ABSTRACT
Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.
Subject(s)
Caspase 8/metabolism , Dibenzazepines/pharmacology , Paneth Cells/drug effects , Receptor, Notch1/antagonists & inhibitors , Animals , Caspase 8/genetics , Cell Death/drug effects , Cell Proliferation/drug effects , Male , Metaplasia , Mice, Inbred C57BL , Mice, Knockout , Paneth Cells/enzymology , Paneth Cells/pathology , Permeability , Phenotype , Receptor, Notch1/metabolism , Secretory Pathway , Wnt Signaling Pathway/drug effectsABSTRACT
In people over 50, age-related macular degeneration (ARMD) has become the most common cause for severe visual loss and legal blindness in all industrialized nations. Currently, there is no effective treatment for the majority of patients. To develop new and effective modes of therapy, understanding of the molecular basis of the disease in mandatory. However, the pathogenesis of ARMD is still poorly understood. Several lines of evidence suggest that aging changes of the retinal pigment epithelium (RPE), in particular the accumulation of autofluorescent lipofuscin granules in the lysosomal compartment of postmitotic RPE cells, play a key role in the pathogenesis of the disease. Recent studies indicate that lipidic compounds of lipofuscin, represented by the retinoid A2-E, and protein damage by lipid peroxidation products, in particular malondialdehyde and 4-hydroxynonenal, induce lysosomal dysfunction and lipofuscinogenesis in the RPE. The possible mechanisms underlying this lysosomal dysfunction and the resulting adverse effects on overall RPE function are discussed.
Subject(s)
Lipid Metabolism , Lipid Peroxidation , Lipofuscin/metabolism , Macular Degeneration/etiology , Macular Degeneration/metabolism , Age Factors , Humans , Molecular Structure , Pigment Epithelium of Eye/metabolism , Pigment Epithelium of Eye/pathologyABSTRACT
OBJECTIVE: To review terbutaline pump tocolytic therapy as part of the management of high-order multiple gestations (triplet and quadruplet pregnancies). STUDY DESIGN: We performed a retrospective review of the medical records of triplet and quadruplet pregnancies cared for by Phoenix Perinatal Associates from August 1988 to January 1992 in whom terbutaline pump tocolysis was administered. RESULTS: The study group consisted of 15 triplet pregnancies and 6 quadruplet pregnancies. The 15 patients with triplets delivered at a mean (+/- SD) gestational age of 33.0 +/- 1.9 weeks. The six patients with quadruplets delivered at 33.0 +/- 1.3 weeks. Only 2 of 15 (13%) of the triplets and 1 of 6 (17%) of the quadruplets were delivered for tocolytic failure. CONCLUSION: Terbutaline pump tocolysis provides safe and effective tocolytic therapy in a select group of high-order multifetal gestations.
Subject(s)
Quadruplets , Terbutaline/administration & dosage , Terbutaline/pharmacology , Tocolysis/methods , Triplets , Adult , Female , Humans , Obstetric Labor, Premature/drug therapy , Pregnancy , Pregnancy Outcome , Retrospective StudiesSubject(s)
Brain Ischemia/drug therapy , Ergolines/therapeutic use , Nicergoline/therapeutic use , Aged , Blood Pressure/drug effects , Cardiac Output/drug effects , Cerebrovascular Circulation/drug effects , Chronic Disease , Electroencephalography , Female , Heart Rate/drug effects , Humans , Male , Middle AgedABSTRACT
The significance of directional Ultrasound-Doppler-Sonography with measurements at the fronto-medial and fronto-lateral arteries for the presence of a haemodynamically effective stenosis of the internal carotid artery between the bifurcation and the origin of the ophthalmic artery tells us more than Infratone-ophthalmodynamography (Hager). This paper compares results in a neurological practice obtained during a period of 2 years, from which some cases in the publication complete with the curves obtained are presented.
