A case-control study examining the association of smad7 and TLR single nucleotide polymorphisms on the risk of colorectal cancer in ulcerative colitis.

AIM: Ulcerative colitis (UC) is characterized by chronic mucosal inflammation and an increased risk of colorectal cancer. smad7, TLR2 and TLR4 modulate intestinal inflammation and their polymorphisms affect the risk of development of sporadic colorectal cancer. The aim of the current study was to examine the association between single nucleotide polymorphisms (SNPs) in smad7, TLR2 and TLR4 and the development of colorectal cancer in patients with UC. METHOD: DNA was extracted from formalin-fixed, paraffin-embedded tissue from 90 patients with UC who had undergone panproctocolectomy between 1985 and 2013 (30 with UC-associated colorectal cancer and 60 control UC patients). Control cases were matched 2:1 for age at diagnosis of colitis, duration of disease and gender. Genotyping was performed for the smad7 rs4464148, rs11874392, rs12953717 and rs4939827 SNPs, the TLR2 rs5743704 and rs5743708 SNPs and the TLR4 rs4986790 and rs4986791 SNPs. RESULTS: Sixty three of the 90 patients (70%) were men and the mean age at diagnosis of UC was 38.6 ± 1.6 years. The mean time to the diagnosis of UC-associated colorectal cancer was 13.5 ± 1.9 years. The 5-year recurrence-free and cancer-specific survival rates were 76% and 88%, respectively. All eight SNPs were in Hardy-Weinberg equilibrium. None of the eight SNPs assessed in smad7, TLR2 or TLR4 were associated with the development of UC-associated colorectal cancer at an allelic or genotypic level. CONCLUSIONS: These data do not support an association between polymorphisms in smad7, TLR2 or TLR4 and the development of UC-associated colorectal cancer.

The projection of anorectal afferents to spinal cord and effect of sacral neuromodulation on dorsal horn neurons which receive such input in the rat.

BACKGROUND: The rat has served usefully as a model for fecal incontinence and exploration of the mechanism of action of sacral neuromodulation (SNM). There remains a deficit in information regarding the location and type of spinal neurons which receive anorectal input and the effect of SNM on those neurons. METHODS: Single neuronal extracellular recordings of neurons receiving anorectal input were made at the S1 level of the spinal cord using sharp glass electrodes. SNM at S1 was delivered at 2 Hz for 3 minutes and its effect on discharge was quantified. KEY RESULTS: In total, 31 units (n = 14 animals) receiving anorectal synaptic input were recorded at the first sacral (S1) segmental level in either lamina III or IV of the dorsal horn. The inputs were classified according to afferent fiber conduction speed (16 Aδ, 11 Aß, and 4 C-fiber). The baseline firing frequency (ie, the mean firing frequency before the application of SNM) was 0.48 Hz ± 0.49 (mean ± SD) and 58% of units responded to acute SNM with either an increase or decrease in mean firing frequency. CONCLUSIONS & INFERENCES: In this study, the majority of spinal neurons receiving anorectal input changed their activity in response to SNM. These findings provide the basis for future studies which aim to explore the precise cellular mechanism of action of SNM on this fecal continence pathway.