Mortalidad de los médicos en Honduras, 2001-2015 / Doctor's Mortality in Honduras, 2001- 2015

Existen reportes con diversos propósitos sobre las causas de mortalidad del profesional médico. Objetivo: Caracterizar las causas de muerte de los médicos fallecidos en Honduras en el período 2001-2015. Material y métodos: Estudio retrospectivo descriptivo, del 1 de enero 2001 al 31 de diciembre 2015. La muestra del estudio fueron 408 médicos fallecidos, según la base de datos del Colegio Médico de Honduras. Variables estudiadas: edad, sexo y causas de muerte. Se cotejaron las bases de datos del Colegio Médico de Honduras, Registro Nacional de las Personas, Instituto Nacional de Estadísticas y Dirección de Medicina Forense. Se catalogaron las causas de muerte reportadas según Clasificación Internacional de Enfermedades, CIE-10, 2008. Resultados: 408 médicos fallecidos, 365(89.5%) hombres y 43(10.5%) mujeres; la edad promedio al fallecimiento: hombres 69 años y mujeres 51. Las causas de muerte por su orden: cardiovasculares 117(28.7%), neoplasias malignas 90(22%), 76(18.6%) por causas externas, entre ellas, accidentes automovilísticos, homicidios y suicidios, diabetes mellitus 39(9.6%) y cirrosis hepática 20 (4.9%). Conclusiones: el 50.7% de las muertes de los médicos en Honduras, del 2001 al 2015 ocurrieron por enfermedades cardiovasculares y cáncer. Las causas externas y la diabetes mellitus tienen un papel importante en la mortalidad. La enfermedad cardiovascular predominó en el sexo masculino...(AU)

Effect of the addition of insulin-transferrin-selenium and/or L-ascorbic acid to the in vitro maturation of prepubertal bovine oocytes on cytoplasmic maturation and embryo development.

This study examines the effects of adding insulin-transferrin-selenium (ITS) and/or L-ascorbic acid (ASC) to a conventional medium for maturing prepubertal calf oocytes on chromosome organization, cortical granule (CG) distribution, and embryo development to the blastocyst stage. Cumulus-oocyte complexes (COCs) were matured in medium TCM 199 containing PVA and EGF (control), and supplemented with ITS and/or ASC for 12 or 24 h at 38.5 °C in a 5% CO(2) atmosphere. Calf oocytes matured with ITS + ASC or ASC for 12 h showed significantly higher percentages of peripherally distributed CG (83.3% and 86.2% respectively) than control oocytes (71.4%) or those matured with ITS alone (71.4%). No effects on chromosome organization were detected. Conversely, 24 h of supplementation did not affect CG distribution patterns, while the addition of ASC gave rise to significantly higher percentages of oocytes showing a normal alignment of their chromosomes (72.9%) compared to controls (58.7%). At 48 hpi, similar cleavage rates were observed among treatments regardless of the treatment time. However, the presence of ITS + ASC for 12 h rendered significantly higher blastocyst rates than those recorded in the remaining groups. Supplementation for 24 h with ITS or ITS + ASC had no significant effects on the percentage of blastocysts obtained, while the presence of ASC significantly reduced the proportions of embryos developing to the blastocyst stage. Our data suggest that ITS plus L-ascorbic acid supplementation during the first 12 h of in vitro maturation improves cytoplasm maturation and the developmental competence of embryos produced from prepubertal calf oocytes.

Queratodermias palmoplantares adquiridas: revisión bibliográfica / Acquired palmoplantar keratoderma: bibliographic review

Las queratodermias palmo plantares son un grupo diverso de trastornos caracterizados por el engrosamiento anormal de la piel de las palmas y pantas, que puede ser hereditario o adquirido. Este últimos se define como una hiperqueratosis no hereditaria, no friccionar, de las palmas y/o las plantas que afecta al 50% o más de estas superficies ocrales. Es un trastorno de múltiples etiologías, entre las cuales destacan: el climaterio, asociada a malignidad, a otras dermatosis, acuagénica, causada por infecciones, asociada a medicamentos, a enfermedades sistémicas, y la hiperqueratosis palmo plantar filiforme (queratodemia espinosa). El tratamiento tiende a ser sintomático y puede variar desde medidas simples a queratoliticos tópicos, retinoides sistémicos o cirugía reconstructiva. En algunas queratodermias especificas, como la climatérica y aquellas asociadas a hipotiroidismo, el tratamiento indicado es el reemplazo hormonal, y en las asociadas a malignidad, la extirpación del tumor habitualmente produce la mejoría de to hiperqueratosis.

Palmoplantar keratodermas are a diverse group of disorders characterized by an abnormal thickening of the skin of the palms and soles, which can be hereditary or acquired. The last form above mentioned is defined as a non-hereditary, non-frictional hyperkeratosis of the palms and/or soles that involves 50 percent or more of the surface of these acral areas. This is a disorder produced by multiple causes, among which highlight climacteric, associated with malignancies, related with another dermatoses, aquagenic, infectious, drug-related, related with systemic disease and palmar/plantar filiform hyperkeratosis (spiny keratoderma). Treatment tends to be symptomatic and may vary from simple advices to topical keratolytics, systemic retinoids or reconstructive surgery. In some specific keratodermas like the climacteric one and in those associated with hypothyroidism the recommended treatment corresponds to hormonal replacement and in those associated with malignancies the removal of the tumor usually results in improvement of the hyperkeratosis.

Terapia fotodinámica: aplicación en dos pacientes con metástasis endobronquiales de adenocarcinoma extrapulmonar / Photodynamic therapy: application in 2 patients with extrapulmonary adenocarcinoma and endobronchial metastases

La terapia fotodinámica consiste en la administración de un fármaco fotosensibilizante (generalmente derivado de la hematoporfirina), que se ávida y especialmente captado por las células tumorales. Posteriormente se aplica una fotoestimulación con láser con una potencia y una longitud de onda previamente establecidas por medio de una broncoscopía flexible. Con este método se generan moléculas con oxígeno en estado excitado de singlete, produciendo una serie de cambios estructurales que llevan a la destrucción celular²,ü. Basándose en este principio se ha utilizado esta terapia en multiples parénquimas: piel, esófago, veliga, retina y árbol bronquial entre otros. En relacion a este último, la evidencia publicada favorece a esta técnica por inducir períodos prolongados de permeabilizacion de tumores bronquiales obstructivos, en cánceres no de células pequeñas y metástasis endobronquiales de cánceres primarios de otro origen4. En esta primera experiencia nacional presentamos dos pacientes en etapas avanzadas de adenocarcinoma extrapulmonar con metastasis endobronquial. En ambas pacientes (la primera con un cáncer de colon y la segunda con un cáncer de mama), hemos conseguido permeabilización bronquial satisfactoria y prolongada del árbol bronquialderecho, por períodos de 5 y 3 meses respectivamente. El inicio de esta terapia en nuestro país ha continuado con otras aplicaciones exitosas realizadas por nuestro grupo en esófago y en piel, creando un área de trabajo y estudio en este campo. Revisamos además su fundamento teórico y su forma de aplicación

Tratamiento actual del rabdomiosarcoma pediátrico en Chile: presentación de 2 casos clínicos / Treatment of rhabdomyosarcoma in chilean children: a report of 2 cases

Introducción: El tratamiento del rabdomiosarcoma (RMS) es multidiciplinario. La radioterapia tiene un rol fundamental. los estudios internacionales como el de International Rhabdomysarcoma Study Group (IRSG) demostraron que la radioterapia moderna, conformacional, tiene un impacto en términos de control local y de sabrevida global de los pacientes. Los resultados publicados en el ámbito nacional son claramente inferiores a los internacionles. Creemos que la técnica de radioterapia empleada puede ser en parte responsable de estos resultados. Objetivo: mostrar las distintas modalidades de radioterapia disponibles actualmente en nuestro pais para este tipo de patología y destacar la importacia de utilizar técnicas modernas. Material y método: análisis retrospectivo de un caso representativo para cada una de las modalidades de radioterapia moderna, branquiterapia y radioterapia conformacional. Conclusiones: actualmente es factible utilizar radioterapia utilizando los mismos criterios de calidad que el IRSG en todos los pacientes portadores de rebdomiosarcoma en Chile. Esto debiera repercutir en el control local y sobrevida, permitiéndolos alcanzar valores más cercanos a los descritos en la literatura

DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).

Synthesis and evaluation of novel quinolinones as HIV-1 reverse transcriptase inhibitors.

A series of 4,4-disubstituted quinolinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The C-3 substituted compound 9h displayed improved antiviral activity against clinically significant single (K103N) and double (K103N/L100I) mutant viruses.

Synthesis and evaluation of efavirenz (Sustiva) analogues as HIV-1 reverse transcriptase inhibitors: replacement of the cyclopropylacetylene side chain.

Two series of efavirenz analogues have been developed: one in which the cyclopropane ring has been replaced by small heterocycles and another in which the entire acetylenic side chain has been replaced by alkyloxy groups. Several members of both series show equivalent potency to efavirenz against both wild-type virus and the key K103N mutant.

Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy.

Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.

4,1-Benzoxazepinone analogues of efavirenz (Sustiva) as HIV-1 reverse transcriptase inhibitors.

A series of 4,1-benzoxazepinone analogues of efavirenz (Sustiva) as potent NNRTIs has been discovered. The cis-3-alkylbenzoxazepinones are more potent then the trans isomers and can be synthesized preferentially by a novel stereoselective cyclization. The best compounds are potent orally bioavailable inhibitors of both wild-type HIV-1 and its clinically relevant K103N mutant virus, but are highly protein-bound in human plasma.

Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor efavirenz.

Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.

Trifluoromethyl-containing 3-alkoxymethyl- and 3-aryloxymethyl-2-pyridinones are potent inhibitors of HIV-1 non-nucleoside reverse transcriptase.

3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the most potent compound 24 exhibiting an IC90 = 32 nM. Compound 24 also possessed a potent resistance profile as demonstrated by submicromolar IC90s against several clinically meaningful mutant virus strains.

3,3a-Dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones are potent non-nucleoside reverse transcriptase inhibitors.

A series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione were found to be HIV-1 non-nucleoside reverse transcriptase inhibitors. One of these compounds, as the racemate, possessed an IC90 = 4.6 nM against wild-type virus in a whole cell antiviral assay and had an IC90 = 76 and 897 nM against the clinically significant K103N and K103N/L100I mutant viruses, respectively.

Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease.

BACKGROUND: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. RESULTS: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. CONCLUSIONS: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.

Synthesis and evaluation of quinoxalinones as HIV-1 reverse transcriptase inhibitors.

A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X.

Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors.

A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.

Novel 2,2-dioxide-4,4-disubstituted-1,3-H-2,1,3-benzothiadiazines as non-nucleoside reverse transcriptase inhibitors.

Benzothiadiazine non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV have been synthesized via a novel process to afford active inhibitors, with the most potent compound exhibiting an IC90 = 180 nM in a whole cell assay. The 2,2-dioxide-1H-2,1,3-benzothiadiazine ring system was constructed in one step from 2-amino-5-chlorobenzonitrile.

Unsymmetrical cyclic ureas as HIV-1 protease inhibitors: novel biaryl indazoles as P2/P2' substituents.

The preparation of unsymmetrical cyclic ureas bearing novel biaryl indazoles as P2/P2' substituents was undertaken, utilizing a Suzuki coupling reaction as the key step. Compound 6i was equipotent to the lead compound of the series SE063.

Synthesis and evaluation of benzoxazinones as HIV-1 reverse transcriptase inhibitors. Analogs of Efavirenz (SUSTIVA).

Two series of benzoxazinones differing in the aromatic substitution pattern were prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The 5-fluoro (5a-d) and 6-nitro (5e-h) substituted compounds displayed activity comparable or better than Efavirenz, the lead structure of the series.

Synthesis and evaluation of analogs of Efavirenz (SUSTIVA) as HIV-1 reverse transcriptase inhibitors.

Efavirenz (SUSTIVA) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro (4f) and the 6-methoxy (4m) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.