Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis.

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

A National Survey of the Training and Practice Patterns of Practicing Pediatric Advanced Endoscopists in the United States.

BACKGROUND AND AIMS: Pediatric advanced endoscopy consists primarily of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) and is becoming more common in pediatrics. This study aims to characterize the current landscape of pediatric advanced endoscopy training and practice by directly surveying independently practicing pediatric advanced endoscopists (PAEs). We also aim to ascertain expert opinion on competency in pediatric ERCP and EUS. METHODS: A 66-question REDCap survey and a 73-question Qualtrics survey were distributed to members of the ERCP Special Interest Group of North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Respondents currently performing ERCP or EUS independently in children were included. Statistical analysis was performed using Mann-Whitney U test. RESULTS: Of 41 PAEs surveyed, 38 (92.7%) responded and 27 independent practitioners were included. Thirteen respondents performed EUS. PAEs who completed an advanced endoscopy fellowship (AEF) were more comfortable performing American Society for Gastrointestinal Endoscopy grade 3 or grade 4 ERCPs ( P < 0.0008) and felt more prepared to practice EUS independently than other trainees. Expert opinion of PAEs felt a threshold of 200 procedures was needed to attain competency in either ERCP or EUS. Pediatric duodenoscope exposure improved comfort in performing ERCP in children <10 kg ( P = 0.009). CONCLUSIONS: Training of pediatric gastroenterologists in ERCP and EUS are highly variable, though the skills attained are similar. AEF-trained specialists reported greater training volumes and felt more prepared to practice independently than those who did not. Competency thresholds determined by expert PAEs for ERCP and EUS agree with American Society for Gastrointestinal Endoscopy guidelines for adult advanced endoscopy trainees.

A critical review of bile acids and their receptors in hepatic encephalopathy.

Hepatic encephalopathy describes an array of neurological complications that arise due to liver insufficiency. The pathogenesis of hepatic encephalopathy shares a longstanding association with hyperammonemia and inflammation, and recently, aberrant bile acid signaling has been implicated in the development of key features of hepatic encephalopathy. These key features include neuronal dysfunction, neuroinflammation and blood-brain barrier permeability. This review summarizes the findings of recent studies demonstrating a role for bile acids in the pathogenesis of hepatic encephalopathy via one of three main bile acid receptors and speculates on the possible downstream consequences of aberrant bile acid signaling.

Severe Acute Respiratory Syndrome Coronavirus-2 Infection in Children With Liver Transplant and Native Liver Disease: An International Observational Registry Study.

OBJECTIVE: Increased mortality risk because of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry. METHODS: In this multicenter observational cohort study, we collected data from 91 patients <21 years (LD 44, LT 47) with laboratory-confirmed SARS-CoV2 infection between April 21 and September 17, 2020. RESULTS: Patients with LD were more likely to require admission (70% vs 43% LT, P = 0.007) and pediatric intensive care unit (PICU) management (32% vs 4% LT, P = 0.001). Seven LD patients required mechanical ventilation (MV) and 2 patients died; no patients in the LT cohort died or required MV. Four LD patients presented in pediatric acute liver failure (PALF), 2 with concurrent multisystem inflammatory syndrome in children (MIS-C); all recovered without LT. Two LD patients had MIS-C alone and 1 patient died. Bivariable logistic-regression analysis found that patients with nonalcoholic fatty LD (NAFLD) (odds ratio [OR] 5.6, P = 0.02) and LD (OR 6.1, P = 0.01, vs LT) had higher odds of severe disease (PICU, vasopressor support, MV, renal replacement therapy or death). CONCLUSIONS: Although not directly comparable, LT recipients had lower odds of severe SARS-CoV2 infection (vs LD), despite immunosuppression burden. NAFLD patients reported to the registry had higher odds of severe SARS-CoV2 disease. Future controlled studies are needed to evaluate effective treatments and further stratify LD and LT patients with SARS-CoV2 infection.

Two cases of adenodermatofibroma.

Dermatofibromas (DF) are common skin lesions composed of a dermal proliferation of fibroblasts and histiocytes. Among the variants of DFs, adenodermatofibroma are characterized by a dense proliferation of fibroblasts and histiocytes admixed with entrapped dilated glandular structures. We report two additional cases of adenodermatofibromas, review the literature, theorize on the histopathogenesis of this variant, and suggest that there are different patterns among adenodermatofibromas, from primarily cystic to primarily glandular.

Overexpression of NEIL3 associated with altered genome and poor survival in selected types of human cancer.

Base excision repair, which is initiated by the DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. Several base excision repair genes are deregulated in cancer and affect cellular outcomes to chemotherapy and carcinogenesis. Endonuclease VIII-like 3 (NEIL3) is a DNA glycosylase protein that is involved in oxidative and interstrand crosslink DNA damage repair. Our previous work has showed that NEIL3 is required to maintain replication fork integrity. It is unknown whether NEIL3 overexpression could contribute to cancer phenotypes, and its prognostic value and use as potential drug target remain unexplored. Our analysis of cancer genomics data sets reveals that NEIL3 frequently undergoes overexpression in several cancers. Furthermore, patients who exhibited NEIL3 overexpression with pancreatic adenocarcinoma, lung adenocarcinoma, lower grade glioma, kidney renal clear cell carcinoma, and kidney papillary cell carcinoma had worse overall survival. Importantly, NEIL3 overexpressed tumors accumulate mutation and chromosomal variations. Furthermore, NEIL3 overexpressed tumors exhibit simultaneous overexpression of homologous recombination genes (BRCA1/2) and mismatch repair genes (MSH2/MSH6). However, NEIL3 overexpression is negatively correlated with tumor overexpressing nucleotide excision repair genes (XPA, XPC, ERCC1/2). Our results suggest that NEIL3 might be a potential prognosis marker for high-risk patients, and/or an attractive therapeutic target for selected cancers.

Trends in the management of pelvic fractures, 2008-2010.

BACKGROUND: Bleeding from pelvic fractures can be lethal. Angioembolization (AE) and external fixation (EXFIX) are common treatments to control bleeding, but it is not known how frequently they are used. We hypothesized that AE would be increasingly more common compared with EXFIX over time. METHODS: The National Trauma Data Bank for the years from 2008-2010 were used. Patients were included in the study if they had an International Classification of Diseases, ninth edition, Clinical Modification codes for pelvic fractures and were aged ≥18 y. Patients were excluded if they had isolated acetabular fractures, were not admitted, or had minor injuries. Outcomes included receiving a procedure and in-hospital mortality. RESULTS: A total of 22,568 patients met study criteria. AE and EXFIX were performed in 746 (3.3%) and 663 (2.9%) patients, respectively. AE was performed more often as the study period progressed (2.5% in 2007 to 3.7% in 2010; P < 0.001). This remained significant in adjusted analysis (odds ratio per year 1.15; P = 0.008). Having a procedure was associated with higher mortality in unadjusted analyses compared with those with no procedure (11.0% for no procedure versus 20.5% and 13.4% for AE or EXFIX, respectively; P < 0.001). In adjusted analyses, only AE remained associated with higher mortality (odds ratio 1.63; P < 0.001). CONCLUSIONS: AE in severely injured pelvic fracture patients is increasing. AE is associated with higher mortality, which may reflect the fact that it is used for patients at higher risk of death. The role of AE for bleeding should be examined in future studies.

Does an Upper Endoscopy Before Transesophageal Echocardiography Change Patient Management?

GOAL: To determine if esophagogastroduodenoscopy (EGD) before transesophageal echocardiography (TEE) will change patient management. BACKGROUND: Before TEE gastroenterologists are often consulted to evaluate patients with a history of dysphagia, known gastrointestinal (GI) disease, or GI bleed. There are no known published data on the clinical utility of EGD before TEE. DESIGN AND SETTING: Retrospective study at an inner city tertiary-care center. PATIENTS: A total of 134 patients were included who were at least 18 years old and underwent an EGD to evaluate the safety of the blind passage of a TEE probe. RESULTS: In total, 134 patients were identified. Twenty patients (15%) were not cleared for TEE due to esophageal surface abnormalities (n=3; esophagitis, ulcer, mucosal tear), esophageal structural abnormalities (n=10; varices, stricture, ring, web, hernia, Zenker), and combinations thereof (n=7). Of the 20 patients not cleared for TEE, 17 never underwent a TEE and 3 patients underwent a TEE 7 to 180 days later. Two patients undergoing EGD and 5 patients undergoing TEE experienced adverse cardiopulmonary events. CONCLUSIONS: Our results demonstrate that an EGD before TEE can elucidate findings that may preclude the passage of a blind probe in patients with upper GI symptoms or known esophageal disease. Therefore, we propose that an EGD is clinically beneficial before TEE and can change patient management.

Prospective diagnostic test accuracy comparison of computed tomography during arterial portography and Primovist magnetic resonance imaging in the pre-operative assessment of colorectal cancer liver metastases.

OBJECTIVES: To assess and compare the accuracy and inter-observer agreement for the detection of liver lesions using Primovist magnetic resonance imaging (pMRI) and computed tomography during arterial portography (CTAP). METHODS: Patients evaluated at St George Hospital Liver Unit for colorectal liver metastases (CRCLM) underwent CTAP as part of standard staging. pMRI was added to the pre-operative assessment. Two radiologists reported CTAP and two reported pMRI. The sensitivity and specificity of CTAP and pMRI were calculated using histopathology as the gold standard. RESULTS: Complete data were available for 62 patients corresponding to 219 lesions confirmed on histopathology. Agreement on the detection of lesions between the two radiologists that reported pMRI was higher than for CTAP (Kappa = 0.80 versus 0.74). Specificity of lesion detection for pMRI was 0.88 and 0.83 for CTAP (P = 0.112). Sensitivity for pMRI was 0.83 and 0.81 for CTAP. For patients who had chemotherapy before evaluation, pMRI had a significantly higher specificity than CTAP (0.79 versus 0.63, P = 0.011). CONCLUSIONS: pMRI is less invasive, has a good inter-observer agreement, has comparable sensitivity and specificity to CTAP in the pre-chemotherapy population and demonstrates better specificity in patients assessed post-chemotherapy. pMRI is a valid alternative to CTAP in the assessment of CRCLM.

Multiorgan Metabolomics and Lipidomics Provide New Insights Into Fat Infiltration in the Liver, Muscle Wasting, and Liver-Muscle Crosstalk Following Burn Injury.

Burn injury mediated hypermetabolic syndrome leads to increased mortality among severe burn victims, due to liver failure and muscle wasting. Metabolic changes may persist up to 2 years following the injury. Thus, understanding the underlying mechanisms of the pathology is crucially important to develop appropriate therapeutic approaches. We present detailed metabolomic and lipidomic analyses of the liver and muscle tissues in a rat model with a 30% body surface area burn injury located at the dorsal skin. Three hundred and thirty-eight of 1587 detected metabolites and lipids in the liver and 119 of 1504 in the muscle tissue exhibited statistically significant alterations. We observed excessive accumulation of triacylglycerols, decreased levels of S-adenosylmethionine, increased levels of glutamine and xenobiotics in the liver tissue. Additionally, the levels of gluconeogenesis, glycolysis, and tricarboxylic acid cycle metabolites are generally decreased in the liver. On the other hand, burn injury muscle tissue exhibits increased levels of acyl-carnitines, alpha-hydroxyisovalerate, ophthalmate, alpha-hydroxybutyrate, and decreased levels of reduced glutathione. The results of this preliminary study provide compelling observations that liver and muscle tissues undergo distinctly different changes during hypermetabolism, possibly reflecting liver-muscle crosstalk. The liver and muscle tissues might be exacerbating each other's metabolic pathologies, via excessive utilization of certain metabolites produced by each other.

Rapid and accurate left ventricular chamber quantification using a novel CMR segmentation algorithm: a clinical validation study.

PURPOSE: To evaluate the clinical performance of a novel automated left ventricle (LV) segmentation algorithm (LV-METRIC) that involves no geometric assumptions. MATERIALS AND METHODS: LV-METRIC and manual tracing (MT) were used independently to quantify LV volumes and LVEF (ejection fraction) for 151 consecutive patients who underwent cine-CMR (steady-state free precession). Phase contrast imaging was used to independently measure stroke volume. RESULTS: LV-METRIC was successful in all cases. Mean LVEF was within 1 point of MT (Delta 0.6 +/- 2.3%, P < 0.05), with smaller differences among patients with (0.5 +/- 2.5%) versus those without (0.9 +/- 2.3%; P = 0.01) advanced systolic dysfunction (LVEF

Chronic diarrhea.

Chronic diarrhea is a complex and common problem faced by primary care clinicians. Its causes can range from the common and relatively benign excessive juice consumption to the more alarming inflammatory bowel disease (IBD). This paper will review the definition and etiology of chronic diarrhea and aims to provide a simple approach to its diagnosis and management including when, if appropriate, to refer to GI specialist.

Occupational Contact Dermatitis: Common Occupational Allergens.

The prevalence of occupational contact dermatitis is estimated to be between 6.7% and 10.6% and can lead to missed work and job loss. Although treatment may provide temporary relief, identifying the culprit allergen may help the clinician counsel on how to avoid or reduce exposure. Some of the most common high-risk occupations for allergic contact dermatitis include agricultural workers, construction workers, health care workers, hairdressers, mechanics, and machinists. In this article, we discuss the common occupational exposures of these high-risk professions, and summarize the common culprit allergens.

Paradoxical modulation of influenza by intranasal administration of non-replicating adenovirus particles.

Respiratory mucosal infection by airborne microbes is a common event that occurs every day. We report here that intranasal administration of non-replicating adenovirus (Ad) particles to mice could either confer rapid protection against influenza virus (IFV) challenge independent of adaptive immunity, or exacerbate influenza by triggering rapid death. The life-or-death outcome hinges on the time interval between Ad administration and IFV challenge in conjunction with specific mouse/IFV strains. Intranasal instillation of Ad particles 1-47 days prior to IFV challenge conferred rapid protection against influenza in Balb/c mice whereas exposure to Ad 39 days prior to challenge with a specific IFV strain or 1 day post-challenge with that IFV strain induced rapid death in C57BL/6 mice. Notably, consecutive administrations of Ad prior to IFV challenge conferred a synergy in triggering a potent anti-influenza state; even a detrimental Ad exposure 39 days before challenge with the deadly IFV strain was reversed to a beneficial one by subsequent Ad boosts. Results revealed an intricate relationship between infection and innate immunity that is a linchpin around which effects revolve from protective immunity to collateral damage. It is urgent to repeat the experiments with an expanded scope for characterizing the status that defines susceptibility or resistance to IFV infection and subsequently reveal the underlying mechanisms. Whether broad heterologous protective effects induced by AdE and adaptive immunity elicited by vaccination could confer synergy during mitigation of a pandemic remains to be seen.

Prevalence of Abnormal Ultrasound Findings in Asymptomatic Posterior Tibial Tendons.

BACKGROUND: Posterior tibial tendon dysfunction (PTTD) is a pathological condition that can cause failure of the posterior tibial tendon (PTT). Initially, patients with PTTD are often asymptomatic, making early identification and treatment challenging. Certain ultrasound (US) characteristics have been implicated in the presence of tendinopathy, but their frequency has yet to be assessed in the PTT. The purpose of this study was to identify and report on the frequency of incidental, or potentially early subclinical, tendinopathic US characteristics in asymptomatic PTTs. METHODS: Following institutional review board approval, 150 participants underwent a bilateral-comprehensive US assessment. The resulting images were reviewed and assessed to identify the presence of abnormalities demonstrated to represent tendinopathy. RESULTS: Overall, 266 tendons were assessed and 128 (48.1%) were determined to have at least one tendinopathic trait. Specifically, 51 (19.2%) had circumferential fluid, 69 (25.9%) had noncircumferential fluid, 22 (8.3%) had thickening, 31 (11.7%) had heterogenicity, 19 (7.1%) had hyperemia, and 2 (0.8%) had calcification. Additionally, Caucasian participants were found to be nearly 3 times more likely to have tendinopathic findings when compared with African American participants. CONCLUSION: Sixty-seven percent of participants and 48.1% of PTTs evaluated had at least one tendinopathic feature identified on US. The prevalence rates of these findings, observed in participants, were as follows: noncircumferential fluid, circumferential fluid, heterogenicity, and thickening. Knowing the frequency of these traits may help clinicians to identify subclinical tendinopathy in the PTT before it progresses to PTTD. LEVEL OF EVIDENCE: Level IV, case series.

Concentration of polychlorinated biphenyls in serum from New Jersey biomonitoring study: 2016-2018.

The first statewide New Jersey Biomonitoring (NJBM) of serum polychlorinated biphenyls (PCBs) was conducted from 2016 to 2018. Forty ortho-substituted PCBs were measured in serum samples collected from 920 NJ residents in compliance with the CDC method. The lipid adjusted geometric mean (GM) of ∑40PCB concentration for all the 920 measured subjects was 65.5 ng/g lipid (95% CIs: 56.9-75.4 ng/g lipid). Age stratified serum concentration showed that the lowest GM (33.3 ng/g lipid) was observed in the 20-39 years age group (n = 282), followed by a concentration of 76.05 ng/g lipid (n = 382) in the 40-59 years age group, and the highest GM (168.4 ng/g lipid) was found in the 60-74 years age group (n = 256). A survey regression model revealed that ∑40PCBs was significantly associated with age, moderately associated with geographic region, and not significantly associated with sex. The comparison of serum PCB levels in NJBM with the sequential National Health and Nutrition Examination Survey (NHANES) data suggested that the serum PCBs in NJ adults declined 52-59% at all age groups over the last decade. Positive Matrix Factorization (PMF) suggests that ongoing and recent exposure to lower molecular weight PCBs contributes about 15% to total serum PCB levels and more in younger subjects, while higher molecular weight PCBs contribute 52% of the total serum PCB levels and more in older subjects.

Wernicke's Encephalopathy Presenting as Sensorineural Hearing Loss.

Sleeve gastrectomy is a restrictive-type weight loss surgery that can result in nutritional deficiencies, such as vitamin B1 (thiamine) deficiency. Although Wernicke's encephalopathy is a known complication following bariatric surgery, bilateral sensorineural hearing loss is a rare presenting symptom of this condition. We present a case of a patient two months postoperative following a sleeve gastrectomy whose chief complaint was hearing loss. While initial laboratory evaluation of her complaint showed elevated inflammatory markers, prompting an autoimmune workup, ultimately the diagnosis of Wernicke's encephalopathy was confirmed by a low thiamine level and magnetic resonance imaging findings. A correction of the patient's thiamine deficiency led to an improvement of her symptoms.