Lessons from helminth infections: ES-62 highlights new interventional approaches in rheumatoid arthritis

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialised countries, this "Hygiene Hypothesis" has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. Here we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine Collagen Induced Arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of IL-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by Th17 and γδ T cells, whilst leaving that of CD49b+ Natural Killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologics, such as "IL-17 blockers", that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Jurisprudential and Legal Perspectives on the Protection of Rights and Freedoms in the 2021 Basic Statute of the Sultanate of Oman

In this paper, we examine the constitutional protection of economic rights and freedoms in the Basic Statute of the Sultanate of Oman. Through descriptive, analytical, and historical approaches, the study identifies the protection and mechanisms for attaining social justice according to the Basic Statute to achieve Omans 2040 vision. The study concludes that courts must refrain from applying laws that violate the Basic Statute, and that weak guarantees of economic and social rights and freedoms hinder their protection and prevent the achievement of Oman Vision 2040. The study recommends spreading a culture of human rights and education on economic, social, and cultural rights, as well as adhering to international human rights conventions and covenants ratified by Oman

Successful Salvage Treatment of Resistant Acute Antibody-Mediated Kidney Transplant Rejection with Eculizumab

Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 μmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 μmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR

Utilization Pattern of Vancomycin in a University Teaching Hospital in Oman: Comparison with International Guidelines

Purpose: To assess the prescribing and utilization pattern of vancomycin in Sultan Qaboos University Hospital (SQUH) in Oman.Methods: A retrospective study that included in-patients at SQUH who had used vancomycin from January 1 2009 to December 31 2009 was conducted to determine the utilization patterns of the drug vis a vis to the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines and the North American Therapeutic Drug Monitoring Consensus (NATDMC) recommendations. Information regarding patient characteristics and vancomycin therapy were obtained from patients’ medical records.Statistical analyses were performed using descriptive statistics.Results: Out of 478 prescriptions for 365 patients, 79.1 % were considered inappropriate, based on HICPAC guidelines. This was mainly due to the continuous use of vancomycin following negative microbiological cultures for â-lactam-resistant Gram-positive microorganisms. Vancomycin wasprescribed mostly for treatment of sepsis (27.1 %), followed by prophylaxis against various clinical conditions (20.8 %). Therapeutic drug monitoring (TDM) practices at SQUH did not comply with NATDMC recommendations on the use of trough concentration in the specified range as a guide for monitoring of therapy.Conclusion: Irrational use of vancomycin was recorded in this study. The need for a restrictive policy and a revision of the current TDM in the setting are recommended..Keywords: Vancomycin, Drug utilization, Therapeutic drug monitoring, Infectio

Comparative analysis of maternal and neonatal outcomes between elective and emergency caesarean section at a single tertiary hospital: a retrospective COHORT study

Background: Caesarean section rates have been increasing worldwide despite it’s known complications. The aim of this study was to determine maternal and neonatal complications related to caesarean section at Sultan Qaboos University Hospital (SQUH) and to compare the outcomes between emergency and elective caesarean sections. Methods: This retrospective cohort study was conducted in the department of obstetrics and gynecology at SQUH from 1st January 2016 to 31st December 2016. This comparative study involved 300 women who underwent caesarean section, 150 in elective caesarean section group and 150 in emergency caesarean section group. Results: The mean maternal age was 29.66 (±4.96) and 33.22 (±4.63) years in the elective and emergency caesarean section groups respectively (p=001). The main risk factor for both the groups was maternal diabetes and the most common indication was previous caesarean section. Hypotension related anesthetic complication was noted more in elective caesarean section (15.3%) than in emergency caesarean section group (4.0%) with p value=0.002. Post-partum fever was seen in 12.0% of women in emergency group as compared to 4% in elective group (p=0.019). Anemia was observed in 79.2% and 65.3% in emergency and elective groups respectively (p=0.011). Respiratory distress syndrome and transient tachypnea of the newborn were the main neonatal complications in both groups. Conclusions: There was no significant difference between emergency and elective caesarean section related maternal and neonatal complications except for transient intraoperative hypotension, maternal postoperative febrile morbidity and anemia. Future prospective studies including larger sample size and multiple centers is recommended.

Asymptomatic Ileal Schwannoma presenting as a Mesenteric Tumour : Case report and review of literature

A schwannoma is a benign tumour which arises from the schwann cells of the central or peripheral nervous system. Common sites include the head and limbs; it is rare that this tumour arises from the gastrointestinal tract’s neural plexus. It is even rarer to find the ileum as the site of origin. We report a patient who presented with a central abdominal mass which was preoperatively diagnosed as a mesenteric tumour. However, immunohistochemistry of the surgically-removed specimen proved it to be a benign ileal schwannoma

Contribution à l’automatisation des processus de fragmentation, de duplication et de réplication des Bases de Données Distribuées à base des Protocoles Réseaux

La gestion distribuée des données nécessite des processus automatisés, bien adaptés aux règles de fragmentation, de duplication et de réplication de ces données sur plusieurs serveurs de Bases De Données (BDD). Notre contribution consiste à mettre en place des processus pour l’amélioration de la stratégie de gestion distribuée des données en intégrant tous les aspects d’analyse lexicale et syntaxique concernant les besoins en données significatives de chaque serveur, en particulier celles qui répondent aux différentes requêtes ou demandes les plus fréquemment soumises par les utilisateurs locaux. Il s’agit du développement d’un compilateur d’algèbre relationnelle et de requêtes SQL. L’automatisation de ces processus permettra aux administrateurs de BDD distribuées d’utiliser plus facilement les sous BDD en fonction du nombre de sites (serveurs de BDD) et des contraintes de division exprimées par les besoins des utilisateurs locaux. Les principaux apports de cette automatisation peuvent être résumés ainsi : Répartition automatique d’une BDD globale en plusieurs sous BDD locales,Extraction de données recherchées indépendamment de l’emplacement physique de leurs sources,Transfert global des données en cascade entre sites,Amélioration de l’équilibre de charges sur les serveurs,Allocation dynamique des fragments de données à plusieurs serveurs

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma