Lichen planus esophagitis.

PURPOSE OF REVIEW: Dysphagia is one of the most common reasons for patients' visits to a gastroenterologist. Esophageal lichen planus (ELP) has historically been felt to be a rare disease, when in fact it is often misdiagnosed and unrecognized. Often first diagnosed as an unusual esophagitis, all gastroenterologists will see ELP in their practice, and need to be able to recognize this condition. RECENT FINDINGS: Although there is still a relative paucity of data on this condition, this article will update the typical presenting symptoms, endoscopic findings, and ways to differentiate ELP from other inflammatory mucosal diseases. There is still no standardized treatment algorithm, but we will also present the most recent treatment approaches. SUMMARY: It is critical that physicians maintain an increased awareness of ELP and have a high clinical suspicion in the appropriate patients. While management remains challenging, it is important to treat both the inflammatory and stricturing components of the disease. A multidisciplinary approach is also often required, utilizing dermatologists, gynecologists, and dentists who are familiar with managing patients with LP.

HuR inhibition reduces post-ischemic cardiac remodeling by dampening acute inflammatory gene expression and the innate immune response.

Myocardial ischemia/reperfusion (I/R) injury and the resulting cardiac remodeling is a common cause of heart failure. The RNA binding protein Human Antigen R (HuR) has been previously shown to reduce cardiac remodeling following both I/R and cardiac pressure overload, but the full extent of the HuR-dependent mechanisms within cells of the myocardium have yet to be elucidated. In this study, we applied a novel small molecule inhibitor of HuR to define the functional role of HuR in the acute response to I/R injury and gain a better understanding of the HuR-dependent mechanisms during post-ischemic myocardial remodeling. Our results show an early (two hours post-I/R) increase in HuR activity that is necessary for early inflammatory gene expression by cardiomyocytes in response to I/R. Surprisingly, despite the reductions in early inflammatory gene expression at two hours post-I/R, HuR inhibition has no effect on initial infarct size at 24-hours post-I/R. However, in agreement with previously published work, we do see a reduction in pathological remodeling and preserved cardiac function at two weeks post-I/R upon HuR inhibition. RNA-sequencing analysis of neonatal rat ventricular myocytes (NRVMs) at two hours post-LPS treatment to model damage associated molecular pattern (DAMP)-mediated activation of toll like receptors (TLRs) demonstrates a broad HuR-dependent regulation of pro-inflammatory chemokine and cytokine gene expression in cardiomyocytes. We show that conditioned media from NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory gene expression in bone marrow derived macrophages (BMDMs) compared to NRVMs treated with LPS alone. Functionally, HuR inhibition in NRVMs also reduces their ability to induce endocrine migration of peripheral blood monocytes in vitro and reduces post-ischemic macrophage infiltration to the heart in vivo. In summary, these results suggest a HuR-dependent expression of pro-inflammatory gene expression by cardiomyocytes that leads to subsequent monocyte recruitment and macrophage activation in the post-ischemic myocardium.

Update on the Diagnosis and Treatment of Achalasia.

Achalasia is a rare disease of the esophagus with impaired relaxation of the lower esophageal sphincter and aperistalsis. The etiology is unknown but speculations include a viral or autoimmune etiology. All specialists dealing with swallowing and esophageal diseases should recognize the classic symptoms of dysphagia for solids/liquids, regurgitation, and choking, especially at night. High-resolution manometry is critical for the diagnosis with endoscopy and barium esophagram having a supportive role. The disease cannot be cured but most can return to near normal swallowing and a regular diet with appropriate therapy. Treatment includes smooth muscle relaxants, botulinum toxin injections to the lower sphincter, pneumatic dilation, Heller myotomy, and peroral endoscopic myotomy. One treatment does not fit all and a tailored approach through a multidiscipline team will give the best long-term outcomes.

HuR-dependent expression of Wisp1 is necessary for TGFß-induced cardiac myofibroblast activity.

Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFß-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFß-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFß treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, WNT1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFß. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFß, in part through post-transcriptional regulation of Wisp1.

Accuracy of Achalasia Quality of Life and Eckardt scores for assessment of clinical improvement post treatment for achalasia.

Achalasia Quality of Life (ASQ) and Eckardt scores are two patient-reported instruments widely used to assess symptom severity in achalasia patients. ASQ is validated and reliable. Although Eckardt is commonly used, it has not been rigorously assessed for validity or reliability. This study aims to evaluate (i) the accuracy of Eckardt and ASQ for assessing improvement post-treatment (predictive validity), (ii) accuracy of Eckardt and ASQ for assessing improvement post-treatment with pneumatic dilatation (PD) versus surgical myotomy (predictive validity), and (iii) convergent validity of Eckardt and ASQ tools. Patients with achalasia treated between 2011 and 2018 were eligible. Both instruments were administered by telephone. Treatment failure was determined by the review of medical records by two clinicians. The predictive ability of ASQ and Eckardt instruments in identifying treatment successes and failures was determined using receiver operating characteristics analysis and summarized as area under the curve (AUC). A total of 106 patients met inclusion criteria with 39 PD, 51 Heller myotomy, and 16 per-oral endoscopic myotomy. A review of medical records and esophageal testing revealed 13 failures (12%). AUC for Eckardt was 0.96 (95% confidence interval [CI] 0.87-0.99] and ASQ 0.97 (95% CI 0.92-0.99). The Eckardt cutoff 4, and ASQ, cutoff 15, were 94% and 87% accurate in identifying treatment successes versus failures, respectively. The correlation coefficient between the two tools was 0.85. In conclusions, (i) ASQ and Eckardt scores are valid and reliable tools to assess symptom severity in achalasia patients, (ii) both instruments accurately classify treatment successes versus failures, and (iii) the choice of tool should be informed by the physicians and patients' values and preferences and repeat physiologic testing may be reserved for treatment failures with either instrument and patients classified, as treatment successes may be spared routine physiologic testing in the long term.

Relapsed Acute Lymphoblastic Leukemia Presenting as Acute Renal Failure.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. It is an aggressive hematologic neoplasm, with a bimodal age distribution typically presenting in childhood and the 6th decade of life (Terwilliger and Abdul-Hay, 2017). Renal injury in ALL is common and can occur through many different mechanisms, such as prerenal acute kidney injury, acute tubular necrosis, renovascular disease, obstruction, glomerulonephritis, and parenchymal infiltration of tumor cells (Luciano and Brewster, 2014). Infiltration of kidneys by leukemia cells is common; however a resultant injury only occurs in about 1% of patients, and renal failure is even more rare (Luciano and Brewster, 2014). Renal failure due to bilateral infiltration of tumor cells has been reported in only a few cases and is thought to be a poor prognostic indicator (Luciano and Brewster, 2014; Sherief et al., 2015). Biopsy is essential to the diagnosis of renal infiltration of leukemia. We present a case of acute renal failure secondary to bilateral renal infiltration of ALL presenting as the first sign of relapse in a young man.

Human antigen R as a therapeutic target in pathological cardiac hypertrophy.

RNA binding proteins represent an emerging class of proteins with a role in cardiac dysfunction. We show that activation of the RNA binding protein human antigen R (HuR) is increased in the failing human heart. To determine the functional role of HuR in pathological cardiac hypertrophy, we created an inducible cardiomyocyte-specific HuR-deletion mouse and showed that HuR deletion reduces left ventricular hypertrophy, dilation, and fibrosis while preserving cardiac function in a transverse aortic constriction (TAC) model of pressure overload-induced hypertrophy. Assessment of HuR-dependent changes in global gene expression suggests that the mechanistic basis for this protection occurs through a reduction in fibrotic signaling, specifically through a reduction in TGF-ß (Tgfb) expression. Finally, pharmacological inhibition of HuR at a clinically relevant time point following the initial development of pathological hypertrophy after TAC also yielded a significant reduction in pathological progression, as marked by a reduction in hypertrophy, dilation, and fibrosis and preserved function. In summary, this study demonstrates a functional role for HuR in the progression of pressure overload-induced cardiac hypertrophy and establishes HuR inhibition as a viable therapeutic approach for pathological cardiac hypertrophy and heart failure.

Tefillin use induces remote ischemic preconditioning pathways in healthy men.

The present study assessed whether tefillin use (tight, nonocclusive, wrapping of the arm) elicits a remote ischemic preconditioning (RIPC)-like effect in subjects with both acute and chronic use. RIPC, created by short bursts of ischemia-reperfusion, has not been successfully taken to the bedside. Several large population studies have found that Orthodox Jewish men (who wear tefillin almost daily) have decreased cardiovascular mortality compared with non-Orthodox counterparts. We hypothesized that tefillin use is a relevant component in triggering a preconditioning effect. Jewish men ( n = 20) were enrolled; 9 men were daily tefillin users (conditioned) and 11 men were nonusers of tefillin as controls (naïve). Subjects were evaluated for adherence to traditional Jewish practice, had vital signs measured, blood drawn for analysis of circulating cytokines and monocyte function, and underwent brachial flow-mediated dilation to evaluate vascular reactivity at baseline (basal) and after 30 min of using tefillin (acute treatment). Under basal conditions, both groups had similar peak systolic velocity (SV), diameter, and flow volume, although the conditioned group had higher SV at 120 s postdeflation ( P = 0.05). Acute tefillin use augmented artery diameter and flow volume in both groups, with conditioned subjects experiencing higher SV than control subjects at 90 and 120 s postdeflation ( P = 0.03 and P = 0.02, respectively). Conditioned subjects had decreased inflammation, monocyte migration and adhesion, and endothelial activation compared with control subjects at baseline. Acute use of tefillin did not significantly alter monocyte function in either group. In this pilot study, acute tefillin use improves vascular function, whereas chronic tefillin use is associated with an anti-inflammatory RIPC-like phenotype. NEW & NOTEWORTHY We hypothesized that tefillin use among Orthodox Jewish men (who practice a nonocclusive leather banding of their nondominant arm) will induce a remote ischemic preconditioning phenotype. Chronic use of tefillin in Orthodox Jewish men was associated with increased systolic velocity and attenuated inflammation and monocyte chemotaxis and adhesion versus Jewish men who do not wear tefillin. Acute use of tefillin in both populations augmented brachial artery diameter and blood flow but not inflammatory profiles compared with baseline.

Tranilast Blunts the Hypertrophic and Fibrotic Response to Increased Afterload Independent of Cardiomyocyte Transient Receptor Potential Vanilloid 2 Channels.

Tranilast is clinically indicated for the treatment of allergic disorders and is also a nonselective blocker of the transient receptor potential vanilloid 2 (TRPV2) channel. Previous studies have found that it has protective effects in various animal models of cardiac disease. Our laboratory has found that genetic deletion of TRPV2 results in a blunted hypertrophic response to increased afterload; thus, this study tested the hypothesis that tranilast through cardiomyocyte TRPV2 blockade can inhibit the hypertrophic response to pressure overload in vivo through transverse aortic constriction and ex vivo through isolated myocyte studies. The in vivo studies demonstrated that tranilast blunted the fibrotic response to increased afterload and, to a lesser extent, the hypertrophic response. After 4 weeks, this blunting was associated with improved cardiac function, although at 8 weeks, the cardiac function deteriorated similarly to the control group. Finally, the in vitro studies demonstrated that tranilast was not inhibiting these responses at the cardiomyocyte level. In conclusion, we demonstrated that tranilast blunting of the fibrotic and hypertrophic response occurs independently of cardiac TRPV2 channels and may be cardioprotective in the short term but not after prolonged administration.

Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy.

The RNA binding protein Human antigen R (HuR) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes. Specifically, HuR cytoplasmic translocation is significantly increased in NRVMs (neonatal rat ventricular myocytes) following treatment with phenylephrine or angiotensin II, agonists of two independent Gαq-coupled GPCRs known to induce hypertrophy. This Gq-mediated HuR activation is dependent on p38 MAP kinase, but not canonical Gq-PKC signaling. Furthermore, we show that HuR activation is necessary for Gq-mediated hypertrophic growth of NRVMs as siRNA-mediated knockdown of HuR inhibits hypertrophy as measured by cell size and expression of ANF (atrial natriuretic factor). Additionally, HuR overexpression is sufficient to induce hypertrophic cell growth. To decipher the downstream mechanisms by which HuR translocation promotes cardiomyocyte hypertrophy, we assessed the role of HuR in the transcriptional activity of NFAT (nuclear factor of activated T cells), the activation of which is a hallmark of cardiac hypertrophy. Using an NFAT-luciferase reporter assay, we show an acute inhibition of NFAT transcriptional activity following pharmacological inhibition of HuR. In conclusion, our results identify HuR as a novel mediator of cardiac hypertrophy downstream of the Gq-p38 MAPK pathway, and suggest modulation of NFAT activity as a potential mechanism.