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Background and Purpose: There is growing evidence that inflammation plays a major role in the pathogenesis of neural damage caused by deposition of amyloid β (Aβ) in the brain. Nimodipine has received attention as a drug that might improve learning and reduce cognitive deficits in Alzheimer's disease, but the mechanism of action is poorly known. In this study, we tested the hypothesis that nimodipine inhibited Aβ-stimulated IL-1β release from microglia.Experimental Approach: Cultures of N13 microglia cells or primary mouse microglia were treated with nimodipine, and intracellular accumulation and release of IL-1β in response to Aβ or to the P2 receptor agonists ATP and benzoyl ATP (BzATP) were measured. Accumulation of IL-1β was measured in vivo after intrahippocampal inoculation of Aβ in the absence or presence of nimodipine. The effect of nimodipine on Aβ-triggered cytotoxicity was also investigated.Key Results: We show here that nimodipine dose-dependently inhibited Aβ-stimulated IL-1β synthesis and release from primary microglia and microglia cell lines. Furthermore, nimodipine also inhibited Aβ-induced IL-1βin vivo accumulation at concentrations known to be reached in the CNS. Finally, nimodipine protected microglia from Aβ-dependent cytotoxicity.Conclusion and Implications: These data suggest that alleviation of symptoms of Alzheimer's disease following nimodipine administration might be due to an anti-inflammatory effect and point to a novel role for nimodipine as a centrally acting anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

Understanding how variations in genetic sequences are conveyed into structural and biochemical properties is of increasing interest in the field of molecular evolution. In order to gain insight into this process, we studied the ecdysone receptor (EcR), a transcription factor that controls moulting and metamorphosis in arthropods. Using an in silico homology model, we identified a region in the lepidopteran EcR that has no direct interaction with the natural hormone but is under strong evolutionary constraint. This region causes a small indentation in the three-dimensional structure of the protein which facilitates the binding of tebufenozide. Non-Mecopterida are considered much older, evolutionarily, than Lepidoptera and they do not have this extended cavity. This location shows differences in evolutionary constraint between Lepidoptera and other insects, where a much lower constraint is observed compared with the Lepidoptera. It is possible that the higher flexibility seen in the EcR of Lepidoptera is an entirely new trait and the higher constraint could then be an indication that this region does have another important function. Finally, we suggest that Try123, which is evolutionarily constrained and is up to now exclusively present in Lepidoptera EcRs, could play a critical role in discriminating between steroidal and non-steroidal ligands. [ABSTRACT FROM AUTHOR]

Galanin participates in the pathogenesis of acute pancreatitis (AP). The galanin receptor (GALR) sub-types involved, however, are unclear. We aimed to determine GALRs messenger RNA (mRNA) expression in mouse pancreas, describe their localization, and ascertain if GALR2 and GALR3 are involved in AP. Galanin receptor expression in murine whole pancreas, acinar, and islet cells was quantified by polymerase chain reaction amplification of reverse-transcribed RNA for mRNA, Western blot analysis for protein and in situ hybridization for GALR localization. Isolated acinar cells were used to determine galanin's effect on amylase secretion. Acute pancreatitis was induced in mice by caerulein injections. Mice, with and without AP, were treated with the highly selective GALR2 antagonist M871, or the specific GALR3 antagonist SNAP-37889. Indices of AP were measured at 12 h. Murine pancreas expresses mRNA for GALRs. In islets the expression of all GALR are comparable, whereas in acinar cells GALR3 is predominantly expressed. Western blot analysis confirmed that the GALR proteins are expressed by acinar cells. In situ hybridization analysis confirmed that GALR3 mRNA is present in islet and acinar cells, while mRNA for GALR1 and 2 is confined to islets. Galanin did not influence basal and caerulein-stimulated amylase release from acinar cells. M871 treatment reduced some, whereas SNAP-37889 treatment reduced all indices of AP (by 40-80%). Galanin receptor mRNA and protein are expressed in mouse pancreas, with GALR3 mRNA predominating. GALR3 antagonism reduced the severity of AP whereas GALR2 antagonism was less effective. GALR3 is a potential target for treatment of AP. [ABSTRACT FROM AUTHOR]

Background and purpose: Depression is common in early phases of Alzheimer's disease (AD) and may represent prodromal symptoms of dementia. Recent reports suggest that early memory deficits and neuropsychiatric symptoms are caused by soluble rather than aggregated βamyloid (Aβ). Thus, we investigated the effects of soluble Aβ1-42 on working memory and depressive/anxiety-related behaviour in rats and on 5-hydroxytryptaminergic neurotransmission and neurotrophin content in various brain regions. Experimental approach: Behavioural reactivity to novel object recognition, open field, elevated plus maze and forced swimming test were assessed 7 days after i.c.v. injection of Aβ1-42 or its vehicle. BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) mRNA and protein levels and 5-hydroxytriptamine (5-HT) content were measured in the prefrontal cortex (PFC), striatum (STR) and nucleus accumbens (NAc). Key results: Aβ1-42 did not affect the ability to distinguish between familiar and novel objects, but Aβ-treated rats exhibited an increase in forced swimming immobility. No differences were revealed between experimental groups in the elevated plus maze test or in self-grooming (evaluated in the open field). In the PFC, but not STR or NAc, Aβ-injected rats exhibited a selective reduction in 5-HT content, BDNF and NGF expression. Conclusions and implications: Our data suggest that soluble Aβ-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent alterations in the expression of neurotrophins and 5-hydroxytryptaminergic neurotransmission. Hence, these alterations induced by soluble Aβ might be sensitive indicators of early phases of AD and possible risk factors for the expression of neuropsychiatric symptoms in AD. [ABSTRACT FROM AUTHOR]

This report describes the diagnosis and management of a 16-year-old boy who developed neurological signs and symptoms suggestive of cerebral aspergillosis following a haploidentical bone marrow transplant. A new sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of Aspergillus galactomannan circulating antigens (Platelia Aspergillus, Sanofi Diagnostic Pasteur, France) was used on serum and cerebrospinal fluid to obtain a presumptive diagnosis and to monitor the course of the disease. Having failed conventional therapy with amphotericin B, the patient received compassionate treatment with voriconazole for a period of 37 days. High levels of voriconazole were observed in both serum and cerebrospinal fluid (CSF), with a trend toward accumulation. After 7 days a marked improvement in the patient’s neurological symptoms was noted, and ELISA data indicated a corresponding decrease in Aspergillus galactomannan levels in both serum and CSF. Voriconazole was well tolerated, with only transient increases in ALT/AST recorded during therapy. Although the patient survived the acute Aspergillus infection, he subsequently died of an unrelated infection. [ABSTRACT FROM AUTHOR]

Aim: The rate of physiological bone remodelling (PBR) occurring after implant placement has been associated with the later onset of progressive bone loss and peri-implantitis, leading to medium- and long-term implant therapy failure. It is still questionable, however, whether PBR is associated with specific bone characteristics. The aim of this study was to assess whether radiomic analysis could reveal not readily appreciable bone features useful for the prediction of PBR., Materials and Methods: Radiomic features were extracted from the radiographs taken at implant placement (T0) using LifeX software. Because of the multi-centre design of the source study, ComBat harmonization was applied to the cohort. Different machine-learning models were trained on selected radiomic features to develop and internally validate algorithms capable of predicting high PBR. In addition, results of the algorithm were included in a multivariate analysis with other clinical variables (tissue thickness and depth of implant position) to test their independent correlation with PBR., Results: Specific radiomic features extracted at T0 are associated with higher PBR around tissue-level implants after 3 months of unsubmerged healing (T1). In addition, taking advantage of machine-learning methods, a naive Bayes model was trained using radiomic features selected by fast correlation-based filter (FCBF), which showed the best performance in the prediction of PBR (AUC = 0.751, sensitivity = 66.0%, specificity = 68.4%, positive predictive value = 73.3%, negative predictive value = 60.5%). In addition, results of the whole model were included in a multivariate analysis with tissue thickness and depth of implant position, which were still found to be independently associated with PBR (p-value < .01)., Conclusion: The combination of radiomics and machine-learning methods seems to be a promising approach for the early prediction of PBR. Such an innovative approach could be also used for the study of not readily disclosed bone characteristics, thus helping to explain not fully understood clinical phenomena. Although promising, the performance of the radiomic model should be improved in terms of specificity and sensitivity by further studies in this field., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

The solid-phase synthesis and full chemical characterization of the medium-length (14-amino acid residues) peptaibol with antibiotic properties of tylopeptin B, originally extracted from the fruiting body of the mushroom Tylopilus neofelleus, are described. These data are accompanied by the results on the solution-phase synthesis via the segment condensation approach of a selected, side-chain protected, analog. A solution conformational analysis, performed by the combined use of FTIR absorption, circular dichroism, and 2D-NMR (the latter technique coupled to molecular dynamics calculations), favors the conclusion that the 3D-structure of tylopeptin B is largely helical with a preference for the alpha- or the 3(10)-helix type depending upon the nature of the solvent. Helix topology and (partial) amphiphilic character are responsible for the observed membrane-modifying properties of this peptaibiotic.