Pancreatic pseudocyst eroding into the splenoportal venous confluence and mimicking an arterial aneurysm

We report the case of a 62-year-old man with chronic pancreatitis who presented with increasing abdominal pain. Sonography, magnetic resonance imaging, contrast-enhanced computed tomography, and ultimately catheter angiography demonstrated a pancreatic pseudocyst that had eroded into the splenoportal venous confluence, mimicking an arterial aneurysm. The diagnostic was confirmed at the time of surgical treatment. This case demonstrates the use of imaging to diagnose complications of pancreatitis, and the difficulty of distinguishing an eroding pseudocyst from an arterial aneurysm

6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer

Metastasis is the cause of death in the majority (∼90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5-N,N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Advancing the field of health systems research synthesis.

Those planning, managing and working in health systems worldwide routinely need to make decisions regarding strategies to improve health care and promote equity. Systematic reviews of different kinds can be of great help to these decision-makers, providing actionable evidence at every step in the decision-making process. Although there is growing recognition of the importance of systematic reviews to inform both policy decisions and produce guidance for health systems, a number of important methodological and evidence uptake challenges remain and better coordination of existing initiatives is needed. The Alliance for Health Policy and Systems Research, housed within the World Health Organization, convened an Advisory Group on Health Systems Research (HSR) Synthesis to bring together different stakeholders interested in HSR synthesis and its use in decision-making processes. We describe the rationale of the Advisory Group and the six areas of its work and reflects on its role in advancing the field of HSR synthesis. We argue in favour of greater cross-institutional collaborations, as well as capacity strengthening in low- and middle-income countries, to advance the science and practice of health systems research synthesis. We advocate for the integration of quasi-experimental study designs in reviews of effectiveness of health systems intervention and reforms. The Advisory Group also recommends adopting priority-setting approaches for HSR synthesis and increasing the use of findings from systematic reviews in health policy and decision-making

A Conserved Supergene Locus Controls Colour Pattern Diversity in Heliconius Butterflies

We studied whether similar developmental genetic mechanisms are involved in both convergent and divergent evolution. Mimetic insects are known for their diversity of patterns as well as their remarkable evolutionary convergence, and they have played an important role in controversies over the respective roles of selection and constraints in adaptive evolution. Here we contrast three butterfly species, all classic examples of Müllerian mimicry. We used a genetic linkage map to show that a locus, Yb, which controls the presence of a yellow band in geographic races of Heliconius melpomene, maps precisely to the same location as the locus Cr, which has very similar phenotypic effects in its co-mimic H. erato. Furthermore, the same genomic location acts as a “supergene”, determining multiple sympatric morphs in a third species, H. numata. H. numata is a species with a very different phenotypic appearance, whose many forms mimic different unrelated ithomiine butterflies in the genus Melinaea. Other unlinked colour pattern loci map to a homologous linkage group in the co-mimics H. melpomene and H. erato, but they are not involved in mimetic polymorphism in H. numata. Hence, a single region from the multilocus colour pattern architecture of H. melpomene and H. erato appears to have gained control of the entire wing-pattern variability in H. numata, presumably as a result of selection for mimetic “supergene” polymorphism without intermediates. Although we cannot at this stage confirm the homology of the loci segregating in the three species, our results imply that a conserved yet relatively unconstrained mechanism underlying pattern switching can affect mimicry in radically different ways. We also show that adaptive evolution, both convergent and diversifying, can occur by the repeated involvement of the same genomic regions

Implementation of preductal and postductal oxygen saturation screening in babies born in a district general hospital.

Peer reviewed: Tru