Genetic modification of the effect of maternal household air pollution exposure on birth weight in Guatemalan newborns

Low birth weight is associated with exposure to air pollution during pregnancy. The purpose of this study was to evaluate whether null polymorphisms of Glutathione S-transferases (GSTs), specifically GSTM1 and GSTT1 genes in infants or mothers, modify the association between high exposures to household air pollution (HAP) from cooking fires and birth weight. Pregnant women in rural Guatemala were randomized to receive a chimney stove or continue to use open fires for cooking. Newborns were measured within 48 h of birth. 132 mother–infant pairs provided infant genotypes (n = 130) and/or maternal genotypes (n = 116). Maternal null GSTM1 was associated with a 144 g (95% CI, −291, 1) and combined maternal/infant null GSTT1 was associated with a 155 g (95% CI, −303, −8) decrease in birth weight. Although there was a trend toward higher birth weights with increasing number of expressed GST genes, the effect modification by chimney stove use was not demonstrated.     

The association of bisphenol-A urinary concentrations with antral follicle counts and other measures of ovarian reserve in women undergoing infertility treatments

In this prospective cohort of women undergoing infertility treatments, we measured specific-gravity adjusted urinary BPA (SG-BPA) concentrations and used regression models to evaluate the association of BPA with antral follicle count (AFC), day-3 serum follicle stimulating hormone levels (FSH), and ovarian volume (OV). BPA, detected in >80% of women, had a geometric mean (±GSD) of 1.6 ± 2.0, 1.7 ± 2.1, and 1.5 ± 1.8 μg/L for the women contributing to the AFC (n = 154), day-3 FSH (n = 120), and OV (n = 114) analyses, respectively. There was an average decrease in AFC of 12% (95% CI: −23%, −0.6%), 22% (95% CI: −31%, −11%), and 17% (95% CI: −27%, −6%), in the 2nd, 3rd, and 4th SG-BPA quartile compared to the 1st quartile, respectively (p-trend: <0.001). No association of SG-BPA with FSH or OV was observed. Among women from an infertility clinic, higher urinary BPA concentrations were associated with lower AFC, raising concern for possible accelerated follicle loss and reproductive aging.     

Prenatal exposure to lead in relation to risk of preterm low birth weight: A matched case–control study in China

We investigated the association between prenatal exposure to lead (Pb) and the risk of preterm low birth weight (PLBW). Pb concentrations in maternal urine collected at birth from 408 subjects (102 cases and 306 matched controls) were analyzed and adjusted by creatinine. The median Pb concentration in the PLBW cases (10.60 μg Pb/g creatinine) was higher than that of the controls (7.28 μg Pb/g creatinine). An adjusted odds ratio (OR) of 2.96 (95% CI = 1.49–5.87) for PLBW was observed when the highest tertile was compared to the lowest tertile of Pb levels. The association was more pronounced among female infants (adjusted OR = 3.67 for the highest tertile; 95% CI = 1.35–9.93) than male infants (adjusted OR = 1.91 for the highest tertile; 95% CI = 0.74–4.95). Our study suggests that prenatal exposure to levels of Pb encountered today in China is associated with an elevated risk of PLBW.     

Effect of prenatal manganese intoxication on [3H]glucose uptake in the brain of rats lesioned as neonates with 6-hydroxydopamine

In the present study we examined the effects of prenatal manganese (Mn) intoxication on [³H]glucose uptake in the brain of rats lesioned as neonates with 6-hydroxydopamine (6-OHDA). MnCl₂ ? 4H2O (10,000 ppm) was added to the drinking water of pregnant Wistar rats for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive to the drinking water. The control group consisted of rats that consumed water without Mn. Three days after birth, rats in both groups (control and Mn) were pretreated with desipramine hydrochloride (20 mg/kg) and pargyline hydrochloride (50 mg/kg) and injected bilaterally icv with one of three doses of 6-OHDAhydrobromide (15 μg, 30 μg or 67 μg base form in saline on each side) or with saline (control). 6-[³H]-Dglucose (500 μCi/kg, ip) was administered to male offspring in adulthood; after 15 min, brain specimens were taken (frontal cortex, hippocampus, striatum, thalamus with hypothalamus, pons and cerebellum) for determination of radioactivity in a liquid scintillation counter. Low dose 6-OHDA (15 μg icv) increased [³H]glucose uptake in all brain regions (p < 0.05) in both control and Mnintoxicated animals. In rats lesioned with a moderate dose of 6-OHDA(30 μg icv), [3H]glucose uptake was unaltered in both control and Mn-exposed rats. High dose 6-OHDA(67 μg icv) reduced [³H]glucose uptake in all brain regions of Mn-exposed rats (except for cerebellum) compared with the saline group (all, p < 0.05). There was no change in regional brain uptake of [³H]glucose in control rats. In conclusion, this study shows that mild neuronal insult (15 μg icv 6-OHDA) increased glucose uptake in the brain while severe damage (concomitant 60 μg icv 6-OHDA and Mn treatment) significantly diminished this process.     

Essential trace and toxic element concentrations in organic and conventional milk in NW Spain

Dietary composition and husbandry practices largely determine essential trace element status and toxic element exposure of livestock, and consequently their concentrations in animal products. This study evaluates the main essential trace (Co, Cr, Cu, Fe, I, Mn, Mo, Ni, Se and Zn) and toxic (As, Cd, Hg and Pb) element concentrations in milk from organic and conventional farms in NW Spain (n = 50). Milk samples were acid digested and analyzed by ICP-MS. Essential trace element concentrations in organic milk were significantly lower compared to conventional milk, this was especially evident for elements that are routinely supplemented at high concentrations in the conventional concentrate feed: Cu (41.0 and 68.9 μg/L in organic and conventional milk, respectively), Zn (3326 and 3933 μg/L), I (78 and 265 μg/L) and Se (9.4 and 19.2 μg/L). Toxic metal concentrations in milk were in general very low and no statistically significant differences were observed between organic and conventional milk. In addition, the mineral content of organic milk showed a seasonal pattern, the significantly higher As (65%) and Fe (13%) concentrations found in the winter sampling possibly being related to a higher consumption of concentration feed and soil ingestion when grazing.     

Methodological agreement on the in vitro activity of ceftaroline against cefotaxime-susceptible and -resistant pneumococci

Ceftaroline reportedly has lower minimum inhibitory concentrations (MICs) than established cephalosporins for Streptococcus pneumoniae. We further evaluated this activity using 155 pneumococci chosen by serotype and cefotaxime MIC. MICs were determined by agar dilution on Mueller–Hinton agar and Iso-Sensitest agar and by Etest. Inhibition zones were measured for 5 μg and 30 μg ceftaroline discs using both CLSI/EUCAST and BSAC methodology. Ceftaroline was more active than cefotaxime, with MICs 2–8-fold lower for isolates with cefotaxime MICs of ≤1 mg/L and mostly in the range 0.125–0.5 mg/L for those with cefotaxime MICs of 2 mg/L to ≥16 mg/L. Twelve isolates belonging to serotypes 14 (n = 2), 19A (n = 6) and 19F (n = 4) were ceftaroline-resistant, with MICs of 0.5–1 mg/L. Essential agreement between MIC methods was excellent, with values on Iso-Sensitest agar and Mueller–Hinton agar identical ±1 doubling dilution in all cases, and with 154/155 values identical ±1 doubling dilution between agar dilution and Etest. Nevertheless, 5/11 isolates with agar dilution MICs of 0.5 mg/L (i.e. just resistant) ‘had’ MICs of 0.25 mg/L (just susceptible) by Etest. Inhibition zones also correlated with MICs, but discrimination around the breakpoint MICs was poor irrespective of method and disc type. In summary, the results confirm the good activity of ceftaroline against pneumococci, but susceptibility testing will present challenges in routine laboratories, with discs poorly discriminatory and with Etest prone to give susceptible results for isolates with MICs one doubling dilution above the breakpoint.     

Evidence that birth weight is decreased by maternal lead levels below 5 μg/dl in male newborns

To assess the association between birth weight and maternal blood lead (BPb) levels, 386 pregnant women and their newborn offspring were surveyed. Mean ± SD (range) maternal BPb concentrations were 0.98 ± 0.55 (0.10–3.99), 0.92 ± 0.63 [<0.09 (limit of quantification)–3.96], and 0.99 ± 0.66 (<0.09–3.96) μg/dl at 12, 25 and 36 weeks’ gestation, respectively. Mean ± SD (range) gestational age at delivery was 38.9 ± 1.3 (35–41) weeks. In male newborns, a significant correlation between birth weight and logBPb at 12 weeks’ gestation was observed (Spearman's rank correlation coefficient = −0.145, p < 0.05). Multiple regression analysis indicated that birth weight was significantly inversely associated with logBPb at 12 weeks’ gestation, controlling for possible confounding variables. These results suggest that low-level exposure to lead in early gestation could be a risk factor for reduced birth weight in male offspring.     

Maternal–fetal transfer of indocyanine green across the perfused human placenta

Indocyanine green (ICG) is an FDA-approved near-infrared imaging probe, given also to pregnant women. We aimed to characterize ICG's transplacental transfer using the ex-vivo perfusion model. Placentas were obtained from caesarean deliveries. Cotyledons were cannulated and dually perfused. ICG, 9.6 μg/mL and antipyrine (50 μg/mL) were added to the maternal circulation in the absence (n = 4) or the presence of the organic anion transporting polypeptide (OATPs) inhibitor rifampin (10 μg/mL; n = 5) or the P-glycoprotein inhibitor valspodar (2 μg/mL; n = 3). ICG's maternal-to-fetal transfer was evaluated over 180 min. The cumulative percent of ICG in the fetal reservoir was minor. When ICG transfer was normalized to that of antipyrine, it was lower in the presence of rifampin (a 41% decrease; p < 0.05). Valspodar did not appear to modify the kinetics of ICG. ICG's transplacental transfer is minimal and is probably OATP-mediated. The placenta is an effective protective barrier to ICG's distribution into the fetus.     

Environmental cadmium and lead exposure and anti-Müllerian hormone in pregnant women

BackgroundAnti-Müllerian Hormone (AMH) has been suggested as a marker for ovarian function. Cadmium and lead have been suggested to reduce female fecundity. In this study we aimed to investigate whether environmental exposure to cadmium and lead was associated with alterations in serum-AMH.Materials and methodThe associations between serum-AMH and whole blood cadmium or lead were investigated by general linear models in a population-based sample of 117 pregnant women.ResultsThe mean concentrations of blood cadmium and lead were 0.71 μg/L and 17.4 μg/L, respectively. The mean serum-AMH was 17.3 pmol/L. No association between lead and AMH was detected. In the cadmium analysis the adjusted mean AMH level (95% CI) in the highest exposure tertile was 12.4 (6.4;23.8) compared to 5.6 (2.7;11.4) in the lowest exposure tertile (p = 0.06).ConclusionThe study provides suggestive evidence that environmental exposure to cadmium, but not lead, may alter the level of AMH.     

A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization

BackgroundRecombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize haematopoietic stem cells. We compared the efficacy and safety of a biosimilar G-CSF (Zarzio^®, Sandoz Biopharmaceuticals) with the originator G-CSF (Neupogen^®, Amgen) in patients with haematological malignancies.MethodsA total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19–69). Patients had multiple myeloma (n = 46), non-Hodgkin's lymphoma (n = 28), Hodgkin's lymphoma (n = 26), or other diagnosis (n = 8). After administration of mobilizing regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomized to a standard daily 10 μg/kg dose of biosimilar G-CSF (n = 54) or originator G-CSF (n = 54).ResultsMedian duration of G-CSF administration was 8 days with both biosimilar G-CSF (range 4–17) and originator G-CSF (range 4–14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean ± SD number of mobilized CD34+ cells/μL in peripheral blood or the number of CD34+ cells/kg body weight. Five patients (9%) in the originator G-CSF group and six patients in the biosimilar G-CSF group (11%) did not mobilize sufficient CD34+ cells. The adverse event profile was similar between groups.ConclusionsA biosimilar G-CSF (Zarzio^®) demonstrated similar efficacy and safety as the reference originator G-CSF (Neupogen^®) in hematopoietic stem cell mobilization in patients with haematological malignancies.     

A new mucoadhesive dosage form for the management of oral lichen planus: Formulation study and clinical study

The work aimed at studying a new mucoadhesive prolonged release tablet containing 24 μg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl₂. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n = 16) who received three applications-a-day over 4 weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123 μg/application) extemporary mixed with Orabase™ (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n = 2) and taste alteration (n = 4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24 μg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment.     

DNA methylation changes in the placenta are associated with fetal manganese exposure

Adequate micronutrient intake, including manganese (Mn), is important for fetal development. Both Mn deficiencies and excess exposures are associated with later-life disease, and Mn accumulates in the placenta. Placental functional alterations may alter fetal programming and lifelong health, and we hypothesized that prenatal exposures to Mn may alter placental function through epigenetic mechanisms. Using Illumina's HumanMethylation450 BeadArray, DNA methylation of >485,000 CpG loci genome-wide was interrogated in 61 placental samples and Mn associations assessed genome-wide via omnibus test (p = 0.045). 713 loci were associated with Mn exposure (p < 0.0001). Five significantly differentially-methylated (p < 1.3 × 10⁻⁷) loci reside in neurodevelopmental, fetal growth and cancer-related genes. cg22284422, within the uncharacterized LOC284276 gene, was associated with birth weight; for every 10% increase in methylation, lower birth weights were observed, with an average decrease of 293.44 g. Our observations suggest a link between prenatal micronutrient levels, placental epigenetic status and birth weight, although these preliminary results require validation.     

The role of essential metals in the placental transfer of lead from mother to child

Epidemiological studies have found adverse birth and child health outcomes from prenatal lead exposure, but little is known about factors influencing placental transfer. In this study we describe the placental transfer of lead in a Taiwanese population, and investigate whether three essential metals – zinc, manganese, or selenium – influence transfer. Maternal and cord blood samples (308 pairs) from a birth cohort study were analyzed using multiple linear regression. There was a clear correlation between mother and child lead concentration (r = 0.48, p < 0.001), although lead concentration in cord blood (mean = 1.29, SD = 0.72 μg/dL) was lower than that for mothers (mean = 1.58, SD = 1.11 μg/dL). Cord blood lead was lower where the mother had a higher blood concentration of zinc (p < 0.001) or manganese (p = 0.02). Thus maternal blood zinc and manganese, but not selenium, appeared to decrease the placental transfer of lead. These findings raise the possibility of reducing placental transfer of lead by increasing zinc levels via nutritional supplementation during pregnancy.     

Continuous versus intermittent infusion of cefepime in neurosurgical patients with post-operative intracranial infections

Cefepime is administered as an intermittent infusion (II); however, continuous infusion (CI) may be advantageous because β-lactam antibiotics exhibit time-dependent antibacterial activity. This retrospective, non-randomised, comparative study included 68 neurosurgical patients with post-operative intracranial infections treated with 4 g/day cefepime over 24 h as a CI (n = 34) or 2 g every 12 h as II (n = 34). CI controlled the intracranial infection more rapidly and effectively than II (6.6 ± 1.9 days vs. 7.8 ± 2.6 days; P = 0.036). By considering the minimum inhibitory concentrations (MICs) to be 4 μg/mL and 8 μg/mL, the percentage of time when the cefepime plasma or CSF concentrations were higher than the MIC (%T_>MIC) was calculated for each patient. For plasma cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 8 μg/mL, 100% vs. 75%, respectively). The mean calculated area under the curve (AUC) in the CI group was similar to the II group (1197.99 ± 72.15 μg h/mL vs. 890.84 ± 140.78 μg h/mL; P = 0.655). For CSF cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 4 μg/mL and 8 μg/mL, 83.3% and 75% vs. 25% and 0%, respectively). The mean calculated AUC for the CI group was higher than the II group (220.56 ± 13.59 μg h/mL vs. 86.34 ± 5.69 μg h/mL; P = 0.003). Therefore, CI of cefepime significantly enhanced the antibacterial effect and reduced the treatment duration in neurosurgical patients with post-operative intracranial infections.     

Systematic review of social media interventions for smoking cessation

BackgroundPopular social media could extend the reach of smoking cessation efforts. In this systematic review, our objectives were: 1) to determine whether social media interventions for smoking cessation are feasible, acceptable, and potentially effective; 2) to identify approaches for recruiting subjects; and 3) to examine the specific intervention design components and strategies employed to promote user engagement and retention.MethodsWe searched Scopus, Medline, EMBASE, Cochrane Central, PsychINFO, CINAHL, and Web of Science through July 2016 and reference lists of relevant articles. Included studies described social media interventions for smoking cessation and must have reported outcomes related to feasibility, acceptability, usability, or smoking-related outcomes.ResultsWe identified 7 studies (all were published since 2014) that enrolled 9755 participants (median = 136 [range 40 to 9042]). Studies mainly used Facebook (n = 4) or Twitter (n = 2), and emerged as feasible and acceptable. Five studies reported smoking-related outcomes such as greater abstinence, reduction in relapse, and an increase in quit attempts. Most studies (n = 6) recruited participants using online or Facebook advertisements. Tailored content, targeted reminders, and moderated discussions were used to promote participant engagement. Three studies found that active participation through posting comments or liking content may be associated with improved outcomes. Retention ranged from 35% to 84% (median = 70%) across the included studies.ConclusionsOur review highlights the feasibility, acceptability and preliminary effectiveness of social media interventions for smoking cessation. Future research should continue to explore approaches for promoting user engagement and retention, and whether sustained engagement translates to clinically meaningful smoking cessation outcomes.     

Effects of perinatal ethinyl estradiol exposure in male and female Wistar rats

Perinatal exposure to endocrine disrupting chemicals with estrogenic activity can adversely affect reproductive development, but few studies evaluating estrogen-sensitive endpoints have been performed in Wistar rats. Therefore, time-mated Wistar rats (n = 10) were gavaged during gestation and lactation with 0, 5, 15 or 50 μg/kg bw/day of ethinyl estradiol.This potent estrogen was found to induce an increased number of nipples and reduced ovary weight in female offspring. Malformations of female genitalia were found in young as well as adult offspring, as an increased AGD was seen at birth and a deeper urethral slit length was seen in adulthood. In prepubertal male offspring, estrogen-regulated gene expression in ventral prostate was increased dose-dependently and a decreased ventral prostate weight was seen at 15 μg/kg.Female external sexual characteristics and prostate development were found to be targets for exposure to estrogenic compounds and may be of interest in studies on estrogenic environmental compounds.     

Detection of furan levels in select Chinese foods by solid phase microextraction–gas chromatography/mass spectrometry method and dietary exposure estimation of furan in the Chinese population

In this study, a solid phase microextraction–gas chromatography/mass spectrometry (SPMEGC/MS) method was developed to detection the levels of furan in 191 selected food products obtained from the Chinese markets. The performance of the analysis method was evaluated by some quality parameters such as limit of detection (LOD), limit of quantification (LOQ), linearity, recovery, and runto-run (n = 6) and day-to-day (n = 18) precisions. The LOD and the LOQ of the method were 0.059 ng/g and 0.175 ng/g, respectively. The recovery of the method in fruit juice, canned jam, and infant formula ranged from 93.25% to 104.69%. The results from this study showed that furan was detected in almost all analyzed samples. Furan contents in different food samples varied greatly according to the raw materials and processing conditions. The higher contents of furan were detected in traditional Chinese liquor (61.63 ng/g), coffee (71.36 ng/g), tea (68.28 ng/g) and pickle (85.63 ng/g). The dietary intake of furan was estimated to be 0.093 μg/kg b.w.t/day in adults and 0.333 μg/kg b.w.t/day in infants at 6 months. Further studies are needed to reveal other sources of dietary furan exposure.     

Hair mercury concentrations and in vitro fertilization (IVF) outcomes among women from a fertility clinic

Total hair mercury (Hg) was measured among 205 women undergoing in vitro fertilization (IVF) treatment and the association with prospectively collected IVF outcomes (229 IVF cycles) was evaluated. Hair Hg levels (median = 0.62 ppm, range: 0.03–5.66 ppm) correlated with fish intake (r = 0.59), and exceeded the recommended EPA reference of 1 ppm in 33% of women. Generalized linear mixed models with random intercepts accounting for within-woman correlations across treatment cycles were used to evaluate the association of hair Hg with IVF outcomes adjusted for age, body mass index, race, smoking status, infertility diagnosis, and protocol type. Hair Hg levels were not related to ovarian stimulation outcomes (peak estradiol levels, total and mature oocyte yields) or to fertilization rate, embryo quality, clinical pregnancy rate or live birth rate.     

Cylindrospermopsin,a blue-green algal toxin,inhibited human luteinised granulosa cell protein synthesis in vitro

The blue-green algal toxin cylindrospermopsin (CYN) inhibits protein synthesis, and CYP450 enzymes metabolise CYN to cytotoxic endproducts. Human chorionic gonadotrophin (hCG) stimulates the de novo synthesis of StAR and CYP450 aromatase. Human IVF-derived granulosa cells (GC) (n = 7) were exposed to 0–5 μM CYN ± 1 IU/ml hCG for 2–24 h. After 24 h pre-culture GC responded to hCG by increasing estradiol 17β (E₂) and progesterone (P₄) synthesis. Three micromolar of CYN ± 1 IU/ml hCG for 24 h was not cytotoxic and did not affect basal or hCG-stimulated E₂ or P₄ production, but did inhibit protein synthesis (p < 0.05, n = 4). hCG-stimulated steroidogenesis was not reduced by CYN, suggesting a lack of effect on StAR or CYP450 aromatase protein synthesis. hCG enhanced the effects of CYN on GC protein synthesis. Twenty four hours exposure to 0.1 μM CYN did not affect GC, supporting the establishment of a 0.0024 μM Guideline level for CYN in public water supplies.     

Phthalate and di-(2-ethylhexyl) adipate (DEHA) intake by German infants based on the results of a duplicate diet study and biomonitoring data (INES 2)

Phthalates as well as di-(2-ethylhexyl) adipate (DEHA) are used as plasticizers in diverse applications and are of toxicological concern.The study was conducted with a study population of 25 German subjects aged between 15 and 21 months. Overall, 16 phthalates and DEHA were measured by gas chromatography–mass spectrometry in a total of 171 duplicate diet samples collected over 7 consecutive days, and 20 phthalate metabolites were analyzed in the urine samples collected over 7 consecutive days using a liquid chromatography–tandem mass spectrometry method.The median “high” daily dietary intake based on 95th percentiles was 4.66 μg/kg b.w. for di-2-ethylhexyl phthalate (DEHP), 1.03 μg/kg b.w. for di-isobutyl phthalate (DiBP), and 0.70 μg/kg b.w. for di-n-butyl phthalate (DnBP), and 1.0 μg/kg b.w. for DEHA. The “high” daily total intake from biomonitoring data was 4.9 μg/kg b.w. for DEHP, 2.2 μg/kg b.w. for DnBP, 3.9 μg/kg b.w. for DiBP, and 2.6 μg/kg b.w. for di-isononyl phthalate.The comparison of the two intake estimates indicates that the dominant intake source of DEHP was food ingestion, whereas other sources considerably contributed to the total intake of other phthalates. Using our “high” intake scenario, none of the analyzed phthalates reached the recommended tolerable daily intake levels.