In vivo pathology: seeing with molecular specificity and cellular resolution in the living body.
ABSTRACT The emerging tools of in vivo molecular imaging are enabling dynamic cellular and molecular analyses of disease mechanisms in living animal models and humans. These advances have the potential to dramatically change a number of fields of study, including pathology, and to contribute to the development of regenerative medicine and stem cell therapies. The new tools of molecular imaging, which have already had a tremendous impact on preclinical studies, hold great promise for bringing important and novel information to the clinician and the patient. These approaches are likely to enable early diagnosis, rapid typing of molecular markers, immediate assessment of therapeutic outcome, and ready measures of the extent of tissue regeneration after damage. However, the full impact of these new techniques will be determined by our ability to translate them to the clinic and to develop a general strategy that integrates them with other advances in molecular diagnostics and molecular medicine.
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ABSTRACT: Mislocalization and aggregation of the axonal protein tau are hallmarks of Alzheimer's disease and other tauopathies. Here, we studied the relationship between tau aggregation, loss of spines and neurons, and reversibility by aggregation inhibitors. To this end we established an in vitro model of tauopathy based on regulatable transgenic hippocampal organotypic slice cultures prepared from mice expressing proaggregant Tau repeat domain with mutation ΔK280 (Tau(RD)ΔK). Transgene expression was monitored by a bioluminescence reporter assay. We observed abnormal tau phosphorylation and mislocalization of exogenous and endogenous tau into the somatodendritic compartment. This was paralleled by a reduction of dendritic spines, altered dendritic spine morphology, dysregulation of Ca(++) dynamics and elevated activation of microglia. Neurotoxicity was mediated by Caspase-3 activation and correlated with the expression level of proaggregant Tau(RD)ΔK. Finally, tau aggregates appeared in areas CA1 and CA3 after three weeks in vitro. Neurodegeneration was relieved by aggregation inhibitors or by switching off transgene expression. Thus the slice culture model is suitable for monitoring the development of tauopathy and the therapeutic benefit of antiaggregation drugs.Neurobiology of aging 11/2012; 34(5). DOI:10.1016/j.neurobiolaging.2012.10.024 · 4.85 Impact Factor
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ABSTRACT: The blood–brain barrier (BBB) is a highly complex structure, which separates the extracellular fluid of the central nervous system (CNS) from the blood of CNS vessels. A wide range of neurologic conditions, including stroke, epilepsy, Alzheimer’s disease, and brain tumors, are associated with perturbations of the BBB that contribute to their pathology. The common consequence of a BBB dysfunction is increased permeability, leading to extravasation of plasma constituents and vasogenic brain edema. The BBB impairment can persist for long periods, being involved in secondary inflammation and neuronal dysfunction, thus contributing to disease pathogenesis. Therefore, reliable imaging of the BBB impairment is of major importance in both clinical management of brain diseases and in experimental research. From landmark studies by Ehrlich and Goldman, the use of dyes (probes) has played a critical role in understanding BBB functions. In recent years methodologic advances in morphologic and functional brain imaging have provided insight into cellular and molecular interactions underlying BBB dysfunction in animal disease models. These imaging techniques, which range from in situ staining to noninvasive in vivo imaging, have different spatial resolution, sensitivity, and capacity for quantitative and kinetic measures of the BBB impairment. Despite significant advances, the translation of these techniques into clinical applications remains slow. This review outlines key recent advances in imaging techniques that have contributed to the understanding of BBB dysfunction in disease and discusses major obstacles and opportunities to advance these techniques into the clinical realm.Epilepsia 11/2012; 53(s6). DOI:10.1111/j.1528-1167.2012.03698.x · 4.58 Impact Factor
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ABSTRACT: Clinical microbiology has always been a slowly evolving and conservative science. The sub-field of bacteriology has been and still is dominated for over a century by culture-based technologies. The integration of serological and molecular methodologies during the seventies and eighties of the previous century took place relatively slowly and in a cumbersome fashion. When nucleic acid amplification technologies became available in the early nineties, the predicted "revolution" was again slow but in the end a real paradigm shift did take place. Several of the culture-based technologies were successfully replaced by tests aimed at nucleic acid detection. More recently a second revolution occurred. Mass spectrometry was introduced and broadly accepted as a new diagnostic gold standard for microbial species identification. Apparently, the diagnostic landscape is changing, albeit slowly, and the combination of newly identified infectious etiologies and the availability of innovative technologies has now opened new avenues for modernizing clinical microbiology. However, the improvement of microbial antibiotic susceptibility testing is still lagging behind. In this review we aim to sketch the most recent developments in laboratory-based clinical bacteriology and to provide an overview of emerging novel diagnostic approaches.Annals of Laboratory Medicine 01/2013; 33(1):14-27. DOI:10.3343/alm.2013.33.1.14 · 1.48 Impact Factor