Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities. METHODS: We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. RESULTS: A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%]. CONCLUSIONS: Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

Plasmon-Accelerated Generation of Singlet Oxygen on an Au/MoS2 Nanohybrid for Enhanced Photodynamic Killing of Bacterial Pathogens/Cancerous Cells.

Benefiting from its strong cytotoxic features, singlet oxygen (1O2) has garnered considerable research attention in photodynamic therapy (PDT) and thus, plenty of inorganic PDT agents have been recently developed. However, inorganic PDT agents consisting of metal/semiconductor hybrids are surprisingly rare, bearing very low 1O2 quantum yield, and their in vivo PDT applications remain elusive. Herein, we provide an unprecedented report that the Au/MoS2 hybrid under plasmon resonant excitation can sensitize 1O2 generation with a quantum yield of about 0.22, which is much higher than that of the reported hybrid-based photosensitizers (PSs). This significant enhancement in 1O2 quantum yield is attributed to the hot-electron injection from plasmonic AuNPs to MoS2 NSs due to the matched energy levels. Electron paramagnetic resonance (EPR) spectroscopy with spin trapping and spin labeling verifies the plasmonic generation of hot charge carriers and reactive oxygen species such as superoxide and 1O2. This plasmonic PDT agent shows a remarkable photodynamic bacterial inactivation in vitro and anti-cancer therapeutic ability both in vitro and in vivo, which is solely attributed to high 1O2 generation rather than the plasmonic photothermal effect. Hence, plasmonic Au/MoS2 with enhanced 1O2 quantum yield and appreciable in vivo cancer plasmonic PDT performance holds great promise as an inorganic PS to treat near-surface tumors. As a first demonstration of how metal localized surface plasmon resonance could enhance 1O2 generation, the present study opens up promising opportunities for enhancing 1O2 quantum yield of hybrid-based PSs, leading to achieving a high therapeutic index in plasmon PDT.

Bladder Necrosis at Time of Presentation with Ulcerative Colitis in an 8-year-old Female: A Case Report.

A case of bladder necrosis in an 8-year-old female at time of presentation of ulcerative colitis (UC) is presented. A case of bladder necrosis in a pediatric patient outside of the neonatal period has not been reported. The patient presented with abdominal pain, bloody stools, hematuria, and acute renal failure. She was acutely management with bilateral nephrostomy tube placement. Bladder and colon biopsies revealed diagnosis of UC and bladder necrosis. The UC was medically managed. The bladder did not regenerate after several months of observation and ileal conduit urinary diversion was performed. A right proximal ureteral stricture was managed by pyeloplasty at time of ileal conduit. The patient is doing well over 1 year after surgery.

Pediatric autoimmune gastritis: clinical correlates and histologic features.

Autoimmune gastritis is a well-known pathologic entity, but there are few studies that examine its clinical and histologic presentation in children. This is a single institution, retrospective study performed on patients diagnosed from 2011 through 2019. Patients were identified by their pathologic diagnosis within the laboratory information system. The electronic medical record and archived slides were reviewed. Twenty-two children (3 months to 18 years; median, 10.9 years) with autoimmune gastritis were diagnosed of a total of 14,257 nonconsultation gastric biopsies from unique patients (0.15% prevalence). Patients with autoimmune gastritis were diagnosed at an average age of 10.9 years and were mostly female (68.2% women, 31.8% men). The majority had extragastric immune disorders (13/22; 59.1%). All patients in the study had gastric body mucosa with enterochromaffin-like cell hyperplasia, atrophy, and histologic features of chronic injury. Most biopsies showed gastric body metaplasia (n = 19) or active gastric inflammation. However, antral atrophy was also observed in 12 patients, and antral metaplasia was identified in one patient; four patients had active chronic antral gastritis. All biopsies were negative for Helicobacter pylori. Pediatric autoimmune gastritis is a rare disorder that should be recognized because of its systemic effects with long-term morbidity. In addition, the possibility of tandem extragastric immune disorders should be considered when a diagnosis of pediatric autoimmune gastritis is established.

Esophagitis Dissecans Superficialis in Children.

OBJECTIVES: Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the superficial esophageal epithelium with variable clinical characteristics. Endoscopically, there is an appearance of superficial peeling of sheets of epithelium. Histologically there is 2-toned epithelium with coagulative necrosis of the superficial epithelium. Currently, there is paucity of data regarding this condition in children. METHODS: A 10-year retrospective search of the pathology information system was performed for cases with a pathologic diagnosis of EDS in a tertiary care pediatric center. Demographic data, clinical history, endoscopic findings, and histopathologic reports were reviewed. RESULTS: Thirteen patients (9 girls; ages 3-18 years), were identified with histologic findings of EDS. Esophageal food impaction, dysphagia, vomiting, and abdominal pain were the most common presenting symptoms. Sixty-nine percentage of the patients had underlying comorbidities and 76% were on at least 1 medication chronically. Eosinophilic esophagitis (23%), inflammatory bowel disease (23%), and gastroesophageal reflux disease (GERD) (15%) were the most common associated diagnoses. Of the 13 patients, 5 had repeat endoscopies showing complete resolution of EDS with no complications. CONCLUSIONS: EDS is an under-recognized entity that endoscopists should be familiar with. In our series, the most prevalent associations were with food impaction and eosinophilic esophagitis (EoE). Contact injury and/or inflammation may precede the development of EDS. Pediatric EDS appears to be an incidental finding without significant morbidity or mortality.

Smart J-aggregate of cyanine photosensitizer with the ability to target tumor and enhance photodynamic therapy efficacy.

Photodynamic therapy (PDT) has been demonstrated to be effective for cancer treatment. Design of photosensitizers (PS) featuring tumor targeting, long excitation wavelengths, and high singlet oxygen quantum yields (Φ(1O2)) is the crucial point of highly efficient PDT. However, it is especially difficult to integrate above features into one photosensitizer. Herein, we put forwards a PS J-aggregation method, simultaneously endowing PS with the ability of tumor targeting, the red-shift of spectra, and the increase of Φ(1O2). Cyanine PS 4-((E)-3-((E)-5-iodo-1,3,3-trimethylindolin-2-ylidene)prop-1-en-1-yl)-1-methylquinolin-1-ium iodide (IDMQ) is firstly designed and synthesized by us. IDMQ can form smart response-type J-aggregates under the control of negatively charge in microenvironments. In blood, IDMQ J-aggregates target tumor via "enhanced permeability and retention (EPR)" effect. Then the intracellular IDMQ J-aggregates assembled by RNA facilitate the red shift of absorption peak with deeper penetration, and compared to free state IDMQ, improve the Φ(1O2), resulting in the bathochromic shift of optimal PDT wavelength from 630 (free state IDMQ) to 700 nm (IDMQ J-aggregates). This intelligent J-aggregation method establishes a promising way for endowing photosensitizer with the ability of tumor-targeting and the synchronous improvement of PDT efficacy and further boosts the development of PDT.

IV Ibuprofen for Prevention of Post-ERCP Pancreatitis in Children: A Randomized Placebo-controlled Feasibility Study.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) is reported to occur in up to 11% of pediatric patients. To date, no study has prospectively evaluated an intervention to prevent PEP in children. It is unclear if such a study is even feasible. OBJECTIVE: The aim of the study was to evaluate the feasibility of studying IV ibuprofen for PEP prevention in the pediatric population. METHODS: This was a prospective randomized double-blind placebo-controlled feasibility study. Patients younger than 19 years of age undergoing ERCP were randomized to receive 10 mg/kg IV ibuprofen (max of 800 mg) or placebo (saline) at the time of ERCP. The primary outcome was PEP. Secondary outcomes included post-ERCP-related bleeding, rates of other procedural and medication-related adverse events. RESULTS: Fifty-eight patients were randomized and received either IV ibuprofen or placebo. Preprocedure- and procedure-related factors were not significantly different between the groups except that patients in the placebo group tended to weigh less (48.7 vs 63.7 kg, P = 0.03). There were 7 episodes of PEP (12%). PEP was less frequently identified in the Ibuprofen group than in the control group (7% vs 17%), but this was not statistically significant (P = 0.42). Mean postprocedural abdominal pain scores were significantly lower in the IV Ibuprofen group than in the control group (1.1 vs 3.1, P = 0.01) and the number of patients who had increased abdominal pain after the procedure was significantly lower in ibuprofen group than in the control group (3% vs 38%, P = 0.002). There were no significant differences in procedure-related or drug-related adverse events. CONCLUSIONS: Postprocedural pain scores and the number of patients who had increased abdominal pain after the procedure were significantly lower in the IV ibuprofen group. The current study provides encouraging, but only very weak evidence that IV ibuprofen decreases PEP in children. Power analysis suggests that a small handful of high-volume pediatric centers would be able to perform an adequate clinical trial in a reasonable time frame. Focusing on all cause postprocedural pain (PEP and non-PEP) may allow for a more efficiency study design and be just as clinically relevant.

Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn's disease: a retrospective chart review.

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn's disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient's clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 µg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 µg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

Recent advances in understanding and managing pediatric inflammatory bowel disease.

The landscape of pediatric inflammatory bowel disease is rapidly evolving. The therapeutic advances seen in the adult arena are rapidly being adopted by pediatric gastroenterologists and evaluated in both controlled trials and real-world experience. Though anti-tumor necrosis factor agents have been the primary therapy over the last decade, recently there has been an expansion of therapeutic targets and alternative mechanism of action drugs with a focus on individualized and personalized therapy. By reviewing epidemiology, pathophysiology, and goals of treatment, we hope to frame the discussion of current and novel therapeutics for the pediatric gastroenterologist. As scientific discovery continues to push the envelope in defining our understanding of pediatric inflammatory bowel disease, the current era of therapeutics gives us hope that a cure may be realized soon.

Fecal microbiota transplantation in children: current concepts.

PURPOSE OF REVIEW: Administration of fecal material into the gastrointestinal tract, termed fecal microbiota transplantation (FMT), is increasingly recognized as an effective treatment option for recurrent Clostridium difficile infection (RCDI). The impact of FMT on host microbial communities and subsequent disease states has also been explored in recent years for conditions as varied as inflammatory bowel disease especially ulcerative colitis, metabolic diseases, such as diabetes, graft-versus-host disease in hematopoietic stem cell transplant recipients, and autism and autism spectrum disorders. The purpose of this article is to review the evidence for FMT as a treatment option in various pediatric illnesses. RECENT FINDINGS: The rate of C. difficile infection is rising among children, and is associated with significant morbidity and disease, with recurrence in up to 20% of pediatric patients. Several randomized controlled trials evaluating the utility of FMT in RCDI in comparison to vancomycin have been published and demonstrate high rates of efficacy between 70 and 100%. In addition, the safety of FMT in the treatment of RCDI has been well described in the adult population, with several pediatric case series demonstrating similar rates of tolerability and adverse events. FMT in ulcerative colitis appears promising, especially with multiple infusions administered via the lower gastrointestinal tract. However, there are several limitations, including the lack of uniformity of protocols used, source of FMT, route of administration and the lack of standardization of concomitant therapies. The data on usage of FMT for other indications are preliminary and limited. SUMMARY: FMT is recognized as an effective treatment option for RCDI and is increasing sought by parents. Although limited, pediatric studies to date on the use of FMT for RCDI demonstrate similar efficacy rates as in the adult population. FMT has been proposed as a treatment option for an increasing number of pediatric conditions, and additional studies are needed to delineate the efficacy of FMT outside of RCDI, as well as its short and long-term impacts on human health.

Mosaic Tetrasomy 9p Associated With Inflammatory Bowel Disease.

The genetic basis of inflammatory bowel disease remains to be elucidated completely. Here we report on a patient with inflammatory bowel disease who has mosaic tetrasomy of the short arm of chromosome 9, a genomic region that harbours the type I interferon gene cluster. We show that increased interferon activation is present in peripheral blood and intestinal tissue from this patient, similar to previous reports of autoinflammatory organ damage driven by interferon activation in other patients with this chromosomal abnormality. To our knowledge, this is the first case of tetrasomy 9p-associated interferonopathy driving intestinal inflammation and highlights the role that type-I interferon pathways can play in the pathogenesis of intestinal inflammation.

Celecoxib Conjugated Fluorescent Probe for Identification and Discrimination of Cyclooxygenase-2 Enzyme in Cancer Cells.

Cyclooxygenase-2 (COX-2) is an enzyme overexpressed in most types of cancers and has been used for an excellent targetable biomarker. Celecoxib is an effective inhibitor of COX-2, used in anti-inflammation. Herein we report a one and two-photon fluorescence probe (NP-C6-CXB) for COX-2, based on the conjugation of naphthalamide with Celecoxib, by using flexible hexylene linker. NP-C6-CXB is nonfluorescent in buffer solution and normal cells, while it shows bright fluorescence in solutions and cancer cells in the presence of COX-2 with an excellent selectivity. Interestingly, NP-C6-CXB can discriminate cancer cells (MCF-7) from normal cells (COS-7) in the single culture medium under confocal microscopy. Due to the selective binding affinity of NP-C6-CXB with a COX-2 enzyme, the intensity is proportional to the level of COX-2 enzyme in cancer cells. In vivo and in vitro experiments proved that NP-C6-CXB is a potential tool for identification of tumor and might be used in surgical resection of COX-2 expressed tumors.

Outcomes after fecal diversion for colonic and perianal Crohn disease in children.

BACKGROUND: Temporary fecal diversion by means of an ileostomy or colostomy has been used in the surgical management of refractory colonic and perianal Crohn disease (CD). The aims of our study were to evaluate the outcomes after fecal diversion in pediatric patients with colonic and perianal CD. METHODS: The records of patients who underwent fecal diversion for colonic and perianal CD at Children's Hospital of Wisconsin between July 2000 and June 2014 were reviewed retrospectively. Patient demographics, medication use, onset and extent of disease, response to fecal diversion, rate of stoma reversal and relapse rate after stoma reversal were recorded. RESULTS: We identified 28 consecutive patients (20 females, 8 males; median age 13.9years) undergoing fecal diversion for refractory colonic (n=21) and perianal CD (n=7). Median duration of follow-up after fecal diversion was 2.26years (range, 0.79-10.2years). The response to fecal diversion was sustained clinical remission in 13/28 (46%), temporary clinical remission in 10/28 (36%), no change in 5/28 (18%). Intestinal continuity was restored in 14/28 (50%) patients; however, 3 (21%) required permanent stoma after reconnection. Classification tree analysis identified that female patients without perianal CD had higher rates of stoma reversal (p=0.008). CONCLUSIONS: Fecal diversion can induce remission in pediatric patients with refractory colonic and perianal CD. Restoration of intestinal continuity was achieved in about 39%. Female patients without perianal CD carried no risk of a permanent stoma. LEVEL OF EVIDENCE: Level III study.

Paneth cell defects in Crohn's disease patients promote dysbiosis.

BACKGROUND: Paneth cell dysfunction has been implicated in a subset of Crohn's disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients. METHODS: Pediatric CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome. RESULTS: The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome. CONCLUSION: Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop. FUNDING: The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn's and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).

Intact Regulatory T-Cell Function but Defective Generation of IL-17A-Producing CD4+ T Cells in XIAP Deficiency.

OBJECTIVE: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-ß signaling. METHODS AND RESULTS: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4 T cells from xIAP mice compared with colitis induced by naïve CD4 T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP or WT Treg cells with naïve WT CD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL-17A-producing CD4 T cells in mice receiving Tregs from xIAP mice. CONCLUSIONS: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4 T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.