Less impact than suspected: Dietary exposure of three-spined sticklebacks to microplastic fibers does not affect their body condition and immune parameters.

Microplastic fibers are frequent anthropogenic contaminants in most aquatic environments and have consequently been detected in the digestive tract of many fish species. Upon ingestion, microplastic fibers pose risks of interference with nutrient uptake, impaired intestinal health, and as a consequence may alter growth performance and fitness. In addition, foreign particles such as fibers might cause tissue irritations and stress, and thus interfere with immune parameters. In nature, fish regularly encounter microplastic fibers as well as fiber debris from natural sources and materials. Thus, we wanted to test the potential impact of microplastic fibers on growth, organosomatic indices, and immune parameters of subadult fish and compare these to possible effects caused by natural fibers. We administered sticklebacks diets, which were supplemented with either polyester or cotton fibers (each at concentrations of 0.2 mg/g and 2 mg/g feed) or a control diet without fiber supplementation for nine weeks. Mortalities did not occur and sticklebacks grew equally well across treatments. Neither organosomatic indices nor immune parameters revealed significant differences between treatments. While natural differences between males and females were observed for some parameters, no treatment-related gender-specific effects were detected. Our results suggest that the dietary uptake of polyester fibers does not affect growth, body condition, gonad development, and immunity of sticklebacks - even at fiber concentrations higher than what can be encountered in the wild. Furthermore, virgin microplastic fibers do not seem to affect fish differently than fibers from natural origin. The present study implies that at least some species are resilient towards pollution with (virgin) microplastic fibers even at high concentrations.

Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury.

OBJECTIVE: Abnormal myelination is a major pathological sequela of chronic periventricular white matter injury in survivors of premature birth. We tested the hypothesis that myelination failure in chronic hypoxia-ischemia-induced periventricular white matter injury is related to persistent depletion of the oligodendrocyte (OL) precursor pool required to generate mature myelinating OLs. METHODS: A neonatal rat model of hypoxia-ischemia was used where acute degeneration of late OL progenitors (preOLs) occurs via a mostly caspase-independent mechanism. The fate of OL lineage cells in chronic cerebral lesions was defined with OL lineage-specific markers. RESULTS: Acute caspase-3-independent preOL degeneration from hypoxia-ischemia was significantly augmented by delayed preOL death that was caspase-3-dependent. Degeneration of preOLs was offset by a robust regenerative response that resulted in a several-fold expansion in the pool of surviving preOLs in chronic lesions. However, these preOLs displayed persistent maturation arrest with failure to differentiate and generate myelin. When preOL-rich chronic lesions sustained recurrent hypoxia-ischemia at a time in development when white matter is normally resistant to injury, an approximately 10-fold increase in caspase-dependent preOL degeneration occurred relative to lesions caused by a single episode of hypoxia-ischemia. INTERPRETATION: The mechanism of myelination failure in chronic white matter lesions is related to a combination of delayed preOL degeneration and preOL maturation arrest. The persistence of a susceptible population of preOLs renders chronic white matter lesions markedly more vulnerable to recurrent hypoxia-ischemia. These data suggest that preOL maturation arrest may predispose to more severe white matter injury in preterm survivors that sustain recurrent hypoxia-ischemia.

Cerebral blood flow heterogeneity in preterm sheep: lack of physiologic support for vascular boundary zones in fetal cerebral white matter.

Periventricular white matter (PVWM) injury is the leading cause of neurologic disability in survivors of prematurity. To address the role of ischemia in PVWM and cerebral cortical injury, we hypothesized that immaturity of spatially distal vascular 'end zones' or 'border zones' predisposes PVWM to greater decreases in cerebral blood flow (CBF) than more proximal structures. We quantified regional CBF with fluorescently labeled microspheres in 0.65 gestation fetal sheep in histopathologically defined three-dimensional regions by post hoc digital dissection and coregistration algorithms. Basal flow in PVWM was significantly lower than in gyral white matter and cortex, but was equivalent in superficial, middle, and deep PVWM. Absolute and relative CBF (expressed as percentage of basal) did not differ significantly during ischemia or reperfusion between PVWM, gyral white matter, or cortex. Moreover, CBF during ischemia-reperfusion was equivalent in three adjacent PVWM levels and was not consistent with the magnitude of severity of PVWM injury, defined by TUNEL (terminal deoxynucleotidyltransferase-mediated dUPT nick end labeling) staining. However, the magnitude of ischemia was predicted by the severity of discrete cortical lesions. Hence, unlike cerebral cortex, unique CBF disturbances did not account for the distribution of PVWM injury. Previously defined cellular maturational factors, thus, appear to have a greater influence on PVWM vulnerability to ischemic injury than the presence of immature vascular boundary zones.

Maturation-dependent vulnerability of perinatal white matter in premature birth.

Survivors of premature birth have a predilection for perinatal brain injury, especially to periventricular cerebral white matter. Periventricular white matter injury (PWMI) is now the most common cause of brain injury in preterm infants and the leading cause of chronic neurological morbidity. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia) and diffuse myelination disturbances. Recent neuroimaging studies support that the incidence of periventricular leukomalacia is declining, whereas focal or diffuse noncystic injury is emerging as the predominant lesion. In a significant number of infants, PWMI appears to be initiated by perturbations in cerebral blood flow that reflect anatomic and physiological immaturity of the vasculature. Ischemic cerebral white matter is susceptible to pronounced free radical-mediated injury that particularly targets immature stages of the oligodendrocyte lineage. Emerging experimental data supports that pronounced ischemia in the periventricular white matter is necessary but not sufficient to generate the initial injury that leads to PWMI. The developmental predilection for PWMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible oligodendrocyte progenitors. Injury to oligodendrocyte progenitors may contribute to the pathogenesis of PWMI by disrupting the maturation of myelin-forming oligodendrocytes. There has been substantial recent progress in the understanding of the cellular and molecular pathogenesis of PWMI. The oligodendrocyte progenitor is a key target for preventive strategies to reduce ischemic cerebral white matter injury in premature infants.

Auditory processing and learning/memory following erythropoietin administration in neonatally hypoxic-ischemic injured rats.

BACKGROUND: Hypoxia-ischemia (HI) is a common injury arising from prematurity/complications at birth and is associated with later language, auditory, and learning impairments. OBJECTIVE: To investigate the efficacy of two doses (300 or 1000 U/kg) of Erythropoietin (Epo) in protecting against neuropathological and behavioral impairments associated with HI injury in rats. METHODS: HI injury (right carotid artery cauterization and 120 min of 8% O(2)) was induced on postnatal day 7 (P7) and Epo or saline was administered i.p. immediately following the procedure. Auditory processing and learning/memory were assessed throughout development. RESULTS: Both doses of Epo provided behavioral protection following HI injury. Rats given 300 or 1000 U/kg of Epo performed significantly better than HI animals on a short duration complex auditory processing procedure, on a spatial Morris water maze assessing spatial learning/reference memory, and a non-spatial water maze assessing associative learning/reference memory. CONCLUSIONS: Given Epo's extant clinical use (FDA approved for pediatric patients with anemia secondary to prematurity), the current results add to a growing body of literature supporting the use of Epo as a potential protective agent for neurological and behavioral impairments following early HI injury in infants.

Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1.

Developmental malformations of cortex have been shown to co-occur with language, learning, and other cognitive deficits in humans. Rodent models have repeatedly shown that animals with such developmental malformations have deficits related to auditory processing and learning. More specifically, freeze-lesion induced microgyria as well as molecular layer ectopias have been found to impair rapid auditory processing ability in rats and mice. In humans, deficits in rapid auditory processing appear to relate to later impairments of language. Recently, genetic variants of four different genes involved in early brain development have been proposed to associate with an elevated incidence of developmental dyslexia in humans. Three of these, DYX1C1, DCDC2, and KIAA0319, have been shown by in utero RNAi to play a role in neuronal migration in developing neocortex. The present study assessed the effects of in utero RNAi of Dyx1c1 on auditory processing and spatial learning in rats. Results indicate that RNAi of Dyx1c1 is associated with cortical heterotopia and is suggestive of an overall processing deficit of complex auditory stimuli in both juvenile and adult periods (p=.051, one-tail). In contrast, adult data alone reveal a significant processing impairment among RNAi treated subjects compared to shams, indicating an inability for RNAi treated subjects to improve detection of complex auditory stimuli over time (p=.022, one-tail). Further, a subset of RNAi treated rats exhibited hippocampal heterotopia centered in CA1 (in addition to cortical malformations). Malformations of hippocampus were associated with robust spatial learning impairment in this sub-group (p<.01, two-tail). In conclusion, in utero RNAi of Dyx1c1 results in heterogeneous malformations that correspond to distinct behavioral impairments in auditory processing, and spatial learning.

Effect of an Automated Tracking Registry on the Rate of Tracking Failure in Incidental Pulmonary Nodules.

OBJECTIVE: Following incidental lung nodules with interval CT scanning is an accepted method to detect early lung cancer, but delayed tracking or failure to track is reported in up to 40% of patients. METHODS: Our institution developed and implemented an automated lung nodule registry tracking system. This system uses a code at the time that a suspicious nodule is discovered to populate the registry. Suspicious nodules were defined as any nodule, solid or ground glass, <3 cm that the radiologist recorded as a potential malignancy or recommended for follow-up imaging. We exported the system to eight other Veterans Administration Medical Centers (VAMCs) with over 10,000 patients enrolled. We retrospectively reviewed 200 sequential CT scan reports containing incidental nodule(s) from two tertiary care university-affiliated VAMCs, both before and after the implementation of the registry tracking system. The primary outcome was the rate of tracking failure, defined as suspicious nodules that had no follow-up imaging or whose follow-up was delayed when compared with published guidelines. Secondary outcomes were predictors of tracking failure and reasons for tracking failure. RESULTS: After implementation of the registry tracking system in the two VAMCs, we found a significant decrease in tracking failure, from a preimplementation rate of 74% to a postimplementation rate of 10% (P < .001). We found that age, nodule size, number, and nodule characteristics were significant predictors. CONCLUSIONS: The automated lung nodule registry tracking system can be exported to other health care facilities and significantly reduces the rate of tracking failure.

Rapid auditory processing and learning deficits in rats with P1 versus P7 neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits (i.e., impairment in the ability to discriminate rapidly changing acoustic signals), play a causal role in language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal days 1, 7, or 10 (P1, P7, or P10. While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide sufficient power to detect age-at-injury differences within the pooled HI group. The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury on P1 versus P7 in rats. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling age-related differences in premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but deficits in the P1 HI group resolved with repeated testing (compared to shams), while P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 versus P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan.

The effects of erythropoietin on auditory processing following neonatal hypoxic-ischemic injury.

Neonatal hypoxia-ischemia (HI) is a common cause of brain damage and subsequent behavioral deficits in premature/term infants. Rapid auditory processing deficits have been suggested to play a role in later language impairments in this population. We have previously shown auditory deficits in rats with neonatal HI injury and now report novel effects of behavioral sparing and neuroprotection following treatment with a low dose of Erythropoietin using this HI injury model.

Developmental timeframes for induction of microgyria and rapid auditory processing deficits in the rat.

Induction of a focal freeze lesion to the skullcap of a 1-day-old rat pup leads to the formation of microgyria similar to those identified postmortem in human dyslexics. Rats with microgyria exhibit rapid auditory processing deficits similar to those seen in language-impaired (LI) children, and infants at risk for LI and these effects are particularly marked in juvenile as compared to adult subjects. In the current study, a startle response paradigm was used to investigate gap detection in juvenile and adult rats that received bilateral freezing lesions or sham surgery on postnatal day (P) 1, 3 or 5. Microgyria were confirmed in P1 and 3 lesion rats, but not in the P5 lesion group. We found a significant reduction in brain weight and neocortical volume in P1 and 3 lesioned brains relative to shams. Juvenile (P27-39) behavioral data indicated significant rapid auditory processing deficits in all three lesion groups as compared to sham subjects, while adult (P60+) data revealed a persistent disparity only between P1-lesioned rats and shams. Combined results suggest that generalized pathology affecting neocortical development is responsible for the presence of rapid auditory processing deficits, rather than factors specific to the formation of microgyria per se. Finally, results show that the window for the induction of rapid auditory processing deficits through disruption of neurodevelopment appears to extend beyond the endpoint for cortical neuronal migration, although, the persistent deficits exhibited by P1 lesion subjects suggest a secondary neurodevelopmental window at the time of cortical neuromigration representing a peak period of vulnerability.

RETRACTED: Direct imaging discovery of a Jovian exoplanet within a triple-star system.

Direct imaging allows for the detection and characterization of exoplanets via their thermal emission. We report the discovery via imaging of a young Jovian planet in a triple-star system and characterize its atmospheric properties through near-infrared spectroscopy. The semimajor axis of the planet is closer relative to that of its hierarchical triple-star system than for any known exoplanet within a stellar binary or triple, making HD 131399 dynamically unlike any other known system. The location of HD 131399Ab on a wide orbit in a triple system demonstrates that massive planets may be found on long and possibly unstable orbits in multistar systems. HD 131399Ab is one of the lowest mass (4 ± 1 Jupiter masses) and coldest (850 ± 50 kelvin) exoplanets to have been directly imaged.

Auditory processing deficits in unilaterally and bilaterally injured hypoxic-ischemic rats.

Hypoxic-ischemic represents a common cause of damage to the prenatal brain and can co-occur with prematurity. Prematurity is associated with emergent language impairments, and it has been suggested that rapid auditory processing deficits play a causal role in language difficulties. We previously demonstrated rapid auditory processing deficits in juvenile rats receiving neonatal unilateral hypoxic-ischemic injury, but these deficits appeared to resolve by adulthood. The current study compared unilaterally and bilaterally injured hypoxic-ischemic rats on auditory tasks, to assess whether rapid auditory processing recovery in adulthood is related to this aspect of injury. Current results indicate that while neonatal unilateral and bilateral hypoxic-ischemic injury both lead to rapid auditory processing deficits in the juvenile period, only rats with bilateral hypoxic-ischemic injury exhibit deficits that persist into adulthood.

Auditory processing deficits in rats with neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) refers to reduced blood oxygenation and/or a diminished amount of blood perfusing the brain, and is associated with premature birth/very low birth weight (VLBW). HI represents a common cause of injury to the perinatal brain. Indeed, a significant number of premature/VLBW infants go on to demonstrate cognitive/behavioral deficits, with particularly high incidence of disruptions in language development. Auditory processing deficits, in turn, have been suggested to play a causal role in the development of language impairments. Specifically, the inability to identify fast elements in speech is purported to exert cascading detrimental effects on phonological discrimination, processing, and identification. Based on this convergent evidence, the current studies address auditory processing evaluation in a rodent model of HI injury induced on postnatal days 1, 7, or 10 (which in turn is well accepted as modeling HI-related injury to the perinatal human). Induced injuries were followed by a battery of auditory testing, and a spatial maze assessment, performed both during juvenile and adult periods. Results indicate that rats suffering from these early HI insults performed significantly worse than shams on tasks requiring rapid auditory processing, and on a test of spatial learning (Morris water maze (MWM)), although these effects were not seen on simpler versions of auditory tasks or on a water escape assessment (thus ruling out hearing/motor impairments). Correlations were found between performance on rapid auditory and spatial behavioral tasks and neuroanatomical measures for HI animals such as: the volume of the hippocampus, cerebral cortex, ventricles, and/or the area of the corpus callosum. Cumulative findings suggest that perinatal HI injury in the rat may lead to neurodevelopmental damage associated, in turn, with auditory processing and/or learning and memory impairments. As such, the current model may have critical implications for the study of neurophysiological underpinnings of cognitive deficits in premature/VLBW infants.

Severity of focal microgyria and associated rapid auditory processing deficits.

Data from rodent models of induced microgyria suggest that bilateral damage leads to more severe rapid auditory processing deficits than unilateral damage. It is unclear whether this reflects the degree, or bilateral/unilateral nature, of damage. The current study evaluates the effects of microgyric severity by assessing rats with single- vs double-pair bilateral focal microgyric lesions, using auditory discrimination and MGN measures. Behavioral data show a significant auditory processing deficit on rapid processing tasks for microgyric as compared to control subjects, and also reveal more severe deficits for double- than for single-pair bilateral microgyrics. Greater disruptions are also seen in the MGN of double-pair compared to single-pair bilateral microgyric subjects.

Timing of appearance of late oligodendrocyte progenitors coincides with enhanced susceptibility of preterm rabbit cerebral white matter to hypoxia-ischemia.

Emerging evidence supports that premature infants are susceptible to both cerebral white and gray matter injury. In a fetal rabbit model of placental insufficiency, preterm rabbits at embryonic day 22 (E22) exhibited histologic evidence of gray matter injury but minimal white matter injury after global hypoxia-ischemia (H-I). We hypothesized that the dissociation between susceptibility to gray and white matter injury at E22 was related to the timing of appearance of late oligodendrocyte progenitors (preOLs) that are particularly vulnerable in preterm human white matter lesions. During normal rabbit oligodendrocyte (OL) lineage progression, early OL progenitors predominated at E22. PreOL density increased between E24 and E25 in major forebrain white matter tracts. After H-I at E22 and E25, we observed a similar magnitude of cerebral H-I, assessed by cortical microvascular blood flow, and gray matter injury, assessed by caspase activation. However, the increased preOL density at E25 was accompanied by a significant increase in acute white matter injury after H-I that coincided with enhanced preOL degeneration. At E29, significant white matter atrophy developed after H-I at E25 but not E22. Thus, the timing of appearance of preOLs coincided with onset of a developmental window of enhanced white but not gray matter susceptibility to H-I.

Use of a modified prepulse inhibition paradigm to assess complex auditory discrimination in rodents.

Prepulse inhibition (PPI; also termed startle reduction or reflex modification, see Ref. [H.S. Hoffman, J.R. Ison, Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input, Psychol. Rev. 87 (1980) 175-189]) provides an efficient and accurate method to assess both simple and complex acoustic discrimination in rodents [J.R. Ison, G.R. Hammond, Modification of the startle reflex in the rat by changes in the auditory and visual environments, J. Comp. Physiol. Psychol. 75 (1971) 435-452]. Assessment of acoustic processing using PPI is less time consuming than operant conditioning paradigms, allows for the testing of many subjects simultaneously, and largely eliminates confounds due to motivation and attention [M. Clark, G. Rosen, P. Tallal, R.H. Fitch, Impaired processing of complex auditory stimuli in rats with induced cerebrocortical microgyria, J. Cog. Neurosci. 12 (2000) 828-839]. Moreover, PPI procedures allow for data acquisition from the first day of testing, and can be used on rats as young as P14-15 [J.T. Friedman, A. Peiffer, M. Clark, A. Benasich, R.H. Fitch, Age and experience related improvements in gap detection in the rat, Dev. Brain Res. 152 (2004) 83-91; M. McClure, S. Threlkeld, G. Rosen, R.H. Fitch, Rapid auditory processing and learning deficits in rats with P1 versus P7 neonatal hypoxic-ischemic injury, Behav. Brain Res. 172 (2006) 114-121; S.W. Threlkeld, M.M. McClure, G.D. Rosen, R.H. Fitch, Developmental timeframes for the induction of microgyria and rapid auditory processing deficits in the rat, Brain Res. 1109 (2006) 22-31]. For these and additional reasons, the PPI paradigm has more recently been adapted to the assessment of complex acoustic discrimination (tone sequences and FM sweeps), and applied to the study of normally developing as well as neuropathologically affected rodent populations. The purpose of the current review is to provide a background on the PPI paradigm, and to summarize what has been learned more recently using modified versions of PPI with rodent models.