Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists

BACKGROUND AND PURPOSE: Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH: Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS: EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1–300 nM and the selective motilin agonist GSK962040 0.1–30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (E(max)≍ 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS: Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. LINKED ARTICLE: This article is commented on by Depoortere, pp. 760–762 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02046.

Low tumour cell proliferation at the invasive margin is associated with a poor prognosis in Dukes' stage B colorectal cancers

The conflicting results about the prognostic impact of tumour cell proliferation in colorectal cancer might be explained by the heterogeneity observed within these tumours. We have investigated whether a systematic spatial heterogeneity exists between different compartments, and whether the presence of such a systematic heterogeneity has any impact on survival. Fifty-six Dukes' stage B colorectal cancers were carefully morphometrically quantified with respect to the immunohistochemical expression of the proliferative marker Ki-67 at both the luminal border and the invasive margin. The proliferative activity was significantly higher at the luminal border compared with the invasive margin (P < 0.001), although the two compartments were also significantly correlated with each other. Tumours with low proliferation at the invasive margin had a significantly poorer prognosis both in univariate (P = 0.014) and in multivariate survival analyses (P = 0.042). We conclude that Dukes' B colorectal cancers exhibit a systematic spatial heterogeneity with respect to proliferation, and tumours with low proliferation at the invasive margin had a poor prognosis. The present data independently confirm recent results from the authors, and provide new insights into the understanding of tumour cell proliferation in colorectal cancer. © 1999 Cancer Research Campaig

Temperature Tolerance and Stress Proteins as Mechanisms of Invasive Species Success

Invasive species are predicted to be more successful than natives as temperatures increase with climate change. However, few studies have examined the physiological mechanisms that theoretically underlie this differential success. Because correlative evidence suggests that invasiveness is related to the width of a species' latitudinal range, it has been assumed – but largely untested – that range width predicts breadth of habitat temperatures and physiological thermotolerances. In this study, we use empirical data from a marine community as a case study to address the hypotheses that (1) geographic temperature range attributes are related to temperature tolerance, leading to greater eurythermality in invasive species, and (2) stress protein expression is a subcellular mechanism that could contribute to differences in thermotolerance. We examined three native and six invasive species common in the subtidal epibenthic communities of California, USA. We assessed thermotolerance by exposing individuals to temperatures between 14°C and 31°C and determining the temperature lethal to 50% of individuals (LT50) after a 24 hour exposure. We found a strong positive relationship between the LT50 and both maximum habitat temperatures and the breadth of temperatures experience across the species' ranges. In addition, of the species in our study, invasives tended to inhabit broader habitat temperature ranges and higher maximum temperatures. Stress protein expression may contribute to these differences: the more thermotolerant, invasive species Diplosoma listerianum expressed higher levels of a 70-kDa heat-shock protein than the less thermotolerant, native Distaplia occidentalis for which levels declined sharply above the LT50. Our data highlight differences between native and invasive species with respect to organismal and cellular temperature tolerances. Future studies should address, across a broader phylogenetic and ecosystem scope, whether this physiological mechanism has facilitated the current success of invasive species and could lead to greater success of invasives than native species as global warming continues

Climate Change and the Potential Distribution of an Invasive Shrub, Lantana camara L

The threat posed by invasive species, in particular weeds, to biodiversity may be exacerbated by climate change. Lantana camara L. (lantana) is a woody shrub that is highly invasive in many countries of the world. It has a profound economic and environmental impact worldwide, including Australia. Knowledge of the likely potential distribution of this invasive species under current and future climate will be useful in planning better strategies to manage the invasion. A process-oriented niche model of L. camara was developed using CLIMEX to estimate its potential distribution under current and future climate scenarios. The model was calibrated using data from several knowledge domains, including phenological observations and geographic distribution records. The potential distribution of lantana under historical climate exceeded the current distribution in some areas of the world, notably Africa and Asia. Under future scenarios, the climatically suitable areas for L. camara globally were projected to contract. However, some areas were identified in North Africa, Europe and Australia that may become climatically suitable under future climates. In South Africa and China, its potential distribution could expand further inland. These results can inform strategic planning by biosecurity agencies, identifying areas to target for eradication or containment. Distribution maps of risk of potential invasion can be useful tools in public awareness campaigns, especially in countries that have been identified as becoming climatically suitable for L. camara under the future climate scenarios