Clinical Application of Intestinal Ultrasound in Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Intestinal ultrasound (IUS) is a non-invasive, accurate, and well-tolerated tool that provides real-time assessment of inflammatory bowel disease (IBD) activity and is therefore an ideal monitoring tool. This review describes the evolving role of IUS in each phase of clinical management of IBD. RECENT FINDINGS: Accumulating evidence has demonstrated that IUS is an excellent tool for the assessment of suspected IBD, with a very high negative predictive value. It accurately assesses disease activity, disease complications, and in the pre-treatment phase, provides a benchmark for subsequent follow-up. IUS can detect early therapeutic response and correlates well with other established monitoring modalities with arguably superior predictive capabilities and ability to assess a deeper degree of remission, transmural healing (TH). IUS has a crucial role in the management of IBD and has ushered in a new era of monitoring with more rapid evaluation and the opportunity for early optimization, deeper therapeutic targets, and improved outcomes.

Bedside Intestinal Ultrasound Performed in an Inflammatory Bowel Disease Urgent Assessment Clinic Improves Clinical Decision-Making and Resource Utilization.

Background: Patients with inflammatory bowel disease (IBD) require accessible, timely, and noninvasive strategies to monitor disease. The aim was to assess the integration of intestinal ultrasound (IUS) on decision-making and endoscopy utilization in a standardized care pathway. Methods: This prospective, multicenter, international, observational cohort study included patients seen within a centralized model for IBD care was conducted during the COVID pandemic. Patients were evaluated with IUS alone or in combination with an in-clinic, unsedated sigmoidoscopy. Demographic, clinical, laboratory, and imaging data, clinical decisions, and need for urgent endoscopy, hospitalization, and surgeries were recorded. Results: Of the 158 patients included, the majority had an established diagnosis of Crohn's disease (n = 123, 78%), and 47% (n = 75) of patients were on biologic therapy. IUS identified active inflammation in 65% (n = 102) of patients, and strictures in 14% (n = 22). Fecal calprotectin levels correlated with inflammation detected on IUS (median of 50 µg/g [Q1-Q3: 26-107 µg/g] without inflammation and 270 µg/g [Q1-Q3: 61-556 µg/g] with inflammation; p = 0.0271). In the majority of patients, clinical assessment with IUS led to an acute change in IBD-specific medications (57%, n = 90) and avoided or delayed the need for urgent endoscopy (85%, n = 134). Four patients were referred for urgent surgical consultation. Conclusions: Point-of-care IUS used in a flare clinic pathway is a useful strategy to improve effective IBD care delivery and to assist in therapeutic management decisions, in many cases avoiding the acute need for endoscopy.

The 2023 Impact of Inflammatory Bowel Disease in Canada: Treatment Landscape.

The therapeutic landscape for inflammatory bowel disease (IBD) has changed considerably over the past two decades, owing to the development and widespread penetration of targeted therapies, including biologics and small molecules. While some conventional treatments continue to have an important role in the management of IBD, treatment of IBD is increasingly moving towards targeted therapies given their greater efficacy and safety in comparison to conventional agents. Early introduction of these therapies-particularly in persons with Crohn's disease-combining targeted therapies with traditional anti-metabolite immunomodulators and targeting objective markers of disease activity (in addition to symptoms), have been shown to improve health outcomes and will be increasingly adopted over time. The substantially increased costs associated with targeted therapies has led to a ballooning of healthcare expenditure to treat IBD over the past 15 years. The introduction of less expensive biosimilar anti-tumour necrosis factor therapies may bend this cost curve downwards, potentially allowing for more widespread access to these medications. Newer therapies targeting different inflammatory pathways and complementary and alternative therapies (including novel diets) will continue to shape the IBD treatment landscape. More precise use of a growing number of targeted therapies in the right individuals at the right time will help minimize the development of expensive and disabling complications, which has the potential to further reduce costs and improve outcomes.

The 2023 Impact of Inflammatory Bowel Disease in Canada: Special Populations-IBD in Seniors.

Approximately one out of every 88 seniors has inflammatory bowel disease (IBD), and this is expected to increase in the future. They are more likely to have left-sided disease in ulcerative colitis, and isolated colonic disease in Crohn's disease; perianal disease is less common. Other common diagnoses in the elderly must also be considered when they initially present to a healthcare provider. Treatment of the elderly is similar to younger persons with IBD, though considerations of the increased risk of infections and malignancy must be considered when using immune modulating drugs. Whether anti-TNF therapies increase the risk of infections is not definitive, though newer biologics, including vedolizumab and ustekinumab, are thought to be safer with lower risk of adverse events. Polypharmacy and frailty are other considerations in the elderly when choosing a treatment, as frailty is associated with worse outcomes. Costs for IBD-related hospitalizations are higher in the elderly compared with younger persons. When elderly persons with IBD are cared for by a gastroenterologist, their outcomes tend to be better. However, as elderly persons with IBD continue to age, they may not have access to the same care as younger people with IBD due to deficiencies in their ability to use or access technology.

Lung ultrasound: A comparison of image interpretation accuracy between curvilinear and phased array transducers.

Introduction: Both curvilinear and phased array transducers are commonly used to perform lung ultrasound (LUS). This study seeks to compare LUS interpretation accuracy of images obtained using a curvilinear transducer with those obtained using a phased array transducer. Methods: We invited 166 internists and trainees to interpret 16 LUS images/cineloops of eight patients in an online survey: eight curvilinear and eight phased array, performed on the same lung location. Images depicted normal lung, pneumothorax, pleural irregularities, consolidation/hepatisation, pleural effusions and B-lines. Primary outcome for each participant is the difference in image interpretation accuracy scores between the two transducers. Results: A total of 112 (67%) participants completed the survey. The mean paired accuracy score difference between the curvilinear and phased array images was 3.0% (95% CI: 0.6 to 5.4%, P = 0.015). For novices, scores were higher on curvilinear images (mean difference: 5.4%, 95% CI: 0.9 to 9.9%, P = 0.020). For non-novices, there were no differences between the two transducers (mean difference: 1.4%, 95% CI: -1.1 to 3.9%, P = 0.263). For pleural-based findings, the mean of the paired differences between transducers was higher in the novice group (estimated mean difference-in-differences: 9.5%, 95% CI: 0.6 to 18.4%; P = 0.036). No difference in mean accuracies was noted between novices and non-novices for non-pleural-based pathologies (estimated mean difference-in-differences: 0.6%, 95% CI to 5.4-6.6%; P = 0.837). Conclusions: Lung ultrasound images obtained using the curvilinear transducer are associated with higher interpretation accuracy than the phased array transducer. This is especially true for novices interpreting pleural-based pathologies.

Gastrointestinal Manifestations of CLOVES Syndrome.

Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies (CLOVES) is a recently recognized syndrome. It is caused by somatic mutations in the PIK3CA gene that regulates cell growth and division. Although gastrointestinal manifestations of other PIK3CA-associated disorders have been described, they have not been well-characterized in CLOVES syndrome. We present a case report of a 34-year-old man with an established diagnosis of CLOVES syndrome who underwent a diagnostic colonoscopy for hematochezia and colonic wall thickening on imaging. Colonoscopy revealed widespread variceal-like submucosal lesions. Computed tomography/angiography showed the absence of the inferior mesenteric vein, impairing venous drainage.

Children after motor vehicle crashes: Restraint utilization and injury severity.

BACKGROUND: Although injury patterns after motor vehicle crashes (MVCs) are well documented, association between adequate restraint and injury severity is unclear. We aimed to determine if improper restraint affects injury rates and severity. METHODS: A retrospective chart review of 477 children hospitalized in Pediatric Trauma Center after MVC was performed. Injuries in various age groups (0-7, 8-12, 13-16, 17-18 years) with different restraint quality measures (proper [PR] and improper/unrestrained [IUR]) as well as injury severity score (ISS: mild [1-9], moderate [10-15], severe [16-25], and profound [>25]) were evaluated and compared. Chi-square and Wilcoxon rank-sum tests were used for statistics. RESULTS: In all age groups head/neck injuries were most common (55-63%), while abdominal and pelvic injuries were least likely except group 8-12 years where abdominal injuries ranked third (17.1%). Overall, 64.5% had PR and 35.5% IUR. Interestingly, that greatest proportion of IUR was in the youngest age group (0-7). It decreased with aging and children aged 17-18 years were significantly less likely to be IUR compared to those 0-7 years (OR[odds ratio] = 0.58; 95%CI[confidence interval] 0.35-0.94). We did not find significant differences in rates of various injuries between PR and IUR. However, ISS severity in IUR was significantly greater than in PR (median with interquartile range 6(2-14) and 5(1-9), respectively; P = 0.001). As a result, IUR compared to PR were less likely to have mild ISS (OR = 0.6, 95%CI 0.39-0.90) but more likely to have profound ISS (OR = 3.3, 95%CI 1.48-7.43). CONCLUSION: Restraint quality has significant impact on injury severity in children after MVC. LEVEL OF EVIDENCE: Level III.

The macrophage cytoskeleton acts as a contact sensor upon interaction with Entamoeba histolytica to trigger IL-1ß secretion.

Entamoeba histolytica (Eh) is the causative agent of amebiasis, one of the major causes of dysentery-related morbidity worldwide. Recent studies have underlined the importance of the intercellular junction between Eh and host cells as a determinant in the pathogenesis of amebiasis. Despite the fact that direct contact and ligation between Eh surface Gal-lectin and EhCP-A5 with macrophage α5ß1 integrin are absolute requirements for NLRP3 inflammasome activation and IL-1ß release, many other undefined molecular events and downstream signaling occur at the interface of Eh and macrophage. In this study, we investigated the molecular events at the intercellular junction that lead to recognition of Eh through modulation of the macrophage cytoskeleton. Upon Eh contact with macrophages key cytoskeletal-associated proteins were rapidly post-translationally modified only with live Eh but not with soluble Eh proteins or fragments. Eh ligation with macrophages rapidly activated caspase-6 dependent cleavage of the cytoskeletal proteins talin, Pyk2 and paxillin and caused robust release of the pro-inflammatory cytokine, IL-1ß. Macrophage cytoskeletal cleavages were dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4 but not EhCP-A5 based on pharmacological blockade of Eh enzyme inhibitors and EhCP-A5 deficient parasites. These results unravel a model where the intercellular junction between macrophages and Eh form an area of highly interacting proteins that implicate the macrophage cytoskeleton as a sensor for Eh contact that leads downstream to subsequent inflammatory immune responses.

A Discussion of High-Risk HPV in a 6-Year-Old Female Survivor of Child Sexual Abuse.

BACKGROUND: Human papilloma viruses (HPVs) cause a variety of clinical manifestations in children including skin warts, laryngeal papillomas, and condyloma acuminatum. Whereas the mode of transmission is well understood and management of HPV infection is clearly defined by guidelines in adults, less is known about the mode of transmission, natural history of disease, and appropriate management of high-risk anogenital HPV infections in children. CASE: The patient is a previously healthy 6-year-old female who presented with multiple vaginal lesions causing pain and discomfort and was diagnosed with HPV 18 positive CIN I. SUMMARY AND CONCLUSION: Children infected with high-risk HPV subtypes remain a vulnerable patient population, and there is minimal literature on the natural history of disease and effects of overtreatment. Based on a literature review, conservative management, HPV vaccination, and consideration of the cervical cancer screening guidelines for adolescent females are an appropriate treatment course until more studies are reported on cervical cancer screening in survivors of child sexual abuse.

The future for vaccine development against Entamoeba histolytica.

Entamoeba histolytica is the causative agent of amebiasis, one of the top three parasitic causes of mortality worldwide. In the majority of infected individuals, E. histolytica asymptomatically colonizes the large intestine, while in others, the parasite breaches the mucosal epithelial barrier to cause amebic colitis and can disseminate to soft organs to cause abscesses. Vaccinations using native and recombinant forms of the parasite Gal-lectin have been successful in protecting animals against intestinal amebiasis and amebic liver abscess. Protection against amebic liver abscesses has also been reported by targeting other E. histolytica components including the serine-rich protein and the 29-kDa-reductase antigen. To date, vaccines against the Gal-lectin hold the most promise but clinical trials will be required to validate its efficacy in humans. Here, we review the current strategies and future perspectives involved in the development of a vaccine against E. histolytica.

A role for the protein tyrosine phosphatase CD45 in macrophage adhesion through the regulation of paxillin degradation.

CD45 is a protein tyrosine phosphatase expressed on all cells of hematopoietic origin that is known to regulate Src family kinases. In macrophages, the absence of CD45 has been linked to defects in adhesion, however the molecular mechanisms involved remain poorly defined. In this study, we show that bone marrow derived macrophages from CD45-deficient mice exhibit abnormal cell morphology and defective motility. These defects are accompanied by substantially decreased levels of the cytoskeletal-associated protein paxillin, without affecting the levels of other proteins. Degradation of paxillin in CD45-deficient macrophages is calpain-mediated, as treatment with a calpain inhibitor restores paxillin levels in these cells and enhances cell spreading. Inhibition of the tyrosine kinases proline-rich tyrosine kinase (Pyk2) and focal adhesion kinase (FAK), kinases that are capable of mediating tyrosine phosphorylation of paxillin, also restored paxillin levels, indicating a role for these kinases in the CD45-dependent regulation of paxillin. These data demonstrate that CD45 functions to regulate Pyk2/FAK activity, likely through the activity of Src family kinases, which in turn regulates the levels of paxillin to modulate macrophage adhesion and migration.

Peliosis hepatis in a child with myotubular myopathy: successful treatment using hepatic artery embolization.

Peliosis hepatis (PH) is a rare condition characterized by multiple blood-filled spaces within the hepatic parenchyma that can lead to fatal hemorrhage. There is no consensus on the best treatment algorithm for PH, and therapy is directed at removing the potential causative agent with operative intervention when necessary. Here we present the first known case of PH in a child with myotubular myopathy who was successfully treated with angiography and hepatic artery embolization as a first line therapy, without the need for operative intervention. Awareness of this condition and the available treatment modalities may lead to favorable outcomes in future cases.

Enhanced immunogenicity of a tricomponent mannan tetanus toxoid conjugate vaccine targeted to dendritic cells via Dectin-1 by incorporating ß-glucan.

In a previous attempt to generate a protective vaccine against Candida albicans, a ß-mannan tetanus toxoid conjugate showed poor immunogenicity in mice. To improve the specific activation toward the fungal pathogen, we aimed to target Dectin-1, a pattern-recognition receptor expressed on monocytes, macrophages, and dendritic cells. Laminarin, a ß-glucan ligand of Dectin-1, was incorporated into the original ß-mannan tetanus toxoid conjugate providing a tricomponent conjugate vaccine. A macrophage cell line expressing Dectin-1 was employed to show binding and activation of Dectin-1 signal transduction pathway by the ß-glucan-containing vaccine. Ligand binding to Dectin-1 resulted in the following: 1) activation of Src family kinases and Syk revealed by their recruitment and phosphorylation in the vicinity of bound conjugate and 2) translocation of NF-κB to the nucleus. Treatment of immature bone marrow-derived dendritic cells (BMDCs) with tricomponent or control vaccine confirmed that the ß-glucan-containing vaccine exerted its enhanced activity by virtue of dendritic cell targeting and uptake. Immature primary cells stimulated by the tricomponent vaccine, but not the ß-mannan tetanus toxoid vaccine, showed activation of BMDCs. Moreover, treated BMDCs secreted increased levels of several cytokines, including TGF-ß and IL-6, which are known activators of Th17 cells. Immunization of mice with the novel type of vaccine resulted in improved immune response manifested by high titers of Ab recognizing C. albicans ß-mannan Ag. Vaccine containing laminarin also affected distribution of IgG subclasses, showing that vaccine targeting to Dectin-1 receptor can benefit from augmentation and immunomodulation of the immune response.

Life-threatening hemorrhage from a congenital hemangioma caused by birth trauma.

Pediatric surgeons frequently diagnose and treat vascular malformations. We present the case of a boy born with a large congenital hemangioma of the flank that ruptured during birth, resulting in life-threatening hemorrhage, requiring emergent excision. Prenatal diagnosis may help to identify such lesions, and pediatric surgeons must be ready to treat emergent complications of vascular malformations.

Hypophosphorylated and inactive Pyk2 associates with paxillin at the microtubule organizing center in hematopoietic cells.

Pyk2 is a non-receptor tyrosine kinase that regulates cellular adhesion. We generated antibodies to a peptide corresponding to the N-terminus (NT) of Pyk2 and another to a portion of the C-terminal (CT) domain. Only the CT antiserum recovered paxillin-associated Pyk2. These antibodies recognized overlapping but biochemically distinct molecular species of Pyk2 since the CT antiserum recovered Pyk2 after NT antibody immunodepletion. Furthermore, the CT antibody could not immunoblot NT antibody-captured Pyk2. Phosphorylation partially accounts for the differential binding of these antibodies as dephosphorylation of Pyk2 recovered with the NT antibodies allows for recognition by the CT antibody. Additionally, Pyk2 recovered with the NT antibody displays increased serine/threonine phosphorylation. We suggest that the NT epitope is inaccessible to the antibody because Pyk2 is in a closed confirmation in association with paxillin. Upon induction of serine and/or threonine phosphorylation of Pyk2, it opens to a confirmation that allows for antibody binding to the NT epitope but at the same time no longer binds paxillin or the CT antiserum. These antibodies also display differential staining of Pyk2 in both T cells and macrophages. Pyk2 recognized by the CT antibody, but not the NT antibody, colocalized with paxillin at the microtubule-organizing center (MTOC). The MTOC-bound Pyk2 was not tyrosine phosphorylated upon T cell activation. We hypothesize that a reservoir of primarily inactive Pyk2 associates with paxillin at the MTOC, which may allow for rapid delivery of Pyk2 to specific sites of adhesion.

Pancreatic regenerating protein I in chronic pancreatitis and aging: implications for new therapeutic approaches to diabetes.

OBJECTIVES: We investigated the relationship of pancreatic regenerating protein (reg) in models of acinar cell atrophy and aging, and the effect of reg I protein replacement on glucose tolerance. METHODS: Rats underwent pancreatic duct ligation (PDL) and were followed through 12 months. Aging rats were studied at 12 and 20 months. Intraperitoneal glucose tolerance tests (IPGTTs) were performed, pancreatic reg I, reg I receptor, insulin gene expression, and reg I protein levels were measured. Pancreatic duct ligation and aged animals were treated with exogenous reg I protein and assessed for glucose metabolism. RESULTS: After PDL, chronic atrophic pancreatitis developed, with a progressive loss of acinar cells and pancreatic reg I. During aging, a similar depression of reg I gene expression was also noted. The reg I levels correlated with pancreatic insulin levels. Twelve months after PDL, IPGTT results were abnormal, which were significantly improved by administration of reg I protein. Aged animals demonstrated depressed IPGTT, which marginally improved after reg I administration. Anti-reg antibody administration to young rats depressed IPGTT to elderly levels. CONCLUSIONS: Depletion of the acinar product reg I is associated with the pathogenesis of impaired glucose tolerance of pancreatitis-associated diabetes and aging, and replacement therapy could be useful in these patients. Reg I is an acinar cell product, which affects islet function.

Sophorolipids improve sepsis survival: effects of dosing and derivatives.

INTRODUCTION: Sophorolipids, a family of natural and easily chemo-enzymatically modified microbial glycolipids, are promising modulators of the immune response. We have previously demonstrated that sophorolipids mediate anti-inflammatory effects, including decreasing sepsis-related mortality at 36 h in vivo in a rat model of septic peritonitis and in vitro by decreasing nitric oxide and inflammatory cytokine production. Here we assessed the effect of sophorolipids on sepsis-related mortality when administered as a (1) single bolus versus sequential dosing and (2) natural mixture versus individual derivatives compared with vehicle alone. METHODS: Intra-abdominal sepsis was induced in male, Sprague Dawley rats, 200 to 240 g, via cecal ligation and puncture. Sophorolipids (5-750 mg/kg) or vehicle (ethanol/sucrose/physiological saline) were injected intravenously (i.v.) via tail vein or inferior vena cava at the end of the operation either as a single dose or sequentially (q24 h x 3 doses); natural mixture was compared with select sophorolipid derivatives (n = 10-15 per group). Sham-operated animals served as nonsepsis controls. Survival rates were compared at 1 through 6 d post sepsis induction and tissue was analyzed by histopathology. Significance was determined by Kruskal-Wallis analysis with Bonferroni adjustment and Student's t-test. RESULTS: Sophorolipid treatment at 5 mg/kg body weight improved survival in rats with cecal ligation and puncture-induced septic shock by 28% at 24 h and 42% at 72 h for single dose, 39% at 24 h and 26% at 72 h for sequential doses, and 23% overall survival for select sophorolipid derivatives when compared with vehicle control (P < 0.05 for sequential dosing). Toxicity was evident and dose-dependent with very high doses of sophorolipid (375-750 mg/kg body weight) with histopathology demonstrating interstitial and intra-alveolar edema with areas of microhemorrhage in pulmonary tissue when compared with vehicle controls (P < 0.05). No mortality was observed in sham operated controls at all doses tested. CONCLUSIONS: Administration of sophorolipids after induction of intra-abdominal sepsis improves survival. The demonstration that sophorolipids can reduce sepsis-related mortality with different dosing regimens and derivatives provides continuing evidence toward a promising new therapy. Toxicity is evident at 75 to 150x the therapeutic dose in septic animals.