Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Novel Use of AXIOS Stent for Concurrent Management of Achalasia and Esophageal Varices in a Cirrhotic Patient.

AXIOS stents create an anastomotic connection between 2 lumens, facilitating bypass of blockages and strictures as well as drainage of large fluid collections. Historically, AXIOS stents have primarily been used for draining pancreatic fluid collections, with no documented cases of their use within the esophagus until now. In this article, we present a case of a 65-year-old man with cirrhosis admitted for dysphagia. On evaluation, he was diagnosed with type 1 achalasia and concurrent esophageal varices. A novel approach was used, utilizing an AXIOS stent, to provide both symptomatic relief and targeted treatment for his varices.

Carboxylesterase 1 mediates a distinctive metabolic profile of dendritic cells to attain an inflammatory phenotype.

The metabolic profile of dendritic cells (DCs) shapes their phenotype and functions. Carboxylestrase 1 (CES1) enzyme is highly expressed in mononuclear myeloid cells however its exact role in DCs is elusive. We used a CES1 inhibitor (WWL113) and genetic overexpression to explore the role of CES1 in DCs differentiation in inflammatory models. CES1 expression was analyzed during CD14+ monocytes differentiation to DCs (MoDCs) using quantitative PCR. CES1 Inhibitor (WWL113) was applied during MoDCs differentiation. Surface markers, secreted cytokines, lactic acid production, phagocytic and T cell polarization capacity were analyzed. Transcriptomic and metabolic profile were assessed with RNA-sequencing and mass spectrometry. Cellular respiration was assessed with seahorse respirometry. Transgenic mice were used to assess CES1 overexpression in DCs in inflammatory models. CES1 expression peaks early during MoDCs differentiation. Pharmacological inhibition of CES1 led to higher expression of CD209, CD86 and MHCII. WWL113 treated MoDCs secreted higher quantities of IL6, IL8, TNF and IL10 and demonstrated stronger phagocytic ability and higher capacity to polarize Th17 differentiation in autologous DCs-T cells co-culture model. Transcriptomic profiling revealed enrichment of multiple inflammatory and metabolic pathways. Functional metabolic analysis shows impaired maximal mitochondrial respiration capacity, increased lactate production and decreased intracellular amino acids and TCA intermediates. Transgenic human CES1 overexpression in murine DCs generated less inflammatory phenotype and increased resistance to T cell mediated colitis. In conclusion, CES1 inhibition directs DCs differentiation towards more inflammatory phenotype, that shows stronger phagocytic capacity and supports Th17 skewing. This is associated with disrupted mitochondrial respiration and amino acids depletion.

Hyperammonemia Encephalopathy due to Urea Cycle Disorder Precipitated by Gastrointestinal Bleed in the Setting of Prior Bariatric Surgery.

The urea cycle is a metabolic pathway that excretes nitrogenous waste products from the body. Urea cycle disorders (UCDs) result from enzymatic deficiencies within this pathway, which can lead to life-threatening hyperammonemia. Gastric bypass-related hyperammonemia in patients who have undergone Roux-en-Y gastric bypass surgery has been previously reported. UCDs have been implicated as a cause of gastric bypass-related hyperammonemia. In this report, we present the case of a patient with a history of bariatric surgery who experienced severe hyperammonemia encephalopathy triggered by a gastrointestinal bleed due to an undiagnosed UCD.

The Association Between Gastroesophageal Reflux Disease and Non-Small Cell Lung Cancer: A Retrospective Case-Control Study.

Background: Lung cancer is a leading cause of mortality in the USA. Non-small cell lung cancer (NSCLC) contributes to 85% of all lung cancers. It is the most prevalent subtype amongst non-smokers, and its incidence has risen in the last 20 years. In addition, gastroesophageal reflux disease (GERD) has been associated with several lung pathologies, namely idiopathic pulmonary fibrosis and asthma. We aimed to investigate the association between GERD and NSCLC by performing a retrospective, multicenter, case-control study. This is the first study of this nature to be carried out in the USA. Methods: Data were retrieved from 17 Northwell health care facilities in the New York area between the years 2010 and 2018. Inclusion criteria were patients > 18 years of age with NSCLC (large cell, adenocarcinoma, and squamous cell). They were appropriately matched with controls based on age, gender, weight, comorbidities, and medication use. Our exposure group had a diagnosis of GERD based on the International Classification of Diseases, Ninth/10th Revision (ICD 9/10) codes and endoscopic, in addition to histological evidence if present. We excluded patients with secondary lung cancers, esophageal adenocarcinoma, other primary malignancies, Barrett's esophagus, and smokers. Logistic regression was conducted to determine the adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between NSCLC and GERD. Results: A total of 1,083 subjects were included in our study: 543 (50%) patients were diagnosed with NSCLC. In this population, GERD was twice as prevalent compared to controls (20.4% vs. 11.6%, P < 0.001). Multivariate analysis demonstrated that GERD was associated with a higher risk of NSCLC compared to matched controls (OR = 1.86, 95% CI = 1.26 - 2.73). In addition, GERD patients treated with either antihistamines or proton pump inhibitors did not demonstrate an overall reduced risk of NSCLC (OR = 1.01, 95% CI = 0.48 - 2.12). Conclusions: Our study demonstrates that GERD is associated with a higher risk of NSCLC, irrespective of GERD treatment. We postulate that GERD patients suffer from chronic micro-aspirations leading to a prolonged inflammatory state within the lung parenchyma, triggering specific proliferative signaling pathways that may lead to malignant transformation.

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn's Disease.

BACKGROUND: Myeloid cells are critical determinants of the sustained inflammation in Crohn's Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. METHODS: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. RESULTS: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1ß, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. CONCLUSIONS: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.

Carboxylesterase-1 Assisted Targeting of HDAC Inhibitors to Mononuclear Myeloid Cells in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1]. This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease [IBD]. METHODS: CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells, and Crohn's disease [CD] colon mucosa, by mass cytometry, quantitative polymerase chain reaction [PCR], and immunofluorescence staining, respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in dextran sulphate sodium [DSS]-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promoter. RESULTS: CES1 mRNA was highly expressed in human blood CD14+ monocytes, in vitro differentiated and lipopolysaccharide [LPS]-stimulated macrophages, and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1+ cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-α production 1000 times more potently than its control, HDAC800, in CES1high monocytes. In healthy donor peripheral blood, CES1 expression was significantly higher in CD14++CD16- monocytes compared with CD14+CD16++ monocytes. In CD-inflamed colon, a higher number of mucosal CD68+ macrophages expressed CES1 compared with non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, while having limited potential in ameliorating DSS-induced colitis. CONCLUSIONS: We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD.

Gastrointestinal Bleeding Secondary to Metastatic Duodenal Choriocarcinoma in a Patient with Concomitant Peptic Ulcer Disease.

Testicular tumors are one of the most common solid tumors in young males. Choriocarcinoma usually presents as metastatic disease. Gastrointestinal tract involvement is rare. We report a case of a 40-year-old male presenting to our hospital with a three-day history of dyspnea on exertion and black stool after recent diagnosis of testicular choriocarcinoma. Urgent EGD performed revealed small clean-based fundal ulcer and an antral ulcer without the stigma of recent bleeding. Capsule endoscopy was performed and revealed a bleeding ill-defined mass in the proximal duodenum. A subsequent push enteroscopy showed an ulcerated bleeding mass in the third part of the duodenum that was treated with a hemospray with adequate hemostasis. Pathology was consistent with pure choriocarcinoma. The patient received a cisplatin-based chemotherapy regimen. The patient tolerated the chemotherapy regimen well and was discharged for outpatient follow-up. At the three-month follow-up, the patient did not show evidence of recurrent gastrointestinal bleeding.

Is the Use of Proton Pump Inhibitors a Predisposing Factor for Pyogenic Liver Abscesses?

BACKGROUND: Proton pump inhibitors (PPIs) increase gastric pH by reducing acid production. The resulting alkaline milieu in the stomach increases the risk of bacterial translocation. This study aimed to investigate if there is a correlation between PPI use and developing pyogenic liver abscesses. METHODS: In this retrospective case-control analysis, we studied adult patients diagnosed with cryptogenic liver abscess at Northwell hospitals between 2015 and 2019. Adult patients with the diagnosis of liver abscess were included. We excluded patients with history of liver abscess prior to admission, biliary disease, hepatobiliary malignancy, or intra-abdominal infections. A group of randomly selected patients without liver abscess from the same hospitals' database were enrolled as the control group. A multivariate logistic regression analysis was performed to adjust for potential confounding factors. RESULTS: We identified 277 patients diagnosed with first episode of pyogenic liver abscess. Cases were compared to 554 controls. Klebsiella pneumonia was the most common pathogen. PPI use was associated with an increased risk of developing a first episode of pyogenic liver abscess in univariate (odds ratio (OR): 2.36, 95% confidence interval (CI): 1.70 - 3.27), and multivariate analysis (adjusted OR: 2.27, 95% CI: 1.55 - 3.32). CONCLUSION: This study is the first US population-based analysis to demonstrate that PPI use is associated with increased risk of developing pyogenic liver abscesses. Further prospective studies are needed to shed more light on this association and better evaluate the impact of dose and duration of PPI exposure.

Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives.

Histone deacetylases (HDACs) and bromodomain-containing proteins (BCPs) play a key role in chromatin remodeling. Based on their ability to regulate inducible gene expression in the context of inflammation and cancer, HDACs and BCPs have been the focus of drug discovery efforts, and numerous small-molecule inhibitors have been developed. However, dose-limiting toxicities of the first generation of inhibitors, which typically target multiple HDACs or BCPs, have limited translation to the clinic. Over the last decade, an increasing effort has been dedicated to designing class-, isoform-, or domain-specific HDAC or BCP inhibitors, as well as developing strategies for cell-specific targeted drug delivery. Selective inhibition of the epigenetic modulators is helping to elucidate the functions of individual epigenetic proteins and has the potential to yield better and safer therapeutic strategies. In accordance with this idea, several in vitro and in vivo studies have reported the ability of more selective HDAC/BCP inhibitors to recapitulate the beneficial effects of pan-inhibitors with less unwanted adverse events. In this review, we summarize the most recent advances with these strategies, discussing advantages and limitations of these approaches as well as some therapeutic perspectives, focusing on autoimmune and inflammatory diseases.

Neutropenic Enterocolitis Secondary to Sulfasalazine in a Woman With Psoriatic Arthritis.

Neutropenic enterocolitis (NE) also known as typhlitis is a serious condition that has been described in immunosuppressed hosts including patients with leukemia, HIV and in patients on chemotherapy. We present the first case of female on sulfasalazine for psoriatic arthritis, otherwise healthy, who was diagnosed with NE involving the cecum and rectum. This adds up to the cases of NE diagnosed in nononcologic conditions. A 65-year-old female with a history of psoriatic arthritis on sulfasalazine, presented to the emergency department (ED) after an episode of syncope. She was complaining of a fever and mild generalized abdominal pain. Physical exam was remarkable for peri-umbilical tenderness. Severe neutropenia and acute kidney injury were found on blood work. CT scan of the abdomen showed evidence of colitis, involving the cecum, ascending colon and rectum, which in light of neutropenia was consistent with NE. Clostridium difficile colitis was ruled out. Intravenous fluids and broad-spectrum antibiotics were initiated, and sulfasalazine was discontinued. The patient was subsequently afebrile and was out of neutropenia by day 3 without the need for granulocyte-macrophage colony-stimulating factor (GM-CSF). By day 5, the patient was pain free and was discharged. Even though NE is primarily described in the setting of malignancies and chemotherapy, one should keep in mind that this entity can occur in people on any immunosuppressive therapy. Early discontinuation of sulfasalazine and conservative management were essential in the treatment of NE in this case. Whether neutropenia precipitates colitis or the latter causes agranulocytosis by bone marrow suppression through cytokines remains to be proved. The diagnosis of medication-related adverse reactions remains a big challenge for clinicians and therefore requires a high index of suspicion. Resolution of the symptoms can simply occur with the discontinuation of the offending drug and often does not require extensive workup or treatments that might cause harm to the patient's health.

Polycystic Liver With Cardiac Compression Leading to Atrial Fibrillation: Case Report and Review of the Literature.

Polycystic liver disease (PCLD) is a rare condition that most often occurs in patients with polycystic kidney disease and less commonly as an isolated liver disease. Complications include cyst rupture, infection, hemorrhage, and compression of surrounding organs by large cysts. We present the case of a patient with a history of PCLD who presented to our hospital with palpitations and was found to have atrial fibrillation. Imaging and echocardiograph revealed a dominant large cyst compressing the right atrium. Other etiologies including thyroid disease, ischemic heart disease, and electrolytes abnormalities were excluded. The patient refused surgical intervention and was conservatively treated with rate control and anticoagulation. To the best of our knowledge, this is the first case of new-onset atrial fibrillation secondary to right atrial compression by a liver cyst. Compression of cardiac chambers resulting in new-onset arrhythmia should be considered when evaluating patients with PCLD.

Adult Onset Morgagni Hernia: Medical vs. Surgical Management.

Morgagni hernia is a type of diaphragmatic hernia where bowel content herniates through an irregular opening into the thoracic cavity. Herein, we present the case of an 84-year-old female patient with multiple hospital admissions for abdominal symptoms. Radiological studies confirmed Morgagni hernia. She underwent a laparoscopic intervention with mesh placement. She was discharged in stable condition and was doing well on follow-up.

Yersinia Pseudotuberculosis Modulates Regulatory T Cell Stability via Injection of Yersinia Outer Proteins in a Type III Secretion System-Dependent Manner.

Adaptive immunity is essentially required to control acute infection with enteropathogenic Yersinia pseudotuberculosis (Yptb). We have recently demonstrated that Yptb can directly modulate naïve CD4+ T cell differentiation. However, whether fully differentiated forkhead box protein P3 (Foxp3+) regulatory T cells (Tregs), fundamental key players to maintain immune homeostasis, are targeted by Yptb remains elusive. Here, we demonstrate that within the CD4+ T cell compartment Yptb preferentially targets Tregs and injects Yersinia outer proteins (Yops) in a process that depends on the type III secretion system and invasins. Remarkably, Yop-translocation into ex vivo isolated Foxp3+ Tregs resulted in a substantial downregulation of Foxp3 expression and a decreased capacity to express the immunosuppressive cytokine interleukin-10 (IL-10). Together, these findings highlight that invasins are critically required to mediate Yptb attachment to Foxp3+ Tregs, which allows efficient Yop-translocation and finally enables the modulation of the Foxp3+ Tregs' suppressive phenotype.