Papillary thyroid carcinomas are the most common endocrine cancer and are usually associated with good survival. However, some variants of papillary thyroid carcinomas may behave more aggressively than classic papillary thyroid carcinomas. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and/or to the clinicopathologic features, an issue that remains controversial. The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension. A papillary thyroid carcinoma is designated as solid/trabecular variant when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance. This tumor must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. New to the fourth edition of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. All of these variants are histologically unique and important to recognize due to their aggressive behavior.
Background The endothelial glycocalyx is a vasoprotective barrier between the blood and endothelium. We hypothesized that glycocalyx degradation is present in preeclampsia, a pregnancy‐specific hypertensive disorder characterized by endothelial dysfunction and activation. Methods and Results We examined the sublingual glycocalyx noninvasively using sidestream dark field imaging in the third trimester among women with normotensive pregnancies (n=73), early (n=14) or late (n=29) onset preeclampsia, or gestational diabetes mellitus (n=21). We calculated the width of the glycocalyx that was permeable to red blood cells (called the perfused boundary region , a measure of glycocalyx degradation) and the percentage of vessels that were filled with red blood cells ≥50% of the time (a measure of microvascular perfusion). In addition, we measured circulating levels of glycocalyx components, including heparan sulfate proteoglycans, hyaluronic acid, and SDC1 (syndecan 1), in a subset of participants by ELISA . Repeated‐measures ANOVA was performed to adjust for vessel diameter and caffeine intake. Women with early onset preeclampsia showed higher glycocalyx degradation, indicated by a larger perfused boundary region (mean: 2.14 [95% CI, 2.05–2.20]), than the remaining groups (mean: normotensive: 1.99 [95% CI, 1.95–2.02], P =0.002; late‐onset preeclampsia: 2.01 [95% CI, 1.96–2.07], P =0.024; gestational diabetes mellitus: 1.97 [95% CI, 1.91–2.04], P =0.004). The percentage of vessels that were filled with red blood cells was significantly lower in early onset preeclampsia. These structural glycocalyx changes were accompanied by elevated plasma concentrations of the glycocalyx components, heparan sulfate proteoglycans and hyaluronic acid, in early onset preeclampsia compared with normotensive pregnancy. Conclusions Glycocalyx degradation and reduced microvascular perfusion are associated with endothelial dysfunction and activation and vascular injury in early onset preeclampsia.
Dysregulation of IL-10 has been demonstrated in various animal models of preeclampsia. Decreased IL-10 production in both placenta and peripheral blood mononuclear cells has been reported in human studies, but with inconsistent results. The significance of IL-10 in preeclampsia has shifted from a key biomarker to one with therapeutic potential. As such, a better understanding of the role of this cytokine in the pathophysiology of preeclampsia is of paramount importance.
There is no therapy that promotes maturation and functionality of a dialysis arteriovenous fistula (AVF). The search for such therapies largely relies on evaluating vascular responses and putative therapies in experimental AVFs. We studied an AVF in mice with chronic kidney disease (CKD). We demonstrate numerous stressors in the vein of the AVF-CKD group, including pathologic shear, mitogenic, inflammatory, and hypoxia-reoxygenation stress. Because stress promotes premature senescence, we examined whether senescence is induced in the vein of the AVF-CKD model. We demonstrate a senescence phenotype in the AVF-CKD model as indicated by increased expression of p16Ink4a, p21Cip1, and p53, and expected changes for certain senescence-associated miRNAs. RNA-Seq analysis demonstrated that approximately 10,000 genes were differentially expressed in the vein of the AVF-CKD group, including upregulation of proinflammatory and proliferative genes. The vein in the AVF-CKD group exhibited telomere erosion and increased senescence-associated β-galactosidase activity and staining. Senescence was induced in the artery of the AVF-CKD group, and in the vein of the AVF without CKD. Finally, given the rapidly rising clinical interest in senolytics, we provide proof-of-concept of senolytics as a therapeutic approach by demonstrating that senolytics decrease p16Ink4a expression in the AVF-CKD model. This study introduces a novel concept underlying the basis for maturational and functional failure in human dialysis AVFs and identifies a new target for senolytic therapy.
Destabilized heme proteins release heme, and free heme is toxic. Heme is now recognized as an agonist for the Toll-like receptor-4 (TLR4) receptor. This study examined whether the TLR4 receptor mediates the nephrotoxicity of heme, specifically, the effects of heme on renal blood flow and inflammatory responses. We blocked TLR4 signaling by the specific antagonist TAK-242. Intravenous administration of heme to mice promptly reduced renal blood flow, an effect attenuated by TAK-242. In vitro, TAK-242 reduced heme-elicited activation of NF-κB and its downstream gene monocyte chemoattractant protein-1(MCP-1); in contrast, TAK-242 failed to reduce heme-induced activation of the anti-inflammatory transcription factor Nrf2 and its downstream gene heme oxygenase-1 (HO-1). TAK-242 did not reduce heme-induced renal MCP-1 upregulation in vivo. TAK-242 did not reduce dysfunction and histological injury in the glycerol model of heme protein-induced acute kidney injury (AKI), findings corroborated by studies in TLR4 and TLR4 mice. We conclude that 1) acute heme-mediated renal vasoconstriction occurs through TLR4 signaling; 2) proinflammatory effects of heme in renal epithelial cells involve TLR4 signaling, whereas the anti-inflammatory effects of heme do not; 3) TLR4 signaling does not mediate the proinflammatory effects of heme in the kidney; and 4) major mechanisms underlying glycerol-induced, heme protein-mediated AKI do not involve TLR4 signaling. These findings in the glycerol model are in stark contrast with findings in virtually all other AKI models studied to date and emphasize the importance of TLR4-independent pathways of heme protein-mediated injury in this model. Finally, these studies urge caution when using observations derived in vitro to predict what occurs in vivo.
Inflammation plays an important role in the pathogenesis of renal and cardiovascular disease in renovascular hypertension (RVH). Ccl2 is an important mediator of inflammation, and is induced within 24 hours following surgery to establish RVH in the murine 2 kidney 1 clip model, a time prior to onset of interstitial inflammation, fibrosis, or tubular atrophy. We tested the hypothesis that Ccl2 deficiency protects the stenotic kidney (STK) from development of chronic renal damage in mice with renovascular hypertension due to renal artery stenosis (RAS). RAS surgery was performed on wild type (WT) and Ccl2 knock out (KO) mice; animals were studied for four weeks. Renal blood flow was reduced to similar extent in both WT and Ccl2 KO mice with RVH. Perfusion of the stenotic kidney was significantly reduced in Ccl2 KO mice as assessed by magnetic resonance imaging (MRI). Stenotic kidney volume in WT, but not in Ccl2 KO mice, was significantly reduced following surgery. Cortical hypoxia was observed in the stenotic kidney of Ccl2 KO mice, as assessed by blood oxygen level-dependent MRI (BOLD-MRI). Ccl2 KO mice showed less cortical atrophy than WT RAS mice. Ccl2 deficiency reduced the number of infiltrating mononuclear cells and expression of Ccl5, Ccl7, Ccl8, Ccr2 and Cd206. We conclude that Ccl2 is a critical mediator of chronic renal injury in RVH.
A key immunomodulatory cytokine, IL-10 (interleukin-10), has been shown to be dysregulated in preeclampsia, a pregnancy-specific hypertensive disorder, further characterized by multi-system involvement. However, studies have reported inconsistent findings about circulating IL-10 levels in preeclamptic versus normotensive pregnancies. The aim of the present systematic review and meta-analysis was to assess circulating IL-10 levels in preeclamptic and normotensive pregnancies at 2 time points: before, and at the time of preeclampsia diagnosis. PubMED, EMBASE, and Web of Science databases were searched to include all published studies examining circulating IL-10 levels in preeclamptic and normotensive pregnancies. Differences in IL-10 levels were evaluated by standardized mean differences. Of 876 abstracts screened, 56 studies were included in the meta-analysis. Circulating IL-10 levels were not different before the time of active disease (standardized mean differences, −0.01 [95% CI, −0.11 to 0.08]; P =0.76). At the time of active disease, women with preeclampsia (n=1599) had significantly lower IL-10 levels compared with normotensive controls (n=1998; standardized mean differences, −0.79 [95% CI, −1.22 to −0.35]; P =0.0004). IL-10 levels were lower in both early/severe and late/mild forms of preeclampsia. Subgroup analysis revealed that IL-10 measurement methodology (ELISA or multiplex bead array) and the sample type (plasma or serum) significantly influenced the observed differences, with the use of sera paired with ELISA technology providing the best distinction in IL-10 levels between preeclamptic and normotensive pregnancies. These findings support the role of decreased IL-10 levels in the pathophysiology of preeclampsia. Future studies should address the therapeutic potential of IL-10 in preeclampsia.
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