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Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic β-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic β-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

Fetoscopic Endotracheal Occlusion for Severe Isolated Diaphragmatic Hernia: Initial Experience from a Single Clinic in Brazil

Objective: To report on the initial experience in a single Brazilian university clinic of the use of fetoscopic endotracheal occlusion (FETO) to treat severe isolated congenital diaphragmatic hernia (CDH). Methods: The inclusion criteria for FETO for this prospective study were isolated CDH and intrathoracic herniation of the liver, as well as the lung area to head circumference ratio (LHR) <1.0. The main variables evaluated were LHR and observed to expected (o/e) LHR before and after FETO, gestational age (GA) at FETO, reversal of tracheal occlusion (TO), and birth and discharge of a living child from the hospital. Results: Among 8 isolated left-sided CDH cases with normal karyotypes, the median LHR and o/e LHR before FETO were 0.7 (range: 0.6–0.9) and 0.27 (range: 0.22–0.32), respectively. The median LHR and o/e LHR after FETO were 1.2 (range: 0.9–1.8) and 0.45 (0.31–0.67), respectively. The median GA at FETO, reversal of TO and birth were 26.8 (range: 26–29), 32.5 (range: 31.0–34.0) and 37 weeks (range: 35–37), respectively. Neonatal survival at the time of hospital discharge was 50% (4/8). Conclusion: FETO is feasible at our institution and may help to improve postnatal survival of children with severe CDH in developing countries.

Adrenocortical tumors in Brazilian children : Immunohistochemical markers and prognostic factors

CONTEXTnThe behavior of adrenocortical tumors (ACTs) is usually difficult to establish in childhood, and the role of immunomarkers in predicting outcome has not yet been elucidated.nnnOBJECTIVEnTo investigate the relationship between clinical, pathologic, and immunohistochemical findings and prognosis in a series of children with ACTs.nnnPATIENTS AND METHODSnClinical data were evaluated retrospectively in 33 children with ACTs, including age at diagnosis, sex, time between first symptoms and diagnosis, clinical signs and symptoms, tumor position, and follow-up. Histologic sections were reviewed, each tumor was classified, and staging was performed according to previously published criteria. Immunohistochemical analysis of p53, Ki-67, c-Erb-B2, and Bcl-2 was performed according to previously published techniques.nnnRESULTSnSixty-four percent (n = 21) of the patients were female, and the age at diagnosis in the cohort ranged from 2 to 96 months. Virilization alone affected 70% (n = 23) of the patients, and 18 patients had stage 1 disease, 9 had stage 2 disease, and 3 each had stage 3 and stage 4 disease. Female sex and stage 1 and stage 2 disease were associated with good outcome. None of the histopathologic criteria evaluated correctly predicted outcome. Only tumors with a volume exceeding 200 mL were associated with malignant behavior. Because only a small number of tumors expressed the antigens, results of these immunohistochemical tests were considered inconclusive.nnnCONCLUSIONnIn this sample of pediatric ACTs, the clinical and surgical parameters are the most important prognostic factors, while the immunohistochemical markers evaluated were not predictive of outcome.

Congenital duodenal obstruction: does prenatal diagnosis improve the outcome?

Prenatal diagnosis of congenital duodenal obstruction (CDO) provides information about associated anomalies; helps plan the delivery, resuscitation, and neonatal surgery; and allows for appropriate family counseling. This report compares the outcomes of two groups of newborns: one with prenatal diagnosis of CDO (group I) and the other without (group II). Charts of the 23 newborns with CDO admitted to the Hospital of UNICAMP between 1993 and 2001 were retrospectively reviewed. Ten (44%) newborns had prenatal diagnosis of CDO. Among group I patients, the postnatal diagnosis was confirmed on the 1st day of life, whereas patients without prenatal diagnosis (group II) had the diagnosis of CDO confirmed at a mean age of 5.7xa0days (p=0.004). The mean ages at surgery, at total oral feeding, and at hospital discharge were also statistically lower among infants with prenatal diagnosis, and more complications occurred in group II patients. The earlier care could explain the statistically lower morbidity for patients with prenatal diagnosis, since they were able to undergo further investigation and surgical repair before any impairment to their clinical status could take place. We believe that prenatal diagnosis of CDO, associated with earlier surgery and adequate postoperative support, can provide lower morbidity, decrease the hospitalization period, and, therefore, decrease its costs to the state and to society.

Prenatal retinoic acid improves lung vascularization and VEGF expression in CDH rat.

OBJECTIVEnWe sought to investigate the effects of antenatal retinoic acid on the pulmonary vasculature and vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) expression in a nitrofen-induced congenital diaphragmatic hernia (CDH) model.nnnSTUDY DESIGNnRat fetuses were exposed to nitrofen at gestational day 9.5 and/or all-trans retinoic acid (ATRA) at gestational days 18.5-20.5. We assessed lung growth, airway, and vascular morphometry. VEGF, VEGFR1, and VEGFR2 expression was analyzed by Western blotting and immunohistochemistry. Continuous data were analyzed by analysis of variance and Kruskal-Wallis test.nnnRESULTSnCDH decreased lung to body weight ratio, increased mean linear intercept and mean transection length/airspace, and decreased mean airspace cord length. ATRA did not affect lung growth or morphometry. CDH increased proportional medial wall thickness of arterioles while ATRA reduced it. ATRA recovered expression of VEGF and receptors, which were reduced in CDH.nnnCONCLUSIONnRetinoic acid and VEGF may provide pathways for preventing pulmonary hypertension in CDH.

Expression Profile of Lgi1 Gene in Mouse Brain During Development

Mutations in LGI1 were described in patients with autosomal dominant partial epilepsy with auditory features (ADPEAF), and recent clinical findings have implicated LGI1 in human brain development. However, the precise role of LGI1 in epileptogenesis remains largely unknown. The objective of this study was to determine the expression pattern of Lgi1 in mice brain during development and in adult animals. Real-time polymerase chain reaction (PCR) quantification and Western blot experiments showed a relative low expression during intrauterine stages, increasing until adulthood. In addition, we did not find significant differences between left and right hemispheres. The hippocampus presented higher levels of Lgi1 expression when compared to the neocortex and the cerebellum of adult animals; however, these results did not reach statistical significance. This study was the first to determine a specific profile of Lgi1 gene expression during central nervous system development, which suggests a possible inhibitory function in latter stages of development. In addition, we did not find differences in hemispheric expression that could explain the predominance of left-sided abnormalities in patients with ADPEAF.

Assessment of neurosurgical outcome in children prenatally diagnosed with myelomeningocele and development of a protocol for fetal surgery to prevent hydrocephalus

IntroductionPrenatal diagnosis of myelomeningocele (MMC) has permitted a better planning for optimum management of the disease. More recently, it has allowed for a possible intrauterine repair of the spinal defect.ObjectiveTo describe neurosurgical outcome in children with myelomeningocele and follow-up at a referral center in Fetal Medicine. Patients were characterized for the development of a protocol suitable for fetal surgery, and fetuses who were possible candidates for intrauterine surgery were identified.Materials and methodsA retrospective descriptive analysis was performed of 98 cases of fetal myelomeningocele, seen at CAISM-UNICAMP, from January 1994 to December 2002, identifying cases with a possible indication for fetal surgery.ResultsMean gestational age at diagnosis was 29xa0weeks (17–39); level of lesion was above the sacral region in 92.84%; association with hydrocephalus occurred in 78.57%. During clinical course, 82.5% of patients had neurogenic bladder and 60% had neural and mental deficits. Potential intrauterine repair rate was 11.57%, using criteria from the protocol developed in our service.ConclusionMyelomeningocele is associated with severe and frequent sequelae. In virtually 12% of our cases, fetal surgery could have been offered as a therapeutic option.

Evolution of critically ill patients with gastroschisis from three tertiary centers

OBJECTIVES AND INTRODUCTION: Gastroschisis is a congenital abdominal wall defect with increasing occurrence worldwide over the past 20–30 years. Our aim was to analyze the morbidity of newborns after gastroschisis closure, with emphasis on metabolic and hydroelectrolyte disturbances in patients at three tertiary university centers. METHODS: From January 2003 to June 2009, the following patient data were collected retrospectively: (A) Background maternal and neonatal data: maternal age, prenatal diagnosis, type of delivery, Apgar scores, birth weight, gestational age and sex; (B) Surgical modalities: primary or staged closure; and (C) Hospital course: levels of serum sodium and levels of serum albumin in the two first postoperative days, number of ventilation days, other postoperative variables and survival. Statistical analyses were used to examine the associations between some variables. RESULTS: 163 newborns were included in the study. Primary closure of the abdominal defect was performed in 111 cases (68.1%). The mean serum sodium level was 127.4±6.7 mEq/L, and the mean serum albumin level was 2.35±0.5 g/dL. Among the correlations between variables, it was verified that hyponatremia and hypoalbuminemia correlated with the number of days on the ventilator but not with the number of days on total parenteral nutrition (TPN); mortality rate correlated with infection. The final survival rate was 85.9%. CONCLUSION: In newborns with gastroschisis, more aggressive attention to hyponatremia and hypoalbuminemia would improve the outcome.

Maturity of the myenteric plexus is decreased in the gastroschisis rat model.

Background: Amniotic fluid (AF) and its components, such as fetal urine and meconium, may lead to intestinal alterations in gastroschisis, which cause immaturity of the myenteric plexus and consequent intestinal hypomotility and malabsorption. In this study we identified morphological and histological alterations of the intestine and the myenteric plexus with two different times of exposure to AF. Methods: The experimental gastroschisis was achieved at two different gestational ages, on day 18.5 (E18.5) and day 19.5 (E19.5) of gestation, in fetal rats which were divided into 3 subgroups: control, sham and gastroschisis. We measured fetal body weight (BW), intestinal weight (IW) and intestinal length (IL). The layers of intestinal wall and myenteric plexus were evaluated by hematoxylin and eosin staining (HE staining) and immunofluorescence (α-internexin), respectively. Results: BW was not significantly different among the control, sham and gastroschisis groups at both ages. IW and IL were larger and shorter, respectively, in the gastroschisis fetuses (p < 0.001) at both ages. Intestinal diameters and wall layers presented significant differences among control, sham and gastroschisis fetuses at both ages (p < 0.001), but the time of exposure to AF compromised the serous membrane, D-II (diameter II, p < 0.001) and IL (p = 0.001). α-Internexin presented more intensive immunoreactivity in gastroschisis fetuses at E18.5. Conclusions: In gastroschisis, the longer the time of exposure to AF, the more severe bowel impairment will be, especially with regard to IL and the serous layer, and the more immature the myenteric plexus will be.

VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen

Changes in vascular endothelial growth factor (VEGF) in pulmonary vessels have been described in congenital diaphragmatic hernia (CDH) and may contribute to the development of pulmonary hypoplasia and hypertension; however, how the expression of VEGF receptors changes during fetal lung development in CDH is not understood. The aim of this study was to compare morphological evolution with expression of VEGF receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1), in pseudoglandular, canalicular, and saccular stages of lung development in normal rat fetuses and in fetuses with CDH. Pregnant rats were divided into four groups (n=20 fetuses each) of four different gestational days (GD) 18.5, 19.5, 20.5, 21.5: external control (EC), exposed to olive oil (OO), exposed to 100 mg nitrofen, by gavage, without CDH (N-), and exposed to nitrofen with CDH (CDH) on GD 9.5 (term=22 days). The morphological variables studied were: body weight (BW), total lung weight (TLW), left lung weight, TLW/BW ratio, total lung volume, and left lung volume. The histometric variables studied were: left lung parenchymal area density and left lung parenchymal volume. VEGFR1 and VEGFR2 expression were determined by Western blotting. The data were analyzed using analysis of variance with the Tukey-Kramer post hoc test. CDH frequency was 37% (80/216). All the morphological and histometric variables were reduced in the N- and CDH groups compared with the controls, and reductions were more pronounced in the CDH group (P<0.05) and more evident on GD 20.5 and GD 21.5. Similar results were observed for VEGFR1 and VEGFR2 expression. We conclude that N- and CDH fetuses showed primary pulmonary hypoplasia, with a decrease in VEGFR1 and VEGFR2 expression.