Summary Several clinical trials have shown that the duration of treatment of painful vertebral syndromes can be shortened by using a combination of vitamins B1, B6, B12 and diclofenac instead of diclofenac. In addition, a more efficient pain relief could be achieved by the combination therapy.In order to confirm these results, we compared the clinical efficacy of diclofenac (25 mg) and a combination preparation with diclofenac (25 mg) plus vitamins B1 (thiamine nitrate 50 mg), B6 (pyridoxine hydrochloride 50 mg) and B12 (cyanocobalamin 0.25 mg) in a multicentric randomized double-blind study including 418 patients. All patients received 3×2 capsules daily for a maximum of 2 weeks. In case of total pain relief, therapy should be discontinued after one week.Data of 376 patients could be evaluated. 53 out of 184 patients receiving the combination and 48 out of 192 patients treated with diclofenac alone could stop therapy due to sufficient pain relief after one week.The evaluation of the Hoppe Pain Questionnaire and the data concerning pain intensity also revealed better results for the combination preparation. The differences in favour of the B-vitamin-diclofenac-combination were statistically significant in patients with severe pain at the beginning of therapy.Considering undesirable side-effects (symptoms in 70 out of 418 patients) there were no significant differences between the two medications.This clinical trial provides further evidence that the combination therapy with diclofenac plus B-vitamins is more effective than diclofenac alone for the treatment of painful vertebral syndroms. 相似文献
Previous studies have shown that the induction of P450 cytochrome 2E1 (CYP2E1) is associated with the loss of proteasomal activities. To correlate the loss of proteasomal activity with CYP2E1 induction, ethanol was fed intragastrically for 1, 3, 7, and 15 days. The maximum induction of CYP2E1 (3.5-fold) occurred after 15 days of ethanol feeding. However, there was no significant decrease in the 26 S chymotrypsin-like and trypsin-like activity over this period of time. When ethanol was given to rats for 1 month, CYP2E1 was significantly induced, and the proteasomal activity was significantly decreased. These results indicate that proteasomal activity was not directly affected by ethanol or CYP2E1 induction. Since 4-hydroxynonenal (4-HNE) concentration was significantly increased at 1 month of ethanol feeding, it was suspected that 4-HNE adduct formation with proteasome subunits could be the mechanism of proteasome inhibition. Using an antibody to 4-HNE adducted proteins in Western blot analysis of the 26 S proteasome fraction isolated from the liver of alcohol fed rats, one extra band appeared around 44 kDa. When the antibody to an ATPase Rpt4 was used to stain the stripped membrane, the same band that was detected with the 4-HNE antibody was detected with the Rpt4 antibody. An adduct of 4-HNE formed with the Rpt4 subunit of 26 S could impede the association of 19 S and 20 S and thus account for the observed decrease of proteasomal activity. 相似文献
Summary: The polycondensation of 1‐ethynyl‐2,5‐dihexyl‐4‐iodobenzene in the presence of 1‐ethynyl‐2,5‐dihexyl‐4‐(2‐phenylethynyl)benzene proceeds according to the mechanism of initiated chain growth polycondensation. It has allowed the synthesis of oligomers with a desired molecular weight and a narrow molecular weight distribution. The reasons for the side reaction leading to the formation of diyne compounds are revealed and the presumed mechanism is given. This opens prospects for the preparation of defectless poly(p‐phenyleneethynylene)s with required molecular weights and narrow molecular weight distributions.
AIM: In restitution after superficial injury of the gastric mucosa, the epithelial continuity is restored by cellular migration. We have shown that heat shock preconditioning inhibits restitution after superficial injury. This study investigates the effect of heat shock preconditioning on tissue proliferation and apoptosis. EXPERIMENTAL DESIGN: Paired guinea pig gastric mucosae were mounted and perfused in Ussing chambers (37 degrees C). After heat shock preconditioning (42 degrees C) (30 min) and normothermic recovery (37 degrees C) (150 min) or normothermic perfusion, a superficial injury was induced by luminal exposure to 1.25 mol/L NaCl (5 min) followed by a 3 h restitution. During perfusion, the mucosa was exposed to 30 micromol/L arachidonic acid (AA) to enhance heat shock response, to 50 micromol/L quercetin (Q) to inhibit the metabolism of arachidonic acid via lipoxygenases, to 50 micromol/L indomethacin (In) to inhibit the metabolism of arachidonic acid via cyclo-oxygenases, or to 150 micromol/L cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment the mucosa was prepared for immunohistochemical analysis of the expression of Mib-1 proliferation antigen and pro-apoptotic protein Bax. RESULTS: Heat shock decreased Mib-1/Bax ratio and this effect was maintained after superficial injury and exposure to Q, to AA+CHX or to In+CHX. Exposure to CHX, to AA, to In+Q, to In+AA, In+AA+Q or to In+AA+CHX, however, blocked the effect of heat shock preconditioning. The decreasing effect of heat shock preconditioning on Mib-1/Bax ratio could be reversed by exposure to AA+Q or to In. CONCLUSION: The heat-preconditioning-induced effects on the mucosa are reversible and sensitive to exogenous pharmacological modulation. Heat shock preconditioning inhibits proliferation of superficially injured isolated gastric mucosa by a mechanism involving eicosanoid pathways and de novo protein synthesis. 相似文献
This special issue of the Journal of Immunological Methods brings together articles from some of the leaders in labelling antigen-specific T and NKT cells, describing recent technical advances and their impact on the study of immunology. Although tetramers, or tetrameric MHC class I/peptide complexes, are the best known reagents in the field, various forms of oligomeric complexes are now being successfully used to detect antigen-specific T cells, including cytotoxic T lymphocytes, MHC class II-restricted CD4+ T cells, and glycolipid-specific T cells restricted by CD1 isoforms. The articles presented here detail the breadth of the oligomeric structures being used to probe T, NK and NKT cell function, and cover both the technical and practical aspects of their use, as well as the new biology revealed. In addition to providing a summary of the current state of the art, these contributions also provide clear pointers to strategies likely to succeed in the future. In this introductory chapter, we summarise the work presented in the other articles of this issue, and provide an overarching view of this rapidly evolving field. We also provide a summary of the MHC class I molecules successfully refolded to date, and provide references to other relevant sources of technical information. 相似文献
The aim of this study was to elucidate the clinicopathological significance and prognostic role of loss of claudin-1 in colorectal cancer (CRC).
Methods
The correlations between claudin-1 expression and clinicopathological characteristics, including survival rates, were assessed using immunohistochemistry on 260 archival, paraffin-embedded CRC tissues. In addition, the correlations between cludin-1 and nuclear factor-kappa B (NF-κB), epithelial-mesenchymal transition markers and tumor-infiltrating lymphocytes were investigated.
Results
Claudin-1 expression was markedly lost in 42.7% of the 260 CRCs analyzed. Loss of claudin-1 expression significantly correlated with larger tumor size, vascular invasion, higher pT stage, and high metastatic lymph node ratio. In addition, loss of claudin-1 expression significantly correlated with NF-κB activation (P?<?0.001), high SNAI (P?<?0.001), and low E-cadherin (P?<?0.001) expressions. Patients with high immunoscores showed significantly lower rates of claudin-1 expression loss (P?=?0.020). In detail, loss of claudin-1 expression were frequently found in CRCs low CD3- and CD8-positive lymphocytes. There were significant correlations between claudin-1 expression loss and poor overall and recurrence-free survivals (P?<?0.001 and P?<?0.001, respectively).
Conclusion
Taken together, our results suggest that the loss of claudin-1 expression significantly correlates with aggressive tumor behaviors, high SNAI expression, lower immunoscore, and poor prognoses. 相似文献
Lethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period, develop, upon withdrawal of CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmunity (CsA-AI). This T cell-mediated autoimmune disease is thymus-dependent; it is generally held that this disease is a consequence of aberrant T cell recovery brought about by CsA. In this study we determined mononuclear cell subsets phenotypically by tri-colour flow cytometry. A strong decrease in recent thymic emigrants (Thy1.1+, TCR αβ+) was observed as a consequence of CsA treatment, eventually resulting in decreased absolute peripheral T cell numbers. In these rats no altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4+ and CD8+ cells consisted predominantly of monocytes (CD4dim+, TCR αβ−) and natural killer cells (CD8+, TCR αβ−), respectively. LEW rats, x-irradiated, syngeneic bone marrow-reconstituted and treated with CsA, showed a marked and persistent, relative expansion of mature CD45RC+, RT6− Th cells. In contrast, Brown-Norway rats treated in a similar fashion, or LEW rats subjected to either CsA treatment or x-irradiation, did not show a comparable expansion of mature CD45RC+, RT6− Th cells, nor did these animals develop CsA-AI. The CD45RC+, RT6− Th cells produced IL-2, and moreover constituted the only Th subset producing IFN-γ upon stimulation, and therefore were considered as Th1-like effector cells. These results are consistent with the view that a persistent preponderance of Th1 cells and not the mere presence of autoreactive cells determines whether or not clinically manifest CsA-AI will occur. 相似文献
Recent reports suggest that elevated levels of plasminogen activator inhibitor-1 (PAI-1) may contribute to tumour progression.
The studies reported here were designed to help elucidate PAI-1's contribution to the invasive and migratory phenotype. Antibodies
to PAI-1 dose-dependently, and significantly, inhibited the invasive and migratory potential of human HT1080 fibrosarcoma
cells, as did an antibody to uPA and the plasmin inhibitor aprotinin. Invasion of the human melanoma cell line, BLM, was also
attenuated by the anti-PAI-1 monoclonal antibody MAI-12. The non-invasive human melanoma cell line, IF6, which does not express
uPA, provided further confirmation of PAI-1 and uPA's role as, upon transfection with uPA, this cell line attained an invasive
phenotype, which was again attenuated by MAI- 12. Although antibodies to PAI-1 did not affect the adhesion of HT1080 cells
to vitronectin, the antibody to uPA reduced their attachment. Addition of exogenous PAI-1, however, prevented HT1080 cell
adhesion (IC50 180nM) and promoted cell detachment from vitronectin. Furthermore melanoma cells transfected with a uPA variant, which had
an impaired interaction with PAI-1, were not invasive and had impaired binding to vitronectin. These data highlight the importance
of a balanced proteolysis and suggest an additional role for PAI-1 distinct from its role in proteolysis. These data also
suggest that uPA and PAI-1 may co-operate in the migratory process by respectively facilitating the attachment to, and subsequent
detachment from, vitronectin in the extracellular matrix. These results support the clinical findings and indicate that modulation
of PAI-1 activity may be of therapeutic benefit for the treatment of cancer.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献