RESUMEN
Translocase MraY is the target for bacteriophage ÏX174 lysis protein E, which interacts via a protein-protein interaction mediated by Phe-288 and Glu-287 of E. coli MraY, and an Arg-Trp-x-x-Trp motif on protein E, also found in several cationic antimicrobial peptides. Analogues of Arg-Trp-octyl ester, found previously to show antimicrobial activity, were tested for antimicrobial activity, with Lys-Trp-oct (MIC50P. fluorescens 5 µg/mL) and Arg-Trp-decyl ester (MIC50P. fluorescens 3 µg/mL) showing enhanced antimicrobial activity. Synthesis and testing of α-helix peptidomimetic analogues for this motif revealed improved antibacterial activity (MIC50E. coli 4-7 µg/mL) for analogues containing two aromatic substituents, mimicking the Arg-Trp-x-x-Trp motif, and MraY inhibition (IC50 140 µM) by one such peptidomimetic. Investigation of mechanism of action using the Alamar Blue membrane permeabilisation assay revealed bacteriostatic and bacteriocidal mechanisms in different members of this set of compounds, raising the possibility of more than one biological target. The observed antimicrobial activity and MraY inhibition shown by peptidomimetic compounds confirms that this site could be targeted by drug-like molecules.
Asunto(s)
Antibacterianos/farmacología , Péptidos Antimicrobianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Peptidomiméticos/farmacología , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Péptidos Antimicrobianos/síntesis química , Péptidos Antimicrobianos/química , Proteínas Bacterianas/metabolismo , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-Actividad , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Proteínas Virales/metabolismoRESUMEN
Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4(+) cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ domain. PDZ domains are typically characterized by a defined globular structure, along with a peptide-binding site located in a groove between the αB and ßB structural elements and a highly conserved carboxylate-binding loop. In contrast to other reported PDZ domains, the solution structure previously reported for IL-16 reveals a tryptophan residue obscuring the recognition groove. We have solved the structure of the 14.1Fab fragment in complex with IL-16, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ domain. This involves the rotation of the αB-helix, accompanied movement of the peptide groove obscuring tryptophan residue, and consequent opening up of the binding site for interaction. Our study reveals a surprising mechanism of action for the antibody and identifies new opportunities for the development of IL-16-targeted therapeutics, including small molecules that mimic the interaction of the antibody.
Asunto(s)
Anticuerpos Monoclonales/química , Sitios de Unión de Anticuerpos , Fragmentos Fab de Inmunoglobulinas/química , Interleucina-16/química , Cristalografía por Rayos X , Humanos , Dominios Proteicos , Estructura Secundaria de ProteínaRESUMEN
In this article, we will review common pituitary disorders. There are 6 hormones secreted by the anterior pituitary gland: thyroid-stimulating hormone, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone, and prolactin. The posterior pituitary gland stores and releases the hormones made in the hypothalamus, oxytocin and antidiuretic hormone, based on the body's needs. This article will discuss the role of these hormones, conditions and symptoms that occur with elevated or reduced hormone levels, as well as the evaluation and treatment of these pituitary disorders.
Asunto(s)
Enfermedades de la Hipófisis , Humanos , Enfermedades de la Hipófisis/diagnóstico , Enfermedades de la Hipófisis/terapia , Tirotropina/sangre , Hormona Folículo Estimulante/metabolismo , Prolactina/metabolismo , Atención Primaria de Salud , Hormona Luteinizante/metabolismo , Hormona Adrenocorticotrópica/metabolismoRESUMEN
This article includes a review of information primary care physicians need to know direct their evaluation and treatment of thyroid disorders that include sick euthyroid, hyperthyroidism, hypothyroidism, and subclinical thyroid disorders.
Asunto(s)
Atención Primaria de Salud , Enfermedades de la Tiroides , Humanos , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/terapia , Atención Primaria de Salud/organización & administración , Hipertiroidismo/diagnóstico , Hipertiroidismo/terapia , Hipotiroidismo/diagnóstico , Hipotiroidismo/terapia , Hipotiroidismo/tratamiento farmacológico , Pruebas de Función de la TiroidesRESUMEN
A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach.
Asunto(s)
Diterpenos de Tipo Clerodano/química , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/químicaRESUMEN
OBJECTIVE: High altitude headache (HAH) is the most common neurological complaint at altitude and the defining component of acute mountain sickness (AMS). However, there is a paucity of literature concerning its prevention. Toward this end, we initiated a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya designed to compare the effectiveness of ibuprofen and acetazolamide for the prevention of HAH. METHODS: Three hundred forty-three healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. Outcome measures included headache incidence and severity, AMS incidence and severity on the Lake Louise AMS Questionnaire (LLQ), and visual analog scale (VAS). RESULTS: Two hundred sixty-five of 343 subjects completed the trial. HAH incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%; P = .95), and both agents were significantly more effective than placebo (45.3%; P = .01). AMS incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%; P = .34), and both agents were significantly more effective than placebo (28.6%; P = .03). In fully compliant participants, moderate or severe headache incidence was similar when treated with acetazolamide (3.8%) or ibuprofen (4.7%; P = .79), and both agents were significantly more effective than placebo (13.5%; P = .03). CONCLUSIONS: Ibuprofen and acetazolamide were similarly effective in preventing HAH. Ibuprofen was similar to acetazolamide in preventing symptoms of AMS, an interesting finding that implies a potentially new approach to prevention of cerebral forms of acute altitude illness.
Asunto(s)
Acetazolamida/administración & dosificación , Mal de Altura/complicaciones , Mal de Altura/prevención & control , Antiinflamatorios no Esteroideos/administración & dosificación , Cefalea/etiología , Cefalea/prevención & control , Ibuprofeno/administración & dosificación , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Cefalea/epidemiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Montañismo , Dimensión del Dolor , Placebos , Adulto JovenRESUMEN
A cleavable linker strategy has been used to optimise the enolate alkylation reactions of a recyclable L-tyrosine derived polymer-supported oxazolidin-2-one for the asymmetric synthesis of a series of chiral alpha-alkyl acids.
Asunto(s)
Oxazolidinonas/química , Polímeros/química , Alquilación , Espectroscopía de Resonancia MagnéticaRESUMEN
The reaction of a range of thiols with mono- and bis-glyoxamides derived from secondary anilines, triggers a new, connective Pummerer cyclisation process and leads to the formation of oxindoles.
Asunto(s)
Contractura de Dupuytren/etiología , Traumatismos de la Mano/etiología , Montañismo/lesiones , Traumatismos de los Tendones/etiología , Adulto , Contractura de Dupuytren/epidemiología , Contractura de Dupuytren/patología , Educación Médica Continua , Femenino , Traumatismos de los Dedos/epidemiología , Traumatismos de los Dedos/etiología , Traumatismos de los Dedos/patología , Fracturas Óseas/epidemiología , Fracturas Óseas/etiología , Fracturas Óseas/patología , Traumatismos de la Mano/epidemiología , Traumatismos de la Mano/patología , Humanos , Incidencia , Puntaje de Gravedad del Traumatismo , Imagen por Resonancia Magnética/métodos , Masculino , Pronóstico , Medición de Riesgo , Traumatismos de los Tendones/epidemiología , Traumatismos de los Tendones/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Priapism is a recognized complication of sickle cell anemia (SCA). When initial conventional treatments fail, simple or exchange blood transfusion has been advocated as a secondary intervention. However, recent literature suggests this may not be an effective therapy and may have significant neurologic sequelae. This paper reviews and summarizes the effectiveness and risks of blood transfusion compared with conventional priapism therapy. METHODS: All relevant papers identified from a MEDLINE search were systematically examined for data related to the use of blood transfusion in the setting of priapism due to SCA. The effectiveness of conventional therapy was compared with transfusion therapy using the outcome of "time to detumescence" (TTD). In addition, papers documenting adverse neurologic sequela were reviewed and summarized. RESULTS: Forty-two case reports were identified containing complete information with regard to patient age and TTD. The mean TTD was 8.0 days with conventional therapy (n = 16) and 10.8 days with blood transfusion therapy (n = 26). Adverse neurologic sequelae from blood transfusion therapy was described in 9 cases, with long term outcomes ranging from complete resolution to severe residual deficits. CONCLUSION: The current literature does not support the contention that blood transfusion is an effective therapy in the treatment of priapism due to SCA, as defined by an acceleration of TTD. In fact, numerous reports suggest that serious neurologic sequelae may result from this treatment. We feel the routine use of this therapy cannot be recommended.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Priapismo/terapia , Reacción a la Transfusión , Apnea/etiología , Bradicardia/etiología , Cefalea/etiología , Humanos , Masculino , Náusea/etiología , Paresia/etiología , Priapismo/etiología , Convulsiones/etiología , Accidente Cerebrovascular/etiologíaRESUMEN
In response to the dual challenges of increasingly risky target portfolios and realignment of traditional pharmaceutical company resources away from early-phase research and development (R&D), research groups have sought to engage across the industrial and not-for-profit divide, resulting in the emergence of many different collaborative models. Here, we describe two successful collaborations based upon shared commitment and risk. The risks and complexities of external collaboration can be mitigated by appropriate agreements and tools, but we found that it remains essential that the collaborating scientists adopt a collaborative mindset and embrace the diverse ways of working of partner organizations.
Asunto(s)
Investigación Biomédica/organización & administración , Conducta Cooperativa , Descubrimiento de Drogas , Química Farmacéutica , Industria Farmacéutica , Riesgo , UniversidadesRESUMEN
BACKGROUND: Propionibacterium acnes has been grown on culture in half of the reported cases of chronic infection associated with shoulder arthroplasty. The presence of this organism can be overlooked because its subtle presentation may not suggest the need for culture or because, in contrast to many orthopaedic infections, multiple tissue samples and weeks of culture incubation are often necessary to recover this organism. Surgical decisions regarding implant revision and antibiotic therapy must be made before the results of intraoperative cultures are known. In the present study, we sought clinically relevant prognostic evidence that could help to guide treatment decisions. METHODS: We statistically correlated preoperative and intraoperative observations on 193 shoulder arthroplasty revisions that were performed because of pain, loosening, or stiffness with the results of a Propionibacterium acnes-specific culture protocol. Regression models were used to identify factors predictive of a positive culture for Propionibacterium acnes. RESULTS: One hundred and eight of the 193 revision arthroplasties were associated with positive cultures; 70% of the positive cultures demonstrated growth of Propionibacterium acnes. The rate of positive cultures per shoulder increased with the number of culture specimens obtained from each shoulder. Fifty-five percent of the positive cultures required observation for more than one week. Male sex, humeral osteolysis, and cloudy fluid were each associated with significant increases of ≥ 600% in the likelihood of obtaining a positive Propionibacterium acnes culture. Humeral loosening, glenoid wear, and membrane formation were associated with significant increases of >300% in the likelihood of obtaining a positive Propionibacterium acnes culture. CONCLUSIONS: Preoperative and intraoperative factors can be used to help to predict the risk of a positive culture for Propionibacterium acnes. This evidence is clinically relevant to decisions regarding prosthesis removal or retention and the need for immediate antibiotic therapy at the time of revision shoulder arthroplasty before the culture results become available. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Asunto(s)
Artroplastia de Reemplazo/efectos adversos , Infecciones por Bacterias Grampositivas/diagnóstico , Propionibacterium acnes/aislamiento & purificación , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/cirugía , Articulación del Hombro/cirugía , Antibacterianos/uso terapéutico , Artroplastia de Reemplazo/métodos , Estudios de Cohortes , Intervalos de Confianza , Femenino , Estudios de Seguimiento , Infecciones por Bacterias Grampositivas/terapia , Humanos , Prótesis Articulares , Modelos Logísticos , Masculino , Análisis Multivariante , Oportunidad Relativa , Cuidados Preoperatorios/métodos , Falla de Prótesis , Radiografía , Reoperación/métodos , Estudios Retrospectivos , Medición de Riesgo , Articulación del Hombro/diagnóstico por imagen , Articulación del Hombro/fisiopatología , Resultado del TratamientoRESUMEN
Multiple-ligament injured knees resulting from knee dislocations are uncommon but serious injuries. These injuries can present to the emergency room acutely or in clinic on a delayed basis, but regardless of the setting they require a complete and detailed assessment to evaluate the extent of the injury. Complicating the diagnosis of a knee dislocation is the fact that acute knee dislocations often spontaneously reduce or are reduced by paramedics in the field before evaluation by a physician. In most cases, pain in the knee, a large knee effusion, and swelling of the effected limb are the only signs and symptoms of a knee dislocation. Quick and accurate assessment of these injuries is required to determine the presence of any limb threatening arterial injuries. In this chapter, we present the complete assessment of acute and chronic multiple ligament knee injuries.
Asunto(s)
Luxación de la Rodilla/diagnóstico , Ligamentos Articulares/lesiones , Enfermedad Aguda , Enfermedad Crónica , Humanos , Rodilla/irrigación sanguínea , Luxación de la Rodilla/clasificación , Luxación de la Rodilla/etiología , Masculino , Dolor/diagnóstico , Traumatismos de los Tejidos Blandos/diagnósticoRESUMEN
STUDY DESIGN: Retrospective clinical series. OBJECTIVE: Description of alternative technique for the harvesting of posterior iliac crest bone graft (ICBG) and assessment of associated morbidity. SUMMARY OF BACKGROUND DATA: Although posterior ICBG operations are common, they are often reported to result in significant morbidity. A recent emphasis on the morbidity of ICBG has helped to fuel the costly growth in clinical use of alternatives, such as bone morphogenetic protein-2. Many studies have reported a variety of complications related to iliac crest donor sites, but the most common reported morbidity is pain and/or decreased sensation over the ICBG site. METHODS: This study is a retrospective review of all patients in the practice of the senior author (T.F.A.) during the study period who received a lumbar fusion with autogenous bone harvested from the posterior iliac crest and accessed by the surgical approach described. Outcomes were assessed by a pain questionnaire determining the site of pain and its magnitude on visual analog scale. Pain on the harvested side was compared with that on the contralateral side, and overall procedure satisfaction was assessed. Statistical analysis was performed using analysis of variance, the Pearson chi2 test, and the Student t test. Any value of P < 0.05 was considered significant. RESULTS: Of 120 patients eligible for the study, 92 patients (77%) were available for follow-up. The patients were interviewed on an average of 24 months (+/-14 months) after their operation. The vast majority of patients (88%, n = 81) had no significant difference in pain or had less pain over the ICBG site than the contralateral side. Eleven patients (12%) experienced significantly greater pain at the ICBG site than over the contralateral side (visual analog scale difference >1). There were 7 patients (8%) in the series with significantly greater pain over the contralateral iliac crest than at the ICBG site. The likelihood of significant pain over the harvested ICBG site was not statistically greater than the likelihood of contralateral iliac crest pain (P = 0.23). One patient (1%) had sensory loss in the superior cluneal nerve distribution. There was 1 patient with an infection that involved the ICBG site and required irrigation and debridement and intravenous antibiotics. Seventy-two patients (78%) stated that they were very satisfied with the operation, 13 (14%) were somewhat satisfied, and 7 (8%) were not satisfied. CONCLUSION: Although it is difficult to directly compare our results to those reported in other studies, we conclude that the rate of significant chronic sequelae related to this method of harvesting bone from the posterior iliac crest is low. Our findings may be due to the avoidance in this technique of disruption of the gluteal musculature and preservation of the lateral wall of the ilium. The methods used in other studies to estimate the prevalence of chronic pain related to posterior iliac crest bone grafting after lumbar spinal surgery may grossly overestimate this prevalence.
Asunto(s)
Trasplante Óseo/métodos , Ilion/trasplante , Fusión Vertebral/métodos , Adulto , Anciano , Anciano de 80 o más Años , Nalgas , California/epidemiología , Femenino , Humanos , Vértebras Lumbares/cirugía , Masculino , Persona de Mediana Edad , Morbilidad , Evaluación de Resultado en la Atención de Salud/métodos , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Satisfacción del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Fusión Vertebral/efectos adversos , Vértebras Torácicas/cirugíaAsunto(s)
Comités de Ética Clínica , Comités de Ética , Hospitales , Jurisprudencia , Responsabilidad Legal , Confidencialidad , Toma de Decisiones , Nutrición Enteral , Eutanasia Pasiva , Objetivos , Humanos , Legislación como Asunto , Apoyo Nutricional , Política Organizacional , Atención al Paciente , Revisión por Pares , Competencia Profesional , Pronóstico , Registros , Estándares de Referencia , Gobierno Estatal , Negativa del Paciente al Tratamiento , Estados Unidos , Privación de TratamientoRESUMEN
Treatment of beta-vinyl-beta-hydroxy-N-acyloxazolidin-2-ones with VO(acac)(2) and tert-butyl hydroperoxide results in formation of unstable epoxides that are ring-opened by intramolecular nucleophilic attack of their exocyclic carbonyl fragments to afford highly functionalized trisubstituted hydroxy-gamma-butyrolactones in >95% de, with a polymer-supported oxazolidin-2-one having been used to transfer this methodology to the solid phase.
Asunto(s)
4-Butirolactona/análogos & derivados , 4-Butirolactona/síntesis química , Técnicas Químicas Combinatorias , Oxazolidinonas/química , 4-Butirolactona/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
OBJECTIVE: Cuzco, Peru, is host to a dangerous mix of high altitude and rapid access from low elevation, which results in a high prevalence of acute mountain sickness (AMS). Thus, it is important that travelers entering Cuzco understand the basics of AMS. To this end, we assessed travelers' awareness of AMS, especially the resources used to obtain this knowledge. With this information we make recommendations with regard to better avenues for distribution of AMS information. METHODS: One hundred foreign travelers, representing an international population, completed a 45-item written questionnaire that was subsequently analyzed. RESULTS: Over half of the respondents (51%) rated their knowledge of AMS as "low" or "none." Furthermore, very few respondents knew about acetazolamide (Diamox) as prophylaxis for (9%) or treatment of AMS (5%). People who consulted physicians for AMS information were more likely to know about the utility of acetazolamide than those who depended on a guidebook (P = .0266) but were less likely to correctly identify the symptomatology of AMS (P = .047). While AMS knowledge was poor, the majority of travelers (90%) indicated compliance with recommended pretravel vaccinations. CONCLUSIONS: This survey adds to the body of knowledge that indicates a lack of AMS knowledge among travelers. In addition, this survey identifies 2 potential avenues for improved dispersal of information: 1) guidebooks for countries of concern and 2) national health agency Web sites linked to information on pretravel vaccinations. Recommendations are made to utilize these commonly accessed resources to increase AMS information distribution to the general populous.
Asunto(s)
Acetazolamida/uso terapéutico , Mal de Altura/prevención & control , Mal de Altura/psicología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Conocimientos, Actitudes y Práctica en Salud , Viaje , Femenino , Educación en Salud , Humanos , Masculino , Perú , Encuestas y Cuestionarios , VacunaciónRESUMEN
A polymer-supported analytical construct was used to quantify the reactivity of a range of monomers in the Ugi four-component condensation using positive electrospray ionization mass spectrometry (MS) as a quantitative analytical tool. The construct incorporated a bromo group to act as a peak splitter and a quaternary ammonium to act as a MS sensitizer and ionization leveler, thereby allowing direct quantitation of the cleaved adducts by MS. The relative reactivities of 10 carboxylic acids were quantified by the relative levels of product generated as determined by MS and 10 isonitriles, and 10 aldehydes were investigated in the same way. The effect of concentration variations on monomers reactivity and product profiles were rapidly determined using this approach, and the method opens up the way for studying, in a single pot, multiple reactions with a broad range of monomers under identical and self-consistent reaction conditions.