Novel anti-psoriasis agent-associated cardiotoxicity, analysis of the FDA adverse event reporting system (FAERS).

INTRODUCTION: Psoriasis is a chronic skin condition characterized by hyperproliferation of epidermal keratinocytes, resulting in erythematous and scaling lesions. The US Food and Drug Administration (FDA) has approved nine biologic agents to address the burden of psoriasis, but their cardiovascular risks remain poorly studied. METHODS: This retrospective pharmacovigilance study utilized the FDA Adverse Event Reporting System (FAERS) database to analyze adverse events associated with newly approved therapeutic agents for psoriasis. We employed disproportionally signal analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval. RESULTS: Among the vast FAERS database, which contained >25 million adverse events, a total of 334,399 events were associated with newly approved therapeutic agents for psoriasis. Cardiac adverse events accounted for 3852 cases, including pericarditis, atrial fibrillation, and coronary artery disease. Secukinumab had the highest number of reported adverse events, followed by brodalumab, while tildrakizumab had the lowest. Coronary artery disease was the most reported adverse event (1438 cases), followed by pericarditis (572 cases) and atrial fibrillation (384 cases). Secukinumab had the highest incidence of coronary artery disease, pericarditis, and atrial fibrillation. Risankizumab was significantly associated with an increased risk of coronary artery disease and atrial fibrillation, while tildrakizumab and Ixekizumab were associated with atrial fibrillation. Secukinumab was associated with an elevated risk of pericarditis. CONCLUSIONS: The study uncovers the cardiovascular adverse effects related to biologic agents used in psoriasis treatment. These findings emphasize the importance of monitoring and evaluating the cardiovascular safety profiles of biological agents used in psoriasis treatment.

A multi-mineral intervention to counter pro-inflammatory activity and to improve the barrier in human colon organoids.

Introduction: Ulcerative colitis is a chronic inflammatory condition, and continuous inflammatory stimulus may lead to barrier dysfunction. The goal of this study was to assess barrier proteomic expression by a red algae-derived multi-mineral intervention in the absence or presence of pro-inflammatory insult. Methods: Human colon organoids were maintained in a control culture medium alone or exposed to lipopolysaccharide with a combination of three pro-inflammatory cytokines [tumor necrosis factor-α, interleukin-1ß and interferon-γ (LPS-cytokines)] to mimic the environment in the inflamed colon. Untreated organoids and those exposed to LPS-cytokines were concomitantly treated for 14 days with a multi-mineral product (Aquamin®) that has previously been shown to improve barrier structure/function. The colon organoids were subjected to proteomic analysis to obtain a broad view of the protein changes induced by the two interventions alone and in combination. In parallel, confocal fluorescence microscopy, tissue cohesion and transepithelial electrical resistance (TEER) measurements were used to assess barrier structure/function. Results: The LPS-cytokine mix altered the expression of multiple proteins that influence innate immunity and promote inflammation. Several of these were significantly decreased with Aquamin® alone but only a modest decrease in a subset of these proteins was detected by Aquamin® in the presence of LPS-cytokines. Among these, a subset of inflammation-related proteins including fibrinogen-ß and -γ chains (FGB and FGG), phospholipase A2 (PLA2G2A) and SPARC was significantly downregulated in the presence of Aquamin® (alone and in combination with LPS-cytokines); another subset of proteins with anti-inflammatory, antioxidant or anti-microbial activity was upregulated by Aquamin® treatment. When provided alone, Aquamin® strongly upregulated proteins that contribute to barrier formation and tissue strength. Concomitant treatment with LPS-cytokines did not inhibit barrier formation in response to Aquamin®. Confocal microscopy also displayed increased expression of desmoglein-2 (DSG2) and cadherin-17 (CDH17) with Aquamin®, either alone or in the presence of the pro-inflammatory stimulus. Increased cohesion and TEER with Aquamin® (alone or in the presence of LPS-cytokines) indicates improved barrier function. Conclusion: Taken together, these findings suggest that multi-mineral intervention (Aquamin®) may provide a novel approach to combating inflammation in the colon by improving barrier structure/function as well as by directly altering the expression of certain pro-inflammatory proteins.

Diabetic Myonecrosis: A Vascular Complication.

Diabetic myonecrosis is an unpublicised problem that can occur in patients having either type 1 or type 2 diabetes mellitus. It usually affects patients who have long-standing, uncontrolled diabetes with associated microvascular complications. We report a case of a 78-year female with diabetic myonecroses admitted to a tertiary care hospital. Although it is a self-limiting disease, we lay down the management approach of how to exclude the extensive list of differential diagnoses and limit the life-threatening complications as urgent evaluation is critical. Clinicians taking care of patients with uncontrolled diabetes should be mindful and aware of the complication of diabetic myonecrosis in a patient presenting with pain in any limb and having negative venous doppler ultrasound for deep vein thrombosis. Magnetic resonance imaging (MRI) is the most specific and sensitive modality for diagnosis. Muscle biopsy can be used for anomalous cases. Although diabetic muscle infarction is a rare pathology, it presents a high risk for diabetes-related morbidity and mortality. Key Words: Myonecrosis, Diabetes mellitus, Doppler ultrasound, Magnetic resonance imaging.

Ulcerative Colitis-Derived Colonoid Culture: A Multi-Mineral-Approach to Improve Barrier Protein Expression.

BACKGROUND: Recent studies demonstrated that Aquamin®, a calcium-, magnesium-rich, multi-mineral natural product, improves barrier structure and function in colonoids obtained from the tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC). METHODS: Colonoid cultures were established with colon biopsies from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin® to provide 1.5 - 4.5 mM calcium. Effects on differentiation and barrier protein expression were determined using several approaches: phase-contrast and scanning electron microscopy, quantitative histology and immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy. RESULTS: Although there were no gross changes in colonoid appearance, there was an increase in lumen diameter and wall thickness on histology and greater expression of cytokeratin 20 (CK20) along with reduced expression of Ki67 by quantitative immunohistology observed with intervention. In parallel, upregulation of several differentiation-related proteins was seen in a proteomic screen with the intervention. Aquamin®-treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis demonstrated increased expression of several basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation. Finally, several transporter proteins that affect electrolyte balance (and, thereby affect water resorption) were increased. At the same time, growth and cell cycle regulatory proteins (Ki67, nucleophosmin, and stathmin) were significantly down-regulated. Laminin interactions, matrix formation and extracellular matrix organization were the top three up-regulated pathways with the intervention. CONCLUSION: A majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. To the extent that such deficiencies might contribute to the weakening of the colonic barrier, the findings employing UC tissue-derived colonoids here suggest that adequate mineral intake might improve the colonic barrier.

Calcium-induced differentiation in normal human colonoid cultures: Cell-cell / cell-matrix adhesion, barrier formation and tissue integrity.

BACKGROUND AND AIMS: The goal of the study was to assess calcium alone and Aquamin, a multi-mineral natural product that contains magnesium and detectable levels of 72 trace elements in addition to calcium, for capacity to affect growth and differentiation in colonoid cultures derived from histologically-normal human colon tissue. METHODS: Colonoid cultures were maintained in a low-calcium (0.25 mM) medium or in medium supplemented with an amount of calcium (1.5-3.0 mM), either from calcium alone or Aquamin for a period of two weeks. This was shown in a previous study to induce differentiation in colonoids derived from large adenomas. Changes in growth, morphological features and protein expression profile were assessed at the end of the incubation period using a combination of phase-contrast and scanning electron microscopy, histology and immunohistology, proteomic assessment and transmission electron microscopy. RESULTS: Unlike the previously-studied tumor-derived colonoids (which remained un-differentiated in the absence of calcium-supplementation), normal tissue colonoids underwent differentiation as indicated by gross and microscopic appearance, a low proliferative index and high-level expression of cytokeratin 20 in the absence of intervention (i.e., in control condition). Only modest additional changes were seen in these parameters with either calcium alone or Aquamin (providing up to 3.0 mM calcium). In spite of this, proteomic analysis and immunohistochemistry revealed that both interventions induced strong up-regulation of proteins that promote cell-cell and cell-matrix adhesive functions, barrier formation and tissue integrity. Transmission electron microscopy revealed an increase in desmosomes in response to intervention. CONCLUSIONS: These findings demonstrate that colonoids derived from histologically normal human tissue can undergo differentiation in the presence of a low ambient calcium concentration. However, higher calcium levels induce elaboration of proteins that promote cell-cell and cell-matrix adhesion. These changes could lead to improved barrier function and improved colon tissue health.

Interleukin-18 polymorphism as an inflammatory index in metabolic syndrome: A preliminary study.

AIM: To assess circulatory levels of interleukin-18 (IL-18) and determine whether the presence of IL-18 promoter polymorphism influences metabolic syndrome phenotypes. METHODS: This study recruited one hundred and eighty individuals divided into three groups with sixty subjects each as: Normal weight (18.0-22.9 kg/m2), overweight (23.0-25.9 kg/m2) and obese (> 26.0 kg/m2) according to South Asian criteria of BMI. Fasting blood glucose (FBG), Lipid profile, insulin, IL-18 and tumor necrosis factor (TNF)α were measured using ELISA kits, whereas low density lipoprotein (LDL)-cholesterol, insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) were calculated. The body fat percentage (BF) was measured through bioelectrical impedance analysis; waist and hip circumference were measured. Genotyping of IL-18 -607 C/A polymorphism was performed by using tetra-primer amplification refractory mutation system. Student t test, One-way analysis of variance, Hardy-Weinberg equilibrium, Pearson's χ2 test and Pearson's correlation were used, where a P value < 0.05 was considered significant. RESULTS: In an aged matched study, obese subjects showed higher levels of FBG, cholesterol, triglycerides and LDL levels as compared to normal weight (P < 0.001). Highest levels of IL-18 and TNF levels were also seen in obese subjects (IL-18: 58.87 ± 8.59 ng/L) (TNF: 4581.93 ± 2132.05 pg/mL). The percentage of IL-18 -607 A/A polymorphism was higher in overweight and obese subjects vs normal weight subjects (P < 0.001). Moreover, subjects with AA genotype had a higher BF, insulin resistance, TNFα and IL-18 levels when compared with subjects with AC (heterozygous) or CC (wild type) genotypes. However, we did not find any difference in the lipid profile between three subgroups. CONCLUSION: This preliminary data suggests that IL-18 polymorphism affects IL-18 levels that might cause low grade inflammation, further exacerbated by increased TNFα. All these increase the susceptibility to develop MetS. Further studies are required to validate our findings.