Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa.

Introduction: The pannexin-1 (Panx1) channels are found in many cell types, and ATP released from these channels can act on nearby cells activating purinergic P2X7 receptors (P2X7R) which lead to inflammation. Although Panx1 and P2X7R are implicated in the process of inflammation and cell death, few studies have looked at the role they play in inflammatory bowel disease in human. Hence, the aim of the present study was to investigate the function of Panx1 and P2X7R in an ex vivo colitis model developed from human colonic mucosal explants. Materials and Methods: Healthy human colonic mucosal strips (4 × 10 mm) were incubated in carbogenated culture medium at 37°C for 16 h. Proinflammatory cytokines TNFα and IL-1ß (each 10 ng/mL) were used to induce colitis in mucosal strips, and the effects of Panx1 and P2X7R on cytokines-induced tissue damage were determined in the presence of the Panx1 channel blocker 10Panx1 (100 µM) and P2X7R antagonist A438079 (100 µM). The effects of 10Panx1 and A438079 on cytokines-enhanced epithelial permeability were also studied using Caco-2 cells. Results: Histological staining showed that the mucosal strips had severe structural damage in the cytokines-only group but not in the incubation-control group (P < 0.01). Compared to the cytokines-only group, crypt damage was significantly decreased in groups receiving cytokines with inhibitors (10Panx1, A438079, or 10Panx1 + A438079, P < 0.05). The immunoreactive signals of tight junction protein zonula occludens-1 (ZO-1) were abundant in all control tissues but were significantly disrupted and lost in the cytokines-only group (P < 0.01). The diminished ZO-1 immunoreactivity induced by cytokines was prevented in the presence of 10Panx1 (P = 0.04). Likewise, 10Panx1 significantly attenuated the cytokines-evoked increase in paracellular permeability of Caco-2 cells. Although the inhibition of P2X7R activity by A438079 diminished cytokines-induced crypt damage, its effect on the maintenance of ZO-1 immunoreactivity and Caco-2 epithelial cell integrity was less evident. Conclusion: The blockade of Panx1 and P2X7R reduced the inflammatory cytokines-induced crypt damage, loss of tight junctions and increase in cell permeability. Thus, Panx1 and P2X7R may have roles in causing mucosal damage, a common clinical feature of inflammatory bowel disease.

Surveillance of patients following surgery with curative intent for colorectal cancer.

Surveillance after resection of colorectal cancer with curative intent is an important component of post-operative care. Clinical review, imaging, colonoscopy, and cost to the community are among significant issues to consider in planning a surveillance regime. This review aims to identify the available evidence for the use of surveillance and its individual components. The literature pertaining to follow-up of patients following potentially curative surgery for colorectal cancer was reviewed in order to formulate a summary of the wide range of clinical practice. There is evidence of improved survival of patients undergoing more intense follow-up compared with those having minimal surveillance, with an estimated overall 5-year gain of up to 10%. The efficacy of individual components of follow-up regimes remains unclear, but an overall package of 'intensive' follow-up including clinical review, liver imaging, and colonoscopy appears to be of benefit. It is cost-effective and can be specialist or community-based.

Women's choice between sentinel lymph node biopsy and axillary clearance.

PURPOSE: To determine whether women would choose sentinel lymph node biopsy (SLNB) or axillary clearance (AC) for breast cancer treatment when they are given a single choice based on clear information about morbidity and mortality. METHODS: The expected 5-year survival rate of women with breast cancer after either SLNB or AC was calculated using a utility analysis of established literature. The difference in survival was one in 1000. This and other detailed information on SLNB and AC was presented in a questionnaire, which provided subjects with a scenario and a choice between SLNB and AC. After a pilot study of 40 subjects, the questionnaire was mailed to 400 women (who had no mammographic abnormality) attending Breast Screen and handed to 100 women (who were over 40 years of age and had breast symptoms but not cancer) attending the rooms of two surgical specialists. RESULTS: One hundred and twenty one of the 243 respondents to the mailed questionnaires (49.8%) chose SLNB and 35% of the 100 consulting room subjects chose SLNB rather than AC. CONCLUSIONS: Women faced with the possibility of having breast cancer seem to be very conservative in their choice of treatment, many choosing the increased morbidity of AC rather than the very small (one in 1000) increased risk of death at 5 years from SLNB. This raises questions about proposals to offer SLNB as standard treatment and demands that women are fully informed about any increased risk of death when making their choice between SLNB and AC.