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BackgroundPatients with mild degenerative cervical myelopathy (DCM) are often managed non-operatively, and surgery is recommended if neurological progression occurs. However, detection of progression is often subjective. Quantitative MRI (qMRI) directly measures spinal cord (SC) tissue changes, detecting axonal injury, demyelination, and atrophy. This longitudinal study compared multiparametric qMRI with clinical measures of progression in non-operative DCM patients.Methods26 DCM patients were followed. Clinical data included modified Japanese Orthopedic Association (mJOA) and additional assessments. 3T qMRI data included cross sectional area, diffusion fractional anisotropy, magnetization transfer ratio, and T2*-weighted white/grey matter signal ratio, extracted from the compressed SC and above/below. Progression was defined as 1) patients' subjective impression, 2) 2-point mJOA decrease, 3) ≥3 clinical measures worsening ≥5%, 4) increased compression on MRI, or 5) ≥1 of 10 qMRI measures or composite score worsening (p < 0.004, corrected).ResultsFollow-up (13.5 ± 4.9 months) included mJOA in all 26 patients, MRI in 25, and clinical/qMRI in 22. 42.3% reported subjective worsening, compared with mJOA (11.5%), MRI (20%), comprehensive assessments (54.6%), and qMRI (68.2%). Relative to subjective worsening, qMRI showed 100% sensitivity and 53.3% specificity compared with comprehensive assessments (75%, 60%), mJOA (27.3%, 100%), and MRI (18.2%, 81.3%). A decision-making algorithm incorporating qMRI identified progression and recommended surgery for 11 subjects (42.3%).ConclusionsQuantitative MRI shows high sensitivity to detect myelopathic progression. Our results suggest that neuroplasticity and behavioural adaptation may mask progressive SC tissue injury. qMRI appears to be a useful method to confirm subtle myelopathic progression in individual patients, representing an advance toward clinical translation of qMRI.

[This corrects the article DOI: 10.1371/journal.pone.0195733.].

Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50-100 or GD100-165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life.

Nrf2, a central regulator of the cellular defense against oxidative stress and inflammation, participates in modulating hepatocyte proliferation during liver regeneration. It is not clear, however, whether Nrf2 regulates hepatocyte growth, an important cellular mechanism to regain the lost liver mass after partial hepatectomy (PH). To determine this, various analyses were performed in wild-type and Nrf2-null mice following PH. We found that, at 60 h post-PH, the vast majority of hepatocytes lacking Nrf2 reduced their sizes, activated hepatic progenitor markers (CD133, TWEAK receptor, and trefoil factor family 3), depleted HNF4α protein, and downregulated the expression of a group of genes critical for their functions. Thus, the identity of hepatocytes deficient in Nrf2 was transiently but massively impaired in response to liver mass loss. This event was associated with the coupling of protein depletion of hepatic HNF4α, a master regulator of hepatocyte differentiation, and concomitant inactivation of hepatic Akt1 and p70S6K, critical hepatocyte growth signaling molecules. We conclude that Nrf2 participates in maintaining newly regenerated hepatocytes in a fully differentiated state by ensuring proper regulation of HNF4α, Akt1, and p70S6K during liver regeneration.

BackgroundChronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood.Methodology/principal findingsWe found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47(phox-/-) mice and gp91(phox)-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kappaB activation, and elevated downstream pro-inflammatory cytokines (TNF-alpha, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kappaB activation.Conclusions/significanceThese studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD.

The goal of this study was to assess the goodness-of-fit of theoretical models of population dynamics of Aedes aegypti to trap data collected by a long term entomological surveillance program. The carrying capacity K of this vector was estimated at city and neighborhood level. Adult mosquito abundance was measured via adults collected weekly by a network of sticky traps (Mosquitraps) from January 2008 to December 2011 in Vitória, Espírito Santo, Brazil. K was the only free parameter estimated by the model. At the city level, the model with temperature as a driver captured the seasonal pattern of mosquito abundance. At the local level, we observed a spatial heterogeneity in the estimated carrying capacity between neighborhoods, weakly associated with environmental variables related to poor infrastructure. Model goodness-of-fit was influenced by the number of sticky traps, and suggests a minimum of 16 traps at the neighborhood level for surveillance.