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.
•Air pollution nanoparticles inside human myocardial mitochondria are iron-rich.•The within-mitochondrial particles match iron-rich particles from traffic/industrial sources.•Myocardial iron-rich air pollution nanoparticles abundant even in young children.•Ventricular upregulation of oxidative and ER stress markers in exposed subjects.•Inhalation of iron-rich air pollution a risk factor for cardiovascular disease.
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•The use of oxcarbazepine during gestation has adverse effects in rats.•Oxcarbazepine alters the cytoarchitecture of the hippocampus, increases apoptosis, reduces litter size and ...probably affects postnatal weight body.•The present study shows strong evidence of the apoptosis-inducing effect of Carbamazepine when administered early in gestation.•The safety of the use of OXC and CBZ during pregnancy was tested and it is clear that both have adverse effects.
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 main purpose of this review was to expound upon the mechanism of action of Levetiracetam (LEV) as an antiepileptic, neuroprotective, and hyperalgesic drug. LEV is a second-generation ...anti-epileptic drug (AED) that is approved for clinical use as monotherapy and may also be used for adjunctive treatment of patients with seizures. Several researchers have recommended LEV as a treatment option in different diseases causing neuronal damage, and recently, LEV has been used as an antihyperalgesic drug. LEV exhibits favorable characteristics, including a low potential for interaction, a short elimination half-life, and has neither active metabolites nor major negative effects on cognition. This has generated many new research avenues for the utilization of this drug. However, the precise mechanism of action of LEV has not been fully elucidated. In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies evaluating the effects of LEV as an antiepileptic, neuroprotective, and hyperalgesic drug. A total of 32 studies related to the use of LEV suggested different mechanisms of action, such as binding to the synaptic vesicle glycoprotein 2A (SV2A) protein, inhibition of Ca2+ N-type channels, and its presence as a neuromodulator. These studies concluded that the pharmacodynamics of LEV should be viewed as a single pathway, and should not be based on specific molecular targets that depend on the physiological or pathological conditions prevalent at that time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
Extramedullary hematopoietic tumors are rare and characterized by the presence of hematopoietic elements at various stages of maturity, atypical megakaryocytes, and fibroblastic proliferation. We ...report the case of a patient with sclerosing extramedullary hematopoietic tumor of the spleen.The patient was 71-year-old man with a history of hypertension, diabetes, and hepatitis C virus infection. Multiple spleen lesions were identified in imaging tests during workup due to abdominal discomfort. Although a vascular tumor was suspected, laparoscopic splenectomy was decided after considering other possible causes. The pathology examination revealed a sclerosing extramedullary hematopoietic tumor of the spleen, which was confirmed by immunohistochemical tests. These tumors are usually single or, less frequently, multiple lesions affecting different organs and are associated with chronic myeloproliferative syndromes. The histologic confirmation is mandatory due to their similarity to malignant tumors. Extramedullary hematopoietic tumors are rare, and there is little scientific clinical evidence regarding their diagnosis and management. The histological confirmation is mandatory due to their similarity to malignant tumors.
Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as an important feature during tumor suppression mechanisms and a contributor to ...aging. Senescent cells have an altered secretion pattern called Senescence-Associated Secretory Phenotype (SASP) that comprises a complex mix of factors including cytokines, growth factors, chemokines, and matrix metalloproteinases. SASP has been related with local inflammation that leads to cellular transformation and neurodegenerative diseases. Various pathways for senescence induction have been proposed; the most studied is replicative senescence due to telomere attrition called replicative senescence (RS). However, senescence can be prematurely achieved when cells are exposed to diverse stimuli such as oxidative stress (stress-induced premature senescence, SIPS) or proteasome inhibition (proteasome inhibition-induced premature senescence, PIIPS). SASP has been characterized in RS and SIPS but not in PIIPS. Hence, our aim was to determine SASP components in primary lung fibroblasts obtained from CD-1 mice induced to senescence by PIIPS and compare them to RS and SIPS. Our results showed important variations in the 62 cytokines analyzed, while SIPS and RS showed an increase in the secretion of most cytokines, and in PIIPS only 13 were incremented. Variations in glutathione-redox balance were also observed in SIPS and RS, and not in PIIPS. All senescence types SASP displayed a pro-inflammatory profile and increased proliferation in L929 mice fibroblasts exposed to SASP. However, the behavior observed was not exactly the same, suggesting that the senescence induction pathway might encompass dissimilar responses in adjacent cells and promote different outcomes.
The objective was to measure the effects of VC (a uterotonic drug with vasodilator effects) in eutocic and dystocic sows, on the acid–base balance and some vitality traits of piglets at birth. ...Farrowing was induced with prostaglandin F2α. Four groups of sows (20 sows/group) were monitored; Groups 1 and 2 were eutocic sows, whereas Groups 3 and 4 were dam-fetal dystocic sows. Groups 1 and 3 (control) were given saline, whereas Groups 2 and 4 were given VC im (1.66 mg/kg of body weight) after the first piglet was born. Piglets' physio-metabolic performance was monitored peripartum. Treatment with VC reduced (P < 0.0001) the percentage of intrapartum stillbirths in sows either with eutocic (5.2 vs. 10.0%) and dystocic (7.6 vs. 16.7%) farrowings and increased (P < 0.0001) the number of pigs born alive without any evidence of AFS (89.9 vs. 79.9%, eutocic and 81.6 vs. 65.2%, dystocic). In addition, for the group of pigs with no acute fetal suffering (AFS), VC treatment enhanced survival responses with a half point grater vitality score in Group 4; it also reduced the latency to first teat contact by 6 min (P < 0.05) in both treated groups compared to controls; and it improved the condition of the pigs' umbilical cord, with more adhered (98 vs. 86% in eutocic and 88 vs. 80% in dystocic; P < 0.05) and less ruptured cords. Moreover, VC reduced the severity of adverse physio-metabolic indicators and the acid–base balance of piglets with AFS at birth by lowering blood lactate (89.8 vs. 93.5 mmol/L in eutocic groups and 94.6 vs. 100.2 mmol/L in dystocic groups; P < 0.05), Pₐco₂ and Ca²⁺, and by increasing blood pH, HCO₃ and Pₐo₂ levels (P < 0.05).
It has been discussed that serotonin (5-HT) could be involved in the effects of sleep deprivation (SD) and/or malnutrition (M) on the sleep–wake cycle. The aim of this work was to study the effects ...of the M, SD and its interaction on 5-HT and 5-hydroxy-indole-acetic acid (5-HIAA) contents in the dorsal raphe (DR) and the suprachiasmatic nuclei (SCN), two sleep–wake cycle regulators. Forty-eight puppets rats were obtained from mothers fed with low or normal casein diet. They were allocated in 3 groups (
n
=
16 each): prenatal/postnatal casein malnutrition (6/6%), prenatal casein malnutrition/nutritional casein rehabilitation (6/25%) and prenatal/postnatal casein well-nourished state (25/25%). When rats were 60 days old, 24 animals were exposed to sleep deprivation by means of forced locomotion during 24 h. The remaining 24 were kept under normal conditions of sleep–wake cycle. Then, all animals were sacrificed by decapitation. DR and SCN were dissected and processed to determine the 5-HT and 5-HIAA contents by means of HPLC. It was observed that 6/6% rats showed a 5-HT increase (DR
p
<
0.011; SCN
p
<
0.019) as well as in SD (DR
p
<
0.0008; SCN
p
<
0.0009) with respect to 25/25% rats. No differences were found in 6/25% rats. Therefore, 5-HIAA decreased significantly in both nuclei in all the groups, notably in M
+
SD animals (DR
p
<
0.001; SCN
p
<
0.001). We conclude that the sleep–wake cycle disruptions produced by chronic M and SD are mediated in part by a synergistic effect on 5-HT in the DR-SCN pathway, perhaps due to a delay in the development of such brain structures.
Aim: To analyze the presence of Y chromosome microdeletions in males of Mexican couples with idiopathic recurrent pregnancy losses (RPL).
Methods: Seventy‐one males from couples with RPL and 66 ...fertile males as controls were studied. DNA was isolated from peripheral lymphocytes and used to run multiplex polymerase chain reactions. Regions AZFa (sY84, sY86), AZFb (sY127, sY134) and AZFc (sY254, sY255) of the Y chromosome were analyzed according to valid guidelines recommended by the European Academy of Andrology and the European Molecular Genetics Quality Network. Also, the sequence tagged sites (STSs): DYS262 (sY67), DYS220 (sY129), DYF85S1 (sY150), DYF86S1 (sY152) and DYF87S1 (sY153) were included in order to analyze STSs previously reported as deleted. A power analysis to support our simple size was performed.
Results: Results show an absence of Y chromosome microdeletions in males of couples with RPL and controls with an acceptable statistical power.
Conclusion: The study did not show an association of recurrent pregnancy loss and Y chromosome microdeletions in Mexican male partners. Based on the results, the study of Y chromosome microdeletions in couples with RPL is not considered clinically relevant.
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.
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.
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.
The homologous collagen mersylene membrane allowed for limited structural tracheal growth and was functionally integrated into the segmented tracheal wall in growing dogs.
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