Sequential Flash NanoPrecipitation for the scalable formulation of stable core-shell nanoparticles with core loadings up to 90.

Flash NanoPrecipitation (FNP) is a scalable, single-step process that uses rapid mixing to prepare nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Because the two steps of particle self-assembly - (1) core nucleation and growth and (2) adsorption of a stabilizing polymer onto the growing core surface - occur simultaneously during FNP, nanoparticles formulated at core loadings above approximately 70% typically exhibit poor stability or do not form at all. Additionally, a fundamental limit on the concentration of total solids that can be introduced into the FNP process has been reported previously. These limits are believed to share a common mechanism: entrainment of the stabilizing polymer into the growing particle core, leading to destabilization and aggregation. Here, we demonstrate a variation of FNP which separates the nucleation and stabilization steps of particle formation into separate sequential mixers. This scheme allows the hydrophobic core to nucleate and grow in the first mixing chamber unimpeded by adsorption of the stabilizing polymer, which is later introduced to the growing nuclei in the second mixer. Using this Sequential Flash NanoPrecipitation (SNaP) technique, we formulate stable nanoparticles with up to 90% core loading by mass and at 6-fold higher total input solids concentrations than typically reported.

Chemorepellent-Loaded Nanocarriers Promote Localized Interference of Escherichia coli Transport to Inhibit Biofilm Formation.

To mitigate antimicrobial resistance, we developed polymeric nanocarrier delivery of the chemorepellent signaling agent, nickel, to interfere with Escherichia coli transport to a surface, an incipient biofilm formation stage. The dynamics of nickel nanocarrier (Ni NC) chemorepellent release and induced chemorepellent response required to effectively modulate bacterial transport for biofilm prevention were characterized in this work. Ni NCs were fabricated with the established Flash NanoPrecipitation method. NC size was characterized with dynamic light scattering. Measured with a zincon monosodium salt colorimetric assay, NC nickel release was pH-dependent, with 62.5% of total encapsulated nickel released at pH 7 within 0-15 min, competitive with rapid E. coli transport to the surface. Confocal laser scanning microscopy of E. coli (GFP-expressing) biofilm growth dynamics on fluorescently labeled Ni NC coated glass coupled with a theoretical dynamical criterion probed the biofilm prevention outcomes of NC design. The Ni NC coating significantly reduced E. coli attachment compared to a soluble nickel coating and reduced E. coli biomass area by 61% compared to uncoated glass. A chemical-in-plug assay revealed Ni NCs induced a chemorepellent response in E. coli. A characteristic E. coli chemorepellent response was observed away from the Ni NC coated glass over 10 µm length scales effective to prevent incipient biofilm surface attachment. The dynamical criterion provided semiquantitative analysis of NC mechanisms to control biofilm and informed optimal chemorepellent release profiles to improve NC biofilm inhibition. This work is fundamental for dynamical informed design of biofilm-inhibiting chemorepellent-loaded NCs promising to mitigate the development of resistance and interfere with the transport of specific pathogens.

Tween® Preserves Enzyme Activity and Stability in PLGA Nanoparticles.

Enzymes, as natural and potentially long-term treatment options, have become one of the most sought-after pharmaceutical molecules to be delivered with nanoparticles (NPs); however, their instability during formulation often leads to underwhelming results. Various molecules, including the Tween® polysorbate series, have demonstrated enzyme activity protection but are often used uncontrolled without optimization. Here, poly(lactic-co-glycolic) acid (PLGA) NPs loaded with ß-glucosidase (ß-Glu) solutions containing Tween® 20, 60, or 80 were compared. Mixing the enzyme with Tween® pre-formulation had no effect on particle size or physical characteristics, but increased the amount of enzyme loaded. More importantly, NPs made with Tween® 20:enzyme solutions maintained significantly higher enzyme activity. Therefore, Tween® 20:enzyme solutions ranging from 60:1 to 2419:1 mol:mol were further analyzed. Isothermal titration calorimetry analysis demonstrated low affinity and unquantifiable binding between Tween® 20 and ß-Glu. Incorporating these solutions in NPs showed no effect on size, zeta potential, or morphology. The amount of enzyme and Tween® 20 in the NPs was constant for all samples, but a trend towards higher activity with higher molar rapports of Tween® 20:ß-Glu was observed. Finally, a burst release from NPs in the first hour with Tween®:ß-Glu solutions was the same as free enzyme, but the enzyme remained active longer in solution. These results highlight the importance of stabilizers during NP formulation and how optimizing their use to stabilize an enzyme can help researchers design more efficient and effective enzyme loaded NPs.

Microfluidic Technology for the Production of Hybrid Nanomedicines.

Microfluidic technologies have recently been applied as innovative methods for the production of a variety of nanomedicines (NMeds), demonstrating their potential on a global scale. The capacity to precisely control variables, such as the flow rate ratio, temperature, total flow rate, etc., allows for greater tunability of the NMed systems that are more standardized and automated than the ones obtained by well-known benchtop protocols. However, it is a crucial aspect to be able to obtain NMeds with the same characteristics of the previously optimized ones. In this study, we focused on the transfer of a production protocol for hybrid NMeds (H-NMeds) consisting of PLGA, Cholesterol, and Pluronic® F68 from a benchtop nanoprecipitation method to a microfluidic device. For this aim, we modified parameters such as the flow rate ratio, the concentration of core materials in the organic phase, and the ratio between PLGA and Cholesterol in the feeding organic phase. Outputs analysed were the chemico-physical properties, such as size, PDI, and surface charge, the composition in terms of %Cholesterol and residual %Pluronic® F68, their stability to lyophilization, and the morphology via atomic force and electron microscopy. On the basis of the results, even if microfluidic technology is one of the unique procedures to obtain industrial production of NMeds, we demonstrated that the translation from a benchtop method to a microfluidic one is not a simple transfer of already established parameters, with several variables to be taken into account and to be optimized.

Monitoreo anestésico de la mezcla tiopental-propofol en hembras caninas durante la ovariohisterectomía / Anesthetic monitoring of the thiopental-propofol mixture in canine females during ovariohysterectomy / Monitorização anestésica que mistura tiopental-propofol em cadelas durante ovariohisterectomía

Resumen Objetivo: Monitorizar la fracción espiratoria final de CO2 (capnometría), saturación de oxígeno en la hemoglobina (pulsioxímetria) y la presión arterial media no invasiva (PAM) en perras sanas durante la ovariohisterectomía (OVH), en las cuales la anestesia fue inducida y mantenida con la mezcla Propofol-Tiopental (P-T). Materiales y métodos: Se practicó analítica prequirúrgica. La premedicación incluyo acepromacina, ketoprofeno y tramadol, la inducción anestésica se realizó con una mezcla en partes iguales de propofol 10 % y tiopental 2.5 %. La dosis de inducción se calculó en base al tiopental presente en cada cm3 de la mezcla, y fue de 3 mg / kg de tiopental / IV. Se dieron bolos a efecto de 1 mg /kg de tiopental presente en la mezcla para el mantenimiento. La capnometría, pulsioximetría y PAM se midieron cada cinco minutos utilizando un monitor multiparametrico. Los datos se analizaron con un estudio inferencial destinado a encontrar un intervalo de confianza para la media de saturación de oxígeno en la hemoglobina (SO2), fracción espiratoria final de CO2 (FEFCO2) y PAM, con una confianza del 95%. Resultados: La SO2 mantuvo un promedio de 97%, la PAM estuvo durante toda la intervención por encima de 60 mmHg, la FEFCO2 fue alta inicialmente >45mmHg, pero retorno a valores normales luego de 35 minutos. En promedio no se presentó hipoxemia o hipotensión, pero si hipercapnia leve al comienzo. Conclusión: Para las tres variables estudiadas la mezcla P-T fue segura. Se sugieren otros estudios con un monitoreo más amplio para determinar la seguridad hemodinámica y respiratoria.

Abstrac Objective: to monitor the final expiratory fraction of CO2 (capnometry), oxygen saturation in hemoglobin (pulse oximetry) and non-invasive mean arterial pressure (MAP) in healthy dogs during ovariohysterectomy (OVH), in which anesthesia was induced and maintained with the Propofol-Thiopental (PT) mixture. Materials and methods: Pre-surgical analysis was performed. The premedication included acepromazine, ketoprofen and tramadol, the anesthetic induction was performed with a mixture in equal parts of propofol 10% and thiopental 2.5%. The induction dose was calculated based on the thiopental present in each cm3 of the mixture, and was 3 mg / kg of thiopental / IV. Bowls were given for the effect of 1 mg / kg of thiopental present in the mixture for maintenance. Capnometry, pulse oximetry and MAP were measured every five minutes using a multiparametric monitor. The data were analyzed with an inferential study aimed at finding a confidence interval for the mean oxygen saturation in hemoglobin (SO2), final expiratory fraction of CO2 (FEFCO2) and PAM, with a confidence level of 95%. Results: SO2 maintained an average of 97%, MAP was throughout the intervention above 60 mmHg, FEFCO2 was initially high> 45mmHg, but return to normal values after 25 minutes. On average there was no hypoxia or hypotension, but mild hypercapnia at the beginning. Conclusion: For the three variables studied, the P-T mixture was safe. Studies with broader monitoring are suggested to determine hemodynamic and respiratory safety.

Resumo Objectivo: para monitorar a fracção final de CO2 expiratória (capnometria), saturação de oxigénio na hemoglobina (oximetria de pulso) e pressão arterial média de forma não invasiva (PAM) em cães saudáveis durante ovariohysterectomy (OVH), em que foi induzida a anestesia e mantida com a mistura Propofol-Thiopental (PT). Materiais e métodos: A análise pré-cirúrgica foi realizada. Acepromazina pré-medicação incluem, cetoprofeno e tramadol, a anestesia foi induzida com uma mistura de partes iguais de propofol e tiopental 10% 2,5%. A dose de indução foi calculada com base no tiopental presente em cada cm3 da mistura e foi de 3 mg / kg de tiopental / IV. As taças foram dadas para o efeito de 1 mg / kg de tiopental presente na mistura para manutenção. A capnometria, a oximetria de pulso e a PAM foram medidas a cada cinco minutos usando um monitor multiparamétrico. Os dados foram analisados com um estudo inferencial para encontrar um intervalo de confiança para a saturação média de oxigénio da hemoglobina (SO2), CO2 final (FEFCO2) e fracção expiratório PAM, com 95% de confiança. Resultados: O SO2 mantida uma média de 97%, MAP ao longo do processo era acima de 60 mmHg, a FEFCO2 foi elevada inicialmente> 45 mmHg, mas voltam ao normal após 25 minutos. Em média, não houve hipoxemia ou hipotensão, mas hipercapnia leve no início. Conclusão: Para as três variáveis ​​estudadas, a mistura P-T foi segura. Outros estudos com monitoramento mais amplo são sugeridos para determinar a segurança hemodinâmica e respiratória.

Copper Loading of Preformed Nanoparticles for PET-Imaging Applications.

Nanoparticles (NP) are promising contrast agents for positron emission tomography (PET) radionuclide imaging that can increase signal intensity by localizing clusters of PET radionuclides together. However, methods to load NPs with PET radionuclides suffer from harsh loading conditions or poor loading efficacies or result in NP surface modifications that alter targeting in vivo. We present the formation of water-dispersible, polyethylene glycol coated NPs that encapsulate phthalocyanines into NP cores at greater than 50 wt % loading, using the self-assembly technique Flash NanoPrecipitation. Particles from 70 to 160 nm are produced. Phthalocyanine NPs rapidly and spontaneously chelate metals under mild conditions and can act as sinks for PET radionuclides such as 64-Cu to produce PET-active NPs. NPs chelate copper(II) with characteristic rates of 1845 M-1 h-1 at pH 6 and 37 °C, which produced >90% radionuclide chelation within 1 h. NP physical properties, such as core composition, core fluidity, and size, can be tuned to modulate chelation kinetics. These NPs retain 64Cu even in the presence of the strong chelator ethylene diamine tetraacetic acid. The development of these constructs for rapid and facile radionuclide labeling expands the applications of NP-based PET imaging.

Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide- co-glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance.

Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide- co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-ß), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-ß was coupled to the surface of Ag-NPs such that the loadings of Ag and TGF-ß were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-ß in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-ß codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag-NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction.

Controlled Delivery of Single or Multiple Antigens in Tolerogenic Nanoparticles Using Peptide-Polymer Bioconjugates.

Polymeric nanoparticles (NPs) have demonstrated their potential to induce antigen (Ag)-specific immunological tolerance in multiple immune models and are at various stages of commercial development. Association of Ag with NPs is typically achieved through surface coupling or encapsulation methods. However, these methods have limitations that include high polydispersity, uncontrollable Ag loading and release, and possible immunogenicity. Here, using antigenic peptides conjugated to poly(lactide-co-glycolide), we developed Ag-polymer conjugate NPs (acNPs) with modular loading of single or multiple Ags, negligible burst release, and minimally exposed surface Ag. Tolerogenic responses of acNPs were studied in vitro to decouple the role of NP size, concentration, and Ag loading on regulatory T cell (Treg) induction. CD4+CD25+Foxp3+ Treg induction was dependent on NP size, but CD25 expression of CD4+ T cells was not. NP concentration and Ag loading could be modulated to achieve maximal levels of Treg induction. In relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a murine model of multiple sclerosis, acNPs were effective in inhibiting disease induced by a single peptide or multiple peptides. The acNPs provide a simple, modular, and well-defined platform, and the NP physicochemical properties offer potential to design and answer complex mechanistic questions surrounding NP-induced tolerance.

Detection of batch effects in liquid chromatography-mass spectrometry metabolomic data using guided principal component analysis.

Metabolomics based on liquid chromatography-mass spectrometry (LC-MS) is a powerful tool for studying dynamic responses of biological systems to different physiological or pathological conditions. Differences in the instrumental response within and between batches introduce unwanted and uncontrolled data variation that should be removed to extract useful information. This work exploits a recently developed method for the identification of batch effects in high throughput genomic data based on the calculation of a δ statistic through principal component analysis (PCA) and guided PCA. Its applicability to LC-MS metabolomic data was tested on two real examples. The first example involved the repeated analysis of 42 plasma samples and 6 blanks in three independent batches, and the second data set involved the analysis of 101 plasma and 18 blank samples in a single batch with a total runtime of 50h. The first and second data set were used to evaluate between and within-batch effects using the δ statistic, respectively. Results obtained showed the usefulness of using the δ statistic together with other approaches such as summary statistics of peak intensity distributions, PCA scores plots or the monitoring of IS peak intensities, to detect and identify instrumental instabilities in LC-MS.

A reversed-phase ion-interaction chromatographic method for in-vitro estimation of the percutaneous absorption of water-soluble UV filters.

An analytical method based on ion-interaction chromatography with UV detection for simultaneous in-vitro estimation of the percutaneous absorption of the most used water-soluble UV filters in sunscreen cosmetics is proposed. These UV filters were phenylbenzimidazole sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate, benzophenone-4, and terephthalylidene dicamphor sulfonic acid. The methodology is based on applying the sunscreen containing the target UV filters to human epidermis in a diffusion cell. Analytes are determined in the receptor solution. To ensure skin integrity, screening of the cells was carried out by analytical determination of a marker. Analytical variables such as percentage ethanol, concentration of ion-pairing agent, pH of the mobile phase, and temperature were studied in order to achieve high resolution of the chromatographic peaks in the lowest possible time of analysis. The conditions selected consisted of a mobile phase composed of 35:65 (v/v) ethanol-ammonium acetate buffer solution (pH 4, containing 50 mmol L(-1) tetra-n-butylammonium bromide). The chromatographic determination was carried out with the analytical column at 50 degrees C. UV detection was carried out at the maximum absorption wavelength for each analyte. The limit of detection (3s(y/x)/b) ranged from 16 to 65 ng mL(-1), depending on the analyte.

Heterologous mitochondrial DNA recombination in human cells.

Inter-molecular heterologous mitochondrial DNA (mtDNA) recombination is known to occur in yeast and plants. Nevertheless, its occurrence in human cells is still controversial. To address this issue we have fused two human cytoplasmic hybrid cell lines, each containing a distinct pathogenic mtDNA mutation and specific sets of genetic markers. In this hybrid model, we found direct evidence of recombination between these two mtDNA haplotypes. Recombinant mtDNA molecules in the hybrid cells were identified using three independent experimental approaches. First, recombinant molecules containing genetic markers from both parental alleles were demonstrated with restriction fragment length polymorphism of polymerase chain reaction products, by measuring the relative frequencies of each marker. Second, fragments of recombinant mtDNA were cloned and sequenced to identify the regions involved in the recombination events. Finally, recombinant molecules were demonstrated directly by Southern blot using appropriate combinations of polymorphic restriction sites and probes. This combined approach confirmed the existence of heterogeneous species of recombinant mtDNA molecules in the hybrid cells. These findings have important implications for mtDNA-related diseases, the interpretation of human evolution and population genetics and forensic analyses based on mtDNA genotyping.

Aneurisma aislado gigante de arteria ilíaca común / Giant isolated aneurysm of common iliac artery

Introducción: Los aneurismas solitarios de la arteria ilíaca son poco frecuentes, además de ser difíciles de detectar por su localización en la pelvis, lo cual se asocia a una alta mortalidad cuando se complican de ruptura. En la literatura extranjera existen casuísticas más bien pequeñas que han sido reunidas en un período largo de tiempo. En nuestro medio sólo hay un reporte en la literatura nacional, motivo por el cual presentamos un caso clínico de un aneurisma aislado gigante de arteria ilíaca. Material y Método: Se presenta el caso de un paciente hombre de 84 años, sin antecedentes de patologías preexistentes, quien consulta por masa pulsátil en fosa ilíaca derecha asintomática, demostrándose por ecografía la presencia de aneurisma ilíacos bilaterales, mayor a derecha. Tomografía computada confirma el diagnóstico y las dimensiones, llamando la atención que el aneurisma ilíaco derecho mide cerca de 10 cm de diámetro, sin sintomatología ni amenaza de ruptura. Se somete a cirugía reconstructiva arterial, realizándose reemplazo aortobiilíaco con prótesis bifurcada de Dacrón a través de un abordaje transperitoneal. Resultados: Cirugía bien tolerada con un postoperatorio sin incidentes, controlándose al cuarto mes de operado, encontrándose el paciente asintomático. Discusión: Los aneurismas solitarios de la arteria ilíaca son poco frecuentes. Afectan al adulto mayor principalmente a hombres. La etiología es de tipo degenerativa, pero también se han descrito de tipo micóticos y congénitos o secundarios a Síndrome de Marfán, Ehlers-Danlos, Arteritis de Takayasu, Necrosis quística de la media, disección espontánea y secundarios a trauma. El segmento más afectado es la arteria ilíaca común. La Tomografía Computarizada es el método de elección para confirmar el diagnóstico, sus dimensiones y la localización, la angiografía se emplea en el caso de sospechar enfermedad oclusiva arterial asociada y cuando se plantea su tratamiento vía endovascular. Pueden originar síntomas de comprensión de órganos vecinos y fistulizarse al intestino u otras estructuras. Sin embargo, la mayor complicación es la ruptura que lleva asociada una alta mortalidad. De allí que los mejores resultados de tratamiento se obtienen cuando se operan en forma electiva aquellos con un diámetro mayor de 3 cm. El tratamiento de elección sigue siendo el reemplazo protésico del segmento afectado mediante cirugía vascular convencional.

Oclusión aórtica aguda: una grave emergencia vascular de difícil manejo / Acute abdominal aorta occlusion: difficult management of a serious vascular emergency

Introducción: La oclusión aguda de la aorta abdominal es un evento poco frecuente pero que constituye una real emergencia vascular, siendo potencialmente catastrófica, desde el punto de vista de la morbilidad y mortalidad, si ésta no es tratada precozmente y en forma agresiva desde el punto de vista quirúrgico. En nuestro medio sólo existen dos publicaciones con sólo ocho casos en total en un lapso de cuatro años, motivo por el cual en este reporte se describen dos casos operados en nuestro servicio. Material y Método: Se trata de dos casos clínicos que presentaron oclusión aguda de la aorta abdominal de tipo trombótica secundaria a enfermedad ateroesclerótica, en que ambos requirieron de revasculación aórtica. El primero, aórtica simple acompañado de trombectomía de la aorta proximal y el segundo revascularización aórtica compleja. Resultados: El primer caso, sobrevive y no presenta complicaciones. El segundo caso, fallece a los 18 días del postoperatorio debido a un accidente vascular hemorrágico. Discusión: La oclusión aórtica aguda es una emergencia vascular poco frecuente cuyas causas son principalmente por embolía y enfermedad ateroesclerótica subyacente. Afecta de preferencia a pacientes en edad avanzada y su diagnóstico debe ser sospechado por la clínica, ya que se caracteriza por signos de isquemia aguda de ambas extremidades inferiores. Sin embargo, hay un grupo de pacientes cuya sintomatología, hace difícil plantear el diagnóstico ya que puede simular un cuadro neurológico, una insuficiencia renal o un abdomen agudo quirúrgico por isquemia intestinal. El diagnóstico puede ser confirmado por la Tomografía Computarizada, pero es fundamental la Angiografía, a fin de definir su localización y la extensión de la oclusión para poder planear en buena forma el tratamiento quirúrgico, el cual debe ser precoz y agresivo cuando se requiere una revascularización. Aún así la morbimortalidad sigue siendo alta. Como conclusión, creemos que la precocidad en el diagnóstico y el tratamiento quirúrgico agresivo de revascularización en los casos de trombosis secundaria a enfermedad ateromatosa es la mejor opción de sobrevida para este tipo de pacientes.

Revascularización inframaleolar: utilidad de los puentes a las arterias plantares / Inframalleolar revascularization: usefullnes of bypass to plantar arteries

La revascularización infrainguinal es el mejor tratamiento para una extremidad con isquemia crítica. Excepcionalmente se requiere revascularizar vasos ultradistales como son las ramas derivadas de las arterias del pie, por ausencia de vasos tibiales adecuados. En nuestro medio, la experiencia con los puentes arteriales a las arterias plantares es pequeña, lo que motiva este reporte inicial. En los últimos siete meses se efectuaron 4 puentes arteriales a las plantares en cuatro pacientes, con edades desde los 55 a los 81 años, todos de sexo masculino, diabéticos e hipertensos. Tres son tabáquicos y uno es dislipidémico. Dos pacientes tenían revascularizaciones previas en la extremidad contralateral y dos tenían revascularizaciones previas en la extremidad afectada. La indicación quirúrgica fue necrosis e infección en tres pacientes y dolor de reposo en uno. Todos los puentes fueron efectuados con safena en modalidad invertida. No hubo morbimortalidad en la serie, con buenos resultados funcionales. Si bien no se puede hablar de permeabilidad a largo plazo, todos los puentes están permeables en un lapso desde uno a seis meses. Creemos que estos puentes son técnicamente más factibles de realiza si se los compara con los otros puentes a las ramas de la arteria peia, incluso en términos de resultados de permeabilidad, y que justifican plenamente su uso en estos pacientes, quienes se enfrentan a una amputación mayor como única alternativa

Aneurisma de carótida interna extracraneal / Aneurisma of the extracraneal internal carotide

El aneurisma de la arteria carótida interna extracraneal es una patología infrecuente. Se reporta el caso de una paciente hipertensa de 71 años referida por hallazgos de masa pulsátil cervical. La ecografía Doppler muestra dilatación de carótida interna derecha y la angiografía confirma un aneurisma sacular de 4 cm de diámetro. La paciente se interviene quirúrgicamente practicándose resección del aneurisma y anastosmosis término -terminal de carótida interna. No se usó shunt intraoperatorio. Evolución post-operatoria sin incidentes. La anatomía patológica concluye aneurisma de tipo ateromatoso. El riesgo de eventos neurológicos por embolización indica la cirugía resectiva en esta patología

Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.

BACKGROUND: Previous studies in predominantly bipolar patients have suggested that gabapentin may be useful in treating mood disorders. This report describes its efficacy and tolerability as an adjunctive agent in treatment-resistant depression. METHODS: A chart review was conducted on 27 outpatients presenting with a depressive disorder in whom gabapentin was added to ongoing treatment with a conventional antidepressant to which patients had not responded after at least 6 weeks. The majority of patients had either prominent anxiety or a history of soft bipolar features, but patients with bipolar I disorder were excluded. Clinical state and adverse effects were assessed retrospectively at each visit. RESULTS: Mean gabapentin trial duration was 15.2+/-7.8 weeks, with a mean final dose of 904+/-445 mg/day (range, 300-1800 mg/day). Clinician-rated measures of clinical state improved significantly from baseline to endpoint. Overall, 37.0% (n=10) of patients were responders at endpoint; another 18.5% (n=5) manifested a transient response not sustained to endpoint. Gabapentin was well tolerated; the most common adverse effects were fatigue, sedation, dizziness, and gastrointestinal symptoms. LIMITATIONS: Treatment was uncontrolled and efficacy assessments were retrospective. CONCLUSION: These findings suggest that gabapentin may be of adjunctive benefit in the management of treatment-resistant depression.

Evaluation of the nasal response to histamine provocation with acoustic rhinometry.

The objectives of this study were to evaluate the reproducibility of the nasal response to histamine with the acoustic rhinometer and to compare the responses in normal and rhinitic subjects. Our study comprised 10 normal and 10 rhinitic subjects. Each subject had six sessions of provocation: three with histamine phosphate at a concentration of 4 mg/mL and three with saline phosphate provocation. Basal measurements of the nasal volumes were taken initially and then at 5-minute intervals for 90 minutes. All rhinometric measurements were made bilaterally and in triplicate. The variation between the triplicate measurements (2% +/- 0.1% [95% CI]) and the variation between the basal measurements (7.3% +/- 3.1% [95% CI]) were very low in both normal and rhinitic subjects. The comparison of the average congestive response of the normal subjects revealed that they responded steadily for at least 90 minutes to histamine and saline but that the response to histamine was significantly more important. There was also a low variability in the congestive response between the subjects. The comparison of the average congestive response of the rhinitic subjects revealed that their responses were more dynamic, not steady, compared with those of the normal subjects. The response was statistically significant only in the first few intervals. The comparison of the average congestive response to saline suggests that rhinitic subjects present a more important response than normal subjects. The comparison of the average congestive response to histamine between rhinitic and normal subjects was not statistically different but was different in the shape of the response pattern. Acoustic rhinometry is a highly reproducible method for measuring nasal volume in our provocation protocol. Histamine nasal provocation leads to a pattern of congestive response that is different in normal and rhinitic subjects. Histamine nasal provocation seems to be useful in addition to the study of nasal hyperreactivity and, as such, could permit differentiation between rhinitic and nonrhinitic subjects.

Clinical experience with mirtazapine in the treatment of panic disorder.

Data from treatment trials and biological challenge studies implicate involvement of both the serotonergic and the noradrenergic neurotransmitter systems in the pathophysiology of panic disorder. Mirtazapine, a newer antidepressant with a novel mechanism of action enhancing both norepinephrine and serotonin levels without reuptake inhibition, is a good candidate for the treatment of panic disorder. Ten adult outpatients with a primary diagnosis of panic disorder were treated openly with mirtazapine. Starting dose and titration were determined by individual clinical characteristics. Data on emergent side effects and clinical response were obtained at all follow-up visits, which typically occurred biweekly for 16 weeks. At the first follow-up visit (week 2-3), 4 of 10 patients met the criteria for response. Based on all available data, seven of the original sample demonstrated an acute response (defined as CGI = 2 or 3) by weeks 5-7, and six continued to have a positive long-term response at the 16-week end point. Side effects were reported by seven patients, with increased appetite and weight gain the most common. Prominent antihistaminic side effects such as sedation, enhanced appetite, and anxiolysis were often desired in the initial phase of treatment.

Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru.

To estimate the effect of maternal zinc deficiency on pregnancy outcomes, we conducted a zinc supplementation trial in an urban shantytown in Lima, Peru, a population with habitual low zinc intakes. Beginning at 10-24 wk gestation, 1295 mothers were randomly assigned to receive prenatal supplements containing 60 mg iron and 250 (g folate, with or without 15 mg zinc. Women were followed up monthly during pregnancy. At birth, newborn weight was recorded, and crownheel length, head circumference and other circumferences and skinfold thicknesses were assessed on d 1. At delivery, 1016 remained in the study; duration of pregnancy was known for all women, and birth weight information was available for 957 newborns. No differences were noted in duration of pregnancy (39.4 +/- 2.2 vs. 39. 5 +/- 2.0 wk) or birth weight (3267 +/- 461 vs. 3300 +/- 498 g) by prenatal supplement type (iron + folate + zinc vs. iron + folate; P > 0.05), and there were no differences in the rates of preterm (<37 wk) or post-term (>42 wk) delivery, low birth weight (<2500 g) or high birth weight (>4000 g). Finally, there were no differences by prenatal supplement type in newborn head circumference, crownheel length, chest circumference, mid-upper arm circumference, calf circumference or skinfold thickness at any of three sites. Adjustment for covariates and confounding factors did not alter these results. Adding zinc to prenatal iron and folate tablets did not affect duration of pregnancy or size at birth in this population.