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.

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.

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.

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.

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.

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.