Comparative effectiveness of different antiplatelet agents at reducing TNF-driven inflammatory responses in a mouse model.

Antiplatelet drugs are conventionally used as treatments because of their anti-coagulation functions. However, their pleiotropic effects are of great significance to the treatment of ischaemic cardiovascular diseases. Many studies have reported that an excessive amount of inflammation driven by tumour necrosis factor (TNF) is closely related to the prevalence of atherosclerosis. As the drug selection criteria and evaluation methods related to the anti-TNF activity of antiplatelet drugs remain limited, our investigation of these drugs should prove beneficial. In this study, we compared the anti-TNF activity of three antiplatelet agents, namely clopidogrel, sarpogrelate, and cilostazol, using the TNF-induced inflammatory mouse model. After the oral administration of these drugs, acute inflammation was induced via injection of lipopolysaccharide (LPS) or D-galactosamine (D-gal) and TNF. Serum TNF levels, and the mRNA and protein expression levels of TNF in mouse heart tissue, macrophage accumulation in aortic lesions, and mouse survival were analysed to compare the anti-TNF effects of the three antiplatelet agents. Of the three antiplatelet agents, cilostazol significantly reduced the different levels under the most effective observation. In addition, cilostazol was found to attenuate the TNF-stimulated phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) p65 in the aortic vascular smooth muscle cell line, MOVAS-1 and the D-gal plus TNF-challenged heart tissue of mouse. Therefore, cilostazol is the most ideal of the three antiplatelet drugs for the treatment of TNF-mediated inflammatory disorders.

A Comparison of the Anti-Inflammatory Effects of Four Combined Statin and Antiplatelet Therapies on Tumor Necrosis Factor-Mediated Acute Inflammation in vivo.

BACKGROUND: Combination therapy has been administered to patients with chronic or complex diseases due to its improved therapeutic effects compared with the results of monotherapy. Due to the pleiotropic effects of statins and antiplatelets, these drugs have been studied in combination with other drugs, but not all combinations exerted obvious beneficial effects compared with individual drugs. In this study, we aimed to compare the anti-inflammatory effects of 4 different combination therapies of statins and antiplatelets on the tumor necrosis factor (TNF)-mediated inflammation in vivo. METHODS: Mice were orally administered cilostazol plus pravastatin (CILOP) or cilostazol plus rosuvastatin (CILOR), clopidogrel plus pravastatin (CLOP), or clopidogrel plus rosuvastatin (CLOR); then, acute inflammation was induced by the injection of lipopolysaccharide (LPS) or TNF. Serum TNF levels, macrophage accumulation in the lesioned aortas, and mouse mortality were observed to be comparable to the anti-inflammatory effects of the combination therapies. RESULTS: In mice with LPS-induced inflammation, CILOP and CILOR substantially reduced macrophage infiltration of aortic lesions and the serum TNF levels compared with CLOP and CLOR. Moreover, among the 4 combinations, CILOP significantly improved the survival rate of mice with TNF-mediated acute lethal inflammation. CONCLUSIONS: The combination therapy comprising cilostazol and statins, particularly pravastatin, exerted the best anti-TNF effect compared with clopidogrel and statin therapy; thus, a suitable combination therapy, such as CILOP, can be a potential remedy to cure TNF-related diseases.

Anti-TNF effect of combined pravastatin and cilostazol treatment in an in vivo mouse model.

Objectives: Pravastatin and cilostazol are used as lipid-lowering and antiplatelet agents, respectively. Regarding their well-known anti-inflammatory effects, the additive effect of the two drugs on anti-TNF functions has not yet been investigated. In the present investigation, the beneficial effect of combined pravastatin and cilostazol on their anti-TNF activities was assessed using an in vivo mouse model. Methods: Mice were pretreated with pravastatin and/or cilostazol (40 mg/kg of each), orally once two hour prior to an LPS (5 mg/kg, i.p.) challenge. One hour post challenge, blood and descending aorta were collected for serum TNF levels and immune cell infiltration analyses. For survival analysis, pravastatin and/or cilostazol (40 mg/kg of each) were administered 30 minutes prior to d-galactosamine administration (700 mg/kg, i.p.) and TNF (10 µg/kg, i.p.) challenge and mice survival was monitored. We also examined the effect of either drug or the combination of drugs on TNF-mediated MAPK and NF-κB signaling, using Western blot analysis. Results: Combined treatment of pravastatin and cilostazol significantly decreased serum TNF release and immune cell infiltration in the descending aorta following LPS administration, compared to each single treatment. Additionally, the combined drugs significantly decreased TNF-mediated mouse mortality and downregulated TNF-induced MAPK and NF-κB activation. Conclusions: These findings suggest that combined pravastatin and cilostazol is more effective for reducing TNF-driven inflammation through their anti-TNF activity than monotherapy.

A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor ß Subunit, Glycoprotein 130.

IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.

NSrp70 is significant for embryonic growth and development, being a crucial factor for gastrulation and mesoderm induction.

NSrp70 (nuclear speckle-related protein 70), a recently discovered protein and it belongs to the serine/arginine (SR) rich related protein family. NSrp70 is recognized as an important splicing factor comprising RNA recognition motif (RRM) and arginine/serine (RS)-like regions at the N- and C-terminus respectively, along with two coiled coil domains at each terminus. However, other functions of NSrp70 remain unelucidated. In this study, we investigated the role of NSrp70 in Xenopus embryogenesis and found that its maternal expression plays a critical role in embryonic development. Knockdown of NSrp70 resulted in dramatic reduction in the length of developing tadpoles and mild to severe malformation in Xenopus embryos. In addition, knockdown of NSrp70 resulted in an extremely short axis by blocking gastrulation and convergent extension. Further, animal cap assays along with activin A treatment revealed that NSrp70 is an essential factor for dorsal mesoderm induction as knockdown of NSrp70 caused a dramatic down-regulation of dorsal mesoderm specific genes and its loss significantly shortened the elongation region of animal caps. In conclusion, NSrp70 is crucial for early embryonic development, influencing gastrulation and mesoderm induction.

The influence of a medio-lateral unstable sole on invertor and evertor activation while descending stairs.

[Purpose] This study examined the effects of a medio-lateral unstable sole on invertor and evertor activation while descending stairs. [Subjects and Methods] The subjects were 30 university students with no history of ankle sprain. They descended stairs while wearing the medio-lateral unstable sole or with bare feet. Electromyography was used to record the activity of the tibialis anterior and peroneus longus and brevis muscles and paired t-tests were used to assess statistical significance. [Results] The medio-lateral unstable sole group showed increased tibialis anterior and peroneus longus and brevis muscle activation compared to the barefoot group. [Conclusion] Medio-lateral unstable sole can be used with exercises to prevent further ankle damage by activating both the inversion and eversion muscles.

Factors influencing the confidence in core clinical skills among hospital nurses.

The purpose of this study was to examine the confidence to perform 20 clinical skills and identify factors influencing the confidence of hospital nurses. A descriptive, cross-sectional study was conducted with 550 hospital nurses at four hospitals in B city, Korea. The confidence to perform, frequency of performance and educational needs on 20 clinical skills identified by Korean Accreditation Board of Nursing were measured with a self-reported questionnaire. Data were analysed by SPSS 19.0 (IBM Corporation, Armonk, New York, USA). Participants were 27 years old on average, and 49.5% had less than 3 years of total working experience. The most confident skill was measuring vital signs, whereas the least confident skill was using defibrillator. In results of stepwise regression, confidence to perform was associated with educational needs, total working experience, frequency of performance and position. It is necessary to give opportunities to practice clinical skills at both schools and clinics for producing well-prepared nurses.

Clinical physical therapists research activity reality and barriers to their utilizing research findings.

[Purpose] This research study was performed to investigate the barriers to using the research findings of physical therapists on evidence-based practice. [Subjects] The subjects of this research were physical therapists employed by hospitals that agreed to cooperate with the research in B city. [Methods] A questionnaire made up of 6 research items, 8 physical therapist items, 6 presentation items, and 8 setting items, for a total of 28 items, was distributed. The responses were scored so the higher result scores indicate a higher barrier level to using research findings. Differences in barrier levels related to the likelihood of therapists using research findings in their practice varied according to the general characteristics of the result as according to the t-test and ANOVA. Scheffe's test was used as a post hoc test. [Results] The analysis of 158 returned questionnaires revealed that there were significant relationships between the age, educational level, and professional satisfaction of the therapists and the barriers to using research finding. Significant relationships were also found between the items of "Research participation in clinical research", "Frequency of reading research articles", and "Support of manager to use research" and the barrier level. No relationship was demonstrated between the recognition level of evidence-based practice and the performance level with the barrier score to using research findings. [Conclusion] This study demonstrated that to improve the utilization of research findings, there is a need to provide therapists with continual education and opportunities to participate in research, and environments and ways in which the research results can be given practical applications.

Beneficial anti-inflammatory effects of combined rosuvastatin and cilostazol in a TNF-driven inflammatory model.

BACKGROUND: Due to anti-inflammatory and anti-thrombotic functions, statins and antiplatelets are widely used for patients with cardiovascular-related or coronary artery diseases. Patients with systemic or complex diseases are commonly prescribed multiple targeted medications; thus, a proper combination of two or more drugs for beneficial efficacy is considered in clinical therapy. Recent studies have suggested that combinational therapy with statins and other medications accelerates their single effect to suppress inflammatory responses. However, the therapeutic efficacy and underlying mechanism of combination treatment with rosuvastatin and cilostazol have been poorly studied. METHODS: Mice were administered rosuvastatin alone, cilostazol alone or rosuvastatin and cilostazol in combination, and then injected with LPS or TNF to induce acute inflammation. The serum TNF level, macrophage infiltration of the lesioned aortas and mice mortality were observed in the acute inflammation model. The phosphorylation of MAPK was analyzed in TNF-stimulated HeLa cells. RESULTS: Compared to the treatment with cilostazol alone, the combination treatment with rosuvastatin and cilostazol significantly reduced not only the levels of TNF in the sera but also macrophage infiltration in aortic lesions. In addition, the combination therapy decreased TNF-mediated phosphorylation of the MAPK signaling pathway and improved the survival rate in the TNF-driven inflammatory mice model. CONCLUSION: Rosuvastatin combined with cilostazol therapy can greatly improve the anti-inflammatory effect of monotherapies, resulting in reduced mortality of mice; thus, we propose the potential of use of this combination therapy as anti-TNF agent.

Combination therapy with cilostazol and pravastatin improves antiatherogenic effects in low-density lipoprotein receptor knockout mice.

AIMS: Despite the therapeutic efficacy of statins and antiplatelet agents for atherosclerosis, monotherapy with each drug alone is often insufficient to achieve the patient's therapeutic goals. We previously showed that combined statin/antiplatelet agent/anti-tumor necrosis factor (TNF) agent therapy (pravastatin/sarpogrelate/etanercept) reduces atherosclerotic lesions by inhibiting TNF, an atherogenic cytokine that contributes to the progression of arteriosclerosis. In addition, our previous study showed that combined treatment with pravastatin and cilostazol is effective for reducing TNF-driven inflammation through anti-TNF activity. Therefore, in the present study, we evaluated the additive effects of combined pravastatin and cilostazol therapy on atherosclerotic progression using low-density lipoprotein receptor (LDLR) knockout (KO) mice. METHODS: Ten-week-old LDLR KO mice were fed a high-fat, high-cholesterol diet and orally administered pravastatin and cilostazol alone or in combination. Body weight, plasma lipid levels, and the levels of intracellular adhesion molecules and inflammatory cytokines were analyzed. In addition, aortas and aortic roots were stained with Oil Red O, and atherosclerotic plaques were quantified. RESULTS: The atherosclerotic plaques in the combined pravastatin and cilostazol treatment groups were significantly reduced compared to those in each drug monotherapy group. The combination therapy group also showed the downregulation of ICAM-1, MOMA-2, TNF, interleukin (IL)-6, triglyceride, total cholesterol, and low-density lipoprotein levels and the upregulation of high-density lipoprotein levels compared to those of the pravastatin- or cilostazol-treated groups. CONCLUSIONS: Our results suggest that combination therapy with pravastatin and cilostazol exerts beneficial effects by decreasing atherosclerotic lesion progression and improving the pro-inflammatory state in the vascular endothelium. These effects are mediated by the reduction in adhesion molecule expression, immune cell infiltration, and cytokine levels and the antiatherosclerotic modulation of serum cholesterol levels. Therefore, we conclude that combined treatment with pravastatin and cilostazol may be a more effective antiatherosclerotic strategy than treatment with either agent alone.

[Risk factors for nosocomial urinary tract infection in the intensive care unit with a positive urine culture and foley catheterization].

PURPOSE: The purpose of this study was to identify the risk factors for a nosocomial urinary tract infection in intensive care units with a foley catheterization which showed a positive urine culture. METHOD: Three-hundred eighty-seven patients were included in the study. A retrospective review of the electrical medical record system's databases and medical record sheets in hospitalized patients from January 2003 to December 2003 was used. The collected data was analyzed by descriptive statistics, t-test, chi-square test and logistic regression analysis. RESULT: The frequency of the participants' nosocomial urinary tract infection was 72.9%. Significant risk factors for a nosocomial urinary tract infection were 'age', 'place of catheter insertion', 'frequency of catheter change', and 'duration of catheterization'. These variables explained 18.4% of variance in the experience of nosocomial urinary tract infection in intensive care units with foley catheterization. CONCLUSION: Medical personnel can decrease the incidence of a nosocomial urinary tract infection by recognizing and paying attention to the duration of catheterization, frequency of catheter change, and place of catheter insertion. As a result, specific and scrupulous strategies should be developed to reflect these factors for decreasing nosocomial urinary tract infections.

Critical role of TNF inhibition in combination therapy for elderly mice with atherosclerosis.

AIMS: We have previously shown that the combination of pravastatin and sarpogrelate is synergistically beneficial for atherosclerosis. In this study, we investigated whether the pravastatin-sarpogrelate combination was sufficient for treatment in an old mouse model of atherosclerosis or if additional intervention would be needed to address the newly included aging factor and its complex pathophysiological impact on the atherosclerogenic state. We added an anti-TNF biological to the combination treatment cocktail because of the known pathologic roles of TNF in the aging process. METHODS: Sixty-week-old low-density lipoprotein receptor knockout mice were fed a high-fat, high-cholesterol diet and treated with the sarpogrelate and pravastatin combination, etanercept alone, or the triple combination. RESULTS: Although, etanercept alone did not significantly reduce aortic root and atherosclerotic plaque areas, the pravastatin-sarpogrelate combination, and pravastatin-sarpogrelate-etanercept triple therapy significantly reduced the plaque areas. Surprisingly, TNF inhibition was critically required to reduce the plaque areas of aortic roots and the expression of ICAM-1, MOMA-2, and TNF. More importantly, a lipid-lowering effect by pravastatin was observed only in the triple therapy group and not in the pravastatin and sarpogrelate combination group. CONCLUSIONS: These results suggest that TNF-inhibitory intervention should be added to the conventional therapy as a novel strategy for treating the elderly patients with atherosclerosis.

[A study on health perception and health promoting behavior in chronic back pain patients].

PURPOSE: The purpose of this study was to show a relationship between health perception and health promoting behaviors in chronic low back pain patients. METHOD: The subjects for this study were 213 persons who the visited hospital with low back pain-related problems. RESULTS: The higher the level of the health perception in chronic back pain patients was the higher the rate of the practice of health promoting behaviors (r=0.393, p<.001). The health perception T score was 50.00+/-10.00. As for health promoting behaviors, the T score was 49.99+/-10.00. The subscale of the highest mean score was interpersonal support (2.96+/-0.64) and the subscale of the lowest mean score was exercise (2.13+/-0.99). CONCLUSION: This study showed that chronic low back pain patients had a lower level of perception of their health, and their practice to improve their health was not enough. Therefore, nurses should educate and encourage chronic low back pain patients in proper exercises and correct posture to strengthen and maintain lumbar extension muscle power.

[The effects of a rehabilitation program on physical health, physiological indicator and quality of life in breast cancer mastectomy patients].

PURPOSE: The purpose of this study was to investigate the effects of a rehabilitation program on physical health, physiological indicators and quality of life in breast cancer mastectomy patients. METHODS: The subjects included thirty-one patients with breast cancer (17 in the experimental group and 14 in the control group). The subjects in the experimental group participated in a rehabilitation program for 10 weeks, which was composed of an exercise program, teaching, counseling and support for 2 sessions per week. RESULTS: There was a significant increase in flexion, internal rotation and external rotation but no significant increase in extension in the experimental group compared to the control group. The total cholesterol, triglyceride, HDL, LDL, and CD56 in the experimental group compared to the control group was not significantly decreased after the rehabilitation program. Compared to the control group, quality of life in the experimental group was significantly improved and fatigue in that group was significantly decreased after the rehabilitation program. CONCLUSION: The 10-week rehabilitation program showed a large affirmative effect on physical health, physiological indicators and quality of life in breast cancer mastectomy patients.

Pravastatin and Sarpogrelate Synergistically Ameliorate Atherosclerosis in LDLr-Knockout Mice.

Pravastatin is a lipid-lowering agent that attenuates atherosclerosis. However, the multifactorial pathogenesis of atherosclerosis requires other drugs with different anti-atherogenic mechanisms. We chose sarpogrelate as an anti-platelet agent and a novel component of a complex drug with pravastatin due to its high potential but little information on its beneficial effects on atherosclerosis. Low-density lipoprotein receptor-knockout mice were fed a high-fat, high-cholesterol diet and treated with pravastatin alone, sarpogrelate alone, or a combination of both drugs. Although sarpogrelate alone did not significantly reduce atherosclerotic plaque areas, co-treatment with pravastatin significantly decreased aortic lesions compared to those of the pravastatin alone treated group. The combined therapy was markedly more effective than that of the single therapies in terms of foam cell formation, smooth muscle cell proliferation, and inflammatory cytokine levels. These results suggest that pravastatin and sarpogrelate combined therapy may provide a new therapeutic strategy for treating atherosclerosis.

[Body weight, cardiovascular risk factors, and self-efficacy of diabetic control among obese type II diabetic patients].

PURPOSE: The purpose of this study was to examine the effects of problem solving nursing counseling and walking exercise on weight loss, cardiovascular risk factors, and self-efficacy of diabetic control among obese diabetic patients. The Polar heart rate monitor was used for walking exercise to utilize the Biofeedback mechanism. METHOD: Fifty nine diabetic patients were conveniently placed into experimental (n=35) and control groups (n=24). The experimental group participated in weekly nursing counseling for 12 weeks and was encouraged to do walking exercise using a Polar monitor. The control group remained in the same treatment as before. The data was collected from November 2003 to August 2004 and analyzed using t-tests and ANCOVAs. RESULTS: After 12 weeks, the participants in the experimental group reported significantly decreased body weight (p=.004) and total scores on the Parma scale (p=.001). While the participants in the control group reported significantly increased levels of blood triglyceride (p=.046) and HDL (p=.018). CONCLUSION: Based on the findings, we concluded that problem focused nursing counseling with intensified walking exercise could reduce the risk of cardiovascular complications and body weight among obese diabetic patients. Future research to explore the long-term effects of nursing counseling on diabetic complications is warranted.

[Self care activity, metabolic control, and cardiovascular risk factors in accordance with the levels of depression of clients with type 2 diabetes mellitus].

PURPOSE: The purpose of this study was to explore the levels of depression experienced by clients (N=152) with Type 2 Diabetes Mellitus(DM), and to compare the levels of self care activity, metabolic control and cardiovascular risk factors between depressed and non-depressed clients. METHOD: Participants aged 50 and above were conveniently recruited in B city. The levels of depression, self-care activity, metabolic control of glucose and lipids, and cardiovascular risk factors of the participants were measured by using questionnaires and blood tests from November, 2003 to June, 2004. Data was analyzed with descriptive statistics, Pearson correlation, Spearman rho and t-test using the SPSS WIN 10.0 program. RESULT: The prevalence of depression(CES-D=16) among the participants was 44.1%. The levels of self-care activities(p=.012), glucose(p=.019), total cholesterol(p=.022), LDL(.007) and cardiovascular risk factors(p=.012) were significantly higher in the depressed group than those in the non-depressed group. CONCLUSION: Based on the findings, we concluded that many DM patients experience depression and the depression of type 2 DM clients is significantly related with self care activities, diabetic control, and cardiovascular complications. However, this study did not address causality among these variables. Therefore, further research, such as a longitudinal cohort study, is needed to identify causality among these variables.

[Factors influencing the development of pressure ulcers in surgical patients].

PURPOSE: The purpose of this study was to identify the influencing factors on the development of pressure ulcers in patients undergoing surgery which lasted more than two hours. METHOD: One hundred nineteen surgical adult patients were included in the study. Data was measured on each participant from December 2003 to February 2004. It was collected using a structured researcher-administered sheet and analyzed by descriptive statistics, t-test, chi-square test and logistic regression analysis. RESULT: The prevalence of a perioperative pressure ulcer was 26.1%. The level of moisture, friction and shear, length of surgery, and perioperative irrigation were significantly higher in the pressure ulcer group than those in the non-pressure ulcer group. The level of activity and level of consciousness were significantly lower in the pressure ulcer group than those in the non-pressure ulcer group. Significant influencing factors on the development of pressure ulcer were 'moisture' and 'irrigation' and those variables explained 23.1% of variance in the development of a pressure ulcer during surgery. CONCLUSION: It is necessary to develop a strategy to prevent pressure ulcer by taking 'moisture' and 'irrigation' into account during the preoperative, perioperative and postoperative period.

[The effects of problem solving nursing counseling and intensified walking exercise on diabetic self-care, coping strategies, and glycemic control among clients with DM Type II].

PURPOSE: The purpose of the study was to identify the effects of problem solving nursing counseling and intensified walking exercise on diabetic self-care, coping strategies, and glycemic control among older adults with DM type II. METHOD: Ninety nine DM patients who were older than 50 were recruited from DM clinics or public health centers and conveniently assigned into three groups: the Polar (n=41), counseling (n=30) and control groups (n=28). Participants in both Polar and counseling groups attended weekly problem solving nursing counseling for 12 weeks. Polar heart rate monitors were used in the Polar group to intensify walking exercise. Data was collected from November 2003 to August 2004 and analyzed by ANOVA or ANCOVA using the SPSS WIN program. RESULT: After a 12 week intervention, participants in both the Polar and counseling groups reported increased diabetic self care behaviors and decreased blood glucose levels, which is significantly different from those in the control group. There were no distinctively different program effects between the Polar and counseling groups. CONCLUSION: Based on the findings, we concluded that problem solving counseling alone could have positive effects on diabetic self care and glycemic controls for older adults with DM. Future research is needed to identify long-term effects of the program.

Exacerbation of tumor necrosis factor-induced vascular leak syndrome by aging.

Aging is associated with upregulation of tumor necrosis factor (TNF) and increased vascular inflammation. TNF is a major proinflammatory cytokine that contributes to both vascular inflammation and vascular leak syndrome (VLS). The purpose of this study was to investigate whether the aging affects TNF-induced VLS. Vascular leak, histology, and cytokine assays were performed in young and aged groups of wild-type and TNF overexpressing transgenic (Tg) mice. An aged group of TNF Tg mice showed substantially amplified VLS compared with young Tg mice. Age-related amplification of TNF-induced VLS appears to be related to local vascular fibrosis and the systemic upregulation of TNF and MCP-1 levels in older TNF Tg mice. Our finding suggests that chronic high-grade TNF exposure could mediate the severe vascular pathogenicity of VLS.