This study sought to maximize prenatal and postnatal interventions in order to accelerate lung growth and improve lung function in two animal models. Prenatal interventions consisted of fetal tracheal occlusion (TO), antenatal glucocorticoids and exogenous surfactant at birth (SURF) in an ovine model of congenital diaphragmatic hernia (CDH). CDH, CDH+TO, CDH+SURF, CDH+TO+SURF and unoperated twin control lambs were compared. Prenatal growth of both lungs was accelerated after fetal TO. Prophylactic surfactant did not improve gas exchange or ventilation but did increase lung compliance over 8 hours. The incidence of tension pneumothoraces was slightly decreased after exogenous surfactant. Fetal TO yields the best results in terms of overall postnatal lung function, likely acting via surfactant independent mechanisms. / Postnatal intervention involved perfluorocarbon (PFC) liquid distention of the right upper lobe in healthy newborn piglets. Postnatal lung growth, as measured indirectly by rates of DNA synthesis, was not accelerated after PFC distention.

In a normal inflammatory response, the polymorphonuclear neutrophil (PMN) is recruited to a site of injury or infection through a sequence of events that include margination, rolling, adhesion, diapedesis and chemotaxis. These processes become dysregulated in SIRS, sepsis and MODS. Septic patients demonstrate decreased PMN exudation to peripheral sites and an absence of a C5a chemotactic gradient across the intravascular and extravascular environments. Using both in vitro and in vivo PMN transmigration assays, we evaluated the role of an intact C5a gradient on human PMN recruitment to peripheral inflammatory sites in sepsis. We demonstrated in vitro that a C5a gradient could induce both beta2-integrin dependent and independent transendothelial migration of septic PMN. In vivo, the exogenous re-establishment of the C5a gradient increased septic PMN exudation to normal baseline levels. These observations implicate an intact C5a gradient as an essential component to optimal PMN recruitment in sepsis.

Background. Data indicates that early xenoislet graft failure is due to non specific inflammatory mechanisms that occur prior to T cell mediated rejection. The host hepatic endothelial cell may be important in this process because it is essentially the first cellular barrier encountered by intraportally introduced islets. We have characterized the initial response of endothelium to xenogeneic islets by measuring the expression of 11-1alpha, TNF-alpha, IFN-gamma, and iNOS mRNA in an in vitro dog-to-pig model of xenoislet transplantation. / Materials & methods. Dog islets were co-cultured with either porcine hepatic endothelium or porcine aortic endothelium over a 24-hour period in serum free medium. RNA was extracted at eight time points. RT-PCR was performed in order to visualize II-1alpha, TNF-alpha, IFN-gamma, and BIOS expression. Bands were semiquantitated by comparison to an external standard (GAPDH) using band densitometry. / Results. Hepatic endothelium had early (one hour) expression of IL-1alpha, IFN-gamma, and iNOS transcript. IL-1alpha peaked at two hours, IFN-gamma at 12 hours, and iNOS at one and 12 hours. Aortic endothelium expressed low levels of IL-1alpha and TNF-alpha, but not IFN-gamma or NOS. / Conclusions. We have demonstrated that xenogeneic islets are able to activate host endothelial cells without serum or immune cells. The observed endothelial response corresponds with known islet toxic substances. Furthermore, the response differs between endothelial beds suggesting that these differences may be important in choosing suitable implantation sites for islets. Our findings suggest that host endothelium may play an important part in early injury of islet xenotransplants.

Arsenic trioxide (As2O3) is an effective treatment strategy for acute promyelocytic leukemia (APL), as sensitivity to As2O3 may correlate with the induction of oxidative stress. However, the use of As2O3 in other malignancies is limited at clinically achievable doses. To expand the clinical potential of arsenic to other malignancies, a promising novel arsenical, darinaparsin (S-dimethylarsino-glutathione, ZIO-101) is more potent in vitro than As2O3 in a variety of hematopoietic malignant cell lines. At equimolar concentrations, darinaparsin is significantly more potent than As2O3 in inducing signalling pathways known to be required for arsenic-induced apoptosis. Moreover, unlike As2O3, darinaparsin is a selective inducer of Nrf2 antioxidant responses, thereby generating unopposed oxidative stress response and apoptosis in APL. Interestingly, darinaparsin does not demonstrate sensitivity to inhibition of ABCC1 (Mrp1), a known transporter involved in resistance to arsenic, suggesting that darinaparsin may be an effective treatment in tumours that overexpress ABCC1. / L’anhydride arsénieux (As2O3) est un traitement efficace contre la leucémie aigue myéloide (LAM). La sensibilité envers l’As2O3 peut être attribué à l’induction de stress oxidative. Cependant, l’usage d’ As2O3 dans le cadre d’autres malignités est limité par la posologie clinique. Pour élargir le potential thérapeutique de l’arsenic, un nouveau composé arsenical, le darinaparsin (ZIO-101), est plus efficace in vitro que l’ As2O3 dans une variété de cellules hématopoïétiques malines. Dans des conditions d’équimolarité, le darinaparsin est beaucoup plus puissant que l’ As2O3 pour provoquer des voies métaboliques requises pour l’apoptose. De plus, contrairemet à l’ As2O3, le darinaparsin insite séléctivement l’antioxidant Nrf2. Ce dernier produit un stress oxidative incontesté qui permet l’apoptose dans le cadre de la LAM. Curieusement, le darinaparsin ne répond pas à l’inhibition de l‘ABCC1 (Mrp 1), un transporteur qui confère de la résistance contre l’arsenic. Ceci suggère que le darinaparsin peut être un traitement efficace contre des tumeurs qui possèdent une importante quantitée d’ABCC1.

No description available.

No description available.

The purpose of this study was to determine the effect of reversible fetal tracheal occlusion on lung development. Nine fetal sheep were divided into two groups. Group 1 had intratracheal balloons placed and the balloons left inflated for 21-28 days. Group 2 consisted of littermates that served as controls. They had either uninflated balloons placed or were left unoperated. Tracheal pressure measurements were periodically recorded and the amniotic fluid pressure served as a reference. The animals were sacrificed near term and the lungs, heart and liver were weighed and corrected for body weight. Standard morphometry was used to compare the lungs further and the lung DNA and protein content were measured. Tracheal damage from the balloon catheter was also assessed. / Tracheal pressure was 3.85 ($ pm$.49 S.E.) mm Hg in experimental animals while it was an average of $-$0.27 ($ pm$.27 S.E.) mm Hg in controls (p $<$.0001). Tracheal occlusion increased lung weight and volume by 2-3 times (p $<$.0001 and p =.0006, respectively) while heart and liver weights remained similar to controls. Airspace fraction and radial alveolar counts were raised (p =.044 and p =.0002, respectively) and alveolar number per body weight was doubled (p $<$.0001). The alveolar number per lung volume was preserved, however, as was the DNA and protein content per unit weight of lung tissue. The chronic indwelling balloon catheter caused some mucosal and submucosal damage at the balloon site and proximal to it. / These results show that tracheal occlusion leads to an elevation of intratracheal pressure that is associated with a tremendous increase in lung growth over a short period in the third trimester fetal sheep. The techniques used in this experiment may be easily modified for use with endoscopic surgical equipment.

No description available.

The aim of this study was to examine apo(a)B particles distribution among plasma lipoproteins in two situations in which triglyceride-rich lipoproteins are increased: in normolipidemic subjects after a fat load and in patients with endogenous hypertriglyceridemia. / The results obtained demonstrate that, in hypertriglyceridemic patients, the distribution of apo(a)B particles among lipoprotein fractions is different than that observed in normotriglyceridemic subjects. These differences in distribution are a result of the association of apo(a)B particles with TG-rich lipoproteins. Contrary to apo(a)B particles found in the cholesterol-rich fraction apo(a)B particles in the TG-rich fraction are associated with lipoproteins of different sizes. The amount of apo(a)B particles in the TG-rich fraction could represent up to 50% of its total concentration and may contribute to the atherogenic and the thrombogenic potential of VLDL in HTG.

Body composition studies (BC) by a multiple isotope dilution technique were performed for studying nutritional parameters and nutritional support. A group of anthropometric, biochemical and immunological parameters were measured and the data indicated that these parameters were valid measures of the nutritional state for epidemiological studies; but, of little value in assessing the individual's nutritional state. Of 44 morbidly obese patients undergoing jejunoileal bypass, 33 patients lost only body fat. Eleven patients lost both body fat and body cell mass (BCM) thus developing protein malnutrition. Six of these malnourished patients had abnormal liver function tests (LFT), and both the BC and the LFT improved when calorie free amino acids were infused. BC studies were performed on TPN patients receiving one of four solutions. To evaluate the effect of these solutions on the daily repletion of the BCM a multiple linear regression was used. The regression indicated that the repletion of the depleted BCM was related to the lipid (p < .01) and carbohydrate (p < .001) infused, and the nutritional state (p < .001). Carbohydrate was more efficient than lipid, in repleting the BCM, and increasing protein above 1.26 gm/kg/day had no benefit.