The Antifungal and Anti-Pneumocystis Activities of the Novel Compound A3IS (Mycosinate).

A3IS (Mycosinate) is a synthetic product which only contains ingredients found naturally within honey. A3IS is a broad-spectrum antimicrobial product which produces a sustained release of hydrogen peroxide at low but therapeutic levels. The product elicits this release through an enzymatic reaction between glucose oxidase and the substrate glucose once the product is hydrated. As medical uses for different honeys are being re-evaluated, the purpose of this study was to evaluate the in vitro effects of A3IS against a comprehensive panel of human pathogens, including Pneumocystis species, providing a unique assessment against a panel of eukaryotic pathogens. Without exception, A3IS exhibited significant efficacy at 50% and 100% inhibitory concentrations against a broad spectrum of human pathogens including yeasts, molds (both hyaline and dematiaceous), and dimorphic fungi. Notably, A3IS was effective against fungal strains with a high level of resistance to fluconazole or voriconazole. The 50% inhibitory concentrations for Pneumocystis carinii and P. murina (surrogates for P. jirovecii) were considered "Marked" and "Moderate" on an established rank scale, and would be considered for in vivo studies, based on an established in vitro-in vivo pipeline. These results indicate that A3IS is a novel anti-fungal agent against an extensive range of human fungal pathogens.

Influence of food and lifestyle on the risk of developing inflammatory bowel disease.

BACKGROUND: The Barwon area in Australia has one of the highest incidence rates of inflammatory bowel disease (IBD) and therefore is an ideal location to study the impact of environmental exposures on the disease's development. AIM: To study these exposures prior to the development of IBD in a population-based cohort. METHOD: One hundred and thirty-two incident cases (81 Crohn disease (CD) and 51 ulcerative colitis (UC)) from an IBD registry and 104 controls replied to the International Organization of Inflammatory Bowel Diseases environmental questionnaire. This included 87 questions about pre-illness exposures that included childhood illnesses, vaccinations, breastfeeding, house amenities, pets and swimming, diet and smoking. RESULTS: The factors associated with CD included smoking (odds ratio (OR): 1.42, confidence interval (CI): 1-2.02, P = 0.029); childhood events, including tonsillectomy (OR: 1.74, CI: 1.15-2.6, P = 0.003) and chicken pox infection (OR: 3.89, CI: 1.61-9.4, P = 0.005) and pre-diagnosis intake of frequent fast food (OR: 2.26, CI: 1.76-4.33, P = 0.003). In UC, the risk factors included smoking (OR: 1.39, CI: 1.1-1.92, P = 0.026) and pre-diagnosis intake of frequent fast food (OR: 2.91, CI: 1.54-5.58, P < 0.001), and high caffeine intake was protective (OR: 0.51, 95% CI: 0.3-0.87, P = 0.002). Other protective exposures for UC included high fruit intake (OR: 0.59, CI: 0.4-0.88, P = 0.003) and having pets as a child (OR: 0.36, CI: 0.2-0.79, P = 0.001). CONCLUSION: This first Australian population-based study of environmental risk factors confirms that smoking, childhood immunological events and dietary factors play a role in IBD development; while high caffeine intake and pet ownership offer a protective effect.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Changing face of care for patients with moderate to severe inflammatory bowel disease: the role of specialist nurses in the governance of anti-TNF prescribing.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy is highly effective for inflammatory bowel disease (IBD), but expensive and potentially toxic. Meticulous supervision prior to and during anti-TNF treatment is required to screen and monitor patients for adverse clinical events. In addition, a systematic administrative process is necessary to comply with Australian Medicare requirements and ensure ongoing therapy is uninterrupted. IBD nurses are essential components of multidisciplinary IBD services, but their role in facilitating the safe and timely delivery of anti-TNF drugs is unacknowledged. AIM: The aim of the study was to calculate time spent by IBD nurses on anti-TNF drug governance and its indirect cost. METHODS: Time spent on activities related to anti-TNF governance was retrospectively assessed by questionnaire among IBD nurses employed at Melbourne hospitals. The capacity of IBD clinics at these hospitals was separately evaluated by surveying medical heads of clinics. RESULTS: On average, each Melbourne IBD service handled 150 existing and 40 new anti-TNF referrals in 2013. The average annual time spent by nurses supervising an existing and newly referred anti-TNF patient was 3.5 and 5.25 h respectively, or a minimum of two full working days per week. If clinicians undertook this activity during normal clinic time, the organisational opportunity cost was at least 58%. CONCLUSIONS: Anti-TNF therapy governance is an essential quality component of IBD care that is associated with a definite, indirect cost for every patient treated. IBD nurses are best positioned to undertake this role, but an activity-based funding model is urgently required to resource this element of their work.

Perspectives of paediatric and adult gastroenterologists on transfer and transition care of adolescents with inflammatory bowel disease.

BACKGROUND: Programmes specific to inflammatory bowel disease (IBD) that facilitate transition from paediatric to adult care are currently lacking. AIM: We aimed to explore the perceived needs of adolescents with IBD among paediatric and adult gastroenterologists and to identify barriers to effective transition. METHODS: A web-based survey of paediatric and adult gastroenterologists in Australia and New Zealand employed both ranked items (Likert scale; from 1 not important to 5 very important) and forced choice items regarding the importance of various factors in facilitating effective transition of adolescents from paediatric to adult care. RESULTS: Response rate among 178 clinicians was 41%. Only 23% of respondents felt that adolescents with IBD were adequately prepared for transition to adult care. Psychological maturity (Mean = 4.3, standard deviation (SD) = 0.70) and readiness as assessed by adult caregiver (Mean = 4, SD = 0.72) were prioritised as the most important factors in determining timing of transfer. Self-efficacy and readiness as assessed by adult caregiver were considered the two most important factors to determine timing of transition by both groups of gastroenterologists. Poor medical and surgical handover (Mean = 4.10, SD = 0.8) and patients' lack of responsibility for their own care (Mean= 4.10, SD = 0.82) were perceived as major barriers to successful transition by both paediatric and adult gastroenterologists. CONCLUSIONS: Deficiencies exist in current transition care of adolescents with IBD in Australia and New Zealand. Standardising transition care practices with strategies aimed at optimising communication, patient education, self-efficacy and adherence may improve outcomes.

Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention. AIM: To develop, validate and apply a questionnaire directed towards evaluating these disease aspects. METHODS: A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group. RESULTS: A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P < 0.001). Disability differed between ulcerative colitis and controls, but not between active and inactive disease. CONCLUSIONS: The new disability questionnaire is sensitive for detecting disability, is reliable and reproducible, and correlates with disease activity in Crohn's disease, but not ulcerative colitis. Further prospective testing is now needed in the longer term, larger patient populations and in different countries and ethnicities.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

Preliminary examination of the relations between disease activity, illness perceptions, coping strategies, and psychological morbidity in Crohn's disease guided by the common sense model of illness.

BACKGROUND: An individual's psychological adjustment to illness is influenced by disease severity, illness perceptions, and coping strategies. A more precise understanding of the contribution of each of these factors to a patient's well-being may influence the kind of psychological support required by patients. This study therefore aimed to characterize the contributors to psychological well-being in patients with Crohn's disease (CD). The design was a cross-sectional questionnaire-based study. METHODS: Ninety-six CD patients (34 males, 62 females, mean age 38 years) attending a tertiary hospital inflammatory bowel disease outpatient clinic were studied. Disease severity was evaluated according to the Crohn's Disease Activity Index (CDAI), coping styles assessed with the Carver Brief COPE scale, illness perceptions explored with the Brief Illness Perceptions Questionnaire (BIPQ), and anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Combining the questionnaire data using structural equation modeling resulted in a final model with an excellent fit (χ(2) (7) = 10.42, P = 0.17, χ(2) /N = 1.49, root mean square error of approximation (RMSEA) < 0.07, comparative fit index (CFI) > 0.97, Goodness-of-fit index (GFI) > 0.97). Disease activity had a significant direct influence on illness perceptions (ß = 51, P < 0.001). In turn, illness perceptions had a significant direct influence on depression and anxiety (ß = 41, P < 0.001, ß = 0.40, P < 0.001, respectively). Use of emotional coping strategies was associated significantly (P < 0.001) with the presence of anxiety and depression. CONCLUSIONS: There is an interrelationship between disease activity, illness perceptions, coping strategies, and depression and anxiety. These aspects of psychological processing provide a framework and direction for the psychological support that patients with CD require.

Practical guidelines for treating inflammatory bowel disease safely with anti-tumour necrosis factor therapy in Australia.

Anti-tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long-term administration. Anti-TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti-TNF therapy in IBD by a Working Party commissioned by IBD-Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia.

Cerebral venous thrombosis associated with ulcerative colitis.

Thromboembolic complications, such as deep venous thrombosis and pulmonary embolism, are well recognized in patients with inflammatory bowel disease (IBD). We describe three cases of cerebral venous thrombosis complicating ulcerative colitis. Cerebral venous thrombosis is a rare but potentially devastating complication of IBD, and the diagnosis needs to be considered in any patient with IBD presenting with neurological symptoms.

Transformation processes, pathways, and possible sources of distinctive polychlorinated dibenzo-p-dioxin signatures in sink environments.

In recent years, studies on environmental samples with unusual dibenzo-p-dioxin (PCDD) congener profiles were reported from a range of countries. These profiles, characterized by a dominance of octachlorinated dibenzodioxin (OCDD) and relatively low in dibenzofuran (PCDF) concentrations, could not be attributed to known sources or formation processes. In the present study, the processes that result in these unusual profiles were assessed using the concentrations and isomer signatures of PCDDs from dated estuarine sediment cores in Queensland, Australia. Increases in relative concentrations of lower chlorinated PCDDs and a relative decrease of OCDD were correlated with time of sediment deposition. Preferred lateral, anaerobic dechlorination of OCDD represents a likely pathway for these changes. In Queensland sediments, these transformations result in a distinct dominance of isomers fully chlorinated in the 1,4,6,9-positions (1,4-patterns), and similar 1,4-patterns were observed in sediments from elsewhere. Consequently, these environmental samples may not reflect the signatures of the original source, and a reevaluation of source inputs was undertaken. Natural formation of PCDDs, which has previously been suggested, is discussed; however, based on the present results and literature comparisons, we propose an alternative scenario. This scenario hypothesizes that an anthropogenic PCDD precursor input (e.g. pentachlorophenol) results in the contamination. These results and hypothesis imply further investigations are warranted into possible anthropogenic sources in areas where natural PCDD formation has been suggested.

Rapid response of severe refractory metastatic Crohn's disease to infliximab.

A case is described of a middle-aged female who developed an aggressive form of biopsy-proven metastatic Crohn's disease involving the inguinal, perineal and submammary areas. Her condition had been unresponsive to topical and systemic corticosteroids, antibiotics, immunosuppressives, and repeated surgical debridement. Administration of infliximab resulted in a rapid clinical response with subjective improvements in pain and general well-being, and an objective decline in exudate, erythema and size of the lesions. Infliximab may be a suitable therapeutic option in patients with metastatic Crohn's disease.

Identification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection.

In the course of characterizing a locus involved in heme utilization, we identified a Legionella pneumophila gene predicted to encode a protein with homology to the product of the Salmonella enterica serovar Typhimurium pagP gene. In Salmonella, pagP increases resistance to the bactericidal effects of cationic antimicrobial peptides (CAMPs). Mutants with insertions in the L. pneumophila pagP-like gene were generated and showed decreased resistance to different structural classes of CAMPs compared to the wild type; hence, this gene was designated rcp for resistance to cationic antimicrobial peptides. Furthermore, Legionella CAMP resistance was induced by growth in low-magnesium medium. To determine whether rcp had any role in intracellular survival, mutants were tested in the two most relevant host cells for Legionnaires' disease, i.e., amoebae and macrophages. These mutants exhibited a 1,000-fold-decreased recovery during a Hartmannella vermiformis coculture. Complementation of the infectivity defect could be achieved by introduction of a plasmid containing the intact rcp gene. Mutations in rcp consistently reduced both the numbers of bacteria recovered during intracellular infection and their cytopathic capacity for U937 macrophages. The rcp mutant was also more defective for lung colonization of A/J mice. Growth of rcp mutants in buffered yeast extract broth was identical to that of the wild type, indicating that the observed differences in numbers of bacteria recovered from host cells were not due to a generalized growth defect. However, in low-Mg(2+) medium, the rcp mutant was impaired in stationary-phase survival. This is the first demonstration of a pagP-like gene, involved in resistance to CAMPs, being required for intracellular infection and virulence.