Diazepam and its metabolites in the mothers' and newborns' hair as a biomarker of prenatal exposure

Pregnant women are exposed to benzodiazepines for therapeutic purposes during gestation. The goal of this study was to evaluate prenatal exposure to benzodiazepines. Time of exposure during course of pregnancy is a significant aspect of fetal exposure to drugs. Benzodiazepine concentration assay in hair of mothers and newborns exposed prenatally to these drugs was performed in the studies. Development, validation and evaluation of benzodiazepine determination method in mothers and their newborns enables assessment of health risks for the child and implementation of adequate therapeutic procedures. We used A LC-ESI-MS/MS method that allowed determination of diazepam (the main benzodiazepine used by pregnant women was diazepam) and its metabolites (nordazepam, oxazepam) in hair of mothers and newborns. LOQ 10 pg/mg of hair was used in the study. Results: concentration of nordazepam was higher than parent drug (diazepam) and higher in newborns’ hair when compared to mothers’. The mean concentrations of diazepam in mothers’ hair were 31.6±36.0 and 34.1±42.4 pg/mg in the second and third trimester of pregnancy respectively. The mean concentration of diazepam in newborns’ hair was higher and reached levels of 53.3±36.5 pg/mg. The mean concentration of nordazepam in the mothers’ hair corresponding to the second and third trimester was 52.9±48.1 and 89.9±122.8 pg/mg, respectively. Nordazepam in the newborns’ hair was detected at the mean level of 108.1±144.2 pg/mg. It was concluded that diazepam and nordazepam are permanently incorporated into the hair structure. Presence of diazepam and its metabolites in newborn’s hair confirms that these benzodiazepines permeate placental barrier. Segmental analysis of mothers’ hair enabled the assessment of drug administration time. Diazepam and its metabolites determined in hair of newborns may serve as biomarkers of prenatal exposure to these drugs. The performed LC-MS/MS analysis was accurate enough to determine even low concentrations of benzodiazepines, at the level of few pg/mg of hair. Levels of diazepam detected in hair of newborns were higher than levels determined in mothers. This may confirm the fact, that fetus’s ability to metabolize diazepam is scarce. Nordazepam was found in higher concentrations in hair of newborns than in hair of mothers, which may suggest that it is cumulated in child’s organism. Other metabolites of diazepam - oxazepam and temazepam - were detected in very few cases, in low concentrations

GAME CHROMATIC NUMBER OF CARTESIAN PRODUCT GRAPHS

The game chromatic number χg is considered for the Cartesian product G ✷ H of two graphs G and H. We determine exact values of χg(G✷H) when G and H belong to certain classes of graphs, and show that, in general, the game chromatic number χg(G✷H) is not bounded from above by a function of game chromatic numbers of graphs G and H. An analogous result is proved for the game coloring number colg(G✷H) of the Cartesian product of graphs

Thermal Index for early non-invasive assessment of brain injury in newborns treated with therapeutic hypothermia: preliminary report

Abstract Perinatal asphyxia (PA) is the 3rd most common cause of neonatal death and one of the most common causes of severe neurological impairments in children. Current tools and measurements mainly based on the analysis of clinical evaluation and laboratory and electrophysiological tests do not give consistent data allowing to predict the severity of hypoxic-ischemic encephalopathy (HIE) until a magnetic resonance imaging (MRI) score is performed. The aim of this work is to evaluate the usefulness of the new index, called Thermal Index (TI) in the assessment of the degree of brain damage in newborns in the course of therapeutic hypothermia (TH) due to PA. This was a prospective, observational, pilot study which did not require any changes in the applicable procedures. Analysis has been applied to six newborn babies treated with TH in Neonatal/Paediatric ICU in University Hospital in Opole in 2018 due to PA. They all met criteria for TH according to the current recommendations. Brain MRI was performed after the end of TH when the children were brought back to normal temperature, with the use of a 1.5 T scanner, using T1-, T2-weighted images, fluid-attenuated inversion recovery (FLAIR), inversion recovery (IR), susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI). The images were assessed using MRI score according to the scoring system proposed by Weeke et al. The Thermal Index assessing endogenous heat production was calculated according to the formula proposed in this paper. A high, statistically significant positive correlation was found between MRI scores and TI values (0.98; p = 0.0003) in the 1st hour of therapy. High correlation with MRI assessment, the non-invasiveness of measurements and the availability of results within the first few hours of treatment, allow authors to propose the Thermal Index as a tool for early evaluating of the brain injury in newborns treated with TH. Further research is required to confirm the usefulness of the proposed method

Dysfunction of the thyroid gland during amiodarone therapy: a study of 297 cases

Agata Czarnywojtek,1,2,* Maria Teresa Płazińska,3,* Małgorzata Zgorzalewicz-Stachowiak,4 Kosma Woliński,1 Adam Stangierski,1 Izabela Miechowicz,5 Joanna Waligórska-Stachura,1 Paweł Gut,1 Leszek Królicki,3 Maja Zioncheck,6 Marek Ruchała1 1Department of Endocrinology, Metabolism and Internal Medicine, 2Department of Pharmacology, Poznan University of Medical Sciences, Poznan, 3Nuclear Medicine Department, Medical University of Warsaw, Warsaw, 4Department of Health Prophylaxis, Laboratory of Medical Electrodiagnostics, 5Department of Computer Science and Statistics, 6Poznan University of Medical Sciences, Poznan, Poland *These authors contributed equally to this work Aim: This study aims to explore and compare the efficacy of radioiodine treatment (RIT) in hyperthyroid and euthyroid patients who have been treated with amiodarone (AM) in the past or are currently undergoing AM treatment. Clinical observation of a group of patients with amiodarone-induced hypothyroidism during a 12-month follow-up period was used for comparison.Design: This was a observational, two-centered study. Patients were assessed at baseline and at 2 months, 6 months, 8 months, and 12 months after RIT.Patients: Group A: At baseline (61 males [M] and 17 females [F], mean age 50±19 years), there were 78 euthyroid patients with cardiac arrhythmias, who were treated with AM and developed amiodarone-induced thyrotoxicosis, and currently require retreatment with AM. Group B: Hyperthyroid patients (92 M and 26 F, mean age 72±11.8 years) after AM therapy in the past. Group C: Hyperthyroid patients (66 M and 13 F, mean age 63.9±13.2 years) currently treated by AM. Group D: Hypothyroid patients (6 M and 16 F, mean age 61.4±10.4 years) after AM therapy. The patients from Groups A, B, and C were retreated with AM after ~3–6 weeks of RIT.Results: In Group A, after 12 months of RIT therapy, recurrent thyrotoxicosis was observed in six (7.7%) cases, and persistent hypothyroidism was diagnosed in 42 (53.8%) cases. In Group B, hyperthyroidism occurring during treatment with AM was found in 40 (33.9%) patients, and permanent hypothyroidism was observed in eleven (12.5%) cases. After annual follow-up in Group C, nine (11.4%) patients were diagnosed with hypothyroidism, while 27 (34.1%) patients were diagnosed with hyperthyroidism. In Group D, all patients had permanent hypothyroidism and when the concentration of serum thyroid-stimulating hormone was >10 µIU/mL, l-thyroxine was applied.Conclusion: Our study showed that radioiodine administration is advisable in certain circumstances, even in euthyroid patients. It allows for continuation of further long-term AM treatment. Additionally, RIT allows for the reintroduction of AM therapy that was previously terminated. Hence, it can help control life-threatening tachyarrhythmias and decrease episodes of thyrotoxicosis. Keywords: amiodarone, amiodarone-induced thyrotoxicosis, amiodarone-induced hypothyroidism, radioactive iodine, radioiodine treatment, paroxysmal atrial fibrillation, ventricular tachycardi