Adherence to endoscopic surveillance guidelines for patients with inflammatory bowel disease: An Australian cohort study.

BACKGROUND AND AIM: Patients with inflammatory bowel disease have an increased risk of developing colorectal cancer as compared with the general population. Endoscopic surveillance to detect early dysplastic changes is advised by several published clinical guidelines, which provide recommendations as to the timing and performance of surveillance procedures. There is a paucity of data as to adherence with these guidelines in clinical practice. METHODS: A longitudinal inception cohort study of all new patients diagnosed with inflammatory bowel disease across a service network of Australian hospitals between January 2005 and June 2014, with continuous follow-up in a gastroenterology clinic until December 31, 2022. Patients were included if they warranted surveillance according to the Australian guidelines. Adherence to guidelines and technical and quality measures were reported. RESULTS: A total of 136 patients were included, and a total of 263 surveillance procedures were performed. Ninety-five patients (70%) had their first surveillance colonoscopy within the correct time interval. Fifty patients (37%) were completely adherent to guidelines with respect to timing of all surveillance procedure. The overall dysplasia detection rate for surveillance procedures was 10%. Chromoendoscopy was only performed in 16% of procedures. CONCLUSIONS: Adherence to endoscopic surveillance guidelines with regard to timing of procedures and the utilization of chromoendoscopy is poor. Further clinician education, promotion of the surveillance guidelines and incorporation of chromoendoscopy training as part of the national colonoscopy training program may improve adherence to guidelines.

Blue rubber bleb nevus syndrome in a patient on anticoagulation: a management dilemma.

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition characterised by vascular malformations mostly of the skin and gastrointestinal tract and less commonly of the central nervous system, liver, thyroid, spleen and lungs. We report a rare case of BRBNS in a patient on anticoagulation who presented with gastrointestinal bleeding and no cutaneous or other organ involvement. We discuss the difficulty in balancing bleeding and clotting risks in this patient who developed two episodes of venous thromboembolism while off anticoagulation to minimise gastrointestinal bleeding. We also highlight the potential role of somatostatin analogues such as lanreotide in decreasing gastrointestinal bleeding risk in BRBNS, particularly in the setting of anticoagulation. The occurrence of two episodes of venous thromboembolism within a short time frame in this case, in conjunction with known associations between other vascular anomalies and venous thromboembolism, raises the question of whether BRBNS may be associated with a prothrombotic state.

Safety and efficacy of transitioning inflammatory bowel disease patients from intravenous to subcutaneous infliximab: a single-center real-world experience.

Background: A new subcutaneous (SC) formulation exists for infliximab (CT-P13 SC). The aim of this study was to assess the durability of clinical and endoscopic responses after a switch from intravenous (IV) to SC infliximab. Methods: Patients were transitioned on maintenance infliximab, including those with dose-optimized therapy. The primary outcome was clinical, biochemical and overall remission at 6 months, as defined by a Harvey-Bradshaw Index <5 for Crohn's disease or a partial Mayo score <3 for ulcerative colitis, C-reactive protein less than 10 mg/L, and fecal calprotectin less than 100 µg/g. Results: Forty patients were switched from IV to SC infliximab. Twenty-seven (68%) had a diagnosis of Crohn's disease and 13 (33%) had ulcerative colitis. Twenty-three (58%) were on 5 mg/kg of IV infliximab every 8 weeks and 15 (38%) 5 mg/kg every 6 weeks. There were 2 patients (4%) on 10 mg/kg every 6 weeks. At the time of their switch, 37 (93%) patients were in clinical remission, 25 (76%) were in biochemical remission, and 25 (76%) were in both biochemical and clinical remission. At 6 months the proportion of patients in clinical remission decreased from 93% to 82%, with an overall relapse rate of 11%. Treatment persistence at 6 months was 77.5%. Conclusion: Switching patients from IV infliximab to 120 mg fortnightly SC injections is a safe and effective option for the treatment of inflammatory bowel disease, including for those patients on dose-escalated infliximab or with active disease at the time of switch.

Combination therapy is not associated with improved rates of clinical or endoscopic remission in patients with inflammatory bowel disease treated with ustekinumab or vedolizumab: a retrospective study.

Background: Management of inflammatory bowel disease (IBD) involves biological agents, often in combination with thiopurines or methotrexate. The aim of our study was to compare clinical and endoscopic outcomes in IBD patients treated with vedolizumab or ustekinumab, as monotherapy or in combination with thiopurines or methotrexate. Methods: We conducted a retrospective cohort study of all patients aged ≥18 years with a diagnosis of ulcerative colitis or Crohn's disease, commenced on vedolizumab or ustekinumab between October 2015 and March 2022. Primary outcome was clinical remission or response calculated by partial Mayo score (remission: <3; response: improvement >1) for ulcerative colitis or Harvey-Bradshaw index (<5, >2 respectively) for Crohn's disease over 1 year. Secondary endpoints were treatment failure, relapse, endoscopic remission at 1 year. Statistical analysis was done using 2-sample Student's t and chi-square tests. Results: A total of 159 IBD patients were included in the study, 85 (53%) on vedolizumab and 74 (47%) on ustekinumab. For those on vedolizumab, 61 (72%) patients had ulcerative colitis, and 24 (28%) has Crohn's disease. All patients on ustekinumab had Crohn's disease. Mean disease duration in was 9.4 and 13.5 years respectively. There was no difference in clinical response or remission for vedolizumab or ustekinumab monotherapy compared to combination therapy at 1 year. There was also no difference in treatment failure, relapse or endoscopic remission. Conclusion: Combining vedolizumab or ustekinumab with an immunomodulator is not superior to monotherapy in terms of clinical response or endoscopic remission up to 1 year in IBD.

Toxoplasma gondii HOOK-FTS-HIP Complex is Critical for Secretory Organelle Discharge during Motility, Invasion, and Egress.

Members of the Apicomplexa phylum possess specialized secretory organelles that discharge, apically and in a timely regulated manner, key factors implicated in parasite motility, host cell invasion, egress and subversion of host cellular functions. The mechanisms regulating trafficking and apical docking of these secretory organelles are only partially elucidated. Here, we characterized two conserved endosomal trafficking regulators known to promote vesicle transport and/or fusion, HOOK and Fused Toes (FTS), in the context of organelle discharge in Toxoplasma gondii. TgHOOK and TgFTS form a complex with a coccidian-specific partner, named HOOK interacting partner (HIP). TgHOOK displays an apically enriched vesicular pattern and concentrates at the parasite apical tip where it colocalizes with TgFTS and TgHIP. Functional investigations revealed that TgHOOK is dispensable but fitness conferring. The protein regulates the apical positioning and secretion of micronemes and contributes to egress, motility, host cell attachment, and invasion. Conditional depletion of TgFTS or TgHIP impacted on the same processes but led to more severe phenotypes. This study provides evidence of endosomal trafficking regulators involved in the apical exocytosis of micronemes and possibly as a consequence or directly on the discharge of the rhoptries. IMPORTANCE Toxoplasma gondii affects between 30 and 80% of the human population, poses a life-threatening risk to immunocompromised individuals, and is a cause of abortion and birth defects following congenital transmission. T. gondii belongs to the phylum of Apicomplexa characterized by a set of unique apical secretory organelles called the micronemes and rhoptries. Upon host cell recognition, this obligatory intracellular parasite secretes specific effectors contained in micronemes and rhoptries to promote parasite invasion of host cells and subsequent persistence. Here, we identified novel T. gondii endosomal trafficking regulators and demonstrated that they regulate microneme organelle apical positioning and exocytosis, thereby strongly contributing to host cell invasion and parasite virulence.

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients.

Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia, remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study, we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses, and ex vivo assays. Patterns of clinical features, parasite burden, and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation, and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia, and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, particularly in the haematopoietic niche of bone marrow and spleen.

Infliximab-induced optic neuritis.

Antitumour necrosis factor alpha agents are important treatments in many inflammatory conditions including rheumatoid arthritis, psoriatic arthritis and the inflammatory bowel diseases. However, there have been case reports of optic neuritis and other demyelinating diseases as complications of these agents. This case report presents a patient with ulcerative colitis on infliximab who presented with sudden onset mono-ocular visual field loss and highlights the diagnosis and management of infliximab-induced optic neuritis.

Anti-TNF-induced lupus in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Anti-Tumor Necrosis Factor (TNF)-induced lupus (ATIL) is a distinct clinical entity, increasingly recognized in patients with inflammatory bowel disease treated with anti-TNF therapy. Our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population. METHODS: This observational cohort study reviewed 454 patient treatment courses with anti-TNF therapy (300 infliximab and 154 adalimumab). A diagnosis of ATIL was based on the most widely accepted diagnostic criteria: (i) a temporal relationship between symptoms and anti-TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of Systemic Lupus Erythematosus (SLE); and (iii) at least one nonserological criterion such as arthritis, serositis, or rash. Clinical, demographic, and serological predictors were evaluated. RESULTS: The incidence rate of ATIL was 5.7% for infliximab and 0.6% for adalimumab, which are much higher than previously reported postmarketing estimates. The median duration to diagnosis following commencement of anti-TNF therapy was 15 months (3-62 months). ATIL occurs more commonly patients that commence therapy at an older age (46.47 years ± 13.79 years vs. 38.85 years ± 14.75 years, P = 0.033). CONCLUSIONS: ATIL is a significant complication of anti-TNF therapy, affecting 1 in every 20 patients who commence infliximab. A panel of serological markers is useful to confirm the diagnosis and exclude other conditions that may mimic ATIL. Clinicians using anti-TNF medications should counsel patients about this potential risk and monitor for clinical manifestations of lupus during routine follow up.

Rab11A regulates dense granule transport and secretion during Toxoplasma gondii invasion of host cells and parasite replication.

Toxoplasma gondii possesses an armada of secreted virulent factors that enable parasite invasion and survival into host cells. These factors are contained in specific secretory organelles, the rhoptries, micronemes and dense granules that release their content upon host cell recognition. Dense granules are secreted in a constitutive manner during parasite replication and play a crucial role in modulating host metabolic and immune responses. While the molecular mechanisms triggering rhoptry and microneme release upon host cell adhesion have been well studied, constitutive secretion remains a poorly explored aspect of T. gondii vesicular trafficking. Here, we investigated the role of the small GTPase Rab11A, a known regulator of exocytosis in eukaryotic cells. Our data revealed an essential role of Rab11A in promoting the cytoskeleton driven transport of dense granules and the release of their content into the vacuolar space. Rab11A also regulates transmembrane protein trafficking and localization during parasite replication, indicating a broader role of Rab11A in cargo exocytosis at the plasma membrane. Moreover, we found that Rab11A also regulates extracellular parasite motility and adhesion to host cells. In line with these findings, MIC2 secretion was altered in Rab11A-defective parasites, which also exhibited severe morphological defects. Strikingly, by live imaging we observed a polarized accumulation of Rab11A-positive vesicles and dense granules at the apical pole of extracellular motile and invading parasites suggesting that apically polarized Rab11A-dependent delivery of cargo regulates early secretory events during parasite entry into host cells.

Plasmodium asexual growth and sexual development in the haematopoietic niche of the host.

Plasmodium spp. parasites are the causative agents of malaria in humans and animals, and they are exceptionally diverse in their morphology and life cycles. They grow and develop in a wide range of host environments, both within blood-feeding mosquitoes, their definitive hosts, and in vertebrates, which are intermediate hosts. This diversity is testament to their exceptional adaptability and poses a major challenge for developing effective strategies to reduce the disease burden and transmission. Following one asexual amplification cycle in the liver, parasites reach high burdens by rounds of asexual replication within red blood cells. A few of these blood-stage parasites make a developmental switch into the sexual stage (or gametocyte), which is essential for transmission. The bone marrow, in particular the haematopoietic niche (in rodents, also the spleen), is a major site of parasite growth and sexual development. This Review focuses on our current understanding of blood-stage parasite development and vascular and tissue sequestration, which is responsible for disease symptoms and complications, and when involving the bone marrow, provides a niche for asexual replication and gametocyte development. Understanding these processes provides an opportunity for novel therapies and interventions.

Secretory organelle trafficking in Toxoplasma gondii: A long story for a short travel.

Toxoplasma gondii (T. gondii) possesses a highly polarized secretory system, which efficiently assembles de novo micronemes (MIC) and rhoptries (ROP) during parasite replication. Pioneer works have studied the sorting motifs within MIC and ROP proteins, required for their trafficking towards their final destination. These studies led to the conclusion that protein processing and protein sorting are inter-dependent activities. More recent works have revealed the trafficking routes taken by the MIC and ROP proteins by examining the functions of the endo-exocytic compartments and identified key molecules involved in protein sorting and transport. These recent findings have suggested that T. gondii has repurposed the evolutionarily conserved regulators of the endosomal system to the secretory pathway. This review reports the pioneer as well as the most recent findings on the molecular mechanisms regulating apical organelle and dense granule biogenesis and portrays the parasite as a remarkable secretory machine that has efficiently remodeled its trafficking system to adapt to an intracellular lifestyle.

Synchronous oesophageal and gastric sarcomatoid carcinoma: first reported case in Australia.

A 75-year-old retired teacher presents with dysphagia and weight loss for a duration of 6 months. Her gastroscopy showed two synchronous submucosal masses. A 7 cm polypoid mass was seen at the distal oesophagus, arising from a thick stalk and a 4 cm mass seen at the cardia. The biopsies showed high-grade sarcomatoid cancer. Staging CT scan and Positron Emission Tomography scan did not show any distant metastasis except a lesion in the rectum that was subsequently found to be tubulovillous adenoma on transanal excision. The patient was managed with Ivor Lewis oesophagectomy. The biopsies of resection specimen showed spindle cell/sarcomatoid carcinoma with a component of poorly differentiated neuroendocrine carcinoma in oesophageal tumour and a small component of conventional invasive squamous cell carcinoma in tumour at cardia. The patient recovered well after surgery. Since then, she has completed adjuvant chemoradiotherapy. No recurrence has been noted in 10 months follow-up.

Distinct effects of HIV protease inhibitors and ERAD inhibitors on zygote to ookinete transition of the malaria parasite.

In an effort to eradicate malaria, new interventions are proposed to include compound/vaccine development against pre-erythrocytic, erythrocytic and mosquito stages of Plasmodium. Drug repurposing might be an alternative approach to new antimalarials reducing the cost and the time required for drug development. Previous in vitro studies have examined the effects of protease inhibitors on different stages of the Plasmodium parasite, although the clinical relevance of this remains unclear. In this study we tested the putative effect of three HIV protease inhibitors, two general aspartyl protease inhibitors and three AAA-p97 ATPase inhibitors on the zygote to ookinete transition of the Plasmodium parasite. Apart from the two general aspartyl inhibitors, all other compounds had a profound effect on the development of the parasites. HIVPIs inhibited zygote to ookinete conversion by 75%-90%, while the three AAA-p97 ATPase inhibitors blocked conversion by 50%-90% at similar concentrations, while electron microscopy highlighted nuclear and structural abnormalities. Our results highlight a potential of HIV protease inhibitors and p97 inhibitors as transmission blocking agents for the eradication of malaria.

Vedolizumab-induced acute pancreatitis: the first reported clinical case.

Drug-induced acute pancreatitis (DIAP) is a rare, but clinically significant diagnosis. Vedolizumab, an α4ß7 integrin inhibitor, which was approved in 2015 for treatment of moderate to severe inflammatory bowel disease, is a well-tolerated medication with a favourable safety profile and minimal serious adverse events in premarketing clinical trials. We present the first reported case of acute pancreatitis directly attributable to vedolizumab.

Dual role of the Toxoplasma gondii clathrin adaptor AP1 in the sorting of rhoptry and microneme proteins and in parasite division.

Toxoplasma gondii possesses a highly polarized secretory system, which efficiently assembles de novo micronemes and rhoptries during parasite replication. These apical secretory organelles release their contents into host cells promoting parasite invasion and survival. Using a CreLox-based inducible knock-out strategy and the ddFKBP over-expression system, we unraveled novel functions of the clathrin adaptor complex TgAP1. First, our data indicate that AP1 in T. gondii likely functions as a conserved heterotetrameric complex composed of the four subunits γ, ß, µ1, σ1 and interacts with known regulators of clathrin-mediated vesicular budding such as the unique ENTH-domain containing protein, which we named Epsin-like protein (TgEpsL). Disruption of the µ1 subunit resulted in the mis-sorting of microneme proteins at the level of the Trans-Golgi-Network (TGN). Furthermore, we demonstrated that TgAP1 regulates rhoptry biogenesis by activating rhoptry protein exit from the TGN, but also participates in the post-Golgi maturation process of preROP compartments into apically anchored club-shaped mature organelles. For this latter activity, our data indicate a specific functional relationship between TgAP1 and the Rab5A-positive endosome-like compartment. In addition, we unraveled an original role for TgAP1 in the regulation of parasite division. APµ1-depleted parasites undergo normal daughter cell budding and basal complex assembly but fail to segregate at the end of cytokinesis.

Intramuscular hemangioma of the masseter muscle- a case report and review of literature.

INTRODUCTION: Intramuscular hemangioma, is a distinctive type of vascular tumor occurring within the skeletal muscle. Most IMH are located in the lower extremity, particularly in the muscles of the thigh and rarely in head and neck region. PRESENTATION OF CASE: 35 years old male reported with a swelling in the left cheek region since 3 years. Clinical and radiological evaluation leads to the diagnosis of Intramuscular hemangioma. Surgical excision was performed and histopathology confirmed the diagnosis. DISCUSSION: Hemangiomas of skeletal muscle represent 0.8% of all benign vascular neoplasm Welsch and Hengerer, 1980 [4]. Of these 13.8% occur in the head and neck region, with the masseter muscle being the most common site, followed by the trapezius and sternocleidomastoid muscles respectively. The lesions previously described as deep infiltrating angiolipomas have now been recognized by the WHO as intramuscular hemangiomas. numerous theories proposed for ethiopathogenisis of vascular lesions have been discussed. CONCLUSION: In conclusion, angiolipomas are rare in the head and neck region, and it should be considered in the differential diagnosis of masses in these regions. Proper radiological and clinical examination will reveal the type of vascular lesion. Excellent results can be obtained with timely management and good surgical skills.

Ameloblastic fibro-odontoma.

INTRODUCTION: Ameloblastic fibro-odontoma (AFO) is a quite rare, mixed odontogenic tumour generally seen in the early stages of life. Frequent signs of this tumour are asymptomatic swelling, delayed tooth eruption and mixed radiological appearance within well-defined borders. Management of the lesion includes enucleation of the tumour and long-term follow-up. PRESENTATION OF CASE: A 10-year-old girl was referred to our oral and maxillofacial surgery clinic with an incidental radiological finding of radiopaque mass in the posterior region of maxilla. OPG showed unerupted tooth bud of upper right second molar and was being prevented from eruption by the odontome. Under general anaesthesia, the lesion was enucleated and the permanent right upper second molar tooth bud removed. DISCUSSION: Mixed odontogenic tumours are a group of rare and interesting lesions which can mislead the clinician to variety of differential diagnosis. Adequate clinical and radiological investigations, proper surgical excison, accurate histopathological diagnosis, and long term follow up will ensure the right treatment plan for the patient. CONCLUSION: The possibility of a mixed rare tumour should be kept in mind by the clinician where they deal with the swellings of posterior maxilla in children. Histological assessment revealed a final diagnosis of ameloblastic fibro-odontoma.