Nitinol Stents in the Femoropopliteal Artery: A Mechanical Perspective on Material,Design, and Performance

Endovascular stenting has matured into a commonly used treatment for peripheral arterial disease (PAD) due to its minimally invasive nature and associated reductions in short-term morbidity and mortality. The mechanical properties of the superelastic Nitinol alloy have played a major role in the explosion of peripheral artery stenting, with modern stents demonstrating reasonable resilience and durability. Yet in the superficial femoral and popliteal arteries, even the newest generation Nitinol stents continue to demonstrate clinical outcomes that leave significant room for improvement. Restenosis and progression of native arterial disease often lead to recurrence of symptoms and reinterventions that increase morbidity and health care expenditures. One of the main factors thought to be associated with stent failure in the femoropopliteal artery (FPA) is the unique and highly dynamic mechanical environment of the lower limb. Clinical and experimental data demonstrate that the FPA undergoes significant deformations with limb flexion. It is hypothesized that the inability of many existing stent designs to conform to these deformations likely plays a role in reconstruction failure, as repetitive movements of the leg and thigh combine with mechanical mismatch between the artery and the stent and result in mechanical damage to both the artery and the stent. In this review we will identify challenges and provide a mechanical perspective of FPA stenting, and then discuss current research directions with promise to provide a better understanding of Nitinol, specific features of stent design, and improved characterization of the biomechanical environment of the FPA to facilitate development of better stents for patients with PAD.     

Aggregation induced emission by pyridinium–pyridinium interactions

Non-covalent intermolecular interactions between pyridinium subunits in a crystal-state are an efficient means to accomplish aggregation induced emission and avoid aggregation caused quenching.

Non-covalent intermolecular pyridinium–pyridinium and pyridinium–arene-π system interactions result in aggregation induced emission (AIE).     

The Global Drug Facility as an intervention in the market for tuberculosis drugs

Objective

To investigate funding for the Global Drug Facility since 2001 and to analyse the facility’s influence on the price of high-quality tuberculosis drugs.

Methods

Data on the price of tuberculosis drugs were obtained from the Global Drug Facility for 2001 to 2012 and, for the private sector in 15 countries, from IMS Health for 2002 to 2012. Data on funding of the facility were also collected.

Findings

Quality-assured tuberculosis drugs supplied by the Global Drug Facility were generally priced lower than drugs purchased in the private sector. In 2012, just three manufacturers accounted for 29.9 million United Stated dollars (US$) of US$ 44.5 million by value of first-line drugs supplied. The Global Fund to Fight AIDS, Tuberculosis and Malaria provided 73% (US$ 32.5 million of US$ 44.5 million) and 89% (US$ 57.8 million of US $65.2 million) of funds for first- and second-line drugs, respectively. Between 2010 and 2012, the facility’s market share of second-line tuberculosis drugs increased from 26.1% to 42.9%, while prices decreased by as much as 24% (from US$ 1231 to US$ 939). Conversely, the facility’s market share of first-line drugs fell from 37.2% to 19.2% during this time, while prices increased from US$ 9.53 to US$ 10.2.

Conclusion

The price of tuberculosis drugs supplied through the facility was generally less than that on the private market. However, to realize its full potential and meet the needs of more tuberculosis patients, the facility requires more diverse and stable public funding and greater flexibility to participate in the private market.     

The three-dimensional structure of ryegrass mottle virus at 2.9 A resolution

The crystal structure of the sobemovirus Ryegrass mottle virus (RGMoV) has been determined at 2.9 A resolution. The coat protein has a canonical jellyroll beta-sandwich fold. In comparison to other sobemoviruses the RGMoV coat protein is missing several residues in two of the loop regions. The first loop contributes to contacts between subunits around the quasi-threefold symmetry axis. The altered contact interface results in tilting of the subunits towards the quasi-threefold axis. The assembly of the T=3 capsid of sobemoviruses is controlled by the N-termini of C subunits forming a so-called beta-annulus. The other loop that is smaller in the RGMoV structure contains a helix that participates in stabilization of the beta-annulus in other sobemoviruses. The loss of interaction between the RGMoV loop and the beta-annulus has been compensated for by additional interactions between the N-terminal arms. As a consequence of these differences, the diameter of the RGMoV particle is 8 A smaller than that of the other sobemoviruses. The interactions of coat proteins in sobemovirus capsids involve calcium ions. Depletion of calcium ions results in particle swelling, which is considered a first step in disassembly. We could not identify any density for metal ions in the proximity of the conserved residues normally involved in calcium binding, but the RGMoV structure does not show any signs of swelling. A likely reason is the low pH (3.0) of the crystallization buffer in which the groups interacting with the calcium ions are not charged.     

Focused open necrosectomy in necrotizing pancreatitis

Background

The control of sepsis is the primary goal of surgical intervention in patients with infected necrosis. Simple surgical approaches that are easy to reproduce may improve outcomes when specialists in endoscopy are not available. The aim of the present study was to describe the experience with a focused open necrosectomy (FON) in patients with infected necrosis.

Method

A prospective pilot study conducted to compare a semi-open/closed drainage laparotomy and FON with the assistance of peri-operative ultrasound. The incidence of sepsis, dynamics of C-reactive protein (CRP), intensive care unit (ICU)/hospital stay, complication rate and mortality were compared and analysed.

Results

From a total of 58 patients, 36 patients underwent a conventional open necrosectomy and 22 patients underwent FON. The latter method resulted in a faster resolution of sepsis and a significant decrease in mean CRP on Day 3 after FON, P = 0.001. Post-operative bleeding was in 1 versus 7 patients and the incidence of intestinal and pancreatic fistula was 2 versus 8 patients when comparing FON to the conventional approach. The median ICU stay was 11.6 versus 23 days and the hospital stay was significantly shorter, 57 versus 72 days, P = 0.024 when comparing FON versus the conventional group. One patient died in the FON group and seven patients died in the laparotomy group, P = 0.139.

Discussion

FON can be an alternative method to conventional open necrosectomy in patients with infected necrosis and unresolved sepsis.     

Aggregation induced emission in one easy step: pyridinium AIEgens and counter ion effect

Protonation of pyridines with a strong acid is a general and straightforward approach to achieve efficient aggregation induced emission (AIE) in structurally remarkably simple organic molecules that lack any of the conventional luminophores. The relationship between the nature of counter ion and the AIE efficiency is demonstrated. The superiority of the perchlorate counter ion is attributed to efficient stabilization of the key intermolecular π⁺–π interactions between neighboring luminophore molecules in the crystal lattice.

Protonation of planar organic luminophores with perchloric acid turns on high solid state luminescence.

A large variety of optoelectronic appliances such as photovoltaic devices,¹ organic light emitting diodes,² and organic field-effect transistors³ as well as a number of light harvesting applications including artificial photosynthesis⁴ and photon refining,⁵ rely on solid state luminophores. In 2001, Tang introduced a general method to achieve highly efficient solid state luminescence (SSL) in purely organic molecules, generally known as aggregation induced emission (AIE).⁶ The vast majority of AIE luminogens (AIEgens) are based on sterically hindered, bulky propeller-like molecular structures to reduce the planarity of luminophore,⁷ because the planar architecture is known to be detrimental to the AIE efficiency.^8,7a In the meantime, the majority of luminophores with high emission intensity in solution feature a planar structure, so an approach that would allow for the design of the solid state luminogens based on the planar architecture of the known solution state emitters is highly desirable.We have recently demonstrated that the formation of intermolecular interactions between quaternary nitrogen-containing heteroaromatic cations and aromatic π-system in the solid state is a convenient and general approach to achieve AIE and to turn-on high SSL in planar organic molecules.⁹ The high SSL has been attributed to intermolecular charge transfer (ICT) between quaternary heteroaromatic subunits such as N-methyl pyridinium and N-methyl imidazolium cations and aromatic π-systems.^9b Herein we report on a further development of the conceptual approach to achieve AIE. Specifically, we demonstrate that efficient AIE can be achieved in planar organic luminophores by simple protonation of pyridine with a suitable acid (Fig. 1). Furthermore, our study provides an important insight into the relationship between the nature of counter ion and the AIE efficiency of pyridinium salts.Open in a separate windowFig. 1Effect of counter ions on AIE and SSL.The relationship between the structure of counter ion and luminescence efficiency has been studied in several pyridinium-containing AIE luminogens.¹⁰ The highest luminescence efficiency was observed for pyridinium salts possessing a counter ion that helped to avoid the detrimental aggregation-induced quenching (ACQ) effect by minimizing intermolecular π–π interactions between planar luminophore molecules (eqn (1) and (3), Fig. 1)^10a,b or by stabilizing twisted conformation of luminogens (eqn (2), Fig. 2).^10c In sharp contrast, a completely opposite counter ion effect has been observed in this study. Specifically, counter ions that contributed to strengthening the intermolecular interactions between planar pyridinium luminophores have helped to achieve the highest SSL efficiency (eqn (4), Fig. 1). Perchlorate was found to be superior as the counter-ion, whereas the corresponding mesylate, nitrate as well as halides were inferior. The latter showed apparent negative correlation between the polarizability of the counter ion and SSL emission intensity (Cl > Br > I; see eqn (4), Fig. 1.). The superiority of perchlorate has been rationalized based on X-ray crystallographic analysis as demonstrated below. The striking difference of counter-ion effects in this work (eqn (4)) and in the earlier studies (eqn (1)–(3)) points to an apparent difference in mechanisms that are responsible for the AIE (Fig. 1).Open in a separate windowFig. 2Synthesis of pyridinium salts 2a,b and 4a–f. Reagents and conditions: (a) aq. HClO₄, MeOH or MeCN, rt, 10 min, 83% (2a); 99% (4a); 32% (6). (b) 4 M HCl in dioxane, EtOAc, rt, 10 min, 97% (2b). (c) 4 M HCl in dioxane, 1 : 2 CH₂Cl₂ : hexane, rt, 10 min, 93% (4b). (d) aq. HBr, MeOH, rt, 10 min, 91% (4c). (e) aq. HI, EtOH, rt, 1 h, 61% (4d). (f) MeSO₃H, MeCN, rt, 10 min, 94% (4e). (g) HNO₃, MeCN, rt, 30 min, 99% (4f).Pyridinium salts 2a,b were obtained by protonation of commercially available 4-phenylpyridine 1 with aqueous HClO₄ and hydrochloric acid, respectively. The protonation of previously reported 3^9b with HClO₄, HCl, HBr, HI, MsOH and HNO₃ resulted in the formation of pyridinium salts 4a–f (Fig. 2). All pyridinium salts 2a,b and 4a–f were crystalline materials.UV-vis spectra of all pyridinium salts 2a,b and 4a–f and parent heteroaromatic compounds 1 and 3 were measured in MeCN solutions at room temperature under ambient atmosphere at ca. 10⁻⁵ M concentration (see ESI, pages S11–S28^†). Pyridine 1 displayed one absorption band at 251 nm (

Hidradenitis suppurativa in surgeons' practice: Prevalence and treatment approach according to the Hurley stage in Latvia

Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating, and frequently misdiagnosed inflammatory skin disease that often requires surgical intervention. To assess the prevalence of HS patients in surgeons' practice and surgeons' approach to treating HS patients, we created a self‐administered, Hurley stage‐based questionnaire that was distributed during the Latvian Association of Surgeons meeting. Of the total 60 questionnaires distributed, 56 (93%) were collected and 53 (88%) of them were considered valid. Overall, 73.6% of the surgeons confirmed having seen patients with chronic inflamed suppurative lesions in the skin folds during their practice. Median reported number of HS patients in the surgeons' practice was 3, ranging from 0 to 30. Similarly, 73.6% of surgeons would undertake HS treatment. The proportion of surgeons undertaking treatment was higher if the surgeons had diagnosed HS by themselves but was not affected by personal knowledge of HS. Surgeons chose monotherapy for Hurley stages I, II, and III in 64.2%, 64.2%, and 62.3% of the cases, respectively. The most common therapeutic choice for monotherapy was topical antiseptics (26.4%) or topical antibiotics (20.8%) for Hurley stage I and surgery or systemic antibiotics for Hurley stage II (20.8% or 17.0%, respectively) and Hurley stage III (32.1% or 11.3%, respectively). A wide diversity of treatment approaches in specified clinical scenarios was observed, which indicates the need for local guidelines.     

Application of hydrophilic interaction chromatography for simultaneous separation of six impurities of mildronate substance

The possibility of separating the impurities of mildronate, an antiischemic drug, by hydrophilic interaction chromatography (HILIC) was investigated on different polar stationary phases (silica, amino, cyano and zwitterionic sulfobetaine). The investigations have shown that HILIC is a useful alternative to reversed phase and ion-pair chromatography. The impact of HILIC separation conditions (acetonitrile content, buffer pH in mobile phase) on retention and selectivity has been systematically studied. Importance of these factors was found to be dependent on the structural properties of solutes. A HILIC method using a zwitterionic sulfobetaine stationary phase was developed and validated to determine six impurities in the drug substance. The method was validated in terms of specificity, limit of quantitation, limit of detection, linearity, accuracy and precision.     

Flecainide acetate acetic acid solvates

Flecainide acetate forms acetic acid solvates with 0.5 and 2 acetic acid molecules. Powder X-ray diffraction, differential thermal analysis/thermogravimetric, infrared, and potentiometric titration were used to determine the composition of solvates. Flecainide acetate hemisolvate with acetic acid decomposes to form a new crystalline form of flecainide acetate. This form is less stable than the already known polymorphic form at all temperatures, and it is formed due to kinetic reasons. Both flecainide acetate nonsolvated and flecainide acetate hemisolvate forms crystallize in monoclinic crystals, but flecainide triacetate forms triclinic crystals. Solvate formation was not observed when flecainide base was treated with formic acid, propanoic acid, and butanoic acid. Only nonsolvated flecainide salts were obtained in these experiments.     

Alternative mutations of a positively selected residue elicit gain or loss of functionalities in enzyme evolution

All molecular species in an organism are connected physically and functionally to other molecules. In evolving systems, it is not obvious to what extent functional properties of a protein can change to selective advantage and leave intact favorable traits previously acquired. This uncertainty has particular significance in the evolution of novel pathways for detoxication, because an organism challenged with new xenobiotics in the environment may still require biotransformation of previously encountered toxins. Positive selection has been proposed as an evolutionary mechanism for facile adaptive responses of proteins to changing conditions. Here, we show, by saturation mutagenesis, that mutations of a hypervariable residue in human glutathione transferase M2-2 can differentially change the enzyme's substrate-activity profile with alternative substrates and, furthermore, enable or disable dissimilar chemical reactions. Crystal structures demonstrate that activity with epoxides is enabled through removal of steric hindrance from a methyl group, whereas activities with an orthoquinone and a nitroso donor are maintained in the variant enzymes. Given the diversity of cellular activities in which a single protein can be engaged, the selective transmutation of functional properties has general significance in molecular evolution.