Cascade Synthesis of Fluorinated Spiroheterocyclic Scaffolding for Peptidic Macrobicycles.

Octafluorocyclopentene (OFCP) engages linear, unprotected peptides in polysubstitution cascades that generate complex fluorinated polycycles. The reactions occur in a single flask at 0-25 °C and require no catalysts or heavy metals. OFCP can directly polycyclize linear sequences using native functionality, or fluorospiroheterocyclic intermediates can be intercepted with exogenous nucleophiles. The latter tactic generates molecular hybrids composed of peptides, sugars, lipids, and heterocyclic components. The platform can create stereoisomers of both single- and double-looped macrocycles. Calculations indicate that the latter can mimic diverse protein surface loops. Subsets of the molecules have low energy conformers that shield the polar surface area through intramolecular hydrogen bonding. A significant fraction of OFCP-derived macrocycles tested show moderate to high passive permeability in parallel artificial membrane permeability assays.

Hyper-Cross-Linked Porous Polymer Featuring B-N Covalent Bonds (HCP-BNs): A Stable and Efficient Metal-Free Heterogeneous Photocatalyst.

The first example of a porous polymer containing B-N covalent bonds, prepared from a tetraphene B-N monomer and biphenyl as a comonomer, is reported. It was prepared using the solvent knitting strategy, which allows the connection between the aromatic rings of the two monomers through methylene groups provided by an external cross-linking agent. The new polymer exhibited micromeso porosity with an SBET of 612 m2/g, high thermal stability, and potential properties as a heterogeneous photocatalyst, since it is very active in the aza-Henry coupling reaction (>98% of conversion and selectivity). After the first run, the catalyst improves its photocatalytic activity, shortening the reaction time to only 2 h and maintaining this activity in successive runs. The presence of a radical in this structure that remains stable with successive runs makes it a new type of material with potential applications as a highly stable and efficient photocatalyst.

Efectividad y seguridad de antirretrovirales para terapia de cambio en virus de la inmunodeficiencia humana

RESUMEN Introducción: El aumento de la expectativa de vida en personas que viven con VIH ha obligado a buscar alternativas de terapia antiretroviral simplificadas y con menor potencial de toxicidad que favorezcan la adherencia, y con ello alcanzar metas de indetectabilidad de la carga viral. Varias alternativas se han propuesto en los últimos años y es necesario saber la efectividad de estas a mediano y largo plazo. Objetivo: Determinar la efectividad y seguridad de la terapia de cambio, en pacientes mayores a 12 años que viven con el virus de la inmunodeficiencia humana. Métodos: Se realizó la búsqueda de la literatura en bases de datos electrónicas y literatura gris. La medida de desenlaces para mantenimiento de carga viral (menos de 50 copias por mililitro), niveles de linfocitos T CD4+ y eventos adversos de la terapia de cambio frente a continuación de la terapia estándar se estimó de forma combinada. Resultados: Se incluyeron seis ensayos clínicos aleatorizados que compararon terapia de cambio (Rilpivirina/Emtricitabina/Tenofovir alafenamida, Dolutegravir/Rilpivirina, Abacavir/Dolutegravir/Lamivudina), frente a la continuación de la terapia estándar. El mantenimiento de la carga viral no fue diferente entre los grupos (OR: 0,77; IC95% 0,59; 1,02), tampoco el recuento de linfocitos T CD4+ (DME: 6;76; IC95% -5,05;18,57), al igual que los eventos adversos serios (OR: 1,03; IC95% 0,74; 1,42). Conclusiones: No se encontró diferencia en la efectividad y seguridad de la terapia de cambio frente a continuar la terapia estándar. Los resultados apoyan en uso de estas estrategias terapéuticas para favorecer la adherencia a la terapia antirretroviral.

ABSTRACT Introduction: Increase in the life expectancy of people living with HIV has led to the search for simplified antiretroviral therapy alternatives of lower toxicity potential which foster adherence and thus contribute to achieve viral load undetectability goals. Several options have been proposed in recent years, and it is necessary to be aware of their mid- and long-term effectiveness. Objective: Determine the effectiveness and safety of switch therapy in patients aged over 12 years who live with the human immunodeficiency virus. Methods: A bibliographic search was conducted in electronic databases and the gray literature. Combined estimation was made of the measure of outcomes for viral load maintenance (less than 50 copies per milliliter), CD4+ T lymphocyte levels and adverse events of switch therapy versus continuing standard therapy. Results: Six randomized clinical trials were included which compared switch therapy (rilpivirine / emtricitabine / tenofovir alafenamide, dolutegravir / rilpivirine, abacavir / dolutegravir / lamivudine) with continuing standard therapy. Viral load maintenance was not different between the groups (OR: 0.77; CI 95% 0.59, 1.02), nor was there any difference in the CD4+ T lymphocyte count (DME: 6.76; CI 95% -5.05;18.57) or the serious adverse events (OR: 1.03; CI 95% 0.74; 1.42). Conclusions: Differences were not found in the effectiveness and safety of switch therapy versus continuing standard therapy. Results support the use of these therapeutic strategies to foster adherence to antiretroviral therapy.

1,10a-Dihydro-1-aza-10a-boraphenanthrene and 6a,7-Dihydro-7-aza-6a-boratetraphene: Two New Fluorescent BN-PAHs.

Previously unknown 1,10a-dihydro-1-aza-10a-boraphenanthrene and 6a,7-dihydro-7-aza-6a-boratetraphene have been efficiently synthesized. Bromination of these BN-PAHs proceeds with complete regioselectivity, resulting in the formation of different substituted derivatives via cross-coupling reactions. These compounds exhibit rather high fluorescence quantum yields (up to ϕF = 0.80).

The Role of Bmp- and Fgf Signaling Modulating Mouse Proepicardium Cell Fate.

Bmp and Fgf signaling are widely involved in multiple aspects of embryonic development. More recently non coding RNAs, such as microRNAs have also been reported to play essential roles during embryonic development. We have previously demonstrated that microRNAs, i.e., miR-130, play an essential role modulating Bmp and Fgf signaling during early stages of cardiomyogenesis. More recently, we have also demonstrated that microRNAs are capable of modulating cell fate decision during proepicardial/septum transversum (PE/ST) development, since over-expression of miR-23 blocked while miR-125, miR-146, miR-223 and miR-195 enhanced PE/ST-derived cardiomyogenesis, respectively. Importantly, regulation of these microRNAs is distinct modulated by Bmp2 and Fgf2 administration in chicken. In this study, we aim to dissect the functional role of Bmp and Fgf signaling during mouse PE/ST development, their implication regulating post-transcriptional modulators such as microRNAs and their impact on lineage determination. Mouse PE/ST explants and epicardial/endocardial cell cultures were distinctly administrated Bmp and Fgf family members. qPCR analyses of distinct microRNAs, cardiomyogenic, fibrogenic differentiation markers as well as key elements directly epithelial to mesenchymal transition were evaluated. Our data demonstrate that neither Bmp2/Bmp4 nor Fgf2/Fgf8 signaling is capable of inducing cardiomyogenesis, fibrogenesis or inducing EMT in mouse PE/ST explants, yet deregulation of several microRNAs is observed, in contrast to previous findings in chicken PE/ST. RNAseq analyses in mouse PE/ST and embryonic epicardium identified novel Bmp and Fgf family members that might be involved in such cell fate differences, however, their implication on EMT induction and cardiomyogenic and/or fibrogenic differentiation is limited. Thus our data support the notion of species-specific differences regulating PE/ST cardiomyogenic lineage commitment.

Expanding the BN-embedded PAH family: 4a-aza-12a-borachrysene.

Previously unknown 4a-aza-12a-borachrysene has been synthesized in only four steps. The reactions of this BN-embedded PAH with bromine and organolithium compounds proceed with complete regioselectivity, resulting in the formation of nine derivatives. One of these, a phenylalkynyl-substituted derivative, exhibits a remarkably high fluorescence quantum yield (ΦF = 0.68).

Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and Squaramides.

4-Vinylphenyl-substituted squaramides have been tested as organocatalysts for the diastereo- and enantioselective synthesis of trisubstituted benzopyrans via an oxa-Michael intramolecular nitro-Michael cascade reaction. Both the enantio- and diastereoselection were good to moderate, depending on the nature of the chiral scaffold in the catalyst. The diastereoselection is better for the most active catalyst because the final products epimerize at C-3 along the time. Supported squaramide sq-9 prepared by copolymerization of sq-4 with styrene and divinylbenzene is also effective in promoting the cascade reaction, and it is recoverable and reusable for five cycles maintaining the activity.

Síndrome de QT largo secundario a hipocalcemia / Long - QT Syndrome Secondary to Hypocalcemia

El síndrome de QT largo es causa de muerte súbita por arritmias ventriculares y puede ser de origen congénito o adquirido. Entre las causas adquiridas, las más frecuentes son los trastornos iónicos y los fármacos. En esta presentación se describe el caso de una paciente con síndrome de QT largo secundario a hipocalcemia por hipoparatiroidismo primario. Es indispensable la detección de posibles causas secundarias y reversibles de síndrome de QT largo, que son más frecuentes que el origen genético, dado que tienen tratamiento etiológico eficaz y se evitan medidas diagnósticas y terapéuticas innecesarias.

Long-QT syndrome is a congenital or acquired disorder that produces sudden death due to ventricular arrhythmias. Electrolyte disturbances and medications are the most common causes of acquired long-QT syndrome. We describe the case of a patient with long-QT syndrome secondary to hypocalcemia caused by primary hypoparathyroidism. The secondary causes of long-QT syndrome should be thoroughly examined as they are more common than the genetic causes. Also, as they are reversible with adequate etiological treatment, their correct identification avoids unnecessary diagnostic and therapeutic measures.

Genetic testing of patients with long QT syndrome.

Congenital long QT syndrome is mainly caused by mutations in the KCNQ1, KCNH2 and SCN5A genes. The aim of this study was to investigate the prevalence of mutations in these three genes in patients with long QT syndrome or idiopathic ventricular fibrillation seen at our center. The study included nine patients with long QT syndrome and four with idiopathic ventricular fibrillation. The first-degree relatives of genotype-positive probands were also investigated. Missense mutations were found in seven patients with long QT syndrome and two with idiopathic ventricular fibrillation. Overall, 71.4% of mutations were in KCNH2 and 28.6% were in SCN5A. No mutations in KCNQ1 were found. Only two mutations had been previously observed. Mutations were also found in six of the 19 relatives studied. In conclusion, our initial experience shows that genetic testing had a high sensitivity for diagnosing long QT syndrome. Mutations were found most frequently in the KCNH2 gene.

Estudio genético en el síndrome de QT largo en nuestro medio / Genetic testing of patients with long QT syndrome

El síndrome de QT largo congénito tiene su causa principal en mutaciones de los genes KCNQ1, KCNH2 y SCN5A. Nos proponemos analizar la prevalencia de mutaciones en estos genes en nuestra serie de pacientes con síndrome de QT largo y fibrilación ventricular idiopática. Se incluyó a 9 pacientes con síndrome de QT largo y 4 con fibrilación ventricular idiopática. Se estudió a los familiares de primer grado de los probandos con genotipo positivo. Encontramos mutaciones missense en 7 pacientes con síndrome de QT largo y en 2 con fibrilación ventricular idiopática. El 71,4% de las mutaciones fueron en KCNH2 y el 28,6% en SCN5A. No se halló ninguna mutación en KCNQ1. Sólo dos mutaciones estaban previamente descritas. En 6 familiares de los 19 estudiados se encontró una mutación. En conclusión, en nuestra experiencia inicial el estudio genético tuvo una alta sensibilidad para el diagnóstico de síndrome de QT largo. El gen más frecuentemente mutado fue KCNH2 (AU)

Congenital long QT syndrome is mainly caused by mutations in the KCNQ1, KCNH2 and SCN5A genes. The aim of this study was to investigate the prevalence of mutations in these three genes in patients with long QT syndrome or idiopathic ventricular fibrillation seen at our center. The study included nine patients with long QT syndrome and four with idiopathic ventricular fibrillation. The first-degree relatives of genotype-positive probands were also investigated. Missensemutationswere found in seven patients with long QT syndrome and two with idiopathic ventricular fibrillation. Overall, 71.4% of mutations were in KCNH2 and 28.6% were in SCN5A. No mutations in KCNQ1 were found. Only two mutations had been previously observed. Mutations were also found in six of the 19 relatives studied. In conclusion, our initial experience shows that genetic testing had a high sensitivity for diagnosing long QT syndrome. Mutations were found most frequently in the KCNH2 gene (AU)

Microbiologic evaluation of skin wounds: alarming trend toward antibiotic resistance in an inpatient dermatology service during a 10-year period.

BACKGROUND: Increasing resistance to commonly used antibiotics has been seen for patients with superficial skin wounds and leg ulcers. OBJECTIVES: We sought to evaluate bacterial isolates from leg ulcers and superficial wounds for resistance to commonly used antibiotics and to compare current data with previous data. METHODS: We performed a chart review for patients admitted to a tertiary care dermatology inpatient unit from January to December 2001. Comparison was made with 2 previous surveys of the same inpatient service from 1992 and 1996. RESULTS: Bacterial isolates were cultured from 148 patients, 84% (72 of 86) with leg ulcers and 38% (76 of 202) with superficial wounds. Staphylococcus aureus and Pseudomonas aeruginosa were the most common bacterial isolates in both groups. For patients with leg ulcers, S aureus grew in 67% of isolates (48/72) of which 75% (36/48) were methicillin-resistant (MRSA). Of leg ulcers, 35% (25/72) grew P aeruginosa, which was resistant to quinolones in 56% of cultures (14/25). For patients with superficial wounds, S aureus was isolated in 75% (57/76) and 44% were MRSA (25/57). P aeruginosa grew in 17% of isolates (13/76) and was resistant to quinolones in 18%. We found a marked increase in antibiotic resistance for both leg ulcers and superficial wounds. Over time, MRSA increased in leg ulcers from 26% in 1992 to 75% in 2001. For superficial wounds, MRSA increased from 7% in 1992 to 44% in 2001. P aeruginosa resistance to quinolones in leg ulcers increased from 19% in 1992 to 56% in 2001, whereas for superficial wounds there was no resistance in 1992 and 18% resistance in 2001. CONCLUSION: Rapid emergence of antibiotic-resistant bacteria continues and is a problem of increasing significance in dermatology. Common pathogenic bacteria, S aureus and P aeruginosa, showed increased resistance to commonly used antibiotics. Selection of antibiotics should be on the basis of local surveillance programs.

Hypocomplementemic urticarial vasculitis with angioedema, a rare presentation of systemic lupus erythematosus: rapid response to rituximab.

We report a case of hypocomplementemic urticarial vasculitis and recurrent angioedema in a patient with systemic lupus erythematosus unresponsive to mycophenolate mofetil, high-dose methylprednisolone, and intravenous immunoglobulin that responded rapidly to rituximab. Rituximab is a monoclonal antibody against CD20 transmembrane protein on the surface of mature and malignant B cells. No adverse effects occurred during or after therapy, and the patient was discharged from the hospital for outpatient rituximab infusion and follow-up care.

Managing the patient with venous ulcers.

Venous disease is the most common cause of leg ulcers. The refractory nature of venous ulcers affects the quality of life and work productivity of those persons afflicted. This, in combination with the high costs of long-term therapy, makes venous ulcers a major health problem in developed countries. Management of venous leg ulcers is based on understanding pathophysiologic abnormalities. In recent years, identifying prognostic factors for healing and developing novel therapeutic approaches for venous ulcers have offered valuable tools for the management of patients with this disorder.

Aspectos básicos en la cicatrización de las heridas / Basic science aspects in wound healing

El campo de la cicatrización de heridas ha despertado gran interés entre investigadores en años recientes, y esto ha llevado a un aumento en el conocimiento en esta área tanto en el campo de las ciencias básicas como clínicas. En este artículo se describirán en detalle las tres fases del proceso de cicatrización: la etapa de inflamación, la etapa de proliferación y formación de tejidos, y la etapa de remodelación.Finalmente se describirá la clasificación clínica de heridas, basados en tiempo y modo de cicatrización (AU)