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Monochromatic ocular high-order aberrations in children and adolescents
No full textPurpose:
To investigate the prevalence and repeatability of high-order aberrations (HOAs) from non-cyclopleged eyes in 1515 children and adolescents 2.5–18 years of age.
Methods:
The Leipzig Research Centre for Civilization Diseases (LIFE)-Child study is a population-based, prospective, observational single-centre study that investigates the development of children and adolescents in Germany. Wavefront measurements were repeated three times in each eye of 1515 healthy subjects. Results were described by 36 Zernike coefficients for a 5 mm reference pupil diameter. Short-term repeatability is given for each coefficient. The impact on vision is described by the root mean squared (RMS) value of the HOA Zernike coefficients.
Results:
High-order aberrations were dominated by five contributions. For 1004 right eyes: spherical aberration (c12 = 0.06 ± 0.07 μm), coma (c7 = 0.03 ± 0.09 μm, c8 = 0.03 ± 0.06 μm) and trefoil (c6 = −0.01 ± 0.07 μm, c9 = 0.008 ± 0.06 μm). The RMS value was 0.18 ± 0.06 μm. Modes higher than fourth order do not contribute clinically to the aberrations. HOAs show no clinically significant dependency with age. Instead, HOA values agree well with previous results on aberrations in adult eyes. Spherical aberration was highly correlated between the two eyes. Repeatability was worst for coma, 0.033 μm, due to variability in the alignment of the pupil centre. The left eye showed, on average, a 0.08 mm larger pupil diameter than the right eye (p < 0.02).
Conclusions:
Across the age span from 2.5 to 18 years, we see the same distribution of HOA as for adults. We established that only five Zernike coefficients, spherical aberration, coma and trefoil were of clinical significance in healthy eyes. A high correlation between the two eyes for spherical aberration suggests a common blueprint for each eye in any one subject
Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles
No full textOxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII-catalyzed scaffold-divergent synthesis of spirooxindole–isooxindoles and spirooxindole–oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype
Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
No full textTargeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies
Powerful, metamorphic, mediative: Trees, climate change and the intricate geographies of objects
No full textThis paper unpacks the intricate geographies of trees in the current fight against climate change.
Through a multi-sited ethnography of forestry programming in Uganda, I explore how trees are
entangled in different worlds ranging from global donor paradigms and scientific realisms of
climate change to vernacular cosmologies and life worlds. Denaturalising trees as taken-forgranted
elements in current environmental governance, I trace trees’ various reincarnations
the praxis of development projects, show how they matter to Ugandan post-colonial politics
and nation building and examine how they link up otherwise different rationalities. In doing
so, I advance the current debate on object-oriented geographies. By marrying object-oriented
philosophies and their adoption in geography with post-ANT writings, I present three ways in
which objects are related to the world: powerful, metamorphic and mediative. This approach
does not put ANT-inspired thinking at odds with ‘pure’ object-oriented philosophy but opens
up space for future geographical inquiry. To do so, however, I argue that we need to be more
precise with regard to what kinds of objects we actually envisage
Developing a supportive and palliative care intervention for patients with allogeneic stem cell transplantation: protocol of a multicentre mixed-methods study (allo-PaS)
No full textIntroduction Although allogeneic stem cell transplantation (allo-SCT) is a curative treatment for many haematological malignancies, it is often associated with a high morbidity and mortality. Yet, little is known about the needs for supportive and palliative care among allo-SCT recipients. Moreover, targeted interventions that reduce symptom burden and suffering are still lacking. The present study aims to inform a supportive-palliative care intervention for patients with allo-SCT and their informal carers by exploring their experience and assessing their needs, especially their existential concerns, regarding four research topics: symptom burden and quality of life; coexistence of a chance for cure and a relevant risk of dying; change in goals of care; dying phase.
Methods and analysis This is a descriptive mixed-methods study in progress with a convergent parallel design. Data on the four research topics will be collected and analysed separately in three steps: (1) qualitative semi-structured interviews among 20 patients, 20 informal carers and 12 healthcare providers (HCPs) and focus groups among 12–24 HCPs; (2) a quantitative cross-sectional survey with validated questionnaires and self-developed questions among 100 patients, 100 informal carers and 50 HCPs; (3) a retrospective case analysis of all deceased patients who underwent an allo-SCT between 2010 and 2019, with collection of quantitative and qualitative data. The qualitative and quantitative data sets will be finally merged for comparison and interpretation. Results will serve to develop a supportive-palliative care intervention.
Ethics and dissemination The Ethics Commission of the Faculty of Medicine of the University of Cologne approved this study (20–1370_2). The study results will be published in peer-review journals, be presented at congresses and will be translated into clinical practice through the development of the palliative-supportive care intervention.
Trial registration number DRKS00027290 (German Clinical Trials Register)
Genetische Diagnostik im klinischen Alltag der Kinder- und Jugendpsychiatrie: Indikationen, Rahmenbedingungen, Hürden und Lösungsvorschläge
No full textMedizinisch notwendige genetische Diagnostik ist eine Leistung der gesetzlichen Krankenversicherung. Die steigende Rele-
vanz dieser Diagnostik für die Kinder- und Jugendpsychiatrie (KJP) zeigt sich u. a. durch den zunehmenden Eingang genetischer Diagnostik in
fachrelevante Leitlinien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Die Verankerung in die
Leitlinien geht jedoch bisher nur mit einer begrenzten Umsetzung in den klinischen Alltag einher. Der vorliegende Artikel gibt einen Überblick über
den Stellenwert genetischer Diagnostik in den aktuellen, KJP-relevanten AWMF-Leitlinien, erläutert die in Deutschland geltenden Rahmenbedin-
gungen für eine genetische Diagnostik, zeigt Hürden der Implementierung in den klinischen Alltag sowie mögliche Lösungsansätze auf. Anhand
von Beispielen aus der klinischen Praxis werden die möglichen Nutzen einer genetischen Diagnose für die Patient_innen und ihre Familienange-
hörigen erläutert. Abschließend werden mögliche Zukunftsszenarien bezüglich des Einsatzes genetischer Untersuchungen in der KJP skizziert.Health insurance covers medically necessary genetic testing in Germany. Diagnostic genetic testing has become increasingly impor-
tant for child and adolescent psychiatry (CAP), reflected by the rising number of national guidelines relevant to CAP, including genetic testing in
the recommended diagnostic work-up. However, implementation of theses guidelines in routine clinical care is lacking. This article provides a
concise overview of the relevance of genetic testing in CAP-related national guidelines. It outlines the legal and financial framework for genetic
testing in Germany. Furthermore, it points out barriers to implementation and offers potential solutions. It then provides examples from clinical
practice highlighting the potential benefits patients and their family members might have from receiving a genetic diagnosis. The article closes
by outlining future CAP-relevant areas in which genetic testing may become clinically relevant
Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer
No full textOvercoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a BRCA1-proficient or BRCA1-deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the BRCA1-proficient vs. BRCA1-deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers
Reduced cingulate gyrus volume in Cavalier King Charles Spaniels with syringomyelia and neuropathic pain revealed by voxel-based morphometry: a pilot study
No full textObjective: Pathomorphological alterations of the central nervous system in dogs,
such as syringomyelia and Chiari-like malformation, can cause cranial and cervical
hyperesthesia and neuropathic pain. The long-term activity of the pain network
can induce functional alteration and eventually even morphological changes in the
pain network. This may happen especially in the prefrontal and cingulate cortex,
where atrophy of the gray matter (GM) was observed in humans with chronic
pain, irrespective of the nature of the pain syndrome. We tested the hypothesis
that Cavalier King Charles Spaniels (CKCS) with Chiari-like malformation and
associated syringomyelia (SM) and pain show cerebral morphological differences
compared to animals without signs of syringomyelia and pain.
Methods: Volumetric datasets of 28 different brain structures were analyzed
in a retrospective manner, including voxel-based morphometry, using magnetic
resonance imaging data obtained from 41 dogs.
Results: Volumetric analyses revealed a decrease in GM volumes in the cingulate
gyrus (CG) in CKCS with SM and chronic pain when normalized to brain volume.
This finding was supported by voxel-based morphometry, which showed a cluster
of significance within the CG.
Conclusion: GM atrophy in the CG is associated with chronic pain and thus may
serve as an objective readout parameter for the diagnosis or treatment of canine
pain syndromes