PM10 concentration levels at an urban and background site in Cyprus: the impact of urban sources and dust storms.

Air quality in Cyprus is influenced by both local and transported pollution, including desert dust storms. We examined PM10 concentration data collected in Nicosia (urban representative) from April 1, 1993, through December 11, 2008, and in Ayia Marina (rural background representative) from January 1, 1999, through December 31, 2008. Measurements were conducted using a Tapered Element Oscillating Micro-balance (TEOM). PM10 concentrations, meteorological records, and satellite data were used to identify dust storm days. We investigated long-term trends using a Generalized Additive Model (GAM) after controlling for day of week, month, temperature, wind speed, and relative humidity. In Nicosia, annual PM10 concentrations ranged from 50.4 to 63.8 µg/m3 and exceeded the EU annual standard limit enacted in 2005 of 40 µg/m3 every year A large, statistically significant impact of urban sources (defined as the difference between urban and background levels) was seen in Nicosia over the period 2000-2008, and was highest during traffic hours, weekdays, cold months, and low wind conditions. Our estimate of the mean (standard error) contribution of urban sources to the daily ambient PM10 was 24.0 (0.4) µg/m3. The study of yearly trends showed that PM10 levels in Nicosia decreased from 59.4 µg/m3 in 1993 to 49.0 µg/m3 in 2008, probably in part as a result of traffic emission control policies in Cyprus. In Ayia Marina, annual concentrations ranged from 27.3 to 35.6 µg/m3, and no obvious time trends were observed. The levels measured at the Cyprus background site are comparable to background concentrations reported in other Eastern Mediterranean countries. Average daily PM10 concentrations during desert dust storms were around 100 µg/m3 since 2000 and much higher in earlier years. Despite the large impact ofdust storms and their increasing frequency over time, dust storms were responsible for a small fraction of the exceedances of the daily PM10 limit. Implications: This paper examines PM10 concentrations in Nicosia, Cyprus, from 1993 to 2008. The decrease in PM10 levels in Nicosia suggests that the implementation of traffic emission control policies in Cyprus has been effective. However, particle levels still exceeded the European Uion annual standard, and dust storms were responsible for a small fraction of the daily PM10 limit exceedances. Other natural particles that are not assessed in this study, such as resuspended soil and sea salt, may be responsible in part for the hig particle levels.

Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor.

Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 µM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs.

The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Residential exposure to motor vehicle emissions and the risk of wheezing among 7-8 year-old schoolchildren: a city-wide cross-sectional study in Nicosia, Cyprus.

BACKGROUND: Several studies have reported associations between respiratory outcomes in children and a range of self-reported, administrative or geographical indicators of traffic pollution. First-time investigation into the frequency of asthmatic symptoms among 7-8 year-old Cypriot children in 1999-2000 showed increased prevalence in the capital Nicosia compared to other areas. Geographical differences on an island the size of Cyprus may reflect environmental and/or lifestyle factors. This study investigates the relationship between self-reported symptoms and residential exposure to motor vehicle emissions among Nicosia schoolchildren. METHODS: The addresses of children in the metropolitan area of Nicosia who participated in the original survey (N = 1,735) were geo-coded and the level of exposure of each child was assessed using distance- and emission-based indicators (i.e. estimated levels of particulate matter and nitrogen oxides emissions due to motor vehicles on main roads around the residence). Odds ratios of wheezing and asthma diagnosis in relation to levels of exposure were estimated in logistic regression models adjusting for person-based factors, co-morbidity and intra-school clustering. RESULTS: We found an increased risk of wheezing at distances less than 50 m from a main road and/or only among those experiencing the highest levels of exposure. The strongest effect estimates were observed when exposure was defined in terms of the cumulative burden at all roads around the residence. Adjusted odds ratios for current wheezing were 2.33 (95% CI 1.27, 4.30) amongst the quartile of participants exposed to the highest levels of PM at all roads 50 m of their residence and 2.14 (95% CI 1.05, 4.35) for NOx, with no effect at intermediate levels of exposure. While the direction of effect was apparent at longer distances, differences were generally not statistically significant. CONCLUSIONS: Children experiencing the highest burden of emissions in Nicosia seem to be at a higher risk of reporting asthmatic symptoms. Due to the small number of children residing at close proximity to main roads and lack of evidence of risk at intermediate levels of exposure or longer distances, the observed pattern alone does not explain the generally higher prevalence observed in urban Nicosia compared to other areas.

Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

A 10-year time-series analysis of respiratory and cardiovascular morbidity in Nicosia, Cyprus: the effect of short-term changes in air pollution and dust storms.

BACKGROUND: To date, a substantial body of research has shown adverse health effects of short-term changes in levels of air pollution. Such associations have not been investigated in smaller size cities in the Eastern Mediterranean. A particular feature in the region is dust blown from the Sahara a few times a year resulting in extreme PM10 concentrations. It is not entirely clear whether such natural phenomena pose the same risks. METHODS: The effect of changes in daily levels of particulate matter (PM10) and ozone (O3) on hospitalization for all, cardiovascular and respiratory causes in the two hospitals in Nicosia during 1 January 1995 and 30 December 2004 was investigated using generalized additive Poisson models after controlling for long- and short-term patterns as well as for the effect of weather. Meteorological records were reviewed to identify dust-storm days and analyses were repeated to quantify their effect on cardio-respiratory morbidity. RESULTS: For every 10 microg/m3 increase in daily average PM10 concentrations, there was a 0.9% (95%CI: 0.6%, 1.2%) increase in all-cause and 1.2% (95%CI: -0.0%, 2.4%) increase in cardiovascular admissions. With respect to respiratory causes, an effect was observed only in the warm months. No lagged effects with levels of PM10 were observed. In contrast, positive associations with levels of ozone were only observed the two days prior to admission. These appeared stronger for cardiovascular causes and independent of the effect of PM. All-cause and cardiovascular admissions were 4.8% (95%CI: 0.7%, 9.0%) and 10.4% (95%CI: -4.7%, 27.9%) higher on dust storm days respectively. In both cases the magnitude of effect was comparable to that seen on the quartile of non-storm days with the highest levels of PM10. CONCLUSION: We observed an increased risk of hospitalization at elevated levels of particulate matter and ozone generally consistent with the magnitude seen across several European cities. We also observed an increased risk of hospitalization on dust storm days, particularly for cardiovascular causes. While inference from these associations is limited due to the small number of dust storm days in the study period, it would appear imperative to issue health warnings for these natural events, particularly directed towards vulnerable population groups.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

On the temporal and spatial variation of ozone in Cyprus.

More than sixteen years (1997-2013) of continuous ozone concentrations at the rural Agia Marina (EMEP, 532 ma.s.l.) station in Cyprus, together with a number of ancillary chemical and meteorological parameters have been analyzed on a multiannual, annual and diurnal basis. The observations reveal a) the presence of a prominent seasonality with maxima observed during summer (54±5 ppbv) and the minima in winter (39±3 ppbv) b) a relatively small diurnal variability with the noon levels (50±9 ppbv) being higher by ~4 pbbv compared to nighttime (46±9 ppbv) and c) a non-significant upward trend over the 16 years of 0.11±0.12 ppbv y(-1). To assess the spatial variability over Cyprus, simultaneous measurements in 2011-2012 have been performed at Inia, Stavrovouni and Cavo Greco, three remote marine monitoring sites located to the west, central and the east of the Island, respectively. Our results show that ambient ozone levels over Cyprus are mostly influenced by regional/transported ozone while the local precursor emissions play a minor role in ozone formation. On an annual basis a net ozone reduction of 1.5 and 1.0 ppbv occurs when the air masses originate from northerly and westerly directions, respectively, while this is 2.4 ppbv during southerly wind. This suggests continuous net ozone loss controlled by surface deposition and photochemical destruction, and highlights the importance of long-range transport in controlling ozone levels in Cyprus.

Particulate matter concentrations during desert dust outbreaks and daily mortality in Nicosia, Cyprus.

Ambient particulate matter (PM) has been shown to have short- and long-term effects on cardiorespiratory mortality and morbidity. Most of the risk is associated with fine PM (PM(2.5)); however, recent evidence suggests that desert dust outbreaks are major contributors to coarse PM (PM(10-2.5)) and may be associated with adverse health effects. The objective of this study was to investigate the risk of total, cardiovascular and respiratory mortality associated with PM concentrations during desert dust outbreaks. We used a time-series design to investigate the effects of PM(10) on total non-trauma, cardiovascular and respiratory daily mortality in Cyprus, between 1 January 2004 and 31 December 2007. Separate PM(10) effects for non-dust and dust days were fit in generalized additive Poisson models. We found a 2.43% (95% CI: 0.53, 4.37) increase in daily cardiovascular mortality associated with each 10-µg/m(3) increase in PM(10) concentrations on dust days. Associations for total (0.13% increase, 95% CI: -1.03, 1.30) and respiratory mortality (0.79% decrease, 95% CI: -4.69, 3.28) on dust days and all PM(10) and mortality associations on non-dust days were not significant. Although further study of the exact nature of effects across different affected regions during these events is needed, this study suggests adverse cardiovascular effects associated with desert dust events.

Forecasting hourly PM(10) concentration in Cyprus through artificial neural networks and multiple regression models: implications to local environmental management.

In the present work, two types of artificial neural network (NN) models using the multilayer perceptron (MLP) and the radial basis function (RBF) techniques, as well as a model based on principal component regression analysis (PCRA), are employed to forecast hourly PM(10) concentrations in four urban areas (Larnaca, Limassol, Nicosia and Paphos) in Cyprus. The model development is based on a variety of meteorological and pollutant parameters corresponding to the 2-year period between July 2006 and June 2008, and the model evaluation is achieved through the use of a series of well-established evaluation instruments and methodologies. The evaluation reveals that the MLP NN models display the best forecasting performance with R (2) values ranging between 0.65 and 0.76, whereas the RBF NNs and the PCRA models reveal a rather weak performance with R (2) values between 0.37-0.43 and 0.33-0.38, respectively. The derived MLP models are also used to forecast Saharan dust episodes with remarkable success (probability of detection ranging between 0.68 and 0.71). On the whole, the analysis shows that the models introduced here could provide local authorities with reliable and precise predictions and alarms about air quality if used on an operational basis.

Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.