The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution

Variable fixation promotes callus formation: an experimental study on transverse tibial osteotomies stabilized with locking plates

Background A new locking screw technology, named variable fixation, has been developed aiming at promoting bone callus formation providing initial rigid fixation followed by progressive fracture gap dynamisation. In this study, we compared bone callus formation in osteotomies stabilized with standard locking fixation against that of osteotomies stabilized with variable fixation in an established tibia ovine model. Methods A 3 mm tibial transverse osteotomy gap was stabilized in three groups of six female sheep each with a locking plate and either 1) standard fixation in both segments (group LS) or 2) variable fixation in the proximal and standard fixation in the distal bone segment (group VFLS3) or 3) variable fixation in both segments (group VFLS6). The implantation site and fracture healing were compared between groups by means of radiologic, micro tomographic, biomechanical, and histological investigations. Results Compared to LS callus, VFLS3 callus was 40% larger and about 3% denser, while VFLS6 callus was 93% larger and its density about 7.2% lower. VFLS3 showed 65% and VFLS6 163% larger amount of callus at the cis-cortex. There wasn’t a significant difference in the amount of callus at the cis and trans-cortex in groups featuring variable fixation only. Investigated biomechanical variables were not significantly different among groups and histology showed comparable good healing in all groups. Tissues adjacent to the implants did not show any alteration of the normal structure in all groups. Conclusions Variable fixation promoted the formation of a larger amount of bone callus, equally distributed at the cis and trans cortices. The histological and biomechanical properties of the variable fixation callus were equivalent to those of the standard fixation callus. The magnitude of variable fixation had a biological effect on the formation of bone callus. At the implantation site, the usage of variable fixation did not raise additional concerns with respect to standard fixation. The formation of a larger amount of mature callus suggests that fractures treated with variable fixation might have a higher probability to bridge the fracture gap. The conditions where its usage can be most beneficial for patients needs to be clinically defined

The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution

Variable fixation promotes callus formation: an experimental study on transverse tibial osteotomies stabilized with locking plates

Background A new locking screw technology, named variable fixation, has been developed aiming at promoting bone callus formation providing initial rigid fixation followed by progressive fracture gap dynamisation. In this study, we compared bone callus formation in osteotomies stabilized with standard locking fixation against that of osteotomies stabilized with variable fixation in an established tibia ovine model. Methods A 3 mm tibial transverse osteotomy gap was stabilized in three groups of six female sheep each with a locking plate and either 1) standard fixation in both segments (group LS) or 2) variable fixation in the proximal and standard fixation in the distal bone segment (group VFLS3) or 3) variable fixation in both segments (group VFLS6). The implantation site and fracture healing were compared between groups by means of radiologic, micro tomographic, biomechanical, and histological investigations. Results Compared to LS callus, VFLS3 callus was 40% larger and about 3% denser, while VFLS6 callus was 93% larger and its density about 7.2% lower. VFLS3 showed 65% and VFLS6 163% larger amount of callus at the cis-cortex. There wasn’t a significant difference in the amount of callus at the cis and trans-cortex in groups featuring variable fixation only. Investigated biomechanical variables were not significantly different among groups and histology showed comparable good healing in all groups. Tissues adjacent to the implants did not show any alteration of the normal structure in all groups. Conclusions Variable fixation promoted the formation of a larger amount of bone callus, equally distributed at the cis and trans cortices. The histological and biomechanical properties of the variable fixation callus were equivalent to those of the standard fixation callus. The magnitude of variable fixation had a biological effect on the formation of bone callus. At the implantation site, the usage of variable fixation did not raise additional concerns with respect to standard fixation. The formation of a larger amount of mature callus suggests that fractures treated with variable fixation might have a higher probability to bridge the fracture gap. The conditions where its usage can be most beneficial for patients needs to be clinically defined.ISSN:1471-247