Formation of cyclic structures in the cationic ring-opening polymerization of 1,3-dioxolane

The cationic ring-opening polymerization of acetals is prone to cyclization of the polymer chains. This is also the case for the polymerization of 1,3-dioxolane. Literature states that this cyclization can be reduced by applying the Active Monomer mechanism, at least if no competition with the Active Chain End mechanism occurs. In this work, a detailed characterization of the different distributions resulting from the cationic ring-opening polymerization of 1,3-dioxolane via the Active Monomer mechanism is made by a combination of gel permeation chromatography, ¹H NMR, and for the first time by matrix assisted laser desorption/ionization time of flight mass spectrometry. The influence of monomer addition speed, catalyst to initiator ratio and solvent were studied on both kinetics and composition of the product. Furthermore, it was found that increasing the conversion and monomer to initiator ratios leads to an increased amount of cyclic structures and to broader distributions, in correspondence with the Jacobson–Stockmayer theory. Furthermore, ion trapping experiments using ³¹P NMR provide insights into the actual reaction mechanism. Finally, purification of the products after the reactions led to a reduction of the cyclic fraction.

Elucidating the mechanism of the cationic ring-opening polymerization of dioxolane using gel permeation chromatography, matrix assisted laser desorption/ionization time of flight mass spectrometry and ³¹P NMR.     

Prevalence and correlates of face recognition impairments after acquired brain injury

Impairments of face recognition after acquired brain injury (ABI) are not restricted to prosopagnosia but commonly arise in association with other cognitive deficits and can be psychosocially debilitating. Despite this, the prevalence and cognitive concomitants of such impairments after ABI have not been systematically investigated. We tested 91 adults with ABI on a range of cognitive measures including several indices of face recognition and learning. The proportion of patients who show impaired performance varied across face learning/recognition tests between 21% and 80%. Principal components analyses indicated orthogonality between impairments of “directed facial processing”, associated with memory and visuoperceptual deficits and manifest in slow learning and matching of previously unfamiliar faces, and of “face identification”, associated with deficits on verbal tests and manifest in difficulty in naming famous faces. Theoretical and rehabilitative implications are considered.     

Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.     

Tongue contractions during speech may have led to the development of the bony geometry of the chin following the evolution of human language: a mechanobiological hypothesis for the development of the human chin

One of the most fundamental yet unanswered questions of human evolution is that of the development of the chin. Whereas it is known that the chin, or mentum osseum, is an unique anatomical feature of modern humans that emerged during the Middle and Late Pleistocene, its origin and biomechanical significance are the subjects of intense controversy. Theories range from the suggestion that the chin evolved as a result of progressive reduction of the dental arch, which left it as a protrusion, to the hypothesis that it provided resistance to mandibular bending during mastication. Until now however, no accepted functional explanation of the human chin has emerged. Here, we develop the hypothesis that the actions of the tongue and non-masticatory orofacial muscles may have played a significant role on the development of the human chin. We report numerical simulations of the forces and resultant stresses developed in hypothetical chinned and non-chinned mandibles. Using empirical data and estimates of the forces generated by the human tongue during speech, our hypothesis suggests that the chin might in fact have developed as a result of the actions of the tongue and perioral muscles, rather than as a buttress to withstand masticatory induced stress. This provides a new perspective on the generation of the chin and importantly, suggests that its appearance may be causally related to the development of the human language.     

Prediction of drug‐drug interactions using physiologically‐based pharmacokinetic models of CYP450 modulators included in Simcyp software

In recent years, physiologically based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics. It has been demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio‐pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug–drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism‐based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism‐based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp^® software. The aim of this report was to establish confidence in each CYP‐specific modulator file so they can be used in the future for the prediction of DDIs involving new victim compounds. Our evaluation of these PBPK models suggested that they can be successfully used to evaluate DDIs in untested scenarios. The only noticeable exception concerned a quinidine inhibitor model that requires further improvement. Additionally, other important aspects such as model validation criteria were discussed.     

Absorption des médicaments lors de syndrome du grêle court

Short bowel syndrome (SBS) occurs when a patient is left with less than 200 cm of functional small intestine. Drug absorption is mostly a passive process and can be affected by the surface area of the remaining gastrointestinal tract. Oral medication absorption is often impaired and larger doses, or other administration routes may be required. Although patients with SBS do need pharmacotherapy for symptoms associated with their pathology or for other comorbidities, there are few published case reports on drug absorption, and few studies have been conducted in small patients’ samples. Moreover, due to the highly heterogeneous nature of this patient population, it is difficult to directly apply the findings of the published literature to specific patients. Drug dosages should be guided by the monitoring of clinical endpoints and/or of biomarkers.     

Emerging therapeutic targets in the short QT syndrome

Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable.

Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome.

Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K⁺ channel inhibitors. A combination of K⁺ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K⁺ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.