Long-term neurodevelopmental outcome of neonates born at term with perinatal haemorrhagic stroke: A population-based study.

AIM: To assess the long-term neurodevelopmental outcome of neonates born at term diagnosed with perinatal haemorrhagic stroke (PHS) and investigate the associations among brain territorial involvement, clinical risk factors, and neurodevelopmental outcomes. METHOD: We conducted a population-based study enrolling 55 neonates born at term with PHS confirmed by magnetic resonance imaging born between 2007 and 2017. Long-term neurodevelopmental outcome was assessed using the Bayley Scales of Infant Development, Second Edition, the Brunet-Lézine test, and the Stanford-Binet Intelligence Scales, Fifth Edition. RESULTS: Follow-up was available in 50 (91%) of the infants, at a median age of 60 months (interquartile range 35-88). Forty per cent of the infants developed according to population norms, and developmental disabilities were diagnosed less frequently among neonates with frontal lobe PHS. In a multivariable model, parietal lobe PHS increased the risk for cerebral palsy (odds ratio [OR] 6.7; 95% confidence interval [CI] 1.1-41.4) and cognitive impairment (OR: 23.6; 95% CI: 2.9-194.9), while the involvement of the thalamus and/or basal ganglia was associated with epilepsy (OR: 7.0; 95% CI: 1.3-37.7). Seizures on admission were associated with epilepsy (OR: 10.8; 95% CI: 1.8-64.3). Patients with PHS affecting multiple lobes had poor prognosis. INTERPRETATION: Parietal lobe haemorrhage, the involvement of the thalamus/basal ganglia, PHS affecting multiple lobes, and seizures were independent predictors of chronic neurodevelopmental sequelae, suggesting that the stroke territorial involvement and clinical risk factors influence the outcome of PHS.

The role of brain territorial involvement and infection/inflammation in the long-term outcome of neonates with arterial ischemic stroke: A population-based cohort study.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) carries the risk of significant long-term neurodevelopmental burden on survivors. AIMS: To assess the long-term neurodevelopmental outcome of term neonates diagnosed with NAIS and investigate the associations among brain territorial involvement on MRI, clinical risk factors and neurodevelopmental outcomes. STUDY DESIGN: Population-based cohort study. SUBJECTS: Seventy-nine term neonates with NAIS confirmed by MRI born between 2007 and 2017. OUTCOME MEASURES: Long-term neurodevelopmental outcome assessed using the Bayley Scales of Infant Development-II, the Brunet-Lézine test and the Binet Intelligence scales-V. RESULTS: Follow-up was available in 70 (89%) of the subjects enrolled, at a median age of 60 months [IQR: 35-84]. Normal neurodevelopmental outcome was found in 43% of the patients. In a multivariable model, infants with main MCA stroke had an increased risk for overall adverse outcome (OR: 9.1, 95% CI: 1.7-48.0) and a particularly high risk for cerebral palsy (OR: 55.9, 95% CI: 7.8-399.2). The involvement of the corticospinal tract without extensive stroke also increased the risk for cerebral palsy/fine motor impairment (OR: 13.5, 95% CI: 2.4-76.3). Multiple strokes were associated with epilepsy (OR: 9.5, 95% CI: 1.0-88.9) and behavioral problems (OR: 4.4, 95% CI: 1.1-17.5) and inflammation/infection was associated with cerebral palsy (OR: 9.8, 95% CI: 1.4-66.9), cognitive impairment (OR: 9.2, 95% CI: 1.8-47.8) and epilepsy (OR: 10.3, 95% CI: 1.6-67.9). CONCLUSIONS: Main MCA stroke, involvement of the corticospinal tract, multiple strokes and inflammation/infection were independent predictors of adverse outcome, suggesting that the interplay of stroke territorial involvement and clinical risk factors influence the outcome of NAIS.

Study of the Potential Endocrine-Disrupting Effects of Phenylurea Compounds on Neurohypophysis Cells In Vitro.

Homeostatic disruptor agents, and endocrine disruptor compounds (EDC) specifically, can originate from agricultural and industrial chemicals. If they modify the adaptation of living organisms as direct (e.g., by altering hormone regulation, membrane functions) and/or indirect (e.g., cell transformation mechanisms) factors, they are classified as EDC. We aimed to examine the potential endocrine-disrupting effects of phenylurea herbicides (phenuron, monuron, and diuron) on the oxytocin (OT) and arginine-vasopressin (AVP) release of neurohypophysis cell cultures (NH). In our experiments, monoamine-activated receptor functions of neurohypophyseal cells were used as a model. In vitro NH were prepared by enzymatic (trypsin, collagenase) and mechanical dissociation. In the experimental protocol, the basal levels of OT and AVP were determined as controls. Later, monoamine (epinephrine, norepinephrine, serotonin, histamine, and dopamine) activation (10-6 M, 30 min) and the effects of phenylurea (10-6 M, 60 min) alone and in combination (monoamines 10-6 M, 30 min + phenylureas 10-6 M, 60 min) with monoamine were studied. OT and AVP hormone contents in the supernatant media were measured by radioimmunoassay. The monoamine-activated receptor functions of neurohypophyseal cells were modified by the applied doses of phenuron, monuron, and diuron. It is concluded that the applied phenylurea herbicides are endocrine disruptor agents, at least in vitro for neurohypophysis function.

The Role of Uron and Chlorobenzene Derivatives, as Potential Endocrine Disrupting Compounds, in the Secretion of ACTH and PRL.

Uron herbicides polluting the environment represent a serious concern for environmental health and may be regarded as endocrine-disrupting compounds (EDCs), which influence the regulation of human homeostasis. We aimed to investigate the effect of EDC urons (phenuron: PU, monuron: MU, and diuron: DU) and chlorobenzenes on the basal release of the adrenocorticotropic hormone (ACTH), which is a part of the adenohypophysis-adrenocortical axis. Hormone secretion in the presence of EDC was studied in two cell types: normal adenohypophysis cells (AdH) and cells of prolactinomas (PRLOMA). PRLOMA was induced in female Wistar rats by subcutaneously injecting them with estrone acetate for 6 months. AdH and PRLOMA were separated from treated and untreated experimental animals, dissociated enzymatically and mechanically in order to create monolayer cell cultures, which served as an experimental in vitro model. We investigated the effects of ED agents separately and in combination on ACTH and prolactin (PRL) release through the hypophyseal-adrenal axis. Hormone determination was carried out by the luminescent immunoassay and the radioimmunoassay methods. Our results showed that (1) uron agents separately did not change ACTH and PRL release in AdH culture; (2) ACTH secretion in arginine vasopressin- (AVP-) activated AdH cells was significantly increased by EDC treatment; (3) ED agents increased the basal hormone release (ACTH, PRL) in PRLOMA cells; and (4) EDC exposure increased ACTH release in AVP-activated PRLOMA cells. We conclude that the herbicides PU, MU, and DU carry EDC effects and show human toxicity potential.

Effects of extremely low frequency electromagnetic fields on turkeys.

Several studies have examined the potential biological effects of electromagnetic fields (EMF) on birds; however, little attention has been paid to the extremely low frequency (ELF; 0-300 Hz; 0-50 µT) radiation found in an urbanized environment. For monitoring the effects of ELF EMF, we used a turkey (Meleagris gallopavo) model, because the nucleated erythrocytes of turkeys contain ß-adrenoceptors, and norepinephrine- (NE-) activated ß-adrenoceptors have an important role in physiological and behavioral processes. Our aims were the following: 1) to investigate the intracellular mechanisms; 2) to compare the intracellular mechanisms in the treated and control groups over time, considering inter-individual differences and intra-subject correlations; 3) and to study the reversible nature of the response. The turkeys in the treatment group were treated in vivo with ELF EMF (50 Hz; 10 µT) for 3 wk after a 1-wk-long adaptation period. The animals were not exposed to ELF EMF during the regeneration period (5 wk following the exposure). The NE-activated ß-adrenoceptor function was detected by measuring the amount of 3΄5΄-cyclic-adenosine-monophosphate (cAMP), and the biochemical enzyme parameters were defined. Repeated measurements of cAMP levels were analyzed using marginal models and a piecewise linear mixed model to compare treatment and control groups over time. According to our results, NE-activated ß-adrenoceptor function was decreased in the treated birds in a time-dependent manner, while there were no differences between toxicological parameters in the serum, compared to the normal ranges. The decreased NE-dependent ß-adrenoceptor function could be compensated by the homeostatic complex during the 5-wk regeneration period. Extended experimental periods and more sophisticated analysis methods may help prevent harmful environmental effects on birds; furthermore, these findings could affect public health and the economy.

A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study.

Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during some primary headache disorders. The goal of this study was to compare the effects of two KYNA analogs, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1) and N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2), in the orofacial formalin test of trigeminal pain. Following pretreatment with KA-1 or KA-2, rats were injected with subcutaneous formalin solution in the right whisker pad. Thereafter, the rubbing activity and c-Fos immunoreactivity changes in the spinal trigeminal nucleus pars caudalis (TNC) were investigated. To obtain pharmacokinetic data, KA-1, KA-2 and KYNA concentrations were measured following KA-1 or KA-2 injection. Behavioral tests demonstrated that KA-2 induced larger amelioration of formalin-evoked alterations as compared with KA-1 and the assessment of c-Fos immunoreactivity in the TNC yielded similar results. Although KA-1 treatment resulted in approximately four times larger area under the curve values in the serum relative to KA-2, the latter resulted in a higher KYNA elevation than in the case of KA-1. With regard to TNC, the concentration of KA-1 was under the limit of detection, while that of KA-2 was quite small and there was no major difference in the approximately tenfold KYNA elevations. These findings indicate that the differences between the beneficial effects of KA-1 and KA-2 may be explained by the markedly higher peripheral KYNA levels following KA-2 pretreatment. Targeting the peripheral component of trigeminal pain processing would provide an option for drug design which might prove beneficial in headache conditions.

Diverse effects of Brilliant Blue G administration in models of trigeminal activation in the rat.

Activation of the trigeminal system plays an important role in the pathomechanism of headaches. A better understanding of trigeminal pain processing is expected to provide information helping to unravel the background of these diseases. ATP, a key modulator of nociceptive processing, acts on ligand-gated P2X receptors. Antagonists of the P2X7 receptors, such as Brilliant Blue G (BBG), have proved effective in several models of pain. We have investigated the effects of BBG after electrical stimulation of the trigeminal ganglion and in the orofacial formalin test in the rat. The right trigeminal ganglion of male rats was stimulated either with 5 Hz, 0.5 mA pulses for 5 min (mild procedure) or with 10 Hz, 0.5 mA pulses for 30 min (robust procedure), preceded by 50 mg/kg i.v. BBG. The animals were processed for c-Fos and calcitonin gene-related peptide (CGRP) immunohistochemistry. In the orofacial formalin test, 50 µL of 1.5 % formalin was injected into the right whisker pad of awake rats, following the pre-treatment with BBG. Behaviour was monitored for 45 min, and c-Fos and CGRP immunohistochemistry was performed. BBG attenuated the increase in c-Fos-positive cells in the caudal trigeminal nucleus (TNC) after robust stimulation, but not after mild stimulation. No alterations in CGRP levels were found with either methodology. BBG did not mitigate either the behaviour or the increase in c-Fos-positive cells in the TNC during the orofacial formalin test. These results indicate that P2X7 receptors may have a role in the modulation of nociception in the trigeminal system.

The use of regression methods for the investigation of trends in suicide rates in Hungary between 1963 and 2011.

PURPOSE: Suicide rates in Hungary have been analyzed from different aspects in recent decades. However, only descriptive rates have been reported. The aim of our epidemiological study was to characterize the pattern of annual rates of suicide in Hungary during the period 1963-2011 by applying advanced statistical methods. METHODS: Annual suicide rates per 100,000 population (>6 years) for gender, age group and suicide method were determined from published frequency tables and reference population data obtained from the Hungarian Central Statistical Office. Trends and relative risks of suicide were investigated using negative binomial regression models overall and in stratified analyses (by gender, age group and suicide method). Joinpoint regression analyses were additionally applied to characterize trends and to find turning points during the period 1963-2011. RESULTS: Overall, 178,323 suicides (50,265 females and 128,058 males) were committed in Hungary during the investigated period. The risk of suicide was higher among males than females overall, in all age groups and for most suicide methods. The annual suicide rate exhibited a significant peak in 1982 and remained basically constant after 2006. Different segmented patterns were observed for the suicide rates in the various age groups. CONCLUSIONS: Suicide rates revealed segmented linear pattern. This is the first detailed trend analysis with risk estimates obtained via joinpoint and negative binomial regression methods simultaneously for age-specific suicide frequencies in Hungary.