Inclusion body myositis: from genetics to clinical trials

Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications

Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): a Gene Expression Study

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Reliability of the Spanish Version of the Movement Imagery Questionnaire-3 (MIQ-3) and Characteristics of Motor Imagery in Institutionalized Elderly People

Motor imagery (MI) training is increasingly used to improve the performance of specific motor skills. The Movement Imagery Questionnaire-3 (MIQ-3) is an instrument for assessing MI ability validated in Spanish although its reliability has not yet been studied in the elderly population. The main objective of this study was to test its reliability in institutionalized elderly people. Secondarily, we studied whether there are differences according to gender and age in MI ability (measured by the MIQ-3) and in temporal congruency (measured by mental chronometry of elbow and knee flexion-extension and getting up and sitting down from chair movements). The subjects were 60 elderly, institutionalized, Spanish-speaking individuals without cognitive impairment or dementia, and aged between 70 and 100 years. Cronbach?s alpha showed high internal consistency in the internal visual and external visual subscales and moderate in the kinesthetic subscale. The intraclass correlation coefficient showed good test-retest reliability for all three subscales. Mixed factorial analysis of variances (ANOVAs) showed that MI ability decreased with increasing age range, the imagery time decreased concerning the execution of the same movement, and there were no gender differences in either IM ability or temporal congruence. The Spanish version of the MIQ-3 is a reliable instrument for measuring MI ability in institutionalized elderl

Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational mo difications in histones are pivotal in regulating transcription. Here, we report th at phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signa l-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 ( p - S10H3) as well as fos transcription, a down-stream effect of p -S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p -S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain

CONSCIOUS curriculum projects

Rychlickova, J., Batuca, J. R., Nagy, V., Shiely, F., Cechova, Z., Nebeska, K., Souckova, L., Mouly, S., Kovács, G. L., Németh, A., Oliveira, T., Painho, M., Maia, S., & Monteiro, E. C. (2023). Building key competencies clinical trialists of the future: CONSCIOUS curriculum projects. Poster session presented at ORPHEUS2023, "Putting the i’s and o’s in Doctoral Training; International, Intersectoral, Interdisciplinary, and Open Science", Leuven, Belgium. --- This work was supported by the Erasmus+ Programme of the Europe Union (2018-1-HU01-KA203-047811 and 2021-1-CZ01-KA220-HED-000023177).Investigator-initiated clinical trials (IIT) are a broadly interprofessional field that is becoming increasingly relevant to biomedical postgraduate students, especially to validate their research question in clinical practice. Indeed, IIT represent a way to develop individualized treatment and obtain objective evidence to answer questions of day-to-day practice. On the other hand, IIT place greater demands on investigators as they extend their position to include the coordination and management role of the sponsor. At the same time, little formal training in clinical trials is available across European countries in both undergraduate and postgraduate education, and the understanding of biomedical graduates in clinical research organization may not be optimal. A consortium of six European universities was established to fill this gap by preparing a highly practice-based and -oriented curriculum within two consequent projects – CONSCIOUS and CONSCIOUS II. Especially the CONSCIOUS II is focused on postgraduate students and provides them with e-learning lessons of practical guidance on how to design a research question and a clinical trial, the regulatory requirements that need to be met, how to conduct the trial, what activities can be delegated, and how to analyze the results. The second part targets transdisciplinary skills such as leadership, publishing, and teaching. The CONSCIOUS II pedagogical approach moves on to contextualized, case-based exercises allowing to test the acquired skills in simulated situations. Both CONSCIOUS projects thus offer a comprehensive, free-of-charge curriculum for biomedical students but will also open a pilot course with international participation as a further extension of this curriculum.publishersversionpublishersversionpublishe

Role of Angular Interface Sign in Characterizing Small Exophytic Renal Masses in Computed Tomography; Prospective Study

The widespread use of computed tomography (CT) has increased the incidence of small renal cell masses. We aimed to evaluate the usefulness of the angular interface sign (ice cream cone sign) to differentiate a broad spectrum of small renal masses using CT. The prospective study included CT images of patients with exophytic renal masses ≤ 4 cm in maximal dimension. The presence or absence of an angular interface of the renal parenchyma with the deep part of the renal mass was assessed. Correlation with the final pathological diagnosis was performed. The study included 116 patients with renal parenchymal masses of a mean (± SD) diameter of 28 (± 8.8) mm and a mean age of 47.7 (±12.8) years. The final diagnosis showed 101 neoplastic masses [66 renal cell carcinomas (RCC), 29 angiomyolipomas (AML), 3 lymphomas, and 3 oncocytomas] and 15 non-neoplastic masses [11 small abscesses, 2 complicated renal cysts, and 2 granulomas]. Angular interface sign was statistically comparable in neoplastic versus non-neoplastic lesions (37.6% versus 13.3%, respectively, P = 0.065). There was a statistically higher incidence of the sign when comparing benign versus malignant neoplastic masses (56.25 vs. 29%, respectively, P = 0.009). Also, comparing the sign in AML versus RCC was statistically significant (52% of AML versus 29% of RCC, P = 0.032). The angular interface sign seems beneficial in predicting the nature of small renal masses. The sign suggests benign rather than malignant small renal masses

Role of Angular Interface Sign in Characterizing Small Exophytic Renal Masses in Computed Tomography; Prospective Study

The widespread use of computed tomography (CT) has increased the incidence of small renal cell masses. We aimed to evaluate the usefulness of the angular interface sign (ice cream cone sign) to differentiate a broad spectrum of small renal masses using CT. The prospective study included CT images of patients with exophytic renal masses ≤ 4 cm in maximal dimension. The presence or absence of an angular interface of the renal parenchyma with the deep part of the renal mass was assessed. Correlation with the final pathological diagnosis was performed. The study included 116 patients with renal parenchymal masses of a mean (± SD) diameter of 28 (± 8.8) mm and a mean age of 47.7 (±12.8) years. The final diagnosis showed 101 neoplastic masses [66 renal cell carcinomas (RCC), 29 angiomyolipomas (AML), 3 lymphomas, and 3 oncocytomas] and 15 non-neoplastic masses [11 small abscesses, 2 complicated renal cysts, and 2 granulomas]. Angular interface sign was statistically comparable in neoplastic versus non-neoplastic lesions (37.6% versus 13.3%, respectively, P = 0.065). There was a statistically higher incidence of the sign when comparing benign versus malignant neoplastic masses (56.25 vs. 29%, respectively, P = 0.009). Also, comparing the sign in AML versus RCC was statistically significant (52% of AML versus 29% of RCC, P = 0.032). The angular interface sign seems beneficial in predicting the nature of small renal masses. The sign suggests benign rather than malignant small renal masses

Landscape genomics of a widely distributed snake, Dolichophis caspius (Gmelin, 1789) across Eastern Europe and Western Asia

Across the distribution of the Caspian whipsnake (Dolichophis caspius), populations have become increasingly disconnected due to habitat alteration. To understand population dynamics and this widespread but locally endangered snake’s adaptive potential, we investigated population structure, admixture, and effective migration patterns. We took a landscape-genomic approach to identify selected genotypes associated with environmental variables relevant to D. caspius. With double-digest restriction-site associated DNA (ddRAD) sequencing of 53 samples resulting in 17,518 single nucleotide polymorphisms (SNPs), we identified 8 clusters within D. caspius reflecting complex evolutionary patterns of the species. Estimated Effective Migration Surfaces (EEMS) revealed higher-than-average gene flow in most of the Balkan Peninsula and lower-than-average gene flow along the middle section of the Danube River. Landscape genomic analysis identified 751 selected genotypes correlated with 7 climatic variables. Isothermality correlated with the highest number of selected genotypes (478) located in 41 genes, followed by annual range (127) and annual mean temperature (87). We conclude that environmental variables, especially the day-to-night temperature oscillation in comparison to the summer-to-winter oscillation, may have an important role in the distribution and adaptation of D. caspius

Freeform three-mirror anastigmatic large-aperture telescope and receiver optics for CMB-S4

CMB-S4, the next-generation ground-based cosmic microwave background (CMB) observatory, will provide detailed maps of the CMB at millimeter wavelengths to dramatically advance our understanding of the origin and evolution of the universe. CMB-S4 will deploy large and small aperture telescopes with hundreds of thousands of detectors to observe the CMB at arcminute and degree resolutions at millimeter wavelengths. Inflationary science benefits from a deep delensing survey at arcminute resolutions capable of observing a large field of view at millimeter wavelengths. This kind of survey acts as a complement to a degree angular resolution survey. The delensing survey requires a nearly uniform distribution of cameras per frequency band across the focal plane. We present a large-throughput, large-aperture (5-meter diameter) freeform three-mirror anastigmatic telescope and an array of 85 cameras for CMB observations at arcminute resolutions, which meets the needs of the delensing survey of CMB-S4. A detailed prescription of this three-mirror telescope and cameras is provided, with a series of numerical calculations that indicate expected optical performance and mechanical tolerance