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.     

Body composition and physical activity in end-stage renal disease.

OBJECTIVE: The study objective was to examine the relationship between visceral and somatic protein stores and physical activity in individuals with end-stage renal disease. DESIGN: This was a prospective single-center study. SETTING: The study took place at the Vanderbilt University Outpatient Dialysis Unit and General Clinical Research Center. PATIENTS: Fifty-five patients with prevalent chronic hemodialysis (CHD) were included: 33 males, 22 females, 45 African Americans, 9 Caucasians, and 1 Asian. The mean age was 47.0 +/- 1.6 years, height was 166.4 +/- 13.9 cm, and weight was 83.1 +/- 2.6 kg. METHODS: Body composition was measured by dual-energy x-ray absorptiometry. Minute-by-minute physical activity was assessed over a 7-day period with a triaxial accelerometer. Participants were interviewed by a trained registered dietitian for two 24-hour diet recalls (one from a hemodialysis day; one from a nonhemodialysis day). Laboratory values for serum concentrations of albumin, prealbumin, C-reactive protein, and creatinine were also collected. MAIN OUTCOME MEASURE: Predictors of somatic protein stores were the main outcome measure. RESULTS: Serum albumin was negatively and significantly correlated with the percentage of fat mass (P = .016) and kg of fat mass (P = .044). C-reactive protein was positively and significantly correlated with body weight (P = .006), percentage of fat mass (P = .017), kg of fat mass (P = .006), and body mass index (P = .004). Physical activity and total daily protein intake were the strongest predictors of the amount of lean body mass (P = .01 and .003, respectively). CONCLUSION: The association between somatic protein and visceral protein stores is weak in patients with CHD. Whereas increased levels of physical activity and total daily protein intake are associated with higher lean body mass in patients with CHD, higher adiposity is associated with higher C-reactive protein and lower albumin values.     

Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance.

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.     

Finding temporary relief: strategy for nursing recruitment in northern aboriginal communities.

To address a recurring shortage of nurses in the aboriginal communities of Northwestern Ontario, the First Nations and Inuit Health Branch, Health Canada, commissioned a study to explore the viability of establishing a relief pool among nurses from nearby small industrial towns. An open/close-ended survey completed by a random sample of 237 nurses from the target population documented levels of awareness, willingness, and preparedness for northern practice, as well as recruitment incentives and disincentives. Findings demonstrate an awareness of the overlap between the professional and personal dimensions characteristic of such practices, and suggest support for innovative rotations that would cut across federal/provincial/community jurisdictions. Although complex, given time and willingness, a regional relief system seems viable.