Optimal method for fetal brain age prediction using multiplanar slices from structural magnetic resonance imaging

The accurate prediction of fetal brain age using magnetic resonance imaging (MRI) may contribute to the identification of brain abnormalities and the risk of adverse developmental outcomes. This study aimed to propose a method for predicting fetal brain age using MRIs from 220 healthy fetuses between 15.9 and 38.7 weeks of gestational age (GA). We built a 2D single-channel convolutional neural network (CNN) with multiplanar MRI slices in different orthogonal planes without correction for interslice motion. In each fetus, multiple age predictions from different slices were generated, and the brain age was obtained using the mode that determined the most frequent value among the multiple predictions from the 2D single-channel CNN. We obtained a mean absolute error (MAE) of 0.125 weeks (0.875 days) between the GA and brain age across the fetuses. The use of multiplanar slices achieved significantly lower prediction error and its variance than the use of a single slice and a single MRI stack. Our 2D single-channel CNN with multiplanar slices yielded a significantly lower stack-wise MAE (0.304 weeks) than the 2D multi-channel (MAE = 0.979

Paracrine IL-33 Stimulation Enhances Lipopolysaccharide-Mediated Macrophage Activation

BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation

Comprehensive quantitative analyses of fetal magnetic resonance imaging in isolated cerebral ventriculomegaly

Isolated cerebral ventriculomegaly (IVM) is the most common prenatally diagnosed brain anomaly occurs in 0.2-1 % of pregnancies. However, knowledge of fetal brain development in IVM is limited. There is no prenatal predictor for IVM to estimate individual risk of neurodevelopmental disability occurs in 10 % of children. To characterize brain development in fetuses with IVM and delineate their individual neuroanatomical variances, we performed comprehensive post-acquisition quantitative analysis of fetal magnetic resonance imaging (MRI). In volumetric analysis, brain MRI of fetuses with IVM (n = 20, 27.0 ± 4.6 weeks of gestation, mean ± SD) had revealed significantly increased volume in the whole brain, cortical plate, subcortical parenchyma, and cerebrum compared to the typically developing fetuses (controls, n = 28, 26.3 ± 5.0). In the cerebral sulcal developmental pattern analysis, fetuses with IVM had altered sulcal positional (both hemispheres) development and combined features of sulcal positional, depth, basin area, in both hemispheres compared to the controls. When comparing distribution of similarity index of individual fetuses, IVM group had shifted toward to lower values compared to the control. About 30 % of fetuses with IVM had no overlap with the distribution of control fetuses. This proof-of-concept study shows that quantitative analysis of fetal MRI can detect emerging subtle neuroanatomical abnormalities in fetuses with IVM and their individual variations

Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study

Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4-24.0) and 23.9 (20.6-29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies

IL-33 enhances LPS-mediated cytokine production by macrophages.

<p>TGC-induced peritoneal macrophages derived from B6J-WT mice (A–D) and B6N-WT and -IL-33^−/− mice (E) were cultured in the presence and absence of 100 ng/ml LPS, with and without 100 ng/ml IL-33, for 9, 24 and/or 48 h. (A, E) The levels of IL-6 in the culture supernatants by ELISA. (B) The percentage of PI-positive cells by flow cytometry. (C) LDH levels in the culture supernatants. (D) The number of IL-33-secreting cells by ELISPOT. Data show the mean +/± SEM (n = 3 [A] or 4 [B–E]). *p<0.05 vs. the indicated group (A) or Medium (B–E), and ^†p<0.05 vs. 24 h (C, D) or WT (E). P+I = PMA+ionomycin.</p

IL-33 induces TRAF6-dependent cytokine production by mast cells.

<p>BMCMCs obtained from B6J-WT mice (A) and B6J-WT and -TLR4^−/− mice (B; left panels) and FLCMCs obtained from B6J-WT and -TRAF6^−/− mice (B; right panels) were cultured in the presence of various concentration of rmIL-33 (A) or in the presence and absence of 100 ng/ml rmIL-33 for 6 h (for TNF measurement) and 24 h (for IL-6 and IL-13 measurement). The levels of IL-6, IL-13 and/or TNF in the culture supernatants were determined by ELISA. Data show the mean + SD (n = 3). *p<0.05 vs. WT.</p

Inhibitory effects of anti-IL-33 mAbs on LPS-mediated macrophage activation by paracrine IL-33 stimulation.

<p>(A, B) TGC-induced peritoneal macrophages derived from B6J-WT mice were cultured in the presence of 100 ng/ml LPS, with and without 40 µg/ml of several anti-ST2 mAbs (A), several anti-IL-33 mAbs (B) or control IgG (A, B) for 24 and 48 h. (C) B6J-WT BMCMCs were cultured in the presence of 1 µg/ml anti-DNP IgE (SPE-7), with and without 40 µg/ml of several anti-IL-33 mAbs or control IgG for 24 and 48 h. The levels of IL-6 or IL-13 in the culture supernatants were measured by ELISA. Data show the mean + SEM ([A] n = 7, [B] n = 8 [C] n = 4). *p<0.05 vs. Rat IgG (A) or Mouse IgG (B).</p

Effects of anti-ST2 mAbs on cytokine production by IL-33-stimulated BMCMCs.

<p>B6J-WT BMCMCs were stimulated with 0–1,000 ng/ml (A) or 100 ng/ml (B) rmIL-33 in the presence of 40 µg/ml of several anti-ST2 mAbs or isotype control rat IgG for 24 h. The levels of IL-6 and IL-13 in the culture supernatants were determined by ELISA. Data show the mean + SEM (n = 3). *p<0.05 vs. rat IgG+IL-33. The expression of ST2 on the cell surface of BALB-WT and ST2^−/− BMCMCs was determined using several distinct anti-ST2 mAb clones. Representative data by flow cytometry are shown (C). Shaded area indicates isotype-matched control IgG staining, and bold line indicates anti-ST2 mAb staining.</p

Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

Diabetes is a major cause of kidney disease. Here Kikuchi et al. show that phenol sulfate, a gut microbiota-derived metabolite, is increased in diabetic kidney disease and contributes to the pathology by promoting kidney injury, suggesting phenyl sulfate could be used a marker and therapeutic target for the treatment of diabetic kidney disease