Non-coding RNAs in Kawasaki disease: Molecular mechanisms and clinical implications.

Kawasaki disease (KD) is an acute self-limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high-throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD.

Neonatal cutaneous inflammatory syndrome associated with homozygous epidermal growth factor receptor mutation.

The epidermal growth factor receptor (EGFR) is a transmembrane protein with tyrosine kinase signaling activity regulating many essential cellular functions, and loss of function mutations in EGFR result in a life-threatening neonatal syndrome. We present the case of a preterm boy born with intrauterine growth restriction who developed multisystem disease due to a homozygous mutation in the EGFR gene. He experienced a tumultuous and complex clinical course with recurrent skin infections and sepsis, nephrocalcinosis, failure to thrive, severe electrolyte imbalances, rectal perforation, and thrombus formation, and died after 11 months due to renal failure. This case report builds on work recently published in 2020 describing a case series of 18 similar patients and adds to the growing literature describing the severe phenotype and multisystem disease associated with loss of EGFR mutation in the Roma population.

Exercise testing in patients with multisystem inflammatory syndrome in children-related myocarditis versus idiopathic or viral myocarditis.

BACKGROUND: While most children with multisystem inflammatory syndrome in children have rapid recovery of cardiac dysfunction, little is known about the long-term outcomes regarding exercise capacity. We aimed to compare the exercise capacity among patients with multisystem inflammatory syndrome in children versus viral/idiopathic myocarditis at 3-6 months after initial diagnosis. METHODS: We performed a retrospective cohort study among patients with multisystem inflammatory syndrome in children in June 2020 to May 2021 and patients with viral/idiopathic myocarditis in August 2014 to January 2020. Data from cardiopulmonary exercise test as well as echocardiographic and laboratory data were obtained. Inclusion criteria included diagnosis of multisystem inflammatory syndrome in children or viral/idiopathic myocarditis, exercise test performed within 3-6 months of hospital discharge, and maximal effort on cardiopulmonary exercise test as determined by respiratory exchange ratio >1.10. RESULTS: Thirty-one patients with multisystem inflammatory syndrome in children and 25 with viral/idiopathic myocarditis were included. The mean percent predicted peak VO2 was 90.84% for multisystem inflammatory syndrome in children patients and 91.08% for those with viral/idiopathic myocarditis (p-value 0.955). There were no statistically significant differences between the groups with regard to percent predicted maximal heart rate, metabolic equivalents, percent predicted peak VO2, percent predicted anerobic threshold, or percent predicted O2 pulse. There was a statistically significant correlation between lowest ejection fraction during hospitalisation and peak VO2 among viral/idiopathic myocarditis patients (r: 0.62, p-value 0.01) but not multisystem inflammatory syndrome in children patients (r: 0.1, p-value 0.6). CONCLUSIONS: Patients with multisystem inflammatory syndrome in children and viral myocarditis appear to, on average, have normal exercise capacity around 3-6 months following hospital discharge. For patients with viral/idiopathic myocarditis, those with worse ejection fraction during hospitalisation had lower peak VO2 on cardiopulmonary exercise test.

Advancement of nanomedicines in chronic inflammatory disorders.

Chronic diseases, as stated by the WHO, are a threat to human health which kill 3 out of every 5 people worldwide. Therapeutics for such illnesses can be developed using traditional medicine. However, it is not an easy path from natural products to Western pharmacological and pharmaceutical methods. For several decades, chronic inflammatory disorders, especially in Westernized countries, have increased incidence and prevalence. Several NSAIDs are used to decrease inflammation and pain; however, there are numerous negative consequences of these anti-inflammatory medications, whereas plant-based natural products have anti-inflammatory therapeutic benefits that have little or no adverse effects. Nanoparticles are a new type of drug delivery device that may be designed to provide excellent target selectivity for certain cells and tissues while also having a high drug loading capacity, resulting in better pharmacokinetics, pharmacodynamics (PKPD), and therapeutic bioavailability. The size and polarity of phytochemical compounds make it hard to pass the blood-brain barrier (BBB), blood-vessel endothelial lining, gastrointestinal tract and mucosa. In addition, the gastrointestinal system is enzymatically destroyed. Therefore, nanoparticles or nanocrystals might also be used for encapsulation or conjugation of these chemicals as a method to improve their organic effectiveness through their gastrointestinal stability, absorption rate and dispersion. The therapy of numerous inflammatory illnesses, including arthritis, gastritis, Nephritis, Hepatitis (Type A, B &C), ulcerative colitis, Alzheimer's disease, atherosclerosis, allergic responses (asthma, eczema) or autoimmune disorders, is characterised by nanoparticles. This review paper provides information on the numerous nanosystem described with their probable mechanism to treat chronic inflammatory diseases.

Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review.

Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2'deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

Facial hypopigmentation in skin of color: An atypical presentation of lichen nitidus.

Lichen nitidus is a benign skin condition of unknown etiology that is classically described on the trunk, extremities, and genitalia as pinpoint flat-topped papules. In dark-skinned persons, the lesions may appear shiny or even hypopigmented. Lichen nitidus is less often described on the face. We describe a series of pediatric patients with skin of color who presented with the chief complaint of facial skin lightening and had associated clinical findings consistent with lichen nitidus.

Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis.

The similarity between pustular psoriasis (PP) and acute generalized exanthematous pustulosis (AGEP) poses problems in the diagnosis and treatment of these two conditions. Significant clinical and histopathologic overlap exists between PP and AGEP. PP is an inflammatory disorder that has numerous clinical subtypes, but all with sterile pustules composed of neutrophils. AGEP is a severe cutaneous adverse reaction that is also characterized by non-follicular sterile pustules. Clinical features that suggest a diagnosis of PP over AGEP include a history of psoriasis and the presence of scaling plaques. Histologically, eosinophilic spongiosis, vacuolar interface dermatitis, and dermal eosinophilia favor a diagnosis of AGEP over PP. Importantly, PP and AGEP vary in clinical course and treatment. PP treatment involves topical steroids, oral retinoids, and systemic immunosuppressants. Newer therapies targeting IL-36, IL-23, IL-1, and PDE-4 have been investigated. The removal of the offending agent is a crucial part of the treatment of AGEP.

Clinical, microscopic and molecular presentation in pediatric versus adult old world cutaneous Leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis (CL) is an emerging uncontrolled tropical parasitic disease in endemic and nonendemic areas with a high prevalence in the pediatric age group. METHOD: A total of 382 individuals from Lebanon, Saudi Arabia, Pakistan, and Syria diagnosed with CL by punch biopsy/scrapings were grouped into adults (>18 years) and pediatrics (≤18 years). Data recorded included clinical features [number, location, type, size, and extensiveness (size larger than 3 cm, more than 5 lesions per patient, lesion present for more than 12 months, special types, disfiguring lesion or closeness to vital sensory organs) of lesions] and microscopic findings [Ridley's Parasitic Index and Ridley's Pattern]. In addition, molecular confirmation and speciation were performed. RESULTS: In comparison with adults, patients in the pediatric group (n = 158, 41.4%) showed significantly higher number of lesions, more facial involvement, and more extensive disease (P < .05). Microscopically, a more advanced Ridley's pattern was observed. The other variables did not show statistical difference between the two groups. CONCLUSION: Historically, CL has been known to be a neglected tropical disease of poverty and pediatric predilection. In our pediatric group, CL manifests with more extensive disease clinically mirrored by more advanced lesions microscopically.

Increase Risk of Multiple Sclerosis in Patients with Psoriasis Disease: An Evidence of Observational Studies.

BACKGROUND: Psoriasis, a common chronic inflammatory disease, increases the risk of developing multiple sclerosis (MS), but evidence for this outcome is still unclear. However, we performed a meta-analysis of relevant studies to quantify the magnitude of the association between psoriasis and MS. It will help to assess the current state of knowledge, fill the gaps in our existing concern, and make a recommendation for future research. METHODS: PubMed, EMBASE, and the bibliographies of articles were searched for studies published between January 1, 1990, and November 1, 2017, which reported on the association between psoriasis and MS. Articles were included if they (1) were published in English, (2) reported patients with psoriasis, and the outcome of interest was MS, (3) provided OR/RR/HR with 95% CI or sufficient information to calculate the 95% CI, and (4) if ≥50 patients. All abstracts, full-text articles, and sources were reviewed, with duplicate data excluded. Summary relative risk (ORs) with 95% CI was pooled using a random-effects model. Subgroup and sensitivity analyses were also conducted. RESULTS: We selected 11 articles out of 785 unique abstracts for full-text review using our predetermined selection criteria, and 9 out of these 11 studies met all of our inclusion criteria. The overall pooled increased of developing MS in patients with psoriasis was RR 1.607 (95% CI 1.322-1.953, p < 0.0001) with low heterogeneity (I2 = 37.41%, Q = 12.782, τ2 = 0.027) for the random effect model. In the subgroup analysis, the MS risk in the patient with psoriasis was also significantly higher in the 6 studies from Europe RR 1.57 (95% CI 1.26-1.94, p < 0.001) with moderate heterogeneity (I2 = 50.66%, Q = 10.13, τ2 = 0.03) for the random effect model. CONCLUSION: Our results showed that psoriasis is significantly associated with an increased risk of developing MS. Physicians should carefully be observed symptoms and empower their patients to improve existing knowledge and quality of life. Further studies are warranted to establish the mechanisms underlying this relationship.

Bacteriophages targeting intestinal epithelial cells: a potential novel form of immunotherapy.

In addition to their established role as a physical barrier to invading pathogens and other harmful agents, intestinal epithelial cells (IEC) are actively involved in local immune reactions. In the past years, evidence has accumulated suggesting the role of IEC in the immunopathology of intestinal inflammatory disorders (IBD). Recent advances in research on bacteriophages strongly suggest that-in addition to their established antibacterial activity-they have immunomodulating properties that are potentially useful in the clinic. We suggest that these immunomodulating phage activities targeting IEC may open novel treatment perspectives in disorders of the alimentary tract, particularly IBD.

Current Status of Segmental Colectomy in Select Crohn's Disease Patients.

Crohn's disease is a complex disease with a varying clinical and anatomical spectrum. One-third of patients with Crohn's will have disease confined to the colon. In this article, the authors review the surgical treatment options for colonic Crohn's disease including the current status of performing segmental colectomy in colonic Crohn's, the pros and cons of segmental versus subtotal colectomy, and the influence of biologics on recurrence rates following segmental colectomy.

Chronic Periaortitis: an Update.

PURPOSE OF REVIEW: We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). RECENT FINDINGS: CP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called "diffuse periaortitis"), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos. CP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents.

Fitness and its association with fatigue in persons with multiple sclerosis.

This study compared physical fitness components between fatigued and non-fatigued persons with MS and examined those components as correlates of fatigue. Sixty-two ambulatory persons with MS completed the Modified Fatigue Impact Scale (MFIS) and underwent assessments of cardiorespiratory capacity, lower extremity muscle strength (i.e., peak torque and asymmetry), body composition, and static balance over two different sessions 7 days apart. Participants were allocated into fatigue groups based on MFIS scores (non-fatigued group (i.e., MFIS ≤38), n = 26; and fatigued group (MFIS >38), n = 36). The fatigued group had significantly (P < 0.05) lower cardiorespiratory capacity (VO2peak ) and muscular strength (i.e., knee flexion peak torque) than the non-fatigued group. VO2peak and knee extension peak torque were the two physical fitness components significantly correlated with fatigue scores in the fatigued group (P < 0.05), and follow-up stepwise linear regression revealed that VO2peak was a significant predictor of fatigue scores (R2  = 0.13). Discriminant function analysis further identified VO2peak as a significant (P < 0.05) correlate of fatigue status. This model explained 21% of variance in group status (i.e., fatigued vs non-fatigued) and correctly classified approximately 76% of cases into fatigue status groups. The improvement of cardiorespiratory capacity should be considered in rehabilitation programs for persons with MS, especially those presenting with elevated fatigue.

Syphacia obvelata: A New Hope to Induction of Intestinal Immunological Tolerance in C57BL/6 Mice.

The ability of nematodes to manipulate the immune system of their host towards a Th2 and T regulatory responses has been proposed to suppress the inflammatory response. Clinical trials have proposed a useful effect of helminth infections on improvement of inflammatory disorders. In this study, we investigated the immunomodulatory effect of Syphacia obvelata infection to induce intestinal tolerance in C57BL/6 mice. Mice were infected through the cagemates with self-infected BALB/c mice. Four weeks post-infection, expression levels of IFN-γ, TNF-α, IL-17, and IL-10 were assessed in the supernatant of mesenteric lymph node (MLN) culture. Foxp3+Treg were measured in MLN cells by flow cytometry. In the S. obvelata-infected group, the percentage of Tregs (5.2±0.4) was significantly higher than the control (3.6±0.5) (P<0.05). The levels of IL-10 (55.3±2.2 vs 35.2±3.2), IL-17 (52.9±3.8 vs 41±1.8), IFN-γ (44.8±4.8 vs 22.3±2.3) and TNF-α (71.1±5.8 vs 60.1±3.3) were significantly increased in infected mice compared to the control group (P<0.05). The above results showed the potential effects of S. obvelata to induce intestinal tolerance. Therefore, it seems that S. obvelata may increase the immunological suppressive function in the intestinal tract.

Human whole-blood culture system for ex vivo characterization of designer-cell function.

Encapsulated designer cells implanted into mice are currently used to validate the efficacy of therapeutic gene networks for the diagnosis and treatment of various human diseases in preclinical research. Because many human conditions cannot be adequately replicated by animal models, complementary and alternative procedures to test future treatment strategies are required. Here we describe a novel approach utilizing an ex vivo human whole-blood culture system to validate synthetic biology-inspired designer cell-based treatment strategies. The viability and functionality of transgenic mammalian designer cells co-cultured with primary human immune cells were characterized. We demonstrated that transgenic mammalian designer cells required adequate insulation from the human blood microenvironment to maintain viability and functionality. The biomaterial alginate-(poly-l-lysine)-alginate used to encapsulate the transgenic designer cells did neither affect the viability of primary granulocytes and lymphocytes nor the functionality of lymphocytes. Additionally, alginate-encapsulated transgenic designer cells remained responsive to the release of the pro-inflammatory cytokine tumor necrosis factor (TNF) from the whole-blood culture upon exposure to bacterial lipopolysaccharide (LPS). TNF diffused into the alginate capsules, bound to the specific TNF receptors on the transgenic designer cells' surface and triggered the expression of the reporter gene SEAP (human placental secreted alkaline phosphatase) that was rewired to the TNF-specific signaling cascade. Human whole-blood culture systems can therefore be considered as valuable complementary assays to animal models for the validation of synthetic circuits in genetically modified mammalian cells and may speed up preclinical research in a world of personalized medicine.

The clinical manifestations and treatment outcomes of Behçet's disease: A single-center experience.

Background and Aims: Behçet's disease is a chronic, multisystemic, and relapsing inflammatory disorder. It lacks a permanent cure, the focus of treatment is on mitigating symptoms, decreasing the frequency and severity of relapses, and preventing life-threatening complications. This study aims to report the experience of a single center in managing patients with Behçet's disease and discuss the treatment outcomes. Methods: This study was a retrospective case series conducted over 2 years. All cases were clinically diagnosed according to the International Criteria for Behçet's Disease. The extracted data were demographics, family history, clinical findings, criteria scores, treatment, and outcomes. Results: A total of 31 patients were included, consisting of 13 males (42%) and 18 females (58%). Most cases were over the age of 30, and both genders were nearly equally distributed among age groups. The most commonly affected site was the oral cavity, observed in 96.77% of cases. Genital, cutaneous, and vascular involvements were more common in males, while females were more likely to have oral, ocular, and musculoskeletal involvements. For various treatment regimens, oral, cutaneous, vascular, and musculoskeletal involvements showed complete response in all cases. Among cases with genital involvement, complete response was achieved in seven cases (41.2%), while four cases (23.5%) showed only partial response, and six cases (35.3%) experienced recurrence. In cases with ocular involvement, only partial responses were observed. Conclusion: Oral, cutaneous, vascular, and musculoskeletal involvements may have a higher likelihood of a complete response to treatment regimens. However, genital involvement may be the most recurrent manifestation, followed by ocular involvement.

Deciphering the role of HLF in idiopathic orbital inflammation: integrative analysis via bioinformatics and machine learning techniques.

Idiopathic orbital inflammation, formerly known as NSOI (nonspecific orbital inflammation), is characterized as a spectrum disorder distinguished by the polymorphic infiltration of lymphoid tissue, presenting a complex and poorly understood etiology. Recent advancements have shed light on the HLF (Human lactoferrin), proposing its critical involvement in the regulation of hematopoiesis and the maintenance of innate mucosal immunity. This revelation has generated significant interest in exploring HLF's utility as a biomarker for NSOI, despite the existing gaps in our understanding of its biosynthetic pathways and operational mechanisms. Intersecting multi-omic datasets-specifically, common differentially expressed genes between GSE58331 and GSE105149 from the Gene Expression Omnibus and immune-related gene compendiums from the ImmPort database-we employed sophisticated analytical methodologies, including Lasso regression and support vector machine-recursive feature elimination, to identify HLF. Gene set enrichment analysis and gene set variation analysis disclosed significant immune pathway enrichment within gene sets linked to HLF. The intricate relationship between HLF expression and immunological processes was further dissected through the utilization of CIBERSORT and ESTIMATE algorithms, which assess characteristics of the immune microenvironment, highlighting a noteworthy association between increased HLF expression and enhanced immune cell infiltration. The expression levels of HLF were corroborated using data from the GSE58331 dataset, reinforcing the validity of our findings. Analysis of 218 HLF-related differentially expressed genes revealed statistically significant discrepancies. Fifteen hub genes were distilled using LASSO and SVM-RFE algorithms. Biological functions connected with HLF, such as leukocyte migration, ossification, and the negative regulation of immune processes, were illuminated. Immune cell analysis depicted a positive correlation between HLF and various cells, including resting mast cells, activated NK cells, plasma cells, and CD8 T cells. Conversely, a negative association was observed with gamma delta T cells, naive B cells, M0 and M1 macrophages, and activated mast cells. Diagnostic assessments of HLF in distinguishing NSOI showed promising accuracy. Our investigation delineates HLF as intricately associated with NSOI, casting light on novel biomarkers for diagnosis and progression monitoring of this perplexing condition.

Macrophage-Mimicking Cellular Nanoparticles Scavenge Proinflammatory Cytokines in Specimens of Patients with Inflammatory Disorders.

Effectively neutralizing inflammatory cytokines is crucial for managing a variety of inflammatory disorders. Current techniques that target only a subset of cytokines often fall short due to the intricate nature of redundant and compensatory cytokine networks. A promising solution to this challenge is using cell membrane-coated nanoparticles (CNPs). These nanoparticles replicate the complex interactions between cells and cytokines observed in disease pathology, providing a potential avenue for multiplex cytokine scavenging. While the development of CNPs using experimental animal models has shown great promise, their effectiveness in scavenging multiple cytokines in human diseases has yet to be demonstrated. To bridge this gap, this study selected macrophage membrane-coated CNPs (MФ-CNPs) and assessed their ability to scavenge inflammatory cytokines in serum samples from patients with COVID-19, sepsis, acute pancreatitis, or type-1 diabetes, along with synovial fluid samples from patients with rheumatoid arthritis. The results show that MФ-CNPs effectively scavenge critical inflammatory cytokines, including interleukin (IL)-6, IL-8, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, in a dose-dependent manner. Overall, this study demonstrates MФ-CNPs as a multiplex cytokine scavenging formulation with promising applications in clinical settings to treat a range of inflammatory disorders.