Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Clinical outcomes of bypass-first versus endovascular-first strategy in patients with chronic limb-threatening ischemia due to infrageniculate arterial disease

Background

Chronic limb-threatening ischemia (CLTI), defined as ischemic rest pain or tissue loss secondary to arterial insufficiency, is caused by multilevel arterial disease with frequent, severe infrageniculate disease. The rise in CLTI is in part the result of increasing worldwide prevalence of diabetes, renal insufficiency, and advanced aging of the population. The aim of this study was to compare a bypass-first with an endovascular-first revascularization strategy in patients with CLTI due to infrageniculate arterial disease.

Motivated behavior and the estrous cycle in rats

(1) The estrous cycle in the rat may be used to study recurrent changes in motor behaviors and motivation which are strongly related to cyclic hormonal and CNS changes. (2) The peak in motivated behaviors occurs during a sharply defined period on the night between proestrus and estrus and is evident in facilitated wheel-running, lordosis, and intracranial self-stimulation. (3) Behaviors without a clearly motivated character do not show an estrous cyclicity. (4) The estrous cyclic variation in intracranial self-stimulation was observed at a specific locus — the pars campacta of the substantia nigra. (5) A neurochemical link between sexually motivated behavior, wheel running and intracranial self-stimulation is suggested. This link is in part dopaminergic but is probably also activated by many other systems.     

Neurobiology of obsessive compulsive disorder--a serotonergic basis of Freudian repression

Intrusive thoughts and images, often of a violent, horrific, or blasphemous nature are the hallmark of Obsessive Compulsive Disorder (OCD). OCD patients frequently also often have reductions in normal serotonergic (5-HT) function. This paper proposes a model of 5-HT function involving the routine filtering and suppression of violent or libidinal impulses. This model accounts for OCD as an instance of failed inhibition. The model also appears to resemble Freud's model of ego-id interactions at least in part, suggesting that it may be possible to psychobiologically substantiate a Freudian metaphor.     

Local demineralization as a model for bone strength reductions in lytic transcortical metastatic lesions.

The structural consequences of bone density changes associated with lytic metastatic lesions were investigated using an experimental model of regular, lytic metastatic lesions in bone. Circular holes were drilled in the mid-diaphyseal cortex of paired adult canine femora. The region around the defect was demineralized in one bone of each pair with 0.8 N HCl. Specimens were tested to failure in four-point bending. Defect size was determined from conventional planar radiographs as the maximum apparent defect diameter divided by the periosteal diameter. Demineralization resulted in irregular defect geometries, which increased the maximum defect dimension 33% to 57% with respect to the original drill hole diameter. Demineralization resulted in additional strength reductions beyond those expected from the original drill hole alone. Despite the irregular demineralization patterns observed, strength reductions were in close agreement with those predicted from data for regular, nondemineralized holes (r2 = 0.93). The results demonstrate that irregular diaphyseal defect borders may not require more complex fracture risk predictors than can be determined from analytic and experimental studies of regular defect geometries. Our results also demonstrate that errors of over 100% can occur when measuring diaphyseal defect size from radiographs that are not optimally aligned with respect to the defect.