Male-biased vulnerability of mouse brain tryptophan/kynurenine and glutamate systems to adolescent exposures to concentrated ambient ultrafine particle air pollution.

Air pollution (AP) exposures have been associated with numerous neurodevelopmental and psychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia, all male-biased disorders with onsets from early life to late adolescence/early adulthood. While prior experimental studies have focused on effects of AP exposures during early brain development, brain development actually extends well into early adulthood. The current study in mice sought to extend the understanding of developmental brain vulnerability during adolescence, a later but significant period of brain development and maturation to the ultrafine particulate (UFPs) component of AP, considered its most reactive component. Additionally, it examined adolescent response to UFPs when preceded by earlier developmental exposures, to ascertain the trajectory of effects and potential enhancement or mitigation of adverse consequences. Outcomes focused on shared features associated with multiple neurodevelopmental disorders. For this purpose, C57Bl/6 J mice of both sexes were exposed to ambient concentrated UFPs or filtered air from PND (postnatal day) 4-7 and PND10-13, and again at PND39-42 and 45-49, resulting in 3 exposure postnatal/adolescent treatment groups per sex: Air/Air, Air/UFP, and UFP/UFP. Features common to neurodevelopmental disorders were examined at PND50. Mass exposure concentration from postnatal exposure averaged 44.34 µg/m3 and the adolescent exposure averaged 49.18 µg/m3. Male brain showed particular vulnerability to UFP exposures in adolescence, with alterations in frontal cortical and striatal glutamatergic and tryptophan/serotonergic neurotransmitters and concurrent reductions in levels of astrocytes in corpus callosum and in serum cytokine levels, with combined exposures resulting in significant reductions in corpus callosum myelination and serum corticosterone. Reductions in serum corticosterone in males correlated with reductions in neurotransmitter levels, and reductions in striatal glutamatergic function specifically correlated with reductions in corpus callosum astrocytes. UFP-induced changes in neurotransmitter levels in males were mitigated by prior postnatal exposure, suggesting potential adaptation, whereas reductions in corticosterone and in corpus callosum neuropathological effects were further strengthened by combined postnatal and adolescent exposures. UFP-induced changes in females occurred primarily in striatal dopamine systems and as reductions in serum cytokines only in response to combined postnatal and adolescent exposures. Findings in males underscore the importance of more integrated physiological assessments of mechanisms of neurotoxicity. Further, these findings provide biological plausibility for an accumulating epidemiologic literature linking air pollution to neurodevelopmental and psychiatric disorders. As such, they support a need for consideration of the regulation of the UFP component of air pollution.

A behavioral timing intervention upregulates striatal serotonergic markers and reduces impulsive action in adult male mice.

Many studies support the hypothesis that time-based interventions reduce impulsive behavior in rodents. However, few studies have directly assessed 1) how such interventions affect impulsive action rather than impulsive choice, 2) if intervention effects differ by sex, and 3) how time-based interventions affect neurochemistry in regions mediating decision-making and reward. Thus, we assessed how a fixed-interval (FI) intervention initiated during late adolescence and extending into adulthood affected dopaminergic and serotonergic analytes in the frontal cortex and striatum and subsequent impulsive action in adult male and female mice. Beginning on postnatal day (PND) 45, mice were either trained on a progressive series of FI schedules (FI 20, 40, & 60 s) or remained in the home cage. Following the intervention, increases in striatal serotonergic analytes were found in FI-exposed males and females (n = 8/sex/group) with few changes found in the frontal cortex. Impulsive action was assessed in the remaining mice (n = 10/sex/group) using a fixed-ratio waiting-for-reward (FR-wait) task in which completion of an FR-25 component initiated a "free" pellet component in which pellets were delivered at increasing intervals according to a fixed delay increment that varied across sessions. Responses reset the additive delay and initiated a new FR-25 component. FI-exposed males, but not females, showed fewer delay resets and no-wait resets relative to control mice. Importantly, FI-exposure did not affect discrimination reversal performance in either sex. These data suggest that time-based interventions may reduce impulsive action in addition to impulsive choice perhaps with increased male sensitivity. Additionally, time-based interventions appear to operate through striatal serotonergic augmentation.

Neonatal exposure to ultrafine iron but not combined iron and sulfur aerosols recapitulates air pollution-induced impulsivity in mice.

Air pollution (AP) is becoming recognized as a major threat to neurological health across the lifespan with increased risk of both neurodevelopmental and neurodegenerative disorders. AP is a complex mixture of gases and particulate matter, with adsorbed contaminants including metals and trace elements, which may differentially contribute to its neurodevelopmental impacts. Iron (Fe) is one of the most abundant metals found in AP, and Fe concentrations may drive some behavioral deficits observed in children. Furthermore, brains of neonate mice exposed to concentrated ambient ultrafine particulate matter (UFP) show significant brain accumulation of Fe and sulfur (S) supporting the hypothesis that AP exposure may lead to brain metal dyshomeostasis. The current study determined the extent to which behavioral effects of UFP, namely memory deficits and impulsive-like behavior, could be recapitulated with exposure to Fe aerosols with or without concomitant SO2. Male and female neonate mice were either exposed to filtered air or spark discharge-generated ultrafine Fe particles with or without SO2 gas (n = 12/exposure/sex). Inhalation exposures occurred from postnatal day (PND) 4-7 and 10-13 for 4 hr/day, mirroring our previous UFP exposures. Mice were aged to adulthood prior to behavioral testing. While Fe or Fe + SO2 exposure did not affect gross locomotor behavior, Fe + SO2-exposed females displayed consistent thigmotaxis during locomotor testing. Neither exposure affected novel object memory. Fe or Fe + SO2 exposure produced differential outcomes on a fixed-interval reinforcement schedule with males showing higher (Fe-only) or lower (Fe + SO2) response rates and postreinforcement pauses (PRP) and females showing higher (Fe-only) PRP. Lastly, Fe-exposed, but not Fe + SO2-exposed, males showed increased impulsive-like behavior in tasks requiring response inhibition with no such effects in female mice. These findings suggest that: 1) exposure to realistic concentrations of Fe aerosols can recapitulate behavioral effects of UFP exposure, 2) the presence of SO2 can modulate behavioral effects of Fe inhalation, and 3) brain metal dyshomeostasis may be an important factor in AP neurotoxicity.

Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction.

Developmental exposures to ambient ultrafine particles (UFPs) can produce multiple neuropathological and neurochemical changes that might contribute to persistent alterations in cognitive-type functions. The objective of the current study was to test the hypothesis that developmental UFP exposure produced impairments in learning, memory and impulsive-like behaviors and to determine whether these were selective and thus independent of deficits in other behavioral domains such as motor activity or motivation. Performance on measures of learning (repeated learning), memory (novel object recognition, NOR), impulsive-like behavior (differential reinforcement of low rate (DRL), schedule of reward and delay of reward (DOR)), motor activity (locomotor behavior) and motivation (progressive ratio schedule) were examined in adult mice that had been exposed to concentrated (10-20x) ambient ultrafine particles (CAPS) averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4 h/day. Given the number of behavioral tests, animals were tested in different groups. Results showed male-specific alterations in learning and memory functions (repeated learning, NOR and DRL) specifically during transitions in reinforcement contingencies (changes in rules governing behavior) that did not appear to be related to alterations in locomotor function or motivation. Females did not exhibit cognitive-like deficits at these exposure concentrations, but displayed behaviors consistent with altered motivation, including increases in response rates during repeated learning, significantly increased latencies to respond on the delay of reward paradigm, and reductions in the progressive ratio break point. Consistent with our prior findings, male-specific learning and memory-related deficits were seen and occurred even at relatively low level developmental UFP exposures, while females show alterations in motivational behaviors but not final performance. These findings add to the evidence suggesting the need to regulate UFP levels.

Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood.

Developmental exposure to prenatal stress (PS) and lead (Pb) can affect brain development and adversely influence behavior and cognition. Epigenetic-based gene regulation is crucial for normal brain development and mis-regulation, in any form, can result in neurodevelopmental disorders. Post-translational histone modifications (PTHMs) are an integral and dynamic component of the epigenetic machinery involved in gene regulation. Exposures to Pb and/or PS may alter PTHM profiles, promoting lifelong alterations in brain function observed following Pb±PS exposure. Here we examined the effects of Pb±PS on global levels of activating marks H3K9Ac and H3K4Me3 and repressive marks H3K9Me2 and H3K27Me3 at different developmental stages: E18, PND0, PND6 and PND60. Dams were exposed to 0 or 100ppm Pb beginning 2 months prior to breeding followed by no PS (NS) or PS resulting in 4 offspring treatment groups per sex: 0-NS (control), 0-PS, 100-NS and 100-PS. Global levels of PTHMs varied from E18 through adulthood even in control mice, and were influenced by sex and brain-region. The developmental trajectory of these PTHM levels was further modified by Pb±PS in a sex-, brain region- and age-dependent manner. Females showed a preferential response to Pb alone in frontal cortex (FC) and differentially to PS alone and combined Pb+PS in hippocampus (HIPP). In males, PS-induced increases in PTHM levels in FC, whereas PS produced reductions in HIPP. Pb±PS-based changes in PTHM levels continued to be observed in adulthood (PND60), demonstrating the lasting effect of these early life environmental events on these histone marks. These results indicate that epigenetic consequences of Pb±PS and their contribution to mechanisms of toxicity are sex dependent. Additional studies will assist in understanding the functional significance of these changes in PTHM levels on expression of individual genes, functional pathways, and ultimately, their behavioral consequences.

Cognitive Effects of Air Pollution Exposures and Potential Mechanistic Underpinnings.

PURPOSE OF REVIEW: This review sought to address the potential for air pollutants to impair cognition and mechanisms by which that might occur. RECENT FINDINGS: Air pollution has been associated with deficits in cognitive functions across a wide range of epidemiological studies, both with developmental and adult exposures. Studies in animal models are significantly more limited in number, with somewhat inconsistent findings to date for measures of learning, but show more consistent impairments for short-term memory. Potential contributory mechanisms include oxidative stress/inflammation, altered levels of dopamine and/or glutamate, and changes in synaptic plasticity/structure. Epidemiological studies are consistent with adverse effects of air pollutants on cognition, but additional studies and better phenotypic characterization are needed for animal models, including more precise delineation of specific components of cognition that are affected, as well as definitions of critical exposure periods for such effects and the components of air pollution responsible. This would permit development of more circumscribed hypotheses as to potential behavioral and neurobiological mechanisms.

Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders.

Accumulating evidence from both human and animal studies show that brain is a target of air pollution. Multiple epidemiological studies have now linked components of air pollution to diagnosis of autism spectrum disorder (ASD), a linkage with plausibility based on the shared mechanisms of inflammation. Additional plausibility appears to be provided by findings from our studies in mice of exposures from postnatal day (PND) 4-7 and 10-13 (human 3rd trimester equivalent), to concentrated ambient ultrafine (UFP) particles, considered the most reactive component of air pollution, at levels consistent with high traffic areas of major U.S. cities and thus highly relevant to human exposures. These exposures, occurring during a period of marked neuro- and gliogenesis, unexpectedly produced a pattern of developmental neurotoxicity notably similar to multiple hypothesized mechanistic underpinnings of ASD, including its greater impact in males. UFP exposures induced inflammation/microglial activation, reductions in size of the corpus callosum (CC) and associated hypomyelination, aberrant white matter development and/or structural integrity with ventriculomegaly (VM), elevated glutamate and excitatory/inhibitory imbalance, increased amygdala astrocytic activation, and repetitive and impulsive behaviors. Collectively, these findings suggest the human 3rd trimester equivalent as a period of potential vulnerability to neurodevelopmental toxicity to UFP, particularly in males, and point to the possibility that UFP air pollution exposure during periods of rapid neuro- and gliogenesis may be a risk factor not only for ASD, but also for other neurodevelopmental disorders that share features with ASD, such as schizophrenia, attention deficit disorder, and periventricular leukomalacia.

Spline modelling electron insert factors using routine measurements.

There are many methods available to predict electron output factors; however, many centres still measure the factors for each irregular electron field. Creating an electron output factor prediction model that approaches measurement accuracy--but uses already available data and is simple to implement--would be advantageous in the clinical setting. This work presents an empirical spline model for output factor prediction that requires only the measured factors for arbitrary insert shapes. Equivalent ellipses of the insert shapes are determined and then parameterised by width and ratio of perimeter to area. This takes into account changes in lateral scatter, bremsstrahlung produced in the insert material, and scatter from the edge of the insert. Agreement between prediction and measurement for the 12 MeV validation data had an uncertainty of 0.4% (1SD). The maximum recorded deviation between measurement and prediction over the range of energies was 1.0%. The validation methodology showed that one may expect an approximate uncertainty of 0.5% (1SD) when as little as eight data points are used. The level of accuracy combined with the ease with which this model can be generated demonstrates its suitability for clinical use. Implementation of this method is freely available for download at https://github.com/SimonBiggs/electronfactors.

The dosimetry of eye shields for kilovoltage X-ray beams.

The objective of this work was to evaluate the dosimetry of tungsten eye shields for use with kilovoltage X-ray beam treatments. The eye shields, originally designed for megavoltage electron beams, were made of 2 mm tungsten thickness and inside diameters of 11.6 and 15.0 mm with optional aluminium caps of 0.5 and 1 mm thickness. The relative dosimetry of the eye shields were examined by measurement of transmission doses with full scatter conditions, central axis depth doses and beam profiles underneath the eye shield. The X-ray beams used in this study ranged in energy from 50 to 280 kVp. Transmission measurements were performed using an Advanced Markus ionisation chamber located at the surface of an RMI457 Solid Water phantom with a 3 cm diameter applicator flush against the phantom surface. Depth doses and profiles measurements were performed in a PTW MP3 scanning water tank with a PTW diamond detector. Results for transmission doses for the medium size eye shield increased from 1 to 22 % for 50-280 kVp while for the smaller eye shield the percentage dose increased from 3.5 to 30 % for the same energy range. There were minimal differences between using the 0.5 and 1 mm aluminium caps. Central axis depth doses measured with and without the eye shields demonstrated the 125 and 180 kVp beams had higher peak doses behind the eye shields. These results show that these tungsten eye shields are suitable for use with kilovoltage X-ray beams. However, the clinical impact needs to be considered for the higher X-ray beam energies.

[Fine needle biopsy in diagnosis of lung tumors]. / Biopsja cienkoiglowa w diagnostyce guzów pluc.

Fine-needle biopsy is one of the method used in diagnosis of lung tumors. In this study the results of 192 biopsies performed by x-ray apparatus inspection were analysed. There was shown that lung cancer was recognized in over 50% of patients studied. In another cases non-specific inflammation (31%), lung fibrosis (1%), tuberculosis (1%), purulent inflammation (1%), blood (7%) were recognized. These results indicate for usefulness of this method in diagnosis of not only peripheral, but also central localized lung tumors.

[Role of oxygen free radicals in the pathogenesis of lung diseases]. / Rola wolnych rodników tlenowych w patogenezie chorób pluc.

The authors have tried to compose the characteristics of the free radicals and their role in the pathogenesis od various diseases. They show up both the ways the free radicals appear and the biochemical compounds negating their toxic effects. They stress the meaning of the dynamic equilibrium between them, and asses its value in the lung cancer pathogenesis. They also quote the examples of the medicines, which work towards neutralizing the free radicals.

Absolute Spatially- and Temporally-Resolved Optical Emission Measurements of rf Glow Discharges in Argon.

Spatially- and temporally-resolved measurements of optical emission intensities are presented from rf discharges in argon over a wide range of pressures (6.7 to 133 Pa) and applied rf voltages (75 to 200 V). Results of measurements of emission intensities are presented for both an atomic transition (Ar I, 750.4 nm) and an ionic transition (Ar II, 434.8 nm). The absolute scale of these optical emissions has been determined by comparison with the optical emission from a calibrated standard lamp. All measurements were made in a well-defined rf reactor. They provide detailed characterization of local time-resolved plasma conditions suitable for the comparison with results from other experiments and theoretical models. These measurements represent a new level of detail in diagnostic measurements of rf plasmas, and provide insight into the electron transport properties of rf discharges.