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The capacity of particulate matter (PM) to enhance and stimulate the expression of pro-inflammatory mediators has been previously demonstrated in non-antigen-presenting cells (human bronchial epithelia). Nonetheless, many proposed mechanisms for this are extrapolated from known canonical molecular pathways. This work evaluates a possible mechanism for inflammatory exacerbation after exposure to PM2.5 (from Puerto Rico) and CuSO4, using human bronchial epithelial cells (BEAS-2B) as a model. The induction of CIITA, MHCII genes, and various pro-inflammatory mediators was investigated. Among these, the phosphorylation of STAT1 Y701 was significantly induced after 4 h of PM2.5 exposure, concurrent with a slight increase in CIITA and HLA-DRα mRNA levels. INFγ mRNA levels remained low amidst exposure time, while IL-6 levels significantly increased at earlier times. IL-8 remained low, as expected from attenuation by IL-6 in the known INFγ-independent inflammation pathway. The effects of CuSO4 showed an increase in HLA-DRα expression after 8 h, an increase in STAT1 at 1 h, and RF1 at 8 h We hypothesize and show evidence that an inflammatory response due to PM2.5 extract exposure in human bronchial epithelia can be induced early via an alternate non-canonical pathway in the absence of INFγ. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacists are poised to be the health care professionals best suited to provide medication‐related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx‐driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. Objectives: The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist‐driven CMM. Methods: This is a pre‐ and post‐interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face‐to‐face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication‐Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug‐metabolizing enzymes and transporters (DMET) Plus Array. Results: The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision‐making process of pharmacists. Conclusions: The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx‐guided CMM services. [ABSTRACT FROM AUTHOR]

ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5)) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1–4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM2.5 and BUD). A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5. [ABSTRACT FROM AUTHOR]

Background: For many years, African Dust Storms (ADE) has been thought to be associated with high prevalence of asthma in Puerto Rico (PR). Endotoxins (ENX) have been associated with ADE particulate matter (PM) and are known to promote pro-inflammatory responses in lung cells of susceptible individuals through the Toll-like receptor (TLR2/4) signaling pathways. Genetic variants are plausible contributors to such susceptibility. Therefore, we have evaluated a series of nine single nucleotide polymorphisms (SNPs) in TLR genes, which have been correlated positive and negatively to asthma prevalence and/or risk, in the Puerto Rican asthmatic population.Methods: The following SNPs were evaluated in 62 asthmatics and 61 controls through Taqman® Real Time PCR Assay: TLR4 (+896A/G, +1196C/T, -6687A/G); TLR2 (+596C/T, -16934 T/A, +399A/G, +1349C/T) and CD14 (-159C/T, +1188C/G). Genotypes were assessed for asthma association employing an odds ratio (OR) analysis.Results: Minor allele frequencies (n = 123) were determined for those variants as 0.07, 0.06, 0.35, 0.35, 0.37, 0.29, 0.04, 0.35 and 0.11, respectively. Two (+596C/T, +399A/G) TLR2 SNPs showed to be more represented in the asthmatic group by 89 % and 65 %, respectively. TLR4 SNP +896A/G analysis revealed only 1 G/G genotype (2 %) on the asthmatic group. The CD14 SNPs were similarly represented in the Puerto Rican population. Only the TLR2 +596 SNP was found to be significantly associated to asthma (OR = 3.24 for CT, 2.71 for TT) and particularly to females.Conclusions: The identification of TLR SNPs will reveal potential candidates for gene-environment interactions in Puerto Ricans. As far as we know this is the first study to evaluate this type of TLR gene polymorphisms in Puerto Rican asthmatics, contributing to the current knowledge in the Hispanic population. [ABSTRACT FROM AUTHOR]

African Dust Events (ADE) are a seasonal phenomenon that has been suggested to exacerbate respiratory and proinflammatory diseases in Puerto Rico (PR). Increases in PM10 concentration and the effects of biological endotoxins (ENX) are critical factors to consider during these storms. ENX promote proinflammatory responses in lungs of susceptible individuals through activation of the Toll-like receptors (TLR2/4) signaling pathways. The objective of the study was to evaluate the toxicological and proinflammatory responses stimulated by ADE PM10 ENX reaching PR using human bronchial epithelial cells. PM10 organic extracts from a rural and urban site in PR (March 2004) were obtained from ADE and non-ADE and compared. A retrospective data analysis (PM10 concentration, aerosol images, and pediatric asthma claims) was performed from 2000 to 2012 with particular emphasis in 2004 to classify PM samples. Urban extracts were highly toxic, proinflammatory (IL-6/IL-8 secretion), and induced higher TLR4 expression and NF-κB activation compared to rural extracts. ENX were found to contribute to cytotoxicity and inflammatory responses provoked by urban ADE PM10 exposure suggesting a synergistic potency of local and natural ENX incoming from ADE. The contribution of ADE PM10 ENX is valuable in order to understand interactions and action mechanisms of airborne pollutants as asthma triggers in PR. [ABSTRACT FROM AUTHOR]

Particle pollution from urban and industrialized regions in Rio de Janeiro (RJ), Brazil was analyzed for toxic and pro-inflammatory (cytokines: IL-6, IL-8, IL-10) responses in human bronchial epithelial cells. Trace elements contribution was studied. Airborne particulate matter was collected at: three industrial sites Ind-1 (PM 10 ) and Ind-2a and 2b (PM 2.5 ); Centro urban area (PM 10 ) and two rural sites (PM 2.5 , PM 10 ). PM 10 acetone extracts were toxic and did not elicit cytokine release; aqueous extracts were less toxic and stimulated the release of IL-6 and IL-8. PM 2.5 aqueous extracts from Ind-2 decreased the release of IL-6 and IL-8. Zinc concentration was higher at the industrial and rural reference sites (Ref-1-2) although metals were not associated to cytokines changes. These results demonstrate that PM from RJ can either increase or decrease cytokine secretion in vitro while being site specific and time dependent. [ABSTRACT FROM AUTHOR]

An Aerosol and Oceanographic Science Expedition (AEROSE) on the NOAA Ship Ronald H. Brown collected PM2.5 particles from a Saharan dust storm in March 2004. High levels of PM2.5 (120 μg m−3) were measured during this Saharan storm over the Atlantic Ocean. The particles were characterized for trace element content, with Al and Fe the most abundant metals. These metals were detected in high concentrations during the Saharan event and exhibited good correlations with PM2.5, suggesting its soil origin. Other elements (Pb, Ni, Cd) did not correlate with Al and Fe, indicating their anthropogenic origin. Enrichment factor calculation conducted on these trace elements support our findings. Trace element analyses performed on particulate matter from a reference site on land in Puerto Rico (Fajardo), demonstrated similar results to those obtained in the AEROSE expedition, where high concentrations of PM2.5 and Fe were present concomitantly with Saharan events at this station. [Copyright &y& Elsevier]

Exposure to airborne particulate matter (PM) has been associated with the transcriptional up-regulation of pro-inflammatory mediators. However, the effect of PM on post-transcriptional regulation of pro-inflammatory mediators has not been fully explored. In this study, we examined the acute effect of organic extracts from urban PM, rural PM and diesel exhaust particles (DEP) on the post-transcriptional control of interleukin-6 (IL-6) and interleukin-8 (CXCL8) using a human bronchial epithelial cell line. Both PM and DEP extracts induced the release of IL-6 and CXCL8 after 24 h of exposure. Time-course experiments were conducted to examine changes in mRNA steady-state levels and half-lives. The steady-state levels of CXCL8 mRNA increase at 15 min on cells exposed to both PM and DEP extracts. Meanwhile only the urban extract induced significant increases of IL-6 mRNA levels at 15 min. Indirect measurements of IL-6 mRNA half-life showed a dramatic increase in cells exposed to the organic extracts. CXCL8 mRNA half-life increases in cells exposed to PM extracts and not DEP extract. Nuclear run-ons demonstrated that the urban PM and DEP extracts promoted an up-regulation in the transcription rate of CXCL8 at 15 min but not for IL-6. Urban and rural PM influences the post-transcriptional control of CXCL8. [ABSTRACT FROM AUTHOR]

The health impact of the global African dust event (ADE) phenomenon in the Caribbean has been vaguely investigated. Heavy metals in ADE and non-ADE extracts were evaluated for the formation of reactive oxygen species (ROS) and antioxidant capacity by cells using, deferoxamine mesylate (DF) and N-acetyl- l -cysteine (NAC). Results show that ADE particulate matter 2.5 (PM 2.5 ) induces ROS and stimulates oxidative stress. Pre-treatment with DF reduces ROS in ADE and Non-ADE extracts and in lung cells demonstrating that heavy metals are of utmost importance. Glutathione-S-transferase and Heme Oxygenase 1 mRNA levels are induced with ADE PM and reduced by DF and NAC. ADE extracts induced Nrf2 activity and IL-8 mRNA levels significantly more than Non-ADE. NF-κB activity was not detected in any sample. Trace elements and organic constituents in ADE PM 2.5 enrich the local environment load, inducing ROS formation and activating antioxidant-signaling pathways increasing pro-inflammatory mediator expressions in lung cells. [ABSTRACT FROM AUTHOR]

Background: Phthalate contamination exists in the North Coast karst aquifer system in Puerto Rico. In light of potential health impacts associated with phthalate exposure, targeted action for elimination of exposure sources may be warranted, especially for sensitive populations such as pregnant women. However, information on exposure to phthalates from a variety of sources in Puerto Rico is lacking. The objective of this study was to determine concentrations and predictors of urinary phthalate biomarkers measured at multiple times during pregnancy among women living in the Northern karst area of Puerto Rico. Methods: We recruited 139 pregnant women in Northern Puerto Rico and collected urine samples and questionnaire data at three separate visits (18±2weeks, 22±2weeks, and 26±2weeks of gestation). Urine samples were analyzed for eleven phthalate metabolites: mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-benzyl phthalate, mono-isobutyl phthalate, mono-3-carboxypropyl phthalate (MCPP), mono carboxyisononyl phthalate (MCNP), and mono carboxyisooctyl phthalate (MCOP). Results: Detectable concentrations of phthalate metabolites among pregnant women living in Puerto Rico was prevalent, and metabolite concentrations tended to be higher than or similar to those measured in women of reproductive age from the general US population. Intraclass correlation coefficients ranged from very weak (MCNP; 0.05) to moderate (MEP; 0.44) reproducibility among all phthalate metabolites. We observed significant or suggestive positive associations between urinary phthalate metabolite concentrations and water usage/storage habits (MEP, MCNP, MCOP), use of personal care products (MEP), and consumption of certain food items (MCPP, MCNP, and MCOP). Conclusions: To our knowledge this is the first study to report concentrations, temporal variability, and predictors of phthalate biomarkers among pregnant women in Puerto Rico. Preliminary results suggest several potentially important exposure sources to phthalates in this population and future analysis from this ongoing prospective cohort will help to inform targeted approaches to reduce exposure. [ABSTRACT FROM AUTHOR]

Puerto Ricans have the highest prevalence, morbidity and mortality of asthma than any other ethnic group in the U.S. and can be triggered by different stimuli such as airborne Particle pollution (PM). PM transfers transition metals, including cooper, to the human airways generating reactive oxygen species (ROS). Metallothionein protein (MT1A) is a free radical scavenger expected to be induced in lung cells by PM exposure; however, this has never been proven nor demonstrated. The hypothesis involves the amounts of PM10 in 2004, which would be significantly higher in the urban sites during months of March and June, thereby increasing PM metal exposure and inducing MT1A gene at the urban site. PM10 filters for Urban (Guaynabo) and rural (Fajardo) site were provided by the PREQB. Organic extracts were prepared from filters by means of Soxhlet Extraction and heavy metals were determined using Atomic Absorption Spectrometry. BEAS-2B cells were cultured and exposed to PM10 during 4 hrs. RNA was isolated and relative mRNA levels of MT1A were determined by RT-PCR. Urban PM10 concentrations were 35 ug/m³ and 60ug/m³ for the months of March and June, respectively. Concentrations of copper for this urban PM10 were 29.6 ppm and 50.3 ppm, for March and June, respectively. Exposure to Cu leads to an MT1A expression in lung cells demonstrating its response to metal exposure. Cellular response for the mRNA expression of MT1A was greater in relative high inflammation markers than in PM10 samples. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacists are poised to be the health care professionals best suited to provide medication-related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population., Objectives: The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM., Methods: This is a pre- and post-interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array., Results: The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists., Conclusions: The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services., Competing Interests: CONFLICT OF INTEREST Gualberto Ruaño is a founder and medical director of the Genomas, Inc. The authors have no further conflict of interest to declare.

Background : The island of Vieques (a municipality of Puerto Rico) was used as a military practice range by the US Navy for more than 60 years. Many studies have reported the presence of toxic metals in soil samples taken from Vieques. The bombing range is only 18 km upwind from the Vieques residential area and inhalable resuspended particles resulting from bombing are known to reach the populated area. The current study reports for the first time, the presence of toxic metals' depuration profiles obtained from Vieques and Main Island Puerto Rico human subjects. Objectives : This study was designed to evaluate the distribution of toxic metals in a random population exposed to contaminants originating from military activities and comparing it to a non-exposed random population from Main Island Puerto Rico. Methods : A total of 83 subjects studied; 32 were from Vieques and 51 were from Main Island Puerto Rico. A physician administrated chelation therapy to all subjects and collected urine samples during a 24-h period. A total of 20 trace elements associated with military activities were measured in urine by induced coupled plasma mass spectrometry (ICP-MS). The results were compared between both population samples. Results : Significant differences in the levels of eight trace elements associated with military practices were found between Vieques and Main Island Puerto Rico. Lead (Pb), aluminum (Al), uranium (U) ( p < 0.001), arsenic (As), cadmium (Cd) ( p = 0.02), and gadolinium (Gd) ( p = 0.03) were significantly higher in Vieques while niobium (Nb) and platinum (Pt) levels ( p < 0.006) were lower in the Vieques samples. Discussion : Higher concentrations of Pb, Al, As, Cd, Gd, and U were found in Vieques residents' urine samples compared to Main Island. Nonetheless, Pt and Ga were present in Main Island at higher concentrations than in Vieques. Although limited by its sample size, this report should set a basis for the importance of health assessment in these subjects exposed to military activities remnants throughout the years and further evaluation of their effects on the overall health of the population.

Context: The recombinant human erythropoietin (rHuEPO) stimulates the erythropoiesis process. Because this glycoprotein has a short half-life, it needs to be administrated two to three times a week. One of the technics to solve this issue is the PEGgilation., Aims: To evaluate the pharmacokinetics (PK) and pharmacodynamics of two new branched PEGylated erythropoietins (i.e., an asymmetric 32 kDa-PEG 2 -rHuEPO and a symmetric 40 kDa-PEG 2 -rHuEPO molecule) compared to non-PEGylated ior ® EPOCIM and MIRCERA ® ., Methods: Serum concentrations of both PEGylated and non-PEGylated erythropoietins were measured at various time points in order to determine PK parameters using non-compartmental analysis approach. The reticulocyte (%), erythrocyte count and hemoglobin levels were ascertained in order to compare the effect of these molecules after administrating a single intravenous dose (10 μg/kg) of each product in male New Zealand rabbits., Results: Both branched PEGylated erythropoietin forms exhibited half-lives that were significantly longer than ior ® EPOCIM (p<0.05), but not statistically different to MIRCERA ® . The mean elimination half-life increased from 4 h (ior ® EPOCIM) to 131 h for the 32 kDa-PEG 2 -rHuEPO and 119 h for the 40 kDa-PEG 2 -rHuEPO. Conversely, MIRCERA ® exhibits a half-life of 64 h. Both PEGylated erythropoietin products significantly enhanced the stimulating effect on reticulocytes and erythrocytes formation, as well as on hemoglobin levels, when compared to ior ® EPOCIM treatment up to 42 days post-dose., Conclusions: The PEGylation strategy employed in this study is an effective method to modify the pharmacokinetics and pharmacodynamics of rHuEPO molecule achieving higher half-lives and, therefore, longer in vivo bioactivity. Both of the branched PEGylated-EPO forms tested are promising candidates for human testing., Competing Interests: Declaration of interests: The authors declare no conflict of interest.

ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM 2.5 )) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1-4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM 2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM 2.5 and BUD). A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM 2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM 2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM 2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM 2.5 .

African dust storm events (ADE) travel across the Atlantic Ocean (ADEAO) and reach the Puerto Rican coast (ADEPRC), potentially impacting air quality and human health. To what extent seasonal variations in atmospheric particulate matter (PM) size fractions, composition and sources trigger respiratory-adverse effects to Puerto Ricans is still unclear. In the present study, we investigated the pro-inflammatory and cytotoxic effects of PM samples harvested during ADEAO (PM 10 ), ADEPRC (PM 2.5 and PM 10 ) and Non-ADE (Preand Post-ADEAO and Non-ADEPRC), using BEAS-2B cells. Endotoxins (ENX) in PM 2.5 and PM 10 extracts and traces of metals (TMET) in PM 2.5 extracts were also examined. IL-6 and IL-8 secretion and cytotoxicity were used as endpoints. ADEAO and ADEPRC extracts were found to be more cytotoxic than Non-ADE and ADEAO were more toxic than ADEPRC extracts. PM 10 extracts from ADEAO and Post-ADEAO caused significant secretion of IL-8. IL-6 and IL-8 secretion was higher following treatment with PM 10 and PM 2.5 ADEPRC than with Non-ADEPRC extracts. ENX levels were found to be higher in PM 10 ADEAO than in the rest of the samples tested. TMET levels were higher in PM 2.5 ADEPRC than in Non-ADEPRC extracts. Deferoxamine significantly reduced cytotoxicity and IL-6 and IL-8 secretion whereas Polymyxin B did not. TMET in PM 2.5 fractions is a major determinant in ADEPRC-induced toxicity and work in conjunction with ENX to cause toxicity to lung cells in vitro. ENX and TMET may be responsible, in part, for triggering PM-respiratory adverse responses in susceptible and predisposed individuals.