Fetal Supraventricular Tachycardia: Histologic Evidence of Accessory Pathways Due to Incomplete Annulus Fibrosus Formation.

BACKGROUND: Atrioventricular (AV) reentrant tachycardia is a common type of supraventricular tachycardia (SVT) that occurs in the fetus and neonate. Although many tachycardias resolve within several weeks of birth or respond to medical management, disruptions in the cardiac annulus fibrosus and development of additional accessory pathways may lead to refractory dysrhythmia resulting in fetal hydrops and ultimately, fetal death. OBJECTIVES: While accessory pathways have been well documented anatomically in adult and childhood tachyarrhythmias, there are no reports of the histology of these pathways in human fetuses with SVT. RESEARCH DESIGN, SUBJECTS, MEASURES: This is a small case series of 2 fetuses with a history of SVT that resulted in fetal hydrops. RESULTS: In both cases, examination of the cardiac conduction system was unremarkable and examination of the atrioventricular junction revealed a focally thinned and/or discontinuous annulus fibrosus with documented direct continuity between the atrial and ventricular myocardium in 1 case. CONCLUSIONS: This case series demonstrates that thinning or absence of the annulus fibrosus is a feature seen in fetal SVT, and the development of subsequent aberrant AV connections due to defective formation of the annulus fibrosus suggests a possible cause for these arrhythmias.

Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer.

PD-L1 is expressed in a percentage of lung cancer patients and those patients show increased likelihood of response to PD-1 axis therapies. However, the methods and assays for the assessment of PD-L1 using immunohistochemistry are variable and PD-L1 expression appears to be highly heterogeneous. Here, we examine assay heterogeneity parameters toward the goal of determining variability of sampling and the variability due to pathologist-based reading of the immunohistochemistry slide. SP142, a rabbit monoclonal antibody, was used to detect PD-L1 by both chromogenic immunohistochemistry and quantitative immunofluorescence using a laboratory-derived test. Five pathologists scored the percentage of PD-L1 positivity in tumor- and stromal-immune cells of 35 resected non-small cell lung cancer cases, each represented on three separate blocks. An intraclass correlation coefficient of 94% agreement was seen among the pathologists for the assessment of PD-L1 in tumor cells, but only 27% agreement was seen in stromal/immune cell PD-L1 expression. The block-to-block reproducibility of each pathologist's score was 94% for tumor cells and 75% among stromal/immune cells. Lin's concordance correlation coefficient between pathologists' readings and the mean immunofluorescence score among blocks was 94% in tumor and 68% in stroma. Pathologists were highly concordant for PD-L1 tumor scoring, but not for stromal/immune cell scoring. Pathologist scores and immunofluorescence scores were concordant for tumor tissue, but not for stromal/immune cells. PD-L1 expression was similar among all the three blocks from each tumor, indicating that staining of one block is enough to represent the entire tumor and that the spatial distribution of heterogeneity of expression of PD-L1 is within the area represented in a single block. Future studies are needed to determine the minimum representative tumor area for PD-L1 assessment for response to therapy.

TLR4 mutation reduces microglial activation, increases Aß deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease.

BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aß deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aß deposits and buffer-soluble Aß in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aß deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aß deposits start. METHODS: Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aß were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aß-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. RESULTS: While no difference was found in cerebral Aß load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased Aß deposition and soluble Aß42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1ß, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aß-induced IL-1ß, CCL3, and CCL4 expression in monocytes. CONCLUSION: This is the first demonstration of TLR4-dependent activation of microglia at the early stage of ß-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Aß deposition and that, as Aß deposits start, microglia are activated via TLR4 signaling to reduce Aß deposits and preserve cognitive functions from Aß-mediated neurotoxicity.