Does instillation of lidocaine gel following flexible cystoscopy decrease the severity of post procedure symptoms? A randomised controlled trial assessing the efficacy of lidocaine gel post flexible cystoscopy.

OBJECTIVE: To assess whether instillation of lidocaine gel both before and after flexible cystoscopy is more effective at reducing post procedural symptoms than instillation of lidocaine gel pre flexible cystoscopy alone. We hypothesise that inadequate urethral dwell time and dilution of lidocaine gel by the irrigation fluid during flexible cystoscopy limits its anaesthetic efficacy. Only one other study has attempted to reduce bothersome urinary symptoms through an intervention after flexible cystoscopy. METHODS: This was a randomised controlled trial in which patients were randomised 1:1 to receive lidocaine gel pre and post flexible cystoscopy (treatment) or lidocaine gel pre flexible cystoscopy only (control). Patient-reported outcome measures were used to assess symptoms and quality of life prior to cystoscopy, on day 2 and day 7 post cystoscopy. RESULT: Fifty patients were divided equally between the treatment and control groups. There were no significant differences in baseline characteristics between the groups (p = 1.000). An overall symptoms variable was measured, though no significant difference was found in the distribution of responses between the groups at baseline, 2 or 7 days after the flexible cystoscopy (p = 0.423, 0.651,0.735). In the treatment group, 1 patient (4.0%) presented to a doctor for review following flexible cystoscopy, and 4 patients (16.0%) presented in the control group (p = 0.349). CONCLUSION: Initial study results suggest that post-operative lidocaine does not significantly limit the exacerbation of urinary symptoms following flexible cystoscopy; however, our results are not powered to detect a small difference. We do not recommend a change in practice based on our results.

Bladder cancer in Ireland: a 21-year review.

INTRODUCTION: Bladder carcinoma is one of the most commonly diagnosed cancers worldwide; however, various studies have reported on marked international variation in incidence and mortality rates. The aim of this study was to report national figures on incidence, survival and risk factors of bladder cancer. This retrospective review is the first to offer a comprehensive analysis of incidence rates, mortality and potential risk factors in the Irish population from 1994 to 2015. METHODS: This was a retrospective study of incidence and survival trends in bladder cancer in the Irish population from 1994 to 2014 based on data from the National Cancer Registry of Ireland (NCRI). Patient demographics, pathology and survival data, as well as potential contributing factors, were studied. RESULTS: A total of 9656 cases of bladder cancer were diagnosed from 1994 to 2015, with majority of cases occurring in males (71%). Survival decreased with increasing age, higher grade and higher stage. Bladder cancer is more common in those with a smoking history and with a higher deprivation score. Urothelial cell carcinoma was the most common pathology (95%), with the majority of patients being stage 1 or 2 (44.7%). CONCLUSION: The overall incidence of bladder cancer in Ireland has fallen, in line with reducing smoking rates. Our data reflects international trends in incidence, survival and contributing risk factors.

Origins and evolution of innate lymphoid cells: Wardens of barrier immunity.

The identification, in the late 2000s, of innate lymphoid cells (ILCs) as a new class of non-B, non-T lymphocytes has led to global efforts to understand their functions, plasticity and evolutionary origins and to define their place within the leucocyte family. Although this work has uncovered striking similarities in the developmental cues, lineage-specific transcription factors and functional capacities of innate and adaptive lymphocytes, it has become clear that ILCs play a unique and defining role as stewards of barrier defence and that this sets them apart from their adaptive cousins. This review will explore how the dynamic environment of barrier surfaces has shaped ILC evolution and functionality. We highlight the critical importance of the microbiome and the unique role of ILCs as environmental sensors. We reflect on how these factors may have influenced the development of ILC2s and barrier immunity in the context of exposure to helminth parasites that have been driving forces of our evolution throughout human history. Finally, we argue that the plasticity of ILC function reflects their role as first responders to environmental change.

Fasciola and fasciolosis in ruminants in Europe: Identifying research needs.

Fasciola hepatica is a trematode parasite with a global distribution, which is responsible for considerable disease and production losses in a range of food producing species. It is also identified by WHO as a re-emerging neglected tropical disease associated with endemic and epidemic outbreaks of disease in human populations. In Europe, F. hepatica is mostly associated with disease in sheep, cattle and goats. This study reviews the most recent advances in our understanding of the transmission, diagnosis, epidemiology and the economic impact of fasciolosis. We also focus on the impact of the spread of resistance to anthelmintics used to control F. hepatica and consider how vaccines might be developed and applied in the context of the immune-modulation driven by the parasite. Several major research gaps are identified which, when addressed, will contribute to providing focussed and where possible, bespoke, advice for farmers on how to integrate stock management and diagnosis with vaccination and/or targeted treatment to more effectively control the parasite in the face of increasing the prevalence of infection and spread of anthelmintic resistance that are likely to be exacerbated by climate change.

Fasciola hepatica infection reduces Mycobacterium bovis burden and mycobacterial uptake and suppresses the pro-inflammatory response.

Bovine tuberculosis (BTB), caused by Mycobacterium bovis, has an annual incidence in cattle of 0.5% in the Republic of Ireland and 4.7% in the UK, despite long-standing eradication programmes being in place. Failure to achieve complete eradication is multifactorial, but the limitations of diagnostic tests are significant complicating factors. Previously, we have demonstrated that Fasciola hepatica infection, highly prevalent in these areas, induced reduced sensitivity of the standard diagnostic tests for BTB in animals co-infected with F. hepatica and M. bovis. This was accompanied by a reduced M. bovis-specific Th1 immune response. We hypothesized that these changes in co-infected animals would be accompanied by enhanced growth of M. bovis. However, we show here that mycobacterial burden in cattle is reduced in animals co-infected with F. hepatica. Furthermore, we demonstrate a lower mycobacterial recovery and uptake in blood monocyte-derived macrophages (MDM) from F. hepatica-infected cattle which is associated with suppression of pro-inflammatory cytokines and a switch to alternative activation of macrophages. However, the cell surface expression of TLR2 and CD14 in MDM from F. hepatica-infected cattle is increased. These findings reflecting the bystander effect of helminth-induced downregulation of pro-inflammatory responses provide insights to understand host-pathogen interactions in co-infection.

Two distinct populations of bovine IL-17⁺ T-cells can be induced and WC1⁺IL-17⁺γδ T-cells are effective killers of protozoan parasites.

IL-17 has emerged as a key player in the immune system, exhibiting roles in protection from infectious diseases and promoting inflammation in autoimmunity. Initially thought to be CD4 T-cell-derived, the sources of IL-17 are now known to be varied and belong to both the innate and adaptive arms of the immune system. Mechanisms for inducing IL-17 production in lymphoid cells are thought to rely on appropriate antigenic stimulation in the context of TGF-ß1, IL-6 and/or IL-1ß. Using culture protocols adapted from human studies, we have effectively induced both bovine CD4(+) and WC1(+) γδ T-cells to produce IL-17 termed Th17 and γδ17 cells, respectively. The negative regulatory effect of IFN-γ on mouse and human IL-17 production can be extended to the bovine model, as addition of IFN-γ decreases IL-17 production in both cell types. Furthermore we show that infection with the protozoan Neospora caninum will induce fibroblasts to secrete pro-IL-17 factors thereby inducing a γδ17 phenotype that preferentially kills infected target cells. Our study identifies two T-cell sources of IL-17, and is the first to demonstrate a protective effect of IL-17(+) T-cells in ruminants. Our findings offer further opportunities for future adjuvants or vaccines which could benefit from inducing these responses.

Survival after incidental prostate cancer diagnosis at transurethral resection of prostate: 10-year outcomes.

BACKGROUND: The most appropriate management of incidental prostate cancers diagnosed at transurethral resection of prostate has been debated. It is important to determine the long-term outcomes to establish an appropriate management in patients with incidental prostate cancer. AIMS: We aim to determine 10-year survival and to identify the factors of worse prognosis of incidental prostate cancers diagnosed at transurethral resection of prostate. METHODS: A retrospective analysis of patients with pT1a-pT1b prostate cancers diagnosed between 1998 and 2003. Medical notes, PSA and pathology results were reviewed. Overall and cancer specific survival was calculated at mean 10-year follow-up. RESULTS: Sixty patients with incidental prostate cancer were identified (pT1a = 18, pT1b = 42). Fifty-one percents of the patients were managed on a watchful waiting strategy with overall 84% survival and 9.7% cancer specific mortality. Twenty patients (all with pT1b) received hormone therapy. Overall survival in this cohort was 50% with 20% cancer specific mortality. Nine patients received curative therapy (Radical prostatectomy = 4, Radiotherapy = 5). In this group, overall survival was 88% with no cancer specific mortality. CONCLUSIONS: Stage pT1a disease and preoperative low PSA were associated with favourable survival. However, for pT1b and/or high Gleason score (≥7), mortality was comparatively higher. Hence, patients with high Gleason score and/or pT1b disease should be considered for curative therapy. Additionally, active surveillance may have a role in selected men with incidental prostate cancer.

Reciprocal expression of IL-25 and IL-17A is important for allergic airways hyperreactivity.

BACKGROUND: Interleukin (IL)-25 (IL-17E) is a potent inducer of the type-2 immune effector response. Previously we have demonstrated that a neutralizing anti-IL-25 antibody, given during the establishment of ovalbumin-specific lung allergy, abrogates airways hyperreactivity. OBJECTIVE: Blocking IL-25 results in the suppression of IL-13, a cytokine known to exacerbate pulmonary inflammation, and an unexpected reciprocal increase in IL-17A. The role of IL-17A in asthma is complex with reports of both pro-inflammatory and anti-inflammatory functions. Our aim was to determine the influence of IL-17A in regulating IL-25-dependent lung allergy. METHOD: Neutralizing antibodies to IL-25 and/or IL-17A were administered during an experimental model of allergic asthma. Bronchoalveolar cell infiltrates and lung cytokine production were determined to assess lung inflammation. Invasive plethysmography was undertaken to measure lung function. RESULTS: Neutralization of IL-25 correlated with a decrease in IL-13 levels and an increase in IL-17A production, and an accompanying prevention of airway hyperresponsiveness (AHR). Notably, the blocking of IL-17A reversed the protective effects of treating with anti-IL-25 antibodies, resulting in the re-expression of several facets of the lung inflammatory response, including IL-13 and eotaxin production, eosinophilia and AHR. Using mice over-expressing IL-13 we demonstrate that treatment of these mice with anti-IL-25 fails to suppress IL-13 levels and in turn IL-17A levels remain suppressed. CONCLUSIONS AND CLINICAL RELEVANCE: IL-13 is known to be an important inducer of lung inflammation, causing goblet cell hyperplasia and promoting airways hyperreactivity. Our data now demonstrate that IL-13 also plays an important role in the genesis of lung inflammation downstream of IL-25 by suppressing a protective IL-17A response. These findings also highlight the important reciprocal interplay of the IL-17 family members, IL-25 and IL-17A, in regulating allergic lung responses and suggest that the balance of IL-17A, together with IL-25, will be an important consideration in the treatment of allergic asthma.

Protection of cattle against a natural infection of Fasciola hepatica by vaccination with recombinant cathepsin L1 (rFhCL1).

The liver fluke, Fasciola hepatica causes liver fluke disease, or fasciolosis, in ruminants such as cattle and sheep. An effective vaccine against the helminth parasite is essential to reduce our reliance on anthelmintics, particularly in light of frequent reports of resistance to some frontline drugs. In our study, Friesian cattle (13 per group) were vaccinated with recombinant F. hepatica cathepsin L1 protease (rFhCL1) formulated in mineral-oil based adjuvants, Montanide ISA 70VG and ISA 206VG. Following vaccination the animals were exposed to fluke-contaminated pastures for 13 weeks. At slaughter, there was a significant reduction in fluke burden of 48.2% in the cattle in both vaccinated groups, relative to the control non-vaccinated group, at p

Immune responses directed at egg proteins during experimental infection with the liver fluke Fasciola hepatica.

Fasciola hepatica is responsible for human disease and economic livestock loss on a global scale. Unlike the well characterized schistosomes, only the adult and juvenile stages of F. hepatica are implicated in disease, whereas the freely voided egg is not thought to contribute to host-parasite interactions. We investigated specific immune responses to soluble F. hepatica egg proteins (SFHEP), during a 14-week experimental infection, demonstrating significant increases in anti-SFHEP IgG1 (P = 0.001), transforming growth factor beta-1 (P = 0.008) and IL-10 (P < 0.001) titres at the onset of egg production. Western blot analysis of soluble SFHEP demonstrates that protein bands migrating at 61.6, 54.8 and 44 kDa become sero-reactive before the appearance of eggs within host faeces. Therefore, expression of some egg-associated proteins indicates progression to chronic disease. Antigenic bands were investigated through mass spectrometry, identifying a protein disulphide isomerase (PDI) (61.6 kDa), an enolase and ferritin-related proteins (54.8 kDa), and a cocktail of dehydrogenases (44 kDa). Biochemical analysis of egg secretions reveals proteolytic activity, which increases over time, indicating that proteases may be continually secreted during the course of egg maturation. The implications of egg-specific immune responses and proteolytic secretions are further discussed.

IL-10 and TGF-beta1 are associated with variations in fluke burdens following experimental fasciolosis in sheep.

Infection with Fasciola hepatica causes an economically important disease in ruminants. Variability in parasite load may indicate innate differences in the host immune system. This study aimed to investigate the immunological mechanisms that are associated with variability in parasite burden following experimental F. hepatica infection in cross-bred sheep. Of a total of 16 animals, four were randomly chosen as uninfected controls, and the remainder infected with 100 viable metacercariae. Uninfected animals were used as the control group for evaluation of cytokine gene expression levels. For comparative analysis, specific animals were selected on the basis of extremes of fluke burdens, and were categorised into light (n = 4) and heavy burdened (n = 3) cohorts. Serum antibody levels, haematological parameters, and expression of IL-4 and IFN-gamma genes in hepatic lymph nodes were equivalent in both groups. However, significant differences in mitogen-specific lymphocyte proliferation in vitro and in expression of TGF-beta1 and IL-10 genes in hepatic lymph nodes were observed at acute and chronic phases of infection, respectively. These results provide useful information in developing further understanding of natural resistance to fasciolosis in sheep.

Co-Infection of cattle with Fasciola hepatica and Mycobacterium bovis- immunological consequences.

Fasciola hepatica, the liver fluke, is a common parasite of cattle in much of the world. Previously, we have shown that cattle infected with F. hepatica have altered responsiveness (delayed type hypersensitivity reaction and cytokine responses) to M. bovis BCG infection. We hypothesized that co-infection with F. hepatica would, likewise, alter the immune response of cattle to virulent M. bovis infection, with possible implications for disease diagnosis and disease progression. Our previous work with F. hepatica/M. bovis BCG-infected cattle demonstrated a reduction in interferon (IFN)-gamma responsiveness in co-infected animals. Similar findings are reported here with virulent M. bovis following aerosol infection. The epidemiological significance of these findings, also, require exploration, particularly in view of the considerable resources devoted to the diagnosis and eradication of bovine tuberculosis, and the high prevalence of F. hepatica infection in areas where eradication has proved difficult.

Minimally invasive treatment of female stress urinary incontinence: 100 cases using SPARC sling.

OBJECTIVE: Assess the suitability of SPARC sling as a minimally invasive operation for female stress urinary incontinence. MATERIALS AND METHODS: One hundred consecutive patients were evaluated over 45-month period. All had stress urinary incontinence (SUI), proven on urodynamics and cough stress test, independently or combined with urge incontinence but with predominantly SUI. King's Health Questionnaire 1993 (KHQ) and SF36 Health Survey forms were completed pre and post operatively. Peri-operative features, complications and results were recorded. RESULTS: Mean follow-up was 20 months. SUI was cured or significantly reduced in 88% of cases. Role Limitations and Severity Measures (as per KHQ) were considerably reduced. Post-op retention in 11% cases resolved spontaneously within 2 weeks. One case had readjustment of sling. Complications were small in number and minor in nature. CONCLUSION: SPARC sling is highly effective with low complication rates. It is an alternative to tension free vaginal tape.

Alternative activation of ruminant macrophages by Fasciola hepatica.

The helminth parasite, Fasciola hepatica, has a worldwide distribution and infects a wide variety of mammalian hosts, including ruminants and man. In response to infection, these hosts mount a type 2 helper (Th2) response that is highly polarized and results in the downregulation of type 1 helper (Th1) mechanisms. In a murine macrophage model F. hepatica induces alternative activation of macrophages. These macrophages differ from classically activated cells in that they preferentially use arginase instead of inducible nitric oxide synthase (iNOS) for metabolism of nitrogen. In this study we sought to characterize macrophage phenotype following stimulation of the ovine cell line MOCL7 with recombinant F. hepatica enzymes and crude parasite extracts. An in vitro model using the MOCL7 cell line was established and arginase levels in cells were used to determine the activation status of cells. Stimulation of this cell-line in vitro with F. hepatica products induces alternative activation. We have also found a chitinase-like protein in supernatants which is capable of differentiating alternatively activated from classically activated macrophages.

Cross-validated factor structures and factor-based subscales for PASS and PASSING.

Program Analysis of Service Systems (PASS 3) and Program Analysis of Service Systems' Implementation of Normalization Goals (PASSING) are used internationally to assess service quality in mental retardation and other fields. In two studies, we derived and cross-validated the factor structures of these program evaluation instruments. In Study 1, based on 626 PASS 3 evaluations, four factors provided a good fit to the cross-validation data. In Study 2, based on 633 PASSING evaluations, three factors furnished a good fit to the cross-validation data. Similarities between the two factor structures, parallels with the structural and functional service dimensions emphasized in ecological approaches to evaluation, and practical uses in program evaluation of subscales based on the factors were discussed.

Endoscopic laser ablation of the prostate (ELAP): changes in magnetic resonance imaging and clinical outcome at 1 year.

OBJECTIVE: To assess the ability of magnetic resonance imaging (MRI) to detect tissue changes immediately after laser ablation of the prostate and to correlate these changes with clinical outcome by detecting changes that may improve the outcome by allowing the laser dosimetry to be adjusted during therapy by monitoring effects on gland morphology. PATIENTS AND METHODS: Eight men with proven bladder outlet obstruction had a standard four-quadrant laser ablation of the prostate with a side-firing non-contact fibre. MRI scans were performed before, during and immediately after treatment and again after one week, 3 months and one year. RESULTS: The clinical outcome was a decrease in the American Urological Association (AUA)-7 symptom score from a pre-operative mean of 21.3-12.0 1 year after treatment and a corresponding increase in peak urinary flow rates from a mean of 8.9 mL/s to 12.3 mL/s. Immediately after treatment, MRI showed marked swelling of the gland (mean increase in volume 34%, range 12-75) with the loss of internal architecture. A low-signal thin periurethral band was present in six of the eight patients after 1 week and was replaced by a wider periurethral ring at 3 months in four of the six patients. No patient had evidence of prostatic cavitation after treatment or a significant reduction in prostate volume at 1 year. CONCLUSION: MRI can detect tissue changes after laser ablation of the prostate. The marked swelling seen on MRI immediately after laser prostatectomy may explain the delayed improvement in symptoms. The periurethral ring may indicate the depth to which laser energy has an effect on the tissue and could delineate an area of necrosis. The lack of cavitation at one year questions the durability of the effect of laser treatment delivered in this way.

Long-term follow-up of patients with erectile dysfunction commenced on self injection with intracavernosal papaverine with or without phentolamine.

OBJECTIVES: To determine the usage, complications and satisfaction with intracavernosal agents in patients with erectile dysfunction commenced on self-injection treatment at home. PATIENTS AND METHODS: A total of 344 patients who had commenced intracavernosal treatment before December 1992 and had requested a repeat prescription were sent a questionnaire to determine the usage, complications, satisfaction and reasons for discontinuing treatment. RESULTS: Replies were received from 216 patients; of those who replied, only 126 were still using the treatment. The mean duration of treatment was 3.9 years in those continuing treatment. Whilst satisfaction ratings were high in those continuing therapy, most patients had experienced some side-effects. CONCLUSION: The long-term follow-up revealed a high attrition rate and a significant number of complications. Patients receiving auto-injection therapy should be offered regular long-term follow-up.

Endoscopic laser ablation of the prostate: MR appearances during and after treatment and their relation to clinical outcome.

OBJECTIVE: Endoscopic laser ablation is a new treatment for benign prostatic hypertrophy. The objectives of this study were to determine the appearances of the prostate on MR images obtained during, 1 week after, and 3 months after this procedure and to determine if a correlation exists between the MR findings and the clinical outcome. Such appearances could then be used to guide the application of laser energy during the procedure in order to optimize the clinical result. SUBJECTS AND METHODS: Eight consecutive men 58-74 years old with symptoms of bladder outflow obstruction caused by benign prostatic hypertrophy underwent endoscopic laser ablation of the prostate under spinal or epidural anaesthesia. Imaging was done on a 0.5-T Picker Asset system with an endorectal receiver coil and conventional T1-weighted spin-echo, T2-weighted spin-echo, and gradient-recalled-echo sequences. T1-weighted magnetization transfer images were obtained in three patients. Images were obtained preoperatively, after ablation of the left-sided quadrants, immediately after completion of the procedure, and 1 week and 3 months later. Preoperative and 3-month postoperative symptom scores, peak urine flow rates, and bladder residual volumes were studied. Images were visually assessed for signal-intensity changes and the presence of cavitation by three radiologists in conference. The results were quantitatively analyzed by measuring prostatic volumes on the gradient-recalled-echo images and by measuring the width and area of regions of signal-intensity change on the T2-weighted images. RESULTS: MR images made immediately after treatment showed an increase in the volume of the prostate (mean, 34%) and a poorly defined, low-signal-intensity region around the urethra on the T2-weighted images in six patients. This probably represented coagulative necrosis. The prostate was smaller on MR images made 1 week after treatment, and after 3 months the prostate returned to its preoperative size. After 1 week, the low-signal-intensity periurethral region on the T2-weighted images was less obvious, and at 3 months it was replaced in four patients by a well-demarcated low-signal-intensity ring on the T2-weighted and gradient-recalled-echo images. No evidence of cavity formation in the prostate was seen on MR images in any patient. Symptom scores and peak urinary flow rates improved after 3 months, with a significant difference between the mean increase in symptom scores in the patients with and without the periurethral changes seen immediately after treatment. However, we found no significant difference between the mean increase in peak urinary flow rates in the patients with and without periurethral changes seen either immediately or at 3 months after treatment. No statistically significant correlation was found between the amount of prostatic swelling and the improvement in symptom scores or peak urine flow rates. CONCLUSION: In patients who have had laser prostatectomy, MR imaging shows significant immediate glandular swelling, which may account for the delayed improvement in symptoms reported with this technique. The presence of the periurethral changes immediately after treatment was correlated with a subsequent improvement in symptom scores. After 3 months, no cavity could be seen in the prostate. This may account for the poorer long-term clinical outcome reported with endoscopic laser ablation of the prostate compared with transurethral prostatectomy.

Quality of institutional and community human service programs in Canada and the United States.

This methodological and substantive study was based on Wolfensberger and Thomas' (1983) Program Analysis of Service Systems' Implementation of Normalization Goals (PASSING), a program evaluation method used by teams of trained raters to assess the quality of human service programs. PASSING is based on Social Role Valorization, an internationally influential theoretical and philosophical approach to structuring human services, particularly services for persons with handicaps or other potentially devaluing conditions. The data for this study were derived from a sample of 213 programs evaluated with PASSING during 1983-88 in Canada (45%), the United States (51%), and the United Kingdom (4%). The programs served mainly mentally retarded persons (40%), subgroups of clients with "mixed" (different) impairments and conditions (38%), or psychiatrically impaired persons (6%). The results showed that PASSING has adequate internal consistency and interrater reliability and yields data suitable for statistical treatment with interval-level, parametric procedures. The average level of quality of services in the sample on the total PASSING scale and its five subscales (Program Relevance, Intensity, Integrativeness, Image Projection, and Felicity) was only modest, however. Community group residences (n = 77) were of significantly better quality than community vocational programs (n = 56), and both were superior to institutional residences (n = 20). Also, Canadian programs (n = 76) were of significantly better quality than U.S. programs (n = 77). An outstanding vocational program that was not part of the study sample was used to illustrate concrete ways in which the quality of many human service programs could be greatly improved, typically at little cost.