Intracellular signaling induced by the coagulation factors (F) VIIa and Xa is poorly understood. We report here studies on these processes in a human keratinocyte line (HaCaT), which is a constitutive producer of tissue factor (TF) and responds to both FVIIa and FXa with elevation of cytosolic Ca 2؉ , phosphorylation of extracellular signal-regulated kinase (Erk) 1/2, p38 MAPK , and cJun N-terminal kinase, and up-regulation of transcription of the early growth response gene-1 (egr-1). Using egr-1 as end point, we observed with both agonists that phosphatidylinositol-specific phospholipase C and the mitogen-activated protein kinase/Erk kinase/Erk pathway were mediators of the responses. The responses to FVIIa were TF-dependent and up-regulation of egr-1 mRNA did not require presence of the TF cytoplasmic domain. Antibodies to EPR-1 and factor V had no effect on the response to FXa. We have provided evidence that TF is not the sole component of the FVIIa receptor. The requirement for proteolytic activity of both FVIIa and FXa suggests that protease-activated receptors may be involved. We now report evidence suggesting that protease-activated receptor 2 or a close homologue may be a necessary but not sufficient component of this particular signal transduction pathway. The up-regulation of egr-1 describes one way by which the initiation of blood coagulation may influence gene transcription. The ability of these coagulation proteases to induce intracellular signals at concentrations at or below the plasma concentrations of their zymogen precursors suggests that these processes may occur also in vivo.

AIM To describe walking ability and identify factors predicting walking capacity in adults with spastic cerebral palsy (CP) assessed with the 6-minute walk test (6MWT).METHOD A cross-sectional clinical study as part of the recruitment process for a randomized controlled trial on the effects of botulinum toxin A. Data analysed were the 6MWT, Timed Up and Go (TUG) test, Borg Scale, spasticity, muscle strength, popliteal angle, pain, fatigue, type of CP, foot deformity, Gross Motor Function Classification System (GMFCS) levels, Functional Mobility Scale (FMS) scores, a gait questionnaire, interview, and demographic data. RESULTSIn total, 126 persons were included (53 males, 73 females; mean age 39y [SD 12y]; 59 with unilateral and 67 with bilateral spastic CP; GMFCS level I, n=12; level II, n=94; level III, n=20). Mean distance on the 6MWT was 485m (SD 95m) with FMS scores reflecting independent walking performance in daily life. Multiple regression analysis identified sex, type of CP, popliteal angle, pain, and TUG values as significant predictors, with TUG values as the strongest predictor (standardized regression coefficient =)0.57, p<0.001).INTERPRETATION Our results demonstrate that 39% of the participants had declined one GMFCS level from adolescence to their present age, and that the TUG was the strongest predictor for the 6MWT. This implicates the importance of focusing specifically on the different elements of functional mobility in further studies.Cerebral palsy (CP) is a group of permanent disorders of movement and posture, often accompanied by secondary musculoskeletal problems.1 Literature on children with CP supports a link between the levels of impairment and walking ability.1 However, the relation between self-reported declined walking ability and data on clinical measurements in adults needs more investigation.Surveys of adults with CP report that contractures, spasticity, pain, fatigue, as well as reduced muscle strength and balance, are associated with declined walking ability. 2-4The Gross Motor Function Classification System (GMFCS) categorizes gross motor function into five levels, with level I describing the highest level of function and level V the lowest.5 A study of individuals with CP aged up to 21 years showed that those classified at GMFCS levels III to V have their peak motor function in childhood, whereas individuals at levels I or II have a stable gross motor function. 6 However, surveys of adults with CP indicate that even persons at GMFCS levels I or II experience increasing walking difficulties in young adulthood.

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