Autopsy Case of Pfeiffer Syndrome Type 2, a Phenotype of Fibroblast Growth Factor Receptor-Associated Craniosynostosis Syndromes, with Tracheal Cartilage Sleeve and Abnormal Hyperplasia of Bronchial Cartilages.

BACKGROUND Pfeiffer syndrome (PS) is a fibroblast growth factor receptor (FGFR)-associated craniosynostosis syndrome, characterized by abnormally broad and medially deviated thumbs and great toes. Tracheal cartilage sleeve (TCS) is associated with several FGFR-associated craniosynostosis syndromes, including PS. TCS is an airway malformation in which the tracheal cartilage rings fuse with each other to form a sleeve of cartilage. CASE REPORT The patient was a 4-year-old girl with PS, TCS, and abnormal hyperplasia of non-fused intrapulmonary cartilages. The patient showed cranial dysplasia on prenatal ultrasonography. At birth, a cloverleaf skull in association with hydrocephalus and digital malformations was apparent. These findings were consistent with PS type 2. The diagnosis of PS type 2 was confirmed from a genetic test detecting a FGFR2 mutation (Y340C). During the clinical course, she underwent several surgeries, including ventriculoperitoneal shunts, sequential cranioplasty surgeries, and tracheotomy due to upper airway abnormalities. At 4 years old, she died of multiple organ failure following aspiration pneumonia. The autopsy revealed that the tracheal cartilages had fused with each other, resulting in a condition called TCS, in which the cartilage rings and tracheal ligaments were absent. The lungs were poorly aerated, and the dilated bronchi had thickened walls surrounded by many cartilage fragments, mainly at the hilum. These cartilages tended to overlap at both ends, did not fuse, and were greatly altered in size and shape. CONCLUSIONS We report the results of autopsy for PS with the first histopathological findings for the lungs and other visceral organs.

Survival of an infant with massive fetomaternal hemorrhage with a neonatal hemoglobin concentration of 1.2 g/dL without evident neurodevelopmental sequelae.

Fetomaternal hemorrhage is referred to as the passage of fetal blood into the maternal circulation. Massive hemorrhage can cause severe fetal anemia, affecting fetal and neonatal outcomes. A neonatal hemoglobin concentration (Hb), which is reportedly a significant prognostic factor, of <5.0 g/dL has been reported to carry a high risk of poor outcomes (death and major morbidity). We present a case of massive fetomaternal hemorrhage with the lowest value of neonatal Hb ever previously reported in a survivor, who subsequently met all the developmental milestones at the corrected age of 18 months. A male infant born at 27 weeks gestation, weighing 998 g, presented with severe anemia with an Hb of 1.2 g/dL and an HbF level in the mother's blood of 2.4%, which led to a diagnosis of fetomaternal hemorrhage. Since there were no findings of hypovolemia, exchange transfusion was performed for prompt correction of the severe anemia without precipitating volume overload. The present case suggested that exchange transfusion might promptly correct anemia in patients with fetomaternal hemorrhage without hypovolemia without causing volume overload.

The evaluation of the efficacy and safety of non-invasive neurally adjusted ventilatory assist in combination with INtubation-SURfactant-Extubation technique for infants at 28 to 33 weeks of gestation with respiratory distress syndrome.

OBJECTIVES: The aim of this study is to evaluate the efficacy and safety of non-invasive neurally adjusted ventilatory assist used after INtubation-SURfactant-Extubation in preterm infants with respiratory distress syndrome. METHODS: We conducted a prospective observational study that included 15 inborn preterm infants at 28 (0/7) to 33 (6/7) weeks of gestation with respiratory distress syndrome in the period from April 2017 to October 2018. After INtubation-SURfactant-Extubation, infants underwent non-invasive neurally adjusted ventilatory assist. INtubation-SURfactant-Extubation failure was defined as follows: fraction of inspired oxygen requirement >0.4, respiratory acidosis, and severe apnea within 5 days after surfactant administration. RESULTS: Two of the 15 (13.3%) infants showed INtubation-SURfactant-Extubation failure and required mechanical ventilation. No infants experienced any major complications such as pneumothorax, patent ductus arteriosus ligation, severe intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or death. CONCLUSION: The rate of INtubation-SURfactant-Extubation failure when non-invasive neurally adjusted ventilatory assist was used after INtubation-SURfactant-Extubation for preterm infants with respiratory distress syndrome was 13.3%. Non-invasive neurally adjusted ventilatory assist can be safely performed without severe complications for preterm infants soon after birth.

Successful management of acquired left bronchial stenosis caused by massive atelectasis.

Acquired bronchial stenosis is rare in children, usually caused by infection or traumatic granuloma due to chronic intubation. A case of severe acquired left bronchial stenosis successfully treated by conservative management for gastroesophageal reflux and atelectasis is reported. A male infant born at 24 weeks' gestation, weighing 461 g, presented with massive atelectasis of the left lower lobe and severe left bronchial stenosis, based on chest computed tomography performed for the evaluation of respiratory failure at the age of 8 months. He responded well to the placement of a duodenal tube for gastroesophageal reflux and chest physiotherapy, reducing the symptoms of atelectasis and successfully managing the left bronchial stenosis. Acquired bronchial stenosis could be caused by bronchial shift due to atelectasis, and it can be cured by conservative management. In cases of acquired bronchial stenosis with massive atelectasis, it is important to consider atelectasis as a potential cause of the acquired bronchial stenosis.

Survival of a very low-birthweight infant with Potter sequence on long-term hemodialysis.

Recent advances in neonatal cardiorespiratory management and neonatal renal replacement therapy have led to occasional reports of favorable short-term and long-term outcomes for Potter sequence, once thought to be fatal. The present patient was a girl born at a gestational age of 34 weeks 4 days with a birthweight of 1398 g. She was diagnosed with Potter sequence complicated by pulmonary hypoplasia due to left renal agenesis and small right kidney. Hemodialysis was started because anuria persisted even after persistent pulmonary hypertension receded and cardiorespiratory status improved. Peritoneal dialysis during the clinical course failed to achieve stability because of pericatheter leakage and frequent obstruction of the peritoneal dialysis catheter; in the meantime, hemodialysis was also performed. Once bodyweight passed 3.5 kg, peritoneal dialysis became more feasible with stability; the patient was discharged at 9 months and at the time of writing was on peritoneal dialysis at home, and renal transplantation was planned.

Final height and cardiometabolic outcomes in young adults with very low birth weight (<1500 g).

OBJECTIVE: Individuals with very low birth weight (VLBW; <1500 g) are known to be predisposed to both short final height and cardiometabolic disorders. However, associations between final height and cardiometabolic outcomes including glucose metabolism in VLBW individuals in young adulthood are not fully investigated. METHODS: We investigated glucose metabolism and other cardiometabolic outcomes such as lipid profiles, blood pressure, renal function, urinary albumin, and thyroid function in young adults with VLBW born between 1980 and 1990. Short stature was defined as a final height <10th percentile. Glucose intolerance [diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)] was determined using 75-g oral glucose tolerance tests. Associations between final height and cardiometabolic outcomes were examined using logistic or multiple linear regression. RESULTS: A total of 628 VLBW individuals were screened and 111 young adults with VLBW (19-30 years) participated in the study. Of the participants, 40 subjects (36%) had short stature with a final height <10th percentile. Eight subjects (7.2%) had glucose intolerance (1, diabetes; 6, IGT; 1, IFG). Short stature was correlated with glucose intolerance (odds ratio 11.1; 95% CI 1.92, 99.7; P = 0.006). Final height was inversely associated with the homeostatic model assessment (HOMA) of insulin resistance, HOMA-ß, insulinogenic index, and total/LDL-cholesterol. The associations of final height with insulin sensitivity and lipid profiles remained after adjustment for target height and age at puberty onset. CONCLUSIONS: Shorter final height was associated with less favorable metabolic profiles in young adults with VLBW, and may be partly mediated by reduced insulin sensitivity. These associations were independent of target height or age at puberty onset.

A cross-sectional study of glucose regulation in young adults with very low birth weight: impact of male gender on hyperglycaemia.

OBJECTIVES: To investigate glucose regulation in young adults with very low birth weight (VLBW; <1500 g) in an Asian population. DESIGN: Cross-sectional observational study. SETTING: A general hospital in Hamamatsu, Japan. PARTICIPANTS: 111 young adults (42 men and 69 women; aged 19-30 years) born with VLBW between 1980 and 1990. Participants underwent standard 75 g oral glucose tolerance test (OGTT). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were glucose and insulin levels during OGTT and risk factors for a category of hyperglycaemia defined as follows: diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and non-diabetes/IGT/IFG with elevated 1 h glucose levels (>8.6 mmol/l). The secondary outcomes were the pancreatic ß cell function (insulinogenic index and homeostasis model of assessment for beta cell (HOMA-ß)) and insulin resistance (homeostasis model of assessment for insulin resistance (HOMA-IR)). RESULTS: Of 111 young adults with VLBW, 21 subjects (19%) had hyperglycaemia: one had type 2 diabetes, six had IGT, one had IFG and 13 had non-diabetes/IGT/IFG with elevated 1 h glucose levels. In logistic regression analysis, male gender was an independent risk factor associated with hyperglycaemia (OR 3.34, 95% CI 1.08 to 10.3, p=0.036). Male subjects had significantly higher levels of glucose and lower levels of insulin during OGTT than female subjects (p<0.001 for glucose and p=0.005 for insulin by repeated measures analysis of variance). Pancreatic ß cell function was lower in men (insulinogenic index: p=0.002; HOMA-ß: p=0.001), although no gender difference was found in insulin resistance (HOMA-IR: p=0.477). In male subjects, logistic regression analysis showed that small for gestational age was an independent risk factor associated with hyperglycaemia (OR 33.3, 95% CI 1.67 to 662.6, p=0.022). CONCLUSIONS: 19% of individuals with VLBW already had hyperglycaemia in young adulthood, and male gender was a significant independent risk factor of hyperglycaemia. In male young adults with VLBW, small for gestational age was associated with hyperglycaemia.

Pontocerebellar hypoplasia type 3 with tetralogy of Fallot.

We report a male infant with pontocerebellar hypoplasia type 3 and tetralogy of Fallot. He showed optic nerve atrophy, progressive microcephaly, severe psychomotor developmental delay, and vesicoureteral reflux. Magnetic resonance imaging revealed severe hypoplasia of the cerebellar vermis and hemisphere, and of the brainstem including the pons, and simplified gyral patterns in bilateral frontal lobes. An unknown etiology differing from other cases of PCH type 3 might have caused not only optic nerve atrophy and hypoplasia of the cerebellum and brainstem, but also cerebral and visceral malformations. To the best of our knowledge, this represents the first report of pontocerebellar hypoplasia with congenital cardiac malformation.

Residential proximity to heavy traffic and birth weight in Shizuoka, Japan.

An association between exposure to traffic-related air pollution and reduced birth weight has been suggested. However, previous studies have failed to adjust for maternal size, which is an indicator of individual genetic growth potential. Therefore, we evaluated the association of air pollution with birth weight, term low birth weight (term-LBW), and small for gestational age (SGA), with adjustment for maternal size. Individual data were extracted from a database that is maintained by a maternal and perinatal care center in Shizuoka, Japan. We identified liveborn singleton births (n=14,204). Using geocoded residential information, each birth was assigned a number of traffic-based exposure indicators: distance to a major road; distance-weighted traffic density; and estimated concentration of nitrogen dioxide by land use regression. The multivariate adjusted odds ratios and their 95% confidence intervals (CIs) for the associations between exposure indicators and outcomes were then estimated using logistic regression models. Overall, exposure indicators of air pollution showed no clear pattern of association. Although there are many limitations, we did not find clear associations between birth-weight-related outcomes and the three markers of traffic-related air pollution.

Residential proximity to major roads and preterm births.

BACKGROUND: Preterm births cause a large public-health burden, and air pollution is considered to be a potential risk factor. We evaluated the association between proximity to major roads (as an index for air pollution) and preterm births, classified by gestational age and specific clinical manifestations. METHODS: Data on parental information and birth outcomes were extracted from the database maintained by the perinatal hospital in Shizuoka, Japan. We restricted the analysis to mothers who delivered liveborn single births from 1997 to 2008 (n = 14,226). Using the geocoded residential information, each birth was classified on its proximity to major roads. We estimated the multivariate-adjusted odds ratios and their 95% confidence intervals (CIs) for the association of proximity to major roads with preterm births, using logistic regression. RESULTS: We found positive associations between proximity to major roads and preterm births at all gestational ages. Living within 200 m increased the risk of births before 37 weeks by 1.5 times (95% CI = 1.2-1.8), birth before 32 weeks by 1.6 times (1.1-2.4), and births before 28 weeks by 1.8 times (1.0-3.2). Proximity specifically increased the risk of preterm births with preterm premature rupture of the membranes and with pregnancy hypertension. CONCLUSIONS: This study demonstrates that exposure to traffic-related air pollution increases even the risk of preterm births of less than 30 weeks' gestational age and proposes a possible mechanism.

Intermittent cyanosis due to prominent eustachian valve in a newborn infant.

A full-term neonate presented with cyanosis only when sleeping, which was considered due to a prominent eustachian valve, directing blood flow from the inferior vena cava to the left atrium through the foramen ovale resulting in interatrial right-to-left shunting. In addition to the anatomical features, hemodynamic features shortly after birth, such as patent foramen ovale and high pulmonary vascular resistance, were also probably involved in the mechanism responsible for the patient's cyanosis. This case may provide insight into differential diagnosis for cyanotic infants.

The suppression of proinflammatory cytokines improves heart function from non-heart-beating donors following transplantation in a canine model.

We evaluated the effectiveness of a suppressant of the production of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha on a canine heart transplantation model with non-heart-beating donors (NHBDs).Adult mongrel dogs were divided into 3 groups of 5: a control group; FR-1 in which donors were given FR167653, a potent suppressant of IL-1beta and TNF-alpha production; and FR-2 in which both donors and recipients were given FR167653. After measuring the baseline hemodynamic parameters, including cardiac output (CO), left ventricular pressure (LVP), and maximum and minimum rates of increase in LVP (+/- LVdp/dt), FR167653 was administered continuously for 30 minutes before ischemia in the FR-1 and FR-2 groups. Cardiac arrest was obtained by rapid exsanguination from the abdominal aorta and inferior vena cava. The organ was left in the cadaver for 30 minutes. The coronary vascular beds were washed out with 4 degrees C Celsior solution, and then the donor heart was preserved in 4 degrees C Celsior solution for 4 hours. The donor heart was transplanted orthotopically with cardiopulmonary bypass (CPB). FR167653 was administered intravenously from 15 minutes before aortic-cross clamping until the end of the experiment in the FR-2 group. The recipient was weaned from CPB 1 hour after reperfusion. We compared the hemodynamic parameters at 3 hours after reperfusion with the preoperative values in donor animals with the right atrial pressure at 10 mmHg and a 5 microg/kg/min dopamine infusion. Histopathological analysis was also performed.There were no significant differences in the recovery rates of the hemodynamic parameters between the control and FR-1 groups and between the FR-1 and FR-2 groups. However, the recovery rates of CO and -LVdp/dt in the FR-2 group were significantly (P < 0.05) higher than those in the control group. Histopathological analysis showed that myofilaments were better preserved in the FR-2 group compared with the control group.The administration of a suppressant of proinflammatory cytokines before both ischemia and reperfusion effectively preserves donor heart function after transplantation with NHBDs.

Late-onset circulatory dysfunction of premature infants and late-onset periventricular leukomalacia.

BACKGROUND: The sudden appearance of hypotension and oliguria without obvious cause following stable circulation and respiration in preterm infants is frequent in Japan. Such episodes are referred to as late-onset circulatory dysfunction of premature infants (LCD). Volume expanders and inotropic agents are often ineffective against this condition, whereas i.v. steroids are significantly effective. A major problem is that cystic periventricular leukomalacia (PVL) often develops a few weeks after an episode. The aim of the present study was to clarify the risk factors, including LCD, related to cystic PVL. METHODS: A case-control study was performed for preterm infants who were delivered at <33 weeks of gestation and admitted to seven neonatal intensive care units in Japan. Cystic PVL infants were stratified into early-onset PVL diagnosed within 28 days of age and late-onset PVL diagnosed after more than 28 days of age. The reported and new risk factors for PVL, for each group of PVL infants, and for all PVL infants, were compared with controls. RESULTS: Thirty-two infants were diagnosed with cystic PVL (17 early-onset and 15 late-onset). All PVL infants significantly differed from controls on Apgar score, number of abortions and pregnancies, intraventricular hemorrhage, and LCD. LCD was diagnosed in 28.1% of both PVL groups compared with 6.3% of controls (P = 0.02). Multivariate analysis demonstrated significant association between late-onset PVL and LCD. CONCLUSION: LCD was significantly associated with cystic PVL, especially late-onset PVL. Elucidating the cause of LCD might reduce the incidence of PVL and improve the neurological prognosis of preterm infants.

Endotoxin removal with a polymyxin B-immobilized hemoperfusion cartridge improves cardiopulmonary function after cardiopulmonary bypass.

BACKGROUND: Cardiac surgery using cardiopulmonary bypass (CPB) is performed widely, given the progress in cardioprotective methods. However, endotoxemia caused by CPB leads to systemic inflammatory response syndrome and deterioration of organ function. We evaluated the effectiveness of endotoxin removal with a polymyxin B-immobilized hemoperfusion cartridge (PMX) in CPB. MATERIALS AND METHODS: Pigs weighing about 25 kg were divided into control (n = 5) and PMX (n = 5) groups. Normothermic CPB was performed in the control group, while endotoxin was removed with PMX under normothermic CPB in the PMX group. Endotoxin removal was performed from the start to end of CPB. The end-systolic pressure-volume ratio (E(max)), left ventricular pressure (LVP), maximum and minimum rates of increase in LVP (+/-LVdp/dt), and cardiac output (CO) were measured 2 h after CPB, and the recovery rates of the parameters were compared between the two groups. A histopathological study was also conducted. RESULTS: The recovery rates of E(max), CO, and LVP were significantly better (P < 0.05) in the PMX group than in the control group. The PaO(2) 2 h after CPB was significantly higher (P < 0.05) in the PMX group than in the control group. The interleukin (IL)-8 level 2 h after CPB was significantly lower (P < 0.05) in the PMX group. Histopathologically, the heart and pulmonary tissues were better preserved in the PMX group. CONCLUSION: The PMX treatment reduced the inflammatory reaction caused by CPB, and cardiac and pulmonary functions after normothermic CPB were well preserved.

The comparison of mitogen-activated protein kinases that become activated within the left ventricular and right atrial tissues following heart transplantation in canine model.

The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia/reperfusion injury. Some reports have documented MAPKs activation of the myocardium in human models, using right atrial (RA) tissue for samples. This study compared the activation of MAPKs in left ventricle (LV) and RA tissues in canine heart transplantation. Four dogs were used as baseline data at two points, before and 20 min after warm ischemia (baseline model), and eight dogs (four pairs of donor and recipient) were used at other points: 4 h after cold ischemia, and at 10, 60, and 180 min after reperfusion (transplantation model). In the transplantation model, donor hearts were left in situ for 20 min after cardiac arrest, and were immersed in Celsior solution for 4 h after coronary flushing. Orthotopic heart transplantation was then performed. Two groups were created: the LV and RA groups (n = 4 in each group). Heart tissue was harvested from the left ventricular wall in the LV group and from the right atrial appendage in the RA group. The activation of MAPKs, including p38 MAPK, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated protein kinase (ERK), was evaluated at each point. The activation patterns of p38 MAPK and ERK were similar in the RA and LV groups, but JNK activation was different in the two groups, after ischemia and reperfusion. Thus, RA tissue may be deliberately used as a substitute for LV tissue when investigating the activation of MAPKs in a human model.

A case of spinal cord injury that occurred in utero.

Spinal cord injury is a rare occurrence that is often difficult to diagnose. This report describes a 2-year-old male with cervicothoracic spinal cord injury. The injury is thought to have occurred in the fetal period because the patient's thorax was markedly hypoplastic at birth and his mother had noticed a decrease in fetal movements for several weeks before the birth. The deep tendon reflex of the upper and lower extremities was absent at birth, as observed in other cases of spinal cord injury. It was noteworthy that deep tendon reflex of the upper and lower extremities remained decreased at 2 years of age despite the injury being located at C(7)-T(1). Based on this case, we propose that spinal cord injuries occurring in utero display different reflex responses from those occurring at birth.