Modulatory influence of garlic and tomato on cyclooxygenase-2 activity, cell proliferation and apoptosis during azoxymethane induced colon carcinogenesis in rat

Preventive intervention of colorectal cancer has become essential as a major portion of the population may develop the disease at some points during their lives. Diet and nutrition play an important role during this multistep colon carcinogenic process. Inhibitory activity of aqueous suspensions of garlic and tomato, individually and in combination, were tested on azoxymethane induced colon carcinogenesis in Sprague-Dawley rats. The effect was observed on aberrant crypt foci (ACF), the preneoplastic lesion. To investigate the mechanism of action of the agents used, cell proliferation and the level of apoptosis were determined and the expression of cyclooxygenase-2 (COX-2) protein was analyzed in the colon. Following treatment, significant inhibition of the level of cell proliferation (P<0.01 in garlic; P<0.001 in tomato and P<0.001 in combination treatment group with respect to the carcinogen control group), significant induction of apoptosis (P<0.01 in garlic treated; P<0.01 in tomato treated and P<0.001 in combination treatment group with respect to the carcinogen control group) and suppression of COX-2 expression among the treated groups resulted in significant reduction in the incidences of ACF (by 45.27% in garlic, 68.24% in tomato and 71.62% in combination treatment group). The preventive effect was better when the combination of garlic and tomato was administered in comparison to the individual treatment groups, suggesting the synergistic action of garlic and tomato.     

Improvement in health utility among patients with rheumatoid arthritis treated with adalimumab (a human anti-TNF monoclonal antibody) plus methotrexate

OBJECTIVES: To compare health-related quality of life (HRQoL), as measured by health utility, in patients with rheumatoid arthritis (RA) treated with adalimumab (a human anti-tumour necrosis factor (anti-TNF) monoclonal antibody) plus methotrexate or placebo plus methotrexate. METHODS: HRQoL data were obtained in two randomized, double-blind, placebo-controlled, multidose clinical trials conducted in the United States and Canada. The Health Utilities Index Mark 3 (HUI3) was administered in both studies at baseline, at the end of the study and at two time points in between. Patients' HUI3 scores were compared with population norm scores. Change in HUI3 was defined as the end-of-study score minus the baseline score. Utility gained throughout the study was measured by area under the utility curve and expressed as quality-adjusted life years (QALYs). Statistical testing adjusted for confounders and used the Dunnett test to account for multiple comparisons. RESULTS: Patients' utility scores at baseline were low (range of treatment group means 0.38-0.44) compared with population norms (0.88). HUI3 mean changes from baseline scores for adalimumab-treated patients were 0.22 and 0.21 in the two trials, whereas placebo patients' changes were 0.04 and 0.07. The rate of QALYs gained per year in the treatment group compared with the placebo group were 0.145 in the ARMADA trial and 0.104 in the DE019 trial. All gains were clinically important and statistically significant. CONCLUSIONS: Treatment with adalimumab plus methotrexate provides clinically important and statistically significant improvements in HRQoL as measured by health utility in patients with RA. This translates into measurable and important gains in QALYs.     

Enhanced Skills Training and Health Care Management for Older Persons with Severe Mental Illness

This report describes a combined skills training (ST) and health management (HM) intervention for older adults with severe mental illness (SMI) and one-year pilot study outcomes. Findings are reported for twelve older persons with SMI (age 60+) who received ST+HM and twelve who received only HM. ST addressed interpersonal and independent living skills. HM included promotion of preventive health care. ST+HM was associated with improved social functioning and independent living skills, whereas functioning remained constant or declined for the HM only group. Both groups receiving HM demonstrated increased use of preventive health services and identification of previously undetected medical disorders.     

Infectious response to E. coli: molecular and genetic pathways

Urinary tract infections are most commonly caused by type 1-piliated Escherichia coli (UPEC) and result in urothelial apoptosis, local cytokine release and neutrophil infiltration. A human urothelial cell line was incubated with various E. coli isolates and was then characterized by flow cytometry. UPEC induced rapid urothelial apoptosis that was dependent upon interactions mediated by type 1 pili. Laboratory isolates expressing type 1 pili-induced approximately 50% less apoptosis. UPEC blocked activity of a NF-kappaB-dependent reporter in response to inflammatory stimuli by stabilizing IkappaBalpha and UPEC rapidly altered cellular signalling pathways. Finally, blocking NF-kappaB activity increased the level of the laboratory strain-induced apoptosis to the level of apoptosis induced by UPEC. These results suggest that UPEC blocks NF-kappaB and enhances type 1 pili-induced apoptosis as a component of the uropathogenic programme.     

Education. Teach to his own

The Teaching Company Scheme allows subsidized employment of a graduate on a fixed-term contract. TCS is gradually being taken up by NHS organisations although it can be challenging to reconcile with its traditional focus on private sector criteria. South Tyneside's project involved developing a healthy living and working strategy.     

Intracellular survival of Staphylococcus aureus due to alteration of cellular activity in arsenic and lead intoxicated mature Swiss albino mice

The role of heavy metals like arsenic (As) and lead (Pb) as environmental toxicants is established. However, the exact mechanism of their effect on immunocompetent cell activity is not well known. Staphylococcus aureus is a virulent pathogen that has the ability to cause a variety of potentially life-threatening infections. The objective of our study was to demonstrate in an experimental mouse model of bacteremic S. aureus infection, bacterial clearance from blood and spleen in arsenic, lead treated and control group of mice. Bacterial density was measured in blood and spleen after 0, 24, 48 and 72 h post-infection. Our findings show a significant increase in bacterial load in blood (P<0.025 for arsenic and P<0.01 for lead) and delayed bacterial clearance by spleen in both arsenic (P<0.05) and lead (P<0.025) treated groups as compared to control, thus highlighting an immuno-compromised state following heavy metal exposure. To further elucidate immunomodulatory effects of both arsenic and lead, cell function studies were performed on splenic macrophages (M(phi)) isolated from lead and arsenic treated as well as control group of mice. Our findings show a decrease in cell adhesion property (P<0.005) of splenic M(phi)s from 2.9925+/-0.053 in control to 1.395+/-0.106 in arsenic and 0.8835+/-0.0106 in lead treated mice at 60 min. Morphologic alteration of the splenic M(phi)s showed an increase (As: P<0.05, Pb: P<0.0005) in both arsenic (6.876+/-0.3287%) and lead (16.55+/-1.051%) treated mice to control (2.649+/-1.238%) which may be responsible for the formers' reduced functional status. The chemotactic index, a measure of chemotactic migration of the macrophages toward immune serum, was 16.43+/-1.007 in control cell and was reduced (P<0.0005) to 4.19+/-0.393 in arsenic and 2.92+/-0.649 in lead treated mice at 60 min. These altered cell functions could probably explain the intracellular survival of S. aureus but such a causal relationship awaits further detailed examination.     

Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-kappaB

Urinary tract infections (UTIs) are among the most common inflammatory diseases. Acute UTIs are typically caused by type 1-piliated Escherichia coli and result in urothelial apoptosis, local cytokine release, and neutrophil infiltration. To examine the urothelial apoptotic response, a human urothelial cell line was incubated with various E. coli isolates and was then characterized by flow cytometry. Uropathogenic E. coli (UPEC) induced rapid urothelial apoptosis that was strictly dependent upon interactions mediated by type 1 pili. Interestingly, nonpathogenic HB101 E. coli expressing type 1 pili induced apoptosis at approximately 50% of the level induced by UPEC, suggesting that pathogenic strains contribute to apoptosis by pilus-independent mechanisms. Consistent with this possibility, UPEC blocked activity of an NF-kappaB-dependent reporter in response to inflammatory stimuli, yet this effect was independent of functional type 1 pili and was not mediated by laboratory strains of E. coli. UPEC suppressed NF-kappaB by stabilizing IkappaBalpha, and UPEC rapidly altered cellular signaling pathways. Finally, blocking NF-kappaB activity increased the level of piliated HB101-induced apoptosis to the level of apoptosis induced by UPEC. These results suggest that UPEC blocks NF-kappaB and thereby enhances type 1 pili-induced apoptosis as a component of the uropathogenic program.     

Absence of nasal mucosal atrophy with fluticasone aqueous nasal spray

OBJECTIVE: To evaluate whether 1 year of continuous treatment with intranasal fluticasone propionate would lead to atrophy in the nasal mucosa compared with an active control, oral terfenadine. DESIGN: Prospective, randomized, multicenter, open-label, parallel-group study. SETTING: Two tertiary care academic institutions. PATIENTS: Seventy-five subjects older than 18 years with perennial allergic rhinitis. INTERVENTIONS: Patients received either fluticasone propionate aqueous nasal spray, 200 microg once daily, or terfenadine, 60 mg twice daily, for 1 year. Nasal biopsy specimens were obtained before and after 1 year of treatment and were evaluated for evidence of atrophy. MAIN OUTCOME MEASURES: Epithelial and collagen layer thickness of the nasal mucosa as assessed by light microscopy and the presence and degree of edema, and regularity of collagen fibrils as assessed by electron microscopy. Analyses were performed without knowledge of subject identity or treatment assignment. RESULTS: Neither fluticasone nor terfenadine treatment led to atrophy in the nasal mucosa by clinical or histologic observation. No significant changes from baseline were observed for any assessment of atrophy. In contrast to what would have been expected if atrophy were to occur, mean epithelial layer thickness in the fluticasone group significantly increased compared with terfenadine treatment (P = .03). CONCLUSIONS: Treatment with intranasal fluticasone for 1 year increases the thickness of the nasal epithelium as compared with a year's treatment with terfenadine and does not lead to atrophy in the nasal mucosa. The increased thickness in the fluticasone treatment may represent repair from epithelial damage caused by chronic allergic inflammation.     

QSAR of antineoplastics V: Exploration of receptor interaction sites of antitumor N-(7-indolyl)benzenesulfonamides targeting GI phase using electrotopological state atom index

Quantitative structure activity relationship (QSAR) study of antiproliferative activities of N-(7-indolyl)benzenesulfonamides with electrotopological state atom (ETSA) index corroborates the conclusions of the previously reported Hansch analysis that the structural requirements for interactions with receptors of human KB nasopharynx cell line are different from that for murine colon 38 and P388 leukemia cell lines. The study suggests that both phenyl ring and indole moiety are the important receptor interaction sites present on the ligands for the murine cell lines, while the latter site does not appear to play significant role in case of human KB cell carcinoma.     

Effect of vaginally administered fumagillin on the morphology of implantation stage endometrium in the rhesus monkey

Intravaginal administration of an anti-angiogenic agent, fumagillin, during blastocyst implantation, inhibits pregnancy establishment in a dose-related manner in the rhesus monkey. In the present study, mated female rhesus monkeys were vaginally inserted with tampons containing vehicle (group 1; n = 5) and test agent (fumagillin, 4 mg/animal; group 2; n = 6) on cycle day 20, and endometrial tissue samples were collected on cycle day 24 from all monkeys and processed for morphometric and ultrastructural analysis. Concentrations of estradiol-17beta, progesterone and chorionic gonadotrophin in peripheral circulation were determined. From serum profiles of hormones, two monkeys in group 1, and one animal in group 2 appeared pregnant. Endometrial morphology revealed histologic evidence of pregnancy in three of six fumagillin-treated animals, while other three fumagillin-treated animals showed degenerative changes in glands and venules along with marked extravasation. It is possible that the function of corpus luteum was affected by fumagillin treatment resulting in inadequate progesterone production (p <0.05), and consequent inadequate endometrial secretory preparation and receptivity, as revealed from decline in apical movement of vacuoles (p <0.05) and increase (p <0.05) in extravasation of red cells and leukocytes.