Nana Nakazawa

Congenital diaphragmatic hernia and retinoids: searching for an etiology

Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of respiratory failure in the newborn. Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the epidemiology and pathophysiology of human CDH, the metabolism of retinoids and the implications of retinoids in the development of the diaphragm and lung. Finally, we describe the existing evidence of a disruption of the retinoid-signaling pathway in CDH.

Prenatal treatment with retinoic acid accelerates type 1 alveolar cell proliferation of the hypoplastic lung in the nitrofen model of congenital diaphragmatic hernia

PURPOSE Retinoids play an important role in lung development. A recent study has demonstrated that prenatal treatment with retinoic acid (RA) stimulates alveologenesis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia (CDH). Furthermore, it has also been demonstrated that the differentiation from alveolar epithelial cells type II (AECs-II) into alveolar epithelial cells type I (AECs-I), which is the key process in lung development, is disturbed in this model. We hypothesized that retinoids promote alveologenesis by stimulating differentiation of AECs-II to AECs-I at the end of gestation; and therefore, we investigated the effect of RA on the pulmonary expression of intercellular adhesion molecule 1 (ICAM-1), a marker for AECs-I, and thyroid transcription factor 1 (Ttf-1), a marker for AECs-II, in nitrofen-induced hypoplastic lungs. MATERIALS AND METHODS Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day of gestation (D) 9. Five milligrams per kilogram of RA was given intraperitoneally on D18, D19, and D20; and fetuses were recovered on D21. We had 4 study groups: control (n = 7), control + RA (n = 7), CDH (n = 6), and CDH + RA (n = 6). The expression of ICAM-1 and Ttf-1 was analysed in each lung by real-time reverse transcription polymerase chain reaction and immunohistochemistry. One-way analysis of variance test was used for statistical analysis. RESULTS Expression levels of ICAM-1 were significantly reduced in CDH lungs compared with normal controls, whereas levels increased significantly in CDH group after the addition of RA (P < .05). Expression levels of Ttf-1 were significantly decreased in lungs from RA-treated CDH animals compared with CDH without RA (P < .05). The ICAM-1 and Ttf-1 immunoreactivity demonstrated similar pattern of expression in various groups. CONCLUSIONS Our results demonstrate that prenatal treatment with RA accelerates AEC-I proliferation in the hypoplastic lung in CDH.

Tubularized incised plate urethroplasty with dorsal inlay graft prevents meatal/neourethral stenosis: a single surgeon's experience

BACKGROUND/PURPOSE Snodgrass tubularized incised plate urethroplasty (SUP) is versatile and has good cosmesis. However, postoperative meatal/neourethral stenosis (M/N-S) is common enough for some surgeons to add a dorsal inlay graft (DIG) harvested from the inner prepuce and sutured to cover the longitudinal midline incision of the urethral plate. This is the first formal assessment of the effectiveness of DIG for preventing M/N-S. METHODS We reviewed the medical records of 100 consecutive SUP cases performed by a single surgeon between 2003 and 2010 comparing SUP + DIG (S + D group, n = 50) with SUP - DIG (S - D group, n = 50). Mean follow-up was 3.6 years. Data were analyzed statistically using the χ(2), 2-way ANOVA, and Mann-Whitney tests, with P < .05 considered significant. RESULTS Severity of hypospadias and type of SUP were similar. Mean age at SUP was 3.3 years in S + D and 3.6 years in S-D (P = NS). There were 4 complications in the S + D group: urethrocutaneous fistula (n = 3) and neourethral stenosis without diverticulum (n = 1). There were 15 complications in the S-D group : meatal stenosis (n = 2), neourethral stenosis with or without diverticulum (n = 6), urethrocutaneous fistula (n = 7) (P < .01). M/N-S was significantly less in the S + D group (1 vs 8; P < .05). CONCLUSIONS We strongly recommend that DIG be performed routinely during SUP.

Decreased expression of GATA4 in the diaphragm of nitrofen-induced congenital diaphragmatic hernia.

BACKGROUND The molecular mechanisms underlying the diaphragmatic defect in congenital diaphragmatic hernia (CDH) are still poorly understood. The transcription factor GATA4 is essential for normal development of the diaphragm. Recently, mutations in the GATA4 gene have been linked to human and rodent CDH. We hypothesized that diaphragmatic GATA4 expression is downregulated in the nitrofen CDH model. METHODS Pregnant rats received Nitrofen or vehicle on day 9 of gestation (D9). Fetuses were sacrificed on D13, D18, or D21. Pleuroperitoneal folds (n=20) and fetal diaphragms (n=40) were (micro) dissected and divided into CDH group and controls. RNA and protein were extracted. GATA4 mRNA levels were determined by real-time PCR. Protein levels were determined by ELISA and Immunohistochemistry. RESULTS mRNA levels and Protein levels were significantly decreased in the CDH group compared to controls on D13 (mRNA 15.96±6.99 vs. 38.10±5.01, p<0.05), D18 (mRNA 10.45±1.84 vs. 17.68±2.11, Protein 2.59±0.06 vs. 4.58±0.35 p<0.05) and D21 (mRNA 4.31±0.83 vs. 6.87±0.88, Protein 0.16±0.08 vs. 1.26±0.49, p<0.05). Immunoreactivity of GATA4 was markedly decreased in CDH-diaphragms on D13, D18, and D21. CONCLUSIONS We provide evidence for the first time that diaphragmatic expression of GATA4 is downregulated in the nitrofen model, suggesting that decreased expression of GATA4 may impair diaphragmatic development in nitrofen-induced CDH.

Increase in fetal pulmonary artery diameters during late gestation is a predictor of outcome in congenital diaphragmatic hernia with liver herniation

AIM Liver herniation (LH) in congenital diaphragmatic hernia (CDH) may not be a reliable prognostic indicator. We measured pulmonary artery (PA) diameters in CDH + LH as an alternative. METHODS Of 41 consecutive cases of prenatally diagnosed left-sided CDH treated from 2002 to 2010, 19 had CDH + LH and 22 had CDH - LH. Ultrasonography and magnetic resonance imaging were used to assess LH and echocardiography to measure PA diameters during the third trimester (fetal; 32-34 weeks), at birth, and on day 2 of life. RESULTS In CDH + LH survivors (9/19; 47%), fetal right PA (RPA) diameters were significantly larger than in nonsurvivors (2.58 ± 0.56 vs 1.82 ± 0.35 mm; P < .01), but left PA (LPA) diameters were not (1.73 ± 0.38 vs 1.59 ± 0.22). In survivors, fetal RPA was greater than 2 mm in all but one case, and both PA diameters increased significantly by birth (RPA, 2.58 ± 0.56 vs 3.52 ± 0.54; LPA, 1.73 ± 0.38 vs 2.60 ± 0.40; both P < .01). Final diameters at birth in survivors were at least 2.5 and 2.0 mm, respectively. In nonsurvivors, both PAs were significantly smaller (RPA, 3.52 ± 0.54 vs 2.04 ± 0.31; LPA, 2.60 ± 0.40 vs 1.68 ± 0.18; P < .01), with no observed increase by birth. Survival in CDH - LH was 82% (18/22). CONCLUSION PA diameter appears to be correlated with prognosis in infants with CDH + LH.

Treves' field pouch hernia: our experience and literature review.

Treves’ field pouch hernia (TFPH) is an unusual type of congenital internal hernia. Although eight cases of TFPH have been reported in the English literature, they were seldom diagnosed preoperatively with high mortality rates. We describe a 12-year-old girl with TFPH diagnosed as an internal hernia on computed tomography and confirmed laparoscopically, and review the literature.