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Background: The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. Methods: Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. Results: There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow-up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). Conclusions: Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background: Gastro-oesophageal reflux disease (GERD) is a risk factor for oesophageal adenocarcinoma. Although fundoplication cures reflux symptoms and oesophagitis, it remains controversial whether it is capable of preventing the development of oesophageal adenocarcinoma. Hsp27 and Hsp70 are associated with the development of cancer, whereas the effect of fundoplication on them is not known. Methods: The expression of Hsp27 and Hsp70 was assessed semiquantitatively from biopsies of oesophageal mucosa for a prospective cohort of 19 patients with GERD treated with fundoplication and 7 controls without GERD. Upper gastrointestinal endoscopy with biopsies from the oesophagogastric junction (EGJ) and the distal and proximal oesophagus were performed preoperatively (19 patients) and after recovery from GERD at 6 (19 patients) and 48 months (16 patients) postoperatively. Results: The expressions of both Hsp27 (p = 0.001) and Hsp70 (p = 0.002) in the distal oesophagus were lower in patients preoperatively and at 48 months postoperatively (p < 0.001 for both) than in controls. The patients’ Hsp27 and Hsp70 levels were lower preoperatively in the proximal oesophagus (p = 0.048 for both) than in controls. Both Hsp27 (p = 0.002) and Hsp70 (p = 0.003) were lower in the distal oesophagus preoperatively and at 48 months postoperatively (p = 0.003 for Hsp27, p = 0.004 for Hsp70) than in the proximal oesophagus. Conclusions: Our results indicate that there may be some factor interfering with the mucosal defence system of the distal oesophagus in GERD that is uninfluenced by fundoplication and not associated with the acid-reflux-normalizing effect. [Copyright &y& Elsevier]

Background: Neutrophil activation and tissue sequestration are crucial events in intestinal ischemia-reperfusion injury, but their role in the gut wall after clinical cardiopulmonary bypass (CPB) remains unclear. We tested whether local post-CPB inflammatory response in the gut wall would be associated with intestinal mucosal perfusion. Methods: Twenty pigs underwent 60 min of aortic clamping and 75 min of normothermic perfusion. Intestinal biopsies were taken after 120 min of reperfusion. Based on ileal myeloperoxidase activity (MPO), the animals were divided into 2 groups, CPB-induced increase in MPO (MPO+) versus no such increase (MPO–), for comparison of the parameters that measure gut mucosal perfusion. Ileal pCO2 and intramucosal pH were determined, and arterial gases were analyzed. Additionally, several hemodynamic parameters and blood thrombin-antithrombin complexes (TAT) were measured. Results: Myocyte degeneration, endothelial activation and vasculitis were more pronounced in the MPO+ group (p < 0.05), while the MPO– group showed significantly increased piCO2 and lower mucosal pH values during reperfusion. Hemodynamics and TAT levels did not differ between the groups. Conclusion: Tissue sequestration of neutrophils was poorly associated with perturbed mucosal perfusion after CPB. Mechanisms of gut wall injury after a low-flow/reperfusion setting can differ from those in reperfusion injury after total ischemia. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer. [ABSTRACT FROM AUTHOR]

We investigated the effects of jejunoileal denervation with or without ischemia-reperfusion on mucosal characteristics and small intestinal structure. Growing pigs underwent sham laparotomy, jejunal transection, or extrinsic jejunoileal denervation with or without in situ ischemia-reperfusion. Small intestinal morphology, crypt cell proliferation, enterocyte ultrastructure, and disaccharidase activities were analyzed from jejunum and ileum after eight weeks. Immunohistological analysis of the ileum showed no staining of catecholaminergic neurons after extrinsic denervation. Neural isolation of the jejunoileum with or without ischemia-reperfusion injury reduced weight gain and villous enterocyte density in the ileum, abolished the proximodistal gradient of sucrase activity, and increased mucosal thickness, villus height, and villus surface area in the ileum. However, gross jejunoileal morphology, crypt cell proliferation, and enterocyte ultrastructure remained unchanged. In conclusion, jejunoileal denervation in growing pigs selectively modulates constitutional mucosal characteristics in the ileum, presumably due to altered enterocyte turnover, without a decrease in small intestinal absorptive surface area. These changes are independent of short ischemia and subsequent reperfusion. [ABSTRACT FROM AUTHOR]

The healing of airway anastomoses after tracheal autotransplantation was studied in a rat model. Tracheal autotransplantation in length of five tracheal cartilaginous rings was performed in 46 PVGr[sub 1] female rats. The animals were sacrificed and divided into six groups as follows: 0-day control group, and 3-, 7-, 14-, 21- and 28-day study groups (n = 6–7/group). In laser Doppler measurements, blood flow was significantly increased in the lower anastomosis after day 7 and in the upper anastomosis after day 21 compared with the control group (p < 0.05). The breaking strength of the tracheal autograft increased after day 7 compared with the control group (p < 0.05). The total collagen content of the lower anastomosis was significantly decreased on days 3 and 7 compared with the control group (p < 0.05), but thereafter it increased constantly. In the upper anastomosis on days 3 and 7, there were significant histological alterations, especially in the tracheal epithelium, compared with the control group (p < 0.05). Tracheal anastomosis is most vulnerable during the first 7 days. [ABSTRACT FROM AUTHOR]

This study investigates the effects of ileal autotransplantation on morphology, crypt cell proliferation, and brush border disaccharidases of the remaining jejunoileum and colon in growing pigs with 75% proximal small bowel resection. Resection was performed on 30 pigs, of which 15 underwent an autotransplantation of the remaining ileum. The autotransplanted pigs showed reduced weight gain and remnant ileal length when compared to the resected controls. In the autotransplanted pigs, small bowel diameter and weight, mucosal weight and protein content, villus height and surface area, crypt depth, and the number of proliferating crypt cells were reduced similarly both in the intact jejunum and in the autotransplanted ileal remnant. Autotransplantation also decreased the number of proliferative crypt cells of the colon. Specific activities of maltase and sucrase tended to increase in the autotransplanted ileal remnant, whereas the total enzyme activities decreased. These results suggest that ileal autotransplantation disturbs postresectional adaptation of the remaining gut. [ABSTRACT FROM AUTHOR]

We studied the in vitro effects of two anti-oestrogens (tamoxifen and FC- 1157a) on human lymphocyte functions in pokeweed mitogen (PWM) stimulated cultures. Addition of 1-100 nmol/l of tamoxifen or FC-l157a to PWM cultures significantly increased the number of immunoglobulin secreting cells. This concentration of tamoxifen did not affect the proliferative response. Further experiments with fractionated lymphocyte subpopulations showed that the anti-oestrogens displayed their enhancing effect by inhibiting the suppressive function of T8+ cells. The anti-oestrogens had no significant effect on the T-independent activation of B cells with Epstein-Barr virus. We conclude that the anti-oestrogens display an effect on the functions of human lymphocytes similar to that previously reported for oestradiol (Paavonen, Andersson & Adlercreutz, 1981). [ABSTRACT FROM AUTHOR]

Cyelosporin A inhibited at equal concentrations both pokeweed mitogen and Staphvlococcus aureus Cowan I-induced In vitro proliferative activity of blood leucocytes, intracellular immunoglobulin synthesis and release of immunogiobulin to the culture medium. When the interacting lymphoid cell subpopulations. T cells, B cells, Tγ and Tμ cells were fractionated apart and separately stimulated with these mitogens, cyclosporin A inhibited again at equal concentrations pokeweed mitogen-induced proliferation of blood Tγ, Tμ and B cells and Staphylococcus-induced proliferation of B cells. The 50%, inhibitory concentration varied in separate experiments between 10-2-10-1 μg/ml. Although cyclosporin A efficiently suppressed the blastogenic response, a 100- to 1,000-fold concentration of the drug was required to damage resting lymphocytes in culture. After the blastogenic phase, pokeweed mitogen-stimulated blood leucocytes were again resistant to cyclosporin A: intracellular Ig synthesis and release of Ig to the culture medium proceeded independently of the presence of the drug. As the phagocytic activity of mononuclear phagocytes was not affected by prior culture in cyclosporin A-containing medium, we conclude that in man cyclosporin A suppresses both T and B lymphocyte blastogenesis, and that the suppression is due to a direct effect on the blast cell rather than mediated via a third-party accessory cell. [ABSTRACT FROM AUTHOR]

1,25-dihydroxyvitamin D3[1,25-(OH)2D3] is capable of regulating cells in the immune system and affects cytokine production by both T lymphocytes and by monocytes. We examined the effects of 1,25-(OH)2D3 on the regulation of interleukin-1β (IL-1β) and turnout necrosis factor-alpha (TNF-α) genes in HL-60 and U937 cells. 1,25-(OH)2D3 alone only induced low level expression of the genes for these cytokines. Phorbol 12-myristate 13-acetate (PMA) strongly induced the transcription of these genes, whilst the addition of 1,25-(OH)2D3 to PMA-stimulated cells caused a further dose-dependent synergistic increase in the mRNA for both cytokines in U937 cells. In PMA-stimulated HL-60 cells, 1,25-(OH)2D3 increased the mRNA for IL-1β but not that for TNA-α, These differences may be related to the different stage of myeloid differentiation in HL-60 and U937 cells. [ABSTRACT FROM AUTHOR]

We measured levels of creatine kinase and its three isoenzymes in scrum and blister fluid from 16 healthy volunteers. The BB-isoenzyme was found to be the predominant form in blister fluid while only the MM isoenzyme was found in serum. The levels of BB-isoenzyme in blister fluid decreased as the blisters aged. The source of BB-isoenzyme in blister fluid is most probably the damaged epidermis. [ABSTRACT FROM AUTHOR]

Background: Small-intestinal adaptation to resection has been extensively studied in rats. The present study investigates morphology, crypt cell proliferation, and disaccharidase activities of the remaining small intestine and colon after 75% proximal resection of porcine small intestine. Methods: Specimens were obtained from the proximal jejunum, middle and distal ileum, and proximal colon preoperatively (n = 5) and 14 weeks after small-bowel transection (n = 5) or resection (n = 5). Proliferation was analyzed immunohistochemically with the Ki-67 antigen MIB-1. Disaccharidase activities were determined in accordance with the method of Dahlqvist. Results: In addition to macroscopic enlargement, resection markedly increased the villi and crypts of the remaining small bowel. Crypt cell proliferation decreased with advancing age after transection but remained at the preoperative level after resection. Specific, but not total, activities of maltase and sucrase in the mid-ileum decreased after resection. Conclusion: Small-intestinal adaptation in the pig involves macroscopic enlargement and a prompt increase in villus size, which is associated with high crypt cell proliferation. [ABSTRACT FROM AUTHOR]

The in vitro effects of three potent glucocorticoids (GC) (dexamethasone, prednisolone, cortisone) on human lymphocyte functions were investigated. In pharmacological concentrations GC strongly suppressed lymphocyte transformation induced by T-cell mitogen (concanavalin A and phytohaemagglutinin). After pokeweed mitogen (PWM) stimulation GC enhanced the number of immunoglobulin (Ig)-producing cells without affecting the proliferative response. Mineralocorticoid aldosterone showed no effect. Addition of 3 × 10-8 3 × 10-6 mol/l of different GC to PWM cultures significantly increased the number of Ig-secreting cells, measured by the plaque-forming cell assay. Experiments conducted with fractionated defined lymphocyte subpopulations showed that the T8+, a radiosensitive T suppressor cell, is more sensitive than the T4+ helper cell to GC effects. It is concluded that GC in pharmacological concentrations display a dual effect on human lymphocyte functions in vitro: an inhibition of lectin-induced T lymphocyte proliferation and a rather selective inhibition of T suppressor cell function which leads to an enhanced B-cell maturation and Ig synthesis in PWM-stimulated cultures. No measurable direct effect on the B lymphocytes was noticed. [ABSTRACT FROM AUTHOR]

A study was made of the regulatory influence of a thyroid hormone, triiodothyronine (Ta), on human blood T- and B-lymphocyte responses in vitro. Blood lymphocytes were stimulated with the T-cell mitogens concanavalin A (Con A) and phytohaemagglutinin (PHA), with the T-dependent B-cell activator pokeweed mitogen (PWM), and with the T-independent B-cell activator Staphylococcus aureus Cowan I bacteria in the presence of various hormone concentrations. T3 did not stimulate T-cell proliferation. The number of immunoglobulin-containing and -secreting cells (plasmablasts) was increased in PWM and Staph. aureus cultures treated with T3. The maximal enhancement was reached at a concentration of 10-9-10-7 M T3. Cell fractionation techniques revealed that T3 apparently had a direct stimulatory effect on B-cell differentiation. [ABSTRACT FROM AUTHOR]

Immediate repair of the gastrointestinal epithelium after superficial injury is called restitution. It is based on the migration of the surviving mucoid neck cells over the area of injury. The involvement of growth factors in the process has been recently documented. They are known to enhance the process (ie, EGF, FGF, TGF-beta) and to activate the basolateral Na+-H+-antiport (EGF). They may exert their effect by activating intracellular tyrosine kinases or by inducing chemotaxis. Yet, their precise mechanism of action in the process is unknown. The aim of the present study was to investigate the effect of modulation of the signal transduction pathway on the occurrence of proliferative mucoid neck and foveolar cells in guinea pig gastric epithelium. Therefore guinea pig gastric epithelium was mounted in Ussing chambers in vitro and perfused 4 hr after superficial injury with 1.25 M NaCl. The potential difference over the epithelium and tissue resistance were recorded simultaneously. The tissue was exposed either to cycloheximide, genistein, or to 4-phorbol myristate 13-acetate (PMA) during the 4-hr recovery, and the expression of proliferative cells was assessed by staining the tissue for proliferative cells (Ki-67). The mean proliferative index of tissues subjected to NaCl injury was significantly higher than that of uninjured control tissues after 4 hr of restitution. Inhibition of the signaling pathway with genistein decreased the proliferative index significantly, while its stimulation with phorbol myristate increased it. Both electrophysiologic and morphologic restitution were sensitive to genistein, but not to PMA or cycloheximide. Superficial epithelial injury results in a significantly increased occurrence of proliferative cells in isolated guinea pig gastric epithelium. This endogenous activation of the tissue is sensitive to inhibition by tyrosine kinases and to stimulation by protein kinases. Electrophysiologic and morphologic recovery are also affected by the modulation of the signaling pathway. This suggests that it is involved in the immediate repair process. [ABSTRACT FROM AUTHOR]

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell surface ligand for LFA-1 (CD1 Ia/18). Several cytokines, such as IL-1. TNF-α or IFN-γ, have been shown to increase the ICAM-1 expression on cultured endothelial cells. Here we show that IL-4 decreases the IFN-γ-induced ICAM-1 expression on an endothelial cell line (EA.hy 926), whereas IL-4 alone has practically no effects on ICAM- 1 expression. The down-regulative effect was also seen at the mRNA level suggesting that this regulation process is transcriptional. At the same time IL-4 was unable to alter the TNF-γ-induced ICAM-1 up-regulation. Both IFN-γ and TNF-γ are able to decrease the proliferation of the endothelial cell line, but IL-4 could not modify this response when added together with the other cytokines. Taken together we show in this paper that IL-4 decreases IFN-γ- but not TNF-α-induced up-regulation of ICAM-1 expression on EA.hy 926 cells. [ABSTRACT FROM AUTHOR]

A number of studies have suggested that lymphocytes producing polyreactive antibodies belong to the CD5+ B-cell subset, (n this study we have examined CD5 at the cell surface and mRNA levels in EBV-driven cord blood and fetal liver clones previously characterized in terms of their antibody specificities. We show that EBV-immortalized cells can express surface CD5, and that some of the clones not expressing surface CD5 express it at the mRNA level. The complete absence of CD5 mRNA in some polyreactive clones is consistent with the proposition that the production of auto-antibodies and multispecific antibodies is not restricted to the CD5+ B-cell subset. [ABSTRACT FROM AUTHOR]

1,25-dihydroxyvitamin D3[1,25-(OH)2D3] is capable of regulating cells in the immune system and affects cytokine production by both T lymphocytes and by monocytes. We examined the effects of 1,25-(OH)2D3 on the regulation of interleukin-1β (IL-1β) and turnout necrosis factor-alpha (TNF-α) genes in HL-60 and U937 cells. 1,25-(OH)2D3 alone only induced low level expression of the genes for these cytokines. Phorbol 12-myristate 13-acetate (PMA) strongly induced the transcription of these genes, whilst the addition of 1,25-(OH)2D3 to PMA-stimulated cells caused a further dose-dependent synergistic increase in the mRNA for both cytokines in U937 cells. In PMA-stimulated HL-60 cells, 1,25-(OH)2D3 increased the mRNA for IL-1β but not that for TNA-α, These differences may be related to the different stage of myeloid differentiation in HL-60 and U937 cells. [ABSTRACT FROM AUTHOR]

Abstract Background C4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. In this study C4d staining of grade I-IV astrocytic tumors was studied to explore if there is an association between complement activation and the grade of tumor, or patient survival. Methods Tissue micro-array samples of 102 astrocytomas were stained immunohistochemically. The material consisted of 9 pilocytic astrocytomas and 93 grade II-IV astrocytomas, of which 67 were primary resections and 26 recurrent tumors. The intensity of C4d staining as well as extent of C4d and CD34 staining were evaluated. The intensity of C4d staining was scored semiquantitatively. The extent of the staining was counted morphometrically with a point counting grid yielding a percent of C4d and CD34 positive area of the sample. Results The intensity and extent of C4d staining increased in grade II-IV diffusely infiltrating astrocytoma tumors in line with the malignancy grade (p = 0.034 and p = 0.016, respectively, Kruskal-Wallis test). However, C4d positive tumor area percentages were higher in grade I pilocytic astrocytomas than in grade II-IV diffusely infiltrating astrocytomas (p = 0.041, Mann–Whitney test). There was a significant correlation between CD34 positive and C4d positive endothelial area fraction in diffusely infiltrating astrocytomas (p Conclusion The worsening of patient outcome and malignant progression of tumor cells seem to be connected to microenvironmental changes evoked by chronically activated complement.

Abstract Background Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catalyzing enzyme. It has been suggested that it has a role in lower airway allergic inflammations, but its role in allergic rhinitis has not been investigated. Objective Our aim was to evaluate the expression of IDO in the nasal mucosa of allergic rhinitis patients allergic to birch pollen during peak exposure to birch pollen allergen and compare it to non-atopic patients. Methods IDO expression was immunohistochemically evaluated from nasal specimens obtained in- and off-season from otherwise healthy non-smoking volunteers both allergic to birch pollen (having mild or moderate allergic rhinoconjunctivitis) and non-allergic controls. Results: The IDO expression levels were low in healthy controls and remained low also in patients allergic to birch pollen. There were no differences in the expression of IDO in- and off-season in either healthy or allergic subjects. Conclusions There is a controversy in the role of IDO in upper and lower airways during allergic airway disease. It seems that IDO is associated to allergic inflammations of the lower airways, but does not have a local role in the nasal cavity at least in mild or moderate forms of allergic rhinitis.

Abstract Background Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC. Methods TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery. The TLR9 staining intensity was compared with clinical parameters. Results Of the studied tumours, 112 (81%) exhibited cytoplasmic TLR9 immunostaining. No association was detected between cytoplasmic TLR9 immunoexpression intensity and stage, nuclear grade, histological subtype or tumour necrosis. Cytoplasmic TLR9 immunoexpression was, however, a marker of favourable RCC specific survival both in univariate analysis and in multivariate regression model. Conclusions We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC.

Introduction Tongue squamous cell carcinoma have poor survival rate and therefore new clinical biomarkers and therapeutics options are needed. Indoleamine 2,3-dioxygenase (IDO) is an enzyme expressed in many cells involved in the catabolism of the essential amino acid tryptophan to kynurenine. Elevated IDO expression has been found in many tumors. Cancerous inhibitor of PP2A (CIP2A) is a protein which present in most human tissues. CIP2A is associated to high mortality rate in the tongue squamous cell carcinoma and in the other cancers. The objective of this study was to define the expression of IDO and CIP2A in tongue cancer and lingual mucosal hyperplasia, and evaluate the possible association of IDO and CIP2A expression and occurrence of regional metastasis in tongue cancer. In addition, we studied the effect of IDO expression, CIP2A expression and inflammation reaction of patient surviving. Materials and methods We observed 94 patients that have been treated in Tampere University Hospital. Altogether 129 samples from the tongue squamous cell carcinomas ( n = 64), lingual mucosa hyperplasia ( n = 30) or regional lymph nodes ( n = 35) were immunohistochemically stained with monoclonal antibodies anti-IDO and anti-CIP2A. The percentage of IDO positive cells indicating the IDO staining score, as well as IDO and CIP2A staining intensity were assessed in light microscopic evaluation. We also assessed the inflammation score of the samples. Results There were a statistically significantly higher number of samples with IDO positivity in lingual hyperplasia group than in tongue cancer group. Moreover IDO staining intensity was higher in the hyperlplasia group, whereas the CIP2A staining intensity did not differ between hyperplasia than tongue cancer groups. Interestingly, the inflammation score was higher in the tongue cancer than in the hyperplasia tissue. When observing only the group with tongue cancer IDO expression was associated with poor survival. IDO staining intensity and staining score were stronger in higher TNM group and in higher tumor grades. Conclusion Neither IDO nor CIP2A seem to be specific histological biomarkers for tongue cancer. Further direction of this study would be to observe whether inflammation process associates with the progression of tongue cancer. [ABSTRACT FROM AUTHOR]