Perioperative therapeutic plasma exchange in a patient with rare Factor XIII inhibitor.

INTRODUCTION: Factor XIII deficiency is a rare bleeding disorder which could be severe if inherited or less severe if acquired. We report a case of acquired Factor XIII inhibitor in a 75-year-old male with a suspicious left renal mass treated perioperatively with therapeutic plasma exchange (TPE). PATIENT AND METHOD: To perform kidney biopsy and ablation of the renal mass, six daily TPE treatments were performed before and after biopsy to minimize bleeding risk because the patient did not respond to drug therapy. Both thromboelastography (TEG) and laboratory-based coagulation tests were performed to assess coagulation status prior to and after TPE. RESULTS: The biopsy indicated oncocytoma which was removed by surgical procedure. Factor XIII activity remained below 15 % throughout TPE treatments, but Factor XIII inhibitor titer reduced from initial positive value of 1:40 to negative following the third TPE and remained negative through the sixth TPE. Unfortunately, the inhibitor titer was positive at 1:20 in the fifth month and 1:5 in the sixth month during follow-up. CONCLUSIONS: TPE is useful in removing XIII inhibitory factor, but the effects are only short term.

Malignancy-associated acquired vulvar lymphangioma circumscriptum: A clinicopathologic study of 71 cases.

BACKGROUND: Acquired lymphangioma circumscriptum of the vulva is rare and can occur subsequent to malignancies of the anogenital and pelvic region. We sought to investigate the clinicopathologic characteristics of malignancy-associated acquired vulvar lymphangioma circumscriptum (AVLC). METHODS: We identified all cases of AVLC within our institution with history of prior malignancy between 2005 and 2021. A similar search was performed in the PubMed database to identify published cases to date. The clinical and histopathologic information was recorded. RESULTS: A total of 71 cases were identified. The most common preceding malignancy was cervical carcinoma (71.8%, 51/71). Radiation therapy was given to 91.4% (64/70) of the patients and lymph node dissection was made on 70.2% (40/57). Median interval between the diagnosis of malignancy and the AVLC was 10 years (range 0-32 years). AVLC frequently presented as vesicular (31.6%, 18/57) or verrucous (28.1%, 16/57) lesions clinically. Common treatments for AVLC included excision (53.1%, 26/49) and laser therapy (16.3%, 8/49), with an overall recurrence rate of 42.9% (24/56) at a median follow-up interval of 1.8 years (range 0.04-32.3 years). CONCLUSION: AVLC is a rare, late complication of anogenital and pelvic malignancies causing debilitating physical symptoms and psychological stress. Further studies are warranted to determine the most effective treatment modalities to mitigate recurrence.

Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice.

Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities. Studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. The receptor for advanced glycation end-products (RAGE) is a pro-inflammatory transmembrane receptor increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke-induced IUGR. C57BL/6 mice were exposed to SHS or SHS + semi-synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro. SHS-treated mice demonstrated a significant reduction in fetal weight (7.35-fold, P ≤ 0.0001) and placental weight (1.13-fold, P ≤ 0.0001) compared with controls. Mice co-treated with SHS and SAGEs were protected from SHS-induced fetal weights decreases. SHS treatment of C57BL/6 mice activated placental extracellular signal-regulated kinase (ERK) (3.0-fold, P ≤ 0.05), JNK (2.4-fold, P ≤ 0.05) and p38 (2.1-fold, P ≤ 0.05) and the expression of inflammatory mediators including TNF-α (1.34-fold, P ≤ 0.05) and IL-1ß (1.03-fold, P ≤ 0.05). SHS-mediated activation of these molecules was reduced to basal levels when SAGE was co-administered. Invasion of trophoblast cells decreased 92% (P < 0.002) when treated with CSE and CSE-mediated invasion was completely reversed by SAGEs. We conclude that RAGE inhibition protects against fetal weight loss during SHS-induced IUGR. These studies provide insight into tobacco-mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications.

Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.

Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function.

Antenatal exposure of maternal secondhand smoke (SHS) increases fetal lung expression of RAGE and induces RAGE-mediated pulmonary inflammation.

BACKGROUND: Receptors for advanced glycation end-products (RAGE) are immunoglobulin-like pattern recognition receptors abundantly localized to lung epithelium. Our research demonstrated that primary tobacco smoke exposure increases RAGE expression and that RAGE partly mediates pro-inflammatory signaling during exposure. However, the degree to which RAGE influences developing lungs when gestating mice are exposed to secondhand smoke (SHS) has not been determined to date. METHODS: Timed pregnant RAGE null and wild type control mice were exposed to 4 consecutive days of SHS from embryonic day (E) 14.5 through E18.5 using a state of the art nose-only smoke exposure system (Scireq, Montreal, Canada). RAGE expression was assessed using immunofluorescence, immunoblotting, and quantitative RT-PCR. TUNEL immunostaining and blotting for caspase-3 were performed to evaluate effects on cell turnover. Matrix abnormalities were discerned by quantifying collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. Lastly, TNF-α and IL-1ß levels were assessed in order to determine inflammatory status in the developing lung. RESULTS: Pulmonary RAGE expression was elevated in both dams exposed to SHS and in fetuses gestating within mothers exposed to SHS. Fetal weight, a measure of organismal health, was decreased in SHS-exposed pups, but unchanged in SHS-exposed RAGE null mice. TUNEL assessments suggested a shift toward pulmonary cell apoptosis and matrix in SHS-exposed pups was diminished as revealed by decreased collagen IV and increased MMP-9 expression. Furthermore, SHS-exposed RAGE null mice expressed less TNF-α and IL-1ß when compared to SHS-exposed controls. CONCLUSIONS: RAGE augmentation in developing pups exposed to maternal SHS weakens matrix deposition and influences lung inflammation.

Transgenic up-regulation of Claudin-6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation.

Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-α and IL-1ß were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution.