Newer agents in antiplatelet therapy: a review.

Antiplatelet therapy remains the mainstay in preventing aberrant platelet activation in pathophysiological conditions such as myocardial infarction, ischemia, and stroke. Although there has been significant advancement in antiplatelet therapeutic approaches, aspirin still remains the gold standard treatment in the clinical setting. Limitations in safety, efficacy, and tolerability have precluded many of the antiplatelet inhibitors from use in patients. Unforeseen incidences of increased bleeding risk and recurrent arterial thrombosis observed in patients have hampered the development of superior next generation antiplatelet therapies. The pharmacokinetic and pharmacodynamic profiles have also limited the effectiveness of a number of antiplatelet inhibitors currently in use due to variability in metabolism, time to onset, and reversibility. A focused effort in the development of newer antiplatelet therapies to address some of these shortcomings has resulted in a significant number of potential antiplatelet drugs which target enzymes (phosphodiesterase, cyclooxygenase), receptors (purinergic, prostaglandins, protease-activated receptors, thromboxane), and glycoproteins (αIIbβ3, GPVI, vWF, GPIb) in the platelet. The validation and search for newer antiplatelet therapeutic approaches proven to be superior to aspirin is still ongoing and should yield a better pharmacodynamic profile with fewer untoward side-effects to what is currently in use today

A role for the histone deacetylase HDAC4 in the life-cycle of HIV-1-based vectors

HIV-1 integration is mediated by the HIV-1 integrase protein, which joins 3'-ends of viral DNA to host cell DNA. To complete the integration process, HIV-1 DNA has to be joined to host cell DNA also at the 5'-ends. This process is called post-integration repair (PIR). Integration and PIR involve a number of cellular co-factors. These proteins exhibit different degrees of involvement in integration and/or PIR. Some are required for efficient integration or PIR. On the other hand, some reduce the efficiency of integration. Finally, some are involved in integration site selection. We have studied the role of the histone deacetylase HDAC4 in these processes. HDAC4 was demonstrated to play a role in both cellular double-strand DNA break repair and transcriptional regulation. We observed that HDAC4 associates with viral DNA in an integrase-dependent manner. Moreover, infection with HIV-1-based vectors induces foci of the HDAC4 protein. The related histone deacetylases, HDAC2 and HDAC6, failed to associate with viral DNA after infection. These data suggest that HDAC4 accumulates at integration sites. Finally, overexpression studies with HDAC4 mutants suggest that HDAC4 may be required for efficient transduction by HIV-1-based vectors in cells that are deficient in other DNA repair proteins. We conclude that HDAC4 is likely involved in PIR

Investigating the diastereoselective synthesis of a macrocycle under Curtin–Hammett control †

This work sheds new light on the stereoselective synthesis of chiral macrocycles containing twisted aromatic units, valuable π-conjugated materials for recognition, sensing, and optoelectronics. For the first time, we use the Curtin–Hammett principle to investigate a chiral macrocyclisation reaction, revealing the potential for supramolecular π–π interactions to direct the outcome of a dynamic kinetic resolution, favouring the opposite macrocyclic product to that expected under reversible, thermodynamically controlled conditions. Specifically, a dynamic, racemic perylene diimide dye (1 : 1 P : M) is strapped with an enantiopure (S)-1,1′-bi-2-naphthol group (P-BINOL) to form two diastereomeric macrocyclic products, the homochiral macrocycle (PP) and the heterochiral species (PM). We find there is notable selectivity for the PM macrocycle (dr = 4 : 1), which is rationalised by kinetic templation from intramolecular aromatic non-covalent interactions between the P-BINOL π-donor and the M-PDI π-acceptor during the macrocyclisation reaction

Low dose CT vs plain abdominal radiography for the investigation of the acute abdomen

Background: To compare low-dose abdominal computed tomography (LDCT) with plain abdominal radiography (AR) in the primary investigation of acute abdominal pain to determine if there is a difference in diagnostic yield, the number of additional investigations required and hospital length of stay (LOS). Methods: This randomized controlled trial was approved by the institutional review board, and informed consent was obtained. Patients presenting to the emergency department with an acute abdomen and who would normally be investigated with AR were randomized to either AR or LDCT. The estimated radiation dose of the LDCT protocol was 2–3 mSv compared to 1.1 mSv for AR. Pearson\u27s chi-square and the independent samples t-test were used for the statistical analysis. Results: A total of 142 patients were eligible, and after exclusions and omitting those with incomplete data, 55 patients remained for analysis in the AR arm and 53 in the LDCT arm. A diagnosis could be obtained in 12 (21.8%) patients investigated with AR compared to 34 (64.2%) for LDCT (P \u3c 0.001). Twenty-eight (50.9%) patients in the AR group required further imaging during their admission compared to 14 (26.4%) in the LDCT group (P= 0.009). There was no difference in the median hospital LOS (3.84 days for AR versus 4.24 days for LDCT, P= 0.83). Conclusion: LDCT demonstrates a superior diagnostic yield over AR and reduces the number of subsequent imaging tests for a minimal cost in radiation exposure. However, there is no difference in the overall hospital LOS between the two imaging strategies

Identity and Guilt as Mediators of Pro-environmental Spillover

Policymakers are interested in programs that increase targeted pro-environmental behavior (PEB) and spill over to increase non-targeted PEBs. Theoretically, guilt should lead to negative spillover and identity to positive spillover, though this has rarely been tested empirically. Additionally, little is known about how reminders of past PEB behavior might also lead to downstream spillover effects. Across two studies, participants (Study 1: 377 MTurk workers; Study 2: 172 undergraduates) were randomly assigned to write about a prior PEB, an anti-environmental behavior, or to a control condition. Subsequently, respondents were given an opportunity to perform a PEB2 and completed measures of PEB3 intentions. Results showed some evidence of positive (through increasing identity) and negative (through decreasing guilt) indirect spillover pathways from prior PEB reminders to PEB2 performance and PEB3 curtailment intentions (but not efficiency upgrade intentions). However, there were no overall spillover effects from PEB reminders to PEB2 performance or PEB3 intentions, as the positive and negative indirect effects canceled each other out. Results also showed positive spillover from PEB2 performance to PEB3 curtailment intentions through increasing environmental guilt. The strength of the spillover effects depended on the comparison group for the experimental manipulation, whether environmental guilt or global guilt was measured, and the type of PEB. The results suggest that environmental communications that remind people of their prior PEB may not meaningfully spill over to further PEB performance or intentions. &nbsp;</p