Trypanosomes are monophyletic: evidence from genes for glyceraldehyde phosphate dehydrogenase and small subunit ribosomal RNA.

The genomes of Trypanosoma brucei, Trypanosoma cruzi and Leishmania major have been sequenced, but the phylogenetic relationships of these three protozoa remain uncertain. We have constructed trypanosomatid phylogenies based on genes for glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) and small subunit ribosomal RNA (SSU rRNA). Trees based on gGAPDH nucleotide and amino acid sequences (51 taxa) robustly support monophyly of genus Trypanosoma, which is revealed to be a relatively late-evolving lineage of the family Trypanosomatidae. Other trypanosomatids, including genus Leishmania, branch paraphyletically at the base of the trypanosome clade. On the other hand, analysis of the SSU rRNA gene data produced equivocal results, as trees either robustly support or reject monophyly depending on the range of taxa included in the alignment. We conclude that the SSU rRNA gene is not a reliable marker for inferring deep level trypanosome phylogeny. The gGAPDH results support the hypothesis that trypanosomes evolved from an ancestral insect parasite, which adapted to a vertebrate/insect transmission cycle. This implies that the switch from terrestrial insect to aquatic leech vectors for fish and some amphibian trypanosomes was secondary. We conclude that the three sequenced pathogens, T. brucei, T. cruzi and L. major, are only distantly related and have distinct evolutionary histories

Evaluating the Effectiveness of Undergraduate Clinical Education Programs

Medical schools should use a variety of measures to evaluate the effectiveness of their clinical curricula. Both outcome measures and process measures should be included, and these can be organized according to the four-level training evaluation model developed by Donald Kirkpatrick. Managing evaluation data requires the institution to employ deliberate strategies to monitor signals in real-time and aggregate data so that informed decisions can be made. Future steps in program evaluation includes increased emphasis on patient outcomes and multi-source feedback, as well as better integration of existing data sources

Visual Impairment and Intracranial Hypertension: An Emerging Spaceflight Risk

What is the risk? Given that astronauts exposed to microgravity experience a cephalad fluid shift, and that both symptomatic and asymptomatic astronauts have exhibited optic nerve sheath edema on MRI, there is a high probability that all astronauts have some degree of increased intracranial pressure (ICP; intracranial hypertension), and that those susceptible (via eye architecture, anatomy, narrow optic disc) have a high likelihood of developing papilledema (optic disc edema, globe flattening), choroidal folds, and/or hyperopic shifts and that the degree of edema may determine long-term or permanent vision impairment or loss. Back to back panels on this topic have been developed to address this emerging risk. The first panel will focus on the 6 clinical cases with emphasis on ophthalmic findings and imaging techniques used pre-, in-, and post-flight. The second panel will discuss the operational mitigation and medical requirements, the potential role of CO2 on ISS, and the research approach being developed. In total these back to back panels will explore what is known about this risk, what has been done immediately to address it, and how an integrated research model is being developed

Cardiac Troponin After Percutaneous Coronary Intervention and 1-Year Mortality in Non–ST-Segment Elevation Acute Coronary Syndrome Using Systematic Evaluation of Biomarker Trends

ObjectivesThis study sought to review cardiac troponin (cTn) trends during non–ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndromes) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) studies and to study the relationship between post-PCI cTn and mortality.BackgroundThe prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI).MethodsTime and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-myocardial band and 1-year mortality.ResultsPatients with cTn (re-)elevation post-PCI not evaluable were identified and excluded from further analysis (4,198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (n = 5,772 [57%]), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10× ULN increase: 1.07, 95% confidence interval [CI]: 1.02 to 1.11; p = 0.0038). Peak post-PCI creatine kinase-myocardial band was significantly associated with 1-year mortality (HR for 1× ULN increase: 1.13, 95% CI: 1.05 to 1.21; p = 0.0013).ConclusionsWe used a methodology that differentiated post-PCI cTn (re-)elevation from that of presenting MI in more than one-half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implications for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis

The reductive activation of CO2 across a Ti═Ti double bond: synthetic, structural, and mechanistic studies

[Image: see text] The reactivity of the bis(pentalene)dititanium double-sandwich compound Ti(2)Pn(†)(2) (1) (Pn(†) = 1,4-{Si(i)Pr(3)}(2)C(8)H(4)) with CO(2) is investigated in detail using spectroscopic, X-ray crystallographic, and computational studies. When the CO(2) reaction is performed at −78 °C, the 1:1 adduct 4 is formed, and low-temperature spectroscopic measurements are consistent with a CO(2) molecule bound symmetrically to the two Ti centers in a μ:η(2),η(2) binding mode, a structure also indicated by theory. Upon warming to room temperature the coordinated CO(2) is quantitatively reduced over a period of minutes to give the bis(oxo)-bridged dimer 2 and the dicarbonyl complex 3. In situ NMR studies indicated that this decomposition proceeds in a stepwise process via monooxo (5) and monocarbonyl (7) double-sandwich complexes, which have been independently synthesized and structurally characterized. 5 is thermally unstable with respect to a μ-O dimer in which the Ti–Ti bond has been cleaved and one pentalene ligand binds in an η(8) fashion to each of the formally Ti(III) centers. The molecular structure of 7 shows a “side-on” bound carbonyl ligand. Bonding of the double-sandwich species Ti(2)Pn(2) (Pn = C(8)H(6)) to other fragments has been investigated by density functional theory calculations and fragment analysis, providing insight into the CO(2) reaction pathway consistent with the experimentally observed intermediates. A key step in the proposed mechanism is disproportionation of a mono(oxo) di-Ti(III) species to yield di-Ti(II) and di-Ti(IV) products. 1 forms a structurally characterized, thermally stable CS(2) adduct 8 that shows symmetrical binding to the Ti(2) unit and supports the formulation of 4. The reaction of 1 with COS forms a thermally unstable complex 9 that undergoes scission to give mono(μ-S) mono(CO) species 10. Ph(3)PS is an effective sulfur transfer agent for 1, enabling the synthesis of mono(μ-S) complex 11 with a double-sandwich structure and bis(μ-S) dimer 12 in which the Ti–Ti bond has been cleaved

An Integrated In Vitro and In Vivo High-Throughput Screen Identifies Treatment Leads for Ependymoma

SummaryUsing a mouse model of ependymoma—a chemoresistant brain tumor—we combined multicell high-throughput screening (HTS), kinome-wide binding assays, and in vivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both in vitro and in vivo, e.g., 5-fluorouracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation

SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence. We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis

Eliciting the child's voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative: Reeve et al.

Adverse event (AE) reporting in oncology trials is required, but current practice does not directly integrate the child’s voice. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being developed to assess symptomatic AEs via child/adolescent self-report or proxy-report. This qualitative study evaluates the child’s/adolescent’s understanding and ability to provide valid responses to the PRO-CTCAE to inform questionnaire refinements and confirm content validity