Induction of Indoleamine 2,3-Dioxygenase by Gene Delivery in Allogeneic Islets Prolongs Allograft Survival

Indoleamine 2,3-dioxygenase (IDO), an enzyme that plays a critical role in fetomaternal tolerance, exerts immunoregulatory functions suppressing T-cell responses. The aims of this study were to promote IDO expression in rat islets using a nonviral gene transfer approach, and to analyze the effect of the in vivo induction of IDO in a model of allogeneic islet transplantation. The IDO cDNA was isolated from rat placenta, subcloned into a plasmid and transfected into rat islets using Lipofectamine. The efficiency of transfection was confirmed by qRT-PCR and functional analysis. The in vivo effect of IDO expression was analyzed in streptozotocin-induced diabetic Lewis rats transplanted with allogeneic islets under the renal capsule. Transplantation of IDO-allogeneic islets reversed diabetes and maintained metabolic control, in contrast to transplantation of allogeneic nontransfected islets, which failed shortly after transplantation in all animals. Graft survival of allograft islets transfected with IDO transplanted without any immunosuppression was superior to that observed in diabetic rats receiving nontransfected islets. These data demonstrated that IDO expression induced in islets by lipofection improved metabolic control of streptozotocin-diabetic rats and prolonged allograft survival.

Targeted drug delivery to the skin and deeper tissues: Role of physiology, solute structure and disease

1. Drug delivery through the skin has been used to target the epidermis, dermis and deeper tissues and for systemic delivery, The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region, The polarity of the intercellular region appears to be similar to butanol, with the diffusion of solutes being hindered by saturable hydrogen bonding to the polar head groups of the ceramides, fatty acids and other intercellular lipids, Accordingly, the permeability of the more lipophilic solutes is greatest from aqueous solutions, whereas polar solute permeability is favoured by hydrocarbon-based vehicles. 2. The skin is capable of metabolizing many substances and, through its microvasculature, limits the transport of most substances into regions below the dermis. 3. Although the flux of solutes through the skin should be identical for different vehicles when the solute exists as a saturated solution, the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It is therefore desirable that the regulatory standards required for the bioequivalence of topical products include skin studies. 4. Deep tissue penetration can be related to solute protein binding, solute molecular size and dermal blood flow. 5. Iontophoresis is a promising area of skin drug delivery, especially for ionized solutes and when a rapid effect is required. 6. In general, psoriasis and other skin diseases facilitate drug delivery through the skin. 7. It is concluded that the variability in skin permeability remains an obstacle in optimizing drug delivery by this route.

Cavopulmonary anastomosis improves left ventricular assist device support in acute biventricular failure

Objective: Right ventricular failure during left ventricular assist device (WAD) support can result in severe hemodynamic compromise with high mortality. This study investigated the acute effects of cavopulmonary anastomosis on right ventricular loading and WAD performance in a model of severe biventricular failure. Methods: LVAD support was performed by means of centrifugal pump implantation in 14 anesthetized dogs (20-30 kg) with severe biventricular failure obtained by ventricular fibrillation induction. Animals were randomized to be submitted to classical cavopulmonary anastomosis (Glenn shunt) or to control group and were maintained under WAD support for 2 h. Left and right atrial, right ventricular and systemic pressures were monitored, white total pulmonary flow was simultaneously recorded by transonic flowmeters located on the superior vena cava and pulmonary trunk. Blood gas and venous lactate determinations were also obtained. Results: Ventricular fibrillation maintenance resulted in acute WAD performance impairment after 90 min in the control group, while animals with Glenn circuit maintained normal WAD pump flow (55 +/- 13 ml kg(-1) min(-1) vs 21 +/- 4 ml kg(-1) min(-1), p < 0.001) and better peripheral perfusion (blood lactate of 29 +/- 10 pg/ml vs 46 +/- 9 pg/ml, p < 0.001). Left and right atrial pressures did not change significantly, while right ventricular pressure was tower in animals with Glenn circuit (13 +/- 3 mmHg vs 22 +/- 8 mmHg, p = 0.005). Right ventricular unloading with Glenn shunt also resulted in superior total pulmonary flow (59 +/- 13 ml kg(-1) min(-1) vs 17 +/- 3 ml kg(-1) min(-1), p < 0.001). Conclusion: The concomitant use of cavopulmonary anastomosis during LVAD support in a model of severe biventricular failure limited right ventricular overloading and resulted in better hemodynamic performance. (C) 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3)center dot H(2)O encapsulated in PLGA microparticles for delivery of nitric oxide to B16-F10 cells: Cytotoxicity and phototoxicity

The NO donor trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O (py = pyridine) was loaded into poly-lactic-co-glycolic acid (PLGA) microparticles using the double emulsification technique. Scanning electron microscopy (SEM) and dynamic light scattering revealed that the particles are spherical in shape, have a diameter of 1600 nm, and have low tendency to aggregate. The entrapment efficiency was 25%. SEM analysis of the melanoma cell B16-F10 in the presence of the microparticles containing the complex trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O (pyMP) showed that the microparticles were adhered to the cell surface after 2 h of incubation. The complex with concentrations lower than 1 x 10(-4) M did not show toxicity in B16-F 10 murine cells. The complex in solution is toxic at higher concentrations (> 1 x 10(-3) M), with cell death attributed to NO release following the reduction of the complex. pyMP is not cytotoxic due to the lower bioavailability and availability of the entrapped complex to the medium and its reducing agents. However, pyMP is phototoxic upon light irradiation. The phototoxicity strongly suggests that cell death is due to NO release from trans-[Ru(NO)(NH(3))(4)(py)](3+). This work shows that pyMP can serve as a model for a drug delivery system carrying the NO donor trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O, which can release NO locally at the tumor cell by radiation with light only. (c) 2007 Elsevier Inc. All rights reserved.

Safety of the etonogestrel-releasing implant during the immediate postpartum period: a pilot study

Background: The effects of etonogestrel (ETG)-releasing contraceptive implant during the immediate postpartum period on maternal safety are unknown. Study design: Forty healthy women exclusively breastfeeding were randomized to receive either ETG-releasing implant 24-48 h after delivery (n=20) or depot medroxyprogesterone acetate (DMPA group; n=20) at the sixth week postpartum. We measured blood pressure, maternal and neonatal weight, body mass index (BMI; kg/m(2)), waist circumference (WC), complete blood count, C-reactive protein, interleukin-6, tumor necrosis factor (TNF-alpha), lipid profile, fasting serum glucose and maintenance of exclusive lactation up to the 12th week postpartum. Results: Decreases in mean maternal weight, BMI (kg/m(2)) and WC were significantly greater in the ETG-releasing implant group than in the MPA group during the first 6 weeks postpartum (-4.64 +/- 2.71 kg vs. -2.6 +/- 2.45 kg mean +/- SD, p=.017; -1.77 +/- 1.06 kg/m(2) vs. -0.97 +/- 0.95 kg/m(2), p=.026; -15.3 +/- 6.72 cm vs. -9.05 +/- 5.84 cm, p=.003, respectively). In addition, total cholesterol and HDL, were lower in DMPA users, and TNF-alpha and leukocytes were higher in DMPA users compared to in the implant group, between 6 and 12 weeks after delivery. The newborns of implant users showed a trend towards gaining more weight, as compared with the infants of the DMPA mothers during the first 6 weeks of life (implant group: +1460.50 +/- 621.34 g vs. DMPA group: +1035.0 +/- 562.43 g, p=.05). The remaining variables, including the duration of exclusive breastfeeding, were similar between the groups. Conclusion: The insertion of ETG-releasing contraceptive implant during the immediate postpartum period was not associated with deleterious maternal clinical effects or with significant maternal metabolic alterations or decreased infant weight gain. (C) 2009 Elsevier Inc. All rights reserved.

Comparison of pelvic floor muscle strength between women undergoing vaginal delivery, cesarean section, and nulliparae using a perineometer and digital palpation

Objectives. To compare pelvic floor muscle (PFM) strength between women undergoing vaginal delivery, cesarean section, and nulliparae, investigating the factors associated with PFM strength, and observing the correlation between vaginal digital palpation and use of a perineometer. Methods. A cross-sectional study was conducted, including 31 women following vaginal delivery, 30 women following cesarean section, and 30 nulliparous women. PFM strength was measured by vaginal digital palpation and use of a perineometer. Multiple linear regression analysis with adjustment for covariables was used to compare the mean PFM strength and identify its associated factors. Results. The mean PFM strength of women undergoing vaginal delivery and cesarean section was 25.6 +/- 14.5 cmH(2)O and 39.6 +/- 22.0 cmH(2)O (p < 0.01, adjusted for covariables), respectively. A correlation was observed between measurements of PFM strength obtained by vaginal digital palpation and use of a perineometer (tau = 0.82; p < 0.01). The non-white race/ethnicity was negatively associated with PFM strength (coefficient: -10.2424; p = 0.02). Conclusions. A lower PFM strength was observed in women with a history of vaginal delivery compared to those undergoing cesarean section. Non-white race/ethnicity negatively affected PFM strength. Our data suggest that vaginal digital palpation may be used in clinical practice because of its expressive correlation with use of a perineometer.

Cesarean delivery is associated with an increased risk of obesity in adulthood in a Brazilian birth cohort study

Background: Obesity is epidemic worldwide, and increases in cesarean delivery rates have occurred in parallel. Objective: This study aimed to determine whether cesarean delivery is a risk factor for obesity in adulthood in a birth cohort of Brazilian subjects. Design: We initiated a birth cohort study in Ribeirao Preto, southeastern Brazil, in 1978. A randomly selected sample of 2057 subjects from the original cohort was reassessed in 2002-2004. Type of delivery, birth weight, maternal smoking, and schooling were obtained after birth. The following data from subjects were collected at 23-25 y of age: body mass index (BMI; in kg/m(2)), physical activity, smoking, and income. Obesity was defined as a BMI >= 30. A Poisson multivariable model was performed to determine the association between cesarean delivery and BMI. Results: The obesity rate in adults born by cesarean delivery was 15.2% and in those born by vaginal delivery was 10.4% (P = 0.002). Adults born by cesarean delivery had an increased risk (prevalence ratio: 1.58; 95% CI: 1.23, 2.02) of obesity at adulthood after adjustments. Conclusion: We hypothesize that increasing rates of cesarean delivery may play a role in the obesity epidemic worldwide. Am J Clin Nutr 2011;93:1344-7.

A Simple and Efficient Device for Demonstrating Cross-sectional Anatomy of the Head

Described in this article is a novel device that facilitates study of the cross-sectional anatomy of the human head. In designing our device, we aimed to protect sections of the head from the destructive action of handling during anatomy laboratory while also ensuring excellent visualization of the anatomic structures. We used an electric saw to create 15-mm sections of three cadaver heads in the three traditional anatomic planes and inserted each section into a thin, perforated display box made of transparent acrylic material. The thin display boxes with head sections are kept in anatomical order in a larger transparent acrylic storage box containing formaldehyde solution, which preserves the specimens but also permits direct observation of the structures and their anatomic relationships to each other. This box-within-box design allows students to easily view sections of a head in its anatomical position as well as to examine internal structures by manipulating individual display boxes without altering the integrity of the preparations. This methodology for demonstrating cross-section anatomy allows efficient use of cadaveric material and technician time while also giving learners the best possible handling and visualization of complex anatomic structures. Our approach to teaching cross-sectional anatomy of the head can be applied to any part of human body, and the value of our device design will only increase as more complicated understandings of cross-sectional anatomy are required by advances and proliferation of imaging technology. Anat Sci Educ 3: 141-143, 2010. (C) 2010 American Association of Anatomists.