Potential role of P-gp for flavone-induced diminished apoptosis and increased adenoma size in the small intestine of APC(min/+) mice

APC(min/+) mice, carrying a nonsense mutation in the adenomatous polyposis coli (APC) gene, appear as a perfect model to study development or therapy of intestinal neoplasia. We tested whether the flavonoid flavone is able to affect adenoma development in APC(min/+) mice. Tumor sizes were significantly increased by flavone selectively in small intestine. This was associated with reduced cell numbers displaying cleaved caspase-3 and enhanced expression of phosphoglycoprotein (P-gp). However, according to great variability in P-gp expression in all parts of mice intestines, an association between expression of P-gp and inhibition of apoptosis was demonstrated in human Caco-2 colorectal cancer cells.     

Clinicopathological and immunohistochemical markers after radical gastrectomy for gastric cancer

BACKGROUND/AIMS: The aim of the study was to verify the classic clinicopathological prognostic factors of the expected survival, to determine the frequency of immunohistochemical factors (C-erB-2, p53) and to verify these immunohistochemical factors in their function as prognostic factors in gastric cancer patients after a potentially curative gastric resection. METHODOLOGY: In 78 gastric cancer patients after a potentially curative resection the clinicopathological factors (age, general performance of the patient, tumor diameter, TNM stage, stage according to UICC, type of operation and the extent of lymphadenectomy) and immunohistochemical factors (p53 and C-erB-2) were analyzed. RESULTS: In univariate analysis ASA stage of general performance, size of tumor, TNM stage and stage according to UICC exert significant influence on the median survival. Median survival is higher in patients with C-erB-2 negative reaction and in those with p53 positive reaction, although not significant. In patients with tumor located in proximal two thirds, patients with negative reaction to C-erB-2 have a significantly higher median survival than patients with positive reaction to C-erB-2. The Cox regression model reveals ASA stage and UICC classification to be significant factors whereas immunohistochemical parameters C-erB-2 and p53 do not reveal any significance in the multivariate survival analysis. CONCLUSIONS: According to the results of our study the ASA stage and UICC classification influence the expected survival of potentially radically resected gastric cancer patients significantly, while immunohistochemical parameters C-erB-2 and p53 do not.     

A serology-based approach combined with clinical examination of 125 Ro/SSA-positive patients to define incidence and prevalence of subacute cutaneous lupus erythematosus

OBJECTIVE: To estimate the incidence and prevalence of Ro/SSA-positive subacute cutaneous lupus erythematosus (SCLE) in Stockholm County, Sweden (1.8 million inhabitants) and to investigate the frequency of photosensitivity and other clinical manifestations associated with Ro/SSA autoantibodies. METHODS: Ro/SSA-positive patients in Stockholm were identified via registry-based searches. All patients who tested positive for the presence of Ro/SSA autoantibodies during 1996-2002 (n = 1,323; 85% women) were identified. A questionnaire was sent to all patients still living in Stockholm in 2003 (n = 1,048). Patients who reported having skin symptoms and photosensitivity (n = 125) underwent a clinical examination. RESULTS: Of the 741 (71%) of 1,048 Ro/SSA-positive patients who responded to the questionnaire, 400 (54%) reported having photosensitivity, and of these patients, 125 agreed to be clinically examined. A diagnosis of LE was confirmed in 59 of the 125 patients (SCLE in 20, systemic LE [SLE] in 33, and chronic CLE in 6). Eighty-six patients reported experiencing symptoms consistent with polymorphous light eruption (PLE). Comorbidities such as cardiovascular disease, autoimmune disease, and other skin diseases were common. The incidence of Ro/SSA-positive SCLE during the study period was estimated to be 0.7 cases per 100,000 persons per year and the prevalence was approximately 6.2-14 in 100,000 persons. CONCLUSION: The incidence of Ro/SSA-positive SCLE in Stockholm County, Sweden is estimated to be 0.7 per 100,000 persons per year as compared with an incidence of SLE in Sweden of 4.8 per 100,000 persons per year. The prevalence is estimated to be 6.2-14 in 100,000 persons. Self-reported photosensitivity commonly corresponds to a history of PLE in Ro/SSA-positive patients, even when the clinical profile of SCLE is absent. Photoprotection should therefore be included in the treatment recommendations for these patients.     

The effects of aging and physical activity on Doppler measures of diastolic function

Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70+/-4 years) and 12 fit Masters athlete (68+/-3 years) seniors were recruited. Twelve young healthy (32+/-9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p<0.001), TDI Emean (p<0.001), and propagation velocity of mitral inflow (p<0.001) and an increase in IVRT (p=0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p=0.212), IVRT (p=0.546), or propagation velocity of mitral inflow (p=1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p=0.012) and during maximal lower body negative pressure (p=0.036), but not during saline solution infusion (p=0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.     

Congo red and protein aggregation in neurodegenerative diseases

Congo red is a commonly used histological dye for amyloid detection. The specificity of this staining results from Congo red's affinity for binding to fibril proteins enriched in beta-sheet conformation. Unexpectedly, recent investigations indicate that the dye also possesses the capacity to interfere with processes of protein misfolding and aggregation, stabilizing native protein monomers or partially folded intermediates, while reducing concentration of more toxic protein oligomers. Inhibitory effects of Congo red upon amyloid toxicity may also range from blockade of channel formation and interference with glycosaminoglycans binding or immune functions, to the modulation of gene expression. Particularly, Congo red exhibits ameliorative effect in models of neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's and prion diseases. Another interesting application of Congo red analogues is the development of imaging probes. Based on their small molecular size and penetrability through blood-brain barrier, Congo red congeners can be used for both antemortem and in vivo visualization and quantification of brain amyloids. Therefore, understanding mechanisms involved in dye-amyloidal fibril binding and inhibition of aggregation will provide instructive guides for the design of future compounds, potentially useful for monitoring and treating neurodegenerative diseases.     

Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus

HMGB1 is a pro-inflammatory cytokine that together with TNF-alpha and IL-1beta is involved in the pathogenesis of spontaneously occurring skin lesions in lupus erythematosus. The purpose of the present study was to explore the sequence of events in HMGB1, TNF-alpha and IL-1beta expression under development and resolution of experimentally induced CLE lesions. The study involved investigation of 38 serial skin biopsies acquired from photoprovoked skin lesions of nine CLE patients, using immunohistochemical staining of tissue sections. In biopsies from the clinically most active phase of skin involvement extracellular, secreted HMGB1 and increased cytoplasmic HMGB1 were found, as compared with the late and fading lesions or non-lesional skin. Besides HMGB1, increased expression of TNF-alpha and IL-1beta was observed in dermal infiltrates of the induced CLE lesions. These cytokines were however not upregulated in all lesions, and increased expression of IL-1beta was seen predominantly in late biopsies.In conclusion, extracellular and cytoplasmic HMGB1 coincides with the clinically most active phase of photoinduced lesions of cutaneous lupus, and suggests that HMGB1 is an important factor in the inflammatory autoimmune process of CLE. HMGB1 can induce expression of TNF-alpha and IL-1beta, and formation of a pro-inflammatory loop between HMGB1, TNF-alpha, and IL-1beta may be responsible for the prolonged and sustained inflammation in CLE.