Indoor and outdoor concentrations of polycyclic aromatic hydrocarbons (PAHs) associated with PM2.5 particles were monitored in three microenvironments (schools, homes and offices) in the city of ...Rome, Italy, between winter 2011 and summer 2012. Molecular signatures and indoor/outdoor concentration ratios of PAHs were investigated, with special emphasis on carcinogenic congeners. At indoor locations, total PAHs ranged, on average, from 1.8 to 8.4 ng/m3 in winter and from 0.30 to 1.35 ng/m3 in spring/summer. Outdoors, total PAH concentrations were found to reach 6.3–17.9 ng/m3 in winter and 0.42–1.74 ng/m3 in spring-summer. Indoors, the concentration of benzoapyrene (BaP) was as high as 1.1 ng/m3 in winter and below 0.1 ng/m3 in the warm season, independently of site type; the yearly average remained below the European guideline value. The indoor/outdoor concentration ratios of individual compounds were lower than one for most of congeners, suggesting that outdoor sources were predominant. Nonetheless, the percentages of PAH compounds changed with sites and seasons; in particular, in spring/summer, the concentration of BaP at our sites was more than twice that recorded at the regional network stations.
•We examined the burdens and distribution profiles of PAHs in PM2.5.•Indoor concentrations exceeding environmental guidelines only in winter.•In/out concentration ratios of PAHs changed with locations and compounds.•PAH composition depends on traffic, domestic heating and other urban sources.
Aims
Parkinson’s disease and related disorders are devastating neurodegenerative pathologies. Since α‐synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made ...to clarify the pathogenic mechanisms of α‐synuclein's detrimental effects. α‐synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co‐fostering Parkinson’s disease. However, direct evidence linking inflammation to the harmful activities of α‐synuclein oligomers or to the Parkinson’s disease behavioural phenotype is lacking.
Methods
To clarify whether neuroinflammation influences Parkinson’s disease pathogenesis, we developed: (i) a ‘double‐hit’ approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic ‘double‐hit’ model where lipopolysaccharides were given to A53T α‐synuclein transgenic Parkinson’s disease mice.
Results
Lipopolysaccharides induced a long‐lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS‐activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro‐inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic ‘double‐hit’ A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α‐synuclein oligomer’s actions and aggravates cognitive deficits in A53T mice.
Conclusions
The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α‐synucleinopathies.
The distribution of ambient air n-alkanes and polycyclic aromatic hydrocarbons (PAHs) associated to particles with aerodynamic diameters lesser than 10 μm (PM₁₀) into six fractions (five stages and a ...backup filter) was studied for the first time in Algeria. Investigation took place during September of 2007 at an urban and industrial site of Algiers. Size-resolved samples (<0.49, 0.49–0.95, 0.95–1.5, 1.5–3.0, 3.0–7.2, and7.2–10 μm) were concurrently collected at the two sampling sites using five-stage high-volume cascade impactors. Most of n-alkanes (~72 %) and PAHs (~90 %) were associated with fine particles ≤1.5 μm in both urban and industrial atmosphere. In both cases, the n-alkane contents exhibited bimodal or weakly bimodal distribution peaking at the 0.95–1.5-μm size range within the fine mode and at 7.3–10 μm in the coarse mode. Low molecular weight PAHs displayed bimodal patterns peaking at 0.49–0.95 and 7.3–10 μm, while high molecular weight PAHs exhibited mono-modal distribution with maximum in the <0.49-μm fraction. While the mass mean diameter of total n-alkanes in the urban and industrial sites was 0.70 and 0.84 μm, respectively, it did not exceed 0.49 μm for PAHs. Carbon preference index (~1.1), wax% (10.1–12.8), and the diagnostic ratios for PAHs all revealed that vehicular emission was the major source of these organic compounds in PM₁₀ during the study periods and that the contribution of epicuticular waxes emitted by terrestrial plants was minor. According to benzoapyrene-equivalent carcinogenic power rates, ca. 90 % of overall PAH toxicity across PM₁₀ was found in particles ≤0.95 μm in diameter which could induce adverse health effects to the population living in these areas.
Indoor environments are affected by a number of organic contaminants, whose concentrations can exceed by orders of magnitude those found outdoors in external air. At this regard, polycyclic aromatic ...hydrocarbons (PAHs) deserve a special concern. PAHs occur in the air both in the gaseous and particulate forms; they are associated to fine aerosols and soil dust, and deposit on surfaces. Nonetheless, scarce information exists about the PAH pollution of indoor locations in Northern Africa. PAHs were first investigated in dust of interiors in Ouargla (Saharan Algeria), concurrently with n-alkanes and polar organics. Settled dust was collected from pre-cleaned surfaces (0.5 m2 each) at 7 internal locations in total from a school, the city hospital and university, and a home. Three sample series were collected 15, 30 days and random after the preliminary cleaning of surfaces. Contemporarily, organic compounds were collected at 15 locations of the target sites by deploying diffusive samplers over the whole study period to obtain molecular signatures of semi-volatile organic fraction. A consolidated procedure consisting of ultra-sonic bath extraction, semi-preparative column chromatography and gas chromatographic - mass spectrometric analysis was applied for chemical characterization of dusts. n-Alkanes ranged from 3.8 to 41 μg/m2 in dust and 0.17–2.42 μg/m3 in gas phase. PAHs concentrations were 17–89 ng/m2 and 45–182 ng/m3, respectively. Caffeine and nicotine were found both in dust (63–2,02 ng/m2 and 7–284 ng/m2, respectively) and as vapors in air (4–416 ng/m3 and 3.5–60 ng/m3). Two sites were affected by cannabinoids, while traces of nonylphenols occurred at all locations. External air was, on the average, more affected by PAHs than the interiors of school and hospital, but not of university. The compound concentrations show that Ouargla city is seriously polluted and requires actions to improve air quality.
•n-Alkanes and PAHs were investigated in indoor air in Ouargla, Algeria.•n-Alkanes were of twin origin (anthropogenic and biogenic). Indoor PAHs in Ouargla ranged from 17 to 182 ng/m3.•As for dust, the home was more PAH polluted than the hospital, university and school.•Phthalates, caffeine, nicotine, nonylphenols and cannabinol affected interiors of Ouargla.
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•The bioavailability of 20E is low (ca. 1%).•Plasma 20E concentrations can reach adequate levels to cause physiological effects.•Significant metabolism of 20E begins when it reaches ...the large intestine.•An entero-hepatic cycle helps to maintain plasma ecdysteroid levels.•20E and its metabolites are excreted mainly in the faeces within 24 h.
Phytoecdysteroids are molecules derived from sterol metabolism and found in many plants. They display a wide array of pharmacological effects on mammals (e.g. anabolic, anti-diabetic). Although these effects have been long established, the molecular targets involved remain to be identified. Like endogenous steroid hormones and bile acids, which are biochemically related, ingested or injected phytoecdysteroids undergo a set of reactions in mammals leading to the formation of numerous metabolites, only some of which have been so far identified, and it is presently unknown whether they represent active metabolites or inactivation products. In the large intestine, ecdysteroids undergo efficient 14-dehydroxylation. Other changes (reductions, epimerization, side-chain cleavage) are also observed, but whether these occur in the liver and/or large intestine is not known. The purpose of this study was to investigate the pharmacokinetics of 20-hydroxyecdysone (20E), the most common phytoecdysteroid, when administered to mice and rats, using, when required, tritium-labelled molecules to permit metabolic tracking. Bioavailability, the distribution of radioactivity and the kinetics of formation of metabolites were followed for 24−48 hours after ingestion and qualitative and quantitative analyses of circulating and excreted compounds were performed. In mice, the digestive tract always contains the majority of the ingested 20E. Within 30 min after ingestion, 20E reaches the large intestine, where microorganisms firstly remove the 14-hydroxyl group and reduce the 6-one. Then a very complex set of metabolites (not all of which have yet been identified) appears, which correspond to poststerone derivatives formed in the liver. We have observed that these compounds (like bile acids) undergo an entero-hepatic cycle, involving glucuronide conjugation in the liver and subsequent deconjugation in the intestine. Despite the very short half-life of ecdysteroids in mammals, this entero-hepatic cycle helps to maintain their plasma levels at values which, albeit low (≤0.2 μM), would be sufficient to evoke several pharmacological effects. Similar 20E metabolites were observed in mice and rats; they include in particular 14-deoxy-20E, poststerone and 14-deoxypoststerone and their diverse reduction products; the major products of this metabolism have been unambiguously identified. The major sites of metabolism of exogenous ecdysteroids in mammals are the large intestine and the liver. The entero-hepatic cycle contributes to the metabolism and to maintaining a low, but pharmacologically significant, concentration of ecdysteroids in the blood for ca. 24 h after ingestion. These data, together with parallel in vitro experiments provide a basis for the identification of 20E metabolite(s) possibly involved in the physiological effects associated with ecdysteroids in mammals.
The air quality of three different microenvironments (school, dwelling, and coffee bar) located in the city of Rome, Italy, was assessed. Indoor and outdoor concentrations of polycyclic aromatic ...hydrocarbons (PAHs) associated with PM₂.₅ particles were determined during an intensive 3-week sampling campaign conducted in March 2013. In interiors, total particulate PAHs ranged from 1.53 to 4.96 ng/m³ while outdoor air contained from 2.75 to 3.48 ng/m³. In addition, gaseous toxicants, i.e., NO₂, NO ₓ , SO₂, O₃, and BTEX (benzene, toluene, ethyl-benzene, and xylene isomers), were determined both in internal and external air. To solve the origin of indoor and outdoor PAHs, several source apportionment methods were applied. Multivariate analysis revealed that emissions from motor vehicles, biomass burning for heating purposes, and soil resuspension were the major sources of PAHs in the city. No linear correlation was established between indoor and outdoor values for PM₂.₅ and BTEX; the respective indoor/outdoor concentration ratios exceed unity except for PM₂.₅ in the no smoking home and benzene in all school floors. This suggests that important internal sources such as tobacco smoking, cleaning products, and resuspension dust contributed to indoor pollution. Using the monitoring stations of ARPA Lazio regional network as reference, the percentage within PAH group of benzoapyrene, which is the WHO marker for the carcinogenic risk estimates, was ca. 50 % higher in all locations investigated.
Purpose
To determine whether topical tobramycin 0.3%/dexamethasone 0.1% plus ozonized oil eye drops reduces clinical signs and infectious viral titers of presumed viral conjunctivitis more than ...tobramycin/dexamethasone eye drops alone.
Methods
Prospective, single-blind, randomized, parallel-groups trial. Eighty patients with a clinical diagnosis of presumed viral conjunctivitis were randomizedly divided into two treatment groups: a study group and a control group, 40 for each group. Patients in the study group received topical tobramycin 0.3%/dexamethasone 0.1% eye drops, plus ozonized oil eye drops, both four times daily; patients in the control group received only topical tobramycin 0.3%/dexamethasone eye drops four times daily. The treatment was for seven days in both groups. Swabs were taken from the conjunctival fornix for adenovirus PCR analysis on the day of recruitment and at seven days follow-up. Clinical signs were also recorded on the day of recruitment and at follow-up examination: the main outcomes were conjunctival injection and conjunctival chemosis, graded on a 4-point clinical scale, presence or absence of superficial punctate keratitis and subepithelial corneal infiltrates.
Results
No statistically significant difference was reached in adenoviral infection negativization between the two groups, although the study group showed a higher number of PCR negative results at seven days follow-up. PCR real time detected adenoviral infection in 17 of 24 patients on the day of recruitment and it was positive in 4 patients on the seventh day (viral positivity reduction of 76%). In the control group PCR was positive for adenovirus in 18 of 24 patients on the day of recruitment and in 7 patients at seven days follow-up (reduction of 61%). There was statistically significant difference on conjunctival clinical signs between the study and control groups. Significant difference was also found on superficial punctate keratitis resolution between the study and the control group. In the former superficial punctate keratitis was detected in 14 eyes on the first day and in 5 eyes after seven days while in the latter superficial punctate keratitis was found in 124 eyes on the first day and in 6 eyes on the seventh day. No difference was found in subepithelial corneal infiltrates appearance between the two groups.
Conclusions
The use of ozonized-oil containing eye drops in combination with topical tobramycin 0.3%/dexamethasone 0.1% eye drops four times daily seems to reduce the signs of conjunctivitis, and the duration of viral infection, although it does not affect the subepithelial corneal infiltrates appearance.
Background
The 8th edition of TNM has introduced new rules for staging cutaneous melanoma.
Objective
To compare TNM 7th and 8th editions in defining pathological stages of melanoma.
Methods
A ...population‐based series of 1847 skin melanoma from Romagna cancer registry (Italy) incident during 2003–2012 has been used to measure the agreement (with Cohen's kappa) between TNM 8th and 7th editions in defining melanoma stage. Disease‐specific survival has been computed for each stage according to TNM 7th and 8th.
Results
The agreement between the two TNM editions was quite good when considered on average (kappa = 70.7%), moderate for stage I (61.5%), nearly perfect for stage II (95.0%), but extremely poor for stage III (8.1%). The overall melanoma‐specific observed survival was 90.8% at 5 year and 88.9% at 10 year with a strong prognostic effect of stage.
Conclusion
TNM 8th edition introduces several changes which do not seem really helpful in addressing the care of stage I melanoma and may complicate the definition and comparability of stage III.
Abstract The hypothesis that attention deficits induced by the hypofunction of N-methyl d -aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate ...release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S133 CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by % correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 μM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S133 CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S133 CREB in the frontal cortex but was without effect on the decrease in p-S133 CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.
Abstract The autophagy–lysosomal degradation pathway plays a role in the onset and progression of neurodegenerative diseases. Clinical and genetic studies indicate that mutations of ...β-glucocerebrosidase represent genetic risk factors for synucleinopathies, including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). We recently found a decreased activity of lysosomal hydrolases, namely β-glucocerebrosidase, in cerebrospinal fluid of PD patients. We have thus measured the activity of these enzymes – α-mannosidase (EC 3.2.1.24), β-mannosidase (EC 3.2.1.25), β-glucocerebrosidase (EC 3.2.1.45), β-galactosidase (EC 3.2.1.23) and β-hexosaminidase (EC 3.2.1.52) – in cerebrospinal fluid of patients suffering from DLB, Alzheimer's Disease (AD), Fronto-Temporal Dementia (FTD) and controls. Alpha-mannosidase activity showed a marked decrease across all the pathological groups as compared to controls. Conversely, β-glucocerebrosidase activity was selectively reduced in DLB, further suggesting that this enzyme might specifically be impaired in synucleinopathies.
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