Why is UIP peripheral?

INTRODUCTION: The radiology pattern associated with IPF is called UIP. It is unique because unlike any other form of fibrosis it is peripheral in its distribution. We investigated the peripheral nature of UIP and why it was a key feature of IPF the deadliest of the ILDS. AREAS COVERED: It is not enough to say that UIP is peripheral but instead as scientists we must ask ourselves why it is peripheral. This review dives into the published hypothesis that includes vascular insult, tensile forces, microaspiration, and inflammation and looks at the pros and cons for each argument, and ultimately comes to its own conclusion. PubMed searches using the below keywords were used to identify papers that described pathogenesis of IPF with regard to a particular theory. EXPERT OPINION: In this paper, we will review four ideas that support why UIP is peripheral and propose the most likely explanation given what is currently known about the pathophysiology of IPF.

CD36 deficiency reduces chronic BBB dysfunction and scar formation and improves activity, hedonic and memory deficits in ischemic stroke.

Ameliorating blood-brain barrier disruption and altering scar formation dynamics are potential strategies that may improve post-stroke recovery. CD36 is a class B scavenger receptor that plays a role in innate immunity, inflammation and vascular dysfunction and regulates post-stroke injury, neovascularization, reactive astrogliosis and scar formation. By subjecting WT and CD36KO mice to different MCAo occlusion durations to generate comparable acute lesion sizes, we addressed the role of CD36 in BBB dysfunction, scar formation and recovery. The majority of stroke recovery studies primarily focus on motor function. Here, we employed an extensive behavioral test arsenal to evaluate psychological and cognitive endpoints. While not evident during the acute phase, CD36 deficient mice displayed significantly attenuated BBB leakage and scar formation at three months after stroke compared to wild-type littermates. Assessment of motor (open field, rotarod), anxiety (plus maze, light-dark box), depression (forced swim, sucrose preference) and memory tests (water maze) revealed that CD36 deficiency ameliorated stroke-induced behavioral impairments in activity, hedonic responses and spatial learning and strategy switching. Our findings indicate that CD36 contributes to stroke-induced BBB dysfunction and scar formation in an injury-independent manner, as well as to the chronic motor and neurophysiological deficits in chronic stroke.

Maternal neglect results in reduced telomerase activity and increased oxidative load in rats.

A growing number of studies in humans have linked chronic stress, particularly during early life, to telomere shortening and increased oxidative stress. The effect of stress on telomerase activity, however, is understudied. Given the importance of telomere attrition in a wide range of diseases and immunosenescence, further research to elucidate the mechanisms by which stress alters telomere dynamics is required. However, animal studies are lacking, and it is not clear whether widely used stress models reliably mimic the accelerated telomere shortening observed humans. To this end, we evaluated the effect of maternal separation with early weaning (MSEW) on telomere length, telomerase activity, and oxidative load in rats. A total of 45 animals were used, (17 control: 3 males and 11 females and 28 MSEW: 11 males, 17 females), which were then sacrificed one year after birth. Importantly, we determined that telomerase activity measured in plasma was significantly decreased in the MSEW group, along with a non-significant reduction in telomere length from whole blood cells. We also examined the levels of three oxidative markers: plasma malondialdehyde, glutathione in erythrocytes, and plasma catalase activity. Malondialdehyde was found to be elevated in the plasma, indicating increased lipid peroxidation. Interestingly, while the antioxidant glutathione was upregulated, catalase activity remained unchanged. Our findings indicate that the rat MSEW model induces chronic changes to telomere dynamics and oxidative load and can capitulate long term aspects of human childhood stress.

Biennial Upsurge and Molecular Epidemiology of Enterovirus D68 Infection in New York, USA, 2014 to 2018.

Enterovirus D68 (EV-D68) infection has been associated with outbreaks of severe respiratory illness and increased cases of nonpolio acute flaccid myelitis. The patterns of EV-D68 circulation and molecular epidemiology are not fully understood. In this study, nasopharyngeal (NP) specimens collected from patients in the Lower Hudson Valley, New York, from 2014 to 2018 were examined for rhinovirus/enterovirus (RhV/EV) by the FilmArray respiratory panel. Selected RhV/EV-positive NP specimens were analyzed using two EV-D68-specific real-time RT-PCR assays, Sanger sequencing and metatranscriptomic next-generation sequencing. A total of 2,398 NP specimens were examined. EV-D68 was detected in 348 patients with NP specimens collected in 2014 (n = 94), 2015 (n = 0), 2016 (n = 160), 2017 (n = 5), and 2018 (n = 89), demonstrating a biennial upsurge of EV-D68 infection in the study area. Ninety-one complete or nearly complete EV-D68 genome sequences were obtained. Genomic analysis of these EV-D68 strains revealed dynamics and evolution of circulating EV-D68 strains since 2014. The dominant EV-D68 strains causing the 2014 outbreak belonged to subclade B1, with a few belonging to subclade B2. New EV-D68 subclade B3 strains emerged in 2016 and continued in circulation in 2018. Clade D strains that are rarely detected in the United States also arose and spread in 2018. The establishment of distinct viral strains and their variable circulation patterns provide essential information for future surveillance, diagnosis, vaccine development, and prediction of EV-D68-associated disease prevalence and potential outbreaks.

Developmental decrease in parvalbumin-positive neurons precedes increase in flurothyl-induced seizure susceptibility in the Brd2+/- mouse model of juvenile myoclonic epilepsy.

OBJECTIVE: BRD2 is a human gene repeatedly linked to and associated with juvenile myoclonic epilepsy (JME). Here, we define the developmental stage when increased seizure susceptibility first manifests in heterozygous Brd2+/- mice, an animal model of JME. We wanted to determine (1) whether seizure susceptibility correlates with the proven decrease of γ-aminobutyric acidergic (GABAergic) neuron numbers and (2) whether the seizure phenotype can be affected by sex hormones. METHODS: Heterozygous (Brd2+/-) and wild-type (wt) mice of both sexes were tested for flurothyl-induced seizure susceptibility at postnatal day 15 (P15; wt, n = 13; Brd2+/-, n = 20), at P30 (wt, n = 20; Brd2+/-, n = 20), and in adulthood (5-6 months of age; wt, n = 10; Brd2+/-, n = 12). We measured latency to clonic and tonic-clonic seizure onset (flurothyl threshold). We also compared relative density of parvalbumin-positive (PVA+) and GAD67+ GABA neurons in the striatum and primary motor (M1) neocortex of P15 (n = 6-13 mice per subgroup) and P30 (n = 7-10 mice per subgroup) mice. Additional neonatal Brd2+/- mice were injected with testosterone propionate (females) or formestane (males) and challenged with flurothyl at P30. RESULTS: P15 Brd2+/- mice showed no difference in seizure susceptibility compared to P15 wt mice. However, even at this early age, Brd2+/- mice showed fewer PVA+ neurons in the striatum and M1 neocortex. Compared to wt, the striatum in Brd2+/- mice showed an increased proportion of immature PVA+ neurons, with smaller cell bodies and limited dendritic arborization. P30 Brd2+/- mice displayed increased susceptibility to flurothyl-induced clonic seizures compared to wt. Both genotype and sex strongly influenced the density of PVA+ neurons in the striatum. Susceptibility to clonic seizures remained increased in adult Brd2+/- mice, and additionally there was increased susceptibility to tonic-clonic seizures. In P30 females, neonatal testosterone reduced the number of flurothyl-induced clonic seizures. SIGNIFICANCE: A decrease in striatal PVA+ GABAergic neurons developmentally precedes the onset of increased seizure susceptibility and likely contributes to the expression of the syndrome.

An Increase of Excitatory-to-Inhibitory Synaptic Balance in the Contralateral Cortico-Striatal Pathway Underlies Improved Stroke Recovery in BDNF Val66Met SNP Mice.

Despite negative association in cognition and memory, mice harboring Val66Met BDNF SNP (BDNFM/M) exhibit enhanced motor recovery accompanied by elevated excitatory synaptic markers VGLUT1 and VGLUT2 in striatum contralateral to unilateral ischemic stroke. The cortico-striatal pathway is a critical gateway for plasticity of motor/gait function. We hypothesized that enhanced excitability of the cortico-striatal pathway, especially of the contralateral hemisphere, underlies improved motor recovery. To test this hypothesis, we examined the key molecules involving excitatory synaptogenesis: Thrombospondins (TSP1/2) and their neuronal receptor α2δ-1. In WT brains, stroke induced expressions of TSP1/2-mRNA. The contralateral hemisphere of BDNFM/M mice showed heightened TSP2 and α2δ-1 mRNA and protein specifically at 6 months post-stroke. Immunoreactivities of TSPs and α2δ-1 were increased in cortical layers 1/2 of stroked BDNFM/M animals compared with BDNFM/M sham brains at this time. Areal densities of excitatory synapses in cortical layer 1 and striatum were also increased in stroked BDNFM/M brains, relative to stroked WT brains. Notably, the frequency of GABAergic synapses was greatly reduced along distal dendrites in cortical layer 1 in BDNFM/M brains, whether or not stroked, compared with WT brains. There was no effect of genotype or treatment on the density of GABAergic synapses onto striatal medium spiny neurons. The study identified molecular and synaptic substrates in the contralateral hemisphere of BDNFM/M mice, especially in cortical layers 1/2, which indicates selective region-related synaptic plasticity. The study suggests that an increase in excitatory-to-inhibitory synaptic balance along the contralateral cortico-striatal pathway underlies the enhanced functional recovery of BDNFM/M mice.

Peripheral Mechanisms of Remote Ischemic Conditioning.

Ischemic conditioning induces an endogenous protective mechanism that allows organisms to develop resistance to subsequent insults. The conditioning effect occurs across organs and species. Recently, much attention has been given to remote ischemic limb conditioning due to its non-invasive nature and potential therapeutic applications. While tolerance is induced at the primary injury site (e.g. the heart in cardiac ischemia and the brain in stroke), the site of conditioning application is away from the target organ, suggesting the protective factors are extrinsic in nature rather than intrinsic. This review will focus on the peripheral factors that account for the induction of tolerance. Topics of particular interest are blood flow changes, peripheral neural pathways, humoral factors in circulation, and the peripheral immune system. This review will also discuss how conditioning may negatively affect metabolically compromised conditions, its optimal dose, and window for therapy development.

Estradiol does not affect spasms in the betamethasone-NMDA rat model of infantile spasms.

OBJECTIVE: This study attempted to validate the effects of neonatal estradiol in ameliorating the spasms in the prenatally betamethasone-primed N-methyl-d-aspartate (NMDA) model of infantile spasms in rats as shown previously in a mouse Arx gene knock-in expansion model of infantile spasms. METHODS: Neonatal rats prenatally exposed to betamethasone (on day 15 of pregnancy) were treated with subcutaneous 40 ng/g estradiol benzoate (EB) between postnatal days (P)3-P10 or P0-P5. A synthetic estrogen analogue, diethylstilbestrol, was used between P0 and P5 (2 µg per rat, s.c.). On P12, P13, and P15, the rats were subjected to NMDA-triggered spasms, and latency to onset and number of spasms were evaluated. Rats with EB on P3-P10 were tested after spasms in the open field, novel object recognition, and elevated plus maze to determine effects of treatment on behavior. Additional rats with P3-P10 or P0-P5 EB were investigated for γ-aminobutyric acid (GABA)ergic neurons (glutamate decarboxylase [GAD]67 expression) in the neocortex. As a positive control, a group of rats received either subcutaneous adrenocorticotropic hormone (ACTH) (2 × 0.3 mg/kg on P12 and 3 × 0.3 mg/kg on P13 and P14) or vehicle after the first episode of spasms on P12. RESULTS: Neither EB treatment nor diethylstilbestrol consistently affected expression of spasms in this model, although we found a significant increase in GAD67-immunopositive cells in the neocortex after P3-P10 and P0-P5 EB treatment, consistent with a study in mice. Behavioral tests showed increase in lateralization in male rats treated with P3-P10 EB, a behavioral trait usually associated with female sex. Diethylstilbestrol treatment in male rats resulted in arrested pubertal descent of testes. ACTH had robust effects in suppressing spasms. SIGNIFICANCE: Treatment of infantile spasms (IS) using neonatal EB may be justified in those cases of IS that present with detectable deficits in GABAergic neurons. In other types of IS, the efficacy of neonatal EB and its analogues is not supported.