Diaphragmatic hernias (DH) are an unusual complication after pediatric liver transplantation; however, they have been reported with increased frequency in the past few years. DHs are responsible for nearly half of the small bowel obstructions requiring surgical intervention in this patient population. It has been suggested that the use of a left lobe liver graft, surgical trauma, malnourishment, elevated intra-abdominal pressures, and mTor inhibitors may predispose to development of DH. The use of a segmental graft may increase the recognition of diaphragmatic hernia because the surgically damaged right hemi-diaphragm often remains exposed to underlying viscera, instead of being covered by the right hepatic lobe. Treatment is surgical reduction, with up to 20% of the patients requiring resection of the herniated intestine. Herein we describe a case of DH after left segmental liver transplant in a two- yr-old boy that presented one month post left lobe split liver transplant with abdominal pain, anorexia, and respiratory distress. Just like in the majority of the reported cases, an urgent laparotomy with primary repair was performed. No resection of the herniated segment of intestine was required. For pediatric patients with otherwise unexplained respiratory or gastrointestinal symptoms after a left lateral segment liver transplant, right-sided diaphragmatic hernias should always be high in the differential diagnosis.
Cigarette smoke is known to be a risk for the development of intrauterine growth restriction (IUGR). Our objective was to assess the effects of secondhand smoke (SHS) during pregnancy and to what extent it regulates the activation of mTOR family members and murine trophoblast invasion. Mice were treated to SHS for 4 days. Placental and fetal weights were recorded at the time of necropsy. Immunohistochemistry was used to determine the level of placental trophoblast invasion. Western blots were utilized to assess the activation of caspase 3, XIAP, mTOR, p70 and 4EBP1 in treated and control placental lysates. As compared to controls, treated animals showed: (1) decreased placental (1.4-fold) and fetal (2.3-fold) weights (p < 0.05); (2) decreased trophoblast invasion; (3) significantly decreased active caspase 3 (1.3-fold; p < 0.02) and increased active XIAP (3.6-fold; p < 0.05) in the placenta; and (4) a significant decrease in the activation of placental mTOR (2.1-fold; p < 0.05), p70 (1.9-fold; p < 0.05) and 4EBP1 (1.3-fold; p < 0.05). Confirmatory in vitro experiments revealed decreased trophoblast invasion when SW71 cells were treated with 0.5 or 1.0 % cigarette smoke extract (CSE). Similar to primary smoking, SHS may induce IUGR via decreased activation of the mTOR family of proteins in the placenta. Increased activation of the placental XIAP protein could be a survival mechanism for abnormal trophoblast cells during SHS exposure. Further, CSE reduced trophoblast invasion, suggesting a direct causative effect of smoke on susceptible trophoblast cells involved in IUGR progression. These results provide important insight into the physiological consequences of SHS exposure and smoke-mediated placental disease.
BackgroundGestational diabetes mellitus (GDM) is associated with important factors that influence fetal development. Sphingolipids are known to be associated with the development of diabetes. Our objective was to examine ceramide, a key sphingolipid, hyperosmolarity, and apoptosis in placentas from GDM patients treated with insulin or diet.MethodsCeramide levels were assessed in placental tissues using immunohistochemistry. Immunoblot was performed to quantify serine palmitoyltransferase (SPT), the rate-limiting enzyme in ceramide biosynthesis, NFAT5, SMIT, AR, caspase 3 and the X-linked inhibitor of apoptosis. Trophoblast cells were treated with insulin or ceramide and assessments for mitochondrial respiration, caspase 3 and XIAP were also performed.ResultsImmunohistochemistry showed increased ceramides in the placental villous trophoblasts of the insulin-treated GDM patients. Nuclear SPT was upregulated only in the insulin-treated GDM placenta when compared to controls. Nuclear NFAT5 was also increased in the GDM placenta. Active caspase 3 was elevated in placentas from both insulin- and diet-treated GDM patients. Mitochondrial respiration was decreased in trophoblasts treated with ceramide. Active caspase was not changed while XIAP protein was increased in trophoblasts treated with ceramide.ConclusionsOur findings confirm the presence of ceramide in the human placenta of control and GDM patients. Furthermore, we conclude that ceramide is increased in the placental trophoblast during insulin treatment and that its upregulation correlates with elevated NFAT5, SMIT, increased apoptosis and decreased trophoblast mitochondrial respiration.
Intrauterine growth restriction (IUGR) is an obstetric pathology characterized by an increase in trophoblast apoptosis and decreased cell invasion. Trophoblasts are critical for a successful pregnancy and they mediate important steps such as implantation, immune protection of the fetus, maternal blood flow to the placenta, and delivery. Previous mouse studies in our laboratory showed increased trophoblast apoptosis, decreased cell invasion and increased placental receptors for advanced glycation end‐products (RAGE) during second hand smoke (SHS) treatment. More recently, a role for nuclear RAGE (nRAGE) has been implicated in DNA double strand break (DNA‐DSB) repair. We tested the hypothesis that RAGE is involved during DNA‐DSB repair in trophoblast cells. DSBs were induced in human trophoblasts (Bewo and Sw71) with cigarette smoke extract (CSE) or bleomycin (BLM). Assessment of nRAGE and g‐H2AX (involved in DNA‐DSB repair) was done by immunostaining. Invasion was measured in trophoblast cells after CSE and BLM treatment. Immunoblot was used to quantify nRAGE and g‐H2AX in cells. DNA degradation was used to determine DNA integrity.Increased Co‐expression of RAGE and y‐H2AX was observed in treated trophoblasts when compared to controls. Increases protein expression of RAGE and g‐H2AX was quantified by immunoblot in control and treated trophoblast cells . Trophoblast invasion was decreased 50% with 20ug/ml BLM treatment (p<0.0001) and 80% with 30ug/ml as compared to controls (p<0.0001). Invasion of trophoblast cells was decreased 92% (p<0.002) when treated with 0.5% CSE. Trophoblast DNA degradation was significantly detected following treatment with BLM or CSE. We conclude that CSE and BLM causes DNA‐DSBs in trophoblast cells and repair may plausibly be regulated by nRAGE and g‐H2AX. Confirmatory studies in the absence of RAGE are necessary in order to validate a possible link. DNA‐DSBs could be a factor in inhibited trophoblast invasion observed in compromised placenta. These studies provide a critical initial step in dissecting tobacco‐mediated IUGR progression.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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