Utilization of microsatellites for the analysis of genomic alterations in colorectal cancers in Brazil.

Two different pathogenetic mechanisms are proposed for colorectal cancers. One, the so-called "classic pathway", is the most common and depends on multiple additive mutational events (germline and/or somatic) in tumor suppressor genes and oncogenes, frequently involving chromosomal deletions in key genomic regions. Methodologically this pathway is recognizable by the phenomenon of loss of heterozygosity. On the other hand, the "mutator pathway" depends on early mutational loss of the mismatch repair system (germline and/or somatic) leading to accelerated accumulation of gene mutations in critical target genes and progression to malignancy. Methodologically this second pathway is recognizable by the phenomenon of microsatellite instability. The distinction between these pathways seems to be more than academic since there is evidence that the tumors emerging from the mutator pathway have a better prognosis. We report here a very simple methodology based on a set of tri-, tetra- and pentanucleotide repeat microsatellites allowing the simultaneous study of microsatellite instability and loss of heterozygosity which could allocate 70% of the colorectal tumors to the classic or the mutator pathway. The ease of execution of the methodology makes it suitable for routine clinical typing.

Effects of intestinal secretagogues and distension on small bowel myoelectric activity in fasted and fed conscious dogs.

1. Defined jejunal segments were perfused with solutions of bile salts and of ricinoleic acid during fasting and after feeding in two groups of conscious dogs, one with the segment in continuity, and the other with a Thirty-Vella loop. Myoelectric activity was recorded from chronically implanted electrodes on the jejunal segment and also from the proximal and distal in situ bowel.2. The results in both groups were identical. During fasting, migrating complexes were present in the segment, but were replaced by intermittent spike activity during chenodeoxycholate without and with ricinoleic acid perfusion. After food, when migrating complexes were replaced by intermittent spike activity, none of the solutions produced any consistent effect.3. In fasted animals, low levels of distension (15 mmHg) interrupted the migrating complexes in the segment and induced intermittent spike activity which was similar to that seen with the secretagogues. The migrating complexes in the main bowel continued during distension. In fed animals, spike activity increased in the segment during distension at 25 mmHg and decreased in the main bowel. In both groups, distension of the segment to pressures between 37.5 and 50 mmHg abolished spike activity both in the distended segment and the main bowel in fasted and fed states, and, in fasted dogs, migrating complexes were also abolished.4. These results demonstrate that the inhibitory intestino-intestinal reflex is mediated through extrinsic nerves and does not require an intact myenteric plexus, whereas the altered myoelectric activity induced by secretagogues is a local effect and does not spread to adjacent bowel through either intrinsic or extrinsic neural pathways. It seems likely that the local motor effect of secretagogues is a result of net secretion, producing distension to pressures below the threshold required to activate the intestino-intestinal reflex.