Perinatal lung development following maternal exposure to methylmercuric chloride

Mercury ingested from dietary sources has potent neurotoxic and teratogenic effects. Initial studies have shown that mercury may also affect fetal lung development. Since these pulmonary effects may play a role in subsequent neonatal morbidity and mortality due to compromising of the development of the lung, mercury effects in fetal and neonatal lung were investigated. Methylmercuric chloride (MMC), 1,000 ppm (15 mg/kg of body weight), was administered via an intragastric tube to timed-pregnant Swiss/Webster mice on day 9 of gestation. Lungs from fetuses on gestational day 18 and from neonates on days 1, 5, or 10 after birth were studied. Significant changes in MMC-exposed lungs compared to controls occurred at postnatal day 1. At this time, lung weight per gram body weight increased, phospholipid content per gram of lung or per microgram of DNA decreased, while DNA per gram of lung increased. Methylmercury appears to have delayed lung maturation. Cuboidal epithelial cells in alveolar tubules contained conspicuous glycogen deposits, and differentiation of alveolar type II cells was adversely affected. These results suggest that prenatal exposure to methylmercury may be detrimental to lung development, specifically to the initiation of surfactant synthesis, by delaying the normal pattern of maturation of the alveolar type II cells within the lungs. Pediatr Pulmonol. 1994; 17:11–21 . © 1994 Wiley-Liss. Inc.     

Renal glomerulogenesis in medaka fish, Oryzias latipes

We provide an overview of glomerulogenesis in medaka from the embryo to the adult by means of in situ hybridization with the wt1 gene as a marker as well as histology and three-dimensional images. The pronephric glomus starts to develop in the intermediate mesoderm during early somitogenesis, is completed before hatching, and persists throughout the lifetime of the fish. Within 5 days after hatching, mesonephric glomerulus formation begins in the caudomedial end of the pronephric sinus and duct area. The number of glomeruli reaches approximately 200-300 in each kidney within 2 months after hatching. wt1 expression during nephron maturation served as a marker for the formation of the mesenchymal condensate and the nephrogenic body. Existence of mesenchymal condensates and persistence of wt1 expression in the adult kidney suggest that the mesonephros retains precursor cells that may be capable of contributing to neoglomerulogenesis during adulthood. Developmental Dynamics 237:2342-2352, 2008. (c) 2008 Wiley-Liss, Inc.     

γ-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors

Summary In the present study the actions of wt2vrq5558751156/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0">-hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABA_B-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABA_B-receptor antagonist CGP 35348 (200 mg/kg, i.v.).Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABA_B-receptors. Correspondence to: G. Engberg at the above address     

Diuretic-related hypokalaemia: the role of diuretics,potassium supplements,glucocorticoids and β2-adrenoceptor agonists

All 5,047 consecutive inpatients admitted to the Internal Medicine Division of a teaching hospital (Zieglerspital, Berne) between 1982 and 1985 were registered in accordance with the CHDM (Comprehensive Hospital Drug Monitoring) questionnaire of adverse drug reactions (ADRs). Of them, 2,439 were treated with at least one potassium losing diuretic. The hospital records of the patients were reviewed with particular regard to serum potassium levels, and on the basis of this evaluation, the patients were assigned to four different diuretic treatment groups, and the incidence of hypokalaemia related to diuretic treatment was estimated. The overall rate of occurrence of hypokalaemia was 21.1% at a serum potassium level <3.5 mmol·1^–1, and 3.8% <3.0 mmol·1^–1. Hypokalaemia of less than 3.5 mml·1^–1 developed 24.9% (217/870) of patients treated with potassium losing diuretics alone; in 19.7% (101/513) treated with potassium losing diuretics in conjunction with potassium substitution, in 15.1% (66/438) treated with a combination of diuretics (potassium losing with potassium sparing), and in 20.0% (12/60) treated with combined diuretics and potassium substitution. Only the differences between the first and the two subsequent groups were statistically significant. The overall incidence of hypokalaemia below 3.0+mmol·1^–1 was significantly lower in the patients on combined diuretics without potassium substitution than in the patients on potassium losing diuretics with potassium substitution.Oral or parenteral administration of glucocorticoids (prednisone 5 to 2,000 mg/d) was a significant risk factor for hypokalaemic events. wt5t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-Adrenoceptor agonists had not effect. The patient's age, sex, renal function and numbers of drugs received were evaluated in a multivariate analysis, in order to take into account their influence on the risk of developing hypokalaemia. The number of drugs above 12 (and, less importantly, female sex) was the main risk factor for this ADR.The comparison between hypokalaemia and hyperkalaemia in this group of inpatients showed the significance of reduced renal function in the occurrence of hyperkalaemia.     

Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE₂) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE₂ receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 −/−), were hemizygous for DOCK2 (DOCK2 +/−), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2 −/− mice compared with APPswe-PS1Δe9/DOCK2 +/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ₄₂ was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.     

Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

Background

In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity varies widely and depends on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model.

Methods

Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5.

Results

When the dams in Mthfr^+/− × Mthfr^+/− matings were treated with 7.2 mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr^+/+ × Mthfr^+/−, Mthfr^+/− × Mthfr^+/− and Mthfr^−/− × ^Mthfr+/−) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote × wild-type versus wild-type × nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights.

Conclusions

Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure.     

Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form

BACKGROUND & AIMS: Tumor necrosis factor (TNF) is cleaved proteolytically from a 26-kilodalton transmembrane precursor protein into secreted 17-kilodalton monomers. Transmembrane (tm) and secreted trimeric TNF are biologically active and may mediate distinct activities. We assessed the consequences of a complete inhibition of TNF processing on the course of colitis in recombination activating gene (RAG)2 -/- mice on transfer of CD4 CD45RB hi T cells. METHODS: TNF -/- mice, transgenic for a noncleavable mutant TNF gene, were used as donors of CD4 T cells, and, on a RAG2 -/- background, also as recipients. Kinetics of disease development were compared in the absence of TNF, in the absence of secreted TNF, and in the presence of secreted and tmTNF. The analysis at the end of the observation period included the histopathologic assessment of the intestine and the localization of TNF and interferon gamma (IFNgamma)-expressing cells. RESULTS: The complete prevention of TNF secretion in tmTNF transgenic RAG2 -/- mice neither prevented nor delayed disease induction by transferred transgenic for a noncleavable transmembrane mutant of mouse TNF (tmTNF tg) CD4 CD45RB hi T cells. tmTNF expression by transferred CD4 T cells, however, was not required for disease induction because severe colitis and weight loss also were observed in tmTNF RAG2 -/- recipients of TNF -/- CD4 CD45RB hi T cells. In the presence of tmTNF, the absence of secreted TNF did not affect frequency and distribution of TNF and interferon-gamma messenger RNA (mRNA)-expressing cells. CONCLUSIONS: These results indicate that specific inhibitors of TNF processing are not appropriate for modulating the pro-inflammatory and disease-inducing effects of TNF in chronic inflammatory disorders of the intestine.     

Effect of Vacuum Heat Treatment on the Element Diffusion Behavior and Corrosion Resistance of Al2O3-3wt.%TiO2 Coating of Q235 Steel

In this study, we address the effect of vacuum heat treatment on the morphology of Al₂O₃-3wt.%TiO₂ coating, element diffusion behavior, coating hardness, and corrosion resistance. The pores, cracks, and non-liquefied particles on the as-heat treated coating surface of the vacuum-heat-treated coating were observed and compared with the as-sprayed coating using a scanning electron microscope. The diffusion behavior of the elements in the coating was demonstrated by using a line scanning of a cross-section of the coating. Hardness and corrosion-resistance test results were used to judge the effect of a vacuum heat treatment on the coating. The research results show that compared with atmospheric heat treatment, the vacuum heat treatment had less effect on the pores, cracks, and non-liquefied particles on the surface of the coating. However, in the absence of new oxide formation, the pores and cracks in the cross-section of the coating were significantly improved by the vacuum heat treatment. The surface hardness and corrosion resistance of the coating were significantly improved. The crack defects were eliminated, and the uniformity of TiO₂ distribution was improved, which are the main factors that improved the coating performance after vacuum heat treatment. The combination of the coating and the substrate is strengthened, and an Al₂O₃ and TiO₂ interdiffusion zone is formed when the coating undergoes vacuum heat treatment, which is the main mechanism improving the performance of the AT3 coating.     

A physiological threshold for protection against menadione toxicity by human NAD(P)H:quinone oxidoreductase (NQO1) in Chinese hamster ovary (CHO) cells

NAD(P)H:quinone oxidoreductase 1 (NQO1) has often been suggested to be involved in cancer prevention by means of detoxification of electrophilic quinones. In the present study, a series of Chinese hamster ovary (CHO) cell lines expressing various elevated levels of human NQO1 were generated by stable transfection. The level of NQO1 over-expression ranged from 14 to 29 times the NQO1 activity in the wild-type CHO cells. This panel of cell lines, allowed investigation of the protective role of NQO1 in quinone cytotoxicity. It could be demonstrated that menadione toxicity was significantly reduced in all NQO1-transfected CHO clones compared to the wild-type cells, but the clones did not show differences in their level of protection against menadione. This observation pointed at a critical threshold concentration of NQO1 above which a further increase does not provide further protection against quinone cytotoxicity. Additional studies in which the NQO1 activity was inhibited by dicoumarol showed that only dicoumarol concentrations of about five times the EC(50) for NQO1 inhibition were able to reduce NQO1 levels below the apparent threshold, making the cells more sensitive. The level of this threshold was estimated to be in the range of base line NQO1 activities observed in several tissues and species. Thus, the results of the present study indicate that beneficial effects of NQO1 induction by, for example, cruciferous vegetables might be absent or present depending on the NQO1 activity threshold for optimal protection and the basal level of NQO1 expression in the tissue and species of interest.