Iron-rich air pollution nanoparticles: An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress.

Exposure to particulate air pollution is a major environmental risk factor for cardiovascular mortality and morbidity, on a global scale. Both acute and chronic cardiovascular impacts have so far been attributed to particulate-mediated oxidative stress in the lung and/or via 'secondary' pathways, including endothelial dysfunction, and inflammation. However, increasing evidence indicates the translocation of inhaled nanoparticles to major organs via the circulation. It is essential to identify the composition and intracellular targets of such particles, since these are likely to determine their toxicity and consequent health impacts. Of potential major concern is the abundant presence of iron-rich air pollution nanoparticles, emitted from a range of industry and traffic-related sources. Bioreactive iron can catalyse formation of damaging reactive oxygen species, leading to oxidative stress and cell damage or death. Here, we identify for the first time, in situ, that exogenous nanoparticles (~15-40 nm diameter) within myocardial mitochondria of young, highly-exposed subjects are dominantly iron-rich, and co-associated with other reactive metals including aluminium and titanium. These rounded, electrodense nanoparticles (up to ~ 10 x more abundant than in lower-pollution controls) are located within abnormal myocardial mitochondria (e.g. deformed cristae; ruptured membranes). Measurements of an oxidative stress marker, PrPC and an endoplasmic reticulum stress marker, GRP78, identify significant ventricular up-regulation in the highly-exposed vs lower-pollution controls. In shape/size/composition, the within-mitochondrial particles are indistinguishable from the iron-rich, combustion- and friction-derived nanoparticles prolific in roadside/urban environments, emitted from traffic/industrial sources. Incursion of myocardial mitochondria by inhaled iron-rich air pollution nanoparticles thus appears associated with mitochondrial dysfunction, and excess formation of reactive oxygen species through the iron-catalyzed Fenton reaction. Ventricular oxidative stress, as indicated by PrPC and GRP78 up-regulation, is evident even in children/young adults with minimal risk factors and no co-morbidities. These new findings indicate that myocardial iron overload resulting from inhalation of airborne, metal-rich nanoparticles is a plausible and modifiable environmental risk factor for cardiac oxidative stress and cardiovascular disease, on an international scale.

Prenatal exposure to oxcarbazepine increases hippocampal apoptosis in rat offspring.

This study assessed apoptosis in the offspring of rats exposed to oxcarbazepine (OXC) from day 7 to 15 of gestation. Three groups of pregnant Wistar rats were used: 1) Control, treated with saline solution; 2) treated with 100 mg/kg OXC; 3) treated with 100 mg/kg of carbamazepine (CBZ, as a positive control for apoptosis); the route of administration was intragastric. Apoptosis was detected at three postnatal ages using the TUNEL technique in the CA1, and CA3 regions of the hippocampus and in the dentate gyrus (DG); neurogenesis was assessed in the DG using an antibody against doublecortin. The litter characteristics were recorded. OXC increased apoptosis in all regions (p < 0.01) at the three ages evaluated. Lamination disruption occurred in CA1 and CA3 due to the neuron absence and to ectopic neurons; there were also malformations in the dorsal lamina of the DG in 38% and 25% of the pups born from rats treated with OXC and CBZ respectively. CBZ also increased apoptosis. No clear effect on neurogenesis in the DG was observed. The size of the litter was smaller (p < 0.01) in the experimental groups. Nineteen-day OXC fetuses had low weight (p < 0.01), but 21 and 30 postnatal days old CBZ and OXC pups were overweight (p < 0.01). The results demonstrate that OXC administered during gestation is pro-apoptotic, alters the cytoarchitecture of the hippocampus, reduces litter size, and probably influences postnatal weight. We provide evidence of the proapoptotic effect of CBZ when administered early in gestation.

The invasive potential of Giardia intestinalis in an in vivo model.

Giardiasis is a neglected parasitic disease that affects primarily children, in whom it delays physical and mental development. The pathophysiology of giardiasis in not well understood, and most reports have identified Giardia intestinalis trophozoites only in the lumen and on the brush border of the small intestine. We identified Giardia trophozoites within the epithelium of the small intestine of a lactose intolerance patient. The Giardia trophozoites were obtained and cultured in vitro. In addition, we demonstrated Giardia trophozoite invasion in an animal model. Giardia trophozoites invaded the intestinal mucosa and submucosa of infected gerbils. The invasive trophozoites were observed at 21, 30 and 60 days age, and the average numbers of invaded sites were 17 ± 5, 15 ± 4, and 9 ± 3, respectively. We found trophozoites between epithelial cells, at the base of empty goblet cells, in lacteal vessels and within the submucosa. The morphological integrity of the invasive trophozoites was demonstrated via electron microscopy. The analysis of the gerbils infected with the trophozoites of the WB reference strain did not show intraepithelial trophozoites. These results demonstrate another Giardia pathogenic mechanism, opening the door to numerous future studies.

Clinical and biological acceptance of a fibrocollagen-coated mersylene patch for tracheal repair in growing dogs.

BACKGROUND: Collagen-covered prostheses can be used as a non-circumferential segmental tracheal replacement. However, the applicability of these implants in young subjects has not yet been reported. METHODS: In this experimental, longitudinal study, dogs aged 29-32 days underwent limited segmental tracheal replacement with a polyester prosthesis or were allocated to a control, untreated group. The dogs were evaluated clinically, endoscopically and tomographically for up to one year. RESULTS: Although there was evidence of tracheal growth in the experimental group, tomographic measurements were significantly smaller in this group than in the control group throughout the observation period. At the end of the study, there was no evidence of implant rejection, stenosis or collapse. Normal respiratory epithelium had grown across the implanted membrane in the experimental group. CONCLUSION: The homologous collagen mersylene membrane allowed for limited structural tracheal growth and was functionally integrated into the segmented tracheal wall in growing dogs.

[In vitro measurement of nitazoxanide sensitivity of 4 Giardia duodenalis isolates obtained from different hosts]. / Determinación in vitro de la susceptibilidad a la nitazoxanida de cuatro aislados de Giardia duodenalis obtenidos de diferentes huéspedes.

BACKGROUND: In Mexico giardiosis is the most prevalent parasitic disease in children. Treatment with antiparasitics derived from: nitroimidazoles, benzimidazoles and nitrofuranes have been used; but, some of them have undesirable side effects. Recently nitazoxanide (Ntz) was introduced in Mexico; however, there are few studies on Giardia duodenalis susceptibility to Ntz. OBJECTIVE: To determine G. duodenalis sensitivity to Ntz and compare it to tinidazole (Tnz). MATERIAL AND METHODS: Assays were performed in four G. duodenalis isolates: INP231087MM, INP210897-AXA1 obtained from humans infections, INP170693HG8, INP300693-CP5 from a cat and a dog, respectively. Half million trophozoites were exposed to different Ntz or Tnz concentrations in TYI-S-33, for 24 hours at 37 degrees C. Trophozoite viability was tested by the colorimetric method of MTT-tetrazolium salts reduction to MTT-formazan. To analyze ultrastructural damage, control and experimental samples were processed by standard electron microscopy methods. Experiments were carried out, in a double blind in triplicate and repeated four times. Results were analyzed by variance analysis. RESULTS: Susceptibility at 100% were in a Ntz concentration ranging from 1 microgram to 7 micrograms and in a Tnz concentration ranging from 1 microgram to 4 micrograms. There were significant differences when sensitivities to Ntz were compared between them (P < 0.001). The ultrastructural analysis showed changes in trophozoite volume, loss of characteristic shape and swelling. CONCLUSIONS: This is the first report of G. duodenalis susceptibility to Ntz performed in isolates from different hosts. G. duodenalis isolates were more susceptible to Tnz than Ntz.