There is considerable evidence that consuming fish has numerous health benefits, including a reduced risk of cardiovascular disease. However, fish is also the primary source of human exposure to mercury (Hg). In a cross-sectional study of 9–11 year old children (N = 100), we measured fish consumption, blood lipids, total blood Hg, diurnal salivary cortisol (4 samples collected throughout the day), and performed a proteomic analysis of serum proteins using spectral count shotgun proteomics. Children that consumed fish had a significantly more atheroprotective lipid profile but higher levels of blood Hg relative to children that did not consume fish. Although the levels of blood Hg were very low in these children (M = 0.77 μg/L; all but 1 participant had levels below 3.27 μg/L), increasing blood Hg was significantly associated with blunted diurnal cortisol levels. Blood Hg was also significantly associated with acute-phase proteins suggesting systemic inflammation, and several of these proteins were found to significantly reduce the association between Hg and diminished cortisol when included in the model. This study of a pediatric population is the first to document an association between blood Hg, systemic inflammation, and endocrine disruption in humans, in a pediatric sample. Without a better understanding of the long-term consequences of an atheroprotective lipid profile relative to blunted diurnal cortisol and systemic inflammation, a determination of the risk-benefit ratio for fish consumption by children is not possible.
Children; mercury; fish consumption; inflammation; neuroendocrine
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominantly inherited central nervous system white matter disease with variable clinical presentations including personality and behavioral changes, dementia, depression, parkinsonism, seizures, and others1,2. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 (encoded by CSF1R) in 14 families affected by HDLS. In one kindred, the de novo occurrence of the mutation was confirmed. Follow-up sequencing analyses identified an additional CSF1R mutation in a patient clinically diagnosed with corticobasal syndrome (CBS). In vitro, CSF-1 stimulation resulted in the rapid autophosphorylation of selected tyrosine-residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from a partial loss of CSF1R function. Since CSF1R is a critical mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
A number of studies suggest that Pb exposure increases cardiovascular disease risk in humans. As a potential mechanism for this effect, we recently reported a significant association between early childhood Pb levels and cardiovascular response to acute stress. The current study considers the association between current Pb levels and the autonomic nervous system activation pattern underlying the cardiovascular response to stress in a new cohort of children.
We assessed blood Pb levels as well as cardiovascular responses to acute stress in 9–11 year old children (N = 140). Sympathetic activation (measured with pre-ejection period) and parasympathetic activation (measured with high frequency heart rate variability) were also assessed.
In a sample with very low levels of blood Pb (M = 1.01 μg/dL), we found that increasing blood Pb was associated with coinhibition of sympathetic and parasympathetic activation in response to acute stress. In addition, increasing Pb levels were associated with the hemodynamic stress response pattern typical of coinhibition – significantly greater vascular resistance and reduced stroke volume and cardiac output.
Blood Pb levels were associated with significant autonomic and cardiovascular dysregulation in response to acute psychological stress in children. Moreover, these effects were significant at Pb levels considered to be very low and notably well below the 10 μg/dL the Centers for Disease Control and Prevention definition of an elevated blood Pb level. The potential for autonomic dysregulation at levels of Pb typical for many US children would suggest potentially broad public health ramifications.
Cardiovascular; children; lead; stress; autonomic balance; vascular
Meier-Gorlin syndrome (ear, patella, short stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterised by absent/hypoplastic patellae and markedly small ears1-3. Both pre and post-natal growth are impaired in this disorder and although microcephaly is often evident, intellect is usually normal. We report here that this disorder shows marked locus heterogeneity and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.
Heavy metal exposure in children has been associated with a variety of
physiological and neurological problems. The goal of this study was to utilize
proteomics to enhance the understanding of biochemical interactions responsible
for the health problems related to lead and mercury exposure at concentrations
well below CDC guidelines. Blood plasma and serum samples from 34 children were
depleted of their most abundant proteins using antibody-based affinity columns
and analyzed using two different methods, LC-MS/MS and 2-D electrophoresis
coupled with MALDI-TOF/MS and tandem mass spectrometry. Apolipoprotein E
demonstrated an inverse significant association with lead concentrations
(average being one microgram/deciliter) as deduced from LC-MS/MS and 2-D
electrophoresis and confirmed by Western blot analysis. This coincides with
prior findings that Apolipoprotein E genotype moderates neurobehavioral effects
in individuals exposed to lead. Fifteen other proteins were identified by
LC-MS/MS as proteins of interest exhibiting expressional differences in the
presence of environmental lead and mercury.
Proteomics; children; blood; cardiovascular; lead; mercury; apolipoprotein E; Pb; Hg; ApoE
Meningeal carcinomatosis occurs in 1–18% of patients with solid tumours, most commonly carcinomas of the breast and lung or melanomas. There are relatively few reports of meningeal carcinomatosis in transitional cell carcinoma of the bladder. Isolated meningeal recurrence is particularly uncommon, and we present an unusual case of this in a 58-year-old man. The case was further complicated by the somewhat atypical presentation with a confirmed ischaemic stroke. The patient died one month after presentation.
Meningeal carcinomatosis; Recurrence; Transitional cell carcinoma; Bladder
The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease.
mitochondria; protein targeting; protein translocation; human health and disease