Total Content Research Articles

Intact quantitation of cysteine-conjugated antibody-drug conjugates using native mass spectrometry.

A common strategy for antibody-drug conjugate (ADC) quantitation from in vivo study samples involves measurement of total antibody, conjugated ADC, and free payload concentrations using multiple reaction monitoring (MRM) mass spectrometry. This not only provides a limited picture of biotransformation but can also involve lengthy method development. Quantitation of ADCs directly at the intact protein level in native conditions using high-resolution mass spectrometers presents the advantage of measuring exposure readout as well as monitoring the change in average drug-to-antibody ratio (DAR) and in vivo stability of new linker payloads with minimal method development. Furthermore, site-specific cysteine-conjugated ADCs often rely on non-covalent association to retain their quaternary structure, which highlights the unique capabilities of native mass spectrometry (nMS) for intact ADC quantitation. We developed an intact quantitation workflow involving three stages: automated affinity purification, nMS analysis, and data processing in batch fashion. The sample preparation method was modified to include only volatile ion-pairing reagents in the buffer systems. A capillary size-exclusion chromatography (SEC) column was coupled to a quadrupole time-of-flight high-resolution mass spectrometer for high-throughput nMS analysis. Samples from two mouse pharmacokinetic (PK) studies were analyzed using both intact quantitation workflow and the conventional MRM-based approach. A linear dynamic range of 5-100 μg/mL was achieved using 20 μL of serum sample volume. The results of mouse in vivo PK measurement using the intact quantitation workflow and the MRM-based approach were compared, revealing excellent method agreement. We demonstrated the feasibility of utilizing nMS for the quantitation of ADCs at the intact protein level in preclinical PK studies. Our results indicate that this intact quantitation workflow can serve as an alternative generic method for high-throughput analysis, enabling an in-depth understanding of ADC stability and safety in vivo.

Serum uric acid concentration in acute pancreatitis is significantly higher than healthy population

Acute pancreatitis (AP) is a common disease caused by a variety of causes. Is uric acid associated with the onset of AP? The objective of this study was to assess whether uric acid concentration in AP patients was higher than that in healthy population, and whether there were associations between uric acid concentration and serological indicators related to AP. A total of 205 AP patients were included in this study. Two hundred and five people who underwent physical examination in our hospital were randomly selected as controls. We analyzed whether there was difference in uric acid concentrations between the two groups. If the difference was statistically significant, the correlations between uric acid concentration and serological indicators in AP patients was further analyzed. There was significant difference in uric acid concentration (P < 0.001) between AP patients and healthy population. Serum uric acid concentration in AP group was significantly higher than that in control group. Two hundred and five AP patients were divided into mild AP group and non-mild AP group. There was no statistically significant difference in uric acid concentration between the two groups (P = 0.176). There was a low linear correlation between serum uric acid concentration and triglyceride level (r = 0.316, P < 0.001). But there was no linear correlation between serum uric acid concentration and hypersensitive C-reactive protein (r = 0.126, P = 0.072), white blood cell (r = 0.192, P = 0.006), albumin (r = 0.183, P = 0.009), total cholesterol concentration (r = 0.133, P = 0.058), fasting blood-glucose (r = 0.133, P = 0.058) and blood calcium (r = 0.155, P = 0.026). Uric acid concentration in patients with AP was significantly higher than healthy population. There was correlation between uric acid concentration and triglyceride in AP patients.

Effects of an essential oil blend rich in cinnamaldehyde and carvacrol on rumen biohydrogenation and fatty acid profile in the longissimus lumborum of growing lambs.

Essential oils extracted from cinnamon bark and oregano are rich in cinnamaldehyde and carvacrol and show potential for promoting animal performance. However, their impact on rumen biohydrogenation and the fatty acid composition of meat has not been reported. The hypothesis of this study was that a blend of essential oils rich in cinnamaldehyde and carvacrol would inhibit rumen biohydrogenation and promote the accumulation of polyunsaturated fatty acids (PUFAs) in lamb meat. The present study evaluated the effect of a blend essential oil (EO) rich in cinnamaldehyde and carvacrol on the nutrient digestibility, rumen biohydrogenation, growth performance, and fatty acid profile of the longissimus lumborum of lambs. Sixty male lambs with an average age of 84 ± 0.98 days and initial body mass of 25.4 ± 0.29 kg (mean ± standard deviation) were assigned randomly to four diets, and supplemented with 0 (EO0), 30 (EO30), 60 (EO60), and 120 (EO120) mg kg-1 dry matter of EO for 60 days. Although dry matter and neutral detergent fiber digestibility all showed a linear decrease (P ≤ 0.02) with increasing quantities of EO, final body mass and average daily gain increased linearly (P = 0.04), and average daily weight gain (ADG)/dry matter intake (DMI) tended to increase linearly (P = 0.07). Increasing EO supplementation resulted in a linear decrease in total volatile fatty acid concentration, acetate molar percentage, and acetate-to-propionate ratio (P ≤ 0.03), with the EO120 treatment being lower than the other EO treatments (P ≤ 0.05). Seven lambs from the EO120 treatment and seven lambs from the EO0 treatment were randomly slaughtered. It was observed that the proportions of C18:2n6c and PUFA in longissimus lumborum were higher in the EO120 treatment than the EO0 treatment (P ≤ 0.05). The relative abundance of Firmicutes in the rumen was decreased by the EO120 treatment in comparison with the EO0 treatment (P ≤ 0.05). Furthermore, the predicted relative abundances of genes encoding for conjugated linoleic acid reductase tended to decrease with the EO120 treatment (P = 0.06). We demonstrated that supplementation of the EO blend rich in cinnamaldehyde and carvacrol can enhance lamb growth performance and promote the deposition of desirable PUFAs in meat. © 2024 Society of Chemical Industry.

Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin.

Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults. This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2. The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths. Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.

Novel brominated flame retardants relevant for European aquatic environments: ranking of analytes to monitor and focus on the French Eastern Mediterranean coastline.

Around a hundred of novel brominated flame retardants are currently being used to replace those regulated in the 2000s. However, data about their production, usage, and toxicity is still scarce, as well as their levels of contamination in the Mediterranean Sea and the subsequent risk. Our goal was to select the relevant novel brominated flame retardants to monitor and to apply it along the northeastern Mediterranean Sea. We proposed a ranking for novel brominated flame retardants based on their production or import, occurrence, and ecotoxicology, yielding to a selection of 21 priority molecules. From this list, 16 compounds were analyzed in ten coastal suspended matter samples, together with six related chemicals. To assess their occurrence in comparison to better documented flame retardants, eight legacy polybromodiphenyl ethers, seven polychlorobiphenyls, and short- and medium-chain chlorinated paraffins were also targeted. Novel brominated flame retardants and polychlorobiphenyls were detected in all the samples. Polybromodiphenyl ethers and chlorinated paraffins were detected in nine and seven samples, respectively. Out of the 22 novel brominated flame retardants analyzed, nine were detected, with total concentrations ranging from 0.4 to 18.5ng.g-1 d.w., which was often higher than that of polybromodiphenyl ethers. A high risk for 2,4,6‑tribromophenol and PCB118 was assessed in two and six samples, respectively. To our knowledge, this is the first priority ranking and screening of most of the novel brominated flame retardants selected in the French Mediterranean Sea.

Diagnosis of Nutrient Discharges and Management Alternatives in Developing Countries and the Use of Microalgae as a Potential Solution: A Case Study from Different Provinces in Antioquia, Colombia

This research aims to propose management strategies to mitigate eutrophication caused by inefficient wastewater treatment plants in Colombia. The information analyzed was provided by environmental authorities such as IDEAM, CORANTIOQUIA, and CORNARE in Antioquia, where the average concentrations of phosphorus in wastewater from municipal, livestock, and industrial activities are 5.1, 30.6, and 29.1 mg P/L. The total nitrogen concentrations are 77, 143, and 121 mg N/L, respectively, surpassing the limit concentrations stated by the European Union, the United States, and Mexico, among others, while Colombia has not established its own limits. Including limitations for nutrient concentrations will align Colombia with the 2050 Sustainable Development Goals (SDGs), where microalgae species like Chlorella or Scenedesmus could be used in wastewater treatment systems for municipalities and industries. These microalgae can capture organic matter, nutrients, and greenhouse emissions and reduce the concentrations observed in natural water. They could also be an alternative for capturing heavy metals and some pollutants of emerging concern. In addition to the ecological and social benefits, the algal biomass could be valorized by transforming it into biological products such as fuels, fertilizers, and pigments when micropollutants are not present, reducing operational costs for treatment systems.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Spatial variation, emissions, transport, and risk assessment of organophosphate esters in two large petrochemical complexes in southern China

Organophosphate esters (OPEs) serve as significant flame retardants and plasticizers in various petrochemical downstream products. The petrochemical industry could be a potential source of atmospheric OPEs, but their emissions from this industry are poorly understood. The present study revealed the spatial variation, emission, and atmospheric transport of traditional and novel OPEs (TOPEs and NOPEs, respectively) in atmospheric particulate matter (PM) across Hainan and Guangdong petrochemical complexes (HNPC and GDPC, respectively) in southern China. The total concentrations of TOPEs ranged from 232 to 46,002 pg/m3 and from 200 to 20,347 pg/m3 in the HNPC and GDPC, respectively, which were substantially higher than those of NOPEs (HNPC: 23.5−147 pg/m3, GDPC: 13.9−465 pg/m3). Enterprises involved in the production of downstream petrochemical products presented relatively high concentrations of OPEs, indicating evident emissions of these pollutants in the petrochemical industry. The correlations of PM-bound OPEs in the atmosphere are determined mainly by their coaddition to industrial products or their coexistence in technical mixtures. The annual emissions of TOPEs and NOPEs in the HNPC were 42.6 kg and 0.34 kg, respectively, and those in the GDPC were 116 kg and 1.85 kg, respectively. OPEs from the HNPC can reach Vietnam, Cambodia, and Guangxi Province, China, and those from the GDPC can reach Guangxi Province and Hunan Province via atmospheric transmission after 24 h of emission. The OPE concentrations reaching the receptor regions were generally less than 3.20 pg/m3. Risk assessment revealed that OPE inhalation exposure on two petrochemical complexes likely poses minor risks for people living in the study areas, but the risk resulting from two chlorinated OPEs should be noted since they are close to the threshold values. This study has implications for enhancing control measures for OPE emissions to reduce health risks related to the petrochemical industry.

Nationwide Investigation on Organophosphate Flame Retardants in Tea from China: Migration from Packaging Materials and Implications for Global Risk Assessment.

In this study, we measured 15 common organophosphate flame retardants (OPFRs) in six categories of tea samples across China. OPFRs were found in all the tea samples, with the total concentrations of OPFRs (∑OPFRs) at 3.44-432 ng/g [geometric mean (GM): 17.6 ng/g]. Triphenyl phosphate (TPhP) was the dominant OPFR, accounting for 39.0-76.2% of ∑OPFRs across all tea categories. The potential factors influencing the residual OPFRs in tea were thoroughly examined, including the agricultural environment, fermentation, and packaging of teas. Tea packaging materials (TPMs) were then identified as the primary sources of OPFRs in teas. The migration test revealed that OPFRs with lower molecular weights and log Kow values exhibited a higher propensity for facilitating the migration of OPFRs from TPMs to teas. The estimated daily intakes of OPFRs from teas were relatively higher for the general populations in Mauritania, Gambia, Togo, Morocco, and Senegal (3.18-9.79 ng/kg bw/day) than China (3.12 ng/kg bw/day). The health risks arising from OPFRs in Chinese teas were minor. This study established a baseline concentration and demonstrated the contamination sources of OPFRs in Chinese tea for the first time, with an emphasis on enhancing the hygiene standards for TPMs.

Pharmacokinetics of carprofen in lactating dogs after intravenous treatment

Analgesia is an important component of veterinary care with nonsteroidal antiinflammatory drugs, particularly carprofen (Rimadyl®) commonly used for dogs. Pharmacokinetic studies of carprofen in lactating dogs have not been examined fully, questioning the use and safety of carprofen. The extent to which lactation changes the pharmacokinetics is unknown, nor is the extent of transfer into milk of lactating dogs and their neonates or pups. We hypothesized that after a single dose of intravenous (4.4 mg/kg) to dogs, concentrations in milk are low and not high enough to produce harmful exposure in pups. We tested our hypothesis in healthy, adult lactating dogs (n = 4) using pharmacokinetic methods and nonchiral and chiral specific assays measuring total, R-, and S-enantiomer carprofen concentrations with high performance liquid chromatography in maternal plasma, milk, and neonatal plasma samples. The CMAX, elimination half-life, and clearance for maternal plasma were 9.09 and 7.3 µg/ml (R-, S+), 6.82 and 6.22 hours (R-, S+), and a higher clearance rate of 95.81 ml/hr/kg (R-) and 73.87 ml/hr/kg (S+) than reported. None of the neonatal plasma concentrations at any time point were more than 10% of the total maternal plasma concentrations and milk:plasma ratio was &lt; 1. This study confirmed the approved dose is appropriate for perioperative and chronic pain in lactating dogs and is safe with reduced exposure to nursing pups. This study suggested that the pharmacokinetics of carprofen in lactating dogs may be different from their nonlactating counterparts. However, further pharmacokinetic studies with more dogs are needed to confirm these findings.

Proteomics analysis of carcinogenesis in a rat model of mammary cancer induced by DMBA (7,12-dimethylbenz[a]anthracene)

Background: Mammary cancer, called breast cancer in humans, results from the abnormal growth of cells in the mammary glands that attack the surrounding tissue. The process of carcinogenesis at the molecular level can be monitored through the production of proteins as biomarkers for carcinogenesis. 7,12-Dimethylbenz[a]anthracene (DMBA) is a known carcinogenic compound. This study aimed to analyze the proteomic profile as critical data regarding DMBA-induced carcinogenesis in Sprague‒Dawley rats. Methods: Experimental animals were divided into two groups: a treatment group given DMBA at a dose of 10 mg/kg (intramammary) at intervals of 48 hours for a total of 10 doses, and a negative control group that was not given any treatment. Measurement of the total protein concentration was carried out using a spectrophotometer, and the data were analyzed using a t-test, while the characterization of protein profiles was carried out based on molecular weight data using SDS‒PAGE. Mammary gland histopathology was evaluated by hematoxylin and eosin (H&amp;E) staining. Results: The results showed a significant (p&lt;0.05) increase of 27% in the total protein concentration in the rat mammary cancer model. The results of proteomic characterization showed a protein profile containing proteins of 187, 169, 68, 64, 53, 41, 24, 18, and 14 kDa, which were suspected to be HER-2, Nischarin, COX-2, Albumine, Vimentin, ACTB, TNF, p16, and fatty acid binding protein 3 (FABP3), respectively. Histopathology of the mammary glands showed an irregular and indistinct arrangement of the alveoli and extensive epithelial cell proliferation from the surface to the lumen of the mammary ducts, and the mammary stroma showed the formation of new epithelial cells, which were cancer cells that spread to surrounding tissue. Conclusions: The proteomic profile was strongly associated with morphological alterations in mammary carcinogenesis in a rat model of DMBA-induced mammary cancer.

The use of automatic belt feeders in a Penaeus vannamei pilot scale super-intensive nursery and grow-out with biofloc system

This study aimed to evaluate the effect of using automatic belt feeders (BF) on water quality, growth of Penaeus vannamei, and partial budget in super-intensive pilot scale systems with biofloc technology. A nursery phase (2300 shrimp m−2) and a grow-out phase (400 shrimp m−2) were carried out with the following feeding management strategies, all with three repetitions: T1: by hand, T2: by hand + BF12h; T3: BF24h. In the nursery, a spike in total ammonia concentration was observed in the first weeks of the trial in treatment T1, possibly due to nutrients from uneaten feed. Nitrite was higher in T1 treatment than in T2 and T3. Nitrate was lower in the treatment T1 than in T2 and T3. At the grow-out trial, nitrite was higher in treatment T1 than in T2 and T3. These results indicated a slower nitrification process in T1 and more efficient in treatments where automatic feeders were used since an accumulation of nitrate was observed throughout the trials and low concentrations of nitrite were observed both in the nursery and the grow-out. In the nursery and the grow-out, the T3 treatment had a higher final weight and a lower feed conversion ratio. Furthermore, the T3 treatment had a higher yield than the T1 treatment. Treatment T3 had the highest net benefit/cost, considering the entire production cycle (nursery and grow-out). Our results strongly indicate that using automatic belt feeders allows an improvement in water quality, promotes shrimp growth, improves yield, reduces feed use, and improves the net benefits in P. vannamei super-intensive nursery and grow-out with biofloc systems.

A Mixture of Lactobacillus HY7601 and KY1032 Regulates Energy Metabolism in Adipose Tissue and Improves Cholesterol Disposal in High-Fat-Diet-Fed Mice

We aimed to characterize the anti-obesity and anti-atherosclerosis effects of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 using high-fat diet (HFD)-fed obese C57BL/6 mice. We divided the mice into control (CON), HFD, HFD with 108 CFU/kg/day probiotics (HFD + KL, HY7301:KY1032 = 1:1), and HFD with 109 CFU/kg/day probiotics (HFD + KH, HY7301:KY1032 = 1:1) groups and fed/treated them during 7 weeks. The body mass, brown adipose tissue (BAT), inguinal white adipose tissue (iWAT), and epididymal white adipose tissue (eWAT) masses and the total cholesterol and triglyceride concentrations were remarkably lower in probiotic-treated groups than in the HFD group in a dose-dependent manner. In addition, the expression of uncoupling protein 1 in the BAT, iWAT, and eWAT was significantly higher in probiotic-treated HFD mice than in the HFD mice, as demonstrated by immunofluorescence staining and Western blotting. We also measured the expression of cholesterol transport genes in the liver and jejunum and found that the expression of those encoding liver-X-receptor α, ATP-binding cassette transporters G5 and G8, and cholesterol 7α-hydroxylase were significantly higher in the HFD + KH mice than in the HFD mice. Thus, a Lactobacillus HY7601 and KY1032 mixture with 109 CFU/kg/day concentration can assist with body weight regulation through the management of lipid metabolism and thermogenesis.

Airborne particulate matter and diesel engine exhaust on infrastructure construction sites in the Copenhagen metropolitan area.

Diesel engine exhaust (DEE) is carcinogenic and potentially hazardous for those working in close proximity to diesel-powered machines. This study characterizes workplace exposure to DEE and its associated particulate matter (PM) during outdoor construction activities. We sampled at 4 construction sites in the Copenhagen metropolitan area. We used portable constant-flow pumps and quartz-fiber filters to quantify personal exposure to elemental carbon (EC), and used real-time instruments to collect activity-based information about particle number and size distribution, as well as black carbon (BC) concentration. Full-shift measurements of EC concentration ranged from < 0.3 to 6.4 µg/m3. Geometric mean (GM) EC exposure was highest for ground workers (3.4 µg/m3 EC; geometric standard deviation, GSD = 1.3), followed by drilling rig operators (2.6 µg/m3 EC; GSD = 1.4). Exposure for non-drilling-rig machine operators (1.2 µg/m3 EC; GSD = 2.9) did not differ significantly from background (0.9 µg/m3 EC; GSD = 1.7). The maximum 15-min moving average concentration of BC was 17 µg/m3, and the highest recorded peak concentration was 44 µg/m3. In numbers, the particle size distributions were dominated by ultrafine particles ascribed to DEE and occasional welding activities at the sites. The average total particle number concentrations (PNCs) measured in near-field and far-field positions across all worksites were 10,600 (GSD = 3.0) and 6,000 (GSD = 2.8)/cm3, respectively. Sites with active drilling rigs saw significantly higher average total PNCs at their near-field stations (13,600, 32,000, and 9,700/cm3; GSD = 2.4, 3.4, and 2.4) than sites without (4,700/cm3; GSD = 1.6). Overall, the DEE exposures at these outdoor construction sites were below current occupational exposure limits for EC (10 µg/m3 in Denmark; 50 µg/m3 in the European Union), but extended durations of exposure to the observed DEE levels may still be a health risk.

Source Profile Analysis, Source Apportionment, and Potential Health Risk of Ambient Particle-Bound Polycyclic Aromatic Hydrocarbons in Areas of Specific Interest

Ambient particulate matter (PM10) and its chemical composition in polycyclic aromatic hydrocarbons (PAHs) were studied in areas of specific interest, between September 2015 and July 2016. The principal aim of this study was to assess the different PAH source profiles in each area, as well as their potential health risk. In particular, the studied areas were (a) the semiurban industrialized zone of the Municipality of Peloponnese (Meligalas, Messini) of Messinia prefecture, due to the intensive olive-productive activity in the extensive area, (b) the industrialized zone of Oinofyta in Voiotia prefecture, and (c) the urban/traffic center of Athens (Aristotelous). Intense spatial and seasonal variations in PAH levels were observed among the study areas collectively, but also for each one individually. During the winter period, the total PAHs average concentration was 11.45 and 9.84 ng/m3 at Meligalas–Skala (S1, S2 stations), 8.84 ng/m3 at Messini (S3 station), and 6.30 ng/m3 at the center of Athens (Aristotelous). During the summer campaign, the corresponding levels were 0.99, 1.20, and 0.70 ng/m3 (S1, S2, and S3 stations), and 5.84 ng/m3 (Aristotelous), respectively. The highest potential cancer risk of the PAHs mixture was estimated based on winter season measurements taken at the Municipality of Peloponnese. In order to determine PAH sources, two different source apportionment techniques were applied, i.e., diagnostic ratios (DRs) and the positive matrix factorization (PMF) model.

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.

GIS- and Multivariate-Based Approaches for Assessing Potential Environmental Hazards in Some Areas of Southwestern Saudi Arabia

Soil contamination is a major issue that endangers the ecology in most countries. Total concentrations of As, Cd, Co, Cr, Cu, Mn, Ni, Pb, VFe, and Zn were determined by analyzing soil samples from 32 surface soil samples in southwest Saudi Arabia, including certain areas of Al-Baha. Kriging techniques were used to create maps of the distribution of metal. To assess the levels of soil contamination in the research area, principal component analysis (PCA), contamination factors (CF), and pollution load index were used. The results show the stable model gave the best fit to the As and Zn semivariograms. The circular model fits the Cd, Co, and Ni semivariograms the best, while the exponential model fits the Cr, V, and Fe semivariograms the best. For Ni and Pb, respectively, spherical and Gaussian models are fitted. The findings demonstrated two clusters containing different soil heavy metal concentrations. According to the data, there were two different pollution levels in the research region: 36.58% of it is strongly contaminated, while 63.41% of it has a moderate level of contamination (with average levels of these metals 5.28 ± 5.83, 0.81 ± 0.19, 18.65 ± 6.22, 45.15 ± 23.25, 60.55 ± 23.74, 972.30 ± 223.50, 33.45 ± 14.11, 10.05 ± 5.13, 84.15 ± 30.72, 97.40 ± 30.05, and 43,245.00 ± 8942.95 mg kg−1 for As, Cd, Co, Cr, Cu, Mn, Ni, Pb, V, Fe, and Zn, respectively). The research area’s poor management practices are reflected in the current results, which raised the concentration of harmful elements in the soil’s surface layers. Ultimately, the outcomes of pollution concentration and spatial distribution maps could aid in informing decision-makers when creating suitable heavy metal mitigation strategies.

Modulation of circulating free testosterone fraction by testosterone, dihydrotestosterone, and estradiol during testosterone replacement therapy.

Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction. To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism. Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones. Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model-predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone. During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones.

Polycyclic aromatic hydrocarbons (PAHs) in blood serum of adults living in high and low-traffic volume areas in Malaysia: A comparative cross-sectional study

Ambient polycyclic aromatic hydrocarbons (PAHs) originate predominantly from fuel combustion of motor vehicles and have the potential to affect human health. However, there is insufficient knowledge regarding serum PAHs health risks among the Malaysian population. This study aims to compare PAH concentrations, distributions, correlations, and health risks in 202 blood serum samples drawn from residents living in high-traffic volume areas (Kuala Lumpur) and low-traffic volume areas (Hulu Langat) in Malaysia. Solid phase extraction and gas chromatography-mass spectrometry (GC-MS) were employed to extract and analyze blood serum samples. Questionnaires were distributed to obtain sociodemographic and contributing factors of serum PAHs. The mean total PAHs concentration in serum of the Kuala Lumpur group was 54.44 ng g−1 lipids, double the Hulu Langat group's concentration (25.7 ng g−1 lipids). Indeno(1,2,3-cd)pyrene (IcP) and acenaphthene (ACP) feature the most and least abundant compounds in both study groups. The mean concentrations of IcP and ACP in the Kuala Lumpur and Hulu Langat groups were 26.8 vs 12.68 and 0.27 vs 0.14 ng g−1 lipids, respectively. High-molecular-weight PAHs (HMW-PAHs) composed 85% of serum total PAHs in both groups. Significant correlations were found (i) between the individual serum PAH congeners (p < 0.01) and (ii) between serum PAHs and total lipids (p < 0.01). According to the questionnaire data, high traffic volume and outdoor hobbies were the only contributory factors that confirmed significant relationships with serum PAHs (p < 0.001). Health risk assessment was computed using benzo(a)pyrene (BaP) equivalent (BaPeq) and demonstrated that the Kuala Lumpur group has twofold greater carcinogenic risk than the Hulu Langat group (16.11 vs 7.76 ng g−1 lipids). Our study reveals that traffic volumes notably impact serum PAH levels and general health among the Malaysian population.

Dynamics of Fe, Mn, and potentially harmful elements under reducing conditions in iron ore tailings after dam collapse in the Doce River basin-Brazil: flooded and non-flooded rice cultivations.

Potentially harmful element (PHE) bioavailability is important to environmental contamination and must be checked under several soil conditions. This study aimed to assess Fe, Mn, and PHE uptake by rice (Oryza sativa) grown on flooded and non-flooded Fe tailings collected from the Doce River basin after its collapse in Brazil. After 65days of sowing, shoots and roots were harvested to determine PHE concentrations. The mean concentrations of Mn in shoots and Fe in the roots of rice grown on the flooded tailings were 2140mgkg-1 and 15,219mgkg-1, respectively. Mn was extensively translocated from roots to shoots (translocation factor (TF) = 2). Conversely, Fe accumulated in roots (TF = 0.015) and caused morphological damage to this rice organ. The application of macro and micronutrients lessened Fe toxicity in the roots of rice cultivated on the flooded tailings. The flooding of tailings influenced more Fe accumulation than Mn accumulation by rice plants. The PHE Ag, As, Cd, Ni, Hg, Pb, and Sb exhibited low total concentrations (maximum of 9mgkg-1 for Ni and a minimum of 0.2mgkg-1 for Cd, Hg, and Sb), and it was not observed an increase in their availability under tailings flooding conditions.