Medical complications and patient outcomes in Iranian veterans with spinal cord injury.

BACKGROUND: Spinal cord injury [SCI] occurring in military veterans is a disabling and highly morbid event. Often the victims are young active males who sustain these injuries during military conflict and suffer from the complications of the SCI for the rest of their lives. OBJECTIVES: The aim of the study is to report the epidemiology of Iranian SCI veterans and their health related quality of life, medical complications and patient associated outcomes. MATERIAL AND METHODS: A cohort of 1984 patients was examined to investigate the epidemiology of Iranian SCI veterans of the Iraq-Iran War (1980-1988); 1803 out of the total number of SCI records were included. Health monitoring was carried out through scheduled monthly visits by general physicians, followed by interviews with specialists from March 20, 2007, to March 19, 2010. Additional follow-up was conducted by telephone survey. RESULTS: In all, 174 patients (8.77%) had incomplete injury and the rest had complete injury. the most frequent level of injury was the thoracic level (1256 patients - 63.30%). Pressure ulcers were the most frequent complication (up to 14.7% annual prevalence), followed by reactions to severe stress and adjustment disorders (up to 13.6%) and diabetes (up to 10.1%). In the telephone surveys, kidney and/or urologic disorders were the most frequent reported complaints (21.6%). A total of 101 out of the 1984 SCI veterans died between 2000 and 2010 (~0.5% per year). CONCLUSIONS: In veterans with spinal cord injury, pressure area ulcers (ICD10:L89), reactions to severe stress and adjustment disorders (ICD10:F43), diabetes mellitus (ICD10:E10-E14) and kidney and/or urologic disorders are common and should be addressed aggressively in healthcare planning and management programs for patients with spinal cord injuries.

Health-related quality of life among individuals with long-standing spinal cord injury: a comparative study of veterans and non-veterans.

BACKGROUND: Spinal cord-injured (SCI) patients experience poor health-related quality of life (HRQOL) and they usually report lower HRQOL than the general population or population subgroups in Iran and elsewhere. The aim of this study was to compare HRQOL between veterans and non-veterans with SCI in Iran. METHODS: This was a cross-sectional study. HRQOL was measured using the 36-item Short Form Health Survey (SF-36). Thirty-nine male veterans and 63 non-veteran males with SCI were included in the study. Regression analyses were applied to determine the variables affecting physical and mental health-related quality of life among the patients. RESULTS: The male veterans had a lower HRQOL than the non-veterans with SCI. The differences were significant for all measures except for physical and social functioning. The greatest difference was observed for bodily pain (P = 0.001). The regression analysis results indicated that a longer time since injury was associated (P = 0.01) with better physical health-related quality of life (PCS), while being a veteran (P < 0.001) and having a spinal lesion in the cervical region (P = 0.001) were associated with poorer PCS. Older age (P < 0.001) and higher education (P = 0.01) were associated with better mental health-related quality of life (MCS), while being a veteran and having a spinal lesion in the cervical region (P = 0.02) were associated with poorer MCS. CONCLUSION: The study findings showed that veterans with SCI experienced lower HRQOL than their non-veteran counterparts. A qualitative study is recommended to evaluate why HRQOL was lower in veterans than in non-veterans with SCI although veterans had higher incomes as a result of their pensions and increased access to equipment, and medications. To improve quality of life in both veterans and non-veterans with spinal cord injuries, policy changes or implementation of new interventions may be essential so that veterans could receive additional support (e.g. counseling, recreation therapy, vocational therapy, etc.) and non-veterans could meet their basic needs.

NF-kappaB and ZBP-89 regulate MMP-3 expression via a polymorphic site in the promoter.

A 5T/6T polymorphism in the human MMP-3 promoter affects gene expression and impacts the risk and/or severity of various pathological conditions. Chromatin immunoprecipitation (ChIP) in human fibroblasts homozygous for the 6T site demonstrate that it is bound by NF-kappaB and ZBP-89 transcription factors in its native chromatin. ChIP in COS-1 cells transfected with plasmids containing the 5T and 6T sites in the context of 2kb of the MMP-3 promoter showed that NF-kappaB p50 binds preferentially to the 6T site, while more ZBP-89 binding is detected to the 5T site. Over-expressed ZBP-89 increased transcription from the 5T promoter but not from the 6T, while NF-kappaB decreased transcription from both promoters, even in the presence of excess ZBP-89. A model is suggested in which the physiological impact of the polymorphism is dependent on the relative levels and activities of these competing factors in various cell types and conditions.

Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARgamma activation in human gingival fibroblasts.

BACKGROUND: Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-gamma (PPARgamma) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARgamma by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARgamma may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters. The objective of this study was to determine whether the suppressive effects of IL-4 on the IL-1 induced expression of MMP-3 involve activation of lipoxygenase and/or PPARgamma. RESULTS: Western blotting revealed the presence of PPARgamma in nuclear extract of HGF. IL-1 induced binding of nuclear extract to the putative composite PPRE/AP-1 site was diminished in the presence of pioglitazone, but there was no evidence of any change in the composition of the retarded complexes, and no evidence of PPARgamma binding to this site. Nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase inhibitor, and MK886, a specific inhibitor of 5-lipoxygenase, induced MMP-3 expression synergistically with IL-1. However IL-4 was still able to inhibit MMP-3 expression in the presence of NDGA or MK886 and IL-1. Activation of PPARgamma with pioglitazone not only failed to inhibit IL-1 induced expression of MMP-3 mRNA, but rather super-induced MMP-3 in the presence of IL-1. PPARgamma antagonist GW9662 failed to abolish the suppressive effects of IL-4. Another PPARgamma activator, 15-deoxy-Delta12,14prostaglandin J2 (15dPGJ2), also super-induced MMP-3 mRNA, and this was due at least in part to increased transcription. CONCLUSION: IL-4 suppression of IL-1-induced MMP-3 expression in HGF is independent of lipoxygenase activity and activation of PPARgamma. Super-induction of MMP-3 by pioglitazone may have important implications for patients using pioglitazone to treat type II diabetes in the presence of chronic inflammation.

Interleukin-4 suppresses IL-1-induced expression of matrix metalloproteinase-3 in human gingival fibroblasts.

BACKGROUND: In periodontitis, matrix metalloproteinase-3 (MMP-3, stromelysin 1) is present at increased levels in active disease sites compared to inactive or healthy sites, and the levels are correlated with clinical parameters and associated with progression of the disease. Interleukin (IL)-4 has been shown in human skin and synovial fibroblasts and articular chondrocytes to suppress IL-1-induced expression of MMP-3, but this has not been shown in human gingival fibroblasts. The objective of this study is to determine the effects of IL-4 on the IL-1-induced expression of MMP-3 in human gingival fibroblasts isolated from patients with periodontitis. METHODS: Northern blot analysis was performed to determine the effects of IL-4 on the IL-1 induction of MMP-3 mRNA. MMP-3 protein levels were determined by enzyme-linked immunosorbent assay (ELISA), and prostaglandin E2 (PGE2) levels were measured by enzyme immunoassay (EIA). DNA binding of activator protein (AP)-1 and nuclear factor (NF)-kappaB was assessed by electrophoretic mobility shift assay (EMSA). RESULTS: Northern blot analysis revealed that co-incubation of gingival fibroblasts with IL-1 and IL-4 resulted in a significant decrease in MMP-3 mRNA levels compared to IL-1 alone, with a concomitant decrease in protein levels. This inhibition is dose-dependent, and is apparent as early as 3 hours after stimulation. IL-1-induced production of PGE2 was not affected in four of six cultures isolated from different individuals. Addition of exogenous PGE2 had no effect on the suppressive effects of IL-4. DNA binding of transcription factors AP-1 and NF-kappaB was not affected by IL-4. CONCLUSIONS: IL-4 inhibits the IL-1 induction of MMP-3 in human gingival fibroblasts isolated from patients with periodontitis. This effect is independent of PGE2 and is not due to inhibition of the DNA binding activity of known transcription factors binding to the MMP-3 promoter.

NF-kappaB binds to a polymorphic repressor element in the MMP-3 promoter.

A 5T/6T polymorphic site in the matrix metalloproteinase-3 (MMP-3) promoter has been identified as a repressor element involved in inhibiting induction of MMP-3 transcription by interleukin 1; and the 6T allele has been associated with decreased expression of MMP-3 as compared to the 5T allele. Zinc-binding protein-89 (ZBP-89) was cloned from a yeast one-hybrid assay via its ability to interact with this site, but when the protein was over-expressed, it resulted in activation of the MMP-3 promoter rather than repression. Here we show that in nuclear extracts isolated from human gingival fibroblasts stimulated with IL-1, this site is bound by p50 and p65 components of NF-kappaB in addition to ZBP-89, and that recombinant p50 binds preferentially to the 6T binding site. These results are consistent with a role for NF-kappaB in limiting the cytokine induced expression of MMP-3.