Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain

Objective: Early exposure to common anesthetic and sedative agents causes widespread brain cell degeneration and apoptosis in the developing rat brain, associated with persistent learning deficits in rats. This study was designed to determine whether the α₂ adrenergic receptor agonist, dexmedetomidine, produces brain cell degeneration and apoptosis in postnatal day-7 rats in the same brain areas when compared to ketamine.

Methods: Systemic saline, ketamine 20?mg/kg, or dexmedetomidine at 30 or 45?μg/kg were given six times to postnatal day 7 rats (n = 6/group) every 90?min. Twenty-four hours after the initial injection, brain regions were processed and analyzed for cell degeneration using the silver stain and for apoptosis using activated caspase-3 immunohistochemistry.

Results: Exposure to ketamine resulted in significant cellular degeneration and apoptosis in limbic brain regions, but nonsignificant changes in primary sensory brain regions. In contrast, dexmedetomidine produced significant cellular degeneration and apoptosis in primary sensory brain regions, but nonsignificant changes in limbic regions.

Conclusions: These data show that ketamine and dexmedetomidine result in anatomically distinct patterns of cell degeneration and apoptosis in the brains of 7-day-old rat pups. The meaning and the clinical significance of these findings remain to be established.     

Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis

Neutrophil elastase is a serine protease stored in the azurophilic granules of leukocytes. It has been implicated in the pathology of several lung diseases and is generally presumed to contribute to the tissue destruction and extracellular matrix damage associated with these conditions. To delineate the role of neutrophil elastase in pulmonary inflammation and fibrosis, neutrophil elastase-null mice were intratracheally instilled with bleomycin. In neutrophil elastase-null mice, biochemical and morphological characteristics of pulmonary fibrosis were attenuated for at least 60 days after bleomycin administration despite a typical response to bleomycin as evidenced by assessment of indices of DNA and cell damage. Neutrophil burden of bleomycin-treated wild-type and neutrophil elastase-null mice was comparable, and marked neutrophilic alveolitis was manifest in bleomycin-treated neutrophil elastase-null mice. An absence of immunostaining for active transforming growth factor (TGF)-beta in lung tissue from bleomycin-treated neutrophil elastase-null mice suggested a defect in TGF-beta activation, which was confirmed by biochemical assessment of TGF-beta levels in bronchoalveolar lavage fluid and lung tissue. These data point to novel and unexpected fibrogenic consequences of neutrophil elastase activity in the inflamed lung.     

Identification and dynamics of spontaneous burst initiation zones in unidimensional neuronal cultures

Spontaneous activity is typical of in vitro neural networks, often in the form of large population bursts. The origins of this activity are attributed to intrinsically bursting neurons and to noisy backgrounds as well as to recurrent network connections. Spontaneous activity is often observed to emanate from localized sources or initiation zones, propagating from there to excite large populations of neurons. In this study, we use unidimensional cultures to overcome experimental difficulties in identifying initiation zones in vivo and in dissociated two-dimensional cultures. We found that spontaneous activity in these cultures is initiated exclusively in localized zones that are characterized by high neuronal density but also by recurrent and inhibitory network connections. We demonstrate that initiation zones compete in driving network activity in a winner-takes-most scenario.     

The relationship of three-dimensional joint space width on weight-bearing CT with pain and physical function

Limitations of plain radiographs may contribute to poor sensitivity in the detection of knee osteoarthritis and poor correlation with pain and physical function. Three-dimensional (3D) joint space width (JSW), measured from weight-bearing computed tomography (CT) images, may yield a more accurate correlation with patients’ symptoms. We assessed the cross-sectional association between 3D JSW and self-reported pain and physical function. Five hundred twenty eight knees (57% women) were analyzed from Multicenter Osteoarthritis Study participants. An upright weight-bearing CT scanner was used to acquire bilateral, weight-bearing, fixed-flexion images of the knees. A 3D dataset was reconstructed from cone beam projections and JSW was calculated across the joint surface. The percentages of the apposed medial tibiofemoral joint surface with JSW less than 2.0 and 2.5 mm, respectively, were calculated. Pain and physical function were measured using Western Ontario and McMaster Universities Osteoarthritis Index. Participants who reported greater pain severity tended to have a greater joint area with JSW less than 2.0 mm (P = .07 for the highest vs the lowest tertile). Participants who reported greater functional limitations had a greater joint area with JSW less than 2.0 mm (P = .02 for the highest vs the lowest tertile). There appears to be an association between the medial tibiofemoral area with JSW less than 2.0 mm and pain and physical function.