Loss of NF-kappaB activity during cerebral ischemia and TNF cytotoxicity.

Recent evidence implicates tumor necrosis factor (TNF), a cytokine with both cytotoxic and cytoprotective activities, in the pathogenesis of cerebral ischemia. The development of TNF cytotoxicity is dependent upon the balance between the activities of intracellular signaling pathways that mediate either apoptotic or anti-apoptotic effects. One critical protective signaling mechanism is the activation of nuclear factor (NF)-kappaB, a ubiquitous transcription factor that regulates expression of anti-apoptotic gene products. Here we show the distribution and kinetics of NF-kappaB activation and the correlation between loss of NF-kappaB activity, TNF up-regulation, and apoptosis in a standardized rat model of focal cerebral ischemia. We observed a rapid and progressive ischemia-induced loss of p65 immunoreactivity within the ischemic core and nearby penumbra. These findings were confirmed by Western blot analysis of nuclear extracts and by electrophoretic mobility shift assay. The anatomical area of suppressed NF-kappaB activity overlapped significantly with the zones of TNF overexpression and apoptosis. Loss of NF-kappaB activity and increased TNF expression preceded the onset of cell death. Direct evidence that loss of NF-kappaB activity can sensitize brain cells to TNF cytotoxicity was obtained in vitro by co-administration of MG-132, an inhibitor of NF-kappaB activation, and TNF to neuronal-like and glial-like cell cultures. Inhibition of NF-kappaB significantly increased the sensitivity of these cultures to TNF cytotoxicity, indicating that the observed loss of neuronal NF-kappaB activity during cerebral ischemia can participate in the development of TNF-induced cytotoxicity.

Correction of lower extremity deep venous incompetence by ablation of superficial venous reflux.

Chronic venous insufficiency which produces lipodermatosclerosis, varicosities, or ulceration, is frequently caused by superficial venous reflux and deep venous incompetence. The anatomy of venous insufficiency has been clarified with duplex ultrasound, thus allowing appropriately directed therapy. However, postoperative venous physiology in patients undergoing superficial venous ablation has been infrequently reported. This study was undertaken to document the effect of superficial venous ablation on deep venous reflux. Between April 1994 and May 1995, 45 patients were examined preoperatively with duplex ultrasound. All patients had symptomatic venous insufficiency and were found to have greater saphenous vein reflux. Clinical classification of venous insufficiency (according to the criteria of the joint councils of the vascular societies) included class I in 30 patients, class II in 12, and class III in 3. Seventeen patients (38%) had reflux in the femoral venous system in addition to superficial reflux. All patients underwent removal of the proximal greater saphenous vein in concert with multiple stab avulsions of identified varicosities. Postoperative interrogation of the venous system revealed that in 16 (94%) of 17 patients, coexistent femoral venous insufficiency completely resolved. Thus ablation of superficial venous reflux eliminated incompetence in the deep venous system in patients with combined disease. These preliminary results suggest that superficial venous incompetence may be a cause of deep venous insufficiency. Whereas alternative methods to correct deep venous insufficiency have met with limited success, it appears that saphenectomy (when combined disease is present) may be effective in correction of deep venous reflux.