Search Results (30)

The goals of ulcerative colitis (UC) treatment are focused on improving quality of life, achieving steroid-free remission, and minimizing the risk of cancer. In UC traditional management, a step-up strategy involves introducing increasingly more immunosuppressive medications, thus avoiding unnecessary overexposure to more potent drugs. However, in cases of severe, acute UC, priority is rapid and effective treatment to minimize the risk of complications such as bleeding, intestinal perforation, toxic megacolon or the need for colectomy. Modern approach to UC management shifts to an “accelerated step-up” or “top-down” approach in high-risk patients to prevent bowel damage. A holistic approach—integrating molecular research, clinical management and patient-centered care—enhances our understanding of disease mechanisms and therapeutic strategies, ultimately supporting improved outcomes and overall quality of life. This review aims to present the treatment options for UC along with an overview of the most modern therapies and experimental agents. Full article

Cyclosporine is a selective calcineurin inhibitor used, among other areas, in pediatric gastroenterology as rescue therapy in the treatment of severe ulcerative colitis (ASUC—acute severe ulcerative colitis) in children. The introduction of systemic glucocorticosteroids (GCSs) has significantly reduced mortality in ASUC. However, it should be emphasized that long-term use of these drugs is limited due to the high risk of adverse effects observed during therapy and their limited efficacy. The role of cyclosporine as a second-line therapy is referred to as a ‘rescue therapy,’ which aims to alleviate the symptoms of ASUC, often avoiding life-threatening complications (including toxic megacolon) and postponing the need for urgent colectomy. If colectomy is necessary, this provides time to better prepare the patient nutritionally and psychologically for surgery and to await the effect of slower-acting thiopurine preparations or other chronic treatments; their effectiveness in achieving long-term clinical and endoscopic remission is limited. New therapeutic approaches include cyclosporine as an inducer, which acts as a bridge to new forms of therapy, such as biological drugs, which are used as maintenance preparations in patients. In pediatric patients, there is limited research in the literature on new strategies for the use of cyclosporine. The aim of this review is to assess current evidence on cyclosporine as induction or rescue therapy in pediatric ASUC and explore future integration with biologic and biosimilar strategies, emphasizing its evolving role as a bridging agent toward biologics and novel targeted therapies. Full article

Clostridioides difficile infection (CDI), the most common cause of nosocomial diarrhea, presents with a wide spectrum of clinical manifestations, ranging from mild diarrhea to severe, life-threatening conditions such as pseudomembranous colitis and toxic megacolon. In recent years, both the incidence and severity of CDI have increased, leading to a significant burden in terms of morbidity, mortality, and healthcare costs. We conducted a single-center, retrospective cohort study for 30 months at “Sf. Parascheva” Infectious Diseases Clinical Hospital Iași, in North Eastern Romania, aiming to assess the clinical and laboratory characteristics of CDI, as well as treatment approaches and their association with patient outcomes. A total of 534 patients were included during the study period, of whom 484 had favorable outcomes, while 50 have died of the disease. Fever (p = 0.007) and age over 65 (p = 0.001) were associated with prolonged hospitalization. Patients positive for both A and B toxins and GDH had the highest risk of recurrence (p = 0.020). Among comorbidities, obesity was the only condition significantly linked to recurrence (p = 0.001). In female patients over 65 years old, the probability of survival drops below 60% after 21 days of hospitalization, highlighting a critical risk factor in this population. These results underscore the importance of comprehensive risk assessment in CDI, particularly focusing on advanced age and comorbidities, to guide early therapeutic interventions, optimize patient management, and improve clinical outcomes among high-risk populations. Full article

Ulcerative colitis (UC) is an inflammatory bowel disease in which one-quarter of patients are at risk of developing a severe form of the disease known as acute severe UC (ASUC). This condition exposes patients to serious complications, including toxic megacolon, surgical intervention, and even death. The current therapeutic strategy relies on time-dependent, multi-step algorithms that integrate systemic corticosteroids, calcineurin inhibitors, and biologic agents (specifically infliximab) as medical therapy aimed at avoiding colectomy. Despite this approach, a significant proportion of patients fail to respond to either corticosteroids or infliximab and may require alternative therapeutic options if there is no urgent surgical necessity. These alternatives include other biologics or emerging small molecules, although the evidence supporting these treatments remains extremely low, even considering their well-documented and promising efficacy and safety in moderate-to-severe UC. Conversely, it is necessary to investigate whether infliximab can be effectively replaced or surpassed by other approved biological agents and small molecules as first-line therapy after steroid resistance. This review aims to summarise the available evidence on small molecules, specifically Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. Full article

Background: Hirschsprung’s disease (HD) is a congenital malformation of the enteric nervous system clinically manifested by intestinal obstruction in the neonatal period or severe constipation in childhood. Several surveys on HD have been conducted to evaluate experiences in its management around the world. For the first time in Brazil, we analyze and report the management patterns of HD among pediatric surgeons in Brazil. Methods: A validated questionnaire was disseminated in print at the Congress of Pediatric Surgery in São Paulo-Brazil, and an online version was sent to all the active members of the Brazilian and Paulista Institute of Pediatric Surgery. Results: In total, 361 pediatric surgeons answered the survey. Of these, 329 completed all questions (response rate: 91%). Most Brazilian services treat fewer than 10 cases of HD annually. The preferred diagnostic method was rectal biopsy. For newborns (NBs) and infants, open biopsy was the most commonly used technique. For NBs with HD clinically stable 50% of specialists chose immediate surgery. In NBs and infants with classic HD, the Soave technique (69%) is the most common surgical intervention, and the transanal route (80%) is the preferred surgical approach. In children over 3 years of age with classic HD, the most-used technique is the Duhamel method (54%), with the open approach being the most common (52%). Conclusions: Our study in Brazil found that HD patient management aligns with scientific evidence and international guidelines. Full article

Clostridioides difficile, a Gram-positive anaerobic bacterium, is the leading cause of hospital-acquired antibiotic-associated diarrhea worldwide. The severity of C. difficile infection (CDI) varies, ranging from mild diarrhea to life-threatening conditions such as pseudomembranous colitis and toxic megacolon. Central to the pathogenesis of the infection are toxins produced by C. difficile, with toxin A (TcdA) and toxin B (TcdB) as the main virulence factors. Additionally, some strains produce a third toxin known as C. difficile transferase (CDT). Toxins damage the colonic epithelium, initiating a cascade of cellular events that lead to inflammation, fluid secretion, and further tissue damage within the colon. Mechanistically, the toxins bind to cell surface receptors, internalize, and then inactivate GTPase proteins, disrupting the organization of the cytoskeleton and affecting various Rho-dependent cellular processes. This results in a loss of epithelial barrier functions and the induction of cell death. The third toxin, CDT, however, functions as a binary actin-ADP-ribosylating toxin, causing actin depolymerization and inducing the formation of microtubule-based protrusions. In this review, we summarize our current understanding of the interaction between C. difficile toxins and host cells, elucidating the functional consequences of their actions. Furthermore, we will outline how this knowledge forms the basis for developing innovative, toxin-based strategies for treating and preventing CDI. Full article

Background: Clostridioides difficile infections (CDI) vary in severity from mild diarrhea to life-threatening conditions like pseudomembranous colitis or toxic megacolon, often leading to sepsis and death. The COVID-19 pandemic prompted changes in healthcare practices, potentially affecting CDI incidence, though reported data are inconclusive. We studied factors influencing CDI incidence and outcomes at a university hospital throughout the COVID-19 pandemic years. Methods: We conducted a retrospective study on all adult hospitalized CDI cases from 1 January 2020 to 31 December 2022 in Hospital Universitari de Sant Joan in Reus. We collected demographic information, comorbid conditions, and concurrent infections. Results: While overall CDI and COVID-19 rates decreased in 2022, a notable increase in CDI infections was observed among oncological patients and those undergoing some aggressive treatments, such as colonoscopies or gastroscopies. The prevalence of comorbidities remained unmodified, and there were declines in prior gastrointestinal surgeries and proton pump inhibitor prescriptions. Factors associated with patient fatality or prolonged hospitalization included older age, cancer, chronic kidney disease, higher Charlson and McCabe indices, elevated C-reactive protein, and low albumin concentrations. Conclusions: Our study shows the evolving landscape of CDI during the COVID-19 pandemic and emphasizes the impact of delayed diagnoses and treatments exacerbated by telemedicine adoption. Identified risk factors for CDI-related mortality or prolonged hospital stays underscore the importance of targeted interventions in high-risk populations. Full article

Clostridioides difficile infection (CDI) is a leading nosocomial infection, posing a substantial public health challenge within the United States and globally. CDI typically occurs in hospitalized elderly patients who have been administered antibiotics; however, there has been a rise in the occurrence of CDI in the community among young adults who have not been exposed to antibiotics. C. difficile releases toxins, which damage large intestinal epithelium, leading to toxic megacolon, sepsis, and even death. Unfortunately, existing antibiotic therapies do not always prevent these consequences, with up to one-third of treated patients experiencing a recurrence of the infection. Host factors play a crucial role in the pathogenesis of CDI, and accumulating evidence shows that modulation of host immune responses may potentially alter the disease outcome. In this review, we provide an overview of our current knowledge regarding the role of innate and adaptive immune responses on CDI outcomes. Moreover, we present a summary of non-antibiotic microbiome-based therapies that can effectively influence host immune responses, along with immunization strategies that are intended to tackle both the treatment and prevention of CDI. Full article

Clostridioides difficile (C. difficile), responsible for 15–25% of gastrointestinal infections, causes health problems mainly due to the toxic activity of toxins A and B (Tcds). These are responsible for its clinical manifestations, including diarrhea, pseudomembranous colitis, toxic megacolon and death, with a mortality of 5–30% in primary infection, that increase following relapses. Studies on Tcd-induced cell death have highlighted a key role of caspases, calpains, and cathepsins, with involvement of mitochondria and reactive oxygen species (ROS) in a complex signaling pathway network. The complex response in the execution of various types of cell death (apoptosis, necrosis, pyroptosis and pyknosis) depends on the amount of Tcd, cell types, and Tcd receptors involved, and could have as initial/precocious event the alterations in calcium homeostasis. The entities, peculiarities and cell types involved in these alterations will decide the signaling pathways activated and cell death type. Calcium homeostasis alterations can be caused by calcium influx through calcium channel activation, transient intracellular calcium oscillations, and leakage of calcium from intracellular stores. These increases in cytoplasmic calcium have important effects on all calcium-regulated molecules, which may play a direct role in several cell death types and/or activate other cell death effectors, such as caspases, calpains, ROS and proapoptotic Bcl-2 family members. Furthermore, some support for the possible role of the calcium homeostasis alteration in Tcd-induced cell death originates from the similarity with cytotoxic effects that cause pore-forming toxins, based mainly on calcium influx through plasma membrane pores. Full article

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition’s rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified. Full article

(1) Background: Clostridioides difficile (C. difficile) and SARS-CoV-2 coronavirus represent significant health threats. Our study focused on the impact of concurrent infections on patient outcomes against the backdrop of changes imposed by the pandemic. (2) Materials and methods. We performed a retrospective analysis and included patients diagnosed with CDI who were admitted in our hospital before and during the pandemic. We compared patient exposure to risk factors for CDI in both groups and patient negative outcomes: need for ICU care, prolonged hospitalization, organ failure, toxic megacolon, and death. (3) Results. Overall, 188 patients were included, of which 100 had CDI (the pre-pandemic group), and 88 patients presented both CDI and COVID-19 (the pandemic group). Patients in the pandemic group were significantly older, with a higher Charlson Comorbidity Index (CCI) and a greater exposure to antibiotics and corticosteroids, and were more likely to develop organ dysfunction, to require ICU care and have prolonged hospitalization. The severity of COVID-19, leukocytosis and increased D-dimer levels were indicators of poor prognosis in the pandemic group. Higher CCI scores and leukocytosis increased the risk for negative outcomes in CDI alone patients. (4) Conclusions. The study highlights the negative impact of associated infections on patient outcome. The severity of COVID-19 directly influences the prognosis of patients with concurrent infections Full article

Clostridioides difficile is an obligate anaerobic pathogen among the most common causes of healthcare-associated infections. It poses a global threat due to the clinical outcomes of infection and resistance to antibiotics recommended by international guidelines for its eradication. In particular, C. difficile infection can lead to fulminant colitis associated with shock, hypotension, megacolon, and, in severe cases, death. It is therefore of the utmost urgency to fully characterize this pathogen and better understand its spread, in order to reduce infection rates and improve therapy success. This review aims to provide a state-of-the-art overview of the genetic variation of C. difficile, with particular regard to pathogenic genes and the correlation with clinical issues of its infection. We also summarize the current typing techniques and, based on them, the global distribution of the most common ribotypes. Finally, we discuss genomic surveillance actions and new genetic engineering strategies as future perspectives to make it less difficile. Full article

Our digestive system, particularly our intestines, harbors a vast amount of microorganisms, whose genetic makeup is referred to as the microbiome. Clostridium difficile is a spore-forming Gram-positive bacterium, which can cause an infection whose symptoms range from asymptomatic colonization to fearsome complications such as the onset of toxic megacolon. The relationship between gut microbiota and Clostridium difficile infection has been studied from different perspectives. One of the proposed strategies is to be able to specifically identify which types of microbiota alterations are most at risk for the onset of CDI. In this article, we understood once again how crucial the role of the human microbiota is in health and especially how crucial it becomes, in the case of its alteration, for the individual’s disease. Clostridium difficile infection is an emblematic example of how a normal and physiological composition of the human microbiome can play a very important role in immune defense against such a fearsome disease. Full article

Introduction: This study primarily sought to evaluate the risk factors for toxic megacolon development and treatment outcomes in Clostridium difficile-positive COVID-19 patients, secondarily to determining predictors of survival. Methods: During the second COVID-19 wave (May 2020 to May 2021), we identified 645 patients with confirmed COVID-19 infection, including 160 patients with a severe course in the intensive care unit. We selected patients with Clostridium difficile infection (CDI) (31 patients) and patients with toxic megacolon (9 patients) and analyzed possible risk factors. Results: Patients who developed toxic megacolon had a higher incidence (without statistical significance, due to small sample size) of cancer and chronic obstructive pulmonary disease, a higher proportion of them required antibiotic treatment using cephalosporins or penicillins, and there was a higher rate of extracorporeal circulation usage. C-reactive protein (CRP) and interleukin-6 values showed significant differences between the groups (CRP [median 126 mg/L in the non-toxic megacolon cohort and 237 mg/L in the toxic megacolon cohort; p = 0.037] and interleukin-6 [median 252 ng/L in the group without toxic megacolon and 1127 ng/L in those with toxic megacolon; p = 0.016]). As possible predictors of survival, age, presence of chronic venous insufficiency, cardiac disease, mechanical ventilation, and infection with Candida species were significant for increasing the risk of death, while corticosteroid and cephalosporin treatment and current Klebsiella infection decreased this risk. Conclusions: More than ever, the COVID-19 pandemic required strong up-to-date treatment recommendations to decrease the rate of serious in-hospital complications. Further studies are required to evaluate the interplay between COVID-19 and CDI/toxic megacolon. Full article

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 8 million people, and around 1/3 develop chronic cardiac (CCC) or digestive disease (megaesophagus/megacolon), while the majority remain asymptomatic, in the indeterminate form of Chagas disease (ASY). Most CCC cases in families with multiple Chagas disease patients carry damaging mutations in mitochondrial genes. We searched for exonic mutations associated to chagasic megaesophagus (CME) in genes essential to mitochondrial processes. We performed whole exome sequencing of 13 CME and 45 ASY patients. We found the damaging variant MRPS18B 688C > G P230A, in five out of the 13 CME patients (one of them being homozygous; 38.4%), while the variant appeared in one out of 45 ASY patients (2.2%). We analyzed the interferon (IFN)-γ-induced nitro-oxidative stress and mitochondrial function of EBV-transformed lymphoblastoid cell lines. We found the CME carriers of the mutation displayed increased levels of nitrite and nitrated proteins; in addition, the homozygous (G/G) CME patient also showed increased mitochondrial superoxide and reduced levels of ATP production. The results suggest that pathogenic mitochondrial mutations may contribute to cytokine-induced nitro-oxidative stress and mitochondrial dysfunction. We hypothesize that, in mutation carriers, IFN-γ produced in the esophageal myenteric plexus might cause nitro-oxidative stress and mitochondrial dysfunction in neurons, contributing to megaesophagus. Full article