Search results for: ulcerative colitis
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 51

Search results for: ulcerative colitis

21 Targeting Basic Leucine Zipper Transcription Factor ATF-Like Mediated Immune Cells Regulation to Reduce Crohn’s Disease Fistula Incidence

Authors: Mohammadjavad Sotoudeheian, Soroush Nematollahi

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Crohn’s disease (CD) is a chronic gastrointestinal segment inflammation encompassing immune dysregulation in a genetically susceptible individual in response to the environmental triggers and interaction between the microbiome and immune system. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures and enteric fistulae. Increased production of Th1 and Th17-cell cytokines and defects in T-regulatory cells have been associated with CD. Th17-cells are essential for protection against extracellular pathogens, but their atypical activity can cause autoimmunity. Intrinsic defects in the control of programmed cell death in the mucosal T-cell compartment are strongly implicated in the pathogenesis of CD. The apoptosis defect in mucosal T-cells in CD has been endorsed as an imbalance of the Bcl-2 and the Bax. The immune system encounters foreign antigens through microbial colonization of mucosal surfaces or infections. In addition, FOSL downregulated IL-26 expression, a cytokine that marks inflammatory Th17-populations in patients suffering from CD. Furthermore, the expression of IL-23 is associated with the transcription factor primary leucine zipper transcription factor ATF-like (Batf). Batf-deficiency demonstrated the crucial role of Batf in colitis development. Batf and IL-23 mediate their effects by inducing IL-6 production. Strong association of IL-23R, Stat3, and Stat4 with IBD susceptibility point to a critical involvement of T-cells. IL-23R levels in transfer fistula were dependent on the AP-1 transcription factor JunB that additionally controlled levels of RORγt by facilitating DNA binding of Batf. T lymphocytes lacking JunB failed to induce IL-23- and Th17-mediated experimental colitis highlighting the relevance of JunB for the IL-23/ Th17 pathway. The absence of T-bet causes unrestrained Th17-cell differentiation. T-cells are central parts of immune-mediated colon fistula. Especially Th17-cells were highly prevalent in inflamed IBD tissues, as RORγt is effective in preventing colitis. Intraepithelial lymphocytes (IEL) contain unique T-cell subsets, including cells expressing RORγt. Increased activated Th17 and decreased T-regulatory cells in inflamed intestinal tissues had been seen. T-cells differentiate in response to many cytokines, including IL-1β, IL-6, IL-23, and TGF-β, into Th17-cells, a process which is critically dependent on the Batf. IL-23 promotes Th17-cell in the colon. Batf manages the generation of IL-23 induced IL-23R+ Th17-cells. Batf is necessary for TGF-β/IL-6-induced Th17-polarization. Batf-expressing T-cells are the core of T-cell-mediated colitis. The human-specific parts of three AP-1 transcription factors, FOSL1, FOSL2, and BATF, are essential during the early stages of Th17 differentiation. BATF supports the Th17 lineage. FOSL1, FOSL2, and BATF make possession of regulatory loci of genes in the Th17 lineage cascade. The AP1 transcription factor Batf is identified to control intestinal inflammation and seems to regulate pathways within lymphocytes, which could theoretically control the expression of several genes. It shows central regulatory properties over Th17-cell development and is intensely upregulated within IBD-affected tissues. Here, we demonstrated that targeting Batf in IBD appears as a therapeutic approach that reduces colitogenic T-cell activities during fistula formation while aiming to affect inflammation in the gut epithelial cells.

Keywords: immune system, Crohn’s Disease, BATF, T helper cells, Bcl, interleukin, FOSL

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20 Mesalazine-Induced Myopericarditis in a Professional Athlete

Authors: Tristan R. Fraser, Christopher D. Steadman, Christopher J. Boos

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Myopericarditis is an inflammation syndrome characterised by clinical diagnostic criteria for pericarditis, such as chest pain, combined with evidence of myocardial involvement, such as elevation of biomarkers of myocardial damage, e.g., troponins. It can rarely be a complication of therapeutics used for dysregulated immune-mediated diseases such as inflammatory bowel disease (IBD), for example, mesalazine. The infrequency of mesalazine-induced myopericarditis adds to the challenge in its recognition. Rapid diagnosis and the early introduction of treatment are crucial. This case report follows a 24-year-old professional footballer with a past medical history of ulcerative colitis, recently started on mesalazine for disease control. Three weeks after mesalazine was initiated, he was admitted with fever, shortness of breath, and chest pain worse whilst supine and on deep inspiration, as well as elevated venous blood cardiac troponin T level (cTnT, 288ng/L; normal: <13ng/L). Myocarditis was confirmed on initial inpatient cardiac MRI, revealing the presence of florid myocarditis with preserved left ventricular systolic function and an ejection fraction of 67%. This was a longitudinal case study following the progress of a single individual with myopericarditis over four acute hospital admissions over nine weeks, with admissions ranging from two to five days. Parameters examined included clinical signs and symptoms, serum troponin, transthoracic echocardiogram, and cardiac MRI. Serial measurements of cardiac function, including cardiac MRI and transthoracic echocardiogram, showed progressive deterioration of cardiac function whilst mesalazine was continued. Prior to cessation of mesalazine, transthoracic echocardiography revealed a small global pericardial effusion of < 1cm and worsening left ventricular systolic function with an ejection fraction of 45%. After recognition of mesalazine as a potential cause and consequent cessation of the drug, symptoms resolved, with cardiac MRI performed as an outpatient showing resolution of myocardial oedema. The patient plans to make a return to competitive sport. Patients suffering from myopericarditis are advised to refrain from competitive sport for at least six months in order to reduce the risk of cardiac remodelling and sudden cardiac death. Additional considerations must be taken in individuals for whom competitive sport is an essential component of their livelihood, such as professional athletes. Myopericarditis is an uncommon, however potentially serious medical condition with a wide variety of aetiologies, including viral, autoimmune, and drug-related causes. Management is mainly supportive and relies on prompt recognition and removal of the aetiological process. Mesalazine-induced myopericarditis is a rare condition; as such increasing awareness of mesalazine as a precipitant of myopericarditis is vital for optimising the management of these patients.

Keywords: myopericarditis, mesalazine, inflammatory bowel disease, professional athlete

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19 Use of Proton Pump Inhibitors Medications during the First Years of Life and Late Complications

Authors: Kamelia Hamza

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Background: Proton pump inhibitors (PPIs) are the most prescribed drug classes for pediatric gastroesophageal reflux disease (GERD).Many patients are treated with these drugs for atypical manifestations attributed to gastroesophageal reflux (GER), even in the absence of proved causal relationship. There is an impression of increase use of PPI's treatment for reflux in "clalit health services," the largest health organization in Israel. In the recent years, the medicine is given without restriction, it's not limited to pediatric gastroenterologists only, but pediatricians and family doctors. The objective of this study is to evaluate the hypothesis that exposure to PPIs during the first year of life is associated with an increased risk of developing late adverse diseases: pneumonia, asthma, AGE, IBD, celiac disease, allergic disorders, obesity, attention deficit hyperactivity disorders (ADHD), autism spectrum disorders (ASD). Methods: The study is a retrospective case-control cohort study based on a computerized database of Clalit Health Services (CHS). It includes 9844 children born between 2002-2018 and reported to complain of at least one of the symptoms (reflux/ spitting up, irritability, feeding difficulties, colics). The study population included the study group (n=4922) of children exposed to PPIs at any time prior to the first year of life and a control group (n=4922) child not exposed to PPIs who were matched to each case of the study group on age, race, socioeconomic status, and year of birth. The prevalence of late complications/diseases in the study group was compared with the prevalence of late complications/diseases diagnosis between 2002-2020 in the control group. Odds ratios and 95% confidence intervals were calculated by using logistic regression models. Results: We found that compared to the control group, children exposed to PPIs in the first year of life had an increased risk of developing several late complications/ disorders: pneumonia, asthma, various allergies (urticaria, allergic rhinitis, or allergic conjunctivitis) OR, inhalant allergies, and food allergies. In addition, they showed an increased risk of being diagnosed with ADHD or ASD, but children exposed to PPIs in the first year of life had decrease the risk of obesity by 17% (OR 0.825, 95%CI 0.697-0.976). Conclusions: We found significant associations between the use of PPIs during the first year of life and subsequent development of late complications/diseases such as respiratory diseases, allergy diseases, ADHD, and ASD. More studies are needed to prove causality and determine the mechanism behind the effect of PPIs and the development of late complications.

Keywords: acid suppressing medications, proton pump inhibitors, histamine 2 blocker, late complications, gastroesophageal reflux, gastroesophageal reflux disease, acute gastroenteritis, community acquired pneumonia, asthma, allergic diseases, obesity, inflammatory bowel diseases, ulcerative colitis, crohn disease, attention deficit hyperactivity disorders, autism spectrum disorders

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18 A Multidisciplinary Team Approach for Limb Salvage in a Rare Case of Pyoderma Gangrenosum in a Significant Circumferential Lower Extremity Wound Complicated by Diabetes and End-stage Renal Disease

Authors: Jenee Gooden, Kevin Vasquez-monterroso, Lady Paula Dejesus, Sandra Wainwright, Daniel Kim, Mackenzie Walker

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Introduction: Pyoderma gangrenosum (PG) is a rare, rapidly progressive, neutrophilic ulcerative colitis condition with an incidence of 3 to 10 cases per year ¹ ². Due to the similar appearance, PG is often misdiagnosed as a diabetic ulcer in diabetic patients. Though they may clinically appear similar in appearance, the treatment protocol and diagnostic criteria differ. Also, end-stage renal disease (ESRD) is often a condition seen in diabetic patients, which can have a significant impact on wound healing due to the wide range of uremic toxins³. This case study demonstrates a multidisciplinary team and multimodal treatment approach by podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine for an uncontrolled diabetic with pyoderma gangrenosum of a significant circumferential wound, covering almost the entire right lower extremity. Methods:56 y.o male presents with multiple PG ulcerations, including the chest, right posterior lower extremity and sacrum. All ulcerations were previously managed by the same wound care specialist. His chief complaint was worsening PG ulcerations accompanied by a fever of 103 °F . This case study focuses on the wound to his RLE. Past medical history significant for diabetes mellitus type 2 with hemoglobin A1c of 10% and end stage renal disease (ESRD) on hemodialysis. A multidisciplinary team approach by podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine was successfully used to perform right lower extremity limb salvage. The patient was managed by rheumatology for the continuation of prior medication, as well as the mutual agreement with wound care for the addition of dapsone. A coronary CT angiogram was performed by interventional cardiology, but no significant disease was noted, and no further vascular workup was necessary. Multiple surgical sharp wide excisional debridements with application of allografts and split thickness skin grafts for the circumferential ulceration that encompassed almost the entire right lower extremity were performed by both podiatric surgery and general surgery. Wound cultures and soft tissue biopsies were performed, and infectious disease managed antibiotic therapy. Hyperbaric oxygen therapy and wound vac therapy by wound care were also completed as adjunct management. Results: Prevention of leg amputation by limb salvage of the RLE was accomplished by a multidisciplinary team approach, with the wound size decreasing over a total of 29 weeks from 600 cm² to 12.0 x 3.5 x 0.2 cm. Our multidisciplinary team included podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine. Discussion: Wound healing, in general, can have its challenges, and those challenges are only magnified when accompanied by multiple systemic illnesses. Though the negative impact of diabetes on wound healing is well known, the compound impact of being a diabetic with ESRD and having pyoderma gangrenosum is not. This case demonstrates the necessity for a multidisciplinary team approach with a wide array of treatment modalities to optimize wound healing and perform limb salvage with prevention of lower extremity amputation.

Keywords: diabetes, podiatry, pyoderma gangrenosum, end stage renal disease

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17 Gene Expression Meta-Analysis of Potential Shared and Unique Pathways Between Autoimmune Diseases Under anti-TNFα Therapy

Authors: Charalabos Antonatos, Mariza Panoutsopoulou, Georgios K. Georgakilas, Evangelos Evangelou, Yiannis Vasilopoulos

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The extended tissue damage and severe clinical outcomes of autoimmune diseases, accompanied by the high annual costs to the overall health care system, highlight the need for an efficient therapy. Increasing knowledge over the pathophysiology of specific chronic inflammatory diseases, namely Psoriasis (PsO), Inflammatory Bowel Diseases (IBD) consisting of Crohn’s disease (CD) and Ulcerative colitis (UC), and Rheumatoid Arthritis (RA), has provided insights into the underlying mechanisms that lead to the maintenance of the inflammation, such as Tumor Necrosis Factor alpha (TNF-α). Hence, the anti-TNFα biological agents pose as an ideal therapeutic approach. Despite the efficacy of anti-TNFα agents, several clinical trials have shown that 20-40% of patients do not respond to treatment. Nowadays, high-throughput technologies have been recruited in order to elucidate the complex interactions in multifactorial phenotypes, with the most ubiquitous ones referring to transcriptome quantification analyses. In this context, a random effects meta-analysis of available gene expression cDNA microarray datasets was performed between responders and non-responders to anti-TNFα therapy in patients with IBD, PsO, and RA. Publicly available datasets were systematically searched from inception to 10th of November 2020 and selected for further analysis if they assessed the response to anti-TNFα therapy with clinical score indexes from inflamed biopsies. Specifically, 4 IBD (79 responders/72 non-responders), 3 PsO (40 responders/11 non-responders) and 2 RA (16 responders/6 non-responders) datasetswere selected. After the separate pre-processing of each dataset, 4 separate meta-analyses were conducted; three disease-specific and a single combined meta-analysis on the disease-specific results. The MetaVolcano R package (v.1.8.0) was utilized for a random-effects meta-analysis through theRestricted Maximum Likelihood (RELM) method. The top 1% of the most consistently perturbed genes in the included datasets was highlighted through the TopConfects approach while maintaining a 5% False Discovery Rate (FDR). Genes were considered as Differentialy Expressed (DEGs) as those with P ≤ 0.05, |log2(FC)| ≥ log2(1.25) and perturbed in at least 75% of the included datasets. Over-representation analysis was performed using Gene Ontology and Reactome Pathways for both up- and down-regulated genes in all 4 performed meta-analyses. Protein-Protein interaction networks were also incorporated in the subsequentanalyses with STRING v11.5 and Cytoscape v3.9. Disease-specific meta-analyses detected multiple distinct pro-inflammatory and immune-related down-regulated genes for each disease, such asNFKBIA, IL36, and IRAK1, respectively. Pathway analyses revealed unique and shared pathways between each disease, such as Neutrophil Degranulation and Signaling by Interleukins. The combined meta-analysis unveiled 436 DEGs, 86 out of which were up- and 350 down-regulated, confirming the aforementioned shared pathways and genes, as well as uncovering genes that participate in anti-inflammatory pathways, namely IL-10 signaling. The identification of key biological pathways and regulatory elements is imperative for the accurate prediction of the patient’s response to biological drugs. Meta-analysis of such gene expression data could aid the challenging approach to unravel the complex interactions implicated in the response to anti-TNFα therapy in patients with PsO, IBD, and RA, as well as distinguish gene clusters and pathways that are altered through this heterogeneous phenotype.

Keywords: anti-TNFα, autoimmune, meta-analysis, microarrays

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16 Antiulcer Potential of Heme Oxygenase-1 Inducers

Authors: Gaweł Magdalena, Lipkowska Anna, Olbert Magdalena, Frąckiewicz Ewelina, Librowski Tadeusz, Nowak Gabriel, Pilc Andrzej

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Heme oxygenase-1 (HO-1), also known as heat shock protein 32 (HSP32), has been shown to be implicated in cytoprotection in various organs. Its activation plays a significant role in acute and chronic inflammation, protecting cells from oxidative injury and apoptosis. This inducible isoform of HO catalyzes the first and rate-limiting step in heme degradation to produce equimolar quantities of biologically active products: carbon monoxide (CO), free iron and biliverdin. CO has been reported to possess anti-apoptotic properties. Moreover, it inhibits the production of proinflammatory cytokines and stimulates the synthesis of the anti-inflammatory interleukin-10 (IL-10), as well as promotes vasodilatation at sites of inflammation. The second product of catalytic HO-1 activity, free cytotoxic iron, is promptly sequestered into the iron storage protein ferritin, which lowers the pro-oxidant state of the cell. The third product, biliverdin, is subsequently converted by biliverdin reductase into the bile pigment bilirubin, the most potent endogenous antioxidant among the constituents of human serum, which modulates immune effector functions and suppresses inflammatory response. Furthermore, being one of the so-called stress proteins, HO-1 adaptively responds to different stressors, such as reactive oxygen species (ROS), inflammatory cytokines and heavy metals and thus protects cells against such conditions as ischemia, hemorrhagic shock, heat shock or hypoxia. It is suggested that pharmacologic modulation of HO-1 may represent an effective strategy for prevention of stress and drug-induced gastrointestinal toxicity. HO-1 is constitutively expressed in normal gastric, intestinal and colonic mucosa and up-regulated during inflammation. It has been proven that HO-1 up-regulated by hemin, heme and cobalt-protoporphyrin ameliorates experimental colitis. In addition, the up-regulation of HO-1 partially explains the mechanism of action of 5-aminosalicylic acid (5-ASA), which is used clinically as an anti-colitis agent. In 2009 Ueda et al. has reported for the first time that mucosal protection by Polaprezinc, a chelate compound of zinc and L-carnosine used as an anti-ulcer drug in Japan, is also attributed to induction of HO-1 in the stomach. Since then, inducers of HO-1 are desired subject of research, as they may constitute therapeutically effective anti-ulcer drugs.

Keywords: heme oxygenase-1, gastric lesions, gastroprotection, Polaprezinc

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15 Alternate Optical Coherence Tomography Technologies in Use for Corneal Diseases Diagnosis in Dogs and Cats

Authors: U. E. Mochalova, A. V. Demeneva, Shilkin A. G., J. Yu. Artiushina

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Objective. In medical ophthalmology OCT has been actively used in the last decade. It is a modern non-invasive method of high-precision hardware examination, which gives a detailed cross-sectional image of eye tissues structure with a high level of resolution, which provides in vivo morphological information at the microscopic level about corneal tissue, structures of the anterior segment, retina and optic nerve. The purpose of this study was to explore the possibility of using the OCT technology in complex ophthalmological examination in dogs and cats, to characterize the revealed pathological structural changes in corneal tissue in cats and dogs with some of the most common corneal diseases. Procedures. Optical coherence tomography of the cornea was performed in 112 animals: 68 dogs and 44 cats. In total, 224 eyes were examined. Pathologies of the organ of vision included: dystrophy and degeneration of the cornea, endothelial corneal dystrophy, dry eye syndrome, chronic superficial vascular keratitis, pigmented keratitis, corneal erosion, ulcerative stromal keratitis, corneal sequestration, chronic glaucoma and also postoperative period after performed keratoplasty. When performing OCT, we used certified medical devices: "Huvitz HOCT-1/1F», «Optovue iVue 80» and "SOCT Copernicus Revo (60)". Results. The results of a clinical study on the use of optical coherence tomography (OCT)of the cornea in cats and dogs, performed by the authors of the article in the complex diagnosis of keratopathies of variousorigins: endothelial corneal dystrophy, pigmented keratitis, chronic keratoconjunctivitis, chronic herpetic keratitis, ulcerative keratitis, traumatic corneal damage, sequestration of the cornea of cats, chronic keratitis, complicating the course of glaucoma. The characteristics of the OCT scans are givencorneas of cats and dogs that do not have corneal pathologies. OCT scans of various corneal pathologies in dogs and cats with a description of the revealed pathological changes are presented. Of great clinical interest are the data obtained during OCT of the cornea of animals undergoing keratoplasty operations using various forms of grafts. Conclusions. OCT makes it possible to assess the thickness and pathological structural changes of the corneal surface epithelium, corneal stroma and descemet membrane. We can measure them, determine the exact localization, and record pathological changes. Clinical observation of the dynamics of the pathological process in the cornea using OCT makes it possible to evaluate the effectiveness of drug treatment. In case of negative dynamics of corneal disease, it is necessary to determine the indications for surgical treatment (to assess the thickness of the cornea, the localization of its thinning zones, to characterize the depth and area of pathological changes). According to the OCT of the cornea, it is possible to choose the optimal surgical treatment for the patient, the technique and depth of optically constructive surgery (penetrating or anterior lamellar keratoplasty).; determine the depth and diameter of the planned microsurgical trepanation of corneal tissue, which will ensure good adaptation of the edges of the donor material.

Keywords: optical coherence tomography, corneal sequestration, optical coherence tomography of the cornea, corneal transplantation, cat, dog

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14 Drug Reaction with Eosinophilia and Systemic Symptoms (Dress) Syndrome Presenting as Multi-Organ Failure

Authors: Keshari Shrestha, Philip Vatterott

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Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially fatal drug-related syndrome. DRESS classically presents with a diffuse maculopapular rash, fevers, and eosinophilia more than three weeks after drug exposure. DRESS can present with multi-organ involvement, with liver damage being the most common and severe. Pulmonary involvement is a less common manifestation and is associated with poor clinical outcomes. Chest imaging is often nonspecific, and symptoms can range from mild cough to acute respiratory distress syndrome (ARDS) . This is a case of a 49-year-old female with a history of recent clostridium difficile colitis status post treatment with oral vancomycin who presented with rash, acute liver and kidney failure, as well as diffuse nodular alveolar lung opacities concerning for DRESS syndrome with multi-organ involvement. Clinical Course: This patient initially presented to an outside hospital with clostridium difficile colitis, acute liver injury, and acute kidney injury. She developed a desquamating maculopapular rash in the setting of recent oral vancomycin, meloxicam, and furosemide initiation. She was hospitalized on two additional occasions with worsening altered mental status, liver injury, and acute kidney injury and was initiated on intermittent hemodialysis. Notably, she was found to have systemic eosinophilia (4100 cells/microliter) several weeks prior. She was transferred to this institution for further management where she was found to have encephalopathy, jaundice, lower extremity edema, and diffuse bilateral rhonchorous breath sounds on pulmonary examination. The patient was started on methylprednisolone for suspected DRESS syndrome. She underwent an evaluation for alternative causes of her organ failure. Her workup included a negative infectious, autoimmune, metabolic, toxic, and malignant work-up. Abdominal computed tomography (CT) and ultrasound were remarkable for evidence of hepatic steatosis and possible cirrhotic morphology. Additionally, a chest CT demonstrated diffuse and symmetric nodular alveolar lung opacities with peripheral sparing not consistent with acute respiratory distress syndrome or edema. Ultimately, her condition continued to decline, and she required intubation on several occasions. On hospital day 25 she succumbed to distributive shock in the setting of probable sepsis and multi-organ failure. Discussion: DRESS syndrome occurs in 1 in 1,000 to 10,000 patients with a mortality rate of around 10%. Anti-convulsant, anti-bacterial, anti-viral, and sulfonamide drugs are the most common drugs implicated in the development of DRESS syndrome; however, the list of offending agents is extensive . The diagnosis of DRESS syndrome is made after excluding other causes of disease such as infectious and autoimmune etiologies. The RegiSCAR scoring system is used to diagnose DRESS syndrome with 2-3 points indicating possible disease, 4-5 probable disease, and >5 definite disease. This patient scored a 7 on the RegiSCAR scale for eosinophilia, rash, organ involvement, and exclusion of other causes (infectious and autoimmune). While the pharmacologic trigger in this case is unknown, it is speculated to be caused by vancomycin, meloxicam, or furosemide due to the favorable timeline of initiation. Despite aggressive treatment, DRESS syndrome can often be fatal. Because of this, early diagnosis and treatment of patients with suspected DRESS syndrome is imperative.

Keywords: drug reaction with eosinophilia and systemic symptoms, multi-organ failure, pulmonary involvement, renal failure

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13 Regulation of SHP-2 Activity by Small Molecules for the Treatment of T Cell-Mediated Diseases

Authors: Qiang Xu, Xingxin Wu, Wenjie Guo, Xingqi Wang, Yang Sun, Renxiang Tan

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The phosphatase SHP-2 is known to exert regulatory activities on cytokine receptor signaling and the dysregulation of SHP-2 has been implicated in the pathogenesis of a variety of diseases. Here we report several small molecule regulators of SHP-2 for the treatment of T cell-mediated diseases. The new cyclodepsipeptide trichomides A, isolated from the fermentation products of Trichothecium roseum, increased the phosphorylation of SHP-2 in activated T cells, and ameliorated contact dermatitis in mice. The trichomides A’s effects were significantly reversed by using the SHP-2-specific inhibitor PHPS1 or T cell-conditional SHP-2 knockout mice. Another compound is a cerebroside Fusaruside isolated from the endophytic fungus Fusarium sp. IFB-121. Fusaruside also triggered the tyrosine phosphorylation of SHP-2, which provided a possible mean of selectively targeting STAT1 for the treatment of Th1 cell-mediated inflammation and led to the discovery of the non-phosphatase-like function of SHP-2. Namely, the Fusaruside-activated pY-SHP-2 selectively sequestrated the cytosolic STAT1 to prevent its recruitment to IFN-R, which contributed to the improvement of experimental colitis in mice. Blocking the pY-SHP-2-STAT1 interaction, with SHP-2 inhibitor NSC-87877 or using T cells from conditional SHP-2 knockout mice, reversed the effects of fusaruside. Furthermore, the fusaruside’s effect is independent of the phosphatase activity of SHP-2, demonstrating a novel role for SHP-2 in regulating STAT1 signaling and Th1-type immune responses.

Keywords: SHP-2, small molecules, T cell, T cell-mediated diseases

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12 Determination of the Effect of Kaolin on the Antimicrobial Activity of Metronidazole-Kaolin Interaction

Authors: Omaimah Algohary

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Kaolin is one of the principle intestinal adsorbents, has traditionally been used internally in the treatment of various enteric disorders, colitis, enteritis, dysentery, and diarrhea associated with food and alkaloidal poisoning and in traveler’s diarrhea. It binds to and traps bacteria and its toxins and gases in the gut. It also binds to water in the gut, which helps to make the stools firmer, hence giving symptomatic relief. Metronidazole is a synthetic antibacterial agent that is used primarily in the treatment of various anaerobic infections such as intra-abdominal infections, antiprotozoal, and as amebicidal. The need for safe, therapeutically effective antidiarrheal combination continuously lead to effective treatment. Metronidazol used for treatment of anaerobic bacteria and kaolin , when administered simultaneously, Metronidazole–Kaolin interactions have been reported by FDA but not studied. This project is the first to study the effect of Metronidazole–Kaolin interactions on the antimicrobial activity of metronidazole. Agar diffusion method performed to test the antimicrobial activity of metronidazole–kaolin antidiarrheal combination from aqueous solutions at an in-vivo simulated pHs conditions that obtained at 37+0.5 °C on Helicobacter pylori as anaerobic bacteria and E.coli as aerobic bacteria and used as a control for the technique. The antimicrobial activity of metronidazole combination as 1:1 and 1:2 with kaolin was abolished in acidic media as no zones of inhibition shown compared to only metronidazole that used as a control. In alkaline media metronidazole combination as 1:1 and 1:2 with kaolin showed diminutive activity compared to the control. These results proved that the kaolin adsorb metronidazole and abolish its antimicrobial activity and such combination should be avoided.

Keywords: kaolin, metronidazole, interaction, Helicobacter pylori. E. coli, antimicrobial activity

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11 MiRNA Regulation of CXCL12β during Inflammation

Authors: Raju Ranjha, Surbhi Aggarwal

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Background: Inflammation plays an important role in infectious and non-infectious diseases. MiRNA is also reported to play role in inflammation and associated cancers. Chemokine CXCL12 is also known to play role in inflammation and various cancers. CXCL12/CXCR4 chemokine axis was involved in pathogenesis of IBD specially UC. Supplementation of CXCL12 induces homing of dendritic cells to spleen and enhances control of plasmodium parasite in BALB/c mice. We looked at the regulation of CXCL12β by miRNA in UC colitis. Prolonged inflammation of colon in UC patient increases the risk of developing colorectal cancer. We looked at the expression differences of CXCl12β and its targeting miRNA in cancer susceptible area of colon of UC patients. Aim: Aim of this study was to find out the expression regulation of CXCL12β by miRNA in inflammation. Materials and Methods: Biopsy samples and blood samples were collected from UC patients and non-IBD controls. mRNA expression was analyzed using microarray and real-time PCR. CXCL12β targeting miRNA were looked by using online target prediction tools. Expression of CXCL12β in blood samples and cell line supernatant was analyzed using ELISA. miRNA target was validated using dual luciferase assay. Results and conclusion: We found miR-200a regulate the expression of CXCL12β in UC. Expression of CXCL12β was increased in cancer susceptible part of colon and expression of its targeting miRNA was decreased in the same part of colon. miR-200a regulate CXCL12β expression in inflammation and may be an important therapeutic target in inflammation associated cancer.

Keywords: inflammation, miRNA, regulation, CXCL12

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10 Identification and Isolation of E. Coli O₁₅₇:H₇ From Water and Wastewater of Shahrood and Neka Cities by PCR Technique

Authors: Aliasghar Golmohammadian, Sona Rostampour Yasouri

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One of the most important intestinal pathogenic strains is E. coli O₁₅₇:H₇. This pathogenic bacterium is transmitted to humans through water and food. E. coli O₁₅₇:H₇ is the main cause of Hemorrhagic colitis (HC), Hemolytic Uremic Syndrome (HUS), Thrombotic Thrombocytopenic Purpura (TTP) and in some cases death. Since E. coli O₁₅₇:H₇ can be transmitted through the consumption of different foods, including vegetables, agricultural products, and fresh dairy products, this study aims to identify and isolate E. coli O₁₅₇:H₇ from wastewater by PCR technique. One hundred twenty samples of water and wastewater were collected by Falcom Sterile from Shahrood and Neka cities. The samples were checked for colony formation after appropriate centrifugation and cultivation in the specific medium of Sorbitol MacConkey Agar (SMAC) and other diagnostic media of E. coli O₁₅₇:H₇. Also, the plates were observed macroscopically and microscopically. Then, the necessary phenotypic tests were performed on the colonies, and finally, after DNA extraction, the PCR technique was performed with specific primers related to rfbE and stx2 genes. The number of 5 samples (6%) out of all the samples examined were determined positive by PCR technique with observing the bands related to the mentioned genes on the agarose gel electrophoresis. PCR is a fast and accurate method to identify the bacteria E. coli O₁₅₇:H₇. Considering that E. coli bacteria is a resistant bacteria and survives in water and food for weeks and months, the PCR technique can provide the possibility of quick detection of contaminated water. Moreover, it helps people in the community control and prevent the transfer of bacteria to healthy and underground water and agricultural and even dairy products.

Keywords: E. coli O₁₅₇:H₇, PCR, water, wastewater

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9 Molecular Evolutionary Relationships Between O-Antigens of Enteric Bacteria

Authors: Yuriy A. Knirel

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Enteric bacteria Escherichia coli is the predominant facultative anaerobe of the colonic flora, and some specific serotypes are associated with enteritis, hemorrhagic colitis, and hemolytic uremic syndrome. Shigella spp. are human pathogens that cause diarrhea and bacillary dysentery (shigellosis). They are in effect E. coli with a specific mode of pathogenicity. Strains of Salmonella enterica are responsible for a food-borne infection (salmonellosis), and specific serotypes cause typhoid fever and paratyphoid fever. All these bacteria are closely related in respect to structure and genetics of the lipopolysaccharide, including the O-polysaccharide part (O‑antigen). Being exposed to the bacterial cell surface, the O antigen is subject to intense selection by the host immune system and bacteriophages giving rise to diverse O‑antigen forms and providing the basis for typing of bacteria. The O-antigen forms of many bacteria are unique, but some are structurally and genetically related to others. The sequenced O-antigen gene clusters between conserved galF and gnd genes were analyzed taking into account the O-antigen structures established by us and others for all S. enterica and Shigella and most E. coli O-serogroups. Multiple genetic mechanisms of diversification of the O-antigen forms, such as lateral gene transfer and mutations, were elucidated and are summarized in the present paper. They include acquisition or inactivation of genes for sugar synthesis or transfer or recombination of O-antigen gene clusters or their parts. The data obtained contribute to our understanding of the origins of the O‑antigen diversity, shed light on molecular evolutionary relationships between the O-antigens of enteric bacteria, and open a way for studies of the role of gene polymorphism in pathogenicity.

Keywords: enteric bacteria, O-antigen gene cluster, polysaccharide biosynthesis, polysaccharide structure

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8 Prevalence and Distribution of Verocytotoxigenic Escherichia coli (Vtec) Non-O157 Serotypes in Cattle in Abuja, Nigeria

Authors: S. I. Enem, S. I. Oboegbulem

Abstract:

Objective: The most frequently implicated E. coli serotype causing haemorrhagic colitis and haemorrhagic uraemic syndrome (HUS) is VTEC 0157. However, non-O157 VTEC is now known to be as prevalent as VETC O157 infection (or even more) in most parts of the world. The objective of the study was to establish the occurrence of non-O157 VTEC serotypes in cattle in the Federal Capital Territory (FCT) Abuja, Nigeria. The level of significance of the infection with sex, age and season were also tested. Methods: The study was carried out in the FCT, Abuja, Nigeria which is located between latitude 8o and 90 25` North of the equator and longitude 60 45` and 7045` East of the Greenwich meridian. The cross sectional epidemiological method and multi-staged sampling technique were used in this study. Samples were collected from the freshly voided faeces of both apparently healthy and diarrhoeic cattle in selected abattoirs and cattle herds. Enriched samples were analyzed bacteriologically and biochemically after which they were characterised using commercially prepared latex agglutination test kits. Results: A total of 718 faecal samples from cattle were analyzed for the presence of VTEC non-O157. Thirty eight (5.23%) were positive for non-O157. There was no significant association (p > 0.05) between sex and infection with non-O157 VTEC in cattle. There was a significant association (P < 0.05) between age and infection with non-O157 VTEC in cattle. Calves were more associated than the adults. There was also a significant association (P < 0.05) between season and infection with non-O157 VTEC in cattle. The dry season was more associated than the wet season. Conclusion: The study established the occurrence and prevalence of non-O157 VTEC in cattle in FCT, Abuja, Nigeria. As a major food animal in Nigeria, infection in cattle provides an epidemiological causal association to the infection in humans. The result showed that warmer seasons (dry season) stimulate the presence of VTEC infection in animals and thus, as a consequence, increases the number of human cases. The prevalence was also higher in younger calves (< 6 months) probably as a result of undeveloped immune system.

Keywords: prevalence, distribution, Verocytotoxigenic escherichia coli (VTEC), non-O157 serotypes, cattle

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7 Association of Clostridium difficile Infection and Bone Cancer

Authors: Daniela Prado, Lexi Frankel, Amalia Ardeljan, Lokesh Manjani, Matthew Cardeiro, Omar Rashid

Abstract:

Background: Clostridium difficile (C. diff) is a gram-positive bacterium that is known to cause life-threatening diarrhea and severe inflammation of the colon. It originates as an alteration of the gut microbiome and can be transmitted through spores. Recent studies have shown a high association between the development of C. diff in cancer patients due to extensive hospitalization. However, research is lacking regarding C. diff’s association in the causation or prevention of cancer. The objective of this study was to therefore assess the correlation between Clostridium difficile infection (CDI) and the incidence of bone cancer. Methods: This retrospective analysis used data provided by a Health Insurance Portability and Accountability Act (HIPAA) compliant national database to evaluate the patients infected versus patients not infected with C. diff using ICD-10 and ICD-9 codes. Access to the database was granted by the Holy Cross Health, Fort Lauderdale, for the purpose of academic research. Standard statistical methods were used. Results: Between January 2010 and December 2019, the query was analyzed and resulted in 78863 patients in both the infected and control group, respectively. The two groups were matched by age range and CCI score. The incidence of bone cancer was 659 patients (0.835%) in the C. diff group compared to 1941 patients (2.461%) in the control group. The difference was statistically significant by a P-value < 2.2x10^-16 with an odds ratio (OR)= 0.33 (0.31-0.37) with a 95% confidence interval (CI). Treatment for CDI was analyzed for both C. diff infected and noninfected populations. 91 out of 16,676 (0.55%) patients with a prior C. diff infection and treated with antibiotics were compared to the control group were 275 out of 16,676 (1.65%) patients with no history of CDI and received antibiotic treatment. Results remained statistically significant by P-value <2.2x10-16 with an OR= 0.42 (0.37, 0.48). and a 95% CI. Conclusion: The study shows a statistically significant correlation between C. diff and a reduced incidence of bone cancer. Further evaluation is recommended to assess the potential of C. difficile in reducing bone cancer incidence.

Keywords: bone cancer, colitis, clostridium difficile, microbiome

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6 The Correlation between Clostridium Difficile Infection and Bronchial Lung Cancer Occurrence

Authors: Molnar Catalina, Lexi Frankel, Amalia Ardeljan, Enoch Kim, Marissa Dallara, Omar Rashid

Abstract:

Introduction: Clostridium difficile (C. diff) is a toxin-producing bacteria that can cause diarrhea and colitis. U.S. Center for Disease Control and Prevention revealed that C. difficile infection (CDI) has increased from 31 cases per 100,000 persons per year in 1996 to 61 per 100,000 in 2003. Approximately 500,000 cases per year occur in the United States. After exposure, the bacteria colonize the colon, where it adheres to the intestinal epithelium where it produces two toxins: TcdA and TcdB. TcdA affects the intestinal epithelium, causing fluid secretion, inflammation, and tissue necrosis, while TcdB acts as a cytotoxin purpose of this study was to evaluate the association between C diff infection and bronchial lung cancer development. Methods: Using ICD- 9 and ICD-10 codes, the data was provided by a Health Insurance Portability and Accountability Act (HIPAA) compliant national database to assess the patients infected with C diff as opposed to the non-infected patients. The Holy Cross Health, Fort Lauderdale, granted access to the database for the purpose of academic research. Patients were matched for age and Charlson Comorbidity Index (CCI). Standard statistical methods were used. Results: Bronchial lung cancer occurrence in the population not infected with C diff infection was 4741, as opposed to the population infected with C. diff, where 2039 cases of lung cancer were observed. The difference was statistically significant (p-value < 2.2x10^e-16), which reveals that C diff might be protective against bronchial lung cancer. The data was then matched by treatment to create to minimize the effect of treatment bias. Bronchial cancer incidence was 422 and 861 in infected vs. non-infected (p-value of < 2.2x10^e-16), which once more indicates that C diff infection could be beneficial in diminishing bronchial cancer development. Conclusion: This retrospective study conveys a statistical correlation between C diff infection and decreased incidence of lung bronchial cancer. Further studies are needed to comprehend the protective mechanisms of C. Diff infection on lung cancer.

Keywords: C. diff, lung cancer, protective, microbiology

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5 Fastidious Enteric Pathogens in HIV

Authors: S. Pathak, R. Lazarus

Abstract:

A 25-year-old male HIV patient (CD4 cells 20/µL and HIV viral load 14200000 copies/ml) with a past medical history of duodenal ulcer, pneumocystis carinii pneumonia, oesophageal candidiasis presented with fever and a seizure to hospital. The only recent travel had been a religious pilgrimage from Singapore to Malaysia 5 days prior; during the trip he sustained skin abrasions. The patient had recently started highly active antiretroviral therapy 2 months prior. Clinical examination was unremarkable other than a temperature of 38.8°C and perianal warts. Laboratory tests showed a leukocyte count 12.5x109 cells/L, haemoglobin 9.4 g/dL, normal biochemistry and a C-reactive protein 121 mg/L. CT head and MRI head were unremarkable and cerebrospinal fluid analysis performed after a delay (due to technical difficulties) of 11 days was unremarkable. Blood cultures (three sets) taken on admission showed Gram-negative rods in the anaerobic bottles only at the end of incubation with culture result confirmed by molecular sequencing showing Helicobacter cinaedi. The patient was treated empirically with ceftriaxone for seven days and this was converted to oral co-amoxiclav for a further seven days after the blood cultures became positive. A Transthoracic echocardiogram was unremarkable. The patient made a full recovery. Helicobacter cinaedi is a gram-negative anaerobic fastidious organism affecting patients with comorbidity. Infection may manifest as cellulitius, colitis or as in this case as bloodstream infection – the latter is often attributed to faeco-oral infection. Laboratory identification requires prolonged culture. Therapeutic options may be limited by resistance to macrolides and fluoroquinolones. The likely pathogen inoculation routes in the case described include gastrointestinal translocation due to proctitis at the site of perianal warts, or breach of the skin via abrasions occurring during the pilgrimage. Such organisms are increasing in prevalence as our patient population ages and patients have multiple comorbidities including HIV. It may be necessary in patients with unexplained fever to prolong incubation of sterile sites including blood in order to identify this unusual fastidious organism.

Keywords: fastidious, Helicobacter cinaedi, HIV, immunocompromised

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4 Gastro-Protective Actions of Melatonin and Murraya koenigii Leaf Extract Combination in Piroxicam Treated Male Wistar Rats

Authors: Syed Benazir Firdaus, Debosree Ghosh, Aindrila Chattyopadhyay, Kuladip Jana, Debasish Bandyopadhyay

Abstract:

Gastro-toxic effect of piroxicam, a classical non-steroidal anti-inflammatory drug (NSAID), has restricted its use in arthritis and similar diseases. The present study aims to find if a combination of melatonin and Murraya koenigii leaf extract therapy can protect against piroxicam induced ulcerative damage in rats. For this study, rats were divided into four groups namely control group where rats were orally administered distilled water, only combination treated group, piroxicam treated group and combination pre-administered piroxicam treated group. Each group of rats consisted of six animals. Melatonin at a dose of 20mg/kg body weight and antioxidant rich Murraya koenigii leaf extract at a dose of 50 mg /kg body weight were successively administered at 30 minutes interval one hour before oral administration of piroxicam at a dose of 30 mg/kg body weight to Wistar rats in the combination pre-administered piroxicam treated group. The rats of the animal group which was only combination treated were administered both the drugs respectively without piroxicam treatment whereas the piroxicam treated animal group was administered only piroxicam at 30mg/kg body weight without any pre-treatment with the combination. Macroscopic examination along with histo-pathological study of gastric tissue using haemotoxylin-eosin staining and alcian blue dye staining showed protection of the gastric mucosa in the combination pre-administered piroxicam treated group. Determination of adherent mucus content biochemically and collagen content through Image J analysis of picro-sirius stained sections of rat gastric tissue also revealed protective effects of the combination in piroxicam mediated toxicity. Gelatinolytic activity of piroxicam was significantly reduced by pre-administration of the drugs which was well exhibited by the gelatin zymography study of the rat gastric tissue. Mean ulcer index determined from macroscopic study of rat stomach reduced to a minimum (0±0.00; Mean ± Standard error of mean and number of animals in the group=6) indicating the absence of ulcer spots on pre-treatment of rats with the combination. Gastro-friendly prostaglandin (PGE2) which otherwise gets depleted on piroxicam treatment was also well protected when the combination was pre-administered in the rats prior to piroxicam treatment. The requirement of the individual drugs in low doses in this combinatorial therapeutic approach will possibly minimize the cost of therapy as well as it will eliminate the possibility of any pro-oxidant side effects on the use of high doses of antioxidants. Beneficial activity of this combination therapy in the rat model raises the possibility that similar protective actions might be also observed if it is adopted by patients consuming NSAIDs like piroxicam. However, the introduction of any such therapeutic approach is subject to future studies in human.

Keywords: gastro-protective action, melatonin, Murraya koenigii leaf extract, piroxicam

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3 In vitro and in vivo Effects of 'Sonneratia alba' Extract against the Fish Pathogen 'Aphanomyces invadans'

Authors: S. F. Afzali, W. L. Wong

Abstract:

The epizootic ulcerative syndrome (EUS) causes by the oomycete fungus, Aphanomyces invadans; known to be one of the infectious fish diseases for farmed and wild fishes in fresh and brackish-water from the Asia-pacific region, America and Africa. Although, EUS had been documented by the Office International des Epizooties (OIE) since 1995, hitherto, there is neither standard chemical agents that can be used for successful treatment of this destructive infection in the time of outbreak; nor available vaccine for prevention. Plant-based remedies in controlling fish diseases are gaining much attention recently as an alternative to chemical treatments, which possess negative effects to the environment and human. In present study, Sonneratia alba, a mangrove plant belongs to the Sonneratiaceae family, was screened in vitro and in vivo for its antifungal activity against A. invadans mycelium growth and its effects on fish innate immune system and disease resistant. The in vitro tests was performed using the disc diffusion methods with measurements of minimum inhibitory concentration (MIC) and inhibition zone. For in vivo study, the S. alba extract supplemented diets were administrated at 0.0, 1.0%, 3.0%, and 5.0% on healthy goldfish, Carassius auratus, which challenged with A. invadans zoospores (100 spores/ml). To compare the significant differences in the hematological and immunological parameters obtained from the experiments, the data were analysed using the SPSS. The methanol extract of S. alba effectively inhibited the mycelial growth of A. invadans at a minimum concentration of 1000 ppm for agar and filter paper diffusion experiments. In the agar diffusion test, 500 ppm of the extract inhibited the fungus mycelial growth up to 96 hours after exposure. The mycelial growth from the edge of the pre-inoculated A. invadans agar discs treated with S. alba extracts at concentrations of 100, 500 and 1000 ppm were 15, 8 and 0 mm respectively. The results of the filter paper disc test showed that the S. alba extract at its minimal inhibitory concentration (1000 ppm) has similar qualitative inhibitory effect as malachite green at 1 ppm and formalin at 250 ppm. According to the in vivo tests findings, in the infected fish fed with 3.0% and 5.0% supplementation diet, the numbers of white blood cell and myeloperoxidase activity significantly increased after the second week of treatment. Whilst the numbers of red blood cell significantly decreased in the infected fish fed with 0.0 and 1.0% supplementation diet. After the third week of feeding, significant increases in the total protein, albumin level, lysozyme activity were recorded in the infected fish fed with 3.0% and 5.0% supplementation diet. Also, the enriched diets increased the survival rate as compared to the untreated group that suffered from 90% mortality. The present study indicated that S. alba extract may inhibit the mycelial growth of A. invadans effectively, suggesting an alternative to other chemotherapeutic agents, which brought much environmental and health concerns to the public, for EUS treatment.

Keywords: fungal pathogen, goldfish, organic extract, treatment

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2 Gut Microbial Dynamics in a Mouse Model of Inflammation-Linked Carcinogenesis as a Result of Diet Supplementation with Specific Mushroom Extracts

Authors: Alvarez M., Chapela M. J., Balboa E., Rubianes D., Sinde E., Fernandez de Ana C., Rodríguez-Blanco A.

Abstract:

The gut microbiota plays an important role as gut inflammation could contribute to colorectal cancer development; however, this role is still not fully understood, and tools able to prevent this progression are yet to be developed. The main objective of this study was to monitor the effects of a mushroom extracts formulation in gut microbial community composition of an Azoxymethane (AOM)/Dextran sodium sulfate (DSS) mice model of inflammation-linked carcinogenesis. For the in vivo study, 41 adult male mice of the C57BL / 6 strain were obtained. 36 of them have been induced in a state of colon carcinogenesis by a single intraperitoneal administration of AOM at a dose of 12.5 mg/kg; the control group animals received instead of the same volume of 0.9% saline. DSS is an extremely toxic polysaccharide sulfate that causes chronic inflammation of the colon mucosa, favoring the appearance of severe colitis and the production of tumors induced by AOM. Induction by AOM/DSS is an interesting platform for chemopreventive intervention studies. This time the model was used to monitor gut microbiota changes as a result of supplementation with a specific mushroom extracts formulation previously shown to have prebiotic activity. The animals have been divided into three groups: (i) Cancer + mushroom extracts formulation experimental group: to which the MicoDigest2.0 mushroom extracts formulation developed by Hifas da Terra S.L has been administered dissolved in drinking water at an estimated concentration of 100 mg / ml. (ii) Control group of animals with Cancer: to which normal water has been administered without any type of treatment. (iii) Control group of healthy animals: these are the animals that have not been induced cancer or have not received any treatment in drinking water. This treatment has been maintained for a period of 3 months, after which the animals were sacrificed to obtain tissues that were subsequently analyzed to verify the effects of the mushroom extract formulation. A microbiological analysis has been carried out to compare the microbial communities present in the intestines of the mice belonging to each of the study groups. For this, the methodology of massive sequencing by molecular analysis of the 16S gene has been used (Ion Torrent technology). Initially, DNA extraction and metagenomics libraries were prepared using the 16S Metagenomics kit, always following the manufacturer's instructions. This kit amplifies 7 of the 9 hypervariable regions of the 16S gene that will then be sequenced. Finally, the data obtained will be compared with a database that makes it possible to determine the degree of similarity of the sequences obtained with a wide range of bacterial genomes. Results obtained showed that, similarly to certain natural compounds preventing colorectal tumorigenesis, a mushroom formulation enriched the Firmicutes and Proteobacteria phyla and depleted Bacteroidetes. Therefore, it was demonstrated that the consumption of the mushroom extracts’ formulation developed could promote the recovery of the microbial balance that is disrupted in the mice model of carcinogenesis. More preclinical and clinical studies are needed to validate this promising approach.

Keywords: carcinogenesis, microbiota, mushroom extracts, inflammation

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1 Comprehensive Literature Review of the Humanistic Burden of Clostridium (Clostridiodes) difficile Infection

Authors: Caroline Seo, Jennifer Stephens, Kirstin H. Heinrich

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Background: Clostridiodes (formerly Clostridium) difficile infection (CDI) is an anaerobic, spore-forming bacterium with manifestations including diarrhea, pseudomembranous colitis and toxic megacolon. Despite general understanding that CDI may be associated with marked burden on patients’ health, there has been limited information available on the humanistic burden of CDI. The objective of this literature review was to summarize the published data on the humanistic burden of CDI globally, in order to better inform future research efforts and increase awareness of the patient perspective in this disease. Methods: A comprehensive literature review of the past 15 years (2002-2017) was conducted using MEDLINE, Embase and Cumulative Index of Nursing and Allied Health Literature. Additional searches were conducted from conference proceedings (2015-2017). Articles selected were studies specifically designed to examine the humanistic burden of illness associated with adult patients with CDI. Results: Of 3,325 articles or abstracts identified, 33 remained after screening and full text review. Sixty percent (60%) were published in 2016 or 2017. Data from the United States or Western Europe were most common. Data from Brazil, Canada, China and Spain also exist. Thirteen (13) studies used validated patient-reported outcomes instruments, mostly EQ-5D utility and SF-36 generic instruments. Three (3) studies used CDI-specific instruments (CDiff32, CDI-DaySyms). The burden of CDI impacts patients in multiple health-related quality of life (HRQOL) domains. SF-36 domains with the largest decrements compared to other GI diarrheal diseases (IBS-D and Crohn’s) were role physical, physical functioning, vitality, social functioning, and role emotional. Reported EQ-5D utilities for CDI ranged from 0.35-0.42 compared to 0.65 in Crohn’s and 0.72 in IBS-D. The majority of papers addressed physical functioning and mental health domains (67% for both). Across various studies patients reported weakness, lack of appetite, sleep disturbance, functional dependence, and decreased activities of daily lives due to the continuous diarrhea. Due to lack of control over this infection, CDI also impacts the psychological and emotional quality of life of the patients. Patients reported feelings of fear, anxiety, frustration, depression, and embarrassment. Additionally, the type of disease (primary vs. recurrent) may impact mental health. One study indicated that there is a decrement in SF-36 mental scores in patients with recurrent CDI, in comparison to patients with primary CDI. Other domains highlighted by these studies include pain (27%), social isolation (27%), vitality and fatigue (24%), self-care (9%), and caregiver burden (0%). Two studies addressed work productivity, with 1 of these studies reporting that CDI patients had the highest work productivity and activity impairment scores among the gastrointestinal diseases. No study specifically included caregiver self-report. However, 3 studies did provide mention of patients’ worry on how their diagnosis of CDI would impact family, caregivers, and/or friends. Conclusions: Despite being a serious public health issue there has been a paucity of research on the HRQOL among those with CDI. While progress is being made, gaps exist in understanding the burden on patients, caregivers, and families. Future research is warranted to aid understanding of the CDI patient perspective.

Keywords: burden, Clostridiodes, difficile, humanistic, infection

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