ABSTRACT
Anticholinergic medications are associated with adverse cognitive effects in cognitively normal and impaired individuals, with a greater magnitude of effect observed in individuals with preexisting cognitive impairment due to Alzheimer disease.
Subject(s)
Alzheimer Disease , Cholinergic Antagonists , Cognition/drug effects , Inappropriate Prescribing , Aged , Alzheimer Disease/complications , Alzheimer Disease/physiopathology , Cholinergic Antagonists/administration & dosage , Cholinergic Antagonists/adverse effects , Cholinergic Antagonists/therapeutic use , HumansABSTRACT
Zebrafish are a unique model for pharmacological manipulation of physiological processes such as inflammation; they are small and permeable to many small molecular compounds, and being transparent, they permit the visualization and quantitation of the inflammatory response by observation of transgenically labeled inflammatory cell populations. Using a transgenic line specifically labeling neutrophils in vivo (mpx:GFP), we studied the effects of a range of pharmacological agents on the resolution of inflammation in vivo. These agents were selected for their ability to modulate neutrophil function and lifespan in human neutrophils in vitro. Agents delaying neutrophil apoptosis (LPS, dbcAMP, and several caspase inhibitors) all lead to a delay in resolution of neutrophilic inflammation. Reciprocally, pyocyanin and roscovitine (inducers of neutrophil apoptosis) lead to reduced neutrophil numbers. The occurrence of apoptosis was observed by time-lapse analysis and confirmed by dual staining for neutrophil-specific mpx activity (TSA staining) and an apoptotic marker (TUNEL). During inflammation, macrophages follow neutrophils into the inflamed site, and TUNEL/TSA dual-positive material can be demonstrated within macrophages, consistent with their uptake of apoptotic neutrophils. This model has several advantages over mammalian models and lends itself to the study of pharmaceutical agents modulating inflammation.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Inflammation/drug therapy , Neutrophils/metabolism , Purines/pharmacology , Pyocyanine/pharmacology , Zebrafish/metabolism , Animals , Animals, Genetically Modified , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Inflammation/metabolism , Inflammation/pathology , Neutrophils/pathology , Roscovitine , Zebrafish/geneticsABSTRACT
We have established an in vivo model for genetic analysis of the inflammatory response by generating a transgenic zebrafish line that expresses GFP under the neutrophil-specific myeloperoxidase promoter. We show that inflammation is induced after transection of the tail of zebrafish larvae and that this inflammation subsequently resolves over a similar time course to mammalian systems. Quantitative data can be generated from this model by counting of fluorescent cells or by digital image analysis. In addition, we show that the resolution of experimentally induced inflammation can be inhibited by the addition of a pancaspase inhibitor, zVD.fmk, demonstrating that experimental manipulation of the resolution of inflammation is possible in this model.
Subject(s)
Neutrophils/immunology , Wounds and Injuries/immunology , Zebrafish/immunology , Animals , Animals, Genetically Modified , Cell Count/methods , Disease Models, Animal , Green Fluorescent Proteins , Image Processing, Computer-Assisted , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Neutrophils/pathology , Peroxidase/genetics , Peroxidase/immunology , Promoter Regions, Genetic , Transgenes/immunology , Wounds and Injuries/genetics , Wounds and Injuries/pathology , Zebrafish/geneticsABSTRACT
The clinical pathologist often faces the request for the research of dysmorphism in urinary erythrocytes for evaluation of hematuria. Red cells with a different shape in the urinary sediment is usual but it is difficult to know when its presence has really diagnostic meaning. The last concepts about dysmorphic erythrocytes in urine, mainly the acanthocyte, and its importance in the differential diagnosis of hematuria are presented in this review.
