Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity

BACKGROUND: There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA), a putative chemopreventive agent, exhibited distinct biological effects, yet appeared to act on some of the same signaling molecules. The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA. METHODS: To determine whether there was an overlap in activation of signaling pathways by DCA and UDCA, we mutagenized HCT116 cells and then isolated cell lines resistant to UDCA induced growth arrest. These lines were then tested for their response to DCA induced apoptosis. RESULTS: We found that a majority of the cell lines resistant to UDCA-induced growth arrest were also resistant to DCA-induced apoptosis, implying an overlap in DCA and UDCA mediated signaling. Moreover, the cell lines which were the most resistant to DCA-induced apoptosis also exhibited a greater capacity for anchorage independent growth. CONCLUSION: We conclude that UDCA and DCA have overlapping signaling activities and that disregulation of these pathways can lead to a more advanced neoplastic phenotype

A comparison of the metabolic effects of sustained strenuous activity in polar environments on men and women

This study investigates differences in pre- to post-expedition energy expenditure, substrate utilisation and body composition, between the all-male Spear17 (SP-17) and all-female Ice Maiden (IM) transantarctic expeditions (IM: N = 6, 61 days, 1700 km; SP-17: N = 5, 67 days, 1750 km). Energy expenditure and substrate utilisation were measured by a standardised 36 h calorimetry protocol; body composition was determined using air displacement plethysmography. Energy balance calculation were used to assess the physical challenge. There was difference in the daily energy expenditure (IM: 4,939 kcal day−1; SP-17: 6,461 kcal day−1, p = 0.004); differences related to physical activity were small, but statistically significant (IM = 2,282 kcal day−1; SP-17 = 3,174 kcal day−1; p = 0.004). Bodyweight loss was modest (IM = 7.8%, SP-17 = 6.5%; p > 0.05) as was fat loss (IM = 30.4%, SP-17 = 40.4%; p > 0.05). Lean tissue weight change was statistically significant (IM = − 2.5%, SP-17 = + 1.0%; p = 0.05). No difference was found in resting or sleeping energy expenditure, normalised to lean tissue weight (p > 0.05); nor in energy expenditure when exercising at 80, 100 and 120 steps min−1, normalised to body weight (p > 0.05). Similarly, no difference was found in the change in normalised substrate utilisation for any of the activities (p > 0.05). Analysis suggested that higher daily energy expenditures for the men in Spear-17 was the result of higher physical demands resulting in a reduced demand for energy to thermoregulate compared to the women in Ice Maiden. The lack of differences between men and women in the change in energy expenditure and substrate utilisation, suggests no sex difference in response to exposure to extreme environments

Reproducibility of Transcranial Doppler ultrasound in the middle cerebral artery

Abstract Background Transcranial Doppler ultrasound remains the only imaging modality that is capable of real-time measurements of blood flow velocity and microembolic signals in the cerebral circulation. We here assessed the repeatability and reproducibility of transcranial Doppler ultrasound in healthy volunteers and patients with symptomatic carotid artery stenosis. Methods Between March and August 2017, we recruited 20 healthy volunteers and 20 patients with symptomatic carotid artery stenosis. In a quiet temperature-controlled room, two 1-h transcranial Doppler measurements of blood flow velocities and microembolic signals were performed sequentially on the same day (within-day repeatability) and a third 7–14 days later (between-day reproducibility). Levels of agreement were assessed by interclass correlation co-efficient. Results In healthy volunteers (31±9 years, 11 male), within-day repeatability of Doppler measurements were 0.880 (95% CI 0.726–0.950) for peak velocity, 0.867 (95% CI 0.700–0.945) for mean velocity, and 0.887 (95% CI 0.741–0.953) for end-diastolic velocity. Between-day reproducibility was similar but lower: 0.777 (95% CI 0.526–0.905), 0.795 (95% CI 0.558–0.913), and 0.674 (95% CI 0.349–0.856) respectively. In patients (72±11 years, 11 male), within-day repeatability of Doppler measurements were higher: 0.926 (95% CI 0.826–0.970) for peak velocity, 0.922 (95% CI 0.817–0.968) for mean velocity, and 0.868 (95% CI 0.701–0.945) for end-diastolic velocity. Similarly, between-day reproducibility revealed lower values: 0.800 (95% CI 0.567–0.915), 0.786 (95% CI 0.542–0.909), and 0.778 (95% CI 0.527–0.905) respectively. In both cohorts, the intra-observer Bland Altman analysis demonstrated acceptable mean measurement differences and limits of agreement between series of middle cerebral artery velocity measurements with very few outliers. In patients, the carotid stenoses were 30–40% (n = 9), 40–50% (n = 6), 50–70% (n = 3) and > 70% (n = 2). No spontaneous embolisation was detected in either of the groups. Conclusions Transcranial Doppler generates reproducible data regarding the middle cerebral artery velocities. However, larger studies are needed to validate its clinical applicability. Trial registration ClinicalTrial.gov (ID NCT 03050567), retrospectively registered on 15/05/2017

Potential role for TCD-directed antiplatelet agents in symptomatic carotid artery dissection.

We read with interest the debate regarding the role of anticoagulation in extracranial arterial dissection.1–3 We agree with Norris1 that artery to artery embolism is the most likely cause of stroke, and also agree with Lyrer2 that there is no evidence supporting anticoagulation for extracranial internal carotid artery dissection (CAD). Donnan and Davis3 make a most important contribution when they differentiate between the use of antithrombotic agents and antiplatelet agents in CAD

Self-assessment of acute mountain sickness in adolescents: a pilot study.

OBJECTIVE: To perform a pilot study exploring the prevalence of acute mountain sickness (AMS) in adolescents on ascent to altitude and evaluating whether this age group is capable of self-assessment of AMS using the Lake Louise scoring system. METHODS: Twelve teenagers aged 15 to 18 years old (5 girls) traveled for 21 days between 2400 and 5500 m. Each member of the expedition completed a Lake Louise self-assessment questionnaire on a daily basis. Group leaders (nonmedical) were informed about any subject with a score of 3 or more. Appropriate treatments were then initiated. Detailed analysis of data was undertaken on return to the UK. RESULTS: There was 100% completion of 252 questionnaires. Eleven of the 12 subjects (91.7%) had symptom scores greater than or equal to 3, consistent with a diagnosis of AMS, on at least one day (range, 0-8). Symptoms of AMS were more common in the female group members (P = .041). CONCLUSIONS: AMS is a common problem among adolescents. There are increasing numbers of adolescents traveling to high altitudes, and there appears to be a lack of information about the prevalence of AMS in this age group. Motivated adolescents seemed capable of self-monitoring for AMS using the Lake Louise questionnaire. Combined with an appropriate ascent profile and support, we feel this approach may contribute to safety in the mountains and merits further study