Volume of breast tissue excised during breast-conserving surgery in patients undergoing preoperative systemic therapy

PURPOSE: We aimed to determine whether clinical examination could adequately ascertain the volume of tissue to be resected during breast-conserving surgery after neoadjuvant therapy. METHODS: We reviewed the clinical reports of 279 patients with histologically diagnosed invasive breast carcinomas treated with neoadjuvant therapy followed by surgery or with primary surgery alone. We estimated volumes of excised tissues, the volume of the tumor mass and the optimal volume required for excision based on 1 cm of clear margins. The actual excess of resected volume was estimated by calculating the resection ratio measured as the volume of the resected specimen divided by the optimal specimen volume. The study endpoints were to analyze the extent of tissue resection and to ascertain the effect of excess resected tissue on surgical margins in both groups of patients. RESULTS: The median tumor diameter was 2.0 and 1.5 cm in the surgery and neoadjuvant therapy groups, respectively. The median volume of resected mammary tissue was 64.3 cm³ in the primary surgery group and 90.7 cm³ in the neoadjuvant therapy group. The median resection ratios in the primary surgery and neoadjuvant therapy groups were 2.0 and 3.3, respectively (p<0.0001). Surgical margin data were similar in both groups. Comparison of the volume of resected mammary tissues with the tumor diameters showed a positive correlation in the primary surgery group and no correlation in the neoadjuvant therapy group. CONCLUSION: Surgeons tend to excise large volumes of tissue during breast-conserving surgery after neoadjuvant therapy, thereby resulting in a loss of the correlation between tumor diameter and volume of the excised specimen.

Long-term outcome of 25 children and adolescents with severe aplastic anemia treated with antithymocyte globulin

Severe aplastic anemia (SAA) is probably an immune-mediated disorder, and immunosuppressive therapy is recommended for patients with no available donor for bone marrow transplant. Between October 1984 and November 1987, 25 consecutive children and adolescents with SAA with no HLA-compatible marrow donor received equine antithymocyte globulin (ATG) (15 mg kg-1 day-1) for 10 days. The patients were evaluated 6 weeks, 6 months, and 12 months after starting ATG treatment. Thereafter, patients were evaluated yearly until July 1998. Median age was 10 years (range, 1.5-20 years), granulocyte counts on referral ranged from 0.032 to 1.4 x 10(9)/l (median 0.256 x 10(9)/l), and 12 patients had granulocyte counts <0.2 x 10(9)/l. At a median follow-up of 9.6 years (range, 8.6-11.8 years), 10 patients (40%) remained alive with good marrow function. No morphologic evidence of hematological clonal disorders has been observed, although two patients probably have acquired clonal chromosomal abnormalities (trisomy 8 and del(6)q21, respectively). Responses to ATG were observed between 6 weeks and 6 months from the start of treatment in 60% of evaluable patients. The response rate was not different in patients whose granulocyte count at diagnosis was <0.2 x 10(9)/l, or in those who were <10 years of age. This study supports the view that, when compared with supportive measures, ATG is an effective treatment for children or adolescents with SAA. Although these results are inferior to those reported for marrow transplantation or more intensive immunosuppressive regimens, these patients who responded to ATG are long-term survivors with stable peripheral blood counts and a low rate of relapse.

Dietary fiber, energy intake and nutritional status during the treatment of children with chronic constipation

The present prospective study was carried out to determine dietary fiber and energy intake and nutritional status of children during the treatment of chronic constipation. Twenty-five patients aged 2 to 12 years with chronic constipation were submitted to clinical evaluation, assessment of dietary patterns, and anthropometry before and after 45 and 90 days of treatment. The treatment of chronic constipation included rectal disimpaction, ingestion of mineral oil and diet therapy. The standardized diet prescribed consisted of regular food without a fiber supplement and met the nutrient requirements according to the recommended daily allowance. The fiber content was 9.0 to 11.9 g for patients aged less than 6 years and 12.0 to 18.0 g for patients older than 6 years. Sixteen patients completed the 90-day follow-up and all presented clinical improvement. The anthropometric variables did not change, except midarm circumference and triceps skinfold thickness which were significantly increased. Statistically significant increases were also found in percent calorie intake adequacy in terms of recommended daily allowance (55.5 to 76.5% on day 45 and to 68.5% on day 90; P = 0.047). Percent adequacy of minimum recommended daily intake of dietary fiber (age + 5 g) increased during treatment (from 46.8 to 52.8% on day 45 and to 56.3% on day 90; P = 0.009). Food and dietary fiber intake and triceps skinfold thickness increased during follow-up. We conclude that the therapeutic program provided a good clinical outcome.

Reference value of brachial-ankle pulse wave velocity for the eastern Chinese population and potential influencing factors

The present study was conducted to obtain reference values for brachial-ankle pulse wave velocity (baPWV) and to evaluate influencing factors of baPWV according to gender. Using automatic devices, baPWV was measured simultaneously in 2095 subjects. A total of 647 healthy subjects, none of whom presented atherosclerotic risk factors, were analyzed in the present study. Two different statistical methods were used to obtain reference values for baPWV according to subject gender and age. The association between baPWV value and gender, as well as other features, were analyzed. For male subjects, multiple stepwise analysis showed that age, systolic blood pressure (SBP), heart rate (HR), and plasma levels of triglycerides (TG) were independent predictors of baPWV. For female subjects, age, SBP, HR, and plasma levels of uric acid (UA) were independent predictors of baPWV. In male subjects, the upper limits of baPWV values were 1497.43/1425.00, 1518.67/1513.25, 1715.97/1726.50, 1925.20/1971.90, and 2310.18/2115.00 cm/s, obtained using two different statistical methods for the age ranges of 30-39, 40-49, 50-59, 60-69, and 70 and older, respectively. For females, the upper limits of baPWV values were 1426.70/1411.13, 1559.15/1498.95, 1733.50/1739.00, 1958.63/1973.78, and 2720.80/2577.00 cm/s for the age ranges of 30-39, 40-49, 50-59, 60-69, and 70 and older, respectively. Aging is the most important influencing factor for baPWV value and its effect is more prominent in females. The reference values of baPWV according to age and gender may be useful for the clinical diagnosis and preventive therapy of cardiovascular diseases.

Classical and recent advances in the treatment of inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

Immunosupressive therapy in children with steroid-resistant nephrotic syndrome: single center experience

INTODUCTION: Nephrotic syndrome is one of the most frequent glomerular diseases among children, and steroid therapy remains as the treatment choice. In spite of this, 10 to 15% of the patients are steroidresistant, and the best therapy for such cases has never been defined. Mycophenolate acid (MA) is one of the treatments used in such situations. OBJECTIVE: To describe the clinical behavior of children diagnosed with steroid-resistant nephrotic syndrome (SRNS) and to assess the therapeutic response to MA. METHODS: This was a retrospective and descriptive study. RESULTS: 26 clinical records of patients with SRNS; 70% male and 30% female. All patients underwent kidney biopsies, which showed a predominance of focal segmental glomerulosclerosis (FSGS). The immunosuppresive drugs used were: Mycophenolate mofetil (MMF) 100%, Cyclosporine 69.2%, Cyclophosphamide 23.1%, and Rituximab 23%. One month after treatment initiation with MMF 61.5% achieved remission. The median of relapses per year for the patients was 3 (p25: 2.75 - p75: 4). This median became 1 (p25: 1 - p75: 3.25) after using this medication (p = 0.08). Furthermore, prior to the start of the MMF treatment, the median of the steroid dose was 1 (p25: 0.5- p75: 1.62) mg/k/day. After using MMF, this median became 0.07 (p25: 0 - p75: 0.55) mg/k/day (p < 0.001), in 8 patients prednisolone was stopped. CONCLUSION: In our experience, treatment with MMF showed positive results such as decrease in the frequency of relapses, less proteinuria, and reduction in the dose of steroids administered without deterioration of glomerular filtration rates. However, more studies are needed to assess efficacy, safety, and optimal dosage.

Therapeutic riding : learning and recovery for people with disabilities

The purpose ofthis study was to explore the process oftherapeutic riding as an experiential and holistic approach to learning and recovery for people with disabilities as perceived by the providers oftherapeutic riding. To enhance the connection between theory and practice and to suggest future research, the researcher endeavoured to develop a theory that contributed to the knowledge base oftherapeutic riding, animal-assisted therapy and education, experiential education, and experiential therapy in addition to contributing to connections among them. This topic was investigated because ofthe lack ofresearch about the process of therapeutic riding, particularly from learning and a recovery perspective. Few studies have addressed how therapeutic riding outcomes are achieved or how the therapeutic riding process actually works. This study was identified as grounded theory using qualitative data through interviews and narrative reflections with therapeutic riding providers, a researcher's journal, field notes, and written documents. Grounded theory analysis was used to analyze the qualitative data. This consisted ofdoing open, axial, and selective coding. This study provided detailed descriptions ofthe research approach, researcher's involvement, participant and site selection, data collection and analysis, methodological assumptions and limitations, credibility established, and ethical considerations. The findings ofthe data analysis revealed the theme ofrelationships as central to the learning and recovery process oftherapeutic riding for people with disabilities. The significance ofthe team relationships, the horse and rider relationship, and the providers and rider relationship was found. The essential components ofthe learning and recovery process were presented in a diagram in the selective coding phase. Goals oftherapeutic riding included psycho-education; behavioural and social; physical; and equestrian. Parts ofthe process ofhow outcomes were achieved included motivation; "opens new doors;" risk; task analysis; control; communication; and environmental factors. Outcomes of therapeutic riding included independence and mobility; confidence; and transfer abilities or skills. The implications ofthese findings for theory, practice, and further research were also. explored.

James J. Campbell and Dr. Arthur Flint outside Hashinger Hall

James J. Campbell [right], director of the Chapman College Residence Education Center at the El Toro Marine Corps Air Station, discusses the college's new science scholarship program with Dr. Arthur Flint, chairman of the Chapman Division of Natural Sciences, in front of the new science center, Hashinger Hall, Chapman College, 346 N. Center Street, Orange, California. The late Dr. Edward H. Hashinger, former trustee and past chairman of the board is the man whose name has graced the walls of this building since 1969. The Hashinger Science Center (3 floors, 65,364 sq.ft.) houses all science departments including biology, natural and applied sciences, environmental and chemical sciences, food science and nutrition, kinesiology and physical therapy.

Wait Times to Rheumatology and Rehabilitation Services for Persons with Arthritis in Quebec

L’arthrite est l’une des causes principales de douleur et d’incapacité auprès de la population canadienne. Les gens atteints d’arthrite rhumatoïde (AR) devraient être évalués par un rhumatologue moins de trois mois suivant l’apparition des premiers symptômes et ce afin de débuter un traitement médical approprié qui leur sera bénéfique. La physiothérapie et l’ergothérapie s’avèrent bénéfiques pour les patients atteints d’ostéoarthrite (OA) et d’AR, et aident à réduire l’incapacité. Notre étude a pour but d’évaluer les délais d’attente afin d’obtenir un rendez-vous pour une consultation en rhumatologie et en réadaptation dans le système de santé public québécois, et d’explorer les facteurs associés. Notre étude est de type observationnel et transversal et s’intéresse à la province de Québec. Un comité d’experts a élaboré trois scénarios pour les consultations en rhumatologie : AR présumée, AR possible, et OA présumée ; ainsi que deux scénarios pour les consultations en réadaptation : AR diagnostiquée, OA diagnostiquée. Les délais d’attente ont été mesurés entre le moment de la requête initiale et la date de rendez-vous fixée. L’analyse statistique consiste en une analyse descriptive de même qu’une analyse déductive, à l’aide de régression logistique et de comparaison bivariée. Parmi les 71 bureaux de rhumatologie contactés, et pour tous les scénarios combinés, 34% ont donné un rendez-vous en moins de trois mois, 32% avaient une attente de plus de trois mois et 34% ont refusé de fixer un rendez-vous. La probabilité d’obtenir une évaluation en rhumatologie en moins de trois mois est 13 fois plus grande pour les cas d’AR présumée par rapport aux cas d’OA présumée (OR=13; 95% Cl [1.70;99.38]). Cependant, 59% des cas d’AR présumés n’ont pas obtenu rendez-vous en moins de trois mois. Cent centres offrant des services publics en réadaptation ont été contactés. Pour tous les scénarios combinés, 13% des centres ont donné un rendez-vous en moins de 6 mois, 13% entre 6 et 12 mois, 24% avaient une attente de plus de 12 mois et 22% ont refusé de fixer un rendez-vous. Les autres 28% restant requéraient les détails d’une évaluation relative à l’état fonctionnel du patient avant de donner un rendez-vous. Par rapport aux services de réadaptation, il n’y avait aucune différence entre les délais d’attente pour les cas d’AR ou d’OA. L’AR est priorisée par rapport à l’OA lorsque vient le temps d’obtenir un rendez-vous chez un rhumatologue. Cependant, la majorité des gens atteints d’AR ne reçoivent pas les services de rhumatologie ou de réadaptation, soit physiothérapie ou ergothérapie, dans les délais prescrits. De meilleures méthodes de triage et davantage de ressources sont nécessaires.

The Role of Obsessive Beliefs and Inferential Confusion in Predicting Treatment Outcomes for Different Subtypes of Obsessive-Compulsive Disorder

Essai doctoral d’intégration Présenté en vue de l’obtention du doctorat (D.Psy.)

Interaction entre ventilation mécanique et traumatisme à la moelle épinière : réponses inflammatoires pulmonaires et médullaires

Le traumatisme de la moelle épinière est à l’origine d’une inflammation locale importante caractérisée par l’augmentation massive des cellules inflammatoires et la présence de réactions oxydatives. Cette inflammation locale peut déclencher une réponse inflammatoire systémique par voie hématogène. Au niveau cervical, les lésions médullaires peuvent entraîner des faiblesses ou la paralysie des muscles respiratoires. Le patient, qui ne peut plus respirer de façon autonome, doit avoir recours à un support respiratoire. Bien que la ventilation mécanique soit la thérapie traditionnellement appliquée aux blessés médullaires souffrant d’insuffisance respiratoire, les études ont démontré qu’elle pouvait contribuer à promouvoir une réponse inflammatoire ainsi que des dommages pulmonaires. L’interaction entre le traumatisme médullaire et la ventilation mécanique, indispensable au maintien de l’équilibre des échanges respiratoires, est inconnue à ce jour. En voulant protéger les tissus, cellules et organes, l’organisme met en œuvre toute une panoplie de réponses inflammatoires à différents endroits. Nous pensons que ces réponses peuvent être altérées via l’interaction entre ce traumatisme et cette ventilation mécanique, sous l’influence de la principale source cellulaire de cytokines pour la défense de l’hôte, le macrophage, récemment classé en deux phénotypes principaux: 1) l’activation classique de type M1 et 2) l’activation alternative de type M2. Le phénotype M1 est conduit par le facteur GM-CSF et induit par l’interféron IFN-ɣ ainsi que le lipopolysaccharide. Le phénotype M2 quant à lui, est conduit par le facteur M-CSF et induit par les interleukines IL-4, IL-13 ou IL-21. M1 relâche principalement IL-1β, IL-6, TNF-α et MIP-1α tandis que M2 principalement IL-10 et MCP-1. Toutefois, nous ignorons actuellement par quel type d’activation se manifestera cette réponse immunitaire et si l’application de support respiratoire pourrait entraîner un risque inflammatoire additionnel au site du traumatisme. Nous ignorons également si la ventilation mécanique affecterait, à distance, les tissus de la moelle épinière via une inflammation systémique et amplifierait alors le dommage initial. Il n’existe pas à ce jour, de thérapie qui ait montré d’effet bénéfique réel envers une récupération fonctionnelle des patients blessés médullaires. Il paraît donc essentiel de déterminer si la ventilation mécanique peut moduler l’inflammation post-traumatique à la fois au niveau pulmonaire et au site de la lésion. Ce travail visait à caractériser les liens entre l’inflammation issue du traumatisme médullaire et celle issue de la ventilation, dans le but de fournir une meilleure compréhension des mécanismes inflammatoires activés dans ce contexte. L’étude a été menée sur un modèle animal. Elle consistait à évaluer : 1) si le traumatisme médullaire influençait les réponses inflammatoires pulmonaires induites par la ventilation mécanique, y compris le phénotype des macrophages alvéolaires et 2) si la ventilation pouvait altérer à distance, les tissus de la moelle épinière. L’impact de la blessure médullaire sur l’inflammation pulmonaire et locale, induite par la ventilation fut interprété grâce à l’analyse des cellules inflammatoires dans les lavages broncho-alvéolaires et dans les tissus prélevés à l’endroit de la blessure après 24 heures. Ces analyses ont démontré un profil spécifique des cytokines pulmonaires et médullaires. Elles ont révélé que la ventilation mécanique a engendré un environnement pro-inflammatoire en faveur d’un phénotype M1 chez les animaux ayant bénéficié de la thérapie respiratoire. Inversement, l’atteinte thoracique chez les animaux sans ventilation, a montré qu’une réponse immunitaire avait été activée en faveur d’un environnement anti-inflammatoire de phénotype M2. La lésion cervicale quant à elle a induit un profil de cytokines différent et les réponses au stress oxydatif dans le poumon induites par la ventilation ont été réduites significativement. De plus, une lésion médullaire a augmenté l’expression d’IL-6 et la ventilation a diminué l’IL-1β et augmenté le TNF-α dans les tissus de la moelle. Finalement, ces données ont fourni les premières évidences que la ventilation a induit d’avantage à un phénotype pulmonaire M1 et que le traumatisme médullaire a impacté spécifiquement les réponses inflammatoires et oxydatives dans le poumon. La ventilation a contribué non seulement à distance à une inflammation des tissus médullaires lésés mais aussi des tissus sains.

Are primary and secondary provoked vestibulodynia two different entities? A comparison of pain, psychosocial and sexual characteristics.

Introduction Provoked vestibulodynia (PVD) is suspected to be the most frequent cause of vulvodynia in premenopausal women. Based on the onset of PVD relative to the start of sexual experience, PVD can be divided into primary (PVD1) and secondary PVD (PVD2). Studies comparing these PVD subgroups are inconclusive as to whether differences exist in sexual and psychosocial functioning. Aim The aim of this study was to compare the pain, sexual and psychosocial functioning of a large clinical and community-based sample of premenopausal women with PVD1 and PVD2. Methods A total of 269 women (n = 94 PVD1; n = 175 PVD2) completed measures on sociodemographics, pain, sexual, and psychosocial functioning. Main Outcome Measures Dependent variables were the 0–10 pain numerical rating scale, McGill–Melzack Pain Questionnaire, Female Sexual Function Index, Global Measure of Sexual Satisfaction, Beck Depression Inventory-II, Painful Intercourse Self-Efficacy Scale, Pain Catastrophizing Scale, State-Trait Anxiety Inventory Trait Subscale, Ambivalence over Emotional Expression Questionnaire, Hurlbert Index of Sexual Assertiveness, Experiences in Close Relationships Scale—Revised, and Dyadic Adjustment Scale-Revised. Results At first sexual relationship, women with PVD2 were significantly younger than women with PVD1 (P < 0.01). The average relationship duration was significantly longer in women with PVD2 compared with women with PVD1 (P < 0.01). Although women with PVD1 described a significantly longer duration of pain compared with women with PVD2 (P < 0.01), no significant subtype differences were found in pain intensity during intercourse. When controlling for the sociodemographics mentioned earlier, no significant differences were found in sexual, psychological, and relational functioning between the PVD subgroups. Nevertheless, on average, both groups were in the clinical range of sexual dysfunction and reported impaired psychological functioning. Conclusions The findings show that there are no significant differences in the sexual and psychosocial profiles of women with PVD1 and PVD2. Results suggest that similar psychosocial and sex therapy interventions should be offered to both subgroups of PVD.

A "Trojan horse" strategy to reverse drug-resistance in brain tumors

Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresivos con el peor pronóstico (1). El manejo terapéutico de los tumores del SNC se basa en la cirugía, la radioterapia y la quimioterapia, dependiendo de las características del tumor, el estadio clínico y la edad (2),(3), sin embargo ninguno de los tratamientos estándar es completamente seguro y compatible con una calidad de vida aceptable (3), (4). En general, la quimioterapia es la primera opción en los tumores diseminados, como el glioblastoma invasivo y el meduloblastoma de alto riesgo o con metástasis múltiple, pero el pronóstico en estos pacientes es muy pobre (2),(3). Solamente nuevas terapias dirigidas (2) como las terapias anti-angiogénicas (4); o terapias génicas muestran un beneficio real en grupos limitados de pacientes con defectos moleculares específicos conocidos (4). De este modo, se hace necesario el desarrollo de nuevas terapias farmacológicas para atacar los tumores cerebrales. Frente a las terapias los gliomas malignos son con frecuencia quimioresistentes, y esta resistencia parece depender de al menos dos mecanismos: en primer lugar, la pobre penetración de muchas drogas anticáncer a través de la barrera hematoencefálica (BBB: Blood Brain Barrier), la barrera del fluido sangre-cerebroespinal (BCSFB: Blood-cerebrospinal fluid barrier) y la barrera sangre-tumor (BTB: blood-tumor barrier). Dicha resistencia se debe a la interacción de la droga con varios transportadores o bombas de eflujo de droga ABC (ABC: ATP-binding cassette) que se sobre expresan en las células endoteliales o epiteliales de estas barreras. En segundo lugar, estos transportadores de eflujo de drogas ABC propios de las células tumorales confieren un fenotipo conocido como resistencia a multidrogas (MDR: multidrug resistance), el cual es característico de varios tumores sólidos. Este fenotipo también está presente en los tumores del SNC y su papel en gliomas es objeto de investigación (5). Por consiguiente el suministro de medicamentos a través de la BBB es uno de los problemas vitales en los tratamientos de terapia dirigida. Estudios recientes han demostrado que algunas moléculas pequeñas utilizadas en estas terapias son sustratos de la glicoproteína P (Pgp: P-gycoprotein), así como también de otras bombas de eflujo como las proteínas relacionadas con la resistencia a multidrogas (MRPs: multidrug resistance-related proteins (MRPs) o la proteína relacionada con cáncer de seno (BCRP: breast-cancer resistance related protein)) que no permiten que las drogas de este tipo alcancen el tumor (1). Un sustrato de Pgp y BCRP es la DOXOrubicina (DOXO), un fármaco utilizado en la terapia anti cáncer, el cual es muy eficaz para atacar las células del tumor cerebral in vitro, pero con un uso clínico limitado por la poca entrega a través de la barrera hematoencefálica (BBB) y por la resistencia propia de los tumores. Por otra parte las células de BBB y las células del tumor cerebral tienen también proteínas superficiales, como el receptor de la lipoproteína de baja densidad (LDLR), que podría utilizarse como blanco terapéutico en BBB y tumores cerebrales. Es asi como la importancia de este estudio se basa en la generación de estrategias terapéuticas que promuevan el paso de las drogas a través de la barrera hematoencefalica y tumoral, y a su vez, se reconozcan mecanismos celulares que induzcan el incremento en la expresión de los transportadores ABC, de manera que puedan ser utilizados como blancos terapéuticos.Este estudio demostró que el uso de una nueva estrategia basada en el “Caballo de Troya”, donde se combina la droga DOXOrubicina, la cual es introducida dentro de un liposoma, salvaguarda la droga de manera que se evita su reconocimiento por parte de los transportadores ABC tanto de la BBB como de las células del tumor. La construcción del liposoma permitió utilizar el receptor LDLR de las células asegurando la entrada a través de la BBB y hacia las células tumorales a través de un proceso de endocitosis. Este mecanismo fue asociado al uso de estatinas o drogas anticolesterol las cuales favorecieron la expresión de LDLR y disminuyeron la actividad de los transportadores ABC por nitración de los mismos, incrementando la eficiencia de nuestro Caballo de Troya. Por consiguiente demostramos que el uso de una nueva estrategia o formulación denominada ApolipoDOXO más el uso de estatinas favorece la administración de fármacos a través de la BBB, venciendo la resistencia del tumor y reduciendo los efectos colaterales dosis dependiente de la DOXOrubicina. Además esta estrategia del "Caballo de Troya", es un nuevo enfoque terapéutico que puede ser considerado como una nueva estrategia para aumentar la eficacia de diferentes fármacos en varios tumores cerebrales y garantiza una alta eficiencia incluso en un medio hipóxico,característico de las células cancerosas, donde la expresión del transportador Pgp se vió aumentada. Teniendo en cuenta la relación entre algunas vías de señalización reconocidas como moduladores de la actividad de Pgp, este estudio presenta no solo la estrategia del Caballo de Troya, sino también otra propuesta terapéutica relacionada con el uso de Temozolomide más DOXOrubicina. Esta estrategia demostró que el temozolomide logra penetrar la BBB por que interviene en la via de señalización de la Wnt/GSK3/β-catenina, la cual modula la expresión del transportador Pgp. Se demostró que el TMZ disminuye la proteína y el mRNA de Wnt3 permitiendo plantear la hipótesis de que la droga al disminuir la transcripción del gen Wnt3 en células de BBB, incrementa la activación de la vía fosforilando la β-catenina y conduciendo a disminuir la β-catenina nuclear y por tanto su unión al promotor del gen mdr1. Con base en los resultados este estudio permitió el reconocimiento de tres mecanismos básicos relacionados con la expresión de los transportadores ABC y asociados a las estrategias empleadas: el primero fue el uso de las estatinas, el cual condujo a la nitración de los transportadores disminuyendo su actividad por la via del factor de transcripción NFκB; el segundo a partir del uso del temozolomide, el cual metila el gen de Wnt3 reduciendo la actividad de la via de señalización de la la β-catenina, disminuyendo la expresión del transportador Pgp. El tercero consistió en la determinación de la relación entre el eje RhoA/RhoA quinasa como un modulador de la via (no canónica) GSK3/β-catenina. Se demostró que la proteína quinasa RhoA promovió la activación de la proteína PTB1, la cual al fosforilar a GSK3 indujo la fosforilación de la β-catenina, lo cual dio lugar a su destrucción por el proteosoma, evitando su unión al promotor del gen mdr1 y por tanto reduciendo su expresión. En conclusión las estrategias propuestas en este trabajo incrementaron la citotoxicidad de las células tumorales al aumentar la permeabilidad no solo de la barrera hematoencefálica, sino también de la propia barrera tumoral. Igualmente, la estrategia del “Caballo de Troya” podría ser útil para la terapia de otras enfermedades asociadas al sistema nervioso central. Por otra parte estos estudios indican que el reconocimiento de mecanismos asociados a la expresión de los transportadores ABC podría constituir una herramienta clave en el desarrollo de nuevas terapias anticáncer.

Tratamiento de Artritis reumatoide con antagonistas del factor de necrosis tumoral alfa y su asociación con el desarrollo de melanoma cutáneo: revisión sistemática de la literatura y meta-análisis.

Introducción: El tratamiento con antagonistas del factor de necrosis tumoral alfa (anti TNF) ha impactado el pronóstico y la calidad de vida de los pacientes con artritis reumatoide (AR) positivamente, sin embargo, se interroga un incremento en el riesgo de desarrollar melanoma. Objetivo: Conocer la asociación entre el uso de anti TNF y el desarrollo de melanoma maligno en pacientes con AR. Metodología: Se realizó una búsqueda sistemática en MEDLINE, EMBASE, COCHRANE LIBRARY y LILACS para ensayos clínicos, estudios observacionales, revisiones y meta-análisis en pacientes adultos con diagnóstico de AR y manejo con anti TNF (Certolizumab pegol, Adalimumab, Etanercept, Infliximab y Golimumab). Resultados: 37 estudios clínicos cumplieron los criterios de inclusión para el meta-análisis, con una población de 16567 pacientes. El análisis de heterogeneidad no fue significativo (p=1), no se encontró diferencia en el riesgo entre los grupos comparados DR -0.00 (IC 95% -0.001; -0.001). Un análisis adicional de los estudios en los que se reportó al menos 1 caso de melanoma (4222 pacientes) tampoco mostró diferencia en el riesgo DR -0.00 (IC 95% -0.004 ; -0.003). Conclusión: En la evidencia disponible a la fecha no encontramos asociación significativa entre el tratamiento con anti TNF en pacientes con diagnóstico de AR y el desarrollo de melanoma cutáneo.

Becoming skilled: The cultural and corporeal geographies of teaching and learning Thai Yoga massage

This paper explores the process of learning an embodied knowledge using the work of Dreyfus and Deleuze. Although geographers have begun to acknowledge the role of embodied knowledges in social life, there have been few in-depth case studies of how these skills are learned. This paper offers a case study of Thai Yoga massage (TYM), a ‘complementary and alternative therapy’ which is growing in popularity in the United Kingdom. Having outlined the case study, the paper explores the cultural geographies of the formalisation, documentation and contestation of the set of techniques that have come to cohere in the UK as TYM. The paper then interrogates the messy corporeal geographies of learning a skill, and briefly considers how more advanced practitioners experience their skilled practice.