Keloid fibroblast responsiveness to epidermal growth factor and activation of downstream intracellular signaling pathways.

Keloids, which overgrow the boundaries of the original injury, represent aberrations in the fundamental process of wound healing that include over-abundant cell in-migration, cell proliferation, and inflammation, as well as increased extracellular matrix synthesis and defective remodeling. To understand the key events that result in the formation of these abnormal scars would open new avenues for better understanding of excessive repair, and might provide new therapeutic options. We examined epidermal growth factor receptor (EGFR)-induced cell motility in keloid fibroblasts, as this receptor initiates cell migration during normal wound repair. We show that keloid fibroblasts respond to EGF-induced cell migration but the response is somewhat diminished compared to normal adult fibroblasts (approximately 30% reduced); the mitogenic response was similarly blunted (approximately 5% reduced). Keloid fibroblasts express near normal levels of EGFR (82%), but show a much more attenuated activation of EGFR itself and the motility-associated phospholipase C-gamma. This was reflected in part by rapid loss of EGFR upon exposure to EGF. Interestingly, while extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) activation was relatively robust in keloid fibroblasts, the downstream triggering of the motility-associated calpain activity was blunted. This was reflected by high cell-substratum adhesiveness in the keloid fibroblasts. Thus, the blunted migratory response to EGF noted in keloid fibroblasts appears due to limited activation of two important biochemical switches for cell motility.     

Multiple transduction as a means of preserving ganciclovir chemosensitivity in sarcoma cells carrying retrovirally transduced herpes thymidine kinase genes.

The potential value of retroviral gene transfer as a means of targeting therapeutic genes to neoplastic cells is threatened by the tendency of occasional cells to lose transduced genes or their expression. To determine whether this threat could be reduced by transducing multiple copies of a therapeutic gene, we compared 8 murine sarcoma sublines carrying from 1 to 6 copies of a retrovirally transduced herpes simplex virus thymidine kinase gene, which sensitizes cells to ganciclovir (GCV). When variability consequent to differences in vector integration site was excluded, increased copy number was associated with an increase in GCV sensitivity and a major reduction in the frequency of GCV-resistant mutants. The results suggest a potential means of preserving the efficacy of future antineoplastic gene therapy strategies.     

Asymmetric growth of the lateral cerebral ventricle in infants with posthemorrhagic ventricular dilation

Lateral cerebral ventricular volume in 36 preterm infants with or without an intraventricular hemorrhage, and with or without posthemorrhagic hydrocephalus, was measured longitudinally and compared with the ventricular index measurements of the same ventricles. A poor correlation was found (r2 = 0.67). To determine a reason for this poor relationship, we analyzed the volumes of the regions of the ventricles by a segmental volume analysis. The occipital region of the lateral cerebral ventricle enlarged at a much faster rate (1.904 +/- 0.477 ml/day) than either the anterior region (0.546 +/- 0.253 ml/day; p less than 0.01) or the middle region (-0.209 +/- 0.334 ml/day; p less than 0.01) in infants with posthemorrhagic hydrocephalus. The rate of growth of the middle region of the lateral cerebral ventricles was the same for all infants. Linear indexes, such as the ventricular index and the lateral ventricular ratio, do not allow for accurate serial estimates of ventricular size in posthemorrhagic hydrocephalus because of asymmetric growth of the lateral cerebral ventricle. We conclude that sequential volume measurements are more useful than ventricular index measurements to follow ventricular size sequentially in infants with posthemorrhagic hydrocephalus.     

Cervical lymphadenitis complicated by mycotic carotid artery aneurysm

A case of mycotic carotid artery aneurysm due to cervical lymphadenitis in a four-year old child is presented. Sonography and computed tomography (CT) demonstrated an irregular fluid-containing neck mass, similar in appearance to an uncomplicated abscess. Continuity with the carotid artery was suggested on sonography, and CT demonstrated intense contrast enhancement of the liquid portion of the mass. Mycotic carotid artery aneurysm is a rare, but potentially fatal, complication of cervical lymphadenitis that is detectable with noninvasive diagnostic imaging studies.     

Effect of corticosteroid prophylaxis on lipopolysaccharide levels associated with intestinal ischemia in cats

Ischemia of the intestines damages the permeability of the intestinal wall, allowing lipopolysaccharide (LPS) (endotoxin) to leak from the gut lumen into the blood circulation, causing shock and death. We measured LPS levels associated with corticosteroid treatment vs. no treatment in cats whose superior mesenteric artery had been occluded for 60 min. In untreated cats, the preocclusion mean plasma LPS concentration remained stable at 0.069 +/- 0.015 ng/ml. Toward the end of the occlusion period, mean plasma LPS rose to 0.239 +/- 0.032 ng/ml (p less than .01). Release of the clamp and reperfusion with oxygenated blood was followed within 20 min by a large rise in plasma LPS concentration to 0.825 +/- 0.11 ng/ml (p less than .01), which had returned to preocclusion levels about 80 min later. Methylprednisolone (30 mg/kg) was infused into a second group of cats 1.5 h before SMA occlusion. In these cats there was a complete inhibition of the LPS rise both during and after occlusion. These data suggest that the reported beneficial effect of corticosteroids in the treatment of septic shock may be mediated, in part, by reducing LPS leakage from the gut.     

Coronary sinus thrombosis and myocardial infarction secondary to ventriculoatrial shunt insertion

Coronary sinus thrombosis was found at necropsy in a girl with spina bifida who underwent ventriculoatrial shunt revision. There was secondary myocardial infarction, close to the conducting system within the interventricular septum. We suggest that this led to cardiac arrest and sudden death.