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Purpose: We aimed to assess the changes in body fat distribution, intraorgan lipid accumulation, and cardiometabolic risk factors after 6 months of gender-affirming hormone therapy (GAHT) in transgender men (TM) and transgender women (TW)., Methods: Conducted at the Medical University of Vienna between 2019 and 2022, the study included 15 TW and 20 TM. We conducted magnetic resonance imaging and spectroscopy to determine the visceral (VAT) and subcutaneous adipose tissue (SAT) amounts, the VAT/SAT ratio, and the intraorgan lipid content (liver, pancreas, myocardium), bloodwork, and an oral glucose tolerance test at baseline and after 6 months of GAHT., Results: Pancreatic, hepatic, and intramyocardial lipid contents did not significantly change in either group after 6 months of GAHT. In TW, VAT/SAT ratio decreased significantly from baseline 0,930 (IQR 0,649-1,287) to 0,758 (IQR 0,424-0,900; p = 0,011) after 6 months of GAHT. The updated homeostatic model assessment for insulin sensitivity (HOMA2-%S) significantly decreased from 83,03 % (±31,11) to 64,27 % (±18,01; p = 0,047), indicating decreased insulin sensitivity, while the updated homeostatic model assessment for β-cell function (HOMA2-%β) increased (from 128,11 % (±35,80) to 156,80 % (±39,49); p = 0,020) in TW after 6 months of GAHT. In TM, there were no changes in glucose metabolism parameters except for an increase in HbA 1c (5,1% (±0,3) vs 5,3% (±0,4), p = 0,001)., Conclusions: 6 months of GAHT were not associated with statistically significant changes in myocardial, hepatic, or pancreatic lipid content. Short-term GAHT led to a marked body fat redistribution with a significant decrease in the VAT/SAT ratio in TW., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lana Kosi-Trebotic reports financial support was provided by Medical Scientific Fund of the Mayor of the City of Vienna. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: The objective of this study was to identify sex differences in ntrahepatocellular (HCL) and intramyocardial lipids (MYCL) and cardiac function in participants with different grades of glucometabolic impairment and different BMI strata., Methods: Data from 503 individuals from 17 clinical experimental studies were analyzed. HCL and MYCL were assessed with 3T and 7T scanners by magnetic resonance spectroscopy. Cardiac function was measured with a 3T scanner using electrocardiogram-gated TrueFISP sequences. Participants were classified as having normoglycemia, prediabetes, or type 2 diabetes. Three-way ANCOVA with post hoc simple effects analyses was used for statistical assessment., Results: Consistent increases of HCL with BMI and deterioration of glucose metabolism, especially in female individuals, were detected. MYCL increased with BMI and glucose impairment in female individuals, but not in male individuals. Sex differences were found in cardiac function loss, with significant effects found among male individuals with worsening glucose metabolism. Myocardial mass and volume of the ventricle were higher in male individuals in all groups. This sex difference narrowed with increasing BMI and with progressing dysglycemia., Conclusions: Sex differences in HCL and MYCL may be associated with a higher cardiovascular disease risk observed in female individuals progressing to diabetes. Further studies are needed to elucidate possible sex differences with advancing glucometabolic impairment and obesity and their potential impact on cardiovascular outcomes., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Miyoshi myopathy/dysferlinopathy (MMD) is a rare muscle disease caused by DYSF gene mutations. Apart from skeletal muscles, DYSF is also expressed in the brain. However, the impact of MMD-causing DYSF variants on brain structure and function remains unexplored. To investigate this, we utilized magnetic resonance (MR) modalities (MR volumetry and 31 P MR spectroscopy) in a family with seven children, four of whom have the illness. The MMD siblings showed distinct differences from healthy controls: (1) a significant (p < 0.001) right-sided volume asymmetry (+ 232 mm 3 ) of the inferior lateral ventricles; and (2) a significant (p < 0.001) decrease in [Mg 2+ ], along with a modified energy metabolism profile and altered membrane turnover in the hippocampus and motor and premotor cortices. The patients' [Mg 2+ ], energy metabolism, and membrane turnover measures returned to those of healthy relatives after a month of 400 mg/day magnesium supplementation. This work is the first to describe anatomical and functional abnormalities characteristic of neurodegeneration in the MMD brain. Therefore, we call for further examination of brain functions in larger cohorts of MMD patients and testing of magnesium supplementation, which has proven to be an effective corrective approach in our study., (© 2024. The Author(s).)

Clostridium botulinum C3 exoenzyme (C3bot) exclusively inhibits RhoA, B and C by ADP-ribosylation and is therefore used as a cell-permeable tool for investigating the cellular role of these Rho-GTPases. Rho-GTPases represent a molecular switch integrating different receptor signalling to downstream cascades including transcriptional cascades that regulate various cellular processes, such as regulation of actin cytoskeleton and cell proliferation. C3bot-induced inhibition of RhoA leads to reorganization of the actin cytoskeleton, morphological changes, and inhibition of cell proliferation as well as modulation of inflammatory response. In this study, we characterized the C3bot-mediated effects on a full-thickness skin model exhibiting a psoriasis-like phenotype through the addition of cytokines. Indeed, after the addition of cytokines, a decrease in epidermal thickness, parakeratosis, and induction of IL-6 was detected. In the next step, it was studied whether C3bot caused a reduction in the cytokine-induced psoriasis-like phenotypes. Basal addition of C3bot after cytokine induction of the full-thickness skin models caused less epidermal thinning and reduced IL-6 abundance. Simultaneous basal incubation with cytokines and C3bot, IL-6 abundance was inhibited, but epidermal thickness was only moderately affected. When C3bot was added apically to the skin model, IL-6 abundance was reduced, but no further effects on the psoriasis-like phenotype of the epidermis were observed. In summary, C3bot inhibits the cytokine-induced expression of IL-6 and thus may have an impact on the pro-inflammatory immune response in the psoriasis-like phenotype., (© 2023. The Author(s).)

Acetylcarnitine is an essential metabolite for maintaining metabolic flexibility and glucose homeostasis. The in vivo behavior of muscle acetylcarnitine content during exercise has not been shown with magnetic resonance spectroscopy. Therefore, this study aimed to explore the behavior of skeletal muscle acetylcarnitine during rest, plantar flexion exercise, and recovery in the human gastrocnemius muscle under aerobic conditions. Ten lean volunteers and nine overweight volunteers participated in the study. A 7 T whole-body MR system with a double-tuned surface coil was used to acquire spectra from the gastrocnemius medialis. An MR-compatible ergometer was used for the plantar flexion exercise. Semi-LASER-localized 1 H MR spectra and slab-localized 31 P MR spectra were acquired simultaneously in one interleaved exercise/recovery session. The time-resolved interleaved 1 H/ 31 P MRS acquisition yielded excellent data quality. A between-group difference in acetylcarnitine metabolism over time was detected. Significantly slower τ PCr recovery , τ PCr on-kinetics , and lower Q max in the overweight group, compared to the lean group was found. Linear relations between τ PCr on-kinetics , τ PCr recovery , VO 2max and acetylcarnitine content were identified. In conclusion, we are the first to show in vivo changes of skeletal muscle acetylcarnitine during acute exercise and immediate exercise recovery with a submaximal aerobic workload using interleaved 1 H/ 31 P MRS at 7 T., (© 2024. The Author(s).)

The mechanisms of β -caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses to mechanical stimuli were evaluated using an electronic von Frey anesthesiometer. Endocannabinoids, including 2-arachidonoylglycerol (2-AG), were also evaluated in plasma and tissues using high-performance liquid chromatography-tandem mass spectrometry. Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo. We observed a dose-dependent and time-dependent alleviation of hyperalgesia in incised paws up to 85% of the baseline value at 30 minutes after administration of BCP. We also observed dose-dependent increases in the 2-AG levels of about threefold after administration of BCP as compared with vehicle controls. Incubations of spinal cord tissue homogenates from BCP-treated rats with isotope-labeled 2-arachidonoylglycerol-d8 revealed a reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared with vehicle controls, indicating MAGL enzyme inhibition. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC 50 of 15.8 µM for MAGL inhibition using BCP. These data showed that BCP inhibits MAGL activity in vitro and in vivo, causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose that 2-AG-mediated cannabinoid receptor activation contributes to BCP's mechanism of analgesia. SIGNIFICANCE STATEMENT: β -Caryophyllene (BCP) consumption is relatively safe and is approved by the Food and Drug Administration as a flavoring agent, which can be used in cosmetic and food additives. BCP is a potent anti-inflammatory agent that showed substantial antihyperalgesic properties in this study of acute pain suggesting that BCP might be an alternative to opioids. This study shows an additive mechanism (monoacylglycerol lipase inhibition) by which BCP might indirectly alter CB1 and CB2 receptor activity and exhibit its pharmacological properties., (Copyright © 2024 by The Author(s).)

Background: The National Competence-Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) serves as the foundation for curricular development in undergraduate medical education in Germany. A new version of the NKLM was launched in 2021, and medical faculties are now evaluating the learning objectives (LOs). This paper describes the evaluation process used at Hannover Medical School., Methods: The evaluation process was structured in three steps. LOs were rated as "keep", "modify" or "delete". First, the 1133 LOs were compared with the mapping of the Hannover curriculum from 2017. Then, a small team from the Curricular Development Department conducted a pre-evaluation of the 1133 LOs. Finally, a group of clinical experts and students discussed and agreed on the ratings., Results: For 868 LOs, one or more counterparts were found in the mapping, but 265 new LOs were not found and thus, classified as new. In the first rating, 779 LOs were kept, 300 were modified (172 due to wording), 45 were deleted, and there was no rating for 9 LOs. The expert group changed 47 of the pre-evaluation decisions. The final rating was to keep 738 LOs, modify 356, and delete 39 LOs., Conclusion: This method effectively evaluated the LOs from NKLM 2.0 while balancing expert knowledge and an overview of the curriculum., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Mikuteit et al.)