Biomimetic Domino Knoevenagel/Cycloisomerization Strategy for the Synthesis of Citridone A and Derivatives.

Studies on Knoevenagel condensations between conjugated dienals and 4-hydroxy-2-pyridone/quinolone-type 1,3-dicarbonyl equivalents led to the development of a simple one-pot strategy to access citridone A and related synthetic cyclopenta[b]furopyridones/quinolones. The present work highlights the power of domino cascades in the synthesis of natural product frameworks and may help promote future studies on this promising new class of pyridone alkaloids.

Design of superatomic systems: exploiting favourable conditions for the delocalisation of d-electron density in transition metal doped clusters.

The incorporation of transition metals into superatomic species has led to the proposal of highly tailorable systems, with the transition metal atoms typically acting as magnetic dopants. However, the extent to which d-electrons are able to delocalise from their ionic cores has not been fully recognised. In this work a variety of systems have been explored using a range of exchange-correlation functionals commonly used to explore cluster species, to test the extent of d-electron delocalisation under favourable conditions. Early transition metals have been shown to readily delocalise their valence d-electrons for superatomic shell closing, with higher period atoms showing a greater tendency for delocalisation. Our findings also provide the framework for the design of superatomic systems with large numbers of electrons being contributed from a single atom.

5-Fold symmetry in superatomic scandium clusters: exploiting favourable orbital overlap to sequester spin.

The geometries and electronic structures of icosahedral A13C (A = Sc, Y; C = 0, ±1, ±2) clusters have been determined at a range of multiplicities at each cluster charge, using density functional theory methods. These clusters demonstrate a complex electronic structure which provides insight into the anomalously high magnetic moment of icosahedral group 3 clusters and further contextualises the role of transition metals and d-electrons within the superatomic model. Embedded deeply within the density of states for these clusters are typical superatom orbitals which are populated up to the 2S level. Above the 2S-state there are three states of apparent F symmetry, which are preferentially singly occupied, followed by an abundance of approximately degenerate P-, G-, D- and F-states at the Fermi energy, which are at most singly occupied. In spite of apparent angular symmetry and a nodal structure reminiscent of superatomic orbitals these states are actually formed from preferential overlap of the valence d-orbitals of the cluster atoms. This analysis was further contextualised through analysis of the Sc19 cluster, which shows a similar construction of Kohn-Sham states, but with the breaking of 5-fold symmetry along one of its Cartesian axes. Finally, this work clearly demonstrates the ability of d-electrons to give rise to superatomic orbitals is not just constrained by atomic species but also by the local environment of the atoms.

On the influence of exact exchange on transition metal superatoms.

The electronic structure of A7C (A = Hg, Pd, V, Cr, Mn, Fe, Ni, Cu; C = 0, ±1, ±2) clusters has been determined using density functional theory methods. The A7C (A = Hg, Pd, Cr, Cu; C = 0, ±1, ±2) clusters all conform to the existing superatomic model, with a sufficiently stabilised local structure to prevent perturbation upon the introduction of exact exchange to the exchange correlation functional. For the A7C (A = Mn, Fe, Ni; C = 0, ±1, ±2) clusters the incorporation of exact exchange separates the atomic s- and d-electrons, leading to a net increase in the number of superatomic electrons. Conversely the incorporation of exact exchange into the exchange correlation functional decreases the number of superatomic electrons for the V7C (C = 0, ±1, ±2) clusters, owing to the radial extension of the d-orbitals influencing their ability to contribute into superatomic shells.

On the involvement of d-electrons in superatomic shells: the group 3 and 4 transition metals.

The geometries and electronic structures of small M7C (M = Sc, Y, La, Ti, Zr, Hf; C = 0, ±1, ±2) clusters have been calculated at a range of multiplicities at each cluster charge, using density functional theory methods. These clusters conform to the existing superatom model, with some contextual differences. There are a range of states which are populated by the outermost s and d-electrons of the constituent atoms, with an irregular Aufbau rule for the states formed from the atomic d-electrons. The states comprised of d-electrons present themselves as two states of P-symmetry and two states of F-symmetry, which are nearly degenerate, followed by states of D-symmetry, a shell ordering which arises due to the symmetry, and favourable overlap, of the contributing states. The effect of exact exchange in modulating the localisation of these states is also discussed. In addition, this study shows pseudo-superatomic states which arise due to the 5-fold symmetry of the clusters, materialising as either a ring or plane of electron density. In summary, these observations allow for an expansion of the role that early transition metals have within the existing superatom framework.

Cofilin-1 levels and intracellular localization are associated with melanoma prognosis in a cohort of patients.

Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma in situ (MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi. In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma.

Physician-Assisted Suicide and Midwest Social Workers: Where Do They Stand?

Physician-assisted suicide (PAS) is explicitly legal in five states and by court decision in one. Legislative bills have been introduced in other states including Minnesota, Iowa, and Wisconsin. This quantitative study was designed to understand Midwest, hospice and palliative care at end-of-life social workers' attitudes toward PAS, preferred terminology, perception of preparedness for the implementation, and awareness of PAS legislation in their state. Sixty-two social workers from Minnesota, Iowa, and Wisconsin completed an anonymous online survey. The results indicated that over one-half of the participants supported PAS legislation and is consistent with previous research on social workers across the country. While there was a range of perceived preparedness for implementation, a majority felt moderately to very prepared. Professional and personal values as well as professional experience influenced their perceived preparedness. Few social workers had accurate awareness of PAS legislation in their state or had attended workshops/events for further education or as a policy advocate. To practice competently and advocate at all levels of practice, hospice and palliative care at end-of-life social workers' need to understand their own attitudes and values toward PAS and pursue additional education around this ethical issue.

Superatomic states in nickel clusters: Revising the prospects for transition metal based superatoms.

The geometries and electronic structures of small Ninz clusters (n = 8, 9, 10) (z = 0, ±1, 2) have been elucidated for a range of multiplicities for each cluster size and charge, using density functional theory methods. These clusters have been found to conform in part to the existing superatomic model, with each cluster having a filled superatomic S-orbital, filled or partially filled superatomic P-orbitals, and empty or partially filled superatomic D-orbitals. Despite local states of mixed symmetry being present in the immediate vicinity of the Fermi energy, the addition or removal of a single electron from these systems causes a significant shift in the relative energies of the superatomic orbitals. In addition, this study demonstrates the possibility for d-electrons to contribute into superatomic orbitals to a greater or lesser extent, depending on the local environment. In summary, these observations lead to the prospect of a predictive model for electronic shell closings in some transition metal cluster systems.

Cycloisomerization of Conjugated Trienones and Isomeric 2H-Pyrans: Unified Strategy toward Cyclopenta[b]furans.

Conjugated trienones and isomeric 2H-pyrans were found to engage in a novel cycloisomerization cascade toward cyclopenta[b]furan derivatives. Knoevenagel chemistry and pericyclic reactions meet again to expand the polyene-carbonyl manifold.

Two worlds collide: image analysis methods for quantifying structural variation in cluster molecular dynamics.

Inspired by methods of remote sensing image analysis, we analyze structural variation in cluster molecular dynamics (MD) simulations through a unique application of the principal component analysis (PCA) and Pearson Correlation Coefficient (PCC). The PCA analysis characterizes the geometric shape of the cluster structure at each time step, yielding a detailed and quantitative measure of structural stability and variation at finite temperature. Our PCC analysis captures bond structure variation in MD, which can be used to both supplement the PCA analysis as well as compare bond patterns between different cluster sizes. Relying only on atomic position data, without requirement for a priori structural input, PCA and PCC can be used to analyze both classical and ab initio MD simulations for any cluster composition or electronic configuration. Taken together, these statistical tools represent powerful new techniques for quantitative structural characterization and isomer identification in cluster MD.

Electronic effects on the melting of small gallium clusters.

Motivated by experimental reports of higher-than-bulk melting temperatures in small gallium clusters, we perform first-principles molecular dynamics simulations of Ga(20) and Ga(20)(+) using parallel tempering in the microcanonical ensemble. The respective specific heat (C(V)) curves, obtained using the multiple histogram method, exhibit a broad peak centered at approximately 740 and 610 K--well above the melting temperature of bulk gallium (303 K) and in reasonable agreement with experimental data for Ga(20)(+). Assessment of atomic mobility confirms the transition from solid-like to liquid-like states near the C(V) peak temperature. Parallel tempering molecular dynamics simulations yield low-energy isomers that are ~0.1 eV lower in energy than previously reported ground state structures, indicative of an energy landscape with multiple, competing low-energy morphologies. Electronic structure analysis shows no evidence of covalent bonding, yet both the neutral and charged clusters exhibit greater-than-bulk melting temperatures.

Electronic shell structure in Ga12 icosahedra and the relation to the bulk forms of gallium.

The electronic structure of known cluster compounds with a cage-like icosahedral Ga(12) centre is studied by first-principles theoretical methods, based on density functional theory. We consider these hollow metalloid nanostructures in the context of the polymorphism of the bulk, and identify a close relation to the α phase of gallium. This previously unrecognised connection is established using the electron localisation function, which reveals the ubiquitous presence of radially-pointing covalent bonds around the Ga(12) centre--analogous to the covalent bonds between buckled deltahedral planes in α-Ga. Furthermore, we find prominent superatom shell structure in these clusters, despite their hollow icosahedral motif and the presence of covalent bonds. The exact nature of the electronic shell structure is contrasted with simple electron shell models based on jellium, and we demonstrate how the interplay between gallium dimerisation, ligand- and crystal-field effects can alter the splitting of the partially filled 1F shell. Finally, in the unique compound where the Ga(12) centre is bridged by six phosphorus ligands, the electronic structure most closely resembles that of δ-Ga and there are no well-defined superatom orbitals. The results of this comprehensive study bring new insights into the nature of chemical bonding in metalloid gallium compounds and the relation to bulk gallium metal, and they may also guide the development of more general models for ligand-protected clusters.

Throwing jellium at gallium--a systematic superatom analysis of metalloid gallium clusters.

Motivated by recent developments in the field of so-called "superatom complexes", as well as by the challenge posed to theory in understanding the many polymorphs of gallium, we analyse the electronic structure of several previously synthesised ligand-protected gallium clusters and their model derivatives using density functional theory. The calculated electron charge densities within the respective gallium cores are shown to be consistent with the jellium superatom model, exhibiting well-defined global spherical shells and wide HOMO-LUMO gaps--indicating enhanced chemical stability. It is demonstrated that the HOMO-LUMO gaps are widened due to the presence of covalent gallium-ligand bonds and a closed electron shell (i.e. electron "magic" number). The tendency of retaining a filled electron shell is shown to be particularly apparent in two closely-related clusters, with one derived from the other simply via substituting a doubly negative charge by a single protective moiety containing a lone electron pair. This analysis verifies that spherical electron shells can influence the chemical stability of ligand-protected gallium clusters, and also demonstrates the significant stabilising effects of metal-ligand interactions-something that is poorly accounted for in the current superatom model.

[Acute and long-term clinical results of bare metal coronary stenting]. / Resultados clínicos inmediatos y alejados del implante de stents metálicos no recubiertos. Se justifica un reemplazo total por los stents liberadores de drogas?

BACKGROUND: Since the introduction of stents in 1994, improved clinical results have boosted the development of coronary angioplasty in Chile. Drug eluting stents, that have a reduced rate of restenosis, are being increasingly used. AIM: To assess the acute and long-term results of bare metal stent implantation. PATIENTS AND METHODS: Acute and long-term clinical, procedural and angiographic results were assessed in non acute myocardial infarction patients undergoing coronary stent implantation between August 1996 and December 2003. RESULTS: During the study period, 932 patients aged 30 to 87 years (194 women) had at least one stent implanted. Twenty two percent were diabetic, 33% had recent myocardial infarction, 53% unstable angina and 22% stable angina. Angiographic and clinical success were 99.6% and 98.2%, respectively. In hospital death was 0.5%. During a mean follow-up of 19.1 months, all cause mortality was 3.9%, cardiac death 1.9% and survival free of major cardiac ischemic events was 85.3%. Only 6.4% of lesions underwent target vessel revascularization (TVR). Independent predictors of TVR were previous surgery, left anterior descending artery, small post stent minimum luminal diameter. Ostial location, in-stent restenosis, and younger age were non significant predictors. CONCLUSIONS: Acute and long-term results of bare metal stents in this population were excellent. An intriguingly low rate of TVR was seen. Selective bare metal stenting should continue in lesions and patients with a low risk of clinical restenosis.

Escleredema diabético: presentación de un caso y revisión de la literatura / Diabetic escleredema: presentation of a case and revision of literature

El escleredema es una entidad infrecuente de etiología desconocida, que se caracteriza por el engrosamiento de la piel del cuello, los hombros y la espalda. Generalmente se observa en pacientes diabéticos. Presentamos el caso de un varón de 74 años, diabético tipo II, que cursa internación en la unidad de cuidados intensivos por un accidente cerebro-vascular y neumonía grave. Al examen dermatológico presentaba una placa de escleredema en cuello, hombros y parte alta del dorso, sobre la que asentaba una úlcera provocada por el decúbito obligado.

Periodontal regeneration with a combination of enamel matrix proteins and autogenous bone grafting.

BACKGROUND: Attempts to stimulate periodontal regeneration in the past have focused on either filling the defect with some type of material or providing a space for host cells to repopulate the site and elicit new tissue. In some cases, these approaches have been combined with the assumption that the filler material will help maintain the space necessary for the host cells to invade the area. Growth stimulating substances such as growth factors and other proteins have also been used to encourage periodontal tissue regeneration and histological evaluation supports the use of these substances. Thus, the role for and the necessity of a certain amount of space maintenance for periodontal regeneration is not exactly understood. In addition, it is not known if there is some critical size required for space maintenance or for exactly how long the space must be maintained in order for the host cells to stimulate new cementum, periodontal ligament, and bone. The goal of this study was to evaluate periodontal regeneration in intrabony defects of various sizes treated with a combination of enamel matrix proteins and autogenous bone graft. METHODS: Periodontal defects ranging in size from 1 to 6 mm were randomized and created bilaterally beside three teeth in the mandibles of baboons. Plaque was allowed to accumulate around wire ligatures placed into the defects. After 2 months, the wire ligatures were removed, the teeth and roots scaled and root planed, and a notch was placed with a chisel at the base of the defect. On one side of the mandible, neutral ethylene diamine tetracetic acid and enamel matrix derivative (EMD) were first used to treat the defect. Autogenous bone taken from the same surgical site was treated with enamel matrix derivative in a dampen dish and then added to the EMD-treated defects. The other side of the mandible served as control with neutral ethylene diamine tetracetic acid and scaling and root planing. Flaps were sutured and the animals were allowed to heal without oral hygiene procedures. After 5 months, the animals were sacrificed and the teeth were processed for histological evaluation. RESULTS: The results revealed new cementum, periodontal ligament with Sharpey's fibers, and new bone tissue similar to native periodontal tissues. Remnants of the autogenous bone chips were still present at this 5-month post-healing period. Thus periodontal regeneration occurred in all sizes of the periodontal defects. In general, EMD plus autogenous graft treatment resulted in greater tissue formation than controls. In fact, in many cases, very dramatic tissue formation occurred far coronal to the base of the defects in the EMD plus autogenous graft-treated lesions. In addition, horizontal bone fill occurred in the defects and was prominent in the 4 or 6 mm wide lesions. When evaluating the combined 1 and 2 mm defects, the height of new cementum with EMD plus graft was 3.88 mm versus 2.03 mm in the controls, a statistically significant (P < 0.005) difference. In the wider (4 and 6 mm) lesions, this difference was not significant and was much less between treated and control lesions with 2.78 and 2.57 mm of new cementum respectively. In the case of new bone height, in the smaller lesions EMD plus graft resulted in 4.00 mm new bone versus 2.22 mm in the controls, again a statistically significant (P < 0.005) difference. In the larger lesions, EMD plus autogenous bone graft had 3.24 mm new bone height compared to 2.71 mm in the controls, a difference that was not statistically significant. Additionally, in the smaller lesions, new cementum width at the level of the notch was twice as great (statistically significant, P < 0.015) in the EMD plus graft sites compared to control. The width of the periodontal ligament at the coronal aspect of the new bone tissue was similar in the smaller lesions between treated and control sites. The results from the wider defects must be interpreted cautiously as the interproximal bone heights were remodeled adjacent to the wider defects and likely limited the potential for regeneration. CONCLUSIONS: The combination of enamel matrix derivative plus autogenous bone graft stimulated statistically significant periodontal regeneration in the more narrow 1 and 2 mm lesions. No statistically significant difference was observed in the wider 4 and 6 mm lesions. In many cases, dramatic amounts of new cementum, Sharpey's fibers, periodontal ligament, and bone tissue were formed far above the notch placed at the base of the contaminated defects. This was especially significant considering the width of some of the defects and the fact that no oral hygiene was performed over the 5-month healing period. This periodontal regeneration occurred in the absence of exogenous growth factors or barrier membranes. In summary, the combination of enamel matrix derivative and autogenous bone represents a therapeutic combination that can be highly effective in stimulating significant amounts of periodontal regeneration.

Influence of the size of the microgap on crestal bone levels in non-submerged dental implants: a radiographic study in the canine mandible.

BACKGROUND: Accumulating evidence suggests that alveolar crestal bone resorption occurs as a result of the microgap that is present between the implant-abutment interface in dental implants. The objective of this longitudinal radiographic study was to determine whether the size of the interface or the microgap between the implant and abutment influences the amount of crestal bone loss in unloaded non-submerged implants. METHODS: Sixty titanium implants having sandblasted with large grit, acid-etched (SLA) endosseous surfaces were placed in edentulous mandibular areas of 5 American fox hounds. Implant groups A, B, and C had a microgap between the implant-abutment connection of <10 microm, 50 microm, or 100 microm, respectively, as did groups D, E, and F, respectively. Abutments were either welded (1 -piece) in groups A, B, and C or non-welded (2-piece screwed) in D, E, and F. All abutment interfaces were placed 1 mm above the alveolar crest. Radiographic assessment was undertaken to evaluate peri-implant crestal bone levels at baseline and at 1, 2, and 3 months after implant placement whereupon all animals were sacrificed. RESULTS: The size of the microgap at the abutment/implant interface had no significant effect upon crestal bone loss. At 1 month, most implants developed crestal bone loss compared with baseline levels. However, during this early healing period, the non-welded group (D, E, and F) showed significantly greater crestal bone loss from baseline to one month (P <0.04) and 2 months (P < 0.02) compared with the welded group (A, B, and C). No significant differences were observed between these 2 groups at 3 months (P > 0.70). CONCLUSIONS: Crestal bone loss was an early manifestation of wound healing occurring after 1 month of implant placement. However, the size of the microgap at the implant-abutment interface had no significant effect upon crestal bone resorption. Thus, 2-piece non-welded implants showed significantly greater crestal bone loss compared with 1-piece welded implants after 1 and 2 months suggesting that the stability of the implant/abutment interface may have an important early role to play in determining crestal bone levels. At 3 months, this influence followed a similar trend but was not observed to be statistically significant. This finding implies that implant configurations incorporating interfaces will be associated with biological changes regardless of interface size and that mobility between components may have an early influence on wound healing around the implant.

Factors that modulate the effects of bone morphogenetic protein-induced periodontal regeneration: a critical review.

The healing process initiated by a single molecular species of bone morphogenetic protein (BMP) such as BMP-2 or BMP-7 sets in motion a cascade of cellular events resulting in differentiation of progenitor cells into phenotypes involved in periodontal regeneration. For example, animal studies show that a single dose of recombinant human (rh) BMP-2 increases the rate of normal intramembranous bone formation and enhanced cementum formation during periodontal wound healing. However, the optimal effects of BMPs are modulated by a range of factors that need careful evaluation in clinical studies. These factors include the influence of root conditioning, occlusal loading, BMP dose, and the release characteristics of the carrier as well as the suitability of the model to evaluate the efficacy of BMPs. Each of these factors may affect the rate of BMP-induced osteogenesis and cementogenesis and subsequent periodontal ligament (PDL) formation during the early and late stages of periodontal wound healing. Although BMP-2 initiates stem cells along an osteogenic pathway, the dose may have to be of sufficient concentration to ensure other growth and differentiation factors do not redirect or retard the osteogenic potential of the cell. Understanding when to manipulate the cell's differentiation pathway with the application of single or multiple doses of BMPs at the appropriate concentration is required to optimize the effect of BMPs in periodontal wound healing. Therefore, different release profiles from the same carrier may be particularly important in tissues with mixed cell populations such as in the periodontium, where similar tissues like bone and cementum grow at different rates. Furthermore, treatment of intrabony defects with BMPs are likely to not only require appropriate temporal release of the BMP(s), but also a carrier that can serve as a template for new tissue formation providing space maintenance and supporting the mucoperiosteal flap. Many of these issues have not been adequately addressed from a periodontal standpoint; therefore the purpose of this review is to clarify our current understanding of the factors that are likely to modulate the effects of BMP-induced periodontal regeneration. Moreover, assessing the importance of these factors is essential prior to conducting expensive human clinical trials.

Serum tryptase in allergic rhinitis: effect of cetirizine and fluticasone propionate treatment.

PURPOSE: A specific reaction against several kinds of inhalant allergens characterizes allergic rhinitis. Mast cells play a crucial role in the allergic inflammation releasing histamine and other mediators. Tryptase is considered to be a specific marker of mast cell activation. This study was devoted to evaluate the serum tryptase in allergic rhinitis and to evaluate the effect of cetirizine and fluticasone propionate on mast cell activation. 13 subjects, suffering from perennial allergic rhinitis induced by Dermatophagoides pteronyssinus, were studied. MATERIALS AND METHODS: Tryptase serum levels were detected by the fluoroenzymeimmunoassay (Pharmacia & Upjohn AB, Uppsala, Sweden). Blood samples were taken four times: before starting the study, after two weeks of 10 mg cetirizine treatment once a day, after two weeks of wash-out, and again after 15 days of 100 micrograms intranasal fluticasone propionate therapy twice a day. RESULTS: In allergic rhinitis, the basal values of serum tryptase (M +/- SD: 6.1 +/- 2.4 micrograms/l) were significantly higher than in controls (M +/- SD: 3.0 +/- 1.2 micrograms/l). After the antihistamine treatment, tryptase values (M +/- SD: 4.4 +/- 1.8 micrograms/l) decreased significantly (p < 0.001). After the stop of antihistamine treatment, tryptase levels increased (M +/- SD: 5.5 +/- 2.6 micrograms/l, p < 0.001). After the topical corticosteroid treatment, tryptase values decreased again significantly (M +/- SD: 4.5 +/- 3.1 micrograms/l, p < 0.04). CONCLUSIONS: All these data seem to confirm the effective action of cetirizine and fluticasone propionate on tryptase serum levels. While the action of corticosteroid is well known, the action of cetirizine is still to define, considering the recent reports on anti-inflammatory effect of the second generation of H1 receptor antagonists. Further studies are necessary to understand if the pharmacological effect on tryptase is a specific one of cetirizine, or if it is common to other anti-H1 molecules.