Ischemia (I) and reperfusion (R) trigger a series of events, which culminate in severe injury to the transplanted organ. Cell death resulting from the formation of mitochondrial reactive oxygen species (ROS) coupled with the perturbation of mitochondrial Ca2+ homeostasis is central to the development of IR-associated tissue damage. We and others have shown recently that intracellular signaling pathways critically control these mitochondrial changes, making them potential targets for therapeutic intervention. Using a heterotopic murine heart transplant model as well as primary and immortalized cardiomyocyte cells we established the activity patterns of mitogen-activated protein kinases (MAPKs) ERK, JNK, and p38 during IR, and probed into their role in the perturbation of mitochondrial ROS and Ca2+ homeostasis, which are necessary for cardiomyocyte death. Our results showed a strong activation of all three MAPKs as well as a rise in mitochondrial ROS and Ca2+ during early reoxygenation. Inhibiting p38 kinase most efficiently prevented ROS production, Ca2+ overload and cell death, suggesting that targeting this signaling molecule may provide a possible strategy to limit the effects of IR.

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Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans.

Background: Congenital gastric antral web and congenital pyloric atresia are rare reasons of congenital gastric outlet obstruction (CGOO). Depending on the different forms, the symptoms vary from unspecific epigastric pain to nonbilious "projectile" vomiting, ileus and failure to thrive. Throughout the years, many different treatment options are described, like simple surgical dilatation, incision or excision of the membrane, possibly combined with a pyloroplasty.Patients and Methods: In this retrospective single-center observation study, we present 9 cases with different kinds of webs leading to CGOO. In a time period of 45 years (1970 to 2015) different treatment strategies and limitations of minimal invasive endoscopic treatment on the basis of complications and outcome are discussed.Results: Six patients had an incomplete antrum web. One patient suffered from a complete antrum web. In addition, in 2 patients a complete pyloric web, as well as an incomplete pyloric web was found. During the past 45 years, the treatment options for CGOO due to webs changed, and with the development of smaller and more flexible video endoscopes an endoscopic treatment has become feasible. The treatment strategy and follow-up examination was specific to every patient. Conclusion:On the basis of our review, minimal endoscopic procedures in small newborns and toddlers require a high level of experience. They are technically challenging and need suitable equipment. Overall, endoscopists and pediatric surgeons should equally be prepared for all possible complications in every treatment step. The endoscopic approach to managing this unusual disease may require multiple interventions and is associated with a risk of perforation. Therefore, we are convinced that centers undertaking this treatment modality should be equipped with the proper instrumentation, prepared to perform multiple endoscopic interventions, and supported with an ability to emergently convert to surgery if required.

In normal control subjects, LES measurement using circumferential solid-state transducers yields higher pressures than standard water-perfused manometry. Which system yields the "true" resting pressure of the physiologic LES remains to be determined.