Prenatal methylmercury exposure is associated with decrease heart rate variability in children.

BACKGROUND: Although several epidemiological studies have suggested mercury (Hg) might be associated with cardiotoxicity, the impact of Hg exposure on cardiac autonomic activity and blood pressure in children has not been investigated at Hg exposure levels equivalent to the Environmental Protection Agency (EPA) reference dose. OBJECTIVE: To investigate the association between low dose prenatal and recent methylmercury (MeHg) exposures and cardiac autonomic function and blood pressure with adjustment for factors such as fish consumption among children from a high fish consumption coastal city. METHODS: Children aged 7-8 years were recruited from the birth cohort of our previous study. Heart rate variability (HRV), resting heart rate (RHR) and blood pressure were measured as surrogate markers of cardiac autonomic function. Cord blood and current whole blood Hg concentration were used as biomarkers of prenatal and recent MeHg exposure, respectively. Recent fish consumption information was estimated with a food frequency questionnaire. RESULTS: Among 604 children, median cord blood and whole blood Hg concentrations were 45.9 nmol/L (IQR: 32.8-65.03 nmol/L) and 13.57 nmol/L (IQR: 9.29-19.72 nmol/L), respectively. Our results demonstrated that prenatal MeHg exposure was associated with decreased HRV (i.e. low CVRR, SDRR, and RMSSD), reflecting reduced parasympathetic activity (i.e. low CCVHF and HF), and a sympathovagal balance shift toward sympathetic predominance (i.e. high %LF and LF/HF ratio). Adjustment of recent fish consumption further increased the significance and magnitude of the adverse associations of MeHg. CONCLUSION: The results of this study suggest that prenatal MeHg exposure is associated with decreased parasympathetic modulation of cardiac autonomic function in children.

Impact of fetal and childhood mercury exposure on immune status in children.

BACKGROUND: Mercury exposure have been shown to affect immune status in animals as reflected by cytokine expression. It is unclear whether low levels of exposure during fetal and/or childhood periods could impact on immune status in humans. OBJECTIVES: To test the hypothesis that fetal and childhood mercury exposure is associated with childhood cytokine profiles and to investigate whether childhood selenium levels interact with any of the associations found. METHODS: Children were recruited from a previously established birth cohort between the ages of 6-9 years for assessment and measurement of blood mercury, selenium and cytokine profile (interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13 and TNF-alpha). Multivariable linear regression models were used to assess the adjusted association of cord blood mercury concentration and current mercury concentrations with levels of the cytokine levels. We tested whether the association with current mercury level varied by current selenium level and cord blood mercury level. RESULTS: IL-10 was negatively associated with current blood mercury concentration. The effect was greatest in cases with low cord blood mercury and low current selenium concentrations. None of the other cytokine levels were associated with either cord blood or current blood mercury concentrations, except that cord blood mercury was negatively associated with IL-6. CONCLUSIONS: Childhood mercury exposure was negatively associated with childhood IL-10 levels. It is postulated that while selenium is protective, low levels of fetal mercury exposure may increase the degree of this negative association during childhood. Further studies into the clinical significance of these findings are required.

Development of a novel mouse model of severe glucose-6-phosphate dehydrogenase (G6PD)-deficiency for in vitro and in vivo assessment of hemolytic toxicity to red blood cells.

Studies of hemolytic agents on G6PD-deficient subjects have been extensively performed on red blood cells obtained from donors, only using in vitro methods. However, there has been no adequate G6PD-deficient animal model for in vivo assessment of potentially hemolytic agents. The objective of this study is to establish a novel mouse model of severe G6PD-deficiency, with high susceptibility to hemolytic damage upon oxidative agents. To create this model, G6PD mutant Gpdx allele was introduced into the C57L/J mouse strain background by breeding program. The hemolytic toxicity of naphthalene and its metabolite α-naphthol on G6PD-deficient red blood cells was evaluated. Our data showed that the F2 homozygous Gpdx mutant with C57L/J background exhibiting the G6PD activity was 0.9±0.1 U/g Hb, level similar to those of G6PD deficiency in human. A significantly negative correlation was demonstrated between GSH percentage reduction and G6PD activity (r=-0.51, p<0.001) upon challenge of the red blood cells with alpha-naphthol in vitro. Similar correlation was also found between GSSG elevation and G6PD activity. Our in vivo studies showed that the administration of naphthalene at 250 mg/kg inflicted significant oxidative damage to the G6PD-deficient mice, as illustrated by the decrease of the GSH-to-GSSG ratio (by 34.2%, p=0.005) and the increase of the methemoglobin level (by 1.9 fold, p<0.001). Hemolytic anemia was also found in G6PD-deficient mice at this dosage of naphthalene. In summary, this novel mouse model could be utilized as a screening platform to more accurately determine the hemolytic toxicity of pharmacological agents on G6PD-deficient subjects.

Novel mutations in PHKA2 gene in glycogen storage disease type IX patients from Hong Kong, China.

The diagnosis of glycogen storage disease (GSD) type IX is often complicated by the complexity of the phosphorylase kinase enzyme (PHK), and molecular analysis is the preferred way to provide definitive diagnosis. Here we reported two novel mutations found in two GSD type IX patients with different residual enzyme activities from Hong Kong, China using genetic analysis and, provided the molecular interpretation of the deficient PHK activity. These two newly described mutations would be useful for the study of future GSD patients.

Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity.

Obstructive sleep apnea (OSA) is a common sleep and breathing disorder characterized by repeated episodes of hypoxemia. OSA causes neurocognitive deficits including perception and memory impairment but the underlying mechanisms are unknown. Here we show that in a mouse model of OSA, chronic intermittent hypoxia treatment impairs both early- and late-phase long-term potentiation (LTP) in the hippocampus. In intermittent hypoxia-treated mice the excitability of CA1 neurons was reduced and hippocampal brain-derived neurotrophic factor (BDNF) was down-regulated. We further showed that exogenous application of BDNF restored the magnitude of LTP in hippocampal slices from hypoxia-treated mice. In addition, microinjection of BDNF into the brain of the hypoxic mice prevented the impairment in LTP. These data suggest that intermittent hypoxia impairs hippocampal neuronal excitability and reduces the expression of BDNF leading to deficits in LTP and memory formation. Thus, BDNF level may be a novel therapeutic target for alleviating OSA-induced neurocognitive deficits.

Roles of parental sleep/wake patterns, socioeconomic status, and daytime activities in the sleep/wake patterns of children.

OBJECTIVES: To determine sleep/wake patterns of primary school children and their correlates. STUDY DESIGN: A total of 4470 sets of mother-father-child community-based trios were recruited in this study. We constructed 3 integrated models with structural equation modeling to predict sleep/wake patterns of children (bedtime, wakeup time, and time in bed [TIB]). RESULTS: Our best-fitting models explained 40% to 71% variances of various sleep/wake patterns of the children, which were influenced by a web of interactive factors including school start time, parental sleep/wake patterns, sociodemographics, and daytime activities. The strongest predictor of various sleep/wake patterns was school start time. Higher socioeconomic status would shorten TIB of both children and parents, but through different pathways (by advancing wakeup time and delaying bedtime in children but by delaying bedtime in parents). Media use and homework shortened TIB of children, while leisure extracurricular activities and later school start time lengthened it. The age and sex effects on sleep/wake patterns, at least in part, were mediated by daytime activities. Daytime activities of children also influenced their parental sleep/wake patterns, especially their maternal one. A consistent pattern of stronger mother-child than father-child associations were found in various sleep/wake patterns. CONCLUSIONS: There was a complex and interactive relationship among school schedule, parental sleep/wake patterns, socioeconomic status, and daytime activities in determining the sleep/wake patterns of children. These findings have important clinical implications for the management of childhood sleep/wake habits and problems.

Serum levels of heavy metals in childhood eczema and skin diseases: friends or foes.

The incidence of eczema has been increasing in developed countries. Environmental and hygiene factors have been incriminated. Although air and food pollution with heavy metals have been considered as possible culprits, these factors have never been investigated in Hong Kong. To evaluate if quality of life and eczema severity are associated with abnormal serum levels of six common heavy metals, namely, cadmium, lead, mercury, selenium, copper and zinc. Serum or whole blood was taken for measurement of six heavy metals from patients referred to the pediatric dermatology clinic. Eczema severity (SCORAD and NESS) and quality of life (CDLQI) were recorded. A total of 110 patients with eczema and 41 patients with miscellaneous skin conditions were recruited. Serum levels of the six heavy metals were generally within the upper limits of local reference ranges. Zinc levels were below the lower reference limit of 9.4 mum in 66 patients with eczema (60%) and 22 non-eczema patients (53%). Forty-four patients with eczema (40%) and 24 (58%) in non-eczema group had low copper levels. In eczema patients, lead levels were generally within normal limits but their levels were positively correlated with poor quality of life (CDLQI: r = 0.22 and p < 0.05), disease severity (objective SCORAD: r = 0.33 and p < 0.005; NESS: 0.20, p < 0.05), eosinophil count and log-transformed IgE. Copper/zinc ratio also correlated with NESS and CDLQI and was generally higher than non-eczema skin diseases. Our findings help reassure parents that levels of heavy metals generally do not exceed the local reference ranges for toxicity. However, lead levels have significant correlations with disease severity, quality of life and atopy. Low zinc and copper levels are commonly found in pediatric skin diseases and their significance needs to be determined.

Validation of the Chinese version of the Pediatric Quality of Life Inventory (PedsQL) Cancer Module.

OBJECTIVE: The psychometric properties of the Chinese version of the Pediatric Quality of Life Inventory (PedsQL) Cancer Module were investigated. METHODS: This instrument and the Generic Core Scales were administered to 359 pediatric patients with cancer (5-18 years) and 413 parents of such patients (2-18 years old). RESULTS: Seven and eight factors were, respectively, identified for the patient and parent versions. The Cronbach's alpha coefficients were respectively .89 and .92 for the total scale, and respectively .75-.90 and .76-.93 for the subscales of the patient and parent versions. Test-retest reliability coefficients exceeded .60 for most cases. The total/subscale scores of the Cancer Module significantly correlated with those of the Generic Core Scales. Some of the subscales could distinguish between on-treatment and off-treatment patients. CONCLUSIONS: The psychometric properties of the patient and parent versions of the Chinese PedsQL Cancer Module were found acceptable.

Sodium tanshinone IIA sulfonate increased intestinal hemodynamics without systemic circulatory changes in healthy newborn piglets.

In traditional Chinese medicine, tanshinone IIA is a lipid-soluble component of Danshen that has been widely used for various cardiovascular and cerebrovascular disorders, including neonatal asphyxia. Despite promising effects, little is known regarding the hemodynamic effects of tanshinone IIA in newborn subjects. To examine the dose-response effects of sodium tanshinone IIA sulfonate (STS) on systemic and regional hemodynamics and oxygen transport, 12 newborn piglets were anesthetized and acutely instrumented for the placement of femoral arterial and venous, pulmonary arterial catheters to measure mean arterial, central venous, and pulmonary arterial pressures, respectively. The blood flow at the common carotid, renal, pulmonary, and superior mesenteric (SMA) arteries were continuously monitored after treating the piglets with either STS (0.1-30 mg/kg iv) or saline treatment (n = 6/group). To further delineate the underlying mechanisms for vasorelaxant effects of STS, in vitro vascular myography was carried out to compare its effect on rat mesenteric and carotid arteries (n = 4-5/group). STS dose-dependently increased the SMA blood flow and the corresponding oxygen delivery with no significant effect on systemic and pulmonary, carotid and renal hemodynamic parameters. In vitro studies also demonstrated that STS selectively dilated rat mesenteric but not carotid arteries. Vasodilation in mesenteric arteries was inhibited by apamin and TRAM-34 (calcium-activated potassium channel inhibitors) but not by meclofenamate (cyclooxygenase inhibitor) or N-nitro-l-arginine methyl ester hydrochloride (nitric oxide synthase inhibitor). In summary, without significant hemodynamic effects on newborn piglets, intravenous infusion of STS selectively increased mesenteric perfusion in a dose-dependent manner, possibly via an endothelium-derived hyperpolarizing factor vasodilating pathway.

Adjunctive pharmacotherapy in neonates with respiratory failure.

Whereas oxygen, continuous positive airway pressure (CPAP) and mechanical ventilation are the mainstays of treatment of pulmonary conditions in newborns, there are a number of adjunctive therapies that may improve the pulmonary function of these infants. These include the use of bronchodilators and diuretics given either systemically or through the inhaled route, mucolytic agents, and anti-inflammatory agents. This chapter gives an overview of the use of the most-studied agents including aerosolized bronchodilators, systemic and inhaled diuretics, and systemic and inhaled corticosteroids in the treatment and prevention of, where appropriate, respiratory distress syndrome, bronchopulmonary dysplasia, and meconium aspiration syndrome. Evidence on the use of mucolytic agents including acetylcysteine and deoxyribonuclease, and the anti-inflammatory agents including the macrolide antibiotics, cromolyn, pentoxyfylline, and recombinant human Clara cell protein are also reviewed.