Social support and health-related quality of life in hip and knee osteoarthritis.

OBJECTIVE: To document the association between social support and health-related quality of life (HRQoL) in hip and knee osteoarthritis (OA). METHODS: A prospective survey including the SF-36 and the Social Support questionnaire (SSQ) was administered to 108 hip and knee OA patients attending an outpatient physical rehabilitation and rheumatology clinic. Multiple regression analysis were performed to study the relation between social support and each dimension of the SF-36, controlling for age, sex, body mass index, number of comorbid conditions, socioeconomic status, site of survey completion and severity of OA which was gauged with the pain dimension of the WOMAC, an OA-specific health status instrument. RESULTS: Greater social companionship transactions were associated with higher physical functioning (standardized regression coefficients: beta = 0.26, p < 0.01), general health (beta = 0.32, p < 0.001), mental health (beta = 0.25, p < 0.01), social functioning (beta = 0.20, p < 0.05) and vitality (beta = 0.25, p < 0.05). Satisfaction with problem-oriented emotional support was related to better physical functioning (beta = 0.22, p < 0.01), mental health (beta = 0.38, p < 0.001), role-emotional (B = 0.23, p < 0.01), social functioning (beta = 0.19, p < 0.05) and vitality (beta = 0.26, p < 0.01). CONCLUSION: Social support components significantly account for HRQoL. Health interventions in OA, primary dedicated to pain and physical disability, could be supplemented with social support component to enhance health outcomes.

Curcumin-induced cell death in two leukemia cell lines: K562 and Jurkat.

Curcumin presents strong antioxidant and anticancer properties. However, molecular mechanisms leading to curcumin-induced cell death are poorly understood. The effect of curcumin was compared in two different leukemia cell lines: K562 and Jurkat. Cell death was induced in both cell lines, and apoptosis pathways were investigated by Western blot analysis. Decreases in pro-caspase 8 and 9 levels were observed. BH(3) interacting domain death agonist (Bid) was also cleaved. Jurkat cells appeared to be more sensitive to curcumin, and apoptosis takes place earlier.

Effect of nuclear factor kappaB inhibition on tumor cell sensitivity to natural killer-mediated cytolytic function.

Inhibition of the transcription factor NF-kappaB has been reported to increase cell sensitivity to TNF and some cytotoxic drugs. We investigated the effect of NK-kappaB inhibition on the susceptibility of tumor cells to freshly isolated, nonactivated, human NK cells and to a TCRgamma/delta T cell clone displaying an MHC-unrestricted "NK-like" lysis. Using electrophoretic mobility shift assay, we first demonstrated that NF-kappaB/DNA binding activity was induced in target cells following coculture with NK cells or TCRgamma/delta T cell clone. To investigate the effect of target cell NF-kappaB inhibition on NK-mediated lysis, we blocked NF-kappaB translocation by introducing a human cDNA coding for a mutated IkappaB-alpha. Interestingly, our results indicated that inhibition of NF-kappaB did not induce any increase in either granzyme-dependent non-MHC-restricted cytotoxicity mediated by fresh non-stimulated NK cells and by TCR gamma/delta T cell clone or in CD95-mediated lysis. These results emphasize that NF-kappaB expressed in target cells does not play a role in the molecular process related to the control of target cell susceptibility to NK-mediated lysis and suggest that the NF-kappaB pathway is not a general mechanism for controlling the cytotoxic response.

Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma.

In most cells trans-activating NF-kappaB induces many inflammatory proteins as well as its own inhibitor, IkappaB-alpha, thus assuring a transient response upon stimulation. However, NF-kappaB-dependent inflammatory gene expression is persistent in asthmatic bronchi, even after allergen eviction. In the present report we used bronchial brushing samples (BBSs) from heaves-affected horses (a spontaneous model of asthma) to elucidate the mechanisms by which NF-kappaB activity is maintained in asthmatic airways. NF-kappaB activity was high in granulocytic and nongranulocytic BBS cells. However, NF-kappaB activity highly correlated to granulocyte percentage and was only abrogated after granulocytic death in cultured BBSs. Before granulocytic death, NF-kappaB activity was suppressed by simultaneous addition of neutralizing anti-IL-1beta and anti-TNF-alpha Abs to the medium of cultured BBSs. Surprisingly, IkappaB-beta, whose expression is not regulated by NF-kappaB, unlike IkappaB-alpha, was the most prominent NF-kappaB inhibitor found in BBSs. The amounts of IkappaB-beta were low in BBSs obtained from diseased horses, but drastically increased after addition of the neutralizing anti-IL-1beta and anti-TNF-alpha Abs. These results indicate that sustained NF-kappaB activation in asthmatic bronchi is driven by granulocytes and is mediated by IL-1beta and TNF-alpha. Moreover, an imbalance between high levels of IL-1beta- and TNF-alpha-mediated IkappaB-beta degradation and low levels of IkappaB-beta synthesis is likely to be the mechanism preventing NF-kappaB deactivation in asthmatic airways before granulocytic death.

Nuclear factor-kappa B, cancer, and apoptosis.

The role of nuclear factor (NF)-kappa B in the regulation of apoptosis in normal and cancer cells has been extensively studied in recent years. Constitutive NF-kappa B activity in B lymphocytes as well as in Hodgkin's disease and breast cancer cells protects these cells against apoptosis. It has also been reported that NF-kappa B activation by tumor necrosis factor (TNF)-alpha, chemotherapeutic drugs, or ionizing radiations can protect several cell types against apoptosis, suggesting that NF-kappa B could participate in resistance to cancer treatment. These observations were explained by the regulation of antiapoptotic gene expression by NF-kappa B. However, in our experience, inhibition of NF-kappa B activity in several cancer cell lines has a very variable effect on cell mortality, depending on the cell type, the stimulus, and the level of NF-kappa B inhibition. Moreover, in some experimental systems, NF-kappa B activation is required for the onset of apoptosis. Therefore, it is likely that the NF-kappa B antiapoptotic role in response to chemotherapy is cell type- and signal-dependent and that the level of NF-kappa B inhibition is important. These issues will have to be carefully investigated before considering NF-kappa B as a target for genetic or pharmacological anticancer therapies.

Correlation between nuclear factor-kappaB activity in bronchial brushing samples and lung dysfunction in an animal model of asthma.

Asthma is a chronic inflammatory disease of the airways, in which many inflammatory genes are overexpressed. Transcription factor, nuclear factor-kappaB (NF-kappaB), which is thought to control the transcriptional initiation of inflammatory genes, has been poorly investigated in asthma. In the present report, bronchial cells (BCs), recovered by bronchial brushing in healthy and heaves-affected horses (i.e., an animal model of asthma), were assessed for NF-kappaB activity. Small amounts of active NF-kappaB were present in BCs of healthy horses, whereas high levels of NF-kappaB activity was found during crisis (i.e., acute airway obstruction) in all heaves-affected horses. Three weeks after the crisis, the level of NF-kappaB activity found in BCs of heaves-affected horses was highly correlated (p < 0.01) to the degree of residual lung dysfunction. Unexpectedly, active NF- kappaB complexes found in BCs of heaves-affected horses were mainly p65 homodimers, rather than classic p65-p50 heterodimers. At last, intercellular adhesion molecule-1 (ICAM-1) expression paralleled p65 homodimers activity in these cells. These results demonstrate that the kinetics of NF-kappaB activity is strongly related to the course of the disease and confirm the relevance of NF-kappaB as a putative target in asthma therapy. Moreover, uncommon p65 homodimers could transactivate, in BCs, a subset of genes, such as ICAM-1, characteristic of chronic airway inflammation.

Functional and cooperative interactions between the homeodomain PDX1, Pbx, and Prep1 factors on the somatostatin promoter.

Expression of the somatostatin gene in endocrine pancreatic cells is controlled by several regulatory cis-elements located in the promoter region. Among these, the adjacent UE-A and TSEI elements, located from -113 to -85 relative to the transcription initiation site, function in combination and act as a pancreas-specific mini-enhancer. The TSEI element is recognized by the pancreatic homeodomain factor PDX1. In the present study, we show that the UE-A element binds a heterodimeric complex composed of a Pbx factor and the Prep1 protein, both belonging to the atypical three-amino acid loop extension homeodomain family. Recombinant Pbx1 and Prep1 proteins bind cooperatively to the UE-A site, whereas neither protein can bind this site alone. Transient transfection experiments reveal that both Pbx1 and Prep1 are required to generate a strong transcriptional activation from the UE-A element when this element is inserted close to the TATA box. In contrast, in the context of the intact somatostatin promoter or mini-enhancer, Pbx1 and Prep1 alone have no effect, but they produce a drastic activation when the pancreatic homeodomain factor PDX1 is also coexpressed. Thus, the activity of the somatostatin mini-enhancer is mediated by a cooperative interaction between the Pbx-Prep1 heterodimeric complex and the pancreatic factor PDX1.