Comparison of the endocranial- and brain volumes in brachycephalic dogs, mesaticephalic dogs and Cavalier King Charles spaniels in relation to their body weight

BACKGROUND: A number of studies have attempted to quantify the relative volumes of the endocranial volume and brain parenchyma in association with the pathogenesis of the Chiari-like malformation (CLM) in the Cavalier King Charles spaniel (CKCS). In our study we examine the influence of allometric scaling of the brain and cranial cavity volume on morphological parameters in different dog breeds. MRI scans of 110 dogs (35 mesaticephalic dogs, 35 brachycephalic dogs, 20 CKCSs with SM, and 20 CKCSs without SM) have been used to create 3-dimensional volumetric models of skull and brain parts. Volumes were related to body weight calculating the adjusted means for different breeds. RESULTS: There was a strong global dependency of all volumes to body weight (P<0.0001). The adjusted means of the absolute and relative volumes of brain parenchyma and cranial compartments are not significantly larger in CKCSs in comparison to brachycephalic and mesaticephalic dogs. A difference in absolute or relative volumes between CKCSs with and without SM after relating these values to body weight could not be identified. The relative volume of the hindbrain parenchyma (caudal fossa parenchyma percentage) was larger in brachycephalic dogs than in CKCSs, without causing herniation or SM. CONCLUSION: An influence of body weight exist in dogs, which can be sufficiently large to render conclusions on the difference in volumes of the brain and skull unsafe unless some account of the body weight is taken in the analysis. The results of this study challenge the role of overcrowding for the development of SM in dogs

Charting the Chemical and Mechanistic Scope of Light-Triggered Protein Ligation

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide ($ArN_3$) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies ($^{89}Zr-mAbs$) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers. Here, we report on the synthesis, $^{89}Zr$-radiochemistry, and light-triggered photoradiosynthesis of $^{89}Zr$-labeled human serum albumin (HSA) using a series of 14 different photoactivatable DFO derivatives. The photoactive groups explore a range of substituted, and isomeric $ArN_3$ reagents, as well as derivatives of benzophenone, a para-substituted trifluoromethyl phenyl diazirine, and a tetrazole species. For the compounds studied, efficient photochemical activation occurs inside the UVA-to-visible region of the electromagnetic spectrum (∼365–450 nm) and the photochemical reactions with HSA in water were complete within 15 min under ambient conditions. Under standardized experimental conditions, photoradiosynthesis with compounds 1–14 produced the corresponding $^{89}ZrDFO-PEG_{3}-HSA$ conjugates with decay-corrected isolated radiochemical yields between 18.1 ± 1.8% and 62.3 ± 3.6%. Extensive density functional theory (DFT) calculations were used to explore the reaction mechanisms and chemoselectivity of the light-induced bimolecular conjugation of compounds 1–14 to protein. The photoactivatable DFO-derivatives operate by at least five distinct mechanisms, each producing a different type of bioconjugate bond. Overall, the experimental and computational work presented here confirms that photochemistry is a viable option for making diverse, functionalized protein conjugates

Health technology assessment of public health interventions: an analysis of characteristics and comparison of methods-study protocol

Mathes T, Willms G, Polus S, et al. Health technology assessment of public health interventions: an analysis of characteristics and comparison of methods-study protocol. SYSTEMATIC REVIEWS. 2018;7(1): 79.Background: Conducting a health technology assessment (HTA) of public health interventions (PHIs) poses some challenges. PHIs are often complex interventions, which affect the number and degree of interactions of the aspects to be assessed. Randomized controlled trials on PHIs are rare as they are difficult to conduct because of ethical or feasibility issues. The aim of this study is to provide an overview of the methodological characteristics and to compare the applied assessment methods in HTAs on PHIs. Methods: We will systematically search HTA agencies for HTAs on PHIs published between 2012 and 2016. We will identify the HTAs by screening the webpages of members of international HTA organizations. One reviewer will screen the list of HTAs on the webpages of members of international HTA organization, and a second review will double-check the excluded records. For this methodological review, we define a PHI as a population-based intervention on health promotion or for primary prevention of chronic or non-chronic diseases. Only full HTA reports will be included. At maximum, we will include a sample of 100 HTAs. In the case that we identify more than 100 relevant HTAs, we will perform a random selection. We will extract data on effectiveness, safety and economic as well as on social, cultural, ethical and legal aspects in a priori piloted standardized tables. We will not assess the risk of bias as we focus on exploring methodological features. Data extraction will be performed by one reviewer and verified by a second. We will synthesize data using tables and in a structured narrative way. Discussion: Our analysis will provide a comprehensive and current overview of methods applied in HTAs on PHIs. We will discuss approaches that may be promising to overcome the challenges of evaluating PHIs

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre‐association (non‐covalent ligand‐protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed

Reizende Ereignisse. Irritation als Beunruhigung und als Verschiebung von Ordnungen

Hoffarth B, Klingler B, Plößer M. Reizende Ereignisse. Irritation als Beunruhigung und als Verschiebung von Ordnungen. In: Fegter S, Hoffarth B, Klingler B, et al., eds. Differenz unter Bedingungen von Differenz. Reflexionen zu Lehre an der Hochschule. Wiesbaden: Springer VS; 2013: 51-70

Es macht einen Unterschied – eine Differenz thematisierende, (de)konstruierende Lesehilfe

Fegter S, Hoffarth B, Klingler B, Machold C, Menz M. Es macht einen Unterschied – eine Differenz thematisierende, (de)konstruierende Lesehilfe. In: Kessl F, Plößer M, eds. Differenzierung, Normalisierung, Andersheit. Soziale Arbeit als Arbeit mit den Anderen. Wiesbaden: VS Verlag für Sozialwissenschaften; 2010: 17-22

Wenn Differenz in der Hochschule thematisch wird. Einführung in die Reflexion eines Handlungszusammenhangs

Arens S, Fegter S, Hoffarth B, et al. Wenn Differenz in der Hochschule thematisch wird. Einführung in die Reflexion eines Handlungszusammenhangs. In: Mecheril P, Arens S, Fegter S, et al., eds. Differenz unter Bedingungen von Differenz. Zu Spannungsverhältnissen universitärer Lehre. Wiesbaden: Springer VS; 2013: 7-27

Expanding the Chemistry Palette for Radiotracer Synthesis

The synthesis, characterisation and application of radiolabelled compounds for use in diagnostic and therapeutic medicine requires a diverse skill set. This article highlights a selection of our ongoing projects that aim to provide new synthetic methods and radiochemical tools for building molecular imaging agents with various radionuclides

Differenz unter Bedingungen von Differenz. Zu Spannungsverhältnissen universitärer Lehre

Mecheril P, Arens S, Fegter S, et al. Differenz unter Bedingungen von Differenz. Zu Spannungsverhältnissen universitärer Lehre. Wiesbaden: Springer VS; 2013

Health Technology Assessment of Public Health Interventions. Published 2012 to 2016: An Analysis of Characteristics and Comparison of Methods

Polus S, Mathes T, Klingler C, et al. Health Technology Assessment of Public Health Interventions. Published 2012 to 2016: An Analysis of Characteristics and Comparison of Methods. International journal of technology assessment in health care. 2019;35(4):280-290.OBJECTIVES: The aim of this study was to provide an overview of the methodological characteristics and compare the assessment methods applied in health technology assessments (HTAs) of public health interventions (PHIs).; METHODS: We defined a PHI as a population-based intervention on health promotion or for primary prevention of chronic or nonchronic diseases. HTAs on PHIs were identified by systematically searching the Web pages of members of international HTA networks. We included only full HTA reports published between 2012 and 2016. Two reviewers extracted data on the methods used to assess effectiveness/safety, as well as on economic, social, cultural, ethical, and legal aspects using a-priori standardized tables.; RESULTS: We included ten HTAs provided by four different organizations. Of these, all reports assessed the effectiveness of the interventions and conducted economic evaluations, seven investigated social/cultural aspects, and four each considered legal and ethical aspects, respectively. Some reports addressed applicability, context/setting, and intervention fidelity issues in different ways. We found that most HTAs adapted their methods to some extent, for example, by including nonrandomized studies, expanding the search strategy, involving stakeholders, or applying a framework to guide the HTA process.; CONCLUSIONS: Our analysis provides a comprehensive overview of methods applied in HTAs on public health interventions. We found that a heterogeneous set of approaches is used to deal with the challenges of evaluating complex public health interventions