Drug Transporter Gene Expression in Human Colorectal Tissue and Cell Lines : Modulation with Antiretrovirals for Microbicide Optimization

This work was supported by the European Union's Seventh Programme for research, technological development and demonstration under grant agreement No 305316 as part of the MOTIF (Microbicides Formulation Through Innovative Formulation for Vaginal and Rectal Delivery) project.

Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T cells : Implications for HIV Microbicides

This work was supported by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No 305316 as part of the MOTIF (Microbicides Optimisation Through Innovative Formulation for Vaginal and Rectal Delivery) project. We would like to extend our thanks to all the study participants for their invaluable contribution and to Grampian Biorepository staff for help with collection of fresh colorectal resection tissue.

Application of a new method in the study of pelvic floor muscle passive properties in continent women

The aim of this study was to present a new methodology for evaluating the pelvic floor muscle (PFM) passive properties. The properties were assessed in 13 continent women using an intra-vaginal dynamometric speculum and EMG (to ensure the subjects were relaxed) in four different conditions: (1) forces recorded at minimal aperture (initial passive resistance); (2) passive resistance at maximal aperture; (3) forces and passive elastic stiffness (PES) evaluated during five lengthening and shortening cycles; and (4) percentage loss of resistance after 1 min of sustained stretch. The PFMs and surrounding tissues were stretched, at constant speed, by increasing the vaginal antero-posterior diameter; different apertures were considered. Hysteresis was also calculated. The procedure was deemed acceptable by all participants. The median passive forces recorded ranged from 0.54 N (interquartile range 1.52) for minimal aperture to 8.45 N (interquartile range 7.10) for maximal aperture while the corresponding median PES values were 0.17 N/mm (interquartile range 0.28) and 0.67 N/mm (interquartile range 0.60). Median hysteresis was 17.24 N∗mm (interquartile range 35.60) and the median percentage of force losses was 11.17% (interquartile range 13.33). This original approach to evaluating the PFM passive properties is very promising for providing better insight into the patho-physiology of stress urinary incontinence and pinpointing conservative treatment mechanisms.

Home birth in Ireland 1993-1997: a review of community midwifery practice

To date little is known about the practices of domiciliary midwives and the outcomes of home birth in Ireland. The purpose of this review is to provide some background information on the situation for women seeking a home birth and to document the outcomes of home births in Ireland between 1993 -1997. Design: Descriptive analysis of prospective data collected from domiciliary midwives regarding women who requested a home birth between 1993 and 1997. Participants: The questionnaire was distributed to 15 domiciliary midwives; this included all the domiciliary midwives known to the authors to be practising in Ireland at that time. Findings: During this period, 585 women planned to give birth in their home with the assistance of midwives, 500 women achieved this. The spontaneous vaginal delivery rate for women who commenced their labour at home was 96.9% (n = 554). These women gave birth without medications or other interventions. 544 (93%) of the women breastfed their babies and 538 (92%) were still breastfeeding at 6 weeks. This is the first review of domiciliary midwifery practice in Ireland in recent years. They obtained data from 11 independent midwives on 585 women who planned home births. Findings showed high rates of spontaneous vaginal delivery and breastfeeding. There were 500 babies born at home with three perinatal deaths, including one undiagnosed breech delivery, one infant with abnormal lungs on post-mortem and one infant with Potter's Syndrome who was stillborn.

Mechanistic Models of Anti-HIV Microbicide Drug Delivery

A new modality for preventing HIV transmission is emerging in the form of topical microbicides. Some clinical trials have shown some promising results of these methods of protection while other trials have failed to show efficacy. Due to the relatively novel nature of microbicide drug transport, a rigorous, deterministic analysis of that transport can help improve the design of microbicide vehicles and understand results from clinical trials. This type of analysis can aid microbicide product design by helping understand and organize the determinants of drug transport and the potential efficacies of candidate microbicide products.

Microbicide drug transport is modeled as a diffusion process with convection and reaction effects in appropriate compartments. This is applied here to vaginal gels and rings and a rectal enema, all delivering the microbicide drug Tenofovir. Although the focus here is on Tenofovir, the methods established in this dissertation can readily be adapted to other drugs, given knowledge of their physical and chemical properties, such as the diffusion coefficient, partition coefficient, and reaction kinetics. Other dosage forms such as tablets and fiber meshes can also be modeled using the perspective and methods developed here.

The analyses here include convective details of intravaginal flows by both ambient fluid and spreading gels with different rheological properties and applied volumes. These are input to the overall conservation equations for drug mass transport in different compartments. The results are Tenofovir concentration distributions in time and space for a variety of microbicide products and conditions. The Tenofovir concentrations in the vaginal and rectal mucosal stroma are converted, via a coupled reaction equation, to concentrations of Tenofovir diphosphate, which is the active form of the drug that functions as a reverse transcriptase inhibitor against HIV. Key model outputs are related to concentrations measured in experimental pharmacokinetic (PK) studies, e.g. concentrations in biopsies and blood. A new measure of microbicide prophylactic functionality, the Percent Protected, is calculated. This is the time dependent volume of the entire stroma (and thus fraction of host cells therein) in which Tenofovir diphosphate concentrations equal or exceed a target prophylactic value, e.g. an EC50.

Results show the prophylactic potentials of the studied microbicide vehicles against HIV infections. Key design parameters for each are addressed in application of the models. For a vaginal gel, fast spreading at small volume is more effective than slower spreading at high volume. Vaginal rings are shown to be most effective if inserted and retained as close to the fornix as possible. Because of the long half-life of Tenofovir diphosphate, temporary removal of the vaginal ring (after achieving steady state) for up to 24h does not appreciably diminish Percent Protected. However, full steady state (for the entire stromal volume) is not achieved until several days after ring insertion. Delivery of Tenofovir to the rectal mucosa by an enema is dominated by surface area of coated mucosa and whether the interiors of rectal crypts are filled with the enema fluid. For the enema 100% Percent Protected is achieved much more rapidly than for vaginal products, primarily because of the much thinner epithelial layer of the mucosa. For example, 100% Percent Protected can be achieved with a one minute enema application, and 15 minute wait time.

Results of these models have good agreement with experimental pharmacokinetic data, in animals and clinical trials. They also improve upon traditional, empirical PK modeling, and this is illustrated here. Our deterministic approach can inform design of sampling in clinical trials by indicating time periods during which significant changes in drug concentrations occur in different compartments. More fundamentally, the work here helps delineate the determinants of microbicide drug delivery. This information can be the key to improved, rational design of microbicide products and their dosage regimens.

Application of a new method in the study of pelvic floor muscle passive properties in continent women

The aim of this study was to present a new methodology for evaluating the pelvic floor muscle (PFM) passive properties. The properties were assessed in 13 continent women using an intra-vaginal dynamometric speculum and EMG (to ensure the subjects were relaxed) in four different conditions: (1) forces recorded at minimal aperture (initial passive resistance); (2) passive resistance at maximal aperture; (3) forces and passive elastic stiffness (PES) evaluated during five lengthening and shortening cycles; and (4) percentage loss of resistance after 1 min of sustained stretch. The PFMs and surrounding tissues were stretched, at constant speed, by increasing the vaginal antero-posterior diameter; different apertures were considered. Hysteresis was also calculated. The procedure was deemed acceptable by all participants. The median passive forces recorded ranged from 0.54 N (interquartile range 1.52) for minimal aperture to 8.45 N (interquartile range 7.10) for maximal aperture while the corresponding median PES values were 0.17 N/mm (interquartile range 0.28) and 0.67 N/mm (interquartile range 0.60). Median hysteresis was 17.24 N∗mm (interquartile range 35.60) and the median percentage of force losses was 11.17% (interquartile range 13.33). This original approach to evaluating the PFM passive properties is very promising for providing better insight into the patho-physiology of stress urinary incontinence and pinpointing conservative treatment mechanisms.

The Influence of Gene Environment Interaction on the Risk of Cognitive Impairment: Reducing Sexual Risk Behaviors and Alcohol Use in HIV-infected Adults

Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion Control (HPC) condition in reducing risk behaviors. A total of 267 individuals were genotyped for polymorphisms in the dopamine and serotonin gene systems. Results yielded significant associations for TPH2, GALM, DRD2 and DRD4 genetic variants with impaired executive function, cognitive flexibility and memory. SNPs TPH2 rs4570625 and DRD2 rs6277 showed a risk association with executive function (odds ratio = 2.5, p = .02; 3.6, p = .001). GALM rs6741892 was associated with impaired memory (odds ratio = 1.9, p = .006). At the six-month follow-up, HHRP-A participants were less likely to report trading sex for food, drugs and money (20.0%) and unprotected insertive or receptive oral (11.6%) or vaginal and/or anal sex (3.2%) than HPC participants (49.4%, p

A dyadic perspective on genito-pelvic pain : trauma antecedents and treatment effectiveness

La vestibulodynie provoquée (VP) est la forme la plus répandue de douleur génito-pelvienne/trouble de la pénétration et la cause la plus fréquente de douleur vaginale chez les femmes pré-ménopausées. Les femmes qui en souffrent rapportent plus de détresse psychologique ainsi qu’un fonctionnement sexuel appauvri, une diminution de la fréquence des activités sexuelles et du plaisir, et plus d’attitudes négatives à l’égard de la sexualité. Les recherches portant sur les couples souffrant de VP ont montré le rôle prépondérant des variables relationnelles dans la modulation des conséquences sexuelles et psychologiques pour les femmes et leurs partenaires. Cependant, aucune analyse dyadique n’a été appliquée au facteur de risque étiologique le plus robuste, soit la maltraitance durant l’enfance. Par ailleurs, malgré des recommandations répétées pour inclure le partenaire dans le traitement psychologique pour la VP, aucune étude à ce jour n’a examiné l’efficacité d’une psychothérapie qui inclut systématiquement le partenaire et dont la cible est le couple. L’objectif général de cette thèse a été d’utiliser une perspective dyadique afin d’examiner les antécédents de maltraitance et l’efficacité d’une intervention conçue pour améliorer les issues des couples souffrant de VP. Le premier article vise à examiner les liens entre la maltraitance durant l’enfance des femmes souffrant de VP et leurs partenaires, et leur fonctionnement sexuel, leur ajustement psychologique, leur satisfaction conjugale et enfin avec la douleur rapportée par les femmes durant les relations sexuelles. Quarante-neuf couples souffrant de VP ont complété des questionnaires auto-rapportés. La maltraitance durant l’enfance chez les femmes était associée à un fonctionnement sexuel plus faible chez les femmes et les hommes, une augmentation de l’anxiété chez les femmes seulement, et une douleur affective accrue durant les relations sexuelles. La maltraitance durant l’enfance chez les hommes était associée à un fonctionnement sexuel plus faible, moins de satisfaction conjugale, plus d’anxiété chez les femmes et les hommes, et une douleur affective accrue durant les relations sexuelles rapportée par les femmes. En se basant sur les recommandations issues des études empiriques, une thérapie cognitive et comportementale pour les couples (TCCC) souffrant de VP a été développée. Le deuxième article présente les résultats d’une étude pilote testant son efficacité, fidélité et faisabilité potentielles. Neuf couples ont complété des questionnaires auto-rapportés pré- et post-traitement. La TCCC de 12 rencontres était manualisée. Les femmes ont rapporté une amélioration significative de la douleur, du fonctionnement et de la satisfaction sexuels, et les partenaires ont rapporté une amélioration significative de leur satisfaction sexuelle. Les couples ont rapporté des niveaux élevés de satisfaction quant à la psychothérapie, et les psychothérapeutes ont rapporté suivre le manuel de traitement de manière fidèle. Le troisième article, s’appuyant sur les résultats prometteurs de l’étude pilote, décrit le protocole de recherche pour un essai clinique randomisé mesurant l’efficacité de la TCCC comparée à une intervention médicale de première ligne, la lidocaïne topique, pour le traitement de la VP. Enfin, les implications cliniques et théoriques de la thèse sont discutées.

Valoración de un protocolo asistencial al nacimiento con presentación podálica: resultados perinatales y a los dieciocho meses de vida

Programa de doctorado: Avences en Medicina Interna. La fecha de publicación es la fecha de lectura

Fonction et structure des muscles du plancher pelvien de femmes traitées par chirurgie et radiothérapie à la suite d'un cancer de l'endomètre

Ce mémoire porte sur les propriétés fonctionnelles du plancher pelvien à la suite de traitements pour un cancer de l’endomètre. Chez les femmes, le cancer de l’endomètre est le cancer gynécologique ayant la plus forte prévalence. Les traitements oncologiques de ce cancer ont des conséquences néfastes sur la continence urinaire et il est possible que des altérations aux muscles du plancher pelvien à la suite de ces traitements puissent expliquer en partie cette problématique. Ce mémoire est composé de deux études principales. La première étude porte sur la recension des écrits liés aux impacts de la radiothérapie sur la structure anatomique et la fonction musculaire du plancher pelvien chez des adultes atteints d’un cancer pelvien. La deuxième étude compare les propriétés fonctionnelles du plancher pelvien de femmes avec incontinence urinaire à la suite d’un cancer de l’endomètre traité par chirurgie et une radiothérapie adjuvante (groupe à l’étude), à celles de femmes avec hystérectomie sans incontinence (groupe témoin). Cette étude a permis de mettre en évidence une diminution de l’ouverture maximale à l’entrée vaginale, de la longueur vaginale, de la force maximale volontaire du plancher pelvien, du taux de développement de la force dans un test de force maximale et de la coordination lors d’un test de contractions rapides. Ainsi, les deux études de ce mémoire apportent de nouvelles évidences sur les altérations des propriétés fonctionnelles du plancher pelvien à la suite de traitements pour un cancer génital.

Longitudinal Incidence Study of Clinically-Relevant HPV and Vaccine-Type HPV in Young Online Female Daters

Thesis (Master's)--University of Washington, 2016-08

Sistemas semissólidos à base de nanopartículas lipídicas

As nanopartículas lipídicas foram desenvolvidas no início dos anos 90 e, atendendo às vantagens que apresentam comparativamente a outros sistemas coloidais, têm-se demonstrado muito promissoras, tanto para uso cosmético como farmacêutico. No entanto, atualmente apenas existem comercializados produtos cosméticos à base de nanopartículas lipídicas, o que pode ser justificado pelas restrições regulamentares relacionadas com a introdução de medicamentos no mercado. Existem dois tipos de nanopartículas lipídicas, as nanopartículas de lípidos sólidos (Solid Lipid Nanoparticles, SLN) e os vetores lipídicos nanoestruturados (Nanostructured Lipid Carriers, NLC), consistindo ambos em dispersões aquosas de nanopartículas sólidas. A baixa viscosidade destes sistemas dificulta a sua aplicação tópica. Neste contexto, têm sido desenvolvidas várias formulações semissólidas à base de nanopartículas lipídicas para aplicação tópica, nomeadamente cutânea, ocular, nasal e vaginal. A primeira parte desta dissertação consiste na revisão bibliográfica relativa ao estado da arte dos sistemas semissólidos à base de nanopartículas lipídicas, para uso farmacêutico e cosmético, baseada nos estudos realizados por diversos autores, entre 2012 e 2016. Na segunda parte, são apresentados resultados do trabalho experimental relativo ao desenvolvimento e caraterização de uma formulação semissólida à base de nanopartículas lipídicas.

Fibroma uterino en una hembra canina cruzada de 12 años en Veterinaria Vida, Noviembre Managua, Nicaragua 2013

Se analizó un estudio de caso atendido en la Clínica “VIDA ” el 21 de noviembre del 2013. Inicialmente se procedió a la valoración de su estado físico y de salud considerando la edad de la paciente. A partir de la inspección clínica y anamnesis se procedió a brindar un diagnóstico de la patología que presentaba, para fundamentar las principales causas y consecuencia que gen eran las patologías reproductivas en la especie canina. El estudio de caso es una investigación cualitativa de tipo participativa, cuya base es la descripción de sucesos ocurridos en un momento determinado el cual consistía en el análisis de un estudio de caso que no pueden duplicarse por las condiciones individuales del sujeto y de su entorno en particular . El paciente era una perra de 12 años , llamada princesa que t enía completo su programa de vacunación y desparasitación. Después del último celo tuvo descargas vaginal es hemorrágicas , durante 6 días el cual alarmó a la dueña, ya que no mostró síntomas característicos de postraciones . Era alimentada con concentrado, su estro era normal . Se le brindó atención ambulatoria y s e le realizaron exámenes clínicos , realizando la anamnesis , sin mostrar dolor a la palpación, no se detectaron masas abdominales, no se realizó exploración vagina l debido a que la paciente no habí a sido incorporada para reproducción. Se determinó como piómetra en diagnostico presu ntivo, aplicándole vit. K p or tres días y al cuarto día una dosis de medroxiprogesterona para detener el sangrado. A l no haber efecto en el sangrado, se optó por la extirpación quirúrgica del útero el cual se real izó sin problemas, encontrándose: cuernos uterinos y útero hiperplásicos , endometrio con fibromas y pequeñas neoplasias. Se identificó neoplasia uterina causada por quistes ováricos, estrés, trastorno psicológico de adaptabilidad a la ausencia de la dueña, creando un desorde n en las estructuras de cascada del sistema endocrino, viéndose afectado por la relació n de la edad de la paciente. Terminada la cirugía se le entregó la mascota a su dueña junto con las indicaciones postoperatoria pero ya en su casa la paciente murió por complicaciones post quirúrgica no identificadas .

Hipertensión intra-abdominal y síndrome abdominal compartamental prevalencia postlaparotomía por abdomen agudo, HVCM Cuenca 2010-2011 /

La hipertensión intra-abdominal (HIA) y el síndrome compartamental abdominal (SCA) son causa importante de morbi-mortalidad postoperatoria. Avances en su diagnóstico y tratamiento oportuno han proporcionado mejor sobrevida en estos pacientes. Objetivo. Determinar la prevalencia de HIA, SCA y asociarla con (hallazgos quirúrgicos, presión de perfusión Intra-abdominal (PPI), obesidad) intervenidos por abdomen agudo en el Departamento de Cirugía del Hospital Vicente Corral Moscoso de Cuenca. Metodología. Se realizó un estudio transversal analítico en pacientes mayores de 16 años que ameritaron laparotomía de septiembre de 2010 hasta agosto de 2011 y que cumplieron criterios de exclusión, la PIA fue medida mediante método indirecto y la información se recopilo en un formulario elaborado para el estudio. Resultados: 347 Pacientes fueron incluidos en el estudio, la media de edad se ubicó en 46.72 ± 22.30 años, presentaron sobrepeso el 5.2%, en el estadio pre-quirúrgico se encontró Hipertensión Intra-abdominal en 41.2% y 10.4% de síndrome compartamental; luego de la laparotomía la hipertensión intra-abdominal disminuyó a 37.7% y el síndrome compartamental a 8.4%. La PIA iguales o mayores a 12mmHg aumentan el riesgo de hipo-perfusión intestinal en 3.56 veces (IC 95%: 1.81-6.99), p menor que 0.05; la obesidad se comportó como factor de riesgo con un RP de 1.73 (1.451-2.13); los hallazgo quirúrgico encontrados fueron significativos para Abdomen agudo perforativo: 2.45 con IC 95% 1.91-3.13; Abdomen agudo hemorrágico 1.83 con IC 95% 1.46-2.30 y Abdomen agudo oclusivo intestinal 2.32 con IC 95% 2.05-2.64. Conclusión: La Hipertensión intra-abdominal disminuye progresivamente en el postoperatorio, mientras que en quienes se manifiesta el SCA permaneció elevado por mayor tiempo. Se evidencio que la Obesidad influye incrementando la PIA, la misma que produce disminución de la PPI prediciendo peor pronóstico; los hallazgos quirúrgicos representativos para el incremento de la PIA fueron el abdomen agudo perforativo y oclusivo .au

Fístulas vesico-vaginais: uma visão sobre Moçambique

Introdução: As fístulas vesico-vaginais são, de todas as fístulas do aparelho urinário, as mais frequentes. A etiologia deste tipo de fístulas, varia de acordo com a região do globo. Nos países em vias de desenvolvimento, a principal causa de fístulas vesico vaginais corresponde a complicações obstétricas. A pressão exercida pelo feto, nas paredes da vagina, bexiga e uretra proximal leva muitas vezes à necrose dos tecidos. Esta necrose pode levar a um conjunto de complicações que vão desde as fístulas vesico vaginais, estenose vaginal, atresia rectal, infertilidade secundária, ou mesmo à incompetência do esfíncter anal e osteíte púbica. Apresentamos 3 casos clínicos de fístulas vesico vaginais de causa obstétrica bem como uma revisão dos aspectos teóricos e técnicos do diagnóstico e tratamento desta patologia. Materiais e Métodos: Descrevem-se 3 casos clínicos de fístulas vesico vaginais de causa obstétrica tratadas em 2012. O primeiro caso foi abordado por via vaginal reparado em três planos, utilizando-se o retalho de Martius. Os outros dois casos devido à localização e complexidade da fístula foram abordados por via abdominal com interposição de epíploon. Resultados: No primeiro caso a doente foi seguida noutra instituição, nos outros dois casos não houve recidiva da fístula num follow up de 6 e 12 meses respectivamente. Relativamente à correção cirúrgica obedeceu-se aos seguintes princípios: uma boa exposição do trajecto fistuloso, desbridamento do tecido desvitalizado e isquémico, utilização de retalhos bem vascularizados e preenchimento do espaço livre. O encerramento foi realizado em vários planos, sem sobreposição das suturas, sempre sem tensão. Discussão: As fístulas vesico-vaginais permanecem um enorme desafio do ponto de vista cirúrgico, necessitando de uma abordagem multidisciplinar, bem como da criação de centros de referência.