Prenatal exposure to nickel and atopic dermatitis at age 3 years: a birth cohort study with cytokine profiles.

BACKGROUND: Nickel, the fifth most common element on Earth, is the leading inducer of contact allergies in humans, with potent immunological effects. Nickel-induced contact allergies predominantly affect females. Maternal exposure to nickel has been associated with several developmental abnormalities. However, how a maternal nickel exposure affects the development of atopic diathesis and immune abnormalities in children has never been addressed. OBJECTIVES: We aimed to determine whether maternal nickel exposure affects the development of atopic dermatitis and immune abnormalities in their children. METHODS: Using a birth cohort study, we analysed 140 mother-child pairs recruited in 2012-2015 from central Taiwan. Maternal exposure to nickel was estimated using urinary nickel levels measured by inductively coupled plasma mass spectrometry (ICP-MS). The serum levels of 65 analytes and IgE in 3-year-old children were profiled with a multiplex ELISA. The correlation between the maternal urinary nickel concentration and serum analyte levels was assessed using Spearmen's correlation. Multivariant regression analysis was performed to evaluate the association between maternal urinary nickel levels and serum analyte concentrations in their children. RESULTS: The geometric means of the maternal urinary nickel and the children's serum IgE levels were 2.27 µg/L and 69.71 IU/mL, respectively. The maternal nickel exposure was associated with increased serum levels of IL-1ß, IL-2, TNF-α, and leukaemia inhibitory factor (LIF) but with decreased serum levels of matrix metalloproteinase-1 (MMP-1), IL-2R, and eotaxin-1 in the children. In addition, the development of childhood atopic dermatitis at 3 years old was significantly associated with the child's serum levels of IgE and IL-2R, but it was negatively associated with the maternal nickel exposure. CONCLUSIONS: This is the first study showing the potential immunological effects of maternal nickel exposure in their children at an early developmental stage.

Smallest critical region for microcephaly in a patient with mosaic ring chromosome 13.

A ring chromosome 13 or r(13) exhibits breakage and reunion at breakage points on the long and short arms of chromosome 13, with deletions of the chromosomal segments distal to the breakage points. The r(13) chromosome accounts for approximately 20% of ring chromosomes compatible with life. We describe a female patient with mental retardation, growth retardation, microcephaly, craniofacial dysmorphy, hearing impairment, and prolonged prothrombin time. Chromosomal analysis via GTG banding of peripheral blood lymphocytes revealed a karyotype of 46,XX,r(13)(p13q34)[71]/45,XX,-13[12]/ 46,XX,dic r(13;13)(p13q34;p13q34)[9]/46,XX,-13,+mar[5]/47, XX,+r(13) (p13q34)x2[2]/46,XX[1] at the age of 6 years and 46,XX,r(13)(p13q34)[82]/45,XX,-13[14]/46,XX,dic r(13;13)(p13q34; p13q34)[2]/46,XX, -13,+mar[2]. Array comparative genomic hybridization analysis of the blood demonstrated a 4.37-Mb deletion on chromosome 13q [arr cgh 13q34q34(109,743,729-144,110,721)]. A cytogenetic study of peripheral blood revealed a rare chromosomal abnormality associated with different cell lines that included structural and numerical abnormalities of chromosome 13. This case, along with 14 previously reported cases, indicate that the smallest critical region for chromosome 13 microcephaly is 109,743,729-144,110,721.

Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer.

Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.

Facial asymmetry and clinical manifestations in patients with novel insertion of the TCOF1 gene.

This study explored the role of TCOF1 insertion mutations in Taiwanese patients with craniofacial anomalies. Twelve patients with single or multiple, asymmetrical congenital craniofacial anomalies were enrolled. Genomic DNA was prepared from leukocytes; the coding regions of TCOF1 were analyzed by polymerase chain reaction and direct sequencing. Clinical manifestations were correlated to the TCOF1 mutation. Six of 12 patients diagnosed with hemifacial microsomia exhibited a novel insertion mutation 4127 ins G (frameshift) in exon 24 in the TCOF1 gene. All six patients were diagnosed with anomalies on the left side. In addition, four of these six patients had hearing impairment; three had other major anomalies; and two had developmental delay. The insertion caused a frameshift, an early truncation, the loss of two putative nuclear localization signals (residues 1404-1420 and 1424-1440), and the loss of coiled coil domain (1406-1426) in treacle protein. These findings support the existence of two regulators of growth of the mandibular condyles.

Inhaled nitric oxide in the management of preterm infants with severe respiratory failure.

OBJECTIVE: Elevated pulmonary vascular resistance and poor ventilation-perfusion matching are commonly found in preterm infants with severe respiratory distress syndrome (RDS) and respiratory failure. Inhaled nitric oxide (iNO) can improve gas exchange and decrease pulmonary vascular resistance. This study was conducted to determine whether iNO therapy improves oxygenation in such infants. STUDY DESIGN: Between July 2000 and 2006, 65 preterm infants (birth weight, <1500 g; gestational age, <31 weeks) with severe RDS and respiratory failure requiring mechanical ventilation and an oxygenation index (OI)>or=25 were randomly divided into two groups. Group A infants (n=32) received iNO therapy. iNO was started at a dose of five parts per million (p.p.m.). The maximal dose of NO was 20 p.p.m. Group B infants (n=33) did not receive iNO therapy, receive inhaled oxygen placebo only, was served as control group. Mechanical ventilation and iNO therapy were managed by neonatologists who were not involved in safety monitoring, data analysis and interpretation, or manuscript preparation. This study was randomized but not blinded. RESULT: The OI was significantly lower (P<0.01) in the iNO therapy group than in the control group at 30 min, 3, 12 and 24 h after initiating iNO therapy. Six infants in the iNO-treated group and 10 infants in the control group died. Post hoc analyses did not reveal any significant differences in the incidences of chronic lung disease (CLD), intracranial hemorrhage (ICH), patent ductus arteriosus (PDA), retinopathy of prematurity (ROP) or duration of intubation between the iNO-treated and the control groups. CONCLUSION: We conclude that iNO therapy leads to an improvement in oxygenation without short-term side effects (such as pulmonary hemorrhage, intracranial hemorrhage, pneumothorax or acute deterioration) in premature infants with severe RDS and respiratory failure. However, iNO therapy does not significantly reduce mortality rate or the incidences of CLD, ICH, PDA or ROP.

Histopathologic changes in growth-plate cartilage following ischemic necrosis of the capital femoral epiphysis. An experimental investigation in immature pigs.

BACKGROUND: The developing capital femoral epiphysis consists of a secondary center of ossification surrounded by epiphyseal cartilage. Between the epiphyseal cartilage and the secondary center of ossification is a growth plate, which contributes to the circumferential increase in size of the secondary center of ossification during development. The main objective of this study was to describe the histopathologic changes that occur in the growth plate surrounding the secondary center of ossification during the early and reparative phases following the induction of ischemic necrosis of the capital femoral epiphysis in immature pigs. METHODS: Ischemic necrosis of the capital femoral epiphysis was induced in eighteen piglets by placing a nonabsorbable suture ligature around the femoral neck following a capsulotomy and transection of the ligamentum teres. The animals were killed three days to eight weeks following the induction of ischemia, and visual, radiographic, and histologic assessments were performed. RESULTS: Two to four weeks after the induction of ischemic necrosis, the growth plate surrounding the secondary center of ossification became necrotic. The observed histopathologic changes included chondrocyte death, loss of safranin-O staining of the matrix of the necrotic growth-plate cartilage, an absence of vascular invasion of terminal hypertrophic chondrocytes, and a decrease in the amount of primary spongiosa, indicating cessation of endochondral ossification. In the reparative phase, at four to eight weeks postoperatively, chondrocyte clusters and intense safranin-O staining were observed in the epiphyseal cartilage around the necrotic growth-plate cartilage. In the peripheral region of the femoral head, necrotic growth-plate cartilage surrounding the secondary center of ossification was resorbed by a fibrovascular tissue from the marrow space. By six weeks, new accessory centers of ossification with restored endochondral ossification were observed in the peripheral epiphyseal cartilage. New ossification centers contributed to the fragmented radiographic appearance of the secondary center of ossification. The physis appeared essentially normal in most animals, although five of the eighteen piglets showed mild or moderate histopathologic changes. CONCLUSIONS: In this model, ischemic necrosis of the capital femoral epiphysis resulted in necrosis of the growth plate surrounding the secondary center of ossification. Small new ectopic centers of ossification appeared in the epiphyseal cartilage, explaining in part the fragmented radiographic appearance of the secondary center of ossification.

Inhaled nitric oxide in the management of persistent pulmonary hypertension of term infants.

BACKGROUND AND PURPOSE: Nitric oxide (NO) is an endogenous vasodilator that is responsible for regulating smooth muscle tone via changes in cyclic guanosine monophosphate (cGMP). Inhaled NO (iNO) causes pulmonary vasodilatation without affecting systemic vascular resistance. The aim of this study was to evaluate the efficacy and adverse effects of iNO therapy for the treatment of term infants with persistent pulmonary hypertension of the newborn (PPHN). METHODS: From June 1998 to June 2000, 26 term infants with PPHN were given iNO therapy. Another 21 term infants with PPHN who did not receive iNO therapy served as the control group. All patients had an oxygenation index (OI) of more than 25 at the beginning of the study. iNO was started at a dose of 20 ppm and weaned according to the response achieved within the 3 hours of treatment. RESULTS: The OI decreased rapidly after 30 minutes of iNO therapy and was significantly lower in the iNO group than in the control group at 30 minutes, 3, 12, and 24 hours after iNO therapy (p < 0.01). All cases in the iNO therapy group had serum methemoglobin levels of less than 2.5% and nitric dioxide (NO2) concentrations less than 2 ppm. CONCLUSIONS: We conclude that iNO therapy produces rapid improvement in oxygenation for 24 hours without short-term side-effects in term infants with PPHN. If a high dose of NO (80 ppm) is used, serum methemoglobin and NO2 values should be monitored.

Congenital contractural arachnodactyly (Beals syndrome).

Congenital contractural arachnodactyly (CCA, Beals syndrome) is an autosomal dominant disorder that is phenotypically similar to Marfan syndrome. CCA is characterized by arachnodactyly, dolichostenomelia, scoliosis, multiple congenital contractures and abnormalities of the external ears. We report here 28 patients with CCA, in whom a wide range of phenotypic expression is observed. These individuals usually have abnormally formed ears, limited extension of fingers and toes, arachnodactyly, clinodactyly, delay of developmental milestones and psychomotor retardation. Limited extensions of elbows, knees and hips are not constant features. With time, those affected individuals experience spontaneous improvement of their contractures but the kyphosis, unlike the joint contractures, tends to be progressive. No ocular problems were found in all patients, but congenital heart defects were detected in 32.2% of them. Atrial septal defect and ventricular septal defect are common components in our patients. Within the only one family with two multiply affected siblings there is little phenotypic variation between the patients.

Relationship of serum lactate dehydrogenase, creatine kinase, aspartate aminotransferase concentrations and severe intraventricular hemorrhage/leukomalacia in very low birth body weight preterm neonates.

Estimations of serum enzyme values are widely employed as valuable diagnostic aids in diseases. Most commonly employed enzymes include Aspartate aminotransferase (AST), Lactate dehydrogenase (LDH), and Creatine kinase (CK). The study was designed to determine the relationship of elevated postnatal serum LDH, CK, and AST concentrations within the first day of life and the risk of suffering severe intraventricular hemorrhage (IVH) and/or periventricular leukomalacia (PVL) in VLBW preterm newborns. 81 preterm neonates whose birth body weight < 1500 gm were enrolled. Serums were obtained for measurement within the first postnatal day. Cranial ultrasound scans were performed twice per week after birth until their body weight was above 2300 gm or postconceptional age above 40 weeks. Significant difference was noted in serum LDH and CK concentrations in severe IVH/PVL infants (p < 0.05). No difference was found in serum AST values. Compared with the cut-off values of 1933 IU/L of LDH concentration and 652 IU/L of CK, the predictive values revealed a sensitivity, specificity, negative predictive value and positive predictive value of 76.9%, 89.7%, 95.3% and 58.8%, respectively. In conclusion, higher serum LDH and/or CK concentrations within the first day of life were associated with risk for development of severe IVH/PVL.

Gallbladder volume and contractility in term and preterm neonates: normal values and clinical applications in ultrasonography.

The aim of this study was to establish the normal values and evaluate associated factors of gallbladder volume and contractility in term and preterm neonates by using ultrasonography. Sonographic measurement of gallbladder volume was performed by using the ellipsoid method in 50 preterm and 46 term infants. We collected data soon after delivery and at 6-h fasting, and at 3-h and 6-h fasting following regular milk feeding. Serial postprandial changes of gallbladder volume and contractility were collected at 15-min intervals for one hour. Gallbladder contraction index (C.I.) was determined as percentage decrement of postprandial size from initial size. Fasting gallbladder volume was larger in term group (p < 0.05). Term neonates more readily showed significant contraction (C.I. > 50%; p < 0.05). In preterm infants significant contraction was clearly observed at postconceptional age > 31 weeks or body weight > 1300 g. The presence of hepatobiliary diseases might be detected by evaluating serial changes of gallbladder volume and contractility under ultrasonography in the neonatal stage.

Mucopolysaccharidosis type II (Hunter's syndrome) in Taiwan.

The mucopolysaccharidoses are a group of inherited disorders of lysosomal storage of glycosaminoglycans. Among them, mucopolysaccharidosis (MPS) type II (Hunter's syndrome), caused by a deficiency in iduronate sulfatase, is the only one inherited in an X-linked recessive manner. We describe 12 Hunter's syndrome patients and seven carriers, with precise analysis of glycosaminoglycan content in urine and iduronate sulfatase activity in cultured fibroblasts and plasma. Their ages at the time of diagnosis ranged from 1 year 10 months to 11 years (mean 4.3 yr). The delay in diagnosis was from 1 month to 5 years (mean 2.1 yr) after the initial presentation. The most frequent initial complaints of the patients were delayed developmental milestones (75%) and speech (67%), although all patients were found to have coarsening of facial features at diagnosis. The difficulties in disease recognition allowed disease recurrence in four of the 11 families. Prompt clinical suspicion and referral will be important in genetic counseling for MPS type II and its management, if definitive therapy becomes available.

Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor.

Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.

Changing epidemiology of triplet pregnancy: etiology and outcome over twelve years.

Neonates of 34 triplet pregnancies were admitted to our neonatal unit over a twelve-year period (1983 to 1995), with an incidence of 1 out of 812 deliveries. Thirty (88%) of the pregnancies were the result of ovulation induction and artificial fertilization: artificial insemination from husband (n = 3), in vitro fertilization (n = 9), and gamete intra-fallopian transfer (n = 6). All except one had antenatal sonographic diagnosis, 79% in the first trimester. The most common pregnancy-related complication was preterm labor (56%). Twenty-seven (79%) were delivered by cesarean section. There were 101 live births (one stillborn). Mean gestation age was 33.6 +/- 2.94 weeks, mean birthweight 1809 +/- 485 g, with 7 extremely low birthweight (< 1000 g [6.8%]). Neonatal complications included respiratory distress syndrome (12%), intraventricular hemorrhage (8.8%), retinopathy of prematurity (8%), sepsis (3%), severe asphyxia (3%), and omphalopagus conjoined twins (1%). The perinatal and neonatal mortality was 49 per 1000 and 59 per 1000, respectively. The introduction of advanced artificial fertilization techniques and ovulation induction agents resulted in a major increase in multifetal gestations. Early prenatal diagnosis, judicious prolongation of gestation, and planned delivery by cesarean section combined with major improvement in neonatal care by experienced neonatologists has improved survival of triplet neonates.

Tracheal agenesis: report of one case.

In this report, we present a newborn male infant with tracheal agenesis. At birth the term baby was cyanotic, bradycardic, and had a failure to cry. His Apgar scores were 3 and 3 at 1 and 5 minutes after birth. Immediately after birth, an endotracheal intubation was unsuccessfully attempted; however, a chest excursion was visible with intubation through the esophagus. Tracheal agenesis with esophago-tracheal fistula was highly suspected. Direct endoscopy and emergency computed tomography were performed and revealed tracheal agenesis. The baby died on day 6, and an autopsy confirmed the diagnosis. Tracheal agenesis (TA) is a rare cause of respiratory distress in the newborn. Cyanosis at birth, difficulty to perform an endotracheal intubation and a failure to cry are the characteristics of TA. Although continuous mechanical support through the esophagus can maintain vital functions, there are no effective medical or surgical method to correct the congenital abnormality currently. The longest survivor of all of the infants with TA had no more than 6 wks of live. In a review of the current literature, only a few cases have had the diagnosis established antemortem. We report a case of tracheal agenesis diagnosed by emergency computed tomography(CT). The role of CT in establishing this diagnosis has been very useful.