Tadashi Matsuda

Maternal Feeding Controls Fetal Biological Clock

Background It is widely accepted that circadian physiological rhythms of the fetus are affected by oscillators in the maternal brain that are coupled to the environmental light-dark (LD) cycle. Methodology/Principal Findings To study the link between fetal and maternal biological clocks, we investigated the effects of cycles of maternal food availability on the rhythms of Per1 gene expression in the fetal suprachiasmatic nucleus (SCN) and liver using a transgenic rat model whose tissues express luciferase in vitro. Although the maternal SCN remained phase-locked to the LD cycle, maternal restricted feeding phase-advanced the fetal SCN and liver by 5 and 7 hours respectively within the 22-day pregnancy. Conclusions/Significance Our results demonstrate that maternal feeding entrains the fetal SCN and liver independently of both the maternal SCN and the LD cycle. This indicates that maternal-feeding signals can be more influential for the fetal SCN and particular organ oscillators than hormonal signals controlled by the maternal SCN, suggesting the importance of a regular maternal feeding schedule for appropriate fetal molecular clockwork during pregnancy.

A Rat Model for Arrest of Alveolarization Induced by Antenatal Endotoxin Administration

A possible association between intrauterine inflammation and impairments of lung development has been suggested. The purpose of this study is to determine the influence of a potent proinflammatory agent, intra-amniotic lipopolysaccharide (LPS), on lung development. At 21 d gestation, an intra-amniotic injection of 1 μg LPS was administered to two subgroups of WKAH rats. One subgroup received only LPS and the other received LPS plus a fetal intraperitoneal dose of 0.25 μg granulocyte-colony stimulating factor (hrG-CSF) to produce peripheral blood neutrophilia. A third subgroup received hrG-CSF only, and a control group received maternal intraamniotic and fetal intraperitoneal normal saline. All pups were delivered by cesarean section at 22 d (term, 22.5 d) and maintained under identical conditions. Left upper lungs were obtained for morphometric analysis at 1, 3, 7, 14, 21, 45, and 60 d of age. Morphometric analysis indicated that changes in alveolar surface density (Sv), average alveolar radius (r), and numerical density of alveoli (nv) all showed that there were fewer and larger alveoli in rat lungs that had been exposed to LPS, but not to hrG-CSF alone or saline. LPS-exposed alveoli showed fewer secondary septa, suggesting an arrest of alveolarization. No destructive changes were observed in any alveoli. We concluded that these changes could be caused purely by intra-amniotic LPS. These abnormalities closely mimic those of new bronchopulmonary dysplasia. The LPS damage model may be applicable to further studies of the pathophysiology of new BPD.

Induction of antenatal periventricular leukomalacia by hemorrhagic hypotension in the chronically instrumented fetal sheep

OBJECTIVES: Our purpose was to determine whether systemic hypotension induced by rapid withdrawal of fetal blood would induce periventricular leukomalacia in the brain of premature fetal sheep. STUDY DESIGN: At 113 days gestation, systemic hypotension (mean blood pressure <30 mm Hg) was induced by withdrawing approximately 35% of the fetoplacental blood volume in the hemorrhage group (n = 6), whereas in the control group (n = 4) isovolemic exchange transfusion was carried out. Six days after the insult, fetal brains were removed and processed for histologic analysis. RESULTS: Five of the 6 fetuses in the hemorrhage group exhibited periventricular white-matter lesions, consisting of nodular coagulation necrosis or diffuse axonal swellings or both. No abnormal findings other than these lesions were detected in the fetal brains in either experimental group. CONCLUSION: Hemorrhagic hypotension antenatally induced brain lesions similar to those of periventricular leukomalacia, suggesting that it is an essential element in the pathogenesis of periventricular leukomalacia in premature fetuses.

Antenatal dexamethasone administration impairs normal postnatal lung growth in rats.

Our purpose was to determine the influences of antenatal dexamethasone administration on neonatal lung development in rats. Dexamethasone (0.4 mg/kg maternal body weight per day) was administered i.p. on the 21st d (group 1) or on the 20th and 21st d (group 2) of gestation in Sprague Dawley rats with timed pregnancies. After natural deliveries, the lungs of the pups 1–60 d of age were removed and processed for morphometric analysis. In 60-d-old pups, groups 1 and 2 both showed a lower numerical density of alveoli and a larger mean alveolar radius than control pups. Antenatal administration of dexamethasone to rats impairs the normal postnatal lung growth. Some aspects of the use of antenatal glucocorticoid therapy in humans may require reconsideration.

A case surviving for over a year of renal tubular dysgenesis with compound heterozygous angiotensinogen gene mutations

Renal tubular dysgenesis (RTD) is a developmental abnormality of the renal proximal tubules found in patients with Potter syndrome. We report a female newborn with RTD who has survived for more than 18 months. Infusions of fresh frozen plasma (FFP) in the early neonatal period were effective in raising and maintaining her blood pressure. Peritoneal dialysis was required until the appearance of spontaneous urination at 29 days after birth. Histopathological examinations of the kidney revealed dilated renal tubular lumina and foamy columnar epithelial cells in the renal tubules. Endocrinological studies showed a discrepancy between low plasma renin activity (<0.1 ng/ml/hr) and high active renin concentration (135,000 pg/ml), suggesting an aberration in the renin substrate, angiotensinogen. Direct sequencing analysis revealed two novel mutations in the coding region of the angiotensinogen gene (AGT): a nonsense mutation in exon 2 (c.604Cu2009>u2009T) and a frameshift deletion at nucleotide 1290 in exon 5 (c.1290delT). The mutations were in the compound heterozygous state, because each parent had each mutation. These findings suggest that angiotensinogen deficiency is one of the causes of RTD. A treatment of the condition with FFP may help to promote long survival.

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model

Background:Previous studies aimed at developing an artificial placenta have had limited success. We hypothesized that the introduction of a high-performance membranous oxygenator to a pumpless artificial placenta could prolong the survival time of premature lambs.Methods:Immediately after delivery of the fetuses, the umbilical vessels were cannulated and connected to the pumpless artificial placenta. Both the fetuses and the circuit were submerged in a warm saline bath.Results:Five fetuses survived for 18.2 ± 3.2 (mean ± SEM) h after attachment to the artificial placenta, which maintained fetal circulation. Circuit blood flow was positively correlated with mean arterial pressure and negatively correlated with blood lactate levels. Milrinone administration transiently decreased lactate levels, although dopamine administration unexpectedly induced a marked increase in the lactate levels despite an elevated arterial pressure and improved circuit blood flow.Conclusion:We prolonged the survival of fetal lambs using a high-performance membranous oxygenator with a small priming volume. The increased systemic resistance induced by vasoconstrictors may increase the circuit blood flow excessively, resulting in circulation failure in systemic organs; therefore, vasodilators may be more useful than vasoconstrictors for maintaining organ blood flow within this circuit.

Effect of intrauterine inflammation on fetal cerebral hemodynamics and white-matter injury in chronically instrumented fetal sheep.

OBJECTIVEnThe purpose of this study was to analyze the effects of intrauterine inflammation on cerebral hemodynamics and white-matter injury in premature fetal sheep.nnnSTUDY DESIGNnFetuses were given an intravenous infusion of granulocyte colony-stimulating factor and an intraamniotic infusion of endotoxin; the fetuses were then assigned randomly to an acute hemorrhage group, an exchange transfusion group, or a control group. During each insult, the cerebral hemodynamics were assessed with near-infrared spectroscopy. Finally, the fetuses were processed for neuropathologic analysis and compared statistically.nnnRESULTSnNecrotizing funisitis and chorioamnionitis were induced in all the fetuses. A significant decrease in the blood oxygen content and an increase in the brain total hemoglobin level were observed after the endotoxin infusion. Soon after hemodynamic insult, the fetuses in both the acute hemorrhage and the exchange transfusion groups showed an abrupt decrease in the total brain hemoglobin level; 4 of the 5 fetuses in each treatment group, but none of the fetuses in the control group, exhibited periventricular leukomalacia.nnnCONCLUSIONnHemorrhagic hypotension or anemic hypoxemia might induce a sudden cessation of fetal brain-sparing effects through progressive inflammatory hypoxemia, which results in focal white-matter injuries.

Analyses of factors contributing to vulnerability to antenatal periventricular leukomalacia induced by hemorrhagic hypotension in chronically instrumented fetal sheep

Our purpose was to determine factors contributing to vulnerability to antenatal periventricular leukomalacia (PVL) induced by hemorrhagic hypotension in premature fetal sheep. Systemic hypotension was induced in 10 fetal sheep by acutely withdrawing 35% to 40% of the fetoplacental blood volume at 113 d gestation. Brains were processed for histologic analysis 6 d after the insult. Statistical comparisons of physiologic parameters between fetuses suffering from PVL (n = 5) and those without PVL (n = 5) were performed. Significant correlations were found between induction of PVL and fetal brain weight, changes in fetal mean blood pressure over time, base excess, oxygen content, hematocrit, and plasma arginine vasopressin (AVP) levels in fetal abdominal aortic blood. Brain developmental stage, the magnitude of induced systemic hypotension, and baseline blood oxygen content were important intrinsic factors in the induction of antenatal PVL by hemorrhagic hypotension in premature fetal sheep.

Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration

Abstract:u2003 The authors report a female patient with congenital pulmonary alveolar proteinosis (PAP). She had two brothers who died from the same disease. BAL did not improve her progressive respiratory failure. After intravenous immunoglobulin G (IVIG) administration for complicated hypogammaglobulinemia, she recovered from respiratory failure. The efficacy of IVIG was confirmed by recovery from deterioration in respiratory status and improvement in chest CT findings on two separate occasions. Subsequently, the patient remains free from respiratory symptoms for more than 3u2003years on an ongoing regimen of monthly IVIG. She had no surfactant protein (SP) B deficiency. Alveolar macrophages (AM) obtained from her BAL fluid were small and showed decreased phagocytotic activity. Immunostaining revealed weak expression of PU.1 in her AM, a key protein in AM maturation. All nucleotide sequences of granulocyte‐macrophage colony stimulating factor (GM‐CSF), GM‐CSF‐receptor and PU.1 were normal. Endotoxin‐induced GM‐CSF release from peripheral mononuclear cells (PMNC), and proliferation of PMNC in response to GM‐CSF were normal. In addition, an antibody against GM‐CSF, as seen in adult patients with idiopathic PAP, was not detected in the serum or BAL fluid. Although the patients PMNC secreted only small amounts of IgG and IgM, an EB virus‐derived cell line of her B cells secreted IgM as much as normal control cells. In a flow cytometric study, IgM was expressed on the cell surface. In conclusion, an abnormality in a single gene may have decreased secretion of immunoglobulin from the B cells and the AM phagocytotic activity in the patient.

Prediction of respiratory distress syndrome by the level of pulmonary surfactant protein A in cord blood sera.

The purpose of this study was to determine the utility of measuring the level of pulmonary surfactant protein A (SP-A) in cord blood sera to predict for respiratory distress syndrome (RDS). SP-A levels in cord blood sera from 48 infants born at gestational ages < 32 weeks were measured by a sandwich ELISA system. Mean value of SP-A in cord blood was 5.8 ng/ml in cases with RDS and 15.1 ng/ml in those without RDS (p = 0.002). The best cut-off point of cord blood SP-A to predict RDS was determined as 10 ng/ml. The sensitivity and the specificity of the cut-off point for predicting RDS were 81 and 76%, respectively. Multivariate regression analysis showed that high SP-A level in cord blood, premature rupture of the membranes longer than 24 h and heavy birth weight were all significantly related to the non-RDS outcome.