Cranial Growth and Variation in Edmontosaurs (Dinosauria: Hadrosauridae): Implications for Latest Cretaceous Megaherbivore Diversity in North America

The well-sampled Late Cretaceous fossil record of North America remains the only high-resolution dataset for evaluating patterns of dinosaur diversity leading up to the terminal Cretaceous extinction event. Hadrosaurine hadrosaurids (Dinosauria: Ornithopoda) closely related to Edmontosaurus are among the most common megaherbivores in latest Campanian and Maastrichtian deposits of western North America. However, interpretations of edmontosaur species richness and biostratigraphy have been in constant flux for almost three decades, although the clade is generally thought to have undergone a radiation in the late Maastrichtian. We address the issue of edmontosaur diversity for the first time using rigorous morphometric analyses of virtually all known complete edmontosaur skulls. Results suggest only two valid species, Edmontosaurus regalis from the late Campanian, and E. annectens from the late Maastrichtian, with previously named taxa, including the controversial Anatotitan copei, erected on hypothesized transitional morphologies associated with ontogenetic size increase and allometric growth. A revision of North American hadrosaurid taxa suggests a decrease in both hadrosaurid diversity and disparity from the early to late Maastrichtian, a pattern likely also present in ceratopsid dinosaurs. A decline in the disparity of dominant megaherbivores in the latest Maastrichtian interval supports the hypothesis that dinosaur diversity decreased immediately preceding the end Cretaceous extinction event

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E₂(PGE₂) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE₂cell surface receptors (EP 1–4) to examine the mechanisms by which PGE₂regulates tumour progression.</p> <p>Methods</p> <p>Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue.</p> <p>Results</p> <p>EP4 was the most abundant subtype of PGE₂receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE₂generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE₂(1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21^WAF1/CIP1expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21^WAF1/CIP1was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted.</p> <p>Conclusion</p> <p>COX-2 regulates cell cycle transition via EP4 receptor and altered p21^WAF1/CIP1expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.</p

Transient ischemic attack versus transient ischemic attack mimics : frequency, clinical characteristics and outcome

There is insufficient evidence regarding which clinical features are best suited to distinguish between transient ischemic attack (TIA) and disorders mimicking TIA (TIA mimics)

Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study.

BACKGROUND: The ABCD² score improves stratification of patients with transient ischaemic attack by early stroke risk. We aimed to develop two new versions of the score: one that was based on preclinical information and one that was based on imaging and other secondary care assessments. METHODS: We analysed pooled data from patients with clinically defined transient ischaemic attack who were investigated while in secondary care. Items that contribute to the ABCD² score (age, blood pressure, clinical weakness, duration, and diabetes), other clinical variables, carotid stenosis, and abnormal acute diffusion-weighted imaging (DWI) were recorded and were included in multivariate logistic regression analysis of stroke occurrence at early time intervals after onset of transient ischaemic attack. Scores based on the findings of this analysis were validated in patients with transient ischaemic attack from two independent population-based cohorts. FINDINGS: 3886 patients were included in the study: 2654 in the derivation sample and 1232 in the validation sample. We derived the ABCD³ score (range 0-9 points) by assigning 2 points for dual transient ischaemic attack (an earlier transient ischaemic attack within 7 days of the index event). C statistics (which indicate discrimination better than chance at &gt;0·5) for the ABCD³ score were 0·78 at 2 days, 0·80 at 7 days, 0·79 at 28 days, and 0·77 at 90 days, compared with C statistics for the ABCD² score of 0·71 at 2 days (p=0·083), 0·71 at 7 days (p=0·012), 0·71 at 28 days (p=0·021), and 0·69 at 90 days (p=0·018). We included stenosis of at least 50% on carotid imaging (2 points) and abnormal DWI (2 points) in the ABCD³-imaging (ABCD³-I) score (0-13 points). C statistics for the ABCD³-I score were 0·90 at 2 days (compared with ABCD² score p=0·035), 0·92 at 7 days (p=0·001), 0·85 at 28 days (p=0·028), and 0·79 at 90 days (p=0·073). The 90-day net reclassification improvement compared with ABCD² was 29·1% for ABCD³ (p=0·0003) and 39·4% for ABCD³-I (p=0·034). In the validation sample, the ABCD³ and ABCD³-I scores predicted early stroke at 7, 28, and 90 days. However, discrimination and net reclassification of patients with early stroke were similar with ABCD³ compared with ABCD². INTERPRETATION: The ABCD³-I score can improve risk stratification after transient ischaemic attack in secondary care settings. However, use of ABCD³ cannot be recommended without further validation. FUNDING: Health Research Board of Ireland, Irish Heart Foundation, and Irish National Lottery