontrollseren. Der Vergleich an Patientenproben ergab eine gute bis akzeptable Übereinstimmung, der Vergleich mit den Sollwerten von Richtigkeitskontrollseren zeigte in einigen Seren gewisse methodische Differenzen. Insgesamt ergaben unsere Untersuchungen, daß die immunturbidimetrische Inhibitionstechnik am HA-1000 eine schnelle und zuverlässige Bestimmung der T4-Konzentration ermöglicht.
Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of the islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen-specific T cells. We have previously generated a roadmap of the gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. We focused our attention on CXCL10/CXCR3, CCL5/CCR5, CXCL16/CCR6, CX3CL1/CX3CR1, and XCL1/XCR1. First, we found that the absence of CCR6 and of CX3CR1 diminished T1D incidence in a mouse model for T1D. Further, the XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on convention dendritic cells type 1 (cDC1) that excel by their high capacity for T cell activation. Here we demonstrate that cDC1 expressing XCR1 are present in and around the islets of patients with T1D and of islet-autoantibody positive individuals. Further, in an inducible mouse model for T1D, we show that XCL1 plays an important role in the attraction of highly potent dendritic cells expressing XCR1 to the islets. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and subsequently also a reduced magnitude and activity of islet autoantigen-specific T cells. XCR1-deficient mice display a reduced magnitude and activity of islet autoantigen-specific T cells. A 3D-visualization of the entire pancreas reveals that both XCL1-deficient mice and XCR1-deficient mice indeed maintain most of their functional islets after induction of the disease. Thus, the absence of XCL1 results in a profound decrease in T1D incidence. The XCR1-deficiency also reduces T1D incidence, even if in a less drastic way compared to XCL1-deficiency. An interference with the XCL1/XCR1 chemokine axis might constitute a novel target for the therapy for T1D.
Thibau, Arno ; Dichter, Alexander A. ; Vaca Llerena, Diana Jaqueline ; Linke, Dirk ; Goldman, Adrian ; Kempf, Volkhard A. J.
The current problem of increasing antibiotic resistance and the resurgence of numerous infections indicate the need for novel vaccination strategies more than ever. In vaccine development, the search for and the selection of adequate vaccine antigens is the first important step. In recent years, bacterial outer membrane proteins have become of major interest, as they are the main proteins interacting with the extracellular environment. Trimeric autotransporter adhesins (TAAs) are important virulence factors in many Gram-negative bacteria, are localised on the bacterial surface, and mediate the first adherence to host cells in the course of infection. One example is the Neisseria adhesin A (NadA), which is currently used as a subunit in a licensed vaccine against Neisseria meningitidis. Other TAAs that seem promising vaccine candidates are the Acinetobacter trimeric autotransporter (Ata), the Haemophilus influenzae adhesin (Hia), and TAAs of the genus Bartonella. Here, we review the suitability of various TAAs as vaccine candidates.
Antón-Galindo, Ester ; Adel, Maja ; Garcı́a-Gonzalez, Judit ; Leggieri, Adele ; López-Blanch, Laura ; Irimia, Manuel ; Norton, William H. J. ; Brennan, Caroline H. ; Fernàndez-Castillo, Noèlia ; Cormand, Bru
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
Antón-Galindo, Ester ; Adel, Maja ; Garcı́a-Gonzalez, Judit ; Leggieri, Adele ; López-Blanch, Laura ; Irimia, Manuel ; Norton, William H. J. ; Brennan, Caroline H. ; Fernàndez-Castillo, Noèlia ; Cormand, Bru
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain
(2018)
Mattern, Felix ; Post, Antonia ; Solger, Franziska ; O'Leary, Aet ; Slattery, David A. ; Reif, Andreas ; Haaf, Thomas
To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.
Ottomana, Angela Maria ; Presta, Martina ; O'Leary, Aet ; Sullivan, Mairéad ; Pisa, Edoardo ; Laviola, Giovanni ; Glennon, Jeffrey C. ; Zoratto, Francesca ; Slattery, David A. ; Macrì, Simone
Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer’s disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia – as a proxy of insulin-related metabolic dysfunctions – and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.
Sullivan, Mairéad ; Fernández-Aranda, Fernando ; Camacho-Barcia, Lucía ; Harkin, Andrew ; Macrì, Simone ; Mora-Maltas, Bernat ; Jiménez-Murcia, Susana ; O'Leary, Aet ; Ottomana, Angela Maria ; Presta, Martina ; Slattery, David A. ; Scholtz, Samantha ; Glennon, Jeffrey C.
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer’s Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer’s Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
Cabana-Domínguez, Judit ; Antón-Galindo, Ester ; Fernàndez-Castillo, Noèlia ; Singgih, Euginia L. ; O'Leary, Aet ; Norton, William H. G. ; Strekalova, Tatyana ; Schenck, Annette ; Reif, Andreas ; Lesch, Klaus-Peter J. ; Slattery, David A. ; Cormand, Bru
Highlights
• Overview on functional work performed in rodent, zebrafish and fruit fly models of ADHD and its comorbidities.
• Comprehensive search for new genetically modified mouse models to study ADHD-related and comorbid traits.
• Review of behavioral assays available in animal models to test ADHD-related and comorbid traits.
• Animal models to assess environmental effects contributing to the epigenetic mechanisms of ADHD and comorbidities.
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder resulting from the interaction between genetic and environmental risk factors. It is well known that ADHD co-occurs frequently with other psychiatric disorders due, in part, to shared genetics factors. Although many studies have contributed to delineate the genetic landscape of psychiatric disorders, their specific molecular underpinnings are still not fully understood. The use of animal models can help us to understand the role of specific genes and environmental stimuli-induced epigenetic modifications in the pathogenesis of ADHD and its comorbidities. The aim of this review is to provide an overview on the functional work performed in rodents, zebrafish and fruit fly and highlight the generated insights into the biology of ADHD, with a special focus on genetics and epigenetics. We also describe the behavioral tests that are available to study ADHD-relevant phenotypes and comorbid traits in these models. Furthermore, we have searched for new models to study ADHD and its comorbidities, which can be useful to test potential pharmacological treatments.
Refraktives und visuelles Ergebnis nach Neuausrichtung von rotierten torischen Intraokularlinsen
(2023)
Hintergrund und Ziel der Studie
Das Ziel der Studie ist die Beurteilung des refraktiven und visuellen Ergebnisses von Patienten mit fehlausgerichteten torischen IOLs nach operativer Neuausrichtung, mit und ohne Rückberechnung der torischen Achse nach Implantation der IOL.
Methoden
Dies ist eine retrospektive Analyse von 39 Patienten, die sich von August 2013 bis Dezember 2019 an der Klinik für Augenheilkunde der Goethe-Universität Frankfurt am Main einer zweiten Operation zur Neuausrichtung einer fehlausgerichteten torischen IOL unterzogen haben. Die zweite Operaton zur Korrektur der Achsenlage wurde auf zwei Weisen durchgeführt: In der ersten Gruppe wurde auf die primär berechnete Achse rotiert und in der zweiten Gruppe wurde die Rotation auf eine neu berechnete Achse mit dem Rückrechner von astigmatisfix.com vorgenommen.
Ergebnisse
In dieser retrospektiven Studie wurden 39 Augen von 39 Patienten eingeschlossen. Die Ergebnisse nach der ersten Operation (die Linsenoperation) zeigte eine Besserung der (BCVA) von 0,28 ± 0,22 logMAR (20/40) auf 0,15 ± 0,14 logMAR (20/32). Nach der Linsenoperation zeigten die torischen IOLs durchschnittlich eine postoperative Fehlstellung von 25,69° ± 26,06°. Verglichen vor und nach der Rotation der torischen IOL blieb der BCVA unverändert bei 0,14 ± 0,14 logMAR (20/32), während sich der UDVA signifikant von 0,39 ± 0,29 logMAR (20/50) auf 0,27 ± 0,18 logMAR (20/40) verbesserte. Das refraktive Ergebnis zeigte eine Reduktion sowohl in der Restsphäre sowie in dem Zylinder. Die Ergebnisse der Gruppenanalyse demonstrierte für die erste Gruppe (Neuausrichtung auf die präoperativ berechnete Achse) eine postoperative UDVA 0,24 ± 0,16 logMAR mit einem Zylinder von 0,90 ± 0,90 D. In der zweiten Gruppe (Ausrichtung auf eine zurückberechnete Achse) betrug die UDVA 0,32 ± 0,20 logMAR mit einem Zylinder von 0,76 ± 0,72 D. Die IOLs mit hoher Zylinderstärke (≥ 2 D) zeigten bei der Rückberechnung eine stärkere Abnahme des Restzylinders als IOL mit niedriger Zylinderstärke (< 2 D) (27 % vs. 9 %). Der mittlere sphärische Äquivalent-Vorhersagefehler der Rückberechnung betrug 0,54 ± 0,55 D.
Schlussfolgerung
Die Neuausrichtung von fehlausgerichteten torischen IOLs verbessert die Sehschärfe und reduziert verbleibende Brechungsfehler. Insbesondere bei IOL mit hoher Zylinderstärke kann ein besseres refraktives Ergebnis erzielt werden, wenn vor der Neuausrichtung eine Rückberechnung durchgeführt wird.
A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R2 = 0.18, p = 0.001; flexed: R2 = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R2 = 0.103, p = 0.017; flexed: R2 = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.
Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420.