Background
Multiple myeloma (MM) in dogs typically is treated with melphalan. A daily melphalan dosing schedule reportedly is well tolerated and associated with favorable outcome. Although ...anecdotally a pulse dose regimen has resulted in successful responses, little long‐term outcome and safety data is available regarding this dosing regimen for dogs with MM.
Hypothesis/objectives
(1) To compare outcome and adverse event profiles between pulse dose and daily dose melphalan schedules and (2) to report prognostic factors in dogs with MM treated with melphalan. We hypothesized that both protocols would have similar outcomes and tolerability.
Animals
Thirty‐eight client‐owned dogs diagnosed with MM receiving pulse dose (n = 17) or daily dose (n = 21) melphalan.
Methods
Retrospective cohort study assessing outcome and adverse events in dogs receiving either protocol. Risk factors were evaluated for their prognostic relevance.
Results
Both regimens were well tolerated and similarly effective, with an overall median survival time of 930 days. Renal disease and neutrophil‐to‐lymphocyte ratio (NLR) were negative prognostic factors, whereas hypercalcemia and osteolytic lesions were not prognostic factors in this study population.
Conclusions and Clinical Importance
Positive results support the use of either dosing regimen for the treatment of dogs with MM, and renal disease and NLR were negative prognostic factors. Prospective, controlled, and randomized studies are warranted to confirm these findings.
OBJECTIVE:Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter ...during PHI is unknown.
DESIGN:We used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection.
METHODS:Antiretroviral-naive PHI (defined as <1 year after infection, n = 62), chronic HIV infection (CHI, n = 16), and HIV-uninfected (n = 19) participants had DTI, laboratory, and neuropsychometric performance assessments. DTI metrics were examined using region of interest and whole brain voxelwise analyses. Linear mixed-effects models assessed correlations between DTI measures and laboratory and neuropsychometric performance values.
RESULTS:PHI participants were assessed at a median 4.1 months after estimated infection, and had median CD4 cell count of 573 cells/μl, and HIV-1 RNA viral load of 4.5 log10 copies/ml in plasma and 2.6 log10 copies/ml in cerebrospinal fluid (CSF). DTI metrics in PHI individuals were similar to HIV− participants and correlated with disruptions in the blood–brain barrier (indicated by CSF/plasma albumin ratio and CSF protein). CHI participants had significant loss of white matter integrity that correlated with biomarkers of infection and inflammation (blood viral load, CD4 T-cell count, and neopterin, and CSF white blood cell). Within the PHI group, DTI metrics inversely correlated with increasing days since infection.
CONCLUSION:In individuals assessed during PHI, group DTI measures suggested relative preservation of white matter microstructural integrity, but were associated with disruption of the blood–brain barrier and estimated duration of infection.
Brain metal dyshomeostasis and altered structural dynamics of the presynaptic protein α-synuclein (αS) are both implicated in the pathology of Parkinson’s disease (PD), yet a mechanistic ...understanding of disease progression in the context of αS structure and metal interactions remains elusive. In this Communication, we detail the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N-terminally acetylated αS (NAcαS), the physiologically relevant form in humans. We demonstrate that under aerobic conditions, Fe(II) commits NAcαS to a PD-relevant oligomeric assembly, verified by the oligomer-selective A11 antibody, that does not have any parallel β-sheet character but contains a substantial right-twisted antiparallel β-sheet component based on CD analyses and descriptive deconvolution of the secondary structure. This NAcαS–FeII oligomer does not develop into the β-sheet fibrils that have become hallmarks of PD, even after extended incubation, as verified by TEM imaging and the fibril-specific OC antibody. Thioflavin T (ThT), a fluorescent probe for β-sheet fibril formation, also lacks coordination to this antiparallel conformer. We further show that this oligomeric state is not observed when O2 is excluded, indicating a role for iron(II)-mediated O2 chemistry in locking this dynamic protein into a conformation that may have physiological or pathological implications.
BACKGROUNDEndothelial dysfunction is a crucial step in the pathogenesis of cardiovascular diseases. Reactive oxygen species (ROS) generated in response to lipopolysaccharide (LPS) during sepsis ...promotes progressive endothelial failure. Typically, LPS-stimulated leukocytes produce pro-inflammatory cytokines, which trigger endothelial ROS production through NAD(P)H oxidase (Nox) activation, in a process that takes hours. Noteworthy, endothelial cells exposed to LPS may also generate ROS in just a few minutes. However, the mechanisms underlying this early event and its deleterious effect in endothelial function are unknown. Here, we investigated the mechanisms of early LPS-induced ROS generation and its effect in endothelial cell viability.
METHODSHuman umbilical vein endothelial cells were exposed to LPS for 1–40 min to study ROS generation, cytokines expression, and signaling transduction by confocal microscopy, real-time PCR (RT-PCR), western blot, and immunoprecipation. Fourty-eight hour treatments were used to determine cell death by MTT assay, cell counting, and flow cytometry. Contribution of specific Nox isoform was evaluated using a siRNAs approach.
RESULTSLPS rapidly evoked a cytokine-independent ROS production, eliciting a rapid increase in p47 phosphorylation by a phospholipase C/conventional protein kinase C and PI3-K signaling. It is noteworthy that the early LPS-induced ROS production triggered significant endothelial necrosis, which was prevented by a previous, but not a posterior, antioxidant treatment. The early LPS-induced ROS production as well as endothelial necrosis was totally dependent of Nox2 and Nox4 activity.
CONCLUSIONEndothelial cells exposure to LPS triggers an early ROS production. Remarkably, this single early ROS production is enough to generate extensive endothelial cell death by necrosis dependent on the activity of Nox2 and Nox4. Because, in sepsis, ROS production can cause endothelial dysfunction, results here provided may be relevant when considering the development of strategies for sepsis therapy.
Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson’s disease. Analytical methods to detect post-translational modifications of αS are under ...development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that CuI-bound N-terminally acetylated αS (NAcαS) activates O2 resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region. Substitution of the H50 residue with a disease relevant Q mutation abolishes intermolecular dityrosine cross-linking and limits the CuI/O2 promoted cross-linking to the C-terminal region. Such a dramatic change in reaction behavior establishes a previously unidentified role for H50 in facilitating intermolecular cross-linking. Involvement of H50 in the reaction profile implies that long-range histidine coordination with the upstream CuI coordination site is necessary to stabilize the transition of CuI to CuII as is a required mechanistic outcome of CuI/O2 reactivity. The aggregation propensity of NAcH50Q–CuI is also enhanced in comparison to NAcαS–CuI, suggesting a potential functional role for both copper and intermolecular cross-linking in attenuating NAcαS fibrillization.
Critical defects of the mandibular bone are very difficult to manage with currently available materials and technology. In the present work, we generated acellular and cellular substitutes for human ...bone by tissue engineering using nanostructured fibrin-agarose biomaterials, with and without adipose-tissue-derived mesenchymal stem cells differentiated to the osteogenic lineage using inductive media. Then, these substitutes were evaluated in an immunodeficient animal model of severely critical mandibular bone damage in order to assess the potential of the bioartificial tissues to enable bone regeneration. The results showed that the use of a cellular bone substitute was associated with a morpho-functional improvement of maxillofacial structures as compared to negative controls. Analysis of the defect site showed that none of the study groups fully succeeded in generating dense bone tissue at the regeneration area. However, the use of a cellular substitute was able to improve the density of the regenerated tissue (as determined via CT radiodensity) and form isolated islands of bone and cartilage. Histologically, the regenerated bone islands were comparable to control bone for alizarin red and versican staining, and superior to control bone for toluidine blue and osteocalcin in animals grafted with the cellular substitute. Although these results are preliminary, cellular fibrin-agarose bone substitutes show preliminary signs of usefulness in this animal model of severely critical mandibular bone defect.
Six rhenium(I) κ3 N-dicarbonyl complexes with 4′-(4-substituted phenyl)terpyridine ligands were evaluated in their ground and excited states. These complexes, bearing substituents of different ...electron-donating strengthsfrom CN to NMe2were studied by a combination of transient IR (TRIR), electrochemistry, and IR spectroelectrochemistry, as well as time-dependent density functional theory (TD-DFT). They exhibit panchromatic absorption and can act as stronger photoreductants than their tricarbonyl counterparts. The ground- and excited-state potentials, absorption maxima, and lifetimes (250–750 ps) of these complexes correlate well with the Hammett σp substituent constants, showing the systematic effect of remote substitution in the ligand framework. TRIR spectroscopy allowed us to assign the lowest singlet and triplet excited states to a metal-to-ligand charge-transfer (MLCT) character. This result contrasts our previous report on analogous κ2 N-tricarbonyl complexes, where remote substitution switched the character from MLCT to intraligand charge transfer. With the help of TD-DFT calculations, we dissect the geometric and electronic effects of coordination of the third pyridine, local symmetries, and increasing conjugation length. These results give valuable insights for the design of complexes with long-lived triplet excited states and enhanced absorption throughout the visible spectrum, while showcasing the boundaries of the excited-state switching strategy via remote substitution.
•Floral phenology and fruit set fail when olive tree growing under field conditions are exposed to 4 ºC above ambient temperature.•Olive floral differentiation processes seem to be affected by warmer ...temperatures favoring pistil abortion.•Pistil abortion along with fruit set reduction by heat may impact olive production.•The occurrence and duration of olive flowering processes will be advanced and extended under warmer temperatures.
The increase in air temperature associated to climate change is expected to affect olive (Olea europaea L.) tree fructification. To determine the potential effects of global warming on floral phenology and fruit set under field conditions, olive trees growing in a Mediterranean climate type area were subjected to warmer temperature than ambient by the use of temperature controlled Open-top-Chambers (OTCs). Each OTC, equipped with heating and ventilation devices, was able to maintain a day/night temperature gradient between the tree and the surrounding environment of 4 °C throughout the complete reproductive cycle of this species. After three years of study, the results obtained have shown that increasing temperature 4 °C above the actual ambient temperature may led to an advance of the date of flowering in the olive, an extent of the flowering period, an increase of pistil abortion, and a reduction in fruit set, conditions which may reduce yield.
In October 2022, an outbreak in Europe of highly pathogenic avian influenza (HPAI) A(H5N1) in intensively farmed minks occurred in northwest Spain. A single mink farm hosting more than 50,000 minks ...was involved. The identified viruses belong to clade 2.3.4.4b, which is responsible of the ongoing epizootic in Europe. An uncommon mutation (T271A) in the PB2 gene with potential public health implications was found. Our investigations indicate onward mink transmission of the virus may have occurred in the affected farm.
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