Targeting Inflammation and Oxidative Stress to Improve Outcomes in a TNBS Murine Crohn's Colitis Model.

Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.

In utero Diagnosis of Spinal Dermal Sinus.

INTRODUCTION: Congenital dermal sinus (CDS) is an open neural tube defect (NTD) that occurs in 1 in 2,500 births a year and often goes undetected until patients present with complications like infection and neurological deficits. Early diagnosis and repair of CDS may prevent formation of these complications. In utero diagnosis of these lesions may improve long-term outcomes by enabling referral to specialty services and planned postnatal repair; however, only 2 such cases have been reported in the literature. We present a third case of in utero diagnosis of CDS with a description and discussion of findings from surgical exploration and pathology. CASE PRESENTATION: Routine prenatal ultrasound scan detected a tethered cystic structure arising from the back of the fetus at 20 weeks of gestation. Dedicated fetal ultrasound confirmed the presence of a cystic lesion protruding through a lamina defect, while fetal magnetic resonance imaging showed an intact spinal cord and meninges, suggesting a diagnosis of CDS. Neurosurgery followed along closely and took the child for surgical exploration on day 2 of life. A fibrous stalk with an intradural component and associated cord tethering was excised. Histology showed fibrous tissue without an epithelial-lined lumen. CONCLUSION: CDS is a form of NTD that occurs from nondisjunction of the cutaneous ectoderm and neuroectoderm during formation of the neural tube. Slight differences in how this error occurs can explain variations seen in this spectrum of disease, including CDS without an epithelial-lined lumen as seen in this case. Newborns with CDS can go undiagnosed for years and present with long-term complications. Fetal imaging can assist in early recognition and surgical excision of CDS in newborns.

A Rare Case of Metaplastic Thymoma Presenting With Myasthenia Gravis.

Thymomas are tumors of the mediastinum often associated with autoimmune conditions, in particular myasthenia gravis. In contrast, among the fewer than 40 reports of metaplastic thymoma, myasthenia gravis is rarely found. We describe the fourth patient, and first man, with metaplastic thymoma and myasthenia gravis. A 34-year-old had acute onset of double vision with associated dysphagia and was found to have an elevation of serum acetylcholine receptor antibodies. He underwent a transsternal thymectomy. Tissue sections showed a biphasic proliferation of keratin-positive epithelial cells with a complement of spindle cells confirming the diagnosis of metaplastic thymoma. Terminal deoxynucleotidyl transferase (TDT)-positive T lymphocytes were rare and only found in the periphery of the tumor, consistent with thymic remnant. A YAP1::MAML2 gene fusion, with an in-frame fusion between genes YAP1 Exon5 (NM_001130145) and MAML2 Exon2 (NM_032427) was found, supporting further the diagnosis of metaplastic thymoma (Anchored multiplex RNA sequencing [Archer Dx, Boulder, CO] assay). The patient's gender and relatively young age, the presence of an autoimmune condition, and the lack of lymphocytic infiltrate all contribute unusual features to this case and suggest avenues for further exploration.

CNP-miR146a Decreases Inflammation in Murine Acute Infectious Lung Injury.

Acute respiratory distress syndrome (ARDS) has approximately 40% in-hospital mortality, and treatment is limited to supportive care. Pneumonia is the underlying etiology in many cases with unrestrained inflammation central to the pathophysiology. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA(miR)-146a, reduces bleomycin- and endotoxin-induced acute lung injury (ALI) by decreasing inflammation. We therefore hypothesized that CNP-miR146a would decrease inflammation in murine infectious ALI. Mice were injured with intratracheal (IT) MRSA or saline followed by treatment with IT CNP-miR146a or saline control. Twenty-four hours post-infection, bronchoalveolar lavage fluid (BALF) and whole lungs were analyzed for various markers of inflammation. Compared to controls, MRSA infection significantly increased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1ß; p < 0.05), BALF proinflammatory cytokines (IL-6, IL-8, TNFα, IL-1ß; p < 0.01), and inflammatory cell infiltrate (p = 0.03). CNP-miR146a treatment significantly decreased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1ß; p < 0.05), bronchoalveolar proinflammatory protein leak (IL-6, IL-8, TNFα; p < 0.05), and inflammatory infiltrate (p = 0.01). CNP-miR146a decreases inflammation and improves alveolar-capillary barrier integrity in the MRSA-infected lung and has significant promise as a potential therapeutic for ARDS.

Immunomodulatory biomaterials on chemokine signaling in wound healing.

Normal wound healing occurs through a careful orchestration of cytokine and chemokine signaling in response to injury. Chemokines are a small family of chemotactic cytokines that are secreted by immune cells in response to injury and are primarily responsible for recruiting appropriate immune cell types to injured tissue at the appropriate time. Dysregulation of chemokine signaling is suspected to contribute to delayed wound healing and chronic wounds in diseased states. Various biomaterials are being used in the development of new therapeutics for wound healing and our understanding of their effects on chemokine signaling is limited. It has been shown that modifications to the physiochemical properties of biomaterials can affect the body's immune reaction. Studying these effects on chemokine expression by various tissues and cell type can help us develop novel biomaterial therapies. In this review, we summarize the current research available on both natural and synthetic biomaterials and their effects on chemokine signaling in wound healing. In our investigation, we conclude that our knowledge of chemokines is still limited and that many in fact share both pro-inflammatory and anti-inflammatory properties. The predominance of either a pro-inflammatory or anti-inflammatory profile is mostly likely dependent on timing after injury and exposure to the biomaterial. More research is needed to better understand the interaction and contribution of biomaterials to chemokine activity in wound healing and their immunomodulatory effects.

Effects of microRNAs on angiogenesis in diabetic wounds.

Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.

Clinical Quiz-Newborn Female with an Anorectal Malformation and a Gynecological Abnormality.

We present a case of a newborn female with imperforate anus who on exam was found to have a rectal fistula in the vestibule, no vaginal opening, and a normal urethra. A diagnostic laparoscopy was performed to elucidate the internal anatomy. The case is presented with a focus on surgical strategies in approaching the female patient with anorectal malformation and a Mullerian anomaly, with questions for the readers posed in a quiz format.

Battery Ingestion with Colonic Perforation after Colostomy Closure in a Toddler.

Disc and button battery ingestion in children is common. In fact, data reports a dramatic increase in battery ingestion during the coronavirus disease 2019 pandemic likely as a result of increased household population density and electronic product utilization. These batteries often remain lodged in the esophagus causing potentially devastating complications if they are not removed urgently. Batteries that are passed beyond the esophagus usually do not cause any complications. We present the case of a 15-month-old male who underwent a colostomy takedown 2 months following a posterior sagittal anorectoplasty for imperforate anus. He recovered quickly, was advanced on his diet, and was discharged to home on postoperative day 3. On postoperative day 5 following the stoma closure, he presented with an acute abdomen, pneumoperitoneum and an abdominal X-ray that revealed a 21 mm disc battery in the left lower quadrant. He underwent exploration and the battery was found perforating the anastomosis. There was significant fibropurulent exudate and inflammation. The battery was removed, the anastomosis was excised, and a colostomy with Hartman's pouch was performed. The toddler recovered uneventfully. This case offers an opportunity to discuss the concerns of battery ingestion and postoperative care following intestinal surgery in children. We could find no other similar reports in the world's literature of a disrupted colonic anastomosis due to battery ingestion.

Image of the Month: Decision-Making in Surgery for Late Onset Hirschsprung Disease.

We present a case of a 14-year-old boy with chronic distension, poor growth, and chronic constipation. He undergoes anorectal manometry and rectal biopsy, confirming the diagnosis of Hirschsprung disease (HD). The case is presented with a key image and associated questions to prompt discussion on strategies for management and treatment of HD in late-diagnosed children.

Image of the Month: How to Select the Ideal Surgical Approach in Male Anorectal Malformation with No Visible Fistula.

We present a case of a 6-month-old male infant with an anorectal malformation (ARM) who underwent colostomy as a newborn, and now presents for definitive repair. A colostogram is shown to identify the malformation and to help plan for the ideal surgical approach. The case is presented with a focus on surgical strategies for management of ARM in the male infant, with questions for the readers posed in a quiz format.

Image of the Month: High Pressure Distal Colostogram in a Patient with an Anorectal Malformation.

An adequately performed high pressure distal colostogram is crucial to plan surgery in male patients born with anorectal malformations. We present two male patients that underwent a divided sigmoid colostomy with distal mucus fistula in the neonatal period and at 6 months of age underwent a high pressure distal colostogram. In the discussion, we will give some tricks beyond the known rules: how to correctly interpret a high pressure distal colostogram, how to identify the level of a recto-urinary fistula, and how to accurately plan the surgical approach.

Image of the Month: Enterocolitis Following a Pull-through for Total Colonic Hirschsprung Disease in a 2-Year-Old Boy.

We present a case of a 2-year-old boy with total colonic Hirschsprung disease (HD) who underwent an ileostomy as a newborn, and then colectomy and pull-through at 10 months of age. Since then he has presented four times with enterocolitis. The case is presented with a focus on evaluating patients with HD who present with obstructive symptoms following corrective surgery. A key image is presented along with questions formatted as a quiz to guide readers through critically evaluating the case.

Lead toxicity from retained bullet fragments: A systematic review and meta-analysis.

BACKGROUND: Firearm injury remains a public health epidemic in the United States. A large proportion of individuals with gunshot wounds subsequently have retained bullet fragments (RBF). There are no standard medical guidelines regarding bullet removal and the full extent of the consequences of RBF remains unknown. OBJECTIVE: To determine whether there is an association among RBF, elevated blood lead levels (BLL) and lead toxicity in survivors of firearm injury 16 years and older. METHODS: PubMed, EMBASE, CINAHL, Scopus, Cochrane Library, and Sociological Abstracts electronic databases were searched for all randomized controlled trials, prospective and retrospective cohort, case-control and cross-sectional studies published in the English language between 1988 and 2018. Quality assessment and risk of bias was evaluated using the Newcastle Ottawa Scale. A meta-analysis was performed using a random-effects model. RESULTS: The search yielded 2,012 articles after removal of duplicates. Twelve were included after full article review. Eleven studies supported an association between elevated BLL and RBF. Bony fractures were associated with increased risk of elevated BLL in three studies. A positive relationship between BLL and the number of RBF was also shown in three studies, with one study demonstrating 25.6% increase in BLL for every natural-log increase in RBF (1-228, p < 0.01). Meta-analysis demonstrated BLL significantly higher in individuals with RBF as compared to controls (5.47 µg/dL, p < 0.01). CONCLUSION: Patients with bony fractures or multiple RBF, who are at higher risk of elevated BLL, should be monitored for BLL in intervals of 3 months within the first year of injury. For patients who return with BLL above 5 µg/dL, all efforts must be undertaken to remove fragments if there is no potential to worsen the injury. LEVEL OF EVIDENCE: Systematic review, Meta-analysis, level III.

Development of three quantitative real-time PCR assays for the detection of Rickettsia raoultii, Rickettsia slovaca, and Rickettsia aeschlimannii and their validation with ticks from the country of Georgia and the Republic of Azerbaijan.

A previous surveillance study of human pathogens within ticks collected in the country of Georgia showed a relatively high infection rate for Rickettsia raoultii, R. slovaca, and R. aeschlimannii. These 3 spotted fever group rickettsiae are human pathogens: R. raoultii and R. slovaca cause tick-borne lymphadenopathy (TIBOLA), and R. aeschlimannii causes an infection characterized by fever and maculopapular rash. Three quantitative real-time polymerase chain reaction (qPCR) assays, Rraoul, Rslov, and Raesch were developed and optimized to detect R. raoultii, R. slovaca, and R. aeschlimannii, respectively, by targeting fragments of the outer membrane protein B gene (ompB) using species-specific molecular beacon or TaqMan probes. The 3 qPCR assays showed 100% specificity when tested against a rickettsiae DNA panel (n=20) and a bacteria DNA panel (n=12). The limit of detection was found to be at least 3 copies per reaction for all assays. Validation of the assays using previously investigated tick nucleic acid preparations, which included Rickettsia-free tick samples, tick samples that contain R. raoultii, R. slovaca, R. aeschlimannii, and other Rickettsia spp., gave 100% sensitivity for all 3 qPCR assays. In addition, a total of 65 tick nucleic acid preparations (representing 259 individual ticks) collected from the country of Georgia and the Republic of Azerbaijan in 2009 was tested using the 3 qPCR assays. R. raoultii, R. slovaca, and R. aeschlimannii were not detected in any ticks (n=31) from the Republic of Azerbaijan, but in the ticks from the country of Georgia (n=228) the minimal infection rate for R. raoultii and R. slovaca in Dermacentor marginatus was 10% and 4%, respectively, and for R. aeschlimannii in Haemaphysalis sulcata and Hyalomma spp. it was 1.9% and 20%, respectively.